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Social status
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Social status
Social status is the honor or prestige attached to one's position in society (one's social position). The stratification system, which is the system of distributing rewards to the members of society, determines social status. Social status, the position or rank of a person or group within the stratification system, can be determined two ways. One can earn their social status by their own achievements, which is known as achieved status, or one can be placed in the stratification system by their inherited position, which is called ascribed status.
# Status in different societies
Status- the relative rank that an individual holds, with attendant rights, duties, and lifestyle, in a social hierarchy based upon honor or prestige. Status has two different types that come along with it, achieved, and ascribed. The word status refers to social stratification on a vertical scale.
In modern societies, occupation is usually thought of as the main determinant of status, but other memberships or affiliations (such as ethnic group, religion, gender, voluntary associations, fandom, hobby) can have an influence. For example, a doctor often has higher status than a factory worker, but in some societies a white Protestant doctor has higher status than a non-White, immigrant doctor of a minority religion. The importance of social status can be seen in the peer status hierarchy of geeks, athletes, cheerleaders, nerds, and weirdos in American high schools.
Achieved status is when people are placed in the stratification structure based on their individual merits or achievements. You can achieve this status through education, occupation, and marital status. America most commonly uses this form of status with jobs. The higher up your are in rank the better off you are and the more control you have over your co-workers.
In pre-modern societies, status differentiation is widely varied. In some cases it can be quite rigid and class based, such as with the Indian caste system. In other cases, status exists without class and/or informally, as is true with some Hunter-Gatherer societies such as the Khoisan, and some Indigenous Australian societies. In these cases, status is limited to specific personal relationships. For example, a Khoisan man is expected to take his wife's mother quite seriously (a non-joking relationship), although the mother-in-law has no special "status" over anyone except her son-in-law--and only then in specific contexts. All societies have a form of social status.
Status is an important idea in social stratification. Max Weber distinguishes status from social class, though some contemporary empirical sociologists add the two ideas to create Socio-Economic Status or SES, usually operationalised as a simple index of income, education and occupational prestige.
# Income and status
Status inconsistency is a situation when an individual's social positions have both positive and negative influences on his social status. For example, a teacher has a positive societal image (respect, prestige) which increases his status but may earn little money, which simultaneously decreases his status. In contrast, a drug dealer, may have low social position though have a high income. However, a drug dealer may have high status within his or her own reference group (e.g., inner city gangs) and may be indifferent to his "low status" within the larger society. For example, a wealthy drug dealer who flaunts the proceeds of his trade may have the highest social status on the "street." Thus, "status inconsistency" applies to situations where members of the in-group judge the status of members of an out-group and may not apply to cases of status attainment on all criteria within an in-group.
Economic status occurs when one’s position in the stratification structure is based on their economic status in the world. This is based on income, education, and occupation. Also you must take into consideration inherited wealth, savings, occupational benefits, and ownerships of homes or motor homes.
# Inborn & acquired status
Statuses based on inborn characteristics, such as gender, are called ascribed statuses, while statuses that individuals gained thorough their own efforts are called achieved statuses. Specific behaviors are associated with social stigmas which can affect status.
Ascribed Status is when one’s position is inherited through family, racially, ethnically, and religiously serve as basis for ascribed status. Most kings’ and queen’s use this method so that the ruler stays in the family. This usually occurs at birth without any reference as to how that person may turn out to be a good or bad leader.
# Social Mobility and Social Status
Status can be changed through a process of Social Mobility. Social mobility is the change of position within the stratification system. A change in status can be done upwardly in status, upward mobility, or they can move down in status, downward mobility. Social mobility allows for a person do move to another social status other than that one they were born in. Social mobility is more common in societies where achievement rather than ascription is the primary basis for social status.
# Social Stratification
Social stratification describes the way in which different groups of people are placed with society. It is associated with the ability of individuals to live up to some set of ideals or principles regarded as important by the society or some social group within it. The members of a social group interact mainly within their own group and to a lesser degree with those of higher or lower status.
Groups:
- Wealth and Income (most common)- Ties between persons with the same personal income
- Gender- Ties between persons of the same sex and sexuality
- Political Status- Ties between persons of the same political views/status
- Religion- Ties between persons of the same religion
- Ethnicity/Race- Ties between persons of the same group, defined against other groups
- Social Class- Ties between persons born into the same group
# Max Weber's Three Dimensions of Stratification
Max Weber developed a theory that proposed the idea that stratification is based on three factors that have become known as “the three p’s of stratification.” They are: property, prestige and power. He claimed that social stratification is a result of the interaction among wealth, prestige and power. Property refers to one’s material possessions and their life chances. If someone has control of property, that person has power of others and can use the property to his or her benefit. Prestige is also a significant factor in determining one’s place in the stratification system. The ownership of property is not always going to assure power, but there are frequently people with prestige and little property. Power is the ability to get people to do what one wants, without having much property. For example, some people in charge of the government have an immense amount of power, and yet they do not make much money.
# Networks
Our typical social network are composed of people who are similar to us.
The strongest network ties are typically age, religion, occupation(class), gender, and ethnicity.
Characteristics of networks that are composed of non similar individuals:
- Members tend to form roles within the network
- They tend to dissolve at a higher rate
|
Social status
Template:EducationalAssignment
Social status is the honor or prestige attached to one's position in society (one's social position). The stratification system, which is the system of distributing rewards to the members of society, determines social status. Social status, the position or rank of a person or group within the stratification system, can be determined two ways. One can earn their social status by their own achievements, which is known as achieved status, or one can be placed in the stratification system by their inherited position, which is called ascribed status.
# Status in different societies
Status- the relative rank that an individual holds, with attendant rights, duties, and lifestyle, in a social hierarchy based upon honor or prestige. Status has two different types that come along with it, achieved, and ascribed. The word status refers to social stratification on a vertical scale.
In modern societies, occupation is usually thought of as the main determinant of status, but other memberships or affiliations (such as ethnic group, religion, gender, voluntary associations, fandom, hobby) can have an influence. For example, a doctor often has higher status than a factory worker, but in some societies a white Protestant doctor has higher status than a non-White, immigrant doctor of a minority religion.[citation needed] The importance of social status can be seen in the peer status hierarchy of geeks, athletes, cheerleaders, nerds, and weirdos in American high schools.[1][2]
Achieved status is when people are placed in the stratification structure based on their individual merits or achievements. You can achieve this status through education, occupation, and marital status. America most commonly uses this form of status with jobs. The higher up your are in rank the better off you are and the more control you have over your co-workers.
In pre-modern societies, status differentiation is widely varied. In some cases it can be quite rigid and class based, such as with the Indian caste system. In other cases, status exists without class and/or informally, as is true with some Hunter-Gatherer societies such as the Khoisan, and some Indigenous Australian societies. In these cases, status is limited to specific personal relationships. For example, a Khoisan man is expected to take his wife's mother quite seriously (a non-joking relationship), although the mother-in-law has no special "status" over anyone except her son-in-law--and only then in specific contexts. All societies have a form of social status.
Status is an important idea in social stratification. Max Weber distinguishes status from social class[citation needed], though some contemporary empirical sociologists add the two ideas to create Socio-Economic Status or SES, usually operationalised as a simple index of income, education and occupational prestige.
# Income and status
Status inconsistency is a situation when an individual's social positions have both positive and negative influences on his social status. For example, a teacher has a positive societal image (respect, prestige) which increases his status but may earn little money, which simultaneously decreases his status. In contrast, a drug dealer, may have low social position though have a high income. However, a drug dealer may have high status within his or her own reference group (e.g., inner city gangs) and may be indifferent to his "low status" within the larger society. For example, a wealthy drug dealer who flaunts the proceeds of his trade may have the highest social status on the "street." Thus, "status inconsistency" applies to situations where members of the in-group judge the status of members of an out-group and may not apply to cases of status attainment on all criteria within an in-group.
Economic status occurs when one’s position in the stratification structure is based on their economic status in the world. This is based on income, education, and occupation. Also you must take into consideration inherited wealth, savings, occupational benefits, and ownerships of homes or motor homes.
# Inborn & acquired status
Statuses based on inborn characteristics, such as gender, are called ascribed statuses, while statuses that individuals gained thorough their own efforts are called achieved statuses. Specific behaviors are associated with social stigmas which can affect status.
Ascribed Status is when one’s position is inherited through family, racially, ethnically, and religiously serve as basis for ascribed status. Most kings’ and queen’s use this method so that the ruler stays in the family. This usually occurs at birth without any reference as to how that person may turn out to be a good or bad leader.
# Social Mobility and Social Status
Status can be changed through a process of Social Mobility. Social mobility is the change of position within the stratification system. A change in status can be done upwardly in status, upward mobility, or they can move down in status, downward mobility. Social mobility allows for a person do move to another social status other than that one they were born in. Social mobility is more common in societies where achievement rather than ascription is the primary basis for social status.
# Social Stratification
Social stratification describes the way in which different groups of people are placed with society. It is associated with the ability of individuals to live up to some set of ideals or principles regarded as important by the society or some social group within it. The members of a social group interact mainly within their own group and to a lesser degree with those of higher or lower status.
Groups:
- Wealth and Income (most common)- Ties between persons with the same personal income
- Gender- Ties between persons of the same sex and sexuality
- Political Status- Ties between persons of the same political views/status
- Religion- Ties between persons of the same religion
- Ethnicity/Race- Ties between persons of the same group, defined against other groups
- Social Class- Ties between persons born into the same group
# Max Weber's Three Dimensions of Stratification
Max Weber developed a theory that proposed the idea that stratification is based on three factors that have become known as “the three p’s of stratification.” They are: property, prestige and power. He claimed that social stratification is a result of the interaction among wealth, prestige and power. Property refers to one’s material possessions and their life chances. If someone has control of property, that person has power of others and can use the property to his or her benefit. Prestige is also a significant factor in determining one’s place in the stratification system. The ownership of property is not always going to assure power, but there are frequently people with prestige and little property. Power is the ability to get people to do what one wants, without having much property. For example, some people in charge of the government have an immense amount of power, and yet they do not make much money.
# Networks
Our typical social network are composed of people who are similar to us.
The strongest network ties are typically age, religion, occupation(class), gender, and ethnicity.
Characteristics of networks that are composed of non similar individuals:
- Members tend to form roles within the network
- They tend to dissolve at a higher rate
|
https://www.wikidoc.org/index.php/Social_status
| |
37898bdf9285fa3f6077933bcacac9d90e9120b9
|
wikidoc
|
Social stigma
|
Social stigma
Social stigma is severe social disapproval of personal characteristics or beliefs that are against cultural norms. Social stigma often leads to marginalization.
Examples of existing or historic social stigmas can be physical or mental disabilities and disorders, as well as illegitimacy, homosexuality or affiliation with a specific nationality, religion (or lack of religion) or ethnicity, such as being a Jew, an African American, or a Gypsy. Likewise, criminality carries a strong social stigma.
Stigma comes in three forms: Overt or external deformations. Examples of this are scars, physical manifestations of anorexia nervosa, leprosy, or a physical disability. Second, the known deviations in personal traits. For example, drug addicts, alcoholics, and criminals are stigmatized in this way. Third, "tribal stigmas" are traits of a race, nation, or religion that constitute a deviation from the normative race, nationality or religion. For example, Jewish people in Nazi Germany.
Although the specific social categories that become stigmatized can vary across times and places, the three basic forms of stigma (physical deformity, poor personal traits, and tribal outgroup status) are found in most cultures and time periods, leading some psychologists to hypothesize that the tendency to stigmatize may have evolutionary roots.
# Link and Phelan Stigmatization Model
Bruce Link and Jo Phelan propose that stigma exists when four specific components converge. (1) Individuals differentiate and label human variations. (2) Prevailing cultural beliefs tie those labeled to adverse attributes. (3) Labeled individuals are placed in distinguished groups that serve to establish a sense of disconnection between “us” and “them.” (4) Labeled individuals experience “status loss and discrimination” that leads to unequal circumstances. In this model stigmatization is also contingent on “access to social, economic, and political power that allows the identification of differences, construction of stereotypes, the separation of labeled persons into distinct groups, and the full execution of disapproval, rejection, exclusion, and discrimination.” Subsequently, in this model the term stigma is applied when labeling, stereotyping, disconnection, status loss, and discrimination all exist within a power situation that facilitates stigma to occur.
Differentiation and Labeling
Identifying which human differences are salient, and therefore worthy of labeling, is a social process. There are two primary factors to examine when considering the extent to which this process is a social one. The first issue is the fact that significant oversimplification is needed to create groups. The broad groups of black and white, homosexual and heterosexual, and young and old are all examples of this. Secondly, the differences that are socially judged to be relevant differ vastly according to time and place. An example of this is the emphasis that was put on the size of forehead and faces of individuals in the late nineteenth century – which was believed to be an indication of a person’s degree of criminal nature.
Linking to Stereotypes
The second component of this model centers on the linking of labeled differences with stereotypes. Goffman’s 1963 work made this aspect of stigma prominent and it has remained so ever since. This process of applying certain stereotypes to differentiated groups of individuals has garnered a large amount of attention and research in recent decades as it helps to understand the psychological nature of the thought process taking place as this linkage occurs.
Us and Them
The linking of negative attributes to differentiated groups of individuals described above facilitates a sense of separation between the proverbial “us” and “them.” This sense that the individuals of the labeled group are fundamentally different causes stereotyping to take place with little hesitation. The "us" and "them" component of the stigmatization process implies that the labeled group is slightly less human in nature, and at the extreme not human at all. It is at this extreme that the most horrific events occur.
Disadvantage
The fourth component of stigmatization in this model includes the “status loss and discrimination” that is experienced. Many definitions of stigma do not include this aspect, however it is the belief of these authors that this loss occurs inherently as individuals are “labeled, set apart, and linked to undesirable characteristics.” The members of the labeled groups are subsequently disadvantaged in the most common group of life chances including income, education, mental well-being, housing status, health, and medical treatment. However, the authors are quick to point out that even though some groups are able to escape some of the disadvantages listed, the principle is sound when broadly applied.
Necessity of Power
The authors also emphasize the necessity of power (social, economic, and political power) to stigmatize. While the role of power is clear in some situations, in others it can become masked as the power differences are so stark. An extreme example of a situation in which the power role was explicitly clear was the treatment of Jewish people by the Nazis. On the other hand, an example of a situation in which individuals of a stigmatized group have “stigma-related processes” occurring would be the inmates of a prison. It is very imaginable that each of the steps described above would take place regarding the inmates’ thoughts about the guards. However, this situation cannot involve true stigmatization according to this model because the prisoners do not have the economic, political, or social power to act on these thoughts with any serious discriminatory consequences.
|
Social stigma
Social stigma is severe social disapproval of personal characteristics or beliefs that are against cultural norms. Social stigma often leads to marginalization.
Examples of existing or historic social stigmas can be physical or mental disabilities and disorders, as well as illegitimacy, homosexuality or affiliation with a specific nationality, religion (or lack of religion[1][2]) or ethnicity, such as being a Jew, an African American, or a Gypsy. Likewise, criminality carries a strong social stigma.
Stigma comes in three forms:[3] Overt or external deformations. Examples of this are scars, physical manifestations of anorexia nervosa, leprosy, or a physical disability. Second, the known deviations in personal traits. For example, drug addicts, alcoholics, and criminals are stigmatized in this way. Third, "tribal stigmas" are traits of a race, nation, or religion that constitute a deviation from the normative race, nationality or religion. For example, Jewish people in Nazi Germany.
Although the specific social categories that become stigmatized can vary across times and places, the three basic forms of stigma (physical deformity, poor personal traits, and tribal outgroup status) are found in most cultures and time periods, leading some psychologists to hypothesize that the tendency to stigmatize may have evolutionary roots.
# Link and Phelan Stigmatization Model
Bruce Link and Jo Phelan[4] propose that stigma exists when four specific components converge. (1) Individuals differentiate and label human variations. (2) Prevailing cultural beliefs tie those labeled to adverse attributes. (3) Labeled individuals are placed in distinguished groups that serve to establish a sense of disconnection between “us” and “them.” (4) Labeled individuals experience “status loss and discrimination” that leads to unequal circumstances. In this model stigmatization is also contingent on “access to social, economic, and political power that allows the identification of differences, construction of stereotypes, the separation of labeled persons into distinct groups, and the full execution of disapproval, rejection, exclusion, and discrimination.” Subsequently, in this model the term stigma is applied when labeling, stereotyping, disconnection, status loss, and discrimination all exist within a power situation that facilitates stigma to occur.
Differentiation and Labeling
Identifying which human differences are salient, and therefore worthy of labeling, is a social process. There are two primary factors to examine when considering the extent to which this process is a social one. The first issue is the fact that significant oversimplification is needed to create groups. The broad groups of black and white, homosexual and heterosexual, and young and old are all examples of this. Secondly, the differences that are socially judged to be relevant differ vastly according to time and place. An example of this is the emphasis that was put on the size of forehead and faces of individuals in the late nineteenth century – which was believed to be an indication of a person’s degree of criminal nature.
Linking to Stereotypes
The second component of this model centers on the linking of labeled differences with stereotypes. Goffman’s 1963 work made this aspect of stigma prominent and it has remained so ever since. This process of applying certain stereotypes to differentiated groups of individuals has garnered a large amount of attention and research in recent decades as it helps to understand the psychological nature of the thought process taking place as this linkage occurs.
Us and Them
The linking of negative attributes to differentiated groups of individuals described above facilitates a sense of separation between the proverbial “us” and “them.” This sense that the individuals of the labeled group are fundamentally different causes stereotyping to take place with little hesitation. The "us" and "them" component of the stigmatization process implies that the labeled group is slightly less human in nature, and at the extreme not human at all. It is at this extreme that the most horrific events occur.
Disadvantage
The fourth component of stigmatization in this model includes the “status loss and discrimination” that is experienced. Many definitions of stigma do not include this aspect, however it is the belief of these authors that this loss occurs inherently as individuals are “labeled, set apart, and linked to undesirable characteristics.” The members of the labeled groups are subsequently disadvantaged in the most common group of life chances including income, education, mental well-being, housing status, health, and medical treatment. However, the authors are quick to point out that even though some groups are able to escape some of the disadvantages listed, the principle is sound when broadly applied.
Necessity of Power
The authors also emphasize the necessity of power (social, economic, and political power) to stigmatize. While the role of power is clear in some situations, in others it can become masked as the power differences are so stark. An extreme example of a situation in which the power role was explicitly clear was the treatment of Jewish people by the Nazis. On the other hand, an example of a situation in which individuals of a stigmatized group have “stigma-related processes” occurring would be the inmates of a prison. It is very imaginable that each of the steps described above would take place regarding the inmates’ thoughts about the guards. However, this situation cannot involve true stigmatization according to this model because the prisoners do not have the economic, political, or social power to act on these thoughts with any serious discriminatory consequences.
|
https://www.wikidoc.org/index.php/Social_stigma
| |
c1a687bd83159a44b1bc4ce0ee727086b06fbb06
|
wikidoc
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Sodium borate
|
Sodium borate
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Sodium borate is a OTC pellet that is FDA approved for the treatment of Canker sores (mouth ulcers). Common adverse reactions include vomiting and diarrhoea, abdominal pain, rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Canker sores (mouth ulcers)
### Dosage
- Directions: (adults/children) Dissolve 5 pellets under the tongue 3 times a day until symptoms are relieved or as directed by a physician.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium borate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium borate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Canker sores (mouth ulcers)
### Dosage
- Directions: (adults/children) Dissolve 5 pellets under the tongue 3 times a day until symptoms are relieved or as directed by a physician.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium borate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium borate in pediatric patients.
# Contraindications
There is limited information regarding Sodium borate Contraindications in the drug label.
# Warnings
- Stop use and ask a physician if symptoms persist for more than 3 days or worsen.
- Keep out of reach of children.
- Do not use if pellet-dispenser seal is broken.
# Adverse Reactions
## Clinical Trials Experience
- vomiting and diarrhoea, abdominal pain, rash
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Sodium borate in the drug label.
# Drug Interactions
There is limited information regarding Sodium borate Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast-feeding, ask a health professional before use.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sodium borate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sodium borate during labor and delivery.
### Nursing Mothers
- If pregnant or breast-feeding, ask a health professional before use.
### Pediatric Use
There is no FDA guidance on the use of Sodium borate with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Sodium borate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Sodium borate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sodium borate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sodium borate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sodium borate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sodium borate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sodium borate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Sodium borate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sodium borate in the drug label.
# Overdosage
There is limited information regarding Overdose of Sodium borate in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sodium borate Mechanism of Action in the drug label.
## Structure
- Active Ingredient:
- Inactive Ingredients: Lactose, sucrose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sodium borate in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Sodium borate in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Sodium borate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Sodium borate in the drug label.
# How Supplied
There is limited information regarding Sodium borate How Supplied in the drug label.
## Storage
- Store at room temperature.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Sodium borate in the drug label.
# Precautions with Alcohol
- Alcohol-Sodium borate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BORAX®
# Look-Alike Drug Names
There is limited information regarding Sodium borate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
|
Sodium borate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Sodium borate is a OTC pellet that is FDA approved for the treatment of Canker sores (mouth ulcers). Common adverse reactions include vomiting and diarrhoea, abdominal pain, rash.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Canker sores (mouth ulcers)
### Dosage
- Directions: (adults/children) Dissolve 5 pellets under the tongue 3 times a day until symptoms are relieved or as directed by a physician.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium borate in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium borate in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Indications
- Canker sores (mouth ulcers)
### Dosage
- Directions: (adults/children) Dissolve 5 pellets under the tongue 3 times a day until symptoms are relieved or as directed by a physician.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sodium borate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sodium borate in pediatric patients.
# Contraindications
There is limited information regarding Sodium borate Contraindications in the drug label.
# Warnings
- Stop use and ask a physician if symptoms persist for more than 3 days or worsen.
- Keep out of reach of children.
- Do not use if pellet-dispenser seal is broken.
# Adverse Reactions
## Clinical Trials Experience
- vomiting and diarrhoea, abdominal pain, rash
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Sodium borate in the drug label.
# Drug Interactions
There is limited information regarding Sodium borate Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- If pregnant or breast-feeding, ask a health professional before use.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sodium borate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sodium borate during labor and delivery.
### Nursing Mothers
- If pregnant or breast-feeding, ask a health professional before use.
### Pediatric Use
There is no FDA guidance on the use of Sodium borate with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Sodium borate with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Sodium borate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sodium borate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sodium borate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sodium borate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sodium borate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sodium borate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Sodium borate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sodium borate in the drug label.
# Overdosage
There is limited information regarding Overdose of Sodium borate in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sodium borate Mechanism of Action in the drug label.
## Structure
- Active Ingredient:
- Inactive Ingredients: Lactose, sucrose.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sodium borate in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Sodium borate in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Sodium borate in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Sodium borate in the drug label.
# How Supplied
There is limited information regarding Sodium borate How Supplied in the drug label.
## Storage
- Store at room temperature.
# Images
## Drug Images
## Package and Label Display Panel
### Ingredients and Appearance
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Sodium borate in the drug label.
# Precautions with Alcohol
- Alcohol-Sodium borate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BORAX®[1]
# Look-Alike Drug Names
There is limited information regarding Sodium borate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/Sodium_borate
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66dc023abc3ecd9b64c3da492838e5d31fbc6ce9
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wikidoc
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Sodium iodate
|
Sodium iodate
Sodium iodate (NaIO3) is a chemical compound.
Sodium iodate is an oxidizing agent and as such it can cause fires if in contact with combustible materials or reducing agents. It can be prepared by reacting a sodium-containing base such as sodium hydroxide with iodic acid, for example:
HIO3 + NaOH → NaIO3 + H2O
It can also be prepared by adding iodine to a hot, concentrated solution of sodium hydroxide.
3 I2 + 6 NaOH → NaIO3 + 5 NaI + 3 H2O
Conditions/substances to avoid are: heat, shock, friction, combustible materials, reducing materials, aluminum, organic compounds, carbon, hydrogen peroxide, sulfides.
|
Sodium iodate
Template:Chemical-importance
Template:Chembox new
Sodium iodate (NaIO3) is a chemical compound.
Sodium iodate is an oxidizing agent and as such it can cause fires if in contact with combustible materials or reducing agents. It can be prepared by reacting a sodium-containing base such as sodium hydroxide with iodic acid, for example:
HIO3 + NaOH → NaIO3 + H2O
It can also be prepared by adding iodine to a hot, concentrated solution of sodium hydroxide.
3 I2 + 6 NaOH → NaIO3 + 5 NaI + 3 H2O
Conditions/substances to avoid are: heat, shock, friction, combustible materials, reducing materials, aluminum, organic compounds, carbon, hydrogen peroxide, sulfides.
|
https://www.wikidoc.org/index.php/Sodium_iodate
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c5e123ac7811514b48352de85a2f36eaa64bdb04
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wikidoc
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Sol Boxenbaum
|
Sol Boxenbaum
# Background
Sol Boxenbaum born ca. 1940, Radio Host CJAD, Gambling Critic
Sol Boxenbaum, Chief Executive Officer, President, and co-founder of Viva Consulting Family Life Inc., has an extensive background in addressing issues of problem gambling and its detrimental effect on society. As a crusader for harm-reduction policies and strategies concerning gambling, he is known and respected by experts throughout the world. He is considered one of the principal consumer advocates in Quebec and in Canada on issues concerning the dangers of rapid expansion of legalized gambling. Because of his recognized knowledge and expertise on the subject, coupled with his self-admitted dogged persistence in pursuing public interests, his advice and opinions are sought after by all levels of the government, professionals in the field, the media, and the general public.
Although he holds no academic degrees in this field, Sol Boxenbaum has been studying the cause and effect of problem gambling for more than a decade. In 1995, events in his own life lead him to develop an interest in tracing the origin of gambling addiction, and a desire to develop prevention strategies that might alert the public to the inherent dangers of legalized gambling. Having reached the age of 55 at that time, however, he was reluctant to commence University courses, such as Psychology 101, that might ultimately lead to him achieving accreditation.
Instead, in order to learn as much as possible within a limited time frame, he began to attend Gambling and Risk-Taking Conferences across Canada. At these conferences he met the most learned psychologists and researchers of the time, experts who were lecturing on the various aspects of gambling addiction and the prevention and treatment of gambling addiction. As a result of these efforts, he developed a network of contacts world-wide, meeting many highly qualified professionals who were willing to share their knowledge with him. In 1997, he himself was invited to the 10th International Conference as a presenter. By 1998, he was already receiving letters of reference from colleagues with PhDs in psychology and credentials in addiction counseling, attesting to his expertise in this field.
In 1995, while living in Saskatchewan, Sol established the Canadian Foundation on Compulsive Gambling (Sask.) Inc. His vision for the Foundation included educating the public by providing information on the dangers of excessive gambling, while at the same time facilitating the development of appropriate resources to identify and treat those affected by problem gambling or compulsive gambling.
As Executive Director of the Foundation, Sol worked closely with Saskatchewan Health, Saskatchewan Gaming Corporation, and Saskatchewan Liquor and Gaming Authority. He also sat on Regional Committees throughout the province, to discuss local issues and problems that were a result of the individual demographics of each area, to ensure that the needs of all of the population were being met. He also attended numerous workshops and symposiums across Canada, both as participant and presenter.
He was responsible for staff training courses to develop problem gambling awareness and knowledge of intervention techniques. During his tenure as Executive Director, Sol trained more than five hundred employees at Casino Regina. He also trained fifty executives and field employees of the Saskatchewan Liquor and Gaming Authority, the provincial body responsible for gambling in places where liquor is served.
Having returned to his home province of Quebec, Sol continued to maintain his contacts with the foremost experts on compulsive gambling in North America and abroad. Realizing that the problems associated with government-endorsed gambling were increasing across North America, in 1999 he welcomed the opportunity to collaborate with Brenda Thomas (psychotherapist) in the foundation of Viva Consulting, a Quebec-based company dedicated to issues of problem gambling. In 2002 the company was federally incorporated as a not-for-profit organization under the name Viva Consulting Family Life Inc.
As CEO of Viva Consulting, Sol was invited, along with experts from McGill University and Université de Laval, to appear before a commission at the Quebec National Assembly to discuss the effect of gambling on adolescents (December 1999). This Commission resulted in the passing of a new law (Bill 84) prohibiting the sale of lottery tickets to minors in Quebec.
As consumer advocate with Viva Consulting Family Life Inc., Sol is constantly called upon for his opinions on breaking news in the gambling field. He has been a guest on many radio and television shows, including not only the local stations but also CBC (radio and TV, both French and English stations), and BBC. He has been interviewed for articles in many magazines, including MacLean’s. In addition to the many daily news programs he is regularly called upon to participate in, Sol has also taken part in many radio talk shows, such as Don Hill’s “Wild Rose Forum” (Alberta), Mark Elliot’s “People Helping People” (Ontario), and “The John Rossy Show” (Montreal). As well, he has submitted articles to Toronto Globe and Mail and Ottawa Citizen as a freelance writer.
Sol continues to strive to bring to the attention of both the general public and the government the issues created when gambling is allowed to become a problem. His name and his voice have become an anticipated feature of almost every media article (broadcast or printed) when the issue is gambling.
One highlight of his career was when he was invited to speak at the International Problem Gambling Conference in Nova Scotia (Oct. 2004), where Ralph Nader and Maude Barlow were keynote speakers. A second highlight was being invited to be the keynote speaker Nova Scotia Provincial Volunteer Workshop ("Strength in Community" in Nova Scotia (Oct. 2005).
Each day Sol receives countless phone calls and e-mails from the media for direct and up-to-date responses on current issues. He receives requests for professional consultations from individuals and organizations throughout the world, both on immediate news items and discussions of theory. He is frequently sought after by those doing research for documentaries, tv programs, theatre presentations, and books, as well as post-secondary students whose projects address issues of problem gambling. He has also involved himself several times in helping individuals in need of legal assistance. In addition to all of this, he has given educational presentations to students both at the secondary and post-secondary levels.
Sol makes it a point to respond personally to calls from the problem gamblers who call when they are in crisis. Many of these are referred to Viva Consulting Family Life Inc. from the government sponsored Problem Gambling HelpLine. He listens, consoles, and advises them at the time. If they follow through on his offer of an immediate follow-up appointment, he conducts the initial intake interview, and spends time explaining and demonstrating how electronic gambling machines work. He then arranges to see them further to discuss direct gambling issues, or arranges an appointment for them to meet with a professional to deal with underlying issues.
Sol continues to strive actively to bring to the attention of the government and to the attention of the general public all of the problems created when the Government is the owner, operator and regulator of the gambling industry. To this end, he has been in contact with many different ministries, both at the Municipal, Provincial, and Federal levels.
Sol was invited to become a charter member of a Citizens’ Coalition called EMJEU, a group of individuals deeply concerned about the devastating effects of the government’s expansion and encouragement of gambling. In May, 2004, they announced their intention to “encourage the government and Loto-Quebec to adopt a more ethical and responsible position in the management of gambling”. Sol became the English spokesperson for this bilingual organization.
He was recently involved in a coalition that stopped the movement of the Montreal Casino from its present location to downtown Montreal. He continues to speak out actively, and articulately, on issues brought to the attention of the media. He is also currently involved in several projects dealing with other social injustices in Canada.
|
Sol Boxenbaum
Template:CNG
# Background
Sol Boxenbaum born ca. 1940, Radio Host CJAD, Gambling Critic
Sol Boxenbaum, Chief Executive Officer, President, and co-founder of Viva Consulting Family Life Inc., has an extensive background in addressing issues of problem gambling and its detrimental effect on society. As a crusader for harm-reduction policies and strategies concerning gambling, he is known and respected by experts throughout the world. He is considered one of the principal consumer advocates in Quebec and in Canada on issues concerning the dangers of rapid expansion of legalized gambling. Because of his recognized knowledge and expertise on the subject, coupled with his self-admitted dogged persistence in pursuing public interests, his advice and opinions are sought after by all levels of the government, professionals in the field, the media, and the general public.
Although he holds no academic degrees in this field, Sol Boxenbaum has been studying the cause and effect of problem gambling for more than a decade. In 1995, events in his own life lead him to develop an interest in tracing the origin of gambling addiction, and a desire to develop prevention strategies that might alert the public to the inherent dangers of legalized gambling. Having reached the age of 55 at that time, however, he was reluctant to commence University courses, such as Psychology 101, that might ultimately lead to him achieving accreditation.
Instead, in order to learn as much as possible within a limited time frame, he began to attend Gambling and Risk-Taking Conferences across Canada. At these conferences he met the most learned psychologists and researchers of the time, experts who were lecturing on the various aspects of gambling addiction and the prevention and treatment of gambling addiction. As a result of these efforts, he developed a network of contacts world-wide, meeting many highly qualified professionals who were willing to share their knowledge with him. In 1997, he himself was invited to the 10th International Conference as a presenter. By 1998, he was already receiving letters of reference from colleagues with PhDs in psychology and credentials in addiction counseling, attesting to his expertise in this field.
In 1995, while living in Saskatchewan, Sol established the Canadian Foundation on Compulsive Gambling (Sask.) Inc. His vision for the Foundation included educating the public by providing information on the dangers of excessive gambling, while at the same time facilitating the development of appropriate resources to identify and treat those affected by problem gambling or compulsive gambling.
As Executive Director of the Foundation, Sol worked closely with Saskatchewan Health, Saskatchewan Gaming Corporation, and Saskatchewan Liquor and Gaming Authority. He also sat on Regional Committees throughout the province, to discuss local issues and problems that were a result of the individual demographics of each area, to ensure that the needs of all of the population were being met. He also attended numerous workshops and symposiums across Canada, both as participant and presenter.
He was responsible for staff training courses to develop problem gambling awareness and knowledge of intervention techniques. During his tenure as Executive Director, Sol trained more than five hundred employees at Casino Regina. He also trained fifty executives and field employees of the Saskatchewan Liquor and Gaming Authority, the provincial body responsible for gambling in places where liquor is served.
Having returned to his home province of Quebec, Sol continued to maintain his contacts with the foremost experts on compulsive gambling in North America and abroad. Realizing that the problems associated with government-endorsed gambling were increasing across North America, in 1999 he welcomed the opportunity to collaborate with Brenda Thomas (psychotherapist) in the foundation of Viva Consulting, a Quebec-based company dedicated to issues of problem gambling. In 2002 the company was federally incorporated as a not-for-profit organization under the name Viva Consulting Family Life Inc.
As CEO of Viva Consulting, Sol was invited, along with experts from McGill University and Université de Laval, to appear before a commission at the Quebec National Assembly to discuss the effect of gambling on adolescents (December 1999). This Commission resulted in the passing of a new law (Bill 84) prohibiting the sale of lottery tickets to minors in Quebec.
As consumer advocate with Viva Consulting Family Life Inc., Sol is constantly called upon for his opinions on breaking news in the gambling field. He has been a guest on many radio and television shows, including not only the local stations but also CBC (radio and TV, both French and English stations), and BBC. He has been interviewed for articles in many magazines, including MacLean’s. In addition to the many daily news programs he is regularly called upon to participate in, Sol has also taken part in many radio talk shows, such as Don Hill’s “Wild Rose Forum” (Alberta), Mark Elliot’s “People Helping People” (Ontario), and “The John Rossy Show” (Montreal). As well, he has submitted articles to Toronto Globe and Mail and Ottawa Citizen as a freelance writer.
Sol continues to strive to bring to the attention of both the general public and the government the issues created when gambling is allowed to become a problem. His name and his voice have become an anticipated feature of almost every media article (broadcast or printed) when the issue is gambling.
One highlight of his career was when he was invited to speak at the International Problem Gambling Conference in Nova Scotia (Oct. 2004), where Ralph Nader and Maude Barlow were keynote speakers. A second highlight was being invited to be the keynote speaker Nova Scotia Provincial Volunteer Workshop ("Strength in Community" in Nova Scotia (Oct. 2005).
Each day Sol receives countless phone calls and e-mails from the media for direct and up-to-date responses on current issues. He receives requests for professional consultations from individuals and organizations throughout the world, both on immediate news items and discussions of theory. He is frequently sought after by those doing research for documentaries, tv programs, theatre presentations, and books, as well as post-secondary students whose projects address issues of problem gambling. He has also involved himself several times in helping individuals in need of legal assistance. In addition to all of this, he has given educational presentations to students both at the secondary and post-secondary levels.
Sol makes it a point to respond personally to calls from the problem gamblers who call when they are in crisis. Many of these are referred to Viva Consulting Family Life Inc. from the government sponsored Problem Gambling HelpLine. He listens, consoles, and advises them at the time. If they follow through on his offer of an immediate follow-up appointment, he conducts the initial intake interview, and spends time explaining and demonstrating how electronic gambling machines work. He then arranges to see them further to discuss direct gambling issues, or arranges an appointment for them to meet with a professional to deal with underlying issues.
Sol continues to strive actively to bring to the attention of the government and to the attention of the general public all of the problems created when the Government is the owner, operator and regulator of the gambling industry. To this end, he has been in contact with many different ministries, both at the Municipal, Provincial, and Federal levels.
Sol was invited to become a charter member of a Citizens’ Coalition called EMJEU, a group of individuals deeply concerned about the devastating effects of the government’s expansion and encouragement of gambling. In May, 2004, they announced their intention to “encourage the government and Loto-Quebec to adopt a more ethical and responsible position in the management of gambling”. Sol became the English spokesperson for this bilingual organization.
He was recently involved in a coalition that stopped the movement of the Montreal Casino from its present location to downtown Montreal. He continues to speak out actively, and articulately, on issues brought to the attention of the media. He is also currently involved in several projects dealing with other social injustices in Canada.
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Sol_Boxenbaum
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e854002516f1a88972c619c892c8f2d598c8668e
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wikidoc
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Soleus muscle
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Soleus muscle
# Overview
In humans and some other mammals, the soleus is a powerful muscle in the back part of the lower leg (the calf). It runs from just below the knee to the heel, and is involved in standing and walking. It is closely connected to the gastrocnemius muscle and some anatomists consider them to be a single muscle, the triceps surae. Its name is derived from the solefish whose shape it resembles.
The soleus is located in the superficial posterior compartment of the leg. Not all mammals have a soleus muscle; one notable species that lacks the soleus is the dog.
# Origin and insertion
It originates from the posterior (back) surfaces of the head of the fibula and its upper third, as well as the middle third of the internal border of the tibia.
Its other end forms a common tendon with the gastrocnemius muscle; this tendon is known as the calcaneal tendon or Achilles tendon and inserts onto the posterior surface of the calcaneus, or heel bone.
# Relations
Superficial to the soleus (closer to the skin) is the gastrocnemius muscle.
The plantaris muscle and a portion of its tendon run between the two muscles. Deep to it (farther from the skin) is the transverse intermuscular septum, which separates the superficial posterior compartment of the leg from the deep posterior compartment.
On the other side of the fascia are the tibialis posterior muscle, the flexor digitorum longus muscle, and the flexor hallucis longus muscle, along with the posterior tibial artery and posterior tibial vein and the tibial nerve.
Since the anterior compartment of the leg is lateral to the tibia, the bulge of muscle medial to the tibia on the anterior side is actually the posterior compartment. The soleus is superficial midshaft of the tibia.
# Function
The action of the calf muscles, including the soleus, is to plantar flex the foot (that is, they increase the angle between the foot and the leg).
They are powerful muscles and are vital in walking, running, and dancing.
The soleus specifically plays an important role in standing; if not for its constant pull, the body would fall forward.
Also, in upright posture, it is responsible for pumping venous blood back into the heart from the periphery, and is often called the peripheral heart or the sural (tricipital) pump .
# Additional images
- Bones of the right leg. Posterior surface.
- Cross-section through middle of leg.
- Back of left lower extremity.
|
Soleus muscle
Template:Infobox Muscle
# Overview
In humans and some other mammals, the soleus is a powerful muscle in the back part of the lower leg (the calf). It runs from just below the knee to the heel, and is involved in standing and walking. It is closely connected to the gastrocnemius muscle and some anatomists consider them to be a single muscle, the triceps surae. Its name is derived from the solefish whose shape it resembles.
The soleus is located in the superficial posterior compartment of the leg. Not all mammals have a soleus muscle; one notable species that lacks the soleus is the dog.
# Origin and insertion
It originates from the posterior (back) surfaces of the head of the fibula and its upper third, as well as the middle third of the internal border of the tibia.
Its other end forms a common tendon with the gastrocnemius muscle; this tendon is known as the calcaneal tendon or Achilles tendon and inserts onto the posterior surface of the calcaneus, or heel bone.
# Relations
Superficial to the soleus (closer to the skin) is the gastrocnemius muscle.
The plantaris muscle and a portion of its tendon run between the two muscles. Deep to it (farther from the skin) is the transverse intermuscular septum, which separates the superficial posterior compartment of the leg from the deep posterior compartment.
On the other side of the fascia are the tibialis posterior muscle, the flexor digitorum longus muscle, and the flexor hallucis longus muscle, along with the posterior tibial artery and posterior tibial vein and the tibial nerve.
Since the anterior compartment of the leg is lateral to the tibia, the bulge of muscle medial to the tibia on the anterior side is actually the posterior compartment. The soleus is superficial midshaft of the tibia.
# Function
The action of the calf muscles, including the soleus, is to plantar flex the foot (that is, they increase the angle between the foot and the leg).
They are powerful muscles and are vital in walking, running, and dancing.
The soleus specifically plays an important role in standing; if not for its constant pull, the body would fall forward.
Also, in upright posture, it is responsible for pumping venous blood back into the heart from the periphery, and is often called the peripheral heart or the sural (tricipital) pump [1].
# Additional images
- Bones of the right leg. Posterior surface.
- Cross-section through middle of leg.
- Back of left lower extremity.
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https://www.wikidoc.org/index.php/Soleus
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3ebd2a3ef276ef2569a31385dd87b3828333a45e
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wikidoc
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Southern blot
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Southern blot
# Overview
A Southern blot is a method routinely used in molecular biology to check for the presence of a DNA sequence in a DNA sample. Southern blotting combines agarose gel electrophoresis for size separation of DNA with methods to transfer the size-separated DNA to a filter membrane for probe hybridization. The method is named after its inventor, the British biologist Edwin Southern. Other blotting methods (i.e., western blot, northern blot, southwestern blot) that employ similar principles, but using RNA or protein, have later been named in reference to Southern's name. As the technique was eponymously named, Southern blot should be capitalized, whereas northern and western blots should not.
# Method
- Restriction endonucleases are used to cut high-molecular-weight DNA strands into smaller fragments.
- The DNA fragments are then electrophoresed on an agarose gel to separate them by size.
- If some of the DNA fragments are larger than 15 kb, then prior to blotting, the gel may be treated with an acid, such as dilute HCl, which depurinates the DNA fragments, breaking the DNA into smaller pieces, thus allowing more efficient transfer from the gel to membrane.
- If alkaline transfer methods are used, the DNA gel is placed into an alkaline solution (typically containing sodium hydroxide) to denature the double-stranded DNA. The denaturation in an alkaline environment provides for improved binding of the negatively charged DNA to a positively charged membrane, separates it into single DNA strands for later hybridization to the probe (see below), and destroys any residual RNA that may still be present in the DNA.
- A sheet of nitrocellulose (or, alternatively, nylon) membrane is placed on top of (or below, depending on the direction of the transfer) the gel. Pressure is applied evenly to the gel (either using suction, or by placing a stack of paper towels and a weight on top of the membrane and gel), to ensure good and even contact between gel and membrane. Buffer transfer by capillary action from a region of high water potential to a region of low water potential (usually filter paper and paper tissues) is then used to move the DNA from the gel on to the membrane; ion exchange interactions bind the DNA to the membrane due to the negative charge of the DNA and positive charge of the membrane.
- The membrane is then baked, i.e., exposed to high temperature (60 to 100 °C) (in the case of nitrocellulose) or exposed to ultraviolet radiation (nylon) to permanently and covalently crosslink the DNA to the membrane.
- The membrane is then exposed to a hybridization probe—a single DNA fragment with a specific sequence whose presence in the target DNA is to be determined. The probe DNA is labelled so that it can be detected, usually by incorporating radioactivity or tagging the molecule with a fluorescent or chromogenic dye. In some cases, the hybridization probe may be made from RNA, rather than DNA. To ensure the specificity of the binding of the probe to the sample DNA, most common hybridization methods use salmon testes (sperm) DNA for blocking of the membrane surface and target DNA, deionized formamide, and detergents such as SDS to reduce non-specific binding of the probe.
- After hybridization, excess probe is washed from the membrane, and the pattern of hybridization is visualized on X-ray film by autoradiography in the case of a radioactive or fluorescent probe, or by development of color on the membrane if a chromogenic detection method is used.
# Result
Hybridization of the probe to a specific DNA fragment on the filter membrane indicates that this fragment contains DNA sequence that is complementary to the probe.
The transfer step of the DNA from the electrophoresis gel to a membrane permits easy binding of the labeled hybridization probe to the size-fractionated DNA. It also allows for the fixation of the target-probe hybrids, required for analysis by autoradiography or other detection methods.
|
Southern blot
# Overview
A Southern blot is a method routinely used in molecular biology to check for the presence of a DNA sequence in a DNA sample. Southern blotting combines agarose gel electrophoresis for size separation of DNA with methods to transfer the size-separated DNA to a filter membrane for probe hybridization. The method is named after its inventor, the British biologist Edwin Southern.[1] Other blotting methods (i.e., western blot, northern blot, southwestern blot) that employ similar principles, but using RNA or protein, have later been named in reference to Southern's name. As the technique was eponymously named, Southern blot should be capitalized, whereas northern and western blots should not.
# Method
- Restriction endonucleases are used to cut high-molecular-weight DNA strands into smaller fragments.
- The DNA fragments are then electrophoresed on an agarose gel to separate them by size.
- If some of the DNA fragments are larger than 15 kb, then prior to blotting, the gel may be treated with an acid, such as dilute HCl, which depurinates the DNA fragments, breaking the DNA into smaller pieces, thus allowing more efficient transfer from the gel to membrane.
- If alkaline transfer methods are used, the DNA gel is placed into an alkaline solution (typically containing sodium hydroxide) to denature the double-stranded DNA. The denaturation in an alkaline environment provides for improved binding of the negatively charged DNA to a positively charged membrane, separates it into single DNA strands for later hybridization to the probe (see below), and destroys any residual RNA that may still be present in the DNA.
- A sheet of nitrocellulose (or, alternatively, nylon) membrane is placed on top of (or below, depending on the direction of the transfer) the gel. Pressure is applied evenly to the gel (either using suction, or by placing a stack of paper towels and a weight on top of the membrane and gel), to ensure good and even contact between gel and membrane. Buffer transfer by capillary action from a region of high water potential to a region of low water potential (usually filter paper and paper tissues) is then used to move the DNA from the gel on to the membrane; ion exchange interactions bind the DNA to the membrane due to the negative charge of the DNA and positive charge of the membrane.
- The membrane is then baked, i.e., exposed to high temperature (60 to 100 °C) (in the case of nitrocellulose) or exposed to ultraviolet radiation (nylon) to permanently and covalently crosslink the DNA to the membrane.
- The membrane is then exposed to a hybridization probe—a single DNA fragment with a specific sequence whose presence in the target DNA is to be determined. The probe DNA is labelled so that it can be detected, usually by incorporating radioactivity or tagging the molecule with a fluorescent or chromogenic dye. In some cases, the hybridization probe may be made from RNA, rather than DNA. To ensure the specificity of the binding of the probe to the sample DNA, most common hybridization methods use salmon testes (sperm) DNA for blocking of the membrane surface and target DNA, deionized formamide, and detergents such as SDS to reduce non-specific binding of the probe.
- After hybridization, excess probe is washed from the membrane, and the pattern of hybridization is visualized on X-ray film by autoradiography in the case of a radioactive or fluorescent probe, or by development of color on the membrane if a chromogenic detection method is used.
# Result
Hybridization of the probe to a specific DNA fragment on the filter membrane indicates that this fragment contains DNA sequence that is complementary to the probe.
The transfer step of the DNA from the electrophoresis gel to a membrane permits easy binding of the labeled hybridization probe to the size-fractionated DNA. It also allows for the fixation of the target-probe hybrids, required for analysis by autoradiography or other detection methods.
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https://www.wikidoc.org/index.php/Southern_Blot
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3990c1e3f8120d494ce573384eb33353841676e7
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wikidoc
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Spectrophobia
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Spectrophobia
# Overview
Spectrophobia (from Latin: spectrum, n. specio, an appearance, form, image of a thing; an apparition, spectre) or catoptrophobia (from Greek κάτοπτρον kátoptron, "mirror") is a kind of specific phobia involving a morbid fear of mirrors. This phobia is distinct from eisoptrophobia, which is the Fear processing in the brain|fear of one's own reflection.
# Causes
Generally, an individual that deals with spectrophobia has been traumatized in an event where they believe they have seen or heard apparitions or ghosts. The individual could also become traumatized by horror films, television shows, or by nightmares.
This fear could be the result of a trauma involving mirrors. It could also be the result of the person’s superstitious fear of being watched through the mirror.
# Fear
Sufferers of catoptrophobia can fear the breaking of a mirror bringing extreme bad luck. They can fear the thought of something frightening jumping out of the mirror or seeing something disturbing inside of it next to their own reflection when looking directly at it. Others fear that it is a link to the supernatural world or a gateway into another world. Some also fear their own reflection in the darkness, as it can appear distorted in strange ways. Some people may also fear being pulled into the mirror by some supernatural force.
# Treatment
As with most phobias this fear could be cured with therapy and / or medication. Relaxation techniques or support groups could also be effective.
|
Spectrophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Spectrophobia (from Latin: spectrum, n. specio, an appearance, form, image of a thing; an apparition, spectre) or catoptrophobia (from Greek κάτοπτρον kátoptron, "mirror") is a kind of specific phobia involving a morbid fear of mirrors. This phobia is distinct from eisoptrophobia, which is the Fear processing in the brain|fear of one's own reflection.
# Causes
Generally, an individual that deals with spectrophobia has been traumatized in an event where they believe they have seen or heard apparitions or ghosts. The individual could also become traumatized by horror films, television shows, or by nightmares.[1]
This fear could be the result of a trauma involving mirrors. It could also be the result of the person’s superstitious fear of being watched through the mirror.
# Fear
Sufferers of catoptrophobia can fear the breaking of a mirror bringing extreme bad luck. They can fear the thought of something frightening jumping out of the mirror or seeing something disturbing inside of it next to their own reflection when looking directly at it. Others fear that it is a link to the supernatural world or a gateway into another world. Some also fear their own reflection in the darkness, as it can appear distorted in strange ways. Some people may also fear being pulled into the mirror by some supernatural force.
# Treatment
As with most phobias this fear could be cured with therapy and / or medication. Relaxation techniques or support groups could also be effective.
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https://www.wikidoc.org/index.php/Spectrophobia
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4b42888ddc70e81b742271ba76a7fb16dd3b96e0
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wikidoc
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Sperm washing
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Sperm washing
Sperm washing is a term used to describe the process in which individual sperm are separated from the seminal fluid by spinning it in a centrifuge. The Sperm are then used in Intra-Uterine Insemination or in vitro fertilization.
Sperm washing is a standard procedure used in infertility treatment, however, starting in the mid-1990s it was adopted to help HIV discordant couples conceive without passing the virus from the father to the mother or child . The idea is that when the male is HIV positive it will reduce the risk of transmission to the female.
The HIV infection is carried by the seminal fluid rather than the sperm. However, there are still lingering doubts about the safety of the procedure.
The process was first used in Milan, Italy and has so far resulted in no female becoming HIV positive. The oldest child conceived using this method is now about 11 and is HIV negative. The first known American baby, Baby Ryan was born in 1999 through the Special Program of Assisted Reproduction started by Dr. Ann Kiessling.
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Sperm washing
Sperm washing is a term used to describe the process in which individual sperm are separated from the seminal fluid by spinning it in a centrifuge. The Sperm are then used in Intra-Uterine Insemination or in vitro fertilization.
Sperm washing is a standard procedure used in infertility treatment, however, starting in the mid-1990s it was adopted to help HIV discordant couples conceive without passing the virus from the father to the mother or child [1]. The idea is that when the male is HIV positive it will reduce the risk of transmission to the female.
The HIV infection is carried by the seminal fluid rather than the sperm. However, there are still lingering doubts about the safety of the procedure.
The process was first used in Milan, Italy and has so far resulted in no female becoming HIV positive. The oldest child conceived using this method is now about 11 and is HIV negative. The first known American baby, Baby Ryan was born in 1999 [2] through the Special Program of Assisted Reproduction started by Dr. Ann Kiessling.
Template:Virus-stub
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https://www.wikidoc.org/index.php/Sperm_washing
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3b4e8d02c6f1937c80ba5d7f1d5cae80d902e2fb
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wikidoc
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Sphenoid bone
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Sphenoid bone
# Overview
The sphenoid bone (from Greek sphenoeides, "wedgelike") is a bone situated at the base of the skull in front of the temporals and basilar part of the occipital bone.
The sphenoid bone somewhat resembles a butterfly or bat with its wings extended.
# Portions
It is divided into the following parts:
- a median portion, known as the body of sphenoid bone
- two greater wings and two lesser wings
- Pterygoid processes of the sphenoides which project from it posteriorly (below)
Two sphenoidal conchae are situated at the anterior and posterior part of the body.
# Named features
Various other named features of the sphenoid bone exist:
- pterygoid notch
- pterygoid fossa
- scaphoid fossa
- vaginal process
- pterygoid hamulus
- pterygoid canal
- pterygospinous process
# Additional images
- Facial bones.
- Lateral wall of nasal cavity, showing ethmoid bone in position.
- Sphenoid bone visible center right.
- Base of skull. Inferior surface.
- Lateral view of the skull.
- Horizontal section of nasal and orbital cavities.
- Floor of the skull.
- Roof, floor, and lateral wall of left nasal cavity.
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Sphenoid bone
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The sphenoid bone (from Greek sphenoeides, "wedgelike") is a bone situated at the base of the skull in front of the temporals and basilar part of the occipital bone.
The sphenoid bone somewhat resembles a butterfly or bat with its wings extended.
# Portions
It is divided into the following parts:
- a median portion, known as the body of sphenoid bone
- two greater wings and two lesser wings
- Pterygoid processes of the sphenoides which project from it posteriorly (below)
Two sphenoidal conchae are situated at the anterior and posterior part of the body.
# Named features
Various other named features of the sphenoid bone exist:
- pterygoid notch
- pterygoid fossa
- scaphoid fossa
- vaginal process
- pterygoid hamulus
- pterygoid canal
- pterygospinous process
# Additional images
- Facial bones.
- Lateral wall of nasal cavity, showing ethmoid bone in position.
- Sphenoid bone visible center right.
- Base of skull. Inferior surface.
- Lateral view of the skull.
- Horizontal section of nasal and orbital cavities.
- Floor of the skull.
- Roof, floor, and lateral wall of left nasal cavity.
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https://www.wikidoc.org/index.php/Sphenoid
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48fda1b983b1431d1259ea5a4fadacf77173d2d9
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wikidoc
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Spice essence
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Spice essence
Spice essence is a fictional substance from the Dune universe created by Frank Herbert.
# Qualities
Spice essence is a bright blue liquid. It is a concentrate made from Melange, a substance obtained from the giant sandworms on Arrakis. It has a distinctive odor, described as, "bitter cinnamon," by Murbella in Chapterhouse: Dune. At some point after the transformation of Dune to Arrakis and the extinction death of the sandworms, it appears that spice essence replaced the Water of Life, at least as used in the rituals of the Fremen and the Bene Gesserit.
# Uses
Because it is a concentrated form of melange, spice essence is utilized in many of the same fashions.
## Spacing Guild
Spacing Guild Navigators use the spice to induce the prescient trance which allows them to see through time. Only in this trance can a Navigator plot the safest course through space-time. This is the course that allows the Heighliner that they are piloting to avoid objects with mass.
## Bene Gesserit
The Bene Gesserit use the spice essence as a drug in the spice agony, which gives her potential contact with her Other Memory. She must use her Bene Gesserit-trained metabolic control to change the chemical structure of the essence, rendering the poison harmless. Achieving this unlocks ancestral memories; failure results in death.
The only two men who have ever consumed spice essence and survived are Paul Atreides, the Kwisatz Haderach, and his son Leto Atreides II.
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Spice essence
Spice essence is a fictional substance from the Dune universe created by Frank Herbert.
# Qualities
Spice essence is a bright blue liquid. It is a concentrate made from Melange, a substance obtained from the giant sandworms on Arrakis. It has a distinctive odor, described as, "bitter cinnamon," by Murbella in Chapterhouse: Dune. At some point after the transformation of Dune to Arrakis and the extinction death of the sandworms, it appears that spice essence replaced the Water of Life, at least as used in the rituals of the Fremen and the Bene Gesserit.
# Uses
Because it is a concentrated form of melange, spice essence is utilized in many of the same fashions.
## Spacing Guild
Spacing Guild Navigators use the spice to induce the prescient trance which allows them to see through time. Only in this trance can a Navigator plot the safest course through space-time. This is the course that allows the Heighliner that they are piloting to avoid objects with mass.
## Bene Gesserit
The Bene Gesserit use the spice essence as a drug in the spice agony, which gives her potential contact with her Other Memory. She must use her Bene Gesserit-trained metabolic control to change the chemical structure of the essence, rendering the poison harmless. Achieving this unlocks ancestral memories; failure results in death.
The only two men who have ever consumed spice essence and survived are Paul Atreides, the Kwisatz Haderach, and his son Leto Atreides II.
Template:Dune-stub
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Spice_essence
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b1e1ea96cd1fc92f6488e5bbd4c0119afe5c84a1
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wikidoc
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Spondylolysis
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Spondylolysis
# Overview
Spondylolysis is a defect in the pars interarticularis of a vertebra. The great majority of cases occur in the lowest of the lumbar vertebrae (L5), but spondylolysis may also occur in the other lumbar vertebrae, as well as in the thoracic vertebrae.
Spondylolysis occurs in three to six percent of the population.
# Causes
It is typically caused by stress fracture of the bone, and is associated with certain activities, such as weight lifting and gymnastics. It has been proposed that the pars interarticularis is especially vulnerable when the spine is in an extended position, and a force suddenly presses the vertebrae together, such as when landing on ones feet after a hop. This pressure acts like a nutcracker on the pars interarticularis and can fracture it in susceptible individuals.
Spondylolysis also runs in families and is more prevalent in some populations, suggesting a hereditary component such as a tendency toward thin vertebral bone.
Spondylolysis is the most common cause of spondylolisthesis in pediatric patients. In the older population, degenerative disc disease commonly leads to spondylolisthesis without spondylolysis; in these instances, the spinal canal gets narrowed because the spinolaminar arch at one level slides forward on the lower level effectively flattening the canal. The hereditary factor mentioned above is quite notable, since the frequency of spondylolisthesis in Eskimos is 30–50%.
# Diagnosis
The defect is seen in the oblique lumbar radiograph.
Image of Pars Defect<-- Picture of x-ray.
An oblique x-ray of the lumbar spine shows what appears to be a "scotty dog" first described by Lachapelle. The nose of the dog is the costal/transverse process; the ear, the superior facet; the neck, the pars interarticularis; the collar, the pars defect (dark on x-ray); the eye, the pedicle seen end on; the body, the lamina; the hindefoot, the spinous process; the tail if pointing straight up=opp. superior articular facet and if pointing horizontally is the transverse process of the opposite side; and the forefoot, the inferior articular process.
# Treatment
According to a meta-analysis of randomized controlled trials by the Cochrane Collaboration, the role of surgery compared to for adults with degenerative lumbar spondylosis is unclear. It is not clear if any randomized controlled trials have been performed of pediatric or adolescent patients.
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Spondylolysis
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
# Overview
Spondylolysis is a defect in the pars interarticularis of a vertebra. The great majority of cases occur in the lowest of the lumbar vertebrae (L5), but spondylolysis may also occur in the other lumbar vertebrae, as well as in the thoracic vertebrae.
Spondylolysis occurs in three to six percent of the population.[1][2]
# Causes
It is typically caused by stress fracture of the bone, and is associated with certain activities, such as weight lifting and gymnastics. It has been proposed that the pars interarticularis is especially vulnerable when the spine is in an extended position, and a force suddenly presses the vertebrae together, such as when landing on ones feet after a hop. This pressure acts like a nutcracker on the pars interarticularis and can fracture it in susceptible individuals. [3]
Spondylolysis also runs in families and is more prevalent in some populations, suggesting a hereditary component such as a tendency toward thin vertebral bone.
Spondylolysis is the most common cause of spondylolisthesis in pediatric patients. In the older population, degenerative disc disease commonly leads to spondylolisthesis without spondylolysis; in these instances, the spinal canal gets narrowed because the spinolaminar arch at one level slides forward on the lower level effectively flattening the canal. The hereditary factor mentioned above is quite notable, since the frequency of spondylolisthesis in Eskimos is 30–50%.
# Diagnosis
The defect is seen in the oblique lumbar radiograph.
Image of Pars Defect<-- Picture of x-ray.
An oblique x-ray of the lumbar spine shows what appears to be a "scotty dog" first described by Lachapelle. The nose of the dog is the costal/transverse process; the ear, the superior facet; the neck, the pars interarticularis; the collar, the pars defect (dark on x-ray); the eye, the pedicle seen end on; the body, the lamina; the hindefoot, the spinous process; the tail if pointing straight up=opp. superior articular facet and if pointing horizontally is the transverse process of the opposite side; and the forefoot, the inferior articular process.[3][4]
# Treatment
According to a meta-analysis of randomized controlled trials by the Cochrane Collaboration, the role of surgery compared to for adults with degenerative lumbar spondylosis is unclear.[5] It is not clear if any randomized controlled trials have been performed of pediatric or adolescent patients.
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https://www.wikidoc.org/index.php/Spondylolysis
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6068a128ff8927a86238e364516122babc564174
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wikidoc
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Sports injury
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Sports injury
# Overview
Sports injuries are injuries that occur to athletes in major sporting events. In many cases, these types of injuries are due to overuse of a part of the body when participating in a certain activity. For example, runner's knee is a painful condition generally associated with running, while tennis elbow is a form of repetitive stress injury at the elbow, although it does not often occur with tennis players. Other types of injuries can be caused by a hard contact with something. This can often cause a broken bone or torn ligament or tendon
Injuries are a common occurrence in professional sports and most teams have a staff of Athletic Trainers and close connections to the medical community. Controversy has arisen at times when teams have made decisions that could threaten a players long-term health for short term gain.
# Classification
Sports injuries can be broadly classified as either traumatic or overuse injuries. Traumatic injuries account for most injuries in contact sports such as Football, Rugby, Australian rules football, Gaelic football and American football because of the dynamic and high collision nature of these sports. These injuries range from bruises and muscle strains, to fractures and head injuries.
A bruise or contusion is damage to small blood vessels which causes bleeding within the tissues. A muscle strain is a small tear of muscle fibers and a ligament sprain is a small tear of ligament tissue. The body’s response to these sports injuries is the same in the initial five day period immediately following the traumatic incident - inflammation.
# Signs and symptoms
Inflammation is characterized by pain, localized swelling, heat, redness and a loss of function.
# Mechanism
All of these traumatic injuries cause damage to the cells that make up the soft tissues. The dead and damaged cells release chemicals, which initiate an inflammatory response. Small blood vessels are damaged and opened up, producing bleeding within the tissue. In the body’s normal reaction, a small blood clot is formed in order to stop this bleeding and from this clot special cells (called fibroblasts) begin the healing process by laying down scar tissue.
The inflammatory stage is therefore the first phase of healing. However, too much of an inflammatory response in the early stage can mean that the healing process takes longer and a return to activity is delayed. The sports injury treatments are intended to minimize the inflammatory phase of an injury, so that the overall healing process is accelerated.
# Diagnosis
Diagnosing the underlying cause of sports injuries is usually done by a medical doctor, osteopathic physican, physiotherapist (physical therapist) or by a chiropractor.
## History and Physical Examination
A thorough medical history and physical exam can usually identify any dangerous conditions or family history that may be associated with the pain. The patient describes the onset, site, and severity of the pain; duration of symptoms and any limitations in movement; and history of previous episodes or any health conditions that might be related to the pain. The physician will examine the back and conduct neurologic tests to determine the cause of pain and appropriate treatment. Blood tests may also be ordered. Imaging tests may be necessary to diagnose tumors or other possible sources of the pain.
A variety of diagnostic methods are available to confirm the presence of sports injuries:
## X-Ray
X-ray imaging includes conventional and enhanced methods that can help diagnose the cause and site of pain. A conventional x-ray, often the first imaging technique used, looks for broken bones or an injured vertebra. A technician passes a concentrated beam of low-dose ionized radiation through the back and takes pictures that, within minutes, clearly show the bony structure and any misalignment or fractures. Tissue masses such as injured muscles and ligaments or painful conditions such as a bulging disc are not visible on conventional x-rays. This fast, noninvasive, painless procedure is usually performed in a doctor’s office or at a clinic.
## Ultrasound imaging
Diagnostic musculoskeletal ultrasound imaging, also called ultrasound scanning or sonography, uses high-frequency sound waves to obtain images inside the body. The sound wave echoes are recorded and displayed as a real-time visual image. Ultrasound imaging can show tears in ligaments, muscles, tendons, and other soft tissue masses in the limbs, parvertebral soft tissues and to image various internal organs.
## Electrodiagnostic procedures
Electrodiagnostic procedures include electromyography (EMG), nerve conduction studies, and evoked potential (EP) studies. EMG assesses the electrical activity in a nerve and can detect if muscle weakness results from injury or a problem with the nerves that control the muscles. Very fine needles are inserted in muscles to measure electrical activity transmitted from the brain or spinal cord to a particular area of the body. With nerve conduction studies the doctor uses two sets of electrodes (similar to those used during an electrocardiogram) that are placed on the skin over the muscles. The first set gives the patient a mild shock to stimulate the nerve that runs to a particular muscle. The second set of electrodes is used to make a recording of the nerve’s electrical signals, and from this information the doctor can determine if there is nerve damage. EP tests also involve two sets of electrodes — one set to stimulate a sensory nerve and the other set on the scalp to record the speed of nerve signal transmissions to the brain.
## Computerized tomography
]]Computerized tomography]](CT) is a quick and painless process used when internal organ or spinal pathology is suspected. X-rays are passed through the body at various angles and are detected by a computerized scanner to produce two-dimensional slices (1 mm each) of internal structures under study. This diagnostic exam is generally conducted at an imaging center or hospital.
## Magnetic resonance imaging
Magnetic resonance imaging (MRI) is used to evaluate for bone degeneration or injury or disease in tissues and nerves, muscles, ligaments, and blood vessels. MRI scanning equipment creates a magnetic field around the body strong enough to temporarily realign water molecules in the tissues. Radio waves are then passed through the body to detect the “relaxation” of the molecules back to a random alignment and trigger a resonance signal at different angles within the body. A computer processes this resonance into either a three-dimensional picture or a two-dimensional “slice” of the tissue being scanned, and differentiates between bone, soft tissues and fluid-filled spaces by their water content and structural properties. This noninvasive procedure is often used to identify a condition requiring prompt surgical treatment.
## Bone scans
Bone scan is used to diagnose and monitor infection, fracture, or disorders in the bone. A small amount of radioactive material is injected into the bloodstream and will collect in the bones, particularly in areas with some abnormality. Scanner-generated images are sent to a computer to identify specific areas of irregular bone metabolism or abnormal blood flow, as well as to measure levels of joint disease.
## Thermography
Thermography involves the use of infrared sensing devices to measure small temperature changes between the two sides of the body or the temperature of a specific organ. Thermography may be used to detect the presence or absence of sympathetic nerve involvement (unusual pain, swelling and weather sensitivity.
# Treatment
For the vast majority of patients, sports injuries can be treated with non-surgical care. More recently regenerative techniques such as Stem cell, Platelet rich plasma, and Prolotherapy have become more readily available for those seeing aggressive non-surgical care. For those with acute, short-term pain, certain home remedies may be effective.
Sports injuries can be treated and managed by using the P.R.I.C.E.R... DR. ABC and T.O.T.A.P.S regimes:
- P - Protect
- R - Rest
- I - Ice
- C - Compression
- E - Elevation
- R - Referral
- D - Danger
- R - Response
- A - Airway
- B - Breathing
- C - Circulation
- T - Talk
- O - Observe
- T - Touch
- A - Active movement
- P - Passive movement
- S - Skills test
The inflammatory stage typically lasts around 5 days and all treatment during this time is designed to address the cardinal signs of inflammation – pain, swelling, redness, heat and a loss of function.
Most sports injuries can be treated without surgery. Treatment involves using analgesics, reducing inflammation, restoring proper function and strength, and preventing recurrence of the injury. Most patients recover without residual functional loss. Patients should contact a doctor if there is not a noticeable reduction in pain and inflammation after 72 hours of self-care.
Although ice and heat (the use of cold and hot compresses) have never been scientifically proven to quickly resolve injury, compresses may help reduce pain and inflammation and allow greater mobility for some individuals. As soon as possible following trauma, patients should apply a cold pack or a cold compress (such as a bag of ice or bag of frozen vegetables wrapped in a towel) to the tender spot several times a day for up to 20 minutes. After 2 to 3 days of cold treatment, they should then apply heat (such as a heating lamp or hot pad) for brief periods to relax muscles and increase blood flow. Warm baths may also help relax muscles. Patients should avoid sleeping on a heating pad, which can cause burns and lead to additional tissue damage.
Exercise may be the most effective way to speed recovery and help strengthen muscles. Maintaining and building muscle strength is particularly important for persons with skeletal irregularities. Doctors and physical therapists can provide a list of gentle exercises that help keep muscles moving and speed the recovery process. A routine of healthy activities may include stretching exercises, swimming, walking, and movement therapy to improve coordination and develop proper posture and muscle balance. Yoga is another way to gently stretch muscles and ease pain. Any mild discomfort felt at the start of these exercises should disappear as muscles become stronger. But if pain is more than mild and lasts more than 15 minutes during exercise, patients should stop exercising and contact a doctor.
Medications are often used to treat acute and chronic pain. Effective pain relief may involve a combination of prescription drugs and over-the-counter remedies. Patients should always check with a doctor before taking drugs for pain relief. Certain medicines, even those sold over the counter, are unsafe during pregnancy, may conflict with other medications, may cause side effects including drowsiness, or may lead to liver damage.
- Over-the-counter analgesics, including nonsteroidal anti-inflammatory drugs are taken orally to reduce stiffness, swelling, and inflammation and to ease mild to moderate low back pain. Counter-irritants applied topically to the skin as a cream or spray stimulate the nerve endings in the skin to provide feelings of warmth or cold and dull the sense of pain. Topical analgesics can also reduce inflammation and stimulate blood flow. Many of these compounds contain salicylates, the same ingredient found in oral pain medications containing aspirin.
- Muscle relaxants for acute or chronic pain.
- Opioids such as codeine, oxycodone, hydrocodone, and morphine are often prescribed to manage severe acute pain but should be used only for a short period of time and under a physician’s supervision. Side effects can include drowsiness, decreased reaction time, impaired judgment, and potential for addiction. Many specialists are convinced that chronic use of these drugs is detrimental to the patient, adding to depression and even increasing pain.
Spinal manipulation is literally a "hands-on" approach in which professionally licensed specialists (doctors of chiropractic care) use leverage and a series of exercises to adjust spinal structures and restore back mobility. or chronic pain. A clinical prediction rule can guide who is most likely to respond to manipulation.
When pain does not respond to more conventional approaches, patients may consider the following options:
Acupuncture involves the insertion of needles the width of a human hair along precise points throughout the body. Practitioners believe this process triggers the release of naturally occurring painkilling molecules called peptides and keeps the body’s normal flow of energy unblocked. Clinical studies are measuring the effectiveness of acupuncture in comparison to more conventional procedures in the treatment of acute low back pain.
Interventional therapy can ease pain by blocking nerve conduction between specific areas of the body and the brain. Approaches range from injections of local anesthetics, steroids or proliferative agents (Prolotherapy) into affected soft tissues, joints, or nerve roots. Chronic use of steroid injections may lead to increased functional impairment.
Traction involves the use of weights to apply constant or intermittent force to gradually “pull” the skeletal structure into better alignment. Traction is not recommended for treating acute low back symptoms.
Transcutaneous electrical nerve stimulation (TENS) is administered by a battery-powered device that sends mild electric pulses along nerve fibers to block pain signals to the brain. Small electrodes placed on the skin at or near the site of pain generate nerve impulses that block incoming pain signals from the peripheral nerves. TENS may also help stimulate the brain’s production of endorphins (chemicals that have pain-relieving properties).
- Muscle Energy Technique (MET) may help (PMID 14524509 - small study)
Ultrasound is a noninvasive therapy used to warm the body’s internal tissues, which causes muscles to relax. Sound waves pass through the skin and into the injured muscles and other soft tissues.
Although not proven some professional athletes use hyperbaric chambers to speed healing. Hines Ward of the Steelers sent his personal hyperbaric chamber,(similar to the one pictured), to his hotel to sleep in believing it would help heal his sprained medial collateral ligament he suffered in their playoff win against the Ravens. Hines went on to play in Super Bowl XLIII.
In the most serious cases, when the condition does not respond to other therapies, surgery can be an affective approach for serious musculoskeletal injuries. Some surgical procedures may be performed in a doctor’s office under local anesthesia (such as ultrasound guided percutaneous tenotomy), some are performed as an outpatient (such as arthroscopy) and others require hospitalization. It may be months following surgery before the patient is fully healed, and he or she may suffer permanent loss of flexibility.
# Prevention
A comprehensive warm-up programme has been found to decrease injuries in soccer. Many athletes will partake in HGH Treatment for Athletic Enhancement as a way to prevent injuries.
Compression sportswear is becoming very popular with both professional and amateur athletes. These garments are thought to both reduce the risk of muscle injury and speed up muscle recovery.
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Sports injury
Editor-In-Chief: Robert G. Schwartz, M.D. [1], Piedmont Physical Medicine and Rehabilitation, P.A.
# Overview
Sports injuries are injuries that occur to athletes in major sporting events. In many cases, these types of injuries are due to overuse of a part of the body when participating in a certain activity. For example, runner's knee is a painful condition generally associated with running, while tennis elbow is a form of repetitive stress injury at the elbow, although it does not often occur with tennis players. Other types of injuries can be caused by a hard contact with something. This can often cause a broken bone or torn ligament or tendon
Injuries are a common occurrence in professional sports and most teams have a staff of Athletic Trainers and close connections to the medical community. Controversy has arisen at times when teams have made decisions that could threaten a players long-term health for short term gain.
# Classification
Sports injuries can be broadly classified as either traumatic or overuse injuries. Traumatic injuries account for most injuries in contact sports such as Football, Rugby, Australian rules football, Gaelic football and American football because of the dynamic and high collision nature of these sports. These injuries range from bruises and muscle strains, to fractures and head injuries.
A bruise or contusion is damage to small blood vessels which causes bleeding within the tissues. A muscle strain is a small tear of muscle fibers and a ligament sprain is a small tear of ligament tissue. The body’s response to these sports injuries is the same in the initial five day period immediately following the traumatic incident - inflammation.
# Signs and symptoms
Inflammation is characterized by pain, localized swelling, heat, redness and a loss of function.
# Mechanism
All of these traumatic injuries cause damage to the cells that make up the soft tissues. The dead and damaged cells release chemicals, which initiate an inflammatory response. Small blood vessels are damaged and opened up, producing bleeding within the tissue. In the body’s normal reaction, a small blood clot is formed in order to stop this bleeding and from this clot special cells (called fibroblasts) begin the healing process by laying down scar tissue.
The inflammatory stage is therefore the first phase of healing. However, too much of an inflammatory response in the early stage can mean that the healing process takes longer and a return to activity is delayed. The sports injury treatments are intended to minimize the inflammatory phase of an injury, so that the overall healing process is accelerated.
# Diagnosis
Diagnosing the underlying cause of sports injuries is usually done by a medical doctor, osteopathic physican, physiotherapist (physical therapist) or by a chiropractor.
## History and Physical Examination
A thorough medical history and physical exam can usually identify any dangerous conditions or family history that may be associated with the pain. The patient describes the onset, site, and severity of the pain; duration of symptoms and any limitations in movement; and history of previous episodes or any health conditions that might be related to the pain. The physician will examine the back and conduct neurologic tests to determine the cause of pain and appropriate treatment. Blood tests may also be ordered. Imaging tests may be necessary to diagnose tumors or other possible sources of the pain.
A variety of diagnostic methods are available to confirm the presence of sports injuries:
## X-Ray
X-ray imaging includes conventional and enhanced methods that can help diagnose the cause and site of pain. A conventional x-ray, often the first imaging technique used, looks for broken bones or an injured vertebra. A technician passes a concentrated beam of low-dose ionized radiation through the back and takes pictures that, within minutes, clearly show the bony structure and any misalignment or fractures. Tissue masses such as injured muscles and ligaments or painful conditions such as a bulging disc are not visible on conventional x-rays. This fast, noninvasive, painless procedure is usually performed in a doctor’s office or at a clinic.
## Ultrasound imaging
Diagnostic musculoskeletal ultrasound imaging, also called ultrasound scanning or sonography, uses high-frequency sound waves to obtain images inside the body. The sound wave echoes are recorded and displayed as a real-time visual image. Ultrasound imaging can show tears in ligaments, muscles, tendons, and other soft tissue masses in the limbs, parvertebral soft tissues and to image various internal organs.
## Electrodiagnostic procedures
Electrodiagnostic procedures include electromyography (EMG), nerve conduction studies, and evoked potential (EP) studies. EMG assesses the electrical activity in a nerve and can detect if muscle weakness results from injury or a problem with the nerves that control the muscles. Very fine needles are inserted in muscles to measure electrical activity transmitted from the brain or spinal cord to a particular area of the body. With nerve conduction studies the doctor uses two sets of electrodes (similar to those used during an electrocardiogram) that are placed on the skin over the muscles. The first set gives the patient a mild shock to stimulate the nerve that runs to a particular muscle. The second set of electrodes is used to make a recording of the nerve’s electrical signals, and from this information the doctor can determine if there is nerve damage. EP tests also involve two sets of electrodes — one set to stimulate a sensory nerve and the other set on the scalp to record the speed of nerve signal transmissions to the brain.
## Computerized tomography
]]Computerized tomography]](CT) is a quick and painless process used when internal organ or spinal pathology is suspected. X-rays are passed through the body at various angles and are detected by a computerized scanner to produce two-dimensional slices (1 mm each) of internal structures under study. This diagnostic exam is generally conducted at an imaging center or hospital.
## Magnetic resonance imaging
Magnetic resonance imaging (MRI) is used to evaluate for bone degeneration or injury or disease in tissues and nerves, muscles, ligaments, and blood vessels. MRI scanning equipment creates a magnetic field around the body strong enough to temporarily realign water molecules in the tissues. Radio waves are then passed through the body to detect the “relaxation” of the molecules back to a random alignment and trigger a resonance signal at different angles within the body. A computer processes this resonance into either a three-dimensional picture or a two-dimensional “slice” of the tissue being scanned, and differentiates between bone, soft tissues and fluid-filled spaces by their water content and structural properties. This noninvasive procedure is often used to identify a condition requiring prompt surgical treatment.
## Bone scans
Bone scan is used to diagnose and monitor infection, fracture, or disorders in the bone. A small amount of radioactive material is injected into the bloodstream and will collect in the bones, particularly in areas with some abnormality. Scanner-generated images are sent to a computer to identify specific areas of irregular bone metabolism or abnormal blood flow, as well as to measure levels of joint disease.
## Thermography
Thermography involves the use of infrared sensing devices to measure small temperature changes between the two sides of the body or the temperature of a specific organ. Thermography may be used to detect the presence or absence of sympathetic nerve involvement (unusual pain, swelling and weather sensitivity.
# Treatment
For the vast majority of patients, sports injuries can be treated with non-surgical care. More recently regenerative techniques such as Stem cell, Platelet rich plasma, and Prolotherapy have become more readily available for those seeing aggressive non-surgical care. For those with acute, short-term pain, certain home remedies may be effective.
Sports injuries can be treated and managed by using the P.R.I.C.E.R... DR. ABC and T.O.T.A.P.S regimes:
- P - Protect
- R - Rest
- I - Ice
- C - Compression
- E - Elevation
- R - Referral
- D - Danger
- R - Response
- A - Airway
- B - Breathing
- C - Circulation
- T - Talk
- O - Observe
- T - Touch
- A - Active movement
- P - Passive movement
- S - Skills test
The inflammatory stage typically lasts around 5 days and all treatment during this time is designed to address the cardinal signs of inflammation – pain, swelling, redness, heat and a loss of function.
Most sports injuries can be treated without surgery. Treatment involves using analgesics, reducing inflammation, restoring proper function and strength, and preventing recurrence of the injury. Most patients recover without residual functional loss. Patients should contact a doctor if there is not a noticeable reduction in pain and inflammation after 72 hours of self-care.
Although ice and heat (the use of cold and hot compresses) have never been scientifically proven to quickly resolve injury, compresses may help reduce pain and inflammation and allow greater mobility for some individuals.[1] As soon as possible following trauma, patients should apply a cold pack or a cold compress (such as a bag of ice or bag of frozen vegetables wrapped in a towel) to the tender spot several times a day for up to 20 minutes. After 2 to 3 days of cold treatment, they should then apply heat (such as a heating lamp or hot pad) for brief periods to relax muscles and increase blood flow. Warm baths may also help relax muscles. Patients should avoid sleeping on a heating pad, which can cause burns and lead to additional tissue damage.
Exercise may be the most effective way to speed recovery and help strengthen muscles. Maintaining and building muscle strength is particularly important for persons with skeletal irregularities. Doctors and physical therapists can provide a list of gentle exercises that help keep muscles moving and speed the recovery process. A routine of healthy activities may include stretching exercises, swimming, walking, and movement therapy to improve coordination and develop proper posture and muscle balance. Yoga is another way to gently stretch muscles and ease pain. Any mild discomfort felt at the start of these exercises should disappear as muscles become stronger. But if pain is more than mild and lasts more than 15 minutes during exercise, patients should stop exercising and contact a doctor.
Medications are often used to treat acute and chronic pain. Effective pain relief may involve a combination of prescription drugs and over-the-counter remedies. Patients should always check with a doctor before taking drugs for pain relief. Certain medicines, even those sold over the counter, are unsafe during pregnancy, may conflict with other medications, may cause side effects including drowsiness, or may lead to liver damage.
- Over-the-counter analgesics, including nonsteroidal anti-inflammatory drugs are taken orally to reduce stiffness, swelling, and inflammation and to ease mild to moderate low back pain. Counter-irritants applied topically to the skin as a cream or spray stimulate the nerve endings in the skin to provide feelings of warmth or cold and dull the sense of pain. Topical analgesics can also reduce inflammation and stimulate blood flow. Many of these compounds contain salicylates, the same ingredient found in oral pain medications containing aspirin.
- Muscle relaxants for acute[2] or chronic[3] pain.
- Opioids such as codeine, oxycodone, hydrocodone, and morphine are often prescribed to manage severe acute pain but should be used only for a short period of time and under a physician’s supervision. Side effects can include drowsiness, decreased reaction time, impaired judgment, and potential for addiction. Many specialists are convinced that chronic use of these drugs is detrimental to the patient, adding to depression and even increasing pain. [4]
Spinal manipulation is literally a "hands-on" approach in which professionally licensed specialists (doctors of chiropractic care) use leverage and a series of exercises to adjust spinal structures and restore back mobility.[2] or chronic[3] pain. A clinical prediction rule can guide who is most likely to respond to manipulation.[5]
When pain does not respond to more conventional approaches, patients may consider the following options:
Acupuncture[3] involves the insertion of needles the width of a human hair along precise points throughout the body. Practitioners believe this process triggers the release of naturally occurring painkilling molecules called peptides and keeps the body’s normal flow of energy unblocked. Clinical studies are measuring the effectiveness of acupuncture in comparison to more conventional procedures in the treatment of acute low back pain.[6]
Interventional therapy can ease pain by blocking nerve conduction between specific areas of the body and the brain. Approaches range from injections of local anesthetics, steroids or proliferative agents (Prolotherapy) into affected soft tissues, joints, or nerve roots. Chronic use of steroid injections may lead to increased functional impairment.
Traction involves the use of weights to apply constant or intermittent force to gradually “pull” the skeletal structure into better alignment. Traction is not recommended for treating acute low back symptoms.
Transcutaneous electrical nerve stimulation (TENS) is administered by a battery-powered device that sends mild electric pulses along nerve fibers to block pain signals to the brain. Small electrodes placed on the skin at or near the site of pain generate nerve impulses that block incoming pain signals from the peripheral nerves. TENS may also help stimulate the brain’s production of endorphins (chemicals that have pain-relieving properties).
- Muscle Energy Technique (MET) may help (PMID 14524509 - small study)[7]
Ultrasound is a noninvasive therapy used to warm the body’s internal tissues, which causes muscles to relax. Sound waves pass through the skin and into the injured muscles and other soft tissues.
Although not proven some professional athletes use hyperbaric chambers to speed healing. Hines Ward of the Steelers sent his personal hyperbaric chamber,(similar to the one pictured), to his hotel to sleep in believing it would help heal his sprained medial collateral ligament he suffered in their playoff win against the Ravens. Hines went on to play in Super Bowl XLIII.
In the most serious cases, when the condition does not respond to other therapies, surgery can be an affective approach for serious musculoskeletal injuries. Some surgical procedures may be performed in a doctor’s office under local anesthesia (such as ultrasound guided percutaneous tenotomy), some are performed as an outpatient (such as arthroscopy) and others require hospitalization. It may be months following surgery before the patient is fully healed, and he or she may suffer permanent loss of flexibility.
# Prevention
A comprehensive warm-up programme has been found to decrease injuries in soccer.[8] Many athletes will partake in HGH Treatment for Athletic Enhancement as a way to prevent injuries.
Compression sportswear is becoming very popular with both professional and amateur athletes. These garments are thought to both reduce the risk of muscle injury and speed up muscle recovery.
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https://www.wikidoc.org/index.php/Sports_injuries
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188e4484a72e26cf0a5156686ac202484d2ea3c9
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wikidoc
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Spotted jelly
|
Spotted jelly
The Spotted jelly, the Mastigias papua, or the lagoon jelly is a type of jellyfish. It lives mainly in the South Pacific. Instead of one single mouth, they appear to have several smaller mouth openings in their coral arms. These feed on zooplankton.
In Japan--especially along Pacific coast areas--these are sold as novelty pets, along with photoautotrophic phytoplankton, and are called takokurage (タコクラゲ), or "octopod" or "rammer" jellies.
They seem to have a lifespan of approximately 4 months and are active primarily in mid-summer to early-fall.
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Spotted jelly
The Spotted jelly, the Mastigias papua, or the lagoon jelly is a type of jellyfish. It lives mainly in the South Pacific. Instead of one single mouth, they appear to have several smaller mouth openings in their coral arms. These feed on zooplankton. [1]
In Japan--especially along Pacific coast areas--these are sold as novelty pets, along with photoautotrophic phytoplankton, and are called takokurage (タコクラゲ), or "octopod" or "rammer" jellies.
They seem to have a lifespan of approximately 4 months and are active primarily in mid-summer to early-fall. [2]
# External links
- Animaldiversity entry
- Monterey Bay Aquarium Field Guide
# Footnotes
- ↑ http://www.mbayaq.org/efc/living_species/default.asp?hOri=1&inhab=451
- ↑ http://www.seto.kyoto-u.ac.jp/aquarium/new%20face/atarashiikao.html
Template:Invertebrate-stub
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https://www.wikidoc.org/index.php/Spotted_jelly
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a71401f656a32c97be9d2186eedc9fd4473cd00f
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wikidoc
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Spray-on skin
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Spray-on skin
# Overview
Spray-on skin is a patented skin culturing treatment for burns victims, developed by plastic surgeon Dr Fiona Wood of Perth, Western Australia.
Dr Wood's treatment is under ongoing development. Where previous techniques of skin culturing required 21 days to produce enough cells to cover major burns, Dr Wood has reduced the period to five days. Through research, she found that scarring is greatly reduced if replacement skin could be provided within 10 days. Dr Wood's reported goal is "scarless woundless healing".
Dr Wood established a company called Clinical Cell Culture (C3) in 1993 to commercialise the procedure. Her business came about after a schoolteacher arrived at Royal Perth Hospital in 1992 with petrol burns to 90% of his body. Dr Wood turned to the emerging US-invented technology of cultured skin to save his life, working nights in a laboratory along with scientist Marie Stoner. The two women began to explore tissue engineering. They moved from growing skin sheets to spraying skin cells; earning a world-wide reputation as pioneers in their field. Their company now cultures small biopsies into bigger volumes of skin cell suspensions in as few as five days. This service is used by surgeons in Sydney, Auckland and Birmingham. Cells can be delivered via aircraft and ready for use the next day in many cases. Royalties from licensing are ploughed back into a research fund, called the McComb Foundation.
As well as receiving much praise from both her own patients and the media, she also attracted controversy among other burns surgeons because spray-on skin had not yet been subjected to clinical trials. A clinical trial is planned at Queen Victoria Hospital, England.
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Spray-on skin
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2]
# Overview
Spray-on skin is a patented skin culturing treatment for burns victims, developed by plastic surgeon Dr Fiona Wood of Perth, Western Australia.
Dr Wood's treatment is under ongoing development. Where previous techniques of skin culturing required 21 days to produce enough cells to cover major burns, Dr Wood has reduced the period to five days. Through research, she found that scarring is greatly reduced if replacement skin could be provided within 10 days. Dr Wood's reported goal is "scarless woundless healing".[1]
Dr Wood established a company called Clinical Cell Culture (C3) in 1993 to commercialise the procedure. Her business came about after a schoolteacher arrived at Royal Perth Hospital in 1992 with petrol burns to 90% of his body. Dr Wood turned to the emerging US-invented technology of cultured skin to save his life, working nights in a laboratory along with scientist Marie Stoner. The two women began to explore tissue engineering. They moved from growing skin sheets to spraying skin cells; earning a world-wide reputation as pioneers in their field. Their company now cultures small biopsies into bigger volumes of skin cell suspensions in as few as five days. This service is used by surgeons in Sydney, Auckland and Birmingham. Cells can be delivered via aircraft and ready for use the next day in many cases. Royalties from licensing are ploughed back into a research fund, called the McComb Foundation.[2]
As well as receiving much praise from both her own patients and the media, she also attracted controversy among other burns surgeons because spray-on skin had not yet been subjected to clinical trials[3]. A clinical trial is planned at Queen Victoria Hospital, England.[4]
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https://www.wikidoc.org/index.php/Spray-on_skin
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7db709aa127fa17f203f0be019e69a12681e2841
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wikidoc
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Square planar
|
Square planar
The square planar molecular geometry in chemistry describes the stereochemistry (spatial arrangement of atoms) that is adopted by certain chemical compounds. As the name suggests, molecules of this geometry have their atoms lying in a square about a central atom.
Relatively few compounds adopt this geometry, but these species are often notable and even useful, examples being the first noble gas compound XeF4 and the anticancer drug Cisplatin (PtCl2(NH3)2).
This geometry can be visualised as resulting from the removal of a pair of ligands from the z-axis of an octahedron, leaving four ligands in the x-y plane. For transition metal compounds, the orbital splitting diagram for square planar geometry can thus be derived from the octahedral diagram. The removal of the two ligands stabilizes the dz2 level, leaving the dx2-y2 level as the most destabilized. Consequenly the dx2-y2 remains unoccupied in complexes of metals with the d8 configuration. These compounds typically have 16 valence electrons (eight from ligands, eight from the metal). Examples include Vaska's complex, Zeise's salt and Crabtree's catalyst.
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Square planar
The square planar molecular geometry in chemistry describes the stereochemistry (spatial arrangement of atoms) that is adopted by certain chemical compounds. As the name suggests, molecules of this geometry have their atoms lying in a square about a central atom.
Relatively few compounds adopt this geometry, but these species are often notable and even useful, examples being the first noble gas compound XeF4 and the anticancer drug Cisplatin (PtCl2(NH3)2).
This geometry can be visualised as resulting from the removal of a pair of ligands from the z-axis of an octahedron, leaving four ligands in the x-y plane. For transition metal compounds, the orbital splitting diagram for square planar geometry can thus be derived from the octahedral diagram. The removal of the two ligands stabilizes the dz2 level, leaving the dx2-y2 level as the most destabilized. Consequenly the dx2-y2 remains unoccupied in complexes of metals with the d8 configuration. These compounds typically have 16 valence electrons (eight from ligands, eight from the metal). Examples include Vaska's complex, Zeise's salt and Crabtree's catalyst.[1]
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https://www.wikidoc.org/index.php/Square_planar
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a1c0e1a425c82d65de261628dd4506a6a1b2a587
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wikidoc
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Squat toilets
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Squat toilets
A squat toilet is a toilet used by squatting, rather than sitting. There are several types of squat toilets, but they all consist essentially of a hole in the ground. The only exception is a "pedestal" squat toilet (pictured here), which is the same height as a standard western toilet.
# Types of squat toilets
- The squat toilets (known as alaturka (alla turca) in Turkey or Iranian Toilet in Iran,in contrast to alafranga (alla franca) flush toilets) where the user puts his or her feet on foot rests; the user faces the entrance to the cubicle; it is prevalent in Turkey where flush toilets are now getting more in use for households and can still be found in some public buildings and at motorway services in France, Italy, Balkans and, more often, in the former USSR. In India such a toilet is widely used and is referred to as the Indian water closet or the Jodhpur Pan in contrast with the European water closet or EWC or the Western style of toilet. It is also used in the Middle East and can be found in rural areas of Greece and Italy. It is also very common in Iran and prevalent throughout most of South East Asia.
- The Japanese toilet is shaped differently, and the user faces the flush apparatus.
# Arguments in favor of squat toilets
Proponents of squat toilets argue that:
- It is less expensive and easier to clean and maintain.
- squat toilet does not involve any contact between the buttocks and a potentially unsanitary surface.
- The splashing of water on the buttocks after a heavy defecation does not occur.
- Squatting might help to build the required pressure more comfortably and quickly.
- Squatting makes elimination faster, easier and more complete.
- Elimination in squatting posture protects the nerves that control the prostate, bladder and uterus from becoming stretched and damaged.
- Squatting relaxes the puborectalis muscle which normally chokes the rectum in order to maintain continence.
- Squatting securely seals the ileocecal valve, between the colon and the small intestine. In the conventional sitting position, this valve is unsupported and often leaks during evacuation.
- For pregnant women, squatting avoids pressure on the uterus when using the toilet. Daily squatting helps prepare the mother-to-be for a more natural delivery.
- Haemorrhoids are an extremely common problem, especially in western countries, where surveys suggest that as much as half of the population over 40 years of age may suffer some form of mild to severe discomfort from them. One proposed way to prevent and cure haemorrhoids is to squat for defaecation.
- Squatting may reduce the occurrence or severity of hemorrhoids and possibly other colorectal disorders such as diverticulosis and appendicitis.
# Arguments against squat toilets
- A common argument against the squat toilet is that if toilet paper is used where there is no flushing system installed, it is easy for the inexperienced user to clog the toilet. Those unfamiliar with the squat toilet should be sure to ask the location of the flushing bucket before attempting use. These buckets flush the toilets manually like a tank would.
- Squat toilets are not accessible to handicapped or disabled persons; to use squat toilets a person must have complete use and mobility of both their legs and arms, which would hinder many people with physical challenges.
- Squat toilets are not like normal toilets and urinals, and can be a shock to people who are used to a sit-down type toilet, and may be difficult to use for the unwary, especially if on trains or ships. Many Britons, having encountered the devices in France and other countries, refer to them euphemistically as "stand and deliver" toilets, a reference to the phrase associated with highwaymen.
# Gallery
- Toilet used in passenger trains of China Railway
Toilet used in passenger trains of China Railway
- Squat toilet in Shanghai, China
Squat toilet in Shanghai, China
- A stainless steel squat toilet found in Hong Kong
A stainless steel squat toilet found in Hong Kong
- An older squat toilet
An older squat toilet
- Two older adjacent squat toilets
Two older adjacent squat toilets
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Squat toilets
A squat toilet is a toilet used by squatting, rather than sitting. There are several types of squat toilets, but they all consist essentially of a hole in the ground. The only exception is a "pedestal" squat toilet (pictured here), which is the same height as a standard western toilet.
# Types of squat toilets
- The squat toilets (known as alaturka (alla turca) in Turkey or Iranian Toilet in Iran,in contrast to alafranga (alla franca) flush toilets) where the user puts his or her feet on foot rests; the user faces the entrance to the cubicle; it is prevalent in Turkey where flush toilets are now getting more in use for households and can still be found in some public buildings and at motorway services in France, Italy, Balkans and, more often, in the former USSR. In India such a toilet is widely used and is referred to as the Indian water closet or the Jodhpur Pan in contrast with the European water closet or EWC or the Western style of toilet. It is also used in the Middle East and can be found in rural areas of Greece and Italy. It is also very common in Iran and prevalent throughout most of South East Asia.
- The Japanese toilet is shaped differently, and the user faces the flush apparatus.
# Arguments in favor of squat toilets
Proponents of squat toilets argue that:
- It is less expensive and easier to clean and maintain.[1]
- squat toilet does not involve any contact between the buttocks and a potentially unsanitary surface.[2]
- The splashing of water on the buttocks after a heavy defecation does not occur.
- Squatting might help to build the required pressure more comfortably and quickly.[3]
- Squatting makes elimination faster, easier and more complete.[4]
- Elimination in squatting posture protects the nerves that control the prostate, bladder and uterus from becoming stretched and damaged.[5]
- Squatting relaxes the puborectalis muscle which normally chokes the rectum in order to maintain continence.[6]
- Squatting securely seals the ileocecal valve, between the colon and the small intestine. In the conventional sitting position, this valve is unsupported and often leaks during evacuation.[7]
- For pregnant women, squatting avoids pressure on the uterus when using the toilet. Daily squatting helps prepare the mother-to-be for a more natural delivery.[8]
- Haemorrhoids are an extremely common problem, especially in western countries, where surveys suggest that as much as half of the population over 40 years of age may suffer some form of mild to severe discomfort from them. One proposed way to prevent and cure haemorrhoids is to squat for defaecation.[9]
- Squatting may reduce the occurrence or severity of hemorrhoids[10] and possibly other colorectal disorders such as diverticulosis[11] and appendicitis.[12]
# Arguments against squat toilets
- A common argument against the squat toilet is that if toilet paper is used where there is no flushing system installed, it is easy for the inexperienced user to clog the toilet. Those unfamiliar with the squat toilet should be sure to ask the location of the flushing bucket before attempting use. These buckets flush the toilets manually like a tank would.
- Squat toilets are not accessible to handicapped or disabled persons; to use squat toilets a person must have complete use and mobility of both their legs and arms, which would hinder many people with physical challenges.
- Squat toilets are not like normal toilets and urinals, and can be a shock to people who are used to a sit-down type toilet, and may be difficult to use for the unwary, especially if on trains or ships. Many Britons, having encountered the devices in France and other countries, refer to them euphemistically as "stand and deliver" toilets, a reference to the phrase associated with highwaymen.
# Gallery
- Toilet used in passenger trains of China Railway
Toilet used in passenger trains of China Railway
- Squat toilet in Shanghai, China
Squat toilet in Shanghai, China
- A stainless steel squat toilet found in Hong Kong
A stainless steel squat toilet found in Hong Kong
- An older squat toilet
An older squat toilet
- Two older adjacent squat toilets
Two older adjacent squat toilets
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https://www.wikidoc.org/index.php/Squat_toilets
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c1db4a33f5ea31b127b999bc6b3633f074e2104a
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wikidoc
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Staurosporine
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Staurosporine
Staurosporine (antibiotic AM-2282) is a natural product originally isolated in 1977 from bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.
Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive. The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment.
The main biological activity of staurosporine is the inhibition of protein kinases through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase.
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Staurosporine
Staurosporine (antibiotic AM-2282) is a natural product originally isolated in 1977 from bacterium Streptomyces staurosporeus. It was the first of over 50 alkaloids to be isolated with this type of bis-indole chemical structure. The chemical structure of staurosporine was elucidated by X-ray analysis of a single crystal and the absolute stereochemical configuration by the same method in 1994.
Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive.[1] The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment.
The main biological activity of staurosporine is the inhibition of protein kinases through the prevention of ATP binding to the kinase. This is achieved through the stronger affinity of staurosporine to the ATP-binding site on the kinase.
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https://www.wikidoc.org/index.php/Staurosporine
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27f4f887106e5d29903399dbf5f643786e6bd96b
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wikidoc
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Stener lesion
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Stener lesion
A Stener lesion is a type of traumatic injury to the thumb. It occurs when the aponeurosis of the adductor pollicis muscle becomes interposed between the ruptured ulnar collateral ligament (UCL) of the thumb and its site of insertion at the base of the proximal phalanx. No longer in contact with its insertion site, the UCL cannot spontaneously heal.
# Gamekeeper's thumb: history and mechanism of injury
CS Campbell, an orthopedic surgeon, originally coined the term gamekeeper's thumb in 1955, after he observed this condition in a number of Scottish gamekeepers. The injury appeared to occur as a result of the particular manner in which they killed small animals such as rabbits. Specifically, the animals were placed on the ground, and their necks were broken as the gamekeeper exerted downward pressure with the thumb and index fingers. This maneuver would place a valgus force upon the abducted metacarpophalangeal (MCP) joint. Over time, this would lead to insufficiency of the ulnar collateral ligament of the thumb, a condition which Campbell referred to as gamekeeper's thumb.
In 1962, Bertil Stener described a lesion which he observed to occur in a subset of patients suffering from gamekeeper's thumb. In these patients, the distal attachment of the UCL was traumatically avulsed from its site of insertion at the base of the proximal phalanx of the thumb. The severed end of the ligament would become trapped under the aponeurosis of the adductor pollicis muscle and therefore be unable to return to its proper anatomic position. Consequently, the severed ligament would fold on itself and thus be prevented from healing and restoring stability to the MCP joint.
For a Stener lesion to occur, both the proper and accessory collateral ligaments of the thumb must be completely ruptured. The Stener lesion is present in more than 80% of complete ruptures of the UCL of the thumb.
# Treatment
The ulnar collateral ligament is an important stabilizer of the thumb. Thumb instability resulting from disruption of the UCL profoundly impairs the overall function of the involved hand. Because of this, it is critical that these injuries receive appropriate attention and treatment.
Most gamekeeper's thumb injuries are treated by simply immobilizing the joint in a thumb spica splint or a modified wrist splint and allowing the ligament to heal. However, near total or total tears of the UCL may require surgery to achieve a satisfactory repair, especially if accompanied by a Stener lesion.
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Stener lesion
A Stener lesion is a type of traumatic injury to the thumb. It occurs when the aponeurosis of the adductor pollicis muscle becomes interposed between the ruptured ulnar collateral ligament (UCL) of the thumb and its site of insertion at the base of the proximal phalanx. No longer in contact with its insertion site, the UCL cannot spontaneously heal.[1]
# Gamekeeper's thumb: history and mechanism of injury
CS Campbell, an orthopedic surgeon, originally coined the term gamekeeper's thumb in 1955, after he observed this condition in a number of Scottish gamekeepers.[2] The injury appeared to occur as a result of the particular manner in which they killed small animals such as rabbits. Specifically, the animals were placed on the ground, and their necks were broken as the gamekeeper exerted downward pressure with the thumb and index fingers. This maneuver would place a valgus force upon the abducted metacarpophalangeal (MCP) joint. Over time, this would lead to insufficiency of the ulnar collateral ligament of the thumb, a condition which Campbell referred to as gamekeeper's thumb.
In 1962, Bertil Stener described a lesion which he observed to occur in a subset of patients suffering from gamekeeper's thumb. In these patients, the distal attachment of the UCL was traumatically avulsed from its site of insertion at the base of the proximal phalanx of the thumb. The severed end of the ligament would become trapped under the aponeurosis of the adductor pollicis muscle and therefore be unable to return to its proper anatomic position. Consequently, the severed ligament would fold on itself and thus be prevented from healing and restoring stability to the MCP joint.[3]
For a Stener lesion to occur, both the proper and accessory collateral ligaments of the thumb must be completely ruptured. The Stener lesion is present in more than 80% of complete ruptures of the UCL of the thumb.
# Treatment
The ulnar collateral ligament is an important stabilizer of the thumb. Thumb instability resulting from disruption of the UCL profoundly impairs the overall function of the involved hand. Because of this, it is critical that these injuries receive appropriate attention and treatment.
Most gamekeeper's thumb injuries are treated by simply immobilizing the joint in a thumb spica splint or a modified wrist splint and allowing the ligament to heal. However, near total or total tears of the UCL may require surgery to achieve a satisfactory repair, especially if accompanied by a Stener lesion.[4]
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https://www.wikidoc.org/index.php/Stener_lesion
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93b3beb5a192ec45ffcc06d5f99706d56aaa8b3c
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wikidoc
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Step function
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Step function
In mathematics, a function on the real numbers is called a step function (or staircase function) if it can be written as a finite linear combination of indicator functions of intervals. Informally speaking, a step function is a piecewise constant function having only finitely many pieces.
# Definition and first consequences
A function f: \mathbb{R} \rightarrow \mathbb{R} is called a step function if it can be written as
where n\ge 0, \alpha_i are real numbers, A_i are intervals, and \chi_A\, is the indicator function of A:
\left\{
\right.
In this definition, the intervals A_i can be assumed to have the following two properties:
- The intervals are disjoint, A_i\cap A_j=\emptyset for i\ne j
- The union of the intervals is the entire real line, \cup_{i=1}^n A_i=\mathbb R.
Indeed, if that is not the case to start with, a different set of intervals can be picked for which these assumptions hold. For example, the step function
can be written as
# Examples
- A constant function is a trivial example of a step function. Then there is only one interval, A_0=\mathbb R.
- The Heaviside function H(x) is an important step function. It is the mathematical concept behind some test signals, such as those used to determine the step response of a dynamical system.
- The rectangular function, the normalized boxcar function, is the next simplest step function, and is used to model a unit pulse.
## Non-examples
- The integer part function is not a step function according to the definition of this article, since it has an infinite number of "steps".
# Properties
- The sum and product of two step functions is again a step function. The product of a step function with a number is also a step function. As such, the step functions form an algebra over the real numbers.
- A step function takes only a finite number of values. If the intervals A_i, i=0, 1, \dots, n, in the above definition of the step function are disjoint and their union is the real line, then f(x)=\alpha_i\, for all x\in A_i.
- The Lebesgue integral of a step function f = \sum\limits_{i=0}^n \alpha_i \chi_{A_i}\, is \int \!f\,dx = \sum\limits_{i=0}^n \alpha_i \ell(A_i),\, where \ell(A) is the length of the interval A, and it is assumed here that all intervals A_i have finite length. In fact, this equality (viewed as a definition) can be the first step in constructing the Lebesgue integral.
- The derivative of a step function is the Dirac delta function
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Step function
Template:Otheruses4
In mathematics, a function on the real numbers is called a step function (or staircase function) if it can be written as a finite linear combination of indicator functions of intervals. Informally speaking, a step function is a piecewise constant function having only finitely many pieces.
# Definition and first consequences
A function <math>f: \mathbb{R} \rightarrow \mathbb{R}</math> is called a step function if it can be written as
where <math>n\ge 0,</math> <math>\alpha_i</math> are real numbers, <math>A_i</math> are intervals, and <math>\chi_A\,</math> is the indicator function of <math>A</math>:
\left\{
\right.
</math>
In this definition, the intervals <math>A_i</math> can be assumed to have the following two properties:
- The intervals are disjoint, <math>A_i\cap A_j=\emptyset</math> for <math>i\ne j</math>
- The union of the intervals is the entire real line, <math>\cup_{i=1}^n A_i=\mathbb R.</math>
Indeed, if that is not the case to start with, a different set of intervals can be picked for which these assumptions hold. For example, the step function
can be written as
# Examples
- A constant function is a trivial example of a step function. Then there is only one interval, <math>A_0=\mathbb R.</math>
- The Heaviside function H(x) is an important step function. It is the mathematical concept behind some test signals, such as those used to determine the step response of a dynamical system.
- The rectangular function, the normalized boxcar function, is the next simplest step function, and is used to model a unit pulse.
## Non-examples
- The integer part function is not a step function according to the definition of this article, since it has an infinite number of "steps".
# Properties
- The sum and product of two step functions is again a step function. The product of a step function with a number is also a step function. As such, the step functions form an algebra over the real numbers.
- A step function takes only a finite number of values. If the intervals <math>A_i,</math> <math>i=0, 1, \dots, n,</math> in the above definition of the step function are disjoint and their union is the real line, then <math>f(x)=\alpha_i\,</math> for all <math>x\in A_i.</math>
- The Lebesgue integral of a step function <math>f = \sum\limits_{i=0}^n \alpha_i \chi_{A_i}\,</math> is <math>\int \!f\,dx = \sum\limits_{i=0}^n \alpha_i \ell(A_i),\,</math> where <math>\ell(A)</math> is the length of the interval <math>A,</math> and it is assumed here that all intervals <math>A_i</math> have finite length. In fact, this equality (viewed as a definition) can be the first step in constructing the Lebesgue integral.[1]
- The derivative of a step function is the Dirac delta function
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Stephen Fleck
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Stephen Fleck
# Overview
Stephen Fleck (September 18, 1912-December 19, 2002) was a professor in the Psychiatry and Epidemiology and Public Health Departments at the Yale University School of Medicine from 1953 to 1983 and professor emeritus from 1983 until his death.
He had an early effect on the direction that American psychiatry took during the mid- to late-twentieth century. With Theodore Lidz and Alice Cornelison, he was a co-author of the seminal book Schizophrenia and the Family (1965), a significant influence on the modern psychiatric thought and practice regarding the origins and treatments of schizophrenia.
# Early Life
One of four sons and one daughter born in Frankfurt, Germany, to Georg and Anna Fleck, he was a young medical student in 1933 when a professor warned him and several other Jewish students that there were Nazi warrants out for their arrests. Fleck and most of his immediate family fled Hitler's Germany, first to The Netherlands and then, in 1935, to Boston, Massachusetts, where he became a U.S. citizen.
He finished medical school at Harvard, where he was a graduate assistant to John Rock while Rock was performing the preliminary research that led to the invention of the first birth control pill . This helped to spark Fleck's lifelong interest in contraception and family planning issues.
# Military Service
In 1941, Fleck enlisted in the U.S. Army Medical Corps. He was first stationed as a medical officer at the U.S. Army Prisoner of War Camp at Aliceville, Alabama, where he was involved in treating a diphtheria epidemic that spread quickly among the prisoners. Among the Nazi prisoners were a number of Rommel Corps soldiers, some of whom, even while incarcerated in west central Alabama, attempted to assassinate other Nazis they saw as having been disloyal to the Third Reich. Since Fleck kept his national origin and fluency in German secret from the prisoners, he was able to prevent some of these plotted murders.
He was subsequently shipped to the European Theater, and first posted in England in Army camp hospitals. Just before D-Day, Fleck was posted to Bournemouth, England to await transport over the channel with the medical (ambulance) corps. While in Bournemouth, he met Louise Harlan, an American Red Cross volunteer. Fleck stayed with ambulance corps attached to the 72nd and 76th divisions as they moved through Belgium. He was present at the Battle of the Bulge and afterward was briefly in charge of the medical needs of some 30,000 captured German soldiers. Subsequently, he was involved in interrogating POWs and evacuating and treating concentration camp prisoners; he also traveled to several camps to search for records or other signs of friends and extended family.
# Early Medical Career
Fleck and Harlan were shipped home in August and September of 1945; they were married on October 13, 1945. Fleck did his psychiatric residency at Johns Hopkins Hospital in Baltimore, Maryland, where he first met his lifelong colleague Theodore Lidz. He had a faculty position at the University of Washington School of Medicine from 1949 until 1953, when Lidz invited Fleck to join him at the Yale School of Medicine Department of Psychiatry.
# Career at Yale
Fleck and Lidz "worked from the late 1940s on to change the direction of psychiatry from the purely psychoanalytic to a specialty incorporating social-scientific methodology, medical, behavioral, neurological and public-health factors, and especially familial considerations." They focused their long-term research on schizophrenic patients and their families, culminating in the 1966 publication of the ground-breaking Schizophrenia and the Family, for which Lidz, Fleck and Cornelison won the 1985 American Family Therapy Academy "Pioneering Contribution to Family Therapy" award. In addition to his research, professorial, and supervisory roles at the school of medicine, Fleck was also chief psychiatrist at both the Yale Psychiatric Institute and the Connecticut Mental Health Center.
Fleck officially retired from Yale in 1983 but continued to publish and to consult on colleagues' cases until a few months before his 2002 death. The Stephen Fleck Clinician and Teacher Award at the Yale School of Medicine is named in his honor.
# Personal Life
The Flecks had three children in quick succession: Anna Lou (b. 1947), Stephen Harlan (b. 1948), and Carra Ruth (b. 1949). Together, the Flecks were campaigners for legalized birth control and abortion, participating in the activism that led to the landmark 1965 Supreme Court decision Griswold v. Connecticut. Louise Fleck, had grown up in Nome, Alaska among other places, and had traveled and worked internationally before the War and after receiving a BA (honors) in Spanish from the University of Washington. In New Haven, she became active in public school issues, and acquired an MAT-Reading. She tutored many illiterate adults, generally without fee. She and Stephen were married for more than 50 years until her death in 1992.
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Stephen Fleck
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Stephen Fleck (September 18, 1912-December 19, 2002) was a professor in the Psychiatry[2] and Epidemiology and Public Health[3] Departments at the Yale University School of Medicine[4] from 1953 to 1983 and professor emeritus from 1983 until his death.
He had an early effect on the direction that American psychiatry took during the mid- to late-twentieth century. With Theodore Lidz and Alice Cornelison, he was a co-author of the seminal book Schizophrenia and the Family[5] (1965), a significant influence on the modern psychiatric thought and practice regarding the origins and treatments of schizophrenia.
# Early Life
One of four sons and one daughter born in Frankfurt, Germany, to Georg and Anna Fleck, he was a young medical student in 1933 when a professor warned him and several other Jewish students that there were Nazi warrants out for their arrests. Fleck and most of his immediate family fled Hitler's Germany, first to The Netherlands and then, in 1935, to Boston, Massachusetts, where he became a U.S. citizen.
He finished medical school at Harvard, where he was a graduate assistant to John Rock while Rock was performing the preliminary research that led to the invention of the first birth control pill [1]. This helped to spark Fleck's lifelong interest in contraception and family planning issues.[2]
# Military Service
In 1941, Fleck enlisted in the U.S. Army Medical Corps. He was first stationed as a medical officer at the U.S. Army Prisoner of War Camp at Aliceville, Alabama, where he was involved in treating a diphtheria epidemic that spread quickly among the prisoners.[3] Among the Nazi prisoners were a number of Rommel Corps soldiers, some of whom, even while incarcerated in west central Alabama, attempted to assassinate other Nazis they saw as having been disloyal to the Third Reich. Since Fleck kept his national origin and fluency in German secret from the prisoners, he was able to prevent some of these plotted murders.[4]
He was subsequently shipped to the European Theater, and first posted in England in Army camp hospitals. Just before D-Day, Fleck was posted to Bournemouth, England to await transport over the channel with the medical (ambulance) corps. While in Bournemouth, he met Louise Harlan, an American Red Cross volunteer. Fleck stayed with ambulance corps attached to the 72nd and 76th divisions as they moved through Belgium. He was present at the Battle of the Bulge and afterward was briefly in charge of the medical needs of some 30,000 captured German soldiers. Subsequently, he was involved in interrogating POWs and evacuating and treating concentration camp prisoners; he also traveled to several camps to search for records or other signs of friends and extended family.
# Early Medical Career
Fleck and Harlan were shipped home in August and September of 1945; they were married on October 13, 1945. Fleck did his psychiatric residency at Johns Hopkins Hospital in Baltimore, Maryland,[5] where he first met his lifelong colleague Theodore Lidz. He had a faculty position at the University of Washington School of Medicine from 1949 until 1953,[6] when Lidz invited Fleck to join him at the Yale School of Medicine Department of Psychiatry.
# Career at Yale
Fleck and Lidz "worked from the late 1940s on to change the direction of psychiatry from the purely psychoanalytic to a specialty incorporating social-scientific methodology, medical, behavioral, neurological and public-health factors, and especially familial considerations." [7] They focused their long-term research on schizophrenic patients and their families, culminating in the 1966 publication of the ground-breaking Schizophrenia and the Family, for which Lidz, Fleck and Cornelison won the 1985 American Family Therapy Academy "Pioneering Contribution to Family Therapy" award.[8] In addition to his research, professorial, and supervisory roles at the school of medicine, Fleck was also chief psychiatrist at both the Yale Psychiatric Institute and the Connecticut Mental Health Center.[6]
Fleck officially retired from Yale in 1983 but continued to publish and to consult on colleagues' cases until a few months before his 2002 death. The Stephen Fleck Clinician and Teacher Award at the Yale School of Medicine is named in his honor.
# Personal Life
The Flecks had three children in quick succession: Anna Lou (b. 1947), Stephen Harlan[7] (b. 1948), and Carra Ruth (b. 1949). Together, the Flecks were campaigners for legalized birth control and abortion, participating in the activism that led to the landmark 1965 Supreme Court decision Griswold v. Connecticut. Louise Fleck, had grown up in Nome, Alaska among other places, and had traveled and worked internationally before the War and after receiving a BA (honors) in Spanish from the University of Washington. In New Haven, she became active in public school issues, and acquired an MAT-Reading. She tutored many illiterate adults, generally without fee. She and Stephen were married for more than 50 years until her death in 1992.
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Steroid cycle
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Steroid cycle
A steroid cycle is a term commonly used to describe a period in time where an individual intakes anabolic steroids.
A "cycle" can last from two weeks to more commonly 6-12 weeks, or even longer. Supplying the body with exogenous hormones will suppress its own testosterone production.
The longer the body's endogenous supply of testosterone is suppressed, the harder it will be for their hypothalamus/pituitary/testicular axis (HPTA) to recover. More serious health risks are associated with longer cycles, such as testicular atrophy, gynecomastia, heart problems, liver diseases, and in extreme cases, permanent suppression of the HPTA, necessitating permanent testosterone therapy.
Many steroid cycles involve combining two or more drugs together, usually one being a potent androgen. Other drugs which act through more anabolic pathways can then be added as well. Professional and novice bodybuilders all over the world combine many drugs together in what is commonly referred to as a steroid stack.
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Steroid cycle
A steroid cycle is a term commonly used to describe a period in time where an individual intakes anabolic steroids.
A "cycle" can last from two weeks to more commonly 6-12 weeks, or even longer. Supplying the body with exogenous hormones will suppress its own testosterone production.
The longer the body's endogenous supply of testosterone is suppressed, the harder it will be for their hypothalamus/pituitary/testicular axis (HPTA) to recover. More serious health risks are associated with longer cycles, such as testicular atrophy, gynecomastia, heart problems, liver diseases, and in extreme cases, permanent suppression of the HPTA, necessitating permanent testosterone therapy.
Many steroid cycles involve combining two or more drugs together, usually one being a potent androgen. Other drugs which act through more anabolic pathways can then be added as well. Professional and novice bodybuilders all over the world combine many drugs together in what is commonly referred to as a steroid stack.
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Steve Andreas
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Steve Andreas
Steve Andreas, born John O. Stevens, is an American psychotherapist and author specializing in Neuro-linguistic programming. Since 1979, Steve and his partner Connirae Andreas have edited and published a number of titles on the subject. They are best known in the field for their annotated transcripts of a variety of early NLP seminars.
Steve is the son of Barry Stevens, a writer and well-known gestalt therapist. He founded Real People Press, a publisher of works on psychology and personal change in 1967, in order to publish a book by Carl Rogers and Barry Stevens entitled "Person to Person".
Steve Andreas worked as a chemist until 1958, then went to graduate school at Brandeis University under Abraham Maslow for two years, receiving an MA in psychology. After working as a chemist again for a year, he got a junior college teaching credential, and taught psychology and social science at Diablo Valley College in Pleasant Hill CA for 7 years. He was introduced to Gestalt therapy in 1967, and edited Fritz Perls books, Gestalt Therapy Verbatim and In and Out the Garbage Pail, and wrote Awareness, a book of exercises based on Gestalt Therapy in 1971. He became interested in Neuro-linguistic programming in 1977. and has been active in the field ever since.
In 1979 Steve and Connirae established NLP of Colorado, now known as NLP Comprehensive, to develop the training arm of their business. They transferred ownership of to Tom Dotz in 1998. They continue to own Real People Press.
# Books and publications
Richard Bandler and John Grinder titles edited by Steve and Connirae Andreas which are well known in the NLP field include:
- Frogs Into Princes (Bandler & Grinder), 1979)
- Trance-Formations (Grinder & Bandler), 1981)
- Reframing (Bandler and Grinder, 1982)
- Using Your Brain for a Change (Bandler, 1985)
- Change Your Mind and Keep the Change (1987)
- Heart of the Mind (1989)
- Core Transformations (Connirae & Tamara Andreas, 1994).
- Virginia Satir: The Patterns of Her Magic (1991)
- Transforming Your Self (2002)
- Six Blind Elephants, Volumes I & II (2006)
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Steve Andreas
Template:Neuro-linguistic programming
Steve Andreas, born John O. Stevens, is an American psychotherapist and author specializing in Neuro-linguistic programming. Since 1979, Steve and his partner Connirae Andreas have edited and published a number of titles on the subject. They are best known in the field for their annotated transcripts of a variety of early NLP seminars.[1]
Steve is the son of Barry Stevens, a writer and well-known gestalt therapist. He founded Real People Press, a publisher of works on psychology and personal change in 1967, in order to publish a book by Carl Rogers and Barry Stevens entitled "Person to Person".[2]
Steve Andreas worked as a chemist until 1958, then went to graduate school at Brandeis University under Abraham Maslow for two years, receiving an MA in psychology. After working as a chemist again for a year, he got a junior college teaching credential, and taught psychology and social science at Diablo Valley College in Pleasant Hill CA for 7 years. He was introduced to Gestalt therapy in 1967, and edited Fritz Perls books, Gestalt Therapy Verbatim and In and Out the Garbage Pail, and wrote Awareness, a book of exercises based on Gestalt Therapy in 1971. He became interested in Neuro-linguistic programming in 1977.[2][3] and has been active in the field ever since.
In 1979 Steve and Connirae established NLP of Colorado, now known as NLP Comprehensive, to develop the training arm of their business. They transferred ownership of [NLP Comprehensive] to Tom Dotz in 1998.[1] They continue to own Real People Press.
# Books and publications
Richard Bandler and John Grinder titles edited by Steve and Connirae Andreas which are well known in the NLP field include:
- Frogs Into Princes (Bandler & Grinder), 1979)
- Trance-Formations (Grinder & Bandler), 1981)
- Reframing (Bandler and Grinder, 1982)
- Using Your Brain for a Change (Bandler, 1985)
- Change Your Mind and Keep the Change (1987)
- Heart of the Mind (1989)
- Core Transformations (Connirae & Tamara Andreas, 1994).
- Virginia Satir: The Patterns of Her Magic (1991)
- Transforming Your Self (2002)
- Six Blind Elephants, Volumes I & II (2006)
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Steven Hassan
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Steven Hassan
Steven Alan Hassan (born 1954) is a licensed mental health counselor and an exit counselor. Hassan was an early advocate of exit counseling, and is the author of two books on the subject of "cults", and what he describes as their use of mind control, thought reform, and the psychology of influence in order to recruit and retain members.
Himself a former member of the Unification Church, after spending one year assisting with involuntary deprogrammings, he developed what he describes as his own non-coercive methods for helping members of alleged cults to leave their groups, and developed therapeutic approaches for counseling former members in order to help them overcome the purported effects of cult membership.
# Education
- M.Ed., Counselling Psychology, Cambridge College, Cambridge, Massachusetts, 1985
- Licensed Mental Health Counselor (LMHC) in the Commonwealth of Massachusetts, 1992
- Certified as a Nationally Certified Counselor (NCC) by the National Board for Certified Counselors, 2003
# Background
Hassan became a member of the Unification Church in the 1970s, at the age of 19, while studying at Queens College. He describes what he terms as his "recruitment" in his first book, Combatting Cult Mind Control, asserting that this recruitment was the result of the unethical use of powerful psychological influence techniques by members of the Church. He subsequently spent over two years recruiting and indoctrinating new members, as well as performing fundraising and campaigning duties, and ultimately rose to the rank of Assistant Director of the Unification Church at its National Headquarters. In that capacity he met personally with Sun Myung Moon.
Hassan has given an account of his leaving the Unification Church in his 1998 book Combatting Cult Mind Control and on his personal website: After having been awake for two days as the head of a fundraising team, he caused a traffic accident when he fell asleep at the wheel of the Church's van and drove into the back of a truck. He ended up with a broken leg, surgery and a full-leg cast. During his recuperation he was given permission by his superiors in the Church to visit his parents. His parents contacted former members of the Unification Church who engaged in a deprogramming session with Hassan. Because of his cast he was not able to run or drive away, but he resisted to the point that he states that he had an impulse to "escape by reaching over and snapping my father's neck", rather than to potentially succumb to the deprogramming and betray "The Messiah". His father convinced him to stay for five days and talk to the former Church members who were conducting the deprogramming, after which time Hassan would be free to make the choice to return to the Church. Hassan agreed to this. He subsequently decided to leave the Church.
In 1979, following the Jonestown tragedy, Hassan founded a non-profit organization called "Ex-Moon Inc.", whose membership consisted of over four hundred former members of the Unification Church.
According to his biography, "During the 1977-78 Congressional Subcommittee Investigation into South Korean CIA activities in the United States, he consulted as an expert on the Moon organization and provided information and internal documents regarding Moon's desire to influence politics in his bid to 'take over the world.'"
Around 1980, Hassan began investigating methods of persuasion, mind control and indoctrination. He first studied the thought reform theories of Robert Lifton, and was "able to see clearly that the Moon organization uses all eight" of the thought reform methods described by Lifton.
He later attended a seminar on hypnosis with Richard Bandler, which was based on the work that he and transformational grammarian John Grinder had done in developing Neuro-Linguistic Programming (NLP). Hassan felt that this seminar gave him "a handle on techniques of mind control, and how to combat them." He spent "nearly two years studying NLP with everyone involved in its formulation and presentation." During this period, Hassan moved to Santa Cruz, California for an apprenticeship with Grinder. He became concerned about the marketing of NLP as a tool for "power enhancement", left his association with Grinder, and "began to study the works of Milton Erickson M.D., Virginia Satir, and Gregory Bateson, on which NLP is based." His studies gave him the basis for the development of his theories on mind control.
Hassan continued to study hypnosis and is a member of the The American Society for Clinical Hypnosis and the The International Society of Hypnosis.
In 1999, Hassan founded the Freedom of Mind Resource Center. It is registered as a domestic profit corporation in the state of Massachusetts. He is president and treasurer.
In Combatting Cult Mind Control Hassan describes his personal experiences with the Unification Church, as well as his theory of the four components of mind control. The sociologist Eileen Barker, who has studied the Unification Church, has commented on the book. She expressed several concerns but nevertheless recommended the book. The book has been reviewed in the American Journal of Psychiatry, and in the The Lancet, and has been praised by many scholars and cult experts, like Philip Zimbardo and Margaret Singer.
In his second book, Releasing the Bonds: Empowering People to Think for Themselves (2000), Hassan presents what he terms "a much more refined method to help family and friends, called the Strategic Interaction Approach. This non-coercive, completely legal approach is far better than deprogramming, and even exit counseling."
Hassan is a practicing Jew. He describes himself as an "activist who fights to protect people's right to believe whatever they want to believe", and states that his work has the broad support of religious leaders from a variety of spiritual orientations. He further states that "many unorthodox religions have expressed their gratitude to me for my books because it clearly shows them NOT to be a destructive cult."
His wife Aureet Bar-Yam died in 1991 after falling through ice while trying to save their dog.
# Public impact
He consulted as an expert on the Unification Church during the 1977-1978 Congressional investigation of Korean-American relations.
He has appeared on 60 Minutes, Nightline, Dateline, Larry King Live, and The O'Reilly Factor. He has over thirty years of experience with counseling both current and former members of groups he describes as cults.
In his first book, Combatting Cult Mind Control, he describes his experiences as a member the Unification Church, and describes the exit counseling methods that he developed based on those experiences, and based on his subsequent studies of psychological influence techniques. In his latest book Releasing the Bonds, which was published twelve years after Combatting Cult Mind Control, he describes the evolution of his exit counseling procedures into a more advanced procedure that he calls the "Strategic Interaction Approach."
# Mind control
For details see: BITE model
Although he does not name it the "BITE model", in his first book Combatting Cult Mind Control Hassan describes the "four components of mind control as:
- Behavior control
- Thought control
- Emotional control
- Information control
Twelve years later, in Releasing the Bonds: Empowering People to Think for Themselves, he developed these same components into a mind-control model, "BITE", which stands for Behavior, Information, Thoughts, and Emotions. Hassan writes that cults recruit members through a three-step process which he refers to as "unfreezing," "changing," and "refreezing," respectively. This involves the use of an extensive array of various techniques, including systematic deception, behavior modification, withholding of information, and emotionally intense persuasion techniques (such as the induction of phobias), which he collectively terms mind control.
In the same book he also writes "I suspect that most cult groups use informal hypnotic techniques to induce trance states. They tend to use what are called "naturalistic" hypnotic techniques. Practicing meditation to shut down thinking, chanting a phrase repetitively for hours, or reciting affirmations are all powerful ways to promote spiritual growth. But they can also be used unethically, as methods for mind control indoctrination."
He calls groups that employ such psychological influence techniques "destructive cults," a term that he defines by the methods used to recruit and retain members, and by the effect that such methods have on members, rather than by the theological/sociological/moral views the group espouses. He is opposed to the non-consensual deprogramming of cult members, and supports instead counseling them in order that they withdraw voluntarily from the organization. He writes:
My mind control model outlines many key elements that need to be controlled: Behavior, Information, Thoughts and Emotions (BITE). If these four components can be controlled, then an individual's identity can be systematically manipulated and changed. Destructive mind control takes the 'locus of control' away from an individual. The person is systematically deceived about the beliefs and practices of the person (or group) and manipulated throughout the recruitment process — unable to make informed choices and exert independent judgment. The person's identity is profoundly influenced through a set of social influence techniques and a "new identity" is created — programmed to be dependent on the leader or group ideology. The person can't think for him or herself, but believes otherwise.
Hassan is a proponent of non-coercive intervention. He refers to his method as the "Strategic Interaction Approach".
Twelve years after the last publication of Combatting Cult Mind Control, Hassan described his position on deprogramming in Releasing the Bonds. He states that "Deprogramming has many drawbacks. I have met dozens of people who were successfully deprogrammed but, to this day, experience psychological trauma as a result of the method. These people were glad to be released from the grip of cult programming but were not happy about the method used to help them." He further states that "A deprogramming triggers the deepest fears of cult members. They have been taken against their will. Family and friends are not to be trusted. The trauma of being thrown into a van by unknown people, driven away, and imprisoned creates mistrust, anger, and resentment." He quotes a person who was involuntarily deprogrammed as saying "What these deprogrammers did was attempt to change my mind through INFORMATION CONTROL — just like the cult did. They did not deal with the CUT-implanted phobias, which remained with me for years — the fear of certain colors, the identification of certain types of music with CUT rituals, the fear of retaliation and probable death should I ever leave this group."
# Criticism
## Deprogramming
In a research paper presented at the 2000 Society for the Scientific Study of Religion conference, Anson Shupe, professor of Sociology at Indiana/Purdue University, and Susan E. Darnell, manager of a credit union, state Hassan had participated two involuntary deprogrammings in 1976 and 1977.
Hassan confirms that he took part in a number of involuntary deprogrammings in the late-1970s. In one of them a Unification Church member, Arthur Roselle, was kept tied in his home for two days Regarding this, Hassan states that Roselle had already been secured by his family before Hassan arrived. Despite Hassan's claim that Arthur Roselle was tied before he arrived, Joanne Roselle's affidavit states that her "son (Arthur) became violent when confronted by his family friends, and the two ex-members of Unification Church, Steven Hassan and Ellen L. Hassan," and they "were forced to tie his hands and legs so as not to do damage to himself and others." Joanne Roselle's affidavit indicates that Hassan was present when Arthur Roselle was tied. Hassan then states that Roselle decided to leave, but Roselle's mother begged him to stay and talk to Roselle. Hassan then asked Roselle to listen to what Hassan had to say, and if Roselle then wanted to return to the Church he was free to do so. Roselle agreed to listen.
Arthur Roselle's account in a sworn affidavit also contradicts this account. According to Roselle, "Hassan aided, abetted, and conspired in my kidnapping and in my subsequent false imprisonment." Roselle also accused Hassan of actively assisting in depriving him of sleep, insulting and humiliating him, and treating him like "a captured animal in a zoo," as well as attempting to coerce him into signing a false affidavit exonerating Hassan of the kidnapping claims. No criminal or civil charges were filed.
Hassan states that he spent one year assisting with deprogrammings before turning to less controversial methods (see exit counseling). Hassan has spoken out against involuntary deprogramming since 1980. He states that he has not participated in any deprogrammings since then.
However, in Combatting Cult Mind Control, he stated that forcible deprogrammings can be kept as a last resort if all other attempts fail. Concerned that ministers in Japan encouraged to perform forcible deprogramming because of first book," Hassan wrote a "letter" to Reverend Seishi Kojima stating, "I oppose aggressive, illegal methods."
Andy Bacus, an attorney for the Unification Church, against which Hassan testified to Congress, told the Illinois Senate Committee on Education on December 7, 1993 that:
Steve Hassan ... is an ex-member of the Unification Church who was involuntarily deprogrammed. He has spent the last 15 years deprogramming other persons. Mr. Hassan has been most active recently in providing "exit counseling" to members of the Boston Church of Christ. Like other "exit counselors", Hassan relies on the mind control theories of Margaret Singer to justify his actions.
## Rick Ross
Hassan became involved in a dispute with fellow cult critic Rick Ross when Ross posted a disclaimer on his Web site after receiving what he stated were “serious complaints” regarding Hassan’s fees for his services. Hassan responded that the charges were “inappropriate and completely inaccurate,” stating that Ross had misstated Hassan's current fees. Ross's response was that Hassan's fees "were $500.00 per hour and/or $5,000 per day" but that after "Hassan publicly posted his fee schedule, which was reduced to $250.00 per hour and/or $2,500.00 per day...the RI disclaimer was taken down." Hassan stated that "my current fees are not $500 as Ross claims. I charge half that for an hour of counseling and have done so for quite some time."
# Website
Hassan's website "Freedom of Mind" contains what he describes as information on "cults and controversial groups" and on which he offers his counseling and consultation services. Reader discussion take place in an associated Yahoo! group, called freedomofmind. In its discussion of Hassan. The Religious Movements Homepage Project states that Hassan's “entrepreneurial tendencies are baldly evident on his home page.”
On his website Hassan distinguishes between what he terms as destructive cults and benign cults. A destructive cult, according to Hassan, has a "pyramid-shaped authoritarian regime with a person or group of people that have dictatorial control." and "uses deception in recruiting new members." In contrast, benign cults are, according to Hassan, "any group of people who have a set of beliefs and rituals that are non-mainstream." The website further states that "as long as people are freely able to choose to join with full disclosure of the group's doctrine and practices and can choose to disaffiliate without fear or harassment, then it doesn't fall under the behavioral/ psychological destructive cult category."
The site contains a disclaimer that not every group listed is necessarily what Hassan calls a "destructive mind control cult" Many of the groups Hassan lists are not included in the Handbook of Cults and Sects in America.. There is also considerable disagreement about what precisely constitutes a cult. Some cult critics and a some academics use the term "cult" despite its definitional ambiguity, but many academics who study such groups prefer the term "New Religious Movement".
Hassan dedicates his website "to respect for human rights, spirituality, and consumer awareness." A declaration of support for "religious freedom and the United Nations Universal Declaration of Human Rights" appears at the bottom of every page.
# Bibliography
- Combatting Cult Mind Control, 1988. ISBN 0-8928124-3-5.
- Releasing the Bonds: Empowering People to Think for Themselves, 2000. ISBN 0-9670688-0-0.
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Steven Hassan
Template:Infobox Writer
Steven Alan Hassan (born 1954) is a licensed mental health counselor and an exit counselor. Hassan was an early advocate of exit counseling, and is the author of two books on the subject of "cults", and what he describes as their use of mind control, thought reform, and the psychology of influence in order to recruit and retain members.
Himself a former member of the Unification Church, after spending one year assisting with involuntary deprogrammings, he developed what he describes as his own non-coercive methods for helping members of alleged cults to leave their groups, and developed therapeutic approaches for counseling former members in order to help them overcome the purported effects of cult membership.
# Education
- M.Ed., Counselling Psychology, Cambridge College, Cambridge, Massachusetts, 1985
- Licensed Mental Health Counselor (LMHC) in the Commonwealth of Massachusetts, 1992
- Certified as a Nationally Certified Counselor (NCC) by the National Board for Certified Counselors, 2003
# Background
Hassan became a member of the Unification Church in the 1970s, at the age of 19, while studying at Queens College. He describes what he terms as his "recruitment" in his first book, Combatting Cult Mind Control, asserting that this recruitment was the result of the unethical use of powerful psychological influence techniques by members of the Church.[1] He subsequently spent over two years recruiting and indoctrinating new members, as well as performing fundraising and campaigning duties, and ultimately rose to the rank of Assistant Director of the Unification Church at its National Headquarters. In that capacity he met personally with Sun Myung Moon.[2]
Hassan has given an account of his leaving the Unification Church in his 1998 book Combatting Cult Mind Control and on his personal website: After having been awake for two days as the head of a fundraising team, he caused a traffic accident when he fell asleep at the wheel of the Church's van and drove into the back of a truck. He ended up with a broken leg, surgery and a full-leg cast. During his recuperation he was given permission by his superiors in the Church to visit his parents. His parents contacted former members of the Unification Church who engaged in a deprogramming session with Hassan. Because of his cast he was not able to run or drive away, but he resisted to the point that he states that he had an impulse to "escape by reaching over and snapping my father's neck", rather than to potentially succumb to the deprogramming and betray "The Messiah". His father convinced him to stay for five days and talk to the former Church members who were conducting the deprogramming, after which time Hassan would be free to make the choice to return to the Church. Hassan agreed to this. He subsequently decided to leave the Church.[3]
In 1979, following the Jonestown tragedy, Hassan founded a non-profit organization called "Ex-Moon Inc.", whose membership consisted of over four hundred former members of the Unification Church.[2]
According to his biography, "During the 1977-78 Congressional Subcommittee Investigation into South Korean CIA activities in the United States, he consulted as an expert on the Moon organization and provided information and internal documents regarding Moon's desire to influence politics in his bid to 'take over the world.'"[2]
Around 1980, Hassan began investigating methods of persuasion, mind control and indoctrination. He first studied the thought reform theories of Robert Lifton, and was "able to see clearly that the Moon organization uses all eight" of the thought reform methods described by Lifton.[3]
He later attended a seminar on hypnosis with Richard Bandler, which was based on the work that he and transformational grammarian John Grinder had done in developing Neuro-Linguistic Programming (NLP). Hassan felt that this seminar gave him "a handle on techniques of mind control, and how to combat them." He spent "nearly two years studying NLP with everyone involved in its formulation and presentation." During this period, Hassan moved to Santa Cruz, California for an apprenticeship with Grinder. He became concerned about the marketing of NLP as a tool for "power enhancement", left his association with Grinder, and "began to study the works of Milton Erickson M.D., Virginia Satir, and Gregory Bateson, on which NLP is based." His studies gave him the basis for the development of his theories on mind control.[4]
Hassan continued to study hypnosis and is a member of the The American Society for Clinical Hypnosis and the The International Society of Hypnosis.[5]
In 1999, Hassan founded the Freedom of Mind Resource Center. It is registered as a domestic profit corporation in the state of Massachusetts. He is president and treasurer.[6]
In Combatting Cult Mind Control Hassan describes his personal experiences with the Unification Church, as well as his theory of the four components of mind control. The sociologist Eileen Barker, who has studied the Unification Church, has commented on the book[7]. She expressed several concerns but nevertheless recommended the book. The book has been reviewed in the American Journal of Psychiatry,[8] and in the The Lancet, [9] and has been praised by many scholars and cult experts, like Philip Zimbardo [10] and Margaret Singer. [11]
In his second book, Releasing the Bonds: Empowering People to Think for Themselves (2000), Hassan presents what he terms "a much more refined method to help family and friends, called the Strategic Interaction Approach. This non-coercive, completely legal approach is far better than deprogramming, and even exit counseling."[12]
Hassan is a practicing Jew. He describes himself as an "activist who fights to protect people's right to believe whatever they want to believe", and states that his work has the broad support of religious leaders from a variety of spiritual orientations. [13] He further states that "many unorthodox religions have expressed their gratitude to me for my books because it clearly shows them NOT to be a destructive cult."[14]
His wife Aureet Bar-Yam died in 1991 after falling through ice while trying to save their dog. [15]
# Public impact
He consulted as an expert on the Unification Church during the 1977-1978 Congressional investigation of Korean-American relations.
He has appeared on 60 Minutes, Nightline, Dateline, Larry King Live, and The O'Reilly Factor. He has over thirty years of experience with counseling both current and former members of groups he describes as cults.
In his first book, Combatting Cult Mind Control, he describes his experiences as a member the Unification Church, and describes the exit counseling methods that he developed based on those experiences, and based on his subsequent studies of psychological influence techniques. In his latest book Releasing the Bonds, which was published twelve years after Combatting Cult Mind Control, he describes the evolution of his exit counseling procedures into a more advanced procedure that he calls the "Strategic Interaction Approach."
# Mind control
For details see: BITE model
Although he does not name it the "BITE model", in his first book Combatting Cult Mind Control Hassan describes the "four components of mind control as:[16]
- Behavior control
- Thought control
- Emotional control
- Information control
Twelve years later, in Releasing the Bonds: Empowering People to Think for Themselves, he developed these same components into a mind-control model, "BITE", which stands for Behavior, Information, Thoughts, and Emotions. Hassan writes that cults recruit members through a three-step process which he refers to as "unfreezing," "changing," and "refreezing," respectively. This involves the use of an extensive array of various techniques, including systematic deception, behavior modification, withholding of information, and emotionally intense persuasion techniques (such as the induction of phobias), which he collectively terms mind control.[17]
In the same book he also writes "I suspect that most cult groups use informal hypnotic techniques to induce trance states. They tend to use what are called "naturalistic" hypnotic techniques. Practicing meditation to shut down thinking, chanting a phrase repetitively for hours, or reciting affirmations are all powerful ways to promote spiritual growth. But they can also be used unethically, as methods for mind control indoctrination." [4]
He calls groups that employ such psychological influence techniques "destructive cults," a term that he defines by the methods used to recruit and retain members, and by the effect that such methods have on members, rather than by the theological/sociological/moral views the group espouses. He is opposed to the non-consensual deprogramming of cult members, and supports instead counseling them in order that they withdraw voluntarily from the organization. He writes:[18]
My mind control model outlines many key elements that need to be controlled: Behavior, Information, Thoughts and Emotions (BITE). If these four components can be controlled, then an individual's identity can be systematically manipulated and changed. Destructive mind control takes the 'locus of control' away from an individual. The person is systematically deceived about the beliefs and practices of the person (or group) and manipulated throughout the recruitment process — unable to make informed choices and exert independent judgment. The person's identity is profoundly influenced through a set of social influence techniques and a "new identity" is created — programmed to be dependent on the leader or group ideology. The person can't think for him or herself, but believes otherwise.
Hassan is a proponent of non-coercive intervention. He refers to his method as the "Strategic Interaction Approach".[19]
Twelve years after the last publication of Combatting Cult Mind Control, Hassan described his position on deprogramming in Releasing the Bonds. He states that "Deprogramming has many drawbacks. I have met dozens of people who were successfully deprogrammed but, to this day, experience psychological trauma as a result of the method. These people were glad to be released from the grip of cult programming but were not happy about the method used to help them." He further states that "A deprogramming triggers the deepest fears of cult members. They have been taken against their will. Family and friends are not to be trusted. The trauma of being thrown into a van by unknown people, driven away, and imprisoned creates mistrust, anger, and resentment." He quotes a person who was involuntarily deprogrammed as saying "What these deprogrammers did was attempt to change my mind through INFORMATION CONTROL — just like the cult did. They did not deal with the CUT-implanted phobias, which remained with me for years — the fear of certain colors, the identification of certain types of music with CUT rituals, the fear of retaliation and probable death should I ever leave this group."[19]
# Criticism
## Deprogramming
In a research paper presented at the 2000 Society for the Scientific Study of Religion conference, Anson Shupe, professor of Sociology at Indiana/Purdue University, and Susan E. Darnell, manager of a credit union, state Hassan had participated two involuntary deprogrammings in 1976 and 1977.[20]
Hassan confirms that he took part in a number of involuntary deprogrammings in the late-1970s. In one of them a Unification Church member, Arthur Roselle, was kept tied in his home for two days[21] Regarding this, Hassan states that Roselle had already been secured by his family before Hassan arrived. Despite Hassan's claim that Arthur Roselle was tied before he arrived, Joanne Roselle's affidavit states that her "son (Arthur) became violent when confronted by his family friends, and the two ex-members of Unification Church, Steven Hassan and Ellen L. Hassan," and they "were forced to tie his hands and legs so as not to do damage to himself and others." Joanne Roselle's affidavit indicates that Hassan was present when Arthur Roselle was tied.[22] Hassan then states that Roselle decided to leave, but Roselle's mother begged him to stay and talk to Roselle. Hassan then asked Roselle to listen to what Hassan had to say, and if Roselle then wanted to return to the Church he was free to do so. Roselle agreed to listen.[14]
Arthur Roselle's account in a sworn affidavit also contradicts this account. According to Roselle, "Hassan aided, abetted, and conspired in my kidnapping and in my subsequent false imprisonment."[23] Roselle also accused Hassan of actively assisting in depriving him of sleep, insulting and humiliating him, and treating him like "a captured animal in a zoo," as well as attempting to coerce him into signing a false affidavit exonerating Hassan of the kidnapping claims.[23] No criminal or civil charges were filed.[14]
Hassan states that he spent one year assisting with deprogrammings before turning to less controversial methods (see exit counseling).[14] Hassan has spoken out against involuntary deprogramming since 1980.[24][14][5] He states that he has not participated in any deprogrammings since then.
However, in Combatting Cult Mind Control, he stated that forcible deprogrammings can be kept as a last resort if all other attempts fail.[25] Concerned that ministers in Japan [were] encouraged to perform forcible deprogramming because of [his] first book," Hassan wrote a "letter" to Reverend Seishi Kojima stating, "I oppose aggressive, illegal methods."
Andy Bacus, an attorney for the Unification Church, against which Hassan testified to Congress, told the Illinois Senate Committee on Education on December 7, 1993 that:
Steve Hassan ... is an ex-member of the Unification Church who was involuntarily deprogrammed. He has spent the last 15 years deprogramming other persons. Mr. Hassan has been most active recently in providing "exit counseling" to members of the Boston Church of Christ. Like other "exit counselors", Hassan relies on the mind control theories of Margaret Singer to justify his actions.[26]
## Rick Ross
Hassan became involved in a dispute with fellow cult critic Rick Ross when Ross posted a disclaimer on his Web site after receiving what he stated were “serious complaints” regarding Hassan’s fees for his services.[27] Hassan responded that the charges were “inappropriate and completely inaccurate,” stating that Ross had misstated Hassan's current fees.[28] Ross's response was that Hassan's fees "were $500.00 per hour and/or $5,000 per day" but that after "Hassan publicly posted his fee schedule, which was reduced to $250.00 per hour and/or $2,500.00 per day...the RI disclaimer was taken down." Hassan stated that "my current fees are not $500 as Ross claims. I charge half that for an hour of counseling and have done so for quite some time."[28]
# Website
Hassan's website "Freedom of Mind" contains what he describes as information on "cults and controversial groups" and on which he offers his counseling and consultation services. Reader discussion take place in an associated Yahoo! group, called freedomofmind. In its discussion of Hassan. The Religious Movements Homepage Project states that Hassan's “entrepreneurial tendencies are baldly evident on his home page.”[29]
On his website Hassan distinguishes between what he terms as destructive cults and benign cults. A destructive cult, according to Hassan, has a "pyramid-shaped authoritarian regime with a person or group of people that have dictatorial control." and "uses deception in recruiting new members." In contrast, benign cults are, according to Hassan, "any group of people who have a set of beliefs and rituals that are non-mainstream." The website further states that "as long as people are freely able to choose to join with full disclosure of the group's doctrine and practices and can choose to disaffiliate without fear or harassment, then it doesn't fall under the behavioral/ psychological destructive cult category."[30]
The site contains a disclaimer that not every group listed is necessarily what Hassan calls a "destructive mind control cult"[31] Many of the groups Hassan lists are not included in the Handbook of Cults and Sects in America.[32]. There is also considerable disagreement about what precisely constitutes a cult. Some cult critics and a some academics use the term "cult" despite its definitional ambiguity,[33] but many academics who study such groups prefer the term "New Religious Movement". [34]
Hassan dedicates his website "to respect for human rights, spirituality, and consumer awareness."[35] A declaration of support for "religious freedom and the United Nations Universal Declaration of Human Rights" appears at the bottom of every page.
# Bibliography
- Combatting Cult Mind Control, 1988. ISBN 0-8928124-3-5.
- Releasing the Bonds: Empowering People to Think for Themselves, 2000. ISBN 0-9670688-0-0.
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Steven Nissen
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Steven Nissen
Steven Nissen (b.1949), a heart specialist, is chairman of cardiovascular medicine at the Cleveland Clinic.
He first gained prominence when he developed techniques in 1987 to thread miniaturized ultrasound imaging devices into a patient's heart to reveal the exact composition of plaques causing the early stages of artery damage. This allowed much easier evaluation of anticholesterol medications.
His efforts in 2004 linked COX-2 inhibitors such as Celebrex and Merck's Vioxx with heart attacks, and prevented Merck's similar product, Arcoxia, from being approved. In 2005, he attacked the experimental diabetes drug Pargluva, from Bristol-Myers Squibb, for its serious heart risks. A Food and Drug Administration advisory panel had strongly recommended approval, but Pargluva was withdrawn.
In 2007, he found that the Avandia diabetes drug produced by GlaxoSmithKline carried high cardiovascular risks, leading to a warning by the Food and Drug Administration and a sales loss of about 30 percent for the drug.
In 2007, he was named one of the 100 Most Influential People in the world (Time 100) by Time Magazine.
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Steven Nissen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Steven Nissen (b.1949), a heart specialist, is chairman of cardiovascular medicine at the Cleveland Clinic.
He first gained prominence when he developed techniques in 1987 to thread miniaturized ultrasound imaging devices into a patient's heart to reveal the exact composition of plaques causing the early stages of artery damage. This allowed much easier evaluation of anticholesterol medications.
His efforts in 2004 linked COX-2 inhibitors such as Celebrex and Merck's Vioxx with heart attacks, and prevented Merck's similar product, Arcoxia, from being approved. In 2005, he attacked the experimental diabetes drug Pargluva, from Bristol-Myers Squibb, for its serious heart risks. A Food and Drug Administration advisory panel had strongly recommended approval, but Pargluva was withdrawn.
In 2007, he found that the Avandia diabetes drug produced by GlaxoSmithKline carried high cardiovascular risks, leading to a warning by the Food and Drug Administration and a sales loss of about 30 percent for the drug. [1]
In 2007, he was named one of the 100 Most Influential People in the world (Time 100) by Time Magazine. [2]
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https://www.wikidoc.org/index.php/Steven_Nissen
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e110fd4a9db0f97c557d5a811121fa2a4d9f917b
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wikidoc
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Stool culture
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Stool culture
# Overview
A stool test is one where fecal matter is collected for analysis to diagnose the presence or absence of a medical condition.
# Fecal occult blood test
One of the most common stool tests, the Fecal occult blood test can be used to diagnose many conditions that cause in bleeding in the gastrointestinal system including Colorectal cancer or Stomach cancer.
# Microbiology tests
Parasitic diseases such as Ascariasis, Hookworm, Strongyloidiasis and Whipworm can be diagnosed by examining stools under a microscope for the presence of worm larvae or eggs. Some bacterial diseases can be detected with a stool culture. Toxins from bacteria such as Clostridium difficile ('C. diff.') can also be identified. Viruses such as rotavirus can also be found in stools.
# Chemical tests
A fecal pH test may be used determine lactose intolerance or the presence of an infection. Steatorrhea can be diagnosed using a Fecal fat test that checks for the malabsorption of fat.
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Stool culture
# Overview
A stool test is one where fecal matter is collected for analysis to diagnose the presence or absence of a medical condition.
# Fecal occult blood test
One of the most common stool tests, the Fecal occult blood test can be used to diagnose many conditions that cause in bleeding in the gastrointestinal system including Colorectal cancer or Stomach cancer.[1]
# Microbiology tests
Parasitic diseases such as Ascariasis, Hookworm, Strongyloidiasis and Whipworm can be diagnosed by examining stools under a microscope for the presence of worm larvae or eggs. Some bacterial diseases can be detected with a stool culture. Toxins from bacteria such as Clostridium difficile ('C. diff.') can also be identified. Viruses such as rotavirus can also be found in stools.[2]
# Chemical tests
A fecal pH test may be used determine lactose intolerance or the presence of an infection.[3] Steatorrhea can be diagnosed using a Fecal fat test that checks for the malabsorption of fat.[4]
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https://www.wikidoc.org/index.php/Stool_culture
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f24a8d54892df087435d02df7d3ac401f4fd66c0
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wikidoc
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Stramenophile
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Stramenophile
The Stramenopile group is a recently recognised informal monophyletic grouping into which a number of microscopic parasitic organisms from the superkingdom Protista and a number of diatoms and brown seaweeds are placed, such as blastocystis hominis, which is the only organism of this group that is potentially pathogenic.
Labyrinthulomycota, Hyphochytriomycota, Phytophthora, Aphanomyces, Bremia, Pernospora and the Oomycetes are also protists that form part of the Stramenopile group. The Stramenopile group (or clade) is a sister group of another multicellular clade which includes Plantae, Animalia and Fungi.
# Notes
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
- ↑ Stanford Blastocystis hominis retrieved June 9 2007
- ↑ Genescope Blastocystis hominis: Whole genome shotgun retrieved June 6 2007
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
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Stramenophile
The Stramenopile group is a recently recognised[1] informal monophyletic grouping into which a number of microscopic parasitic organisms from the superkingdom Protista and a number of diatoms and brown seaweeds are placed, such as blastocystis hominis,[2] which is the only organism of this group that is potentially pathogenic.
Labyrinthulomycota, Hyphochytriomycota, Phytophthora, Aphanomyces, Bremia, Pernospora and the Oomycetes are also protists that form part of the Stramenopile group.[3] The Stramenopile group (or clade) is a sister group of another multicellular clade which includes Plantae, Animalia and Fungi.[4]
# Notes
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
- ↑ Stanford Blastocystis hominis retrieved June 9 2007
- ↑ Genescope Blastocystis hominis: Whole genome shotgun retrieved June 6 2007
- ↑ An all-taxa biodiversity inventory of the Huron Mountain Club retrieved June 6 2007
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https://www.wikidoc.org/index.php/Stramenophile
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ba81928aaa662140c83b6052591a9b18b55e71b8
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wikidoc
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Stretch marks
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Stretch marks
Synonyms and keywords: Striae, striae atrophicae.
# Overview
Stretch marks or striae, as they are called in dermatology, are a form of scarring on the skin with a silvery white hue. They are caused by tearing of the dermis, and over time can diminish but not disappear completely. Stretch marks are the result of the rapid stretching of the skin associated with rapid growth (common in puberty) or weight gain (e.g. pregnancy). Although the skin is fairly elastic, rapid stretching of the skin will leave permanent stretch marks. (Source: WD Writers). Stretch marks are generally associated with pregnancy, obesity, and can develop during rapid muscle growth from steroid use. Stretch marks are also referred to as striae distensae. Medical terminology for these kinds of markings include striae atrophicae, vergetures, striae cutis distensae, striae gravidarum (in cases where it is caused by pregnancy), lineae atrophicae, striae distensae, linea albicante, or simply striae.
# Symptoms and signs
They first appear as reddish or purple lines, but tend to gradually fade to a lighter color. The affected areas appear empty and soft to the touch.
Human skin has three different layers: the epidermis (outer layer), the dermis (middle layer), and the subcutaneous stratum (innermost layer). Stretch marks occur in the dermis, the resilient middle layer that helps the skin retain its shape.
No stretch marks will form as long as there is support within the dermis. Stretching plays more of a role in where the marks occur and in what direction they run. Stretching alone is not the cause.
Stretch marks can appear anywhere on the body, but are most likely to appear in places where larger amounts of fat are stored. Most common places are the abdomen (especially near the belly-button), breasts, upper arms, underarms, thighs (both inner and outer), hips, and buttocks. They pose no health risk in and of themselves, and do not compromise the body's ability to function normally and repair itself.
# Causes
The glucocorticoid hormones responsible for the development of stretch marks affect the epidermis by preventing the fibroblasts from forming collagen and elastin fibers, necessary to keep rapidly growing skin taut. This creates a lack of supportive material, as the skin is stretched and leads to dermal and epidermal tearing. If the epidermis and the dermis has been penetrated, laser will not remove the stretch marks.
# Physical examination
## Gallery
### Head
- url = >
- url = >
- url = >
- url = >
# Prevention and cure
Between 75% and 90% of women develop stretch marks to some degree during pregnancy. The sustained hormonal levels as a result of pregnancy usually means stretch marks may appear during the sixth or seventh month.
Only one randomised controlled study has been published which claimed to test whether oils or creams prevent the development of stretchmarks. This study found a daily application of a cream (Trofolastin) containing Centella asiatica extract, vitamin E, and collagen-elastin hydrolysates was associated with fewer stretch marks during pregnancy. Another study, though lacking a placebo control, examined a cream (Verum) containing vitamin E, panthenol, hyaluronic acid, elastin and menthol. It was associated with fewer stretch marks during pregnancy versus no treatment.
Though cocoa butter is an effective moisturizer, no research studies have shown its ability to either prevent stretchmarks, or improve their appearance once a stretchmark has already formed.
Various treatments are available for the purpose of improving the appearance of existing stretch marks, including laser treatments, dermabrasion, and prescription retinoids. Used daily for one month, they resulted in significant improvement in the appearance of a stretchmark's length, depth, and irregular surface area. Some cream manufacturers claim the best results are achieved on recent stretch marks; however, few studies exist to support these claims.
A recent study in the journal "Dermatologic Surgery" has shown that radiofrequency combined with 585-nm pulsed dye laser treatment gave "good and very good" subjective improvement in stretch marks in 89.2% of 37 patients, although further studies will be required to follow up on these results. In addition, the use of a pulsed dye laser has shown to increase pigmentation in darker skinned individuals with repeated treatments.
A surgical procedure for removing lower abdominal stretch marks is the tummy tuck, which removes the skin below the navel where stretch marks frequently occur.
A new modality, fractional laser resurfacing, offers a novel approach to treating striae. Using scattered pulses of light only a fraction of the scar is zapped by the laser over the course of several treatments. This creates microscopic wounds and as such is a "no downtime" procedure. The body responds to each treatment by producing new collagen and epithelium. In a 2007 clinical trial, 5-6 treatments has resulted in striae improving by as much as 75 percent. A 2007 Brazilian clinical study has shown Fraxel to improve both texture and appearance of mature, white striae in skin types I-IV: "Fractional Photothermolysis for the treatment of Striae Distensae" Otavio Macedo, Consultório Clínico Dr. Otávio Macedo Ltda, Brazil, 2007.
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Stretch marks
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords: Striae, striae atrophicae.
# Overview
Stretch marks or striae, as they are called in dermatology, are a form of scarring on the skin with a silvery white hue. They are caused by tearing of the dermis, and over time can diminish but not disappear completely. Stretch marks are the result of the rapid stretching of the skin associated with rapid growth (common in puberty) or weight gain (e.g. pregnancy). Although the skin is fairly elastic, rapid stretching of the skin will leave permanent stretch marks. (Source: WD Writers). Stretch marks are generally associated with pregnancy, obesity, and can develop during rapid muscle growth from steroid use. Stretch marks are also referred to as striae distensae. Medical terminology for these kinds of markings include striae atrophicae, vergetures, striae cutis distensae, striae gravidarum (in cases where it is caused by pregnancy), lineae atrophicae, striae distensae, linea albicante, or simply striae.
# Symptoms and signs
They first appear as reddish or purple lines, but tend to gradually fade to a lighter color. The affected areas appear empty and soft to the touch.
Human skin has three different layers: the epidermis (outer layer), the dermis (middle layer), and the subcutaneous stratum (innermost layer). Stretch marks occur in the dermis, the resilient middle layer that helps the skin retain its shape.
No stretch marks will form as long as there is support within the dermis. Stretching plays more of a role in where the marks occur and in what direction they run. Stretching alone is not the cause.
Stretch marks can appear anywhere on the body, but are most likely to appear in places where larger amounts of fat are stored. Most common places are the abdomen (especially near the belly-button), breasts, upper arms, underarms, thighs (both inner and outer), hips, and buttocks. They pose no health risk in and of themselves, and do not compromise the body's ability to function normally and repair itself.
# Causes
The glucocorticoid hormones responsible for the development of stretch marks affect the epidermis by preventing the fibroblasts from forming collagen and elastin fibers, necessary to keep rapidly growing skin taut. This creates a lack of supportive material, as the skin is stretched and leads to dermal and epidermal tearing. If the epidermis and the dermis has been penetrated, laser will not remove the stretch marks.
# Physical examination
## Gallery
### Head
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=435>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=435>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=435>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=435>
# Prevention and cure
Between 75% and 90% of women develop stretch marks to some degree during pregnancy. The sustained hormonal levels as a result of pregnancy usually means stretch marks may appear during the sixth or seventh month.
Only one randomised controlled study has been published which claimed to test whether oils or creams prevent the development of stretchmarks. This study found a daily application of a cream (Trofolastin) containing Centella asiatica extract, vitamin E, and collagen-elastin hydrolysates was associated with fewer stretch marks during pregnancy.[1][2] Another study, though lacking a placebo control, examined a cream (Verum) containing vitamin E, panthenol, hyaluronic acid, elastin and menthol. It was associated with fewer stretch marks during pregnancy versus no treatment.[3]
Though cocoa butter is an effective moisturizer, no research studies have shown its ability to either prevent stretchmarks, or improve their appearance once a stretchmark has already formed.
Various treatments are available for the purpose of improving the appearance of existing stretch marks, including laser treatments, dermabrasion, and prescription retinoids. Used daily for one month, they resulted in significant improvement in the appearance of a stretchmark's length, depth, and irregular surface area. Some cream manufacturers claim the best results are achieved on recent stretch marks; however, few studies exist to support these claims.
A recent study in the journal "Dermatologic Surgery" has shown that radiofrequency combined with 585-nm pulsed dye laser treatment gave "good and very good" subjective improvement in stretch marks in 89.2% of 37 patients, although further studies will be required to follow up on these results. In addition, the use of a pulsed dye laser has shown to increase pigmentation in darker skinned individuals with repeated treatments.[4]
A surgical procedure for removing lower abdominal stretch marks is the tummy tuck, which removes the skin below the navel where stretch marks frequently occur.
A new modality, fractional laser resurfacing, offers a novel approach to treating striae. Using scattered pulses of light only a fraction of the scar is zapped by the laser over the course of several treatments. This creates microscopic wounds and as such is a "no downtime" procedure. The body responds to each treatment by producing new collagen and epithelium. In a 2007 clinical trial, 5-6 treatments has resulted in striae improving by as much as 75 percent.[5] A 2007 Brazilian clinical study has shown Fraxel to improve both texture and appearance of mature, white striae in skin types I-IV: "Fractional Photothermolysis for the treatment of Striae Distensae" Otavio Macedo, Consultório Clínico Dr. Otávio Macedo Ltda, Brazil, 2007.
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https://www.wikidoc.org/index.php/Stretch_mark
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59dbae96158d761c07efed2d656c7b9557ffc22c
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wikidoc
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Stroke volume
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Stroke volume
# Overview
Stroke volume is the amount of blood pumped by the left ventricle of the heart in one contraction.
The stroke volume is not all of the blood contained in the left ventricle. The heart does not pump all the blood out of the ventricle. Normally, only about two-thirds of the blood in the ventricle is put out with each beat. What blood is actually pumped from the left ventricle is the stroke volume and it, together with the heart rate, determines the cardiac output.
# Calculation
Its value is obtained by subtracting end-systolic volume (ESV) from end-diastolic volume (EDV) for a given ventricle:
In a healthy 70-kg man, the left ventricular EDV is 120 ml and the corresponding ESV is 50 ml, giving a stroke volume of 70 ml.
# Determinants
Men, on average, have higher stroke volumes than women due to the larger size of their hearts. However, stroke volume depends on several factors such as heart size, contractility, duration of contraction, preload (end-diastolic volume), and afterload.
## Exercise
Prolonged aerobic exercise may also increase stroke volume, which frequently results in a slower heart rate. Reduced heart rate prolongs ventricular diastole (filling), increasing end-diastolic volume, and ultimately allowing more blood to be ejected.
## Preload
Stroke volume is intrinsically controlled by preload (the degree to which the ventricles are stretched prior to contracting). An increase in the volume or speed of venous return will increase preload and, through the Frank-Starling law of the heart, will increase stroke volume. Decreased venous return has the opposite effect, causing a reduction in stroke volume.
## Afterload
Elevated afterload (commonly measured as the aortic pressure during systole) reduces stroke volume. Though not usually affecting stroke volume in healthy individuals, increased afterload will hinder the ventricles in ejecting blood, causing reduced stroke volume. Increased afterload may be found in aortic stenosis and arterial hypertension.
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Stroke volume
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Stroke volume is the amount of blood pumped by the left ventricle of the heart in one contraction.
The stroke volume is not all of the blood contained in the left ventricle. The heart does not pump all the blood out of the ventricle. Normally, only about two-thirds of the blood in the ventricle is put out with each beat. What blood is actually pumped from the left ventricle is the stroke volume and it, together with the heart rate, determines the cardiac output.
# Calculation
Its value is obtained by subtracting end-systolic volume (ESV) from end-diastolic volume (EDV) for a given ventricle:
In a healthy 70-kg man, the left ventricular EDV is 120 ml and the corresponding ESV is 50 ml, giving a stroke volume of 70 ml.
# Determinants
Men, on average, have higher stroke volumes than women due to the larger size of their hearts. However, stroke volume depends on several factors such as heart size, contractility, duration of contraction, preload (end-diastolic volume), and afterload.
## Exercise
Prolonged aerobic exercise may also increase stroke volume, which frequently results in a slower heart rate. Reduced heart rate prolongs ventricular diastole (filling), increasing end-diastolic volume, and ultimately allowing more blood to be ejected.
## Preload
Stroke volume is intrinsically controlled by preload (the degree to which the ventricles are stretched prior to contracting). An increase in the volume or speed of venous return will increase preload and, through the Frank-Starling law of the heart, will increase stroke volume. Decreased venous return has the opposite effect, causing a reduction in stroke volume.
## Afterload
Elevated afterload (commonly measured as the aortic pressure during systole) reduces stroke volume. Though not usually affecting stroke volume in healthy individuals, increased afterload will hinder the ventricles in ejecting blood, causing reduced stroke volume. Increased afterload may be found in aortic stenosis and arterial hypertension.
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https://www.wikidoc.org/index.php/Stroke_volume
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Structuralism
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Structuralism
Structuralism as a term refers to various theories across the humanities, social sciences and economics many of which share the assumption that structural relationships between concepts vary between different cultures/languages and that these relationships can be usefully exposed and explored.
More accurately it could be described as an approach in academic disciplines in general that explores the relationships between fundamental principal elements in language, literature, and other fields upon which some higher mental, linguistic, social, or cultural "structures" and "structural networks" are built. Through these networks meaning is produced within a particular person, system, or culture. This meaning then frames and motivates the actions of individuals and groups. In its most recent manifestation, structuralism as a field of academic interest began around 1958 and peaked in the late 1960s and early 1970s.
# History
Structuralism appeared in academia for the first time in the 19th century and then reappeared in the second half of the 20th century, when it grew to become one of the most popular approaches in academic fields concerned with the analysis of language, culture, and society. The work of Ferdinand de Saussure concerning linguistics is generally considered to be a starting point of 20th century structuralism. The term "structuralism" itself appeared in the works of French anthropologist Claude Lévi-Strauss, and gave rise, in France, to the "structuralist movement," which spurred the work of such thinkers as Michel Foucault, Louis Althusser, the psychoanalyst Jacques Lacan, as well as the structural Marxism of Nicos Poulantzas. Almost all members of this so-called movement denied that they were part of it. Structuralism is closely related to semiotics. Post-structuralism attempted to distinguish itself from the use of the structural method. Deconstruction was an attempt to break with structuralistic thought. Some intellectuals like Julia Kristeva, for example, took structuralism (and Russian formalism) for a starting point to later become prominent post-structuralists. Structuralism has had varying degrees of influence in the social sciences: a great deal in the field of sociology, but hardly any in economics.
# Structuralism in psychology (19th century)
At the turn of the 19th century the founding father of experimental psychology William Wundt tried to confirm experimentally his hypothesis that conscious mental life can be broken down into fundamental elements, which then form more complex mental structures. In this part of the 19th century, researchers were making great advances in chemistry and physics by analysing complex compounds (molecules) in terms of their elements (atoms). These successes encouraged psychologists to look for the mental elements of which more complex experiences were composed. If the chemist made headway by analysing water into oxygen and hydrogen, perhaps the psychologist could make headway by considering a perception, e.g., the taste of lemonade, to be a "molecule" of conscious experience which can be analysed into elements of conscious experience: e.g., sweet, sour, cold, warm, bitter, and whatever else could be identified by trained introspection. A major believer was the psychologist Edward B. Titchener who was trained by Wundt and worked at Cornell University. Since the goal was to specify mental structures, Titchener used the word "structuralism" to describe this branch of psychology. Titchener's structuralism was quickly abandoned because its objects, conscious experiences, are not easily subjected to controlled experimentation in the same way that behavior is. Note that although early texts list Wundt as a structuralist, strictly speaking he was not. The term was coined by Titchener, and Titchener methods and conclusions were not the same as Wundt's. Both functional psychology and behaviorism were reactions to introspective structuralism.
# Structuralism in linguistics
Ferdinand de Saussure was the originator of the 20th century reappearance of structuralism, and evidence of this can be found in Course in General Linguistics, written by Saussure's colleagues after his death and based on student notes, where he focused not on the use of language (parole, or speech), but rather on the underlying system of language (langue) and called his theory semiology. However, the discovery of the underlying system had to be done via examination of the parole (speech). As such, Structural Linguistics are actually an early form of corpus linguistics(quantification). This approach focused on examining how the elements of language related to each other in the present, that is, 'synchronically' rather than 'diachronically'. Finally, he argued that linguistic signs were composed of two parts, a signifier (the sound pattern of a word, either in mental projection - as when we silently recite lines from a poem to ourselves - or in actual, physical realization as part of a speech act) and a signified (the concept or meaning of the word). This was quite different from previous approaches which focused on the relationship between words and things in the world that they designate.
Key notions in Structural Linguistics are the notions of paradigm, syntagm and value, though these notions were not yet fully developed in De Saussure's thought. A structural paradigm is actually a class of linguistic units (lexemes, morphemes or even constructions) which are possible in a certain position in a given linguistic environment (like a given sentence), which is the syntagm. The different functional role of each of these members of the paradigm is called value (valeur in French).
Saussure's Course influenced many linguists between World War I and WWII. In America, for instance, Leonard Bloomfield developed his own version of structural linguistics, as did Louis Hjelmslev in Denmark and Alf Sommerfelt in Norway. In France Antoine Meillet and Émile Benveniste would continue Saussure's program. Most importantly, however, members of the Prague School of linguistics such as Roman Jakobson and Nikolai Trubetzkoy conducted research that would be greatly influential.
The clearest and most important example of Prague School structuralism lies in phonemics. Rather than simply compile a list of which sounds occur in a language, the Prague School sought to examine how they were related. They determined that the inventory of sounds in a language could be analyzed in terms of a series of contrasts. Thus in English the sounds /p/ and /b/ represent distinct phonemes because there are cases (minimal pairs) where the contrast between the two is the only difference between two distinct words (e.g. 'pat' and 'bat'). Analyzing sounds in terms of contrastive features also opens up comparative scope - it makes clear, for instance, that the difficulty Japanese speakers have differentiating /r/ and /l/ in English is because these sounds are not contrastive in Japanese. While this approach is now standard in linguistics, it was revolutionary at the time. Phonology would become the paradigmatic basis for structuralism in a number of different forms.
# Structuralism in anthropology and sociology
See the main articles at structural anthropology and structural functionalism
According to structural theory in anthropology and social anthropology, meaning is produced and reproduced within a culture through various practices, phenomena and activities which serve as systems of signification. A structuralist studies activities as diverse as food preparation and serving rituals, religious rites, games, literary and non-literary texts, and other forms of entertainment to discover the deep structures by which meaning is produced and reproduced within a culture. For example, an early and prominent practitioner of structuralism, anthropologist and ethnographer Claude Lévi-Strauss in the 1950s, analyzed cultural phenomena including mythology, kinship (the Alliance theory and the incest taboo), and food preparation (see also structural anthropology). In addition to these studies, he produced more linguistically-focused writings where he applied Saussure's distinction between langue and parole in his search for the fundamental mental structures of the human mind, arguing that the structures that form the "deep grammar" of society originate in the mind and operate in us unconsciously. Levi-Strauss was inspired by information theory and mathematics.
Another concept was borrowed from the Prague school of linguistics, where Roman Jakobson and others analysed sounds based on the presence or absence of certain features (such as voiceless vs. voiced). Levi-Strauss included this in his conceptualization of the universal structures of the mind, which he held to operate based on pairs of binary oppositions such as hot-cold, male-female, culture-nature, cooked-raw, or marriageable vs. tabooed women. A third influence came from Marcel Mauss, who had written on gift exchange systems. Based on Mauss, for instance, Lévi-Strauss argued that kinship systems are based on the exchange of women between groups (a position known as 'alliance theory') as opposed to the 'descent' based theory described by Edward Evans-Pritchard and Meyer Fortes.
While replacing Marcel Mauss at his Ecole Pratique des Hautes Etudes chair, Lévi-Strauss' writing became widely popular in the 1960s and 1970s and gave rise to the term "structuralism" itself. In Britain authors such as Rodney Needham and Edmund Leach were highly influenced by structuralism. Authors such as Maurice Godelier and Emmanuel Terray combined Marxism with structural anthropology in France. In the United States, authors such as Marshall Sahlins and James Boon built on structuralism to provide their own analysis of human society. Structural anthropology fell out of favour in the early 1980s for a number of reasons. D'Andrade (1995) suggests that structuralism in anthropology was eventually abandoned because it made unverifiable assumptions about the universal structures of the human mind. Authors such as Eric Wolf argued that political economy and colonialism should be more at the forefront of anthropology. More generally, criticisms of structuralism by Pierre Bourdieu led to a concern with how cultural and social structures were changed by human agency and practice, a trend which Sherry Ortner has referred to as 'practice theory'.
Some anthropological theorists, however, while finding considerable fault with Lévi-Strauss's version of structuralism, did not turn away from a fundamental structural basis for human culture. The Biogenetic Structuralism group for instance argued that some kind of structural foundation for culture must exist because all humans inherit the same system of brain structures. They proposed a kind of Neuroanthropology which would lay the foundations for a more complete scientific account of cultural similarity and variation by requiring an integration of cultural anthropology and neuroscience--a program also embraced by such theorists as Victor Turner.
# Structuralism in the philosophy of mathematics
Structuralism in mathematics is the study of what structures (mathematical objects) are, and how the ontology of these structures should be understood. This is a growing philosophy within mathematics that is not without its share of critics.
Paul Benacerraf's paper "What Numbers Could Not Be" (1965) is of seminal importance to mathematical structuralism in a perverse way: it inspired critique upon which the movement was born. Benacerraf addressed a notion in mathematics to treat mathematical statements at face value, in which case we are committed to an abstract, eternal realm of mathematical objects. Benacerraf's dilemma is how we come to know these objects if we do not stand in causal relation to them. These objects are considered causally inert to the world. Another problem raised by Benacerraf is the multiple set theories that exist by which reduction of elementary number theory to sets is possible. Deciding which set theory is true has not been feasible. Benacerraf concluded in 1965 that numbers are not objects, a conclusion responded to by Mark Balaguer with the introduction of full blooded Platonism (this is essentially the view that all logically possible mathematical objects do exist). With this full blooded Platonism, it does not matter which set-theoretic construction of mathematics is used, nor how we came to know of its existence, since any consistent mathematical theory necessarily exists and is a part of the greater platonic realm.
The answer to Benacerraf's negative claims is how structuralism became a viable philosophical program within mathematics. The structuralist responds to these negative claims that the essence of mathematical objects is relations that the objects bear with the structure.
Important contributions to structuralism in mathematics have been made by Nicolas Bourbaki, and also by the genetic epistemologist, Jean Piaget who, in collaboration with the mathematician, E.W. Beth, developed the notion of "mother structures" from which all mathematical formations are considered transformations.
# Structuralism in literary theory and literary criticism
In literary theory, structuralism is an approach to analyzing the narrative material by examining the underlying invariant structure. For example, a literary critic applying a structuralist literary theory might say that the authors of the West Side Story did not write anything "really" new, because their work has the same structure as Shakespeare's Romeo and Juliet. In both texts a girl and a boy fall in love (a "formula" with a symbolic operator between them would be "Boy + Girl") despite the fact that they belong to two groups that hate each other ("Boy's Group - Girl's Group" or "Opposing forces") and conflict is resolved by their death.
The versatility of structuralism is such that a literary critic could make the same claim about a story of two friendly families ("Boy's Family + Girl's Family") that arrange a marriage between their children despite the fact that the children hate each other ("Boy - Girl") and then the children commit suicide to escape the arranged marriage; the justification is that the second story's structure is an 'inversion' of the first story's structure: the relationship between the values of love and the two pairs of parties involved have been reversed.
Structuralistic literary criticism argues that the "novelty value of a literary text" can lie only in new structure, rather than in the specifics of character development and voice in which that structure is expressed. One branch of literary structuralism, like Freudianism, Marxism, and transformational grammar, posits both a deep and a surface structure. In Freudianism and Marxism the deep structure is a story, in Freud's case the battle, ultimately, between the life and death instincts, and in Marx, the conflicts between classes that are rooted in the economic "base."
Literary structuralism often follows the lead of Vladimir Propp and Claude Levi-Strauss in seeking out basic deep elements in stories and myths, which are combined in various ways to produce the many versions of the ur-story or ur-myth. As in Freud and Marx, but in contrast to transformational grammar, these basic elements are meaning-bearing.
There is considerable similarity between structural literary theory and Northrop Frye's archetypal criticism, which is also indebted to the anthropological study of myths. Some critics have also tried to apply the theory to individual works, but the effort to find unique structures in individual literary works runs counter to the structuralist program and has an affinity with New Criticism.
The other branch of literary structuralism is semiotics, and it is based on the work of Ferdinand de Saussure.
# Structuralism after World War II
Throughout the 1940s and 1950s, existentialism like that propounded by Jean-Paul Sartre was the dominant mood. Structuralism surged to prominence in France after WWII and particularly in the 1960s. The initial popularity of structuralism in France led it to spread across the globe. The social sciences (in particular, sociology) were particularly influenced.
Structuralism rejected the concept of human freedom and choice and focused instead on the way that human behavior is determined by various structures. The most important initial work on this score was Claude Lévi-Strauss's 1949 volume Elementary Structures of Kinship. Lévi-Strauss had known Jakobson during their time together in New York during WWII and was influenced by both Jakobson's structuralism as well as the American anthropological tradition. In Elementary Structures he examined kinship systems from a structural point of view and demonstrated how apparently different social organizations were in fact different permutations of a few basic kinship structures. In the late 1950s he published Structural Anthropology, a collection of essays outlining his program for structuralism.
By the early 1960s structuralism as a movement was coming into its own and some believed that it offered a single unified approach to human life that would embrace all disciplines. Roland Barthes and Jacques Derrida focused on how structuralism could be applied to literature.
Blending Freud and De Saussure, the French (post)structuralist Jacques Lacan applied structuralism to psychoanalysis and, in a different way, Jean Piaget applied structuralism to the study of psychology. But Jean Piaget, who would better defines himself as constructivist, considers structuralism as "a method and not a doctrin" because for him "there exists no structure without a construction, abstract or genetic"
Michel Foucault's book The Order of Things examined the history of science to study how structures of epistemology, or episteme, shaped the way in which people imagined knowledge and knowing (though Foucault would later explicitly deny affiliation with the structuralist movement).
In much the same way, American historian of science Thomas Kuhn addressed the structural formations of science in his seminal work The Structure of Scientific Revolutions - its title alone evincing a stringent structuralist approach. Though less concerned with "episteme," Kuhn nonetheless remarked at how coteries of scientists operated under and applied a standard praxis of 'normal science,' deviating from a standard 'paradigm' only in instances of irreconcilable anomalies that question a significant body of their work.
Blending Marx and structuralism another French theorist Louis Althusser introduced his own brand of structural social analysis, giving rise to "structural Marxism". Other authors in France and abroad have since extended structural analysis to practically every discipline.
The definition of 'structuralism' also shifted as a result of its popularity. As its popularity as a movement waxed and waned, some authors considered themselves 'structuralists' only to later eschew the label.
The term has slightly different meanings in French and English. In the US, for instance, Derrida is considered the paradigm of post-structuralism while in France he is labeled a structuralist. Finally, some authors wrote in several different styles. Barthes, for instance, wrote some books which are clearly structuralist and others which clearly are not.
# Reactions to structuralism
Today structuralism is less popular than approaches such as post-structuralism and deconstruction. There are many reasons for this. Structuralism has often been criticized for being ahistorical and for favoring deterministic structural forces over the ability of individual people to act. As the political turbulence of the 1960s and 1970s (and particularly the student uprisings of May 1968) began affecting academia, issues of power and political struggle moved to the center of people's attention. The ethnologist Robert Jaulin defined another ethnological method which clearly pitted itself against structuralism.
In the 1980s, deconstruction and its emphasis on the fundamental ambiguity of language--rather than its crystalline logical structure--became popular. By the end of the century structuralism was seen as a historically important school of thought, but it was the movements it spawned, rather than structuralism itself, which commanded attention.
# Notes
- ↑ Atkinson, R.L. (1990). Introduction to Psychology, 10th Edition. Harcourt Brace Jovanovich..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jean Piaget, Le structuralisme, ed. PUF, 1968
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Structuralism
Structuralism as a term refers to various theories across the humanities, social sciences and economics many of which share the assumption that structural relationships between concepts vary between different cultures/languages and that these relationships can be usefully exposed and explored.
More accurately it could be described as an approach in academic disciplines in general that explores the relationships between fundamental principal elements in language, literature, and other fields upon which some higher mental, linguistic, social, or cultural "structures" and "structural networks" are built. Through these networks meaning is produced within a particular person, system, or culture. This meaning then frames and motivates the actions of individuals and groups. In its most recent manifestation, structuralism as a field of academic interest began around 1958 and peaked in the late 1960s and early 1970s.
# History
Structuralism appeared in academia for the first time in the 19th century and then reappeared in the second half of the 20th century, when it grew to become one of the most popular approaches in academic fields concerned with the analysis of language, culture, and society. The work of Ferdinand de Saussure concerning linguistics is generally considered to be a starting point of 20th century structuralism. The term "structuralism" itself appeared in the works of French anthropologist Claude Lévi-Strauss, and gave rise, in France, to the "structuralist movement," which spurred the work of such thinkers as Michel Foucault, Louis Althusser, the psychoanalyst Jacques Lacan, as well as the structural Marxism of Nicos Poulantzas. Almost all members of this so-called movement denied that they were part of it. Structuralism is closely related to semiotics. Post-structuralism attempted to distinguish itself from the use of the structural method. Deconstruction was an attempt to break with structuralistic thought. Some intellectuals like Julia Kristeva, for example, took structuralism (and Russian formalism) for a starting point to later become prominent post-structuralists. Structuralism has had varying degrees of influence in the social sciences: a great deal in the field of sociology, but hardly any in economics.
# Structuralism in psychology (19th century)
At the turn of the 19th century the founding father of experimental psychology William Wundt tried to confirm experimentally his hypothesis that conscious mental life can be broken down into fundamental elements, which then form more complex mental structures. In this part of the 19th century, researchers were making great advances in chemistry and physics by analysing complex compounds (molecules) in terms of their elements (atoms). These successes encouraged psychologists to look for the mental elements of which more complex experiences were composed. If the chemist made headway by analysing water into oxygen and hydrogen, perhaps the psychologist could make headway by considering a perception, e.g., the taste of lemonade, to be a "molecule" of conscious experience which can be analysed into elements of conscious experience: e.g., sweet, sour, cold, warm, bitter, and whatever else could be identified by trained introspection. A major believer was the psychologist Edward B. Titchener who was trained by Wundt and worked at Cornell University. Since the goal was to specify mental structures, Titchener used the word "structuralism" to describe this branch of psychology.[1] Titchener's structuralism was quickly abandoned because its objects, conscious experiences, are not easily subjected to controlled experimentation in the same way that behavior is. Note that although early texts list Wundt as a structuralist, strictly speaking he was not. The term was coined by Titchener, and Titchener methods and conclusions were not the same as Wundt's. Both functional psychology and behaviorism were reactions to introspective structuralism.
# Structuralism in linguistics
Ferdinand de Saussure was the originator of the 20th century reappearance of structuralism, and evidence of this can be found in Course in General Linguistics, written by Saussure's colleagues after his death and based on student notes, where he focused not on the use of language (parole, or speech), but rather on the underlying system of language (langue) and called his theory semiology. However, the discovery of the underlying system had to be done via examination of the parole (speech). As such, Structural Linguistics are actually an early form of corpus linguistics(quantification). This approach focused on examining how the elements of language related to each other in the present, that is, 'synchronically' rather than 'diachronically'. Finally, he argued that linguistic signs were composed of two parts, a signifier (the sound pattern of a word, either in mental projection - as when we silently recite lines from a poem to ourselves - or in actual, physical realization as part of a speech act) and a signified (the concept or meaning of the word). This was quite different from previous approaches which focused on the relationship between words and things in the world that they designate.
Key notions in Structural Linguistics are the notions of paradigm, syntagm and value, though these notions were not yet fully developed in De Saussure's thought. A structural paradigm is actually a class of linguistic units (lexemes, morphemes or even constructions) which are possible in a certain position in a given linguistic environment (like a given sentence), which is the syntagm. The different functional role of each of these members of the paradigm is called value (valeur in French).
Saussure's Course influenced many linguists between World War I and WWII. In America, for instance, Leonard Bloomfield developed his own version of structural linguistics, as did Louis Hjelmslev in Denmark and Alf Sommerfelt in Norway. In France Antoine Meillet and Émile Benveniste would continue Saussure's program. Most importantly, however, members of the Prague School of linguistics such as Roman Jakobson and Nikolai Trubetzkoy conducted research that would be greatly influential.
The clearest and most important example of Prague School structuralism lies in phonemics. Rather than simply compile a list of which sounds occur in a language, the Prague School sought to examine how they were related. They determined that the inventory of sounds in a language could be analyzed in terms of a series of contrasts. Thus in English the sounds /p/ and /b/ represent distinct phonemes because there are cases (minimal pairs) where the contrast between the two is the only difference between two distinct words (e.g. 'pat' and 'bat'). Analyzing sounds in terms of contrastive features also opens up comparative scope - it makes clear, for instance, that the difficulty Japanese speakers have differentiating /r/ and /l/ in English is because these sounds are not contrastive in Japanese. While this approach is now standard in linguistics, it was revolutionary at the time. Phonology would become the paradigmatic basis for structuralism in a number of different forms.
# Structuralism in anthropology and sociology
See the main articles at structural anthropology and structural functionalism
According to structural theory in anthropology and social anthropology, meaning is produced and reproduced within a culture through various practices, phenomena and activities which serve as systems of signification. A structuralist studies activities as diverse as food preparation and serving rituals, religious rites, games, literary and non-literary texts, and other forms of entertainment to discover the deep structures by which meaning is produced and reproduced within a culture. For example, an early and prominent practitioner of structuralism, anthropologist and ethnographer Claude Lévi-Strauss in the 1950s, analyzed cultural phenomena including mythology, kinship (the Alliance theory and the incest taboo), and food preparation (see also structural anthropology). In addition to these studies, he produced more linguistically-focused writings where he applied Saussure's distinction between langue and parole in his search for the fundamental mental structures of the human mind, arguing that the structures that form the "deep grammar" of society originate in the mind and operate in us unconsciously. Levi-Strauss was inspired by information theory and mathematics.
Another concept was borrowed from the Prague school of linguistics, where Roman Jakobson and others analysed sounds based on the presence or absence of certain features (such as voiceless vs. voiced). Levi-Strauss included this in his conceptualization of the universal structures of the mind, which he held to operate based on pairs of binary oppositions such as hot-cold, male-female, culture-nature, cooked-raw, or marriageable vs. tabooed women. A third influence came from Marcel Mauss, who had written on gift exchange systems. Based on Mauss, for instance, Lévi-Strauss argued that kinship systems are based on the exchange of women between groups (a position known as 'alliance theory') as opposed to the 'descent' based theory described by Edward Evans-Pritchard and Meyer Fortes.
While replacing Marcel Mauss at his Ecole Pratique des Hautes Etudes chair, Lévi-Strauss' writing became widely popular in the 1960s and 1970s and gave rise to the term "structuralism" itself. In Britain authors such as Rodney Needham and Edmund Leach were highly influenced by structuralism. Authors such as Maurice Godelier and Emmanuel Terray combined Marxism with structural anthropology in France. In the United States, authors such as Marshall Sahlins and James Boon built on structuralism to provide their own analysis of human society. Structural anthropology fell out of favour in the early 1980s for a number of reasons. D'Andrade (1995) suggests that structuralism in anthropology was eventually abandoned because it made unverifiable assumptions about the universal structures of the human mind. Authors such as Eric Wolf argued that political economy and colonialism should be more at the forefront of anthropology. More generally, criticisms of structuralism by Pierre Bourdieu led to a concern with how cultural and social structures were changed by human agency and practice, a trend which Sherry Ortner has referred to as 'practice theory'.
Some anthropological theorists, however, while finding considerable fault with Lévi-Strauss's version of structuralism, did not turn away from a fundamental structural basis for human culture. The Biogenetic Structuralism group for instance argued that some kind of structural foundation for culture must exist because all humans inherit the same system of brain structures. They proposed a kind of Neuroanthropology which would lay the foundations for a more complete scientific account of cultural similarity and variation by requiring an integration of cultural anthropology and neuroscience--a program also embraced by such theorists as Victor Turner.
# Structuralism in the philosophy of mathematics
Structuralism in mathematics is the study of what structures (mathematical objects) are, and how the ontology of these structures should be understood. This is a growing philosophy within mathematics that is not without its share of critics.
Paul Benacerraf's paper "What Numbers Could Not Be" (1965) is of seminal importance to mathematical structuralism in a perverse way: it inspired critique upon which the movement was born. Benacerraf addressed a notion in mathematics to treat mathematical statements at face value, in which case we are committed to an abstract, eternal realm of mathematical objects. Benacerraf's dilemma is how we come to know these objects if we do not stand in causal relation to them. These objects are considered causally inert to the world. Another problem raised by Benacerraf is the multiple set theories that exist by which reduction of elementary number theory to sets is possible. Deciding which set theory is true has not been feasible. Benacerraf concluded in 1965 that numbers are not objects, a conclusion responded to by Mark Balaguer with the introduction of full blooded Platonism (this is essentially the view that all logically possible mathematical objects do exist). With this full blooded Platonism, it does not matter which set-theoretic construction of mathematics is used, nor how we came to know of its existence, since any consistent mathematical theory necessarily exists and is a part of the greater platonic realm.
The answer to Benacerraf's negative claims is how structuralism became a viable philosophical program within mathematics. The structuralist responds to these negative claims that the essence of mathematical objects is relations that the objects bear with the structure.
Important contributions to structuralism in mathematics have been made by Nicolas Bourbaki, and also by the genetic epistemologist, Jean Piaget who, in collaboration with the mathematician, E.W. Beth, developed the notion of "mother structures" from which all mathematical formations are considered transformations.
# Structuralism in literary theory and literary criticism
In literary theory, structuralism is an approach to analyzing the narrative material by examining the underlying invariant structure. For example, a literary critic applying a structuralist literary theory might say that the authors of the West Side Story did not write anything "really" new, because their work has the same structure as Shakespeare's Romeo and Juliet. In both texts a girl and a boy fall in love (a "formula" with a symbolic operator between them would be "Boy + Girl") despite the fact that they belong to two groups that hate each other ("Boy's Group - Girl's Group" or "Opposing forces") and conflict is resolved by their death.
The versatility of structuralism is such that a literary critic could make the same claim about a story of two friendly families ("Boy's Family + Girl's Family") that arrange a marriage between their children despite the fact that the children hate each other ("Boy - Girl") and then the children commit suicide to escape the arranged marriage; the justification is that the second story's structure is an 'inversion' of the first story's structure: the relationship between the values of love and the two pairs of parties involved have been reversed.
Structuralistic literary criticism argues that the "novelty value of a literary text" can lie only in new structure, rather than in the specifics of character development and voice in which that structure is expressed. One branch of literary structuralism, like Freudianism, Marxism, and transformational grammar, posits both a deep and a surface structure. In Freudianism and Marxism the deep structure is a story, in Freud's case the battle, ultimately, between the life and death instincts, and in Marx, the conflicts between classes that are rooted in the economic "base."
Literary structuralism often follows the lead of Vladimir Propp and Claude Levi-Strauss in seeking out basic deep elements in stories and myths, which are combined in various ways to produce the many versions of the ur-story or ur-myth. As in Freud and Marx, but in contrast to transformational grammar, these basic elements are meaning-bearing.
There is considerable similarity between structural literary theory and Northrop Frye's archetypal criticism, which is also indebted to the anthropological study of myths. Some critics have also tried to apply the theory to individual works, but the effort to find unique structures in individual literary works runs counter to the structuralist program and has an affinity with New Criticism.
The other branch of literary structuralism is semiotics, and it is based on the work of Ferdinand de Saussure.
# Structuralism after World War II
Throughout the 1940s and 1950s, existentialism like that propounded by Jean-Paul Sartre was the dominant mood. Structuralism surged to prominence in France after WWII and particularly in the 1960s. The initial popularity of structuralism in France led it to spread across the globe. The social sciences (in particular, sociology) were particularly influenced.
Structuralism rejected the concept of human freedom and choice and focused instead on the way that human behavior is determined by various structures. The most important initial work on this score was Claude Lévi-Strauss's 1949 volume Elementary Structures of Kinship. Lévi-Strauss had known Jakobson during their time together in New York during WWII and was influenced by both Jakobson's structuralism as well as the American anthropological tradition. In Elementary Structures he examined kinship systems from a structural point of view and demonstrated how apparently different social organizations were in fact different permutations of a few basic kinship structures. In the late 1950s he published Structural Anthropology, a collection of essays outlining his program for structuralism.
By the early 1960s structuralism as a movement was coming into its own and some believed that it offered a single unified approach to human life that would embrace all disciplines. Roland Barthes and Jacques Derrida focused on how structuralism could be applied to literature.
Blending Freud and De Saussure, the French (post)structuralist Jacques Lacan applied structuralism to psychoanalysis and, in a different way, Jean Piaget applied structuralism to the study of psychology. But Jean Piaget, who would better defines himself as constructivist, considers structuralism as "a method and not a doctrin" because for him "there exists no structure without a construction, abstract or genetic"[2]
Michel Foucault's book The Order of Things examined the history of science to study how structures of epistemology, or episteme, shaped the way in which people imagined knowledge and knowing (though Foucault would later explicitly deny affiliation with the structuralist movement).
In much the same way, American historian of science Thomas Kuhn addressed the structural formations of science in his seminal work The Structure of Scientific Revolutions - its title alone evincing a stringent structuralist approach. Though less concerned with "episteme," Kuhn nonetheless remarked at how coteries of scientists operated under and applied a standard praxis of 'normal science,' deviating from a standard 'paradigm' only in instances of irreconcilable anomalies that question a significant body of their work.
Blending Marx and structuralism another French theorist Louis Althusser introduced his own brand of structural social analysis, giving rise to "structural Marxism". Other authors in France and abroad have since extended structural analysis to practically every discipline.
The definition of 'structuralism' also shifted as a result of its popularity. As its popularity as a movement waxed and waned, some authors considered themselves 'structuralists' only to later eschew the label.
The term has slightly different meanings in French and English. In the US, for instance, Derrida is considered the paradigm of post-structuralism while in France he is labeled a structuralist. Finally, some authors wrote in several different styles. Barthes, for instance, wrote some books which are clearly structuralist and others which clearly are not.
# Reactions to structuralism
Today structuralism is less popular than approaches such as post-structuralism and deconstruction. There are many reasons for this. Structuralism has often been criticized for being ahistorical and for favoring deterministic structural forces over the ability of individual people to act. As the political turbulence of the 1960s and 1970s (and particularly the student uprisings of May 1968) began affecting academia, issues of power and political struggle moved to the center of people's attention. The ethnologist Robert Jaulin defined another ethnological method which clearly pitted itself against structuralism.
In the 1980s, deconstruction and its emphasis on the fundamental ambiguity of language--rather than its crystalline logical structure--became popular. By the end of the century structuralism was seen as a historically important school of thought, but it was the movements it spawned, rather than structuralism itself, which commanded attention.
# Notes
- ↑ Atkinson, R.L. (1990). Introduction to Psychology, 10th Edition. Harcourt Brace Jovanovich..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jean Piaget, Le structuralisme, ed. PUF, 1968
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https://www.wikidoc.org/index.php/Structuralism
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b03fe086adfa124d8784c1933187c96c7fca9db3
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wikidoc
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Styphnolobium
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Styphnolobium
Styphnolobium is a small genus of three or four species of small trees and shrubs in the subfamily Faboideae of the pea family Fabaceae, formerly included within a broader interpretation of the genus Sophora. The species of Styphnolobium differ from Sophora in lacking the ability to form symbioses with rhizobia (nitrogen fixing bacteria) on their roots. They also differ from the related genus Calia (mescalbeans) in having deciduous leaves and flowers in axillary, not terminal, racemes. The leaves are pinnate, with 9-21 leaflets, and the flowers in pendulous racemes similar to those of the Black locust.
# Species
- Styphnolobium affine (Torr. & A. Gray) Walp., the Coralbean or Eve's Necklace (syn. Sophora affinis) is native to the southern United States in Texas, Oklahoma, Arkansas and Louisiana. It is a large shrub or small tree, growing to 5-7 m tall, with white or pale violet flowers.
- Styphnolobium japonicum (L.) Schott, the Pagoda Tree (Chinese Scholar, Japanese pagodatree; syn. Sophora japonica), is native to eastern Asia (mainly China; despite the name, it is introduced in Japan), is a popular ornamental tree in Europe, North America and South Africa, grown for its white flowers, borne in late summer after most other flowering trees have long finished flowering. It grows into a lofty tree 10-20 m tall with an equal spread, and produces a fine, dark brown timber.
- Styphnolobium monteviridis is native to Central America.
# Uses
The Pagoda Tree is widely used in bonsai gardening. The Guilty Chinese Scholartree was a historic Pagoda Tree in Beijing, on which the last emperor of the Ming Dynasty, Chongzhen, hanged himself.
S. japonicum (Chinese: 槐; pinyin: huái; formerly Sophora japonica) is one of the 50 fundamental herbs used in traditional Chinese medicine.
|
Styphnolobium
Styphnolobium is a small genus of three or four species of small trees and shrubs in the subfamily Faboideae of the pea family Fabaceae, formerly included within a broader interpretation of the genus Sophora. The species of Styphnolobium differ from Sophora in lacking the ability to form symbioses with rhizobia (nitrogen fixing bacteria) on their roots. They also differ from the related genus Calia (mescalbeans) in having deciduous leaves and flowers in axillary, not terminal, racemes. The leaves are pinnate, with 9-21 leaflets, and the flowers in pendulous racemes similar to those of the Black locust.
# Species
- Styphnolobium affine (Torr. & A. Gray) Walp., the Coralbean or Eve's Necklace (syn. Sophora affinis) is native to the southern United States in Texas, Oklahoma, Arkansas and Louisiana. It is a large shrub or small tree, growing to 5-7 m tall, with white or pale violet flowers.
- Styphnolobium japonicum (L.) Schott, the Pagoda Tree (Chinese Scholar, Japanese pagodatree; syn. Sophora japonica), is native to eastern Asia (mainly China; despite the name, it is introduced in Japan), is a popular ornamental tree in Europe, North America and South Africa, grown for its white flowers, borne in late summer after most other flowering trees have long finished flowering. It grows into a lofty tree 10-20 m tall with an equal spread, and produces a fine, dark brown timber.
- Styphnolobium monteviridis is native to Central America.
# Uses
The Pagoda Tree is widely used in bonsai gardening. The Guilty Chinese Scholartree was a historic Pagoda Tree in Beijing, on which the last emperor of the Ming Dynasty, Chongzhen, hanged himself.
S. japonicum (Chinese: 槐; pinyin: huái; formerly Sophora japonica) is one of the 50 fundamental herbs used in traditional Chinese medicine.
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https://www.wikidoc.org/index.php/Styphnolobium
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fe50cda0bc1e22613822858d041191b8a160d788
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wikidoc
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Subependymoma
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Subependymoma
# Historical Perspective
Subependymoma was first discovered by Ilya Mark Scheinker, a Russian physician, in 1945.
# Classification
There is no established system for the classification of subependymoma.
# Pathophysiology
## Pathogenesis
Subependymoma arises from subependymal glial cells, although it can also arise from astrocytes from the subependymal plate, ependymal cells, and mixed ependymal and astrocytic cells.
## Gross Pathology
Subependymoma is most commonly seen in the fourth ventricle, but it can arise anywhere where there is ependyma. The distribution in the ventricular system is as follows:
- Fourth ventricle: 50 - 60%
- Lateral ventricles (usually frontal horns): 30 - 40%
- Third ventricle: rare
- Central canal of the spinal cord: rare
- On gross pathology, subependymoma is characterized by a small, white to grey, firm, well circumscribed, solid, avascular mass attached to the ventricular wall by a narrow pedicle.
## Microscopic Pathology
On microscopic histopathological analysis, subependymoma is characterized by the following features:
- Microcystic spaces and bland appearing cells without appreciable nuclear atypia or mitoses.
- The nuclei tend to form clusters.
- No high grade features (mitoses, Ki-67 / MIBI index > 1.5%, necrosis) are present.
- Loose pseudorosettes are observed.
## Immunohistochemistry
Subependymoma is characterized by positive tumor marker GFAP. Mixed populations of cells may be variably positive for:
- Olig2
- NHERF1
- Sox2
- CD44
# Causes
The cause of the development of subependymoma has not been identified.
# Differentiating Subependymoma from Other Diseases
Subependymoma must be differentiated from:
- Neoplasms of the ventricular wall and septum pellucidum
Ependymoma
Central neurocytoma
Subependymal giant cell astrocytoma
- Ependymoma
- Central neurocytoma
- Subependymal giant cell astrocytoma
- Neoplasms of the choroid plexus
Choroid plexus papilloma and carcinoma
- Choroid plexus papilloma and carcinoma
- Others
Intraventricular meningioma
Intraventricular metastasis
Oligodendroglioma
Pilocytic astrocytoma
Glioblastoma multiforme
Medulloblastoma
Intraventricular teratoma
- Intraventricular meningioma
- Intraventricular metastasis
- Oligodendroglioma
- Pilocytic astrocytoma
- Glioblastoma multiforme
- Medulloblastoma
- Intraventricular teratoma
# Epidemiology and Demographics
## Frequency and Incidence
- The frequency of asymptomatic subependymomas was 0.4% in 1,000 serial routine necropsies and 0.7% in symptomatic subependymomas from 1,000 serial surgical specimens of intracranial neoplasms.
- The incidence of subependymoma was estimated to be 0.7 cases per 100,000 individuals with pathologically proven intracranial neoplasms.
## Age
- Patients of all age groups may develop subependymoma.
- Subependymoma is a rare disease that tends to affect middle-aged adults and the elderly population (typically in the 5th to 6th decades).
## Gender
- Males are more commonly affected with subependymoma than females.
- The male to female ratio is approximately 2.3 to 1.
# Risk Factors
The risk factors in the development of subependymoma are not well defined.
# Natural History, Complications, and Prognosis
- If left untreated, patients with subependymoma may progress to develop seizures and obstructive hydrocephalus.
- Subependymoma is a slow-growing tumor with an indolent course.
- Obstructive hydrocephalus is a common complication of subependymoma.
- The prognosis of subependymoma is excellent with complete excision of the tumor.
- Common complications of subependymoma are hydrocephalus and focal neurological deficits due to mass effect.
# Diagnosis
## Symptoms
- Typically patients of subependymoma are asymptomatic and small lesions are discovered incidentally.
- Symptoms of subependymoma include:
Symptoms due to elevated intracranial pressure
Headache
Nausea
Vomiting
Neurological symptoms
Seizures
Sudden loss of awareness
Transient loss of memory
- Symptoms due to elevated intracranial pressure
Headache
Nausea
Vomiting
- Headache
- Nausea
- Vomiting
- Neurological symptoms
Seizures
Sudden loss of awareness
Transient loss of memory
- Seizures
- Sudden loss of awareness
- Transient loss of memory
## Physical Examination
- Patients with subependymoma usually appear normal.
- Physical examination may be remarkable for:
- Abnormal pupillary reflex
- Visual field defects
- Gait changes
- Bilateral Babinski sign
- Depressed Glasgow coma score (GCS)
- Decreased muscle strength
- Decreased deep tendon reflexes
- Sensation defects
- Hearing problems and abnormal Rinne and Weber tests
## Laboratory Findings
There are no specific laboratory findings associated with subependymoma.
## Electrocardiogram
There are no ECG findings associated with subependymoma.
## X-ray
There are no x-ray findings associated with subependymoma.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with sybependymoma.
## CT scan
Head CT scan is helpful in the diagnosis of subependymoma. On CT scan, subependymoma is characterized by:
- Iso- and hypodense intraventricular mass
- Positive mass effect
- No enhancement
- If large, it may have cystic or even calcific components
- No vasogenic edema
## MRI
Brain MRI is helpful in the diagnosis of subependymoma. On MRI, subependymoma is characterized by:
## Other Imaging Findings
There are no other imaging findings associated with subependymoma.
## Other Diagnostic Studies
There are no other diagnostic studies associated with subependymoma.
## Medical Therapy
There is no medical therapy available for the treatment of subependymoma.
## Surgery
Surgery is the mainstay of therapy for subependymoma. Incidental intraventricular subependymoma can be managed conservatively through MRI surveillance. Surgical resection is indicated for:
- Symptomatic tumors
- Tumors without a clear imaging diagnosis
## Primary Prevention
There are no established measures for the secondary prevention of subependymoma.
## Secondary Prevention
There are no established measures for the primary prevention of subependymoma.
|
Subependymoma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2]Sujit Routray, M.D. [3]
# Historical Perspective
Subependymoma was first discovered by Ilya Mark Scheinker, a Russian physician, in 1945.[1]
# Classification
There is no established system for the classification of subependymoma.
# Pathophysiology
## Pathogenesis
Subependymoma arises from subependymal glial cells, although it can also arise from astrocytes from the subependymal plate, ependymal cells, and mixed ependymal and astrocytic cells.[2][3]
## Gross Pathology
Subependymoma is most commonly seen in the fourth ventricle, but it can arise anywhere where there is ependyma. The distribution in the ventricular system is as follows:[4][3]
- Fourth ventricle: 50 - 60%
- Lateral ventricles (usually frontal horns): 30 - 40%
- Third ventricle: rare
- Central canal of the spinal cord: rare
- On gross pathology, subependymoma is characterized by a small, white to grey, firm, well circumscribed, solid, avascular mass attached to the ventricular wall by a narrow pedicle.[2][3]
## Microscopic Pathology
On microscopic histopathological analysis, subependymoma is characterized by the following features:[4]
- Microcystic spaces and bland appearing cells without appreciable nuclear atypia or mitoses.
- The nuclei tend to form clusters.
- No high grade features (mitoses, Ki-67 / MIBI index > 1.5%, necrosis) are present.
- Loose pseudorosettes are observed.
## Immunohistochemistry
Subependymoma is characterized by positive tumor marker GFAP. Mixed populations of cells may be variably positive for:[4][5]
- Olig2
- NHERF1
- Sox2
- CD44
# Causes
The cause of the development of subependymoma has not been identified.
# Differentiating Subependymoma from Other Diseases
Subependymoma must be differentiated from:[6][3]
- Neoplasms of the ventricular wall and septum pellucidum
Ependymoma
Central neurocytoma
Subependymal giant cell astrocytoma
- Ependymoma
- Central neurocytoma
- Subependymal giant cell astrocytoma
- Neoplasms of the choroid plexus
Choroid plexus papilloma and carcinoma
- Choroid plexus papilloma and carcinoma
- Others
Intraventricular meningioma
Intraventricular metastasis
Oligodendroglioma
Pilocytic astrocytoma
Glioblastoma multiforme
Medulloblastoma
Intraventricular teratoma
- Intraventricular meningioma
- Intraventricular metastasis
- Oligodendroglioma
- Pilocytic astrocytoma
- Glioblastoma multiforme
- Medulloblastoma
- Intraventricular teratoma
# Epidemiology and Demographics
## Frequency and Incidence
- The frequency of asymptomatic subependymomas was 0.4% in 1,000 serial routine necropsies and 0.7% in symptomatic subependymomas from 1,000 serial surgical specimens of intracranial neoplasms.[7]
- The incidence of subependymoma was estimated to be 0.7 cases per 100,000 individuals with pathologically proven intracranial neoplasms.[8]
## Age
- Patients of all age groups may develop subependymoma.
- Subependymoma is a rare disease that tends to affect middle-aged adults and the elderly population (typically in the 5th to 6th decades).[9]
## Gender
- Males are more commonly affected with subependymoma than females.
- The male to female ratio is approximately 2.3 to 1.[9]
# Risk Factors
The risk factors in the development of subependymoma are not well defined.
# Natural History, Complications, and Prognosis
- If left untreated, patients with subependymoma may progress to develop seizures and obstructive hydrocephalus.[10]
- Subependymoma is a slow-growing tumor with an indolent course.[11][5]
- Obstructive hydrocephalus is a common complication of subependymoma.[10]
- The prognosis of subependymoma is excellent with complete excision of the tumor.[2][12]
- Common complications of subependymoma are hydrocephalus and focal neurological deficits due to mass effect.[3]
# Diagnosis
## Symptoms
- Typically patients of subependymoma are asymptomatic and small lesions are discovered incidentally.
- Symptoms of subependymoma include:[13][14][3]
Symptoms due to elevated intracranial pressure
Headache
Nausea
Vomiting
Neurological symptoms
Seizures
Sudden loss of awareness
Transient loss of memory
- Symptoms due to elevated intracranial pressure
Headache
Nausea
Vomiting
- Headache
- Nausea
- Vomiting
- Neurological symptoms
Seizures
Sudden loss of awareness
Transient loss of memory
- Seizures
- Sudden loss of awareness
- Transient loss of memory
-
## Physical Examination
- Patients with subependymoma usually appear normal.
- Physical examination may be remarkable for:[15][16][17][18][3][19]
- Abnormal pupillary reflex
- Visual field defects
- Gait changes
- Bilateral Babinski sign
- Depressed Glasgow coma score (GCS)
- Decreased muscle strength
- Decreased deep tendon reflexes
- Sensation defects
- Hearing problems and abnormal Rinne and Weber tests
## Laboratory Findings
There are no specific laboratory findings associated with subependymoma.
## Electrocardiogram
There are no ECG findings associated with subependymoma.
## X-ray
There are no x-ray findings associated with subependymoma.
## Echocardiography or Ultrasound
There are no echocardiography/ultrasound findings associated with sybependymoma.
## CT scan
Head CT scan is helpful in the diagnosis of subependymoma. On CT scan, subependymoma is characterized by:[20]
- Iso- and hypodense intraventricular mass
- Positive mass effect
- No enhancement
- If large, it may have cystic or even calcific components
- No vasogenic edema
## MRI
Brain MRI is helpful in the diagnosis of subependymoma. On MRI, subependymoma is characterized by:
## Other Imaging Findings
There are no other imaging findings associated with subependymoma.
## Other Diagnostic Studies
There are no other diagnostic studies associated with subependymoma.
## Medical Therapy
There is no medical therapy available for the treatment of subependymoma.
## Surgery
Surgery is the mainstay of therapy for subependymoma. Incidental intraventricular subependymoma can be managed conservatively through MRI surveillance. Surgical resection is indicated for:[3][21][22]
- Symptomatic tumors
- Tumors without a clear imaging diagnosis
## Primary Prevention
There are no established measures for the secondary prevention of subependymoma.
## Secondary Prevention
There are no established measures for the primary prevention of subependymoma.
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https://www.wikidoc.org/index.php/Subependymal_astrocytoma
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457299ba56991489471e05c2b5399b017618d5a4
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wikidoc
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Succinic acid
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Succinic acid
# Overview
Succinic acid (IUPAC systematic name: butanedioic acid; historically known as spirit of amber) is a dicarboxylic acid which plays a biochemical role in the citric acid cycle.
# Physical properties
At room temperature, pure succinic acid is a solid that forms colorless, odorless crystals. It has a melting point of 185 °C and a boiling point of 235 °C. It is a diprotic acid. The carboxylate anion is called 'succinate and esters of succinic acid are called alkyl succinates.
# Biochemical role
Succinate is a component of the citric acid cycle and is capable of donating electrons to the electron transfer chain via the following reaction:
This is catalysed by the enzyme succinate dehydrogenase (or complex II of the mitochondrial ETC). The complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of ubiquinone. Intermediate electron carriers are FAD and three Fe2S2 clusters part of subunit B.
Mark Donnelly from Argonne National Laboratory developed one of the best strains (AFP 184) to convert raw hydrolysates from biomass to succinate.
# History
Spirit of amber was procured from amber by pulverising and distilling it using a sand bath. It was chiefly used externally for rheumatic aches and pains, and internally in inveterate gleets.
# Safety
The acid is combustible and corrosive, capable of causing burns. "Harmful by inhalation, ingestion and through skin absorption. Wash after handling. Eye contact may cause serious damage."
In nutraceutical form as a food additive and dietary supplement, is safe and approved by the FDA.
# Oxidition reaction
Succinic acid can be converted to fumaric acid by oxidation.
|
Succinic acid
Template:Chembox new
# Overview
Succinic acid (IUPAC systematic name: butanedioic acid; historically known as spirit of amber) is a dicarboxylic acid which plays a biochemical role in the citric acid cycle.
# Physical properties
At room temperature, pure succinic acid is a solid that forms colorless, odorless crystals. It has a melting point of 185 °C and a boiling point of 235 °C. It is a diprotic acid. The carboxylate anion is called 'succinate and esters of succinic acid are called alkyl succinates.
# Biochemical role
Succinate is a component of the citric acid cycle and is capable of donating electrons to the electron transfer chain via the following reaction:
This is catalysed by the enzyme succinate dehydrogenase (or complex II of the mitochondrial ETC). The complex is a 4 subunit membrane-bound lipoprotein which couples the oxidation of succinate to the reduction of ubiquinone. Intermediate electron carriers are FAD and three Fe2S2 clusters part of subunit B.
Mark Donnelly from Argonne National Laboratory developed one of the best strains (AFP 184) to convert raw hydrolysates from biomass to succinate.[1]
# History
Spirit of amber was procured from amber by pulverising and distilling it using a sand bath. It was chiefly used externally for rheumatic aches and pains, and internally in inveterate gleets.
# Safety
The acid is combustible and corrosive, capable of causing burns. "Harmful by inhalation, ingestion and through skin absorption. Wash after handling. Eye contact may cause serious damage."
In nutraceutical form as a food additive and dietary supplement, is safe and approved by the FDA.
# Oxidition reaction
Succinic acid can be converted to fumaric acid by oxidation.
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https://www.wikidoc.org/index.php/Succinate
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9cfd08f0631d00c8d9c8820ff1bbf8b9d43ef913
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wikidoc
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Sulfa allergy
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Sulfa allergy
# Overview
Sulfa allergies refer to medications that contain sulfa that may result in an adverse reaction. It is important to note that just because the medication name does not contain the sulfa does not mean it does not contain sulfa, particularly true for the generic names.
Antibiotics that contain sulfonamides include
- Sulfamethoxazole
- Trimethoprim-sulfamethoxazole (Septra, Bactrim)
- Erythromycin-sulfisoxazole
Two medications that are closely related to sulfonamides and should be avoided by those with sulfonamide allergy are:
- Sulfasalazine (Azulfidine)
- Dapsone
Several other medications related to sulfonamides should be used with caution are show below. Though risk of an allergic reaction is significantly lower with these medications you should consult with your health care provider who will weight the risk and benefits.
- Diuretics such as furosemide (Lasix) and hydrochlorothiazide (Microzide)
- Diabetes medications such as glyburide (Glynase, Diabeta, Micronase) and glimepiride (Amaryl)
- Particular nonsteroidal anti-inflammatory drugs, such as celecoxib (Celebrex)
- Migraine treatment with sumatriptan (Imitrex)
HIV/AIDS patients may be more sensitive to sulfonamides or medications similar to sulfonamides. Sulfites and sulfates food preservations are unlikely to cause adverse effects in people with a sulfa allergy.
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Sulfa allergy
Editor-in-Chief: Ann Slater, R.N.
# Overview
Sulfa allergies refer to medications that contain sulfa that may result in an adverse reaction. It is important to note that just because the medication name does not contain the sulfa does not mean it does not contain sulfa, particularly true for the generic names.
Antibiotics that contain sulfonamides include
- Sulfamethoxazole
- Trimethoprim-sulfamethoxazole (Septra, Bactrim)
- Erythromycin-sulfisoxazole
Two medications that are closely related to sulfonamides and should be avoided by those with sulfonamide allergy are:
- Sulfasalazine (Azulfidine)
- Dapsone
Several other medications related to sulfonamides should be used with caution are show below. Though risk of an allergic reaction is significantly lower with these medications you should consult with your health care provider who will weight the risk and benefits.
- Diuretics such as furosemide (Lasix) and hydrochlorothiazide (Microzide)
- Diabetes medications such as glyburide (Glynase, Diabeta, Micronase) and glimepiride (Amaryl)
- Particular nonsteroidal anti-inflammatory drugs, such as celecoxib (Celebrex)
- Migraine treatment with sumatriptan (Imitrex)
HIV/AIDS patients may be more sensitive to sulfonamides or medications similar to sulfonamides. Sulfites and sulfates food preservations are unlikely to cause adverse effects in people with a sulfa allergy.
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https://www.wikidoc.org/index.php/Sulfa_allergy
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589a0716ccebe8ec3e0f6bdde372fcd70a947ef2
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wikidoc
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Sulfadimidine
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Sulfadimidine
# Overview
Sulfadimidine or sulfamethazine is a sulfonamide antibacterial.
There are non-standardizeda abbreviations for it as "sulfadimidine" (abbreviated SDI and more commonly but less reliablyb SDD) and as "sulfamethazine" (abbreviated SMT and more commonly but less reliablyc SMZ). Other names include sulfadimerazine, sulfadimezine, and sulphadimethylpyrimidine.
# Notes
- ^a Abbreviations are not found in the databases (such as ChemDB, ChemIDplus, PubChem), but often seen in the published literature.
- ^b "SDD" is not found in databases, but often seen in the published literature; it could however be confused with Tiferron/Sodium catechol sulfate (1,2-Dihydroxybenzene-3,5-disulfonic acid disodium Salt), uncommon but found officially abbreviated SDD in the ChemIDplus database.
- ^c "SMZ" is not found in databases, but often seen in the published literature; it could however be confused with sulfamethoxazole, also seen abbreviated SMZ.
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Sulfadimidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfadimidine or sulfamethazine is a sulfonamide antibacterial.
There are non-standardizeda abbreviations for it as "sulfadimidine" (abbreviated SDI[1][2] and more commonly but less reliablyb SDD[3][4]) and as "sulfamethazine" (abbreviated SMT[5][6] and more commonly but less reliablyc SMZ[7][8]). Other names include sulfadimerazine, sulfadimezine, and sulphadimethylpyrimidine.
# Notes
- ^a Abbreviations are not found in the databases (such as ChemDB, ChemIDplus, PubChem), but often seen in the published literature.[citation needed]
- ^b "SDD" is not found in databases, but often seen in the published literature; it could however be confused with Tiferron/Sodium catechol sulfate (1,2-Dihydroxybenzene-3,5-disulfonic acid disodium Salt), uncommon but found officially abbreviated SDD in the ChemIDplus database.[9]
- ^c "SMZ" is not found in databases, but often seen in the published literature; it could however be confused with sulfamethoxazole, also seen abbreviated SMZ.[citation needed]
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5369a7778689da28392af20dcf4b197d966bb471
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Sulfamic acid
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Sulfamic acid
Sulfamic acid, also known as amidosulfonic acid, amidosulfuric acid, aminosulfonic acid, and sulfamidic acid, is a molecular compound with the formula H3NSO3. This colorless, water-soluble compound finds many applications.
Sulfamic acid (H3NSO3) may be considered an intermediate compound between sulfuric acid (H2SO4), and sulfamide (H4N2SO2), effectively - though see below - replacing an -OH group with an -NH2 group at each step. This pattern can extend no further in either direction without breaking down the -SO2 group.
# Structure and reactivity
First, it should be noticed that the compound is well described by the formula H3NSO3, not the tautomer H2NSO2(OH). The relevant bond distances are S=O, 1.44 and S-N 1.77 Å. The greater length of the S-N distance is consistent with a single bond. Furthermore, a neutron diffraction study located the hydrogen atoms, all three of which are 1.03 Å distant from nitrogen. The structures shown with this article are for the two main tautomers.
Sulfamic acid is a weak acid, Ka = 1.01 x 10−1. Because the solid is non-hygroscopic, it is used as a standard in acidometry (quantitative assays of acid content). Double deprotonation can be effected in NH3 solution to give 2−.
Sulfamic acid melts at 205 °C before decomposing at higher temperatures to H2O, SO3, SO2, and N2.
With HNO2, sulfamic acid reacts to give N2, while with HNO3, it affords N2O.
The behavior of H3NSO3 resembles that of urea, (H2N)2CO, in some ways. Both feature amino groups linked to electron-withdrawing centers that can participate in delocalized bonding. Both liberate ammonia upon heating in water.
# Applications
The most famous application of sulfamic acid is in the synthesis of compounds that taste sweet. Reaction with cyclohexylamine followed by addition of NaOH gives C6H11NHSO3Na, sodium cyclamate. Related compounds are also sweeteners, see acesulfame potassium.
Sulfamates (O-substituted-, N-substituted-, or di-/tri-substituted derivatives of sulfamic acid) have been used in the design of many types of therapeutic agents such as antibiotics, nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, HIV protease inhibitors (PIs), anti-cancer drugs (steroid sulfatase and carbonic anhydrase inhibitors), anti-epileptic drugs, and weight loss drugs.
Sulfamic acid is used as an acidic cleaning agent, typically for metals and ceramics. It is a replacement for hydrochloric acid for the removal of rust. In households, it is often found as a descaling agent in detergents used for removal of limescale.
Sulfamic acid is used in the S.C. Johnson & Sons, Inc. "Scrubbing Bubbles Fizz-Its Toilet Tablets."
- Catalyst for esterification process
- Dye and pigment manufacturing
- Herbicide
- Ingredient in Denture Tablets
- Coagulator for urea-formaldehyde resins
- Ingredient in fire extinguishing media
- Pulp and paper industry as a chloride stabilizer
- Synthesis of nitrous oxide by reaction with nitric acid
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Sulfamic acid
Template:Chembox new
Sulfamic acid, also known as amidosulfonic acid, amidosulfuric acid, aminosulfonic acid, and sulfamidic acid, is a molecular compound with the formula H3NSO3. This colorless, water-soluble compound finds many applications.
Sulfamic acid (H3NSO3) may be considered an intermediate compound between sulfuric acid (H2SO4), and sulfamide (H4N2SO2), effectively - though see below - replacing an -OH group with an -NH2 group at each step. This pattern can extend no further in either direction without breaking down the -SO2 group.
# Structure and reactivity
First, it should be noticed that the compound is well described by the formula H3NSO3, not the tautomer H2NSO2(OH). The relevant bond distances are S=O, 1.44 and S-N 1.77 Å. The greater length of the S-N distance is consistent with a single bond.[1] Furthermore, a neutron diffraction study located the hydrogen atoms, all three of which are 1.03 Å distant from nitrogen. The structures shown with this article are for the two main tautomers.
Sulfamic acid is a weak acid, Ka = 1.01 x 10−1. Because the solid is non-hygroscopic, it is used as a standard in acidometry (quantitative assays of acid content). Double deprotonation can be effected in NH3 solution to give [HNSO3]2−.
Sulfamic acid melts at 205 °C before decomposing at higher temperatures to H2O, SO3, SO2, and N2.
With HNO2, sulfamic acid reacts to give N2, while with HNO3, it affords N2O.
The behavior of H3NSO3 resembles that of urea, (H2N)2CO, in some ways. Both feature amino groups linked to electron-withdrawing centers that can participate in delocalized bonding. Both liberate ammonia upon heating in water.
# Applications
The most famous application of sulfamic acid is in the synthesis of compounds that taste sweet. Reaction with cyclohexylamine followed by addition of NaOH gives C6H11NHSO3Na, sodium cyclamate. Related compounds are also sweeteners, see acesulfame potassium.
Sulfamates (O-substituted-, N-substituted-, or di-/tri-substituted derivatives of sulfamic acid) have been used in the design of many types of therapeutic agents such as antibiotics, nucleoside/nucleotide human immunodeficiency virus (HIV) reverse transcriptase inhibitors, HIV protease inhibitors (PIs), anti-cancer drugs (steroid sulfatase and carbonic anhydrase inhibitors), anti-epileptic drugs, and weight loss drugs.
Sulfamic acid is used as an acidic cleaning agent, typically for metals and ceramics. It is a replacement for hydrochloric acid for the removal of rust. In households, it is often found as a descaling agent in detergents used for removal of limescale.
Sulfamic acid is used in the S.C. Johnson & Sons, Inc. "Scrubbing Bubbles Fizz-Its Toilet Tablets."
- Catalyst for esterification process
- Dye and pigment manufacturing
- Herbicide
- Ingredient in Denture Tablets
- Coagulator for urea-formaldehyde resins
- Ingredient in fire extinguishing media
- Pulp and paper industry as a chloride stabilizer
- Synthesis of nitrous oxide by reaction with nitric acid
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92593df5a54822ce1089bdc46833e8d45914a62a
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Sulfapyridine
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Sulfapyridine
# Overview
Sulfapyridine, original UK spelling sulphapyridine, is a sulfonamide antibacterial. At one time it was commonly referred to as M&B.
Sulfapyridine is no longer prescribed for treatment of infections in humans. However, it may be used to treat linear IgA disease. It is a good antibacterial drug, but its water solubility is very pH dependent. Thus there is a risk of crystallization within the bladder or urethra, which could lead to pain or blockage. As with other sulfonamides, there is a significant risk of agranulocytosis, and this, rather than the development of resistance by bacteria, is the main reason for its decline in use.
It was discovered by Lionel Whitby at the British firm May & Baker Ltd and logged in their Test Book on 2 November, 1937 under Code No M&B 693. It was successfully used to treat Winston Churchill's bacterial pneumonia in 1942. In a subsequent radio broadcast he said: "This admirable M&B from which I did not suffer any inconvenience, was used at the earliest moment and, after a week's fever, the intruders were repulsed."
In 1944 M&B 693 also saved Nero, the Royal Circus lion, from pneumonia.
The drug sulfasalazine is structurally one molecule of mesalamine linked to one molecule of sulfapyridine with an azo bond.
M&B 693 was one of the first generation of sulphonamide antibiotics. It has been reported as the first chemical cure for pneumonia. It could either be taken in tablet form or the powder could be placed in wounds. It was used so widely during the Second World War that May & Baker had difficulty keeping up with demand. It was later largely superseded by penicillin and other sulfonamides.
# Synthesis
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Sulfapyridine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfapyridine, original UK spelling sulphapyridine, is a sulfonamide antibacterial. At one time it was commonly referred to as M&B.
Sulfapyridine is no longer prescribed for treatment of infections in humans. However, it may be used to treat linear IgA disease. It is a good antibacterial drug, but its water solubility is very pH dependent. Thus there is a risk of crystallization within the bladder or urethra, which could lead to pain or blockage. As with other sulfonamides, there is a significant risk of agranulocytosis, and this, rather than the development of resistance by bacteria, is the main reason for its decline in use.
It was discovered by Lionel Whitby at the British firm May & Baker Ltd and logged in their Test Book on 2 November, 1937 under Code No M&B 693.[1] It was successfully used to treat Winston Churchill's bacterial pneumonia in 1942. In a subsequent radio broadcast he said: "This admirable M&B from which I did not suffer any inconvenience, was used at the earliest moment and, after a week's fever, the intruders were repulsed."
In 1944 M&B 693 also saved Nero, the Royal Circus lion, from pneumonia. [Glasgow Evening News January 1944.]
The drug sulfasalazine is structurally one molecule of mesalamine linked to one molecule of sulfapyridine with an azo bond.
M&B 693 was one of the first generation of sulphonamide antibiotics. It has been reported as the first chemical cure for pneumonia. It could either be taken in tablet form or the powder could be placed in wounds. It was used so widely during the Second World War that May & Baker had difficulty keeping up with demand. It was later largely superseded by penicillin and other sulfonamides.
# Synthesis
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feffa7ddcf43d21b95adb792c42dd8bf81254593
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Sulfathiazole
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Sulfathiazole
# Overview
Sulfathiazole is an organosulfur compound used as a short-acting sulfa drug. It is an organic compound. Formerly, it was a common oral and topical antimicrobial, until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide, and in aquariums.
It exists in various forms (polymorphs). The imide tautomer is dominant, at least in the solid state. In this tautomer, the proton resides on the ring nitrogen, not the structure shown above.
# Cultural references
Sulfathiazole is mentioned in chapter 104 of Kurt Vonnegut's novel Cat's Cradle and New Dictonary, and several of his short stories. Thoma Heggen's 1946 novel Mister Roberts mentions the use of sulfathiazole to treat gonorrhea, and Sonya Dorman's short story When I was Miss Dow in 1966. Also the 1998 movie Dead Heat mentions the chemical as a drug used with reanimation of dead bodies.
Sulfathiazole is mentioned in "The World According To Garp" in chapter 1 where Garps mother winesses it being dispensed to WWII soldiers.
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Sulfathiazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfathiazole is an organosulfur compound used as a short-acting sulfa drug. It is an organic compound. Formerly, it was a common oral and topical antimicrobial, until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide, and in aquariums.
It exists in various forms (polymorphs). The imide tautomer is dominant, at least in the solid state. In this tautomer, the proton resides on the ring nitrogen, not the structure shown above.[1]
# Cultural references
Sulfathiazole is mentioned in chapter 104 of Kurt Vonnegut's novel Cat's Cradle and New Dictonary, and several of his short stories. Thoma Heggen's 1946 novel Mister Roberts mentions the use of sulfathiazole to treat gonorrhea, and Sonya Dorman's short story When I was Miss Dow in 1966. Also the 1998 movie Dead Heat mentions the chemical as a drug used with reanimation of dead bodies.
Sulfathiazole is mentioned in "The World According To Garp" in chapter 1 where Garps mother winesses it being dispensed to WWII soldiers.
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https://www.wikidoc.org/index.php/Sulfathiazole
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918311ca40b4a39933341d19f6fff2109800cd11
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Sulfonic acid
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Sulfonic acid
Sulfonic acid is a hypothetical acid with formula H-S(=O)2-OH. This compound is a less stable tautomer of sulfurous acid HO-S(=O)-OH, so sulfonic acid converts rapidly when it is formed. Derived compounds which replace the sulfur-bonded hydrogen with organic groups are stable. These may then form salts or esters, called sulfonates.
# Sulfonic acids
Sulfonic acids are a class of organic acids with the general formula R-S(=O)2-OH, where R is usually a hydrocarbon side chain. Sulfonic acids are typically much stronger acids than their carboxylic equivalents, and have the unique tendency to bind to proteins and carbohydrates tightly; most "washable" dyes are sulfonic acids (or have the functional sulfonyl group in them) for this reason. They are also used as catalysts and intermediates for a number of different products. Sulfonic acid salts (sulfonates) are important as detergents, and the antibacterial sulfa drugs are also sulfonic acid derivatives.
The simplest example is methanesulfonic acid, CH3SO2OH, which is a reagent regularly used in organic chemistry. p-Toluenesulfonic acid is also an important reagent.
Note that the sulfonic acids and sulfonates are analogous to carboxylic acids and carboxylates; in both cases, -C(=O)- is replaced by -S(=O)2-. Chemical properties are similar as well, although sulfonic acids are often even stronger acids than carboxylic acids, the hydrogen being easier to leave than in most compounds, and they readily form esters.
The sulfonic acid and sulfonate functional groups, -SO2OH and -SO2O-, are found in many chemical compounds, e.g. certain detergents and dyes as well as in strongly acidic cation exchange resins.
# Sulfonic acid chlorides
Sulfonic acid chlorides are a class of organic compounds with the general formula R-SO2-Cl. These compounds react readily with alcohols to sulfonic esters. Important acid chlorides are tosyl chloride, brosyl chloride, nosyl chloride and mesyl chloride. One synthetic procedure to synthesize sulfonic acid chlorides is the Reed reaction.
# Sulfonic esters
Sulfonic esters are a class of organic compounds with the general formula R-SO2-OR. Sulfonic esters are considered good leaving groups in nucleophilic aliphatic substitution.
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Sulfonic acid
Sulfonic acid is a hypothetical acid with formula H-S(=O)2-OH. This compound is a less stable tautomer of sulfurous acid HO-S(=O)-OH, so sulfonic acid converts rapidly when it is formed. Derived compounds which replace the sulfur-bonded hydrogen with organic groups are stable. These may then form salts or esters, called sulfonates.
# Sulfonic acids
Sulfonic acids are a class of organic acids with the general formula R-S(=O)2-OH, where R is usually a hydrocarbon side chain. Sulfonic acids are typically much stronger acids than their carboxylic equivalents, and have the unique tendency to bind to proteins and carbohydrates tightly; most "washable" dyes are sulfonic acids (or have the functional sulfonyl group in them) for this reason. They are also used as catalysts and intermediates for a number of different products. Sulfonic acid salts (sulfonates) are important as detergents, and the antibacterial sulfa drugs are also sulfonic acid derivatives.
The simplest example is methanesulfonic acid, CH3SO2OH, which is a reagent regularly used in organic chemistry. p-Toluenesulfonic acid is also an important reagent.
Note that the sulfonic acids and sulfonates are analogous to carboxylic acids and carboxylates; in both cases, -C(=O)- is replaced by -S(=O)2-. Chemical properties are similar as well, although sulfonic acids are often even stronger acids than carboxylic acids, the hydrogen being easier to leave than in most compounds, and they readily form esters.
The sulfonic acid and sulfonate functional groups, -SO2OH and -SO2O-, are found in many chemical compounds, e.g. certain detergents and dyes as well as in strongly acidic cation exchange resins.
# Sulfonic acid chlorides
Sulfonic acid chlorides are a class of organic compounds with the general formula R-SO2-Cl. These compounds react readily with alcohols to sulfonic esters. Important acid chlorides are tosyl chloride, brosyl chloride, nosyl chloride and mesyl chloride. One synthetic procedure to synthesize sulfonic acid chlorides is the Reed reaction.
# Sulfonic esters
Sulfonic esters are a class of organic compounds with the general formula R-SO2-OR. Sulfonic esters are considered good leaving groups in nucleophilic aliphatic substitution.
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Sulfuric acid
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Sulfuric acid
Sulfuric acid H2SO4, is a strong mineral acid. It is soluble in water at all concentrations. It was once known as oil of vitriol, coined by the 8th-century Muslim alchemist Jabir ibn Hayyan (Geber) after his discovery of the chemical.
Sulfuric acid has many applications, and is one of the top products of the chemical industry. World production in 2001 was 165 million metric tons, with an approximate value of US$8 billion. Principal uses include ore processing, fertilizer manufacturing, oil refining, wastewater processing, and chemical synthesis. Its ability to produce foul-smelling sulfur compounds has lent the word vitriol the additional meaning "bitter, abusive language".
Many proteins are made of sulfur-containing amino acids (such as cysteine and methionine) which produce sulfuric acid (or sulfate ion, SO42- at neutral pH) when metabolized by the body.
# Occurrence
Pure undiluted sulfuric acid is not encountered on Earth, due to sulfuric acid's great affinity for water. Apart from that, sulfuric acid is a constituent of acid rain, which is formed by atmospheric oxidation of sulfur dioxide in the presence of water, i.e., oxidation of sulfurous acid. Sulfur dioxide is the main byproduct produced when sulfur-containing fuels such as coal or oil are burnt.
Sulfuric acid is formed naturally by the oxidation of sulfide minerals, such as iron sulfide. The resulting water can be highly acidic and is called Acid Mine Drainage (AMD). This acidic water is capable of dissolving metals present in sulfide ores, which results in brightly-coloured, toxic streams. The oxidation of iron sulfide pyrite (FeS2) by molecular oxygen produces iron(II), or Fe2+:
The Fe2+ can be further oxidized to Fe3+, according to:
and the Fe3+ produced can be precipitated as the hydroxide or hydrous oxide. The equation for the formation of the hydroxide is
The iron(III) ion ("ferric iron", in casual nomenclature) can also oxidize pyrite. When iron(III) oxidation of pyrite occurs, the process can become rapid. pH values below zero have been measured in AMD produced by this process.
AMD can also produce sulfuric acid at a slower rate, so that the acid neutralizing capacity (ANC) of the aquifer can neutralise the produced acid. In such cases, the total dissolved solids (TDS) concentration of the water can be increased form the dissolution of minerals from the acid-neutralisation reaction with the minerals.
## Extraterrestrial sulfuric acid
Sulfuric acid is produced in the upper atmosphere of Venus by the sun's photochemical action on carbon dioxide, sulfur dioxide, and water vapour. Ultraviolet photons of wavelengths less than 169 nm can photodissociate carbon dioxide into carbon monoxide and atomic oxygen. Atomic oxygen is highly reactive. When it reacts with sulfur dioxide, a trace component of the Venerian atmosphere, the result is sulfur trioxide, which can combine with water vapor, another trace component of Venus's atmosphere, to yield sulfuric acid.
In the upper, cooler portions of Venus's atmosphere, sulfuric acid exists as a liquid, and thick sulfuric acid clouds completely obscure the planet's surface when viewed from above. The main cloud layer extends from 45–70 km above the planet's surface, with thinner hazes extending as low as 30 and as high as 90 km above the surface.
Infrared spectra from NASA's Galileo mission show distinct absorptions on Jupiter's moon Europa that have been attributed to one or more sulfuric acid hydrates. The interpretation of the spectra is somewhat controversial. Some planetary scientists prefer to assign the spectral features to the sulfate ion, perhaps as part of one or more minerals on Europa's surface.
# Manufacture
Sulfuric acid is produced from sulfur, oxygen and water via the contact process.
In the first step, sulfur is burned to produce sulfur dioxide.
This is then oxidised to sulfur trioxide using oxygen in the presence of a vanadium(V) oxide catalyst.
Finally the sulfur trioxide is treated with water (usually as 97-98% H2SO4 containing 2-3% water) to produce 98-99% sulfuric acid.
Note that directly dissolving SO3 in water is not practical due to the highly exothermic nature of the reaction, forming a corrosive mist instead of a liquid.
Alternatively, SO3 can be absorbed into H2SO4 to produce oleum (H2S2O7), which may then be mixed with water to form sulfuric acid.
Oleum is reacted with water to form concentrated H2SO4.
# Physical properties
## Forms of sulfuric acid
Although nearly 100% sulfuric acid can be made, this loses SO3 at the boiling point to produce 98.3% acid. The 98% grade (18M) is more stable in storage, and is the usual form of what is described as concentrated sulfuric acid. Other concentrations are used for different purposes. Some common concentrations are
- 10%, dilute sulfuric acid for laboratory use,
- 33.5%, battery acid (used in lead-acid batteries),
- 62.18%, chamber or fertilizer acid,
- 77.67%, tower or Glover acid,
- 98%, concentrated acid.
Different purities are also available. Technical grade H2SO4 is impure and often colored, but is suitable for making fertilizer. Pure grades such as United States Pharmacopoeia (USP) grade are used for making pharmaceuticals and dyestuffs.
When high concentrations of SO3(g) are added to sulfuric acid, H2S2O7, called pyrosulfuric acid, fuming sulfuric acid or oleum or, less commonly, Nordhausen acid, is formed. Concentrations of oleum are either expressed in terms of% SO3 (called% oleum) or as% H2SO4 (the amount made if H2O were added); common concentrations are 40% oleum (109% H2SO4) and 65% oleum (114.6% H2SO4). Pure H2S2O7 is a solid with melting point 36°C.
## Polarity and conductivity
Anhydrous H2SO4 is a very polar liquid, having a dielectric constant of around 100. It has a high electrical conductivity, caused by dissociation through protonating itself, a process known as autoprotolysis, or autoionization.
The equilibrium constant for the autoprotolysis is
The comparable equilibrium constant for water, Kw is 10−14, a factor of 1010 (10 billion) smaller.
In spite of the viscosity of the acid, the effective conductivities of the H3SO4+ and HSO4− ions are high due to an intra-molecular proton-switch mechanism (analogous to the Grotthuss mechanism in water), making sulfuric acid a good conductor. It is also an excellent solvent for many reactions.
The equilibrium is actually more complex than shown above; 100% H2SO4 contains the following species at equilibrium (figures shown as millimol per kg solvent): HSO4− (15.0), H3SO4+ (11.3), H3O+ (8.0), HS2O7− (4.4), H2S2O7 (3.6), H2O (0.1).
# Chemical properties
## Reaction with water
The hydration reaction of sulfuric acid is highly exothermic. If water is added to the concentrated sulfuric acid, it can react, boil and spit dangerously. One should always add the acid to the water rather than the water to the acid. The necessity for this safety precaution is due to the relative densities of these two liquids. Water is less dense than sulfuric acid, meaning water will tend to float on top of this acid. The reaction is best thought of as forming hydronium ions, by
and then
Because the hydration of sulfuric acid is thermodynamically favorable, sulfuric acid is an excellent dehydrating agent. The affinity of sulfuric acid for water is sufficiently strong that it will remove hydrogen and oxygen atoms from other compounds; for example, mixing starch (C6H12O6)n and concentrated sulfuric acid will give elemental carbon and water which is absorbed by the sulfuric acid (which becomes slightly diluted): (C6H12O6)n → 6C + 6H2O. The effect of this can be seen when concentrated sulfuric acid is spilled on paper; the cellulose reacts to give a burned appearance, the carbon appears much as soot would in a fire. A more dramatic reaction occurs when sulfuric acid is added to a tablespoon of white sugar; a rigid column of black, porous carbon will quickly emerge. The carbon will smell strongly of caramel.
## Other reactions
As an acid, sulfuric acid reacts with most bases to give the corresponding sulfate. For example, copper(II) sulfate. This blue salt of copper, commonly used for electroplating and as a fungicide, is prepared by the reaction of copper(II) oxide (CuO) with sulfuric acid:
Sulfuric acid can also be used to displace weaker acids from their salts. Reaction with sodium acetate, for example, displaces acetic acid:
Similarly, reacting sulfuric acid with potassium nitrate can be used to produce nitric acid and a precipitate of potassium bisulfate. When combined with nitric acid, sulfuric acid acts both as an acid and a dehydrating agent, forming the nitronium ion NO2+, which is important in nitration reactions involving electrophilic aromatic substitution. This type of reaction, where protonation occurs on an oxygen atom, is important in many organic chemistry reactions, such as Fischer esterification and dehydration of alcohols.
Sulfuric acid reacts with most metals via a single displacement reaction to produce hydrogen gas and the metal sulfate. Dilute H2SO4 attacks iron, aluminium, zinc, manganese, magnesium and nickel, but reactions with tin and copper require the acid to be hot and concentrated. Lead and tungsten, however, are resistant to sulfuric acid. The reaction with iron (shown) is typical for most of these metals, but the reaction with tin is unusual in that it produces sulfur dioxide rather than hydrogen.
Sulfuric acid undergoes electrophilic aromatic substitution with aromatic compounds to give the corresponding sulfonic acids:
# Uses
Sulfuric acid is a very important commodity chemical, and indeed, a nation's sulfuric acid production is a good indicator of its industrial strength. The major use (60% of total production worldwide) for sulfuric acid is in the "wet method" for the production of phosphoric acid, used for manufacture of phosphate fertilizers as well as trisodium phosphate for detergents. In this method, phosphate rock is used, and more than 100 million tonnes are processed annually. This raw material is shown below as fluorapatite, though the exact composition may vary. This is treated with 93% sulfuric acid to produce calcium sulfate, hydrogen fluoride (HF) and phosphoric acid. The HF is removed as hydrofluoric acid. The overall process can be represented as:
Sulfuric acid is used in large quantities by the iron and steelmaking industry to remove oxidation, rust and scale from rolled sheet and billets prior to sale to the automobile and white-goods industry. Used acid is often recycled using a Spent Acid Regeneration (SAR) plant. These plants combust spent acid with natural gas, refinery gas, fuel oil or other fuel sources. This combustion process produces gaseous sulfur dioxide (SO2) and sulfur trioxide (SO3) which are then used to manufacture "new" sulfuric acid. SAR plants are common additions to metal smelting plants, oil refineries, and other industries where sulfuric acid is consumed in bulk, as operating a SAR plant is much cheaper than the recurring costs of spent acid disposal and new acid purchases.
Ammonium sulfate, an important nitrogen fertilizer, is most commonly produced as a byproduct from coking plants supplying the iron and steel making plants. Reacting the ammonia produced in the thermal decomposition of coal with waste sulfuric acid allows the ammonia to be crystallized out as a salt (often brown because of iron contamination) and sold into the agro-chemicals industry.
Another important use for sulfuric acid is for the manufacture of aluminium sulfate, also known as paper maker's alum. This can react with small amounts of soap on paper pulp fibers to give gelatinous aluminium carboxylates, which help to coagulate the pulp fibers into a hard paper surface. It is also used for making aluminium hydroxide, which is used at water treatment plants to filter out impurities, as well as to improve the taste of the water. Aluminum sulfate is made by reacting bauxite with sulfuric acid:
Sulfuric acid is used for a variety of other purposes in the chemical industry. For example, it is the usual acid catalyst for the conversion of cyclohexanoneoxime to caprolactam, used for making nylon. It is used for making hydrochloric acid from salt via the Mannheim process. Much H2SO4 is used in petroleum refining, for example as a catalyst for the reaction of isobutane with isobutylene to give isooctane, a compound that raises the octane rating of gasoline (petrol). Sulfuric acid is also important in the manufacture of dyestuffs, pigments (such as titanium dioxide), solutions, and is the "acid" in lead-acid (car) batteries.
Sulfuric acid is also used as a general dehydrating agent in its concentrated form (see Reaction with water).
## Sulfur-iodine cycle
The sulfur-iodine cycle is a series of thermo-chemical processes used to obtain hydrogen. It consists of three chemical reactions whose net reactant is water and whose net products are hydrogen and oxygen.
The sulfur and iodine compounds are recovered and reused, hence the consideration of the process as a cycle. This process is endothermic and must occur at high temperatures, so energy in the form of heat has to be supplied.
The sulfur-iodine cycle has been proposed as a way to supply hydrogen for a hydrogen-based economy. It does not require hydrocarbons like current methods of steam reforming.
The sulfur-iodine cycle is currently being researched as a feasible method of obtaining hydrogen, but the concentrated, corrosive acid at high temperatures poses currently insurmountable safety hazards if the process were built on large-scale.
# History
The discovery of sulfuric acid is credited to the 8th century Arabian chemist and alchemist, Jabir ibn Hayyan (Geber). The acid was later studied by 9th century Persian physician and alchemist Ibn Zakariya al-Razi (Rhazes), who obtained the substance by dry distillation of minerals including iron(II) sulfate heptahydrate, FeSO4 - 7H2O, and copper(II) sulfate pentahydrate, CuSO4 - 5H2O. When heated, these compounds decompose to iron(II) oxide and copper(II) oxide, respectively, giving off water and sulfur trioxide, which combine to produce a dilute solution of sulfuric acid. This method was popularized in Europe through translations of Arabic and Persian treatises, as well as books by European alchemists, such as the 13th-century German Albertus Magnus.
Sulfuric acid was known to medieval European alchemists as oil of vitriol, spirit of vitriol, or simply vitriol, among other names. The word vitriol derives from the Latin vitreus, 'glass', referring to the glassy appearance of the sulfate salts, which also carried the name vitriol. Salts called by this name included copper(II) sulfate (blue vitriol, or rarely Roman vitriol), zinc sulfate (white vitriol), iron(II) sulfate (green vitriol), iron(III) sulfate (vitriol of Mars), and cobalt(II) sulfate (red vitriol).
Vitriol was widely considered the most important alchemical substance, intended to be used as a philosopher's stone. Highly purified vitriol was used as a medium for reacting other substances. This was largely because the acid does not react with gold, production of which was often the final goal of alchemical processes. The importance of vitriol to alchemy is highlighted in the alchemical motto, Visita Interiora Terrae Rectificando Invenies Occultum Lapidem which is a backronym meaning ('Visit the interior of the earth and rectifying (i.e. purifying) you will find the hidden/secret stone'), found in L'Azoth des Philosophes by the 15th Century alchemist Basilius Valentinus, .
In the 17th century, the German-Dutch chemist Johann Glauber prepared sulfuric acid by burning sulfur together with saltpeter (potassium nitrate, KNO3), in the presence of steam. As saltpeter decomposes, it oxidizes the sulfur to SO3, which combines with water to produce sulfuric acid. In 1736, Joshua Ward, a London pharmacist, used this method to begin the first large-scale production of sulfuric acid.
In 1746 in Birmingham, John Roebuck adapted this method to produce sulfuric acid in lead-lined chambers, which were stronger, less expensive, and could be made larger than the previously used glass containers. This lead chamber process allowed the effective industrialization of sulfuric acid production. After several refinements, this method remained the standard for sulfuric acid production for almost two centuries.
Sulfuric acid created by John Roebuck's process only approached a 35–40% concentration. Later refinements to the lead-chamber process by French chemist Joseph-Louis Gay-Lussac and British chemist John Glover improved the yield to 78%. However, the manufacture of some dyes and other chemical processes require a more concentrated product. Throughout the 18th century, this could only be made by dry distilling minerals in a technique similar to the original alchemical processes. Pyrite (iron disulfide, FeS2) was heated in air to yield iron (II) sulfate, FeSO4, which was oxidized by further heating in air to form iron(III) sulfate, Fe2(SO4)3, which, when heated to 480 °C, decomposed to iron(III) oxide and sulfur trioxide, which could be passed through water to yield sulfuric acid in any concentration. However, the expense of this process prevented the large-scale use of concentrated sulfuric acid.
In 1831, British vinegar merchant Peregrine Phillips patented the contact process, which was a far more economical process for producing sulfur trioxide and concentrated sulfuric acid. Today, nearly all of the world's sulfuric acid is produced using this method.
# Safety
## Laboratory hazards
The corrosive properties of sulfuric acid are accentuated by its highly exothermic reaction with water. Hence burns from sulfuric acid are potentially more serious than those of comparable strong acids (e.g. hydrochloric acid), as there is additional tissue damage due to dehydration and particularly due to the heat liberated by the reaction with water; i.e. secondary thermal damage. The danger is obviously greater with more concentrated preparations of sulfuric acid, but it should be remembered that even the normal laboratory "dilute" grade (approx. 1 M, 10%) will char paper by dehydration if left in contact for a sufficient amount of time. Solutions equal to or stronger than 1.5 M should be labeled CORROSIVE, while solutions greater than 0.5 M but less than 1.5 M should be labeled IRRITANT. Fuming sulfuric acid (oleum) is not recommended for use in schools due to it being quite hazardous. The standard first aid treatment for acid spills on the skin is, as for other corrosive agents, irrigation with large quantities of water. However, the acid should be neutralised first by rinsing with a base (e.g. calcium hydroxide solution), because the water used in washing will react with the acid and increase the chance of secondary damage. Washing should be continued for at least ten to fifteen minutes in order to cool the tissue surrounding the acid burn and to prevent secondary damage. Contaminated clothing must be removed immediately and the underlying skin washed thoroughly.
Preparation of the diluted acid can also be dangerous due to the heat released in the dilution process. It is essential that the concentrated acid is added to water and not the other way round, to take advantage of the relatively high heat capacity of water. Addition of water to concentrated sulfuric acid leads at best to the dispersal of a sulfuric acid aerosol, at worst to an explosion. Preparation of solutions greater than 6 M (35%) in concentration is the most dangerous, as the heat produced can be sufficient to boil the diluted acid: efficient mechanical stirring and external cooling (e.g. an ice bath) are essential.
## Industrial hazards
Although sulfuric acid is non-flammable, contact with metals in the event of a spillage can lead to the liberation of hydrogen gas. The dispersal of acid aerosols and gaseous sulfur dioxide is an additional hazard of fires involving sulfuric acid.
Sulfuric acid is not considered toxic besides its obvious corrosive hazard, and the main occupational risks are skin contact leading to burns (see above) and the inhalation of aerosols. Exposure to aerosols at high concentrations leads to immediate and severe irritation of the eyes, respiratory tract and mucous membranes: this ceases rapidly after exposure, although there is a risk of subsequent pulmonary edema if tissue damage has been more severe. At lower concentrations, the most commonly reported symptom of chronic exposure to sulfuric acid aerosols is erosion of the teeth, found in virtually all studies: indications of possible chronic damage to the respiratory tract are inconclusive as of 1997. In the United States, the permissible exposure limit (PEL) for sulfuric acid is fixed at 1 mg/m³: limits in other countries are similar. Interestingly there have been reports of sulfuric acid ingestion leading to vitamin B12 deficiency with subacute combined degeneration. The spinal cord is most often affected in such cases, but the optic nerves may show demyelination, loss of axons and gliosis.
# Legal restrictions
International commerce of sulfuric acid is controlled under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988, which lists sulfuric acid under Table II of the convention as a chemical frequently used in the illicit manufacture of narcotic drugs or psychotropic substances.
In the United States of America, sulfuric acid is included in List II of the list of essential or precursor chemicals established pursuant to the Chemical Diversion and Trafficking Act. Accordingly, transactions of sulfuric acid—such as sales, transfers, exports from and imports to the United States—are subject to regulation and monitoring by the Drug Enforcement Administration.
# In fiction
In several films, cartoons and TV shows, especially Science-Fiction shows and films, sulfuric acid is sometimes depicted as a bubbling green steaming liquid, sometimes capable of dissolving almost anything in an instant. This is purely for visual appeal, since boiling green acid is more dangerous-looking than the actual clear and syrupy form of sulfuric acid. The use of sulfuric acid as a weapon in crimes of assault, known as "vitriol throwing", has at times been sufficiently common (if sensational) to make its way into novels and short stories. Examples include The Adventure of the Illustrious Client by Arthur Conan Doyle, The Love of Long Ago by Guy de Maupassant, Nineteen Eighty-Four by George Orwell and Brighton Rock by Graham Greene. The novel Veronika Decides to Die by Paulo Coelho talks of a girl who has attempted to commit suicide and ends up with vitriol poisoning. The graphic novel, Shake Girl, is dedicated to over 100 Cambodian victims who have suffered from burns caused by sulfuric acid. In the movie Untraceable,Griffin Dowd ( played by Colin Hanks ) is submerged in sulfuric acid.
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Sulfuric acid
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Sulfuric acid H2SO4, is a strong mineral acid. It is soluble in water at all concentrations. It was once known as oil of vitriol, coined by the 8th-century Muslim alchemist Jabir ibn Hayyan (Geber) after his discovery of the chemical.[1]
Sulfuric acid has many applications, and is one of the top products of the chemical industry. World production in 2001 was 165 million metric tons, with an approximate value of US$8 billion. Principal uses include ore processing, fertilizer manufacturing, oil refining, wastewater processing, and chemical synthesis. Its ability to produce foul-smelling sulfur compounds has lent the word vitriol the additional meaning "bitter, abusive language".
Many proteins are made of sulfur-containing amino acids (such as cysteine and methionine) which produce sulfuric acid (or sulfate ion, SO42- at neutral pH) when metabolized by the body.
# Occurrence
Pure undiluted sulfuric acid is not encountered on Earth, due to sulfuric acid's great affinity for water. Apart from that, sulfuric acid is a constituent of acid rain, which is formed by atmospheric oxidation of sulfur dioxide in the presence of water, i.e., oxidation of sulfurous acid. Sulfur dioxide is the main byproduct produced when sulfur-containing fuels such as coal or oil are burnt.
Sulfuric acid is formed naturally by the oxidation of sulfide minerals, such as iron sulfide. The resulting water can be highly acidic and is called Acid Mine Drainage (AMD). This acidic water is capable of dissolving metals present in sulfide ores, which results in brightly-coloured, toxic streams. The oxidation of iron sulfide pyrite (FeS2) by molecular oxygen produces iron(II), or Fe2+:
The Fe2+ can be further oxidized to Fe3+, according to:
and the Fe3+ produced can be precipitated as the hydroxide or hydrous oxide. The equation for the formation of the hydroxide is
The iron(III) ion ("ferric iron", in casual nomenclature) can also oxidize pyrite. When iron(III) oxidation of pyrite occurs, the process can become rapid. pH values below zero have been measured in AMD produced by this process.
AMD can also produce sulfuric acid at a slower rate, so that the acid neutralizing capacity (ANC) of the aquifer can neutralise the produced acid. In such cases, the total dissolved solids (TDS) concentration of the water can be increased form the dissolution of minerals from the acid-neutralisation reaction with the minerals.
## Extraterrestrial sulfuric acid
Sulfuric acid is produced in the upper atmosphere of Venus by the sun's photochemical action on carbon dioxide, sulfur dioxide, and water vapour. Ultraviolet photons of wavelengths less than 169 nm can photodissociate carbon dioxide into carbon monoxide and atomic oxygen. Atomic oxygen is highly reactive. When it reacts with sulfur dioxide, a trace component of the Venerian atmosphere, the result is sulfur trioxide, which can combine with water vapor, another trace component of Venus's atmosphere, to yield sulfuric acid.
In the upper, cooler portions of Venus's atmosphere, sulfuric acid exists as a liquid, and thick sulfuric acid clouds completely obscure the planet's surface when viewed from above. The main cloud layer extends from 45–70 km above the planet's surface, with thinner hazes extending as low as 30 and as high as 90 km above the surface.
Infrared spectra from NASA's Galileo mission show distinct absorptions on Jupiter's moon Europa that have been attributed to one or more sulfuric acid hydrates. The interpretation of the spectra is somewhat controversial. Some planetary scientists prefer to assign the spectral features to the sulfate ion, perhaps as part of one or more minerals on Europa's surface.[2]
# Manufacture
Sulfuric acid is produced from sulfur, oxygen and water via the contact process.
In the first step, sulfur is burned to produce sulfur dioxide.
This is then oxidised to sulfur trioxide using oxygen in the presence of a vanadium(V) oxide catalyst.
Finally the sulfur trioxide is treated with water (usually as 97-98% H2SO4 containing 2-3% water) to produce 98-99% sulfuric acid.
Note that directly dissolving SO3 in water is not practical due to the highly exothermic nature of the reaction, forming a corrosive mist instead of a liquid.
Alternatively, SO3 can be absorbed into H2SO4 to produce oleum (H2S2O7), which may then be mixed with water to form sulfuric acid.
Oleum is reacted with water to form concentrated H2SO4.
# Physical properties
## Forms of sulfuric acid
Although nearly 100% sulfuric acid can be made, this loses SO3 at the boiling point to produce 98.3% acid. The 98% grade (18M) is more stable in storage, and is the usual form of what is described as concentrated sulfuric acid. Other concentrations are used for different purposes. Some common concentrations are
- 10%, dilute sulfuric acid for laboratory use,
- 33.5%, battery acid (used in lead-acid batteries),
- 62.18%, chamber or fertilizer acid,
- 77.67%, tower or Glover acid,
- 98%, concentrated acid.
Different purities are also available. Technical grade H2SO4 is impure and often colored, but is suitable for making fertilizer. Pure grades such as United States Pharmacopoeia (USP) grade are used for making pharmaceuticals and dyestuffs.
When high concentrations of SO3(g) are added to sulfuric acid, H2S2O7, called pyrosulfuric acid, fuming sulfuric acid or oleum or, less commonly, Nordhausen acid, is formed. Concentrations of oleum are either expressed in terms of% SO3 (called% oleum) or as% H2SO4 (the amount made if H2O were added); common concentrations are 40% oleum (109% H2SO4) and 65% oleum (114.6% H2SO4). Pure H2S2O7 is a solid with melting point 36°C.
## Polarity and conductivity
Anhydrous H2SO4 is a very polar liquid, having a dielectric constant of around 100. It has a high electrical conductivity, caused by dissociation through protonating itself, a process known as autoprotolysis, or autoionization.[3]
The equilibrium constant for the autoprotolysis is[3]
The comparable equilibrium constant for water, Kw is 10−14, a factor of 1010 (10 billion) smaller.
In spite of the viscosity of the acid, the effective conductivities of the H3SO4+ and HSO4− ions are high due to an intra-molecular proton-switch mechanism (analogous to the Grotthuss mechanism in water), making sulfuric acid a good conductor. It is also an excellent solvent for many reactions.
The equilibrium is actually more complex than shown above; 100% H2SO4 contains the following species at equilibrium (figures shown as millimol per kg solvent): HSO4− (15.0), H3SO4+ (11.3), H3O+ (8.0), HS2O7− (4.4), H2S2O7 (3.6), H2O (0.1).[3]
# Chemical properties
## Reaction with water
The hydration reaction of sulfuric acid is highly exothermic. If water is added to the concentrated sulfuric acid, it can react, boil and spit dangerously. One should always add the acid to the water rather than the water to the acid. The necessity for this safety precaution is due to the relative densities of these two liquids. Water is less dense than sulfuric acid, meaning water will tend to float on top of this acid. The reaction is best thought of as forming hydronium ions, by
and then
Because the hydration of sulfuric acid is thermodynamically favorable, sulfuric acid is an excellent dehydrating agent. The affinity of sulfuric acid for water is sufficiently strong that it will remove hydrogen and oxygen atoms from other compounds; for example, mixing starch (C6H12O6)n and concentrated sulfuric acid will give elemental carbon and water which is absorbed by the sulfuric acid (which becomes slightly diluted): (C6H12O6)n → 6C + 6H2O. The effect of this can be seen when concentrated sulfuric acid is spilled on paper; the cellulose reacts to give a burned appearance, the carbon appears much as soot would in a fire. A more dramatic reaction occurs when sulfuric acid is added to a tablespoon of white sugar; a rigid column of black, porous carbon will quickly emerge. The carbon will smell strongly of caramel.
## Other reactions
As an acid, sulfuric acid reacts with most bases to give the corresponding sulfate. For example, copper(II) sulfate. This blue salt of copper, commonly used for electroplating and as a fungicide, is prepared by the reaction of copper(II) oxide (CuO) with sulfuric acid:
Sulfuric acid can also be used to displace weaker acids from their salts. Reaction with sodium acetate, for example, displaces acetic acid:
Similarly, reacting sulfuric acid with potassium nitrate can be used to produce nitric acid and a precipitate of potassium bisulfate. When combined with nitric acid, sulfuric acid acts both as an acid and a dehydrating agent, forming the nitronium ion NO2+, which is important in nitration reactions involving electrophilic aromatic substitution. This type of reaction, where protonation occurs on an oxygen atom, is important in many organic chemistry reactions, such as Fischer esterification and dehydration of alcohols.
Sulfuric acid reacts with most metals via a single displacement reaction to produce hydrogen gas and the metal sulfate. Dilute H2SO4 attacks iron, aluminium, zinc, manganese, magnesium and nickel, but reactions with tin and copper require the acid to be hot and concentrated. Lead and tungsten, however, are resistant to sulfuric acid. The reaction with iron (shown) is typical for most of these metals, but the reaction with tin is unusual in that it produces sulfur dioxide rather than hydrogen.
Sulfuric acid undergoes electrophilic aromatic substitution with aromatic compounds to give the corresponding sulfonic acids:[4]
# Uses
Sulfuric acid is a very important commodity chemical, and indeed, a nation's sulfuric acid production is a good indicator of its industrial strength.[5] The major use (60% of total production worldwide) for sulfuric acid is in the "wet method" for the production of phosphoric acid, used for manufacture of phosphate fertilizers as well as trisodium phosphate for detergents. In this method, phosphate rock is used, and more than 100 million tonnes are processed annually. This raw material is shown below as fluorapatite, though the exact composition may vary. This is treated with 93% sulfuric acid to produce calcium sulfate, hydrogen fluoride (HF) and phosphoric acid. The HF is removed as hydrofluoric acid. The overall process can be represented as:
Sulfuric acid is used in large quantities by the iron and steelmaking industry to remove oxidation, rust and scale from rolled sheet and billets prior to sale to the automobile and white-goods industry. Used acid is often recycled using a Spent Acid Regeneration (SAR) plant. These plants combust spent acid with natural gas, refinery gas, fuel oil or other fuel sources. This combustion process produces gaseous sulfur dioxide (SO2) and sulfur trioxide (SO3) which are then used to manufacture "new" sulfuric acid. SAR plants are common additions to metal smelting plants, oil refineries, and other industries where sulfuric acid is consumed in bulk, as operating a SAR plant is much cheaper than the recurring costs of spent acid disposal and new acid purchases.
Ammonium sulfate, an important nitrogen fertilizer, is most commonly produced as a byproduct from coking plants supplying the iron and steel making plants. Reacting the ammonia produced in the thermal decomposition of coal with waste sulfuric acid allows the ammonia to be crystallized out as a salt (often brown because of iron contamination) and sold into the agro-chemicals industry.
Another important use for sulfuric acid is for the manufacture of aluminium sulfate, also known as paper maker's alum. This can react with small amounts of soap on paper pulp fibers to give gelatinous aluminium carboxylates, which help to coagulate the pulp fibers into a hard paper surface. It is also used for making aluminium hydroxide, which is used at water treatment plants to filter out impurities, as well as to improve the taste of the water. Aluminum sulfate is made by reacting bauxite with sulfuric acid:
Sulfuric acid is used for a variety of other purposes in the chemical industry. For example, it is the usual acid catalyst for the conversion of cyclohexanoneoxime to caprolactam, used for making nylon. It is used for making hydrochloric acid from salt via the Mannheim process. Much H2SO4 is used in petroleum refining, for example as a catalyst for the reaction of isobutane with isobutylene to give isooctane, a compound that raises the octane rating of gasoline (petrol). Sulfuric acid is also important in the manufacture of dyestuffs, pigments (such as titanium dioxide), solutions, and is the "acid" in lead-acid (car) batteries.
Sulfuric acid is also used as a general dehydrating agent in its concentrated form (see Reaction with water).
## Sulfur-iodine cycle
The sulfur-iodine cycle is a series of thermo-chemical processes used to obtain hydrogen. It consists of three chemical reactions whose net reactant is water and whose net products are hydrogen and oxygen.
The sulfur and iodine compounds are recovered and reused, hence the consideration of the process as a cycle. This process is endothermic and must occur at high temperatures, so energy in the form of heat has to be supplied.
The sulfur-iodine cycle has been proposed as a way to supply hydrogen for a hydrogen-based economy. It does not require hydrocarbons like current methods of steam reforming.
The sulfur-iodine cycle is currently being researched as a feasible method of obtaining hydrogen, but the concentrated, corrosive acid at high temperatures poses currently insurmountable safety hazards if the process were built on large-scale.
# History
The discovery of sulfuric acid is credited to the 8th century Arabian chemist and alchemist, Jabir ibn Hayyan (Geber). The acid was later studied by 9th century Persian physician and alchemist Ibn Zakariya al-Razi (Rhazes), who obtained the substance by dry distillation of minerals including iron(II) sulfate heptahydrate, FeSO4 • 7H2O, and copper(II) sulfate pentahydrate, CuSO4 • 5H2O. When heated, these compounds decompose to iron(II) oxide and copper(II) oxide, respectively, giving off water and sulfur trioxide, which combine to produce a dilute solution of sulfuric acid. This method was popularized in Europe through translations of Arabic and Persian treatises, as well as books by European alchemists, such as the 13th-century German Albertus Magnus.
Sulfuric acid was known to medieval European alchemists as oil of vitriol, spirit of vitriol, or simply vitriol, among other names. The word vitriol derives from the Latin vitreus, 'glass', referring to the glassy appearance of the sulfate salts, which also carried the name vitriol. Salts called by this name included copper(II) sulfate (blue vitriol, or rarely Roman vitriol), zinc sulfate (white vitriol), iron(II) sulfate (green vitriol), iron(III) sulfate (vitriol of Mars), and cobalt(II) sulfate (red vitriol).
Vitriol was widely considered the most important alchemical substance, intended to be used as a philosopher's stone. Highly purified vitriol was used as a medium for reacting other substances. This was largely because the acid does not react with gold, production of which was often the final goal of alchemical processes. The importance of vitriol to alchemy is highlighted in the alchemical motto, Visita Interiora Terrae Rectificando Invenies Occultum Lapidem which is a backronym meaning ('Visit the interior of the earth and rectifying (i.e. purifying) you will find the hidden/secret stone'), found in L'Azoth des Philosophes by the 15th Century alchemist Basilius Valentinus, .
In the 17th century, the German-Dutch chemist Johann Glauber prepared sulfuric acid by burning sulfur together with saltpeter (potassium nitrate, KNO3), in the presence of steam. As saltpeter decomposes, it oxidizes the sulfur to SO3, which combines with water to produce sulfuric acid. In 1736, Joshua Ward, a London pharmacist, used this method to begin the first large-scale production of sulfuric acid.
In 1746 in Birmingham, John Roebuck adapted this method to produce sulfuric acid in lead-lined chambers, which were stronger, less expensive, and could be made larger than the previously used glass containers. This lead chamber process allowed the effective industrialization of sulfuric acid production. After several refinements, this method remained the standard for sulfuric acid production for almost two centuries.[6][7]
Sulfuric acid created by John Roebuck's process only approached a 35–40% concentration. Later refinements to the lead-chamber process by French chemist Joseph-Louis Gay-Lussac and British chemist John Glover improved the yield to 78%. However, the manufacture of some dyes and other chemical processes require a more concentrated product. Throughout the 18th century, this could only be made by dry distilling minerals in a technique similar to the original alchemical processes. Pyrite (iron disulfide, FeS2) was heated in air to yield iron (II) sulfate, FeSO4, which was oxidized by further heating in air to form iron(III) sulfate, Fe2(SO4)3, which, when heated to 480 °C, decomposed to iron(III) oxide and sulfur trioxide, which could be passed through water to yield sulfuric acid in any concentration. However, the expense of this process prevented the large-scale use of concentrated sulfuric acid.
In 1831, British vinegar merchant Peregrine Phillips patented the contact process, which was a far more economical process for producing sulfur trioxide and concentrated sulfuric acid. Today, nearly all of the world's sulfuric acid is produced using this method.
# Safety
## Laboratory hazards
The corrosive properties of sulfuric acid are accentuated by its highly exothermic reaction with water. Hence burns from sulfuric acid are potentially more serious than those of comparable strong acids (e.g. hydrochloric acid), as there is additional tissue damage due to dehydration and particularly due to the heat liberated by the reaction with water; i.e. secondary thermal damage. The danger is obviously greater with more concentrated preparations of sulfuric acid, but it should be remembered that even the normal laboratory "dilute" grade (approx. 1 M, 10%) will char paper by dehydration if left in contact for a sufficient amount of time. Solutions equal to or stronger than 1.5 M should be labeled CORROSIVE, while solutions greater than 0.5 M but less than 1.5 M should be labeled IRRITANT. Fuming sulfuric acid (oleum) is not recommended for use in schools due to it being quite hazardous. The standard first aid treatment for acid spills on the skin is, as for other corrosive agents, irrigation with large quantities of water. However, the acid should be neutralised first by rinsing with a base (e.g. calcium hydroxide solution), because the water used in washing will react with the acid and increase the chance of secondary damage. Washing should be continued for at least ten to fifteen minutes in order to cool the tissue surrounding the acid burn and to prevent secondary damage. Contaminated clothing must be removed immediately and the underlying skin washed thoroughly.
Preparation of the diluted acid can also be dangerous due to the heat released in the dilution process. It is essential that the concentrated acid is added to water and not the other way round, to take advantage of the relatively high heat capacity of water. Addition of water to concentrated sulfuric acid leads at best to the dispersal of a sulfuric acid aerosol, at worst to an explosion. Preparation of solutions greater than 6 M (35%) in concentration is the most dangerous, as the heat produced can be sufficient to boil the diluted acid: efficient mechanical stirring and external cooling (e.g. an ice bath) are essential.
## Industrial hazards
Although sulfuric acid is non-flammable, contact with metals in the event of a spillage can lead to the liberation of hydrogen gas. The dispersal of acid aerosols and gaseous sulfur dioxide is an additional hazard of fires involving sulfuric acid.
Sulfuric acid is not considered toxic besides its obvious corrosive hazard, and the main occupational risks are skin contact leading to burns (see above) and the inhalation of aerosols.[8] Exposure to aerosols at high concentrations leads to immediate and severe irritation of the eyes, respiratory tract and mucous membranes: this ceases rapidly after exposure, although there is a risk of subsequent pulmonary edema if tissue damage has been more severe. At lower concentrations, the most commonly reported symptom of chronic exposure to sulfuric acid aerosols is erosion of the teeth, found in virtually all studies: indications of possible chronic damage to the respiratory tract are inconclusive as of 1997. In the United States, the permissible exposure limit (PEL) for sulfuric acid is fixed at 1 mg/m³: limits in other countries are similar. Interestingly there have been reports of sulfuric acid ingestion leading to vitamin B12 deficiency with subacute combined degeneration. The spinal cord is most often affected in such cases, but the optic nerves may show demyelination, loss of axons and gliosis.
# Legal restrictions
International commerce of sulfuric acid is controlled under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988, which lists sulfuric acid under Table II of the convention as a chemical frequently used in the illicit manufacture of narcotic drugs or psychotropic substances.[9]
In the United States of America, sulfuric acid is included in List II of the list of essential or precursor chemicals established pursuant to the Chemical Diversion and Trafficking Act. Accordingly, transactions of sulfuric acid—such as sales, transfers, exports from and imports to the United States—are subject to regulation and monitoring by the Drug Enforcement Administration.[10][11][12]
# In fiction
In several films, cartoons and TV shows, especially Science-Fiction shows and films, sulfuric acid is sometimes depicted as a bubbling green steaming liquid, sometimes capable of dissolving almost anything in an instant. This is purely for visual appeal, since boiling green acid is more dangerous-looking than the actual clear and syrupy form of sulfuric acid. The use of sulfuric acid as a weapon in crimes of assault, known as "vitriol throwing", has at times been sufficiently common (if sensational) to make its way into novels and short stories. Examples include The Adventure of the Illustrious Client by Arthur Conan Doyle, The Love of Long Ago by Guy de Maupassant, Nineteen Eighty-Four by George Orwell and Brighton Rock by Graham Greene. The novel Veronika Decides to Die by Paulo Coelho talks of a girl who has attempted to commit suicide and ends up with vitriol poisoning. The graphic novel, Shake Girl, is dedicated to over 100 Cambodian victims who have suffered from burns caused by sulfuric acid. In the movie Untraceable,Griffin Dowd ( played by Colin Hanks ) is submerged in sulfuric acid.
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Sulston score
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Sulston score
The Sulston Score is an equation used in DNA mapping to numerically assess the likelihood that a given "fingerprint" similarity between two DNA clones is merely a result of chance. Used as such, it is a test of statistical significance. That is, low values imply that similarity is significant, suggesting that two DNA clones overlap one another and that the given similarity is not just a chance event. The name is an eponym that refers to John Sulston by virtue of his being the lead author of the paper that first proposed the equation's use.
# The Overlap Problem in Mapping
Each clone in a DNA mapping project has a "fingerprint", i.e. a set of DNA fragment lengths inferred from (1) enzymatically digesting the clone, (2) separating these fragments on a gel, and (3) estimating their lengths based on gel location. For each pairwise clone comparison, one can establish how many lengths from each set match-up. Cases having at least 1 match indicate that the clones might overlap because matches may represent the same DNA. However, the underlying sequences for each match are not known. Consequently, two fragments whose lengths match may still represent different sequences. In other words, matches do not conclusively indicate overlaps. The problem is instead one of using matches to probabilistically classify overlap status.
### Mathematical Scores in Overlap Assessment
Biologists have used a variety of means (often in combination) to discern clone overlaps in DNA mapping projects. While many are biological, i.e. looking for shared markers, others are basically mathematical, usually adopting probabilistic and/or statistical approaches.
# Sulston Score Exposition
The Sulston Score is rooted in the concepts of Bernoulli and Binomial processes, as follows. Consider two clones, \alpha and \beta, having m and n measured fragment lengths, respectively, where m \ge n. That is, clone \alpha has at least as many fragments as clone \beta, but usually more. The Sulston score is the probability that at least h fragment lengths on clone \beta will be matched by any combination of lengths on \alpha. Intuitively, we see that, at most, there can be n matches. Thus, for a given comparison between two clones, one can measure the statistical significance of a match of h fragments, i.e. how likely it is that this match occurred simply as a result of random chance. Very low values would indicate a significant match that is highly unlikely to have arisen by pure chance, while higher values would suggest that the given match could be just a coincidence.
One of the basic assumptions is that fragments are uniformly distributed on a gel, i.e. a fragment has an equal likelihood of appearing anywhere on the gel. Since gel position is an indicator of fragment length, this assumption is equivalent to presuming that the fragment lengths are uniformly distributed. The measured location of any fragment x, has an associated error tolerance of \pm t, so that its true location is only known to lie within the segment x \pm t.
### Derivation
In what follows, let us refer to individual fragment lengths simply as lengths. Consider a specific length j on clone \beta and a specific length i on clone \alpha. These two lengths are arbitrarily selected from their respective sets i \in \{1, 2, \dots, m\} and j \in \{1, 2, \dots, n\}. We assume that the gel location of fragment j has been determined and we want
the probability of the event E_{ij} that the location of fragment i will match that of j. Geometrically, i will be declared to match j if it falls inside the window of size 2 t around j. Since fragment i could occur anywhere in the gel of length G, we have P \langle E_{ij} \rangle = 2 t / G. The probability that i does not match j is simply the complement, i.e. P \langle E_{i,j}^C \rangle = 1 - 2 t / G, since it must either match or not match.
Now, let us expand this to compute the probability that no length on clone \alpha matches the single particular length j on clone \beta. This is simply the intersection of all individual trials i \in \{1, 2, \dots, m\} where the event E_{i,j}^C occurs, i.e. P \langle E_{1,j}^C \cap E_{2,j}^C \cap \cdots \cap E_{m,j}^C \rangle. This can be restated verbally as: length 1 on clone \alpha does not match length j on clone \beta and length 2 does not match length j and length 3 does not match, etc. Since each of these trials is assumed to be independent, the probability is simply
Of course, the actual event of interest is the complement: i.e. there is not "no matches". In other words, the probability of one or more matches is p = 1 - \left(1 - 2 t / G\right)^m. Formally, p is the probability that at least one band on clone \alpha matches band j on clone \beta.
This event is taken as a Bernoulli trial having a "success" (matching) probability of p for band j. However, we want to describe the process over all the bands on clone \beta. Since p is constant, the number of matches is distributed binomially. Given h observed matches, the Sulston score Sis simply the probability of obtaining at least h matches by chance according to
where C_{n,j} are binomial coefficients.
# Mathematical Refinement
In a 2005 paper, Michael Wendl gave an example showing that the assumption of independent trials is not valid. So, although the traditional Sulston score does indeed represent a Probability distribution, it is not the distribution characteristic of the fingerprint problem. Wendl went on to give the general solution for this problem in terms of the Bell polynomials, showing the traditional score overpredicts P-values by orders of magnitude. (P-values are very small in this problem, so we are talking, for example, about probabilities on the order of 10e-14 versus 10e-12, the latter Sulston value being 2 orders of magnitude too high.) This solution provides a basis for determining when a problem has sufficient information content to be treated by the probabilistic approach and is also a general solution to the birthday problem of 2 types.
A disadvantage of the exact solution is that its evaluation is computationally intensive and, in fact, is not feasible for comparing large clones. Some fast approximations for this problem have been proposed.
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Sulston score
The Sulston Score is an equation used in DNA mapping to numerically assess the likelihood that a given "fingerprint" similarity between two DNA clones is merely a result of chance. Used as such, it is a test of statistical significance. That is, low values imply that similarity is significant, suggesting that two DNA clones overlap one another and that the given similarity is not just a chance event. The name is an eponym that refers to John Sulston by virtue of his being the lead author of the paper that first proposed the equation's use[1].
# The Overlap Problem in Mapping
Each clone in a DNA mapping project has a "fingerprint", i.e. a set of DNA fragment lengths inferred from (1) enzymatically digesting the clone, (2) separating these fragments on a gel, and (3) estimating their lengths based on gel location. For each pairwise clone comparison, one can establish how many lengths from each set match-up. Cases having at least 1 match indicate that the clones might overlap because matches may represent the same DNA. However, the underlying sequences for each match are not known. Consequently, two fragments whose lengths match may still represent different sequences. In other words, matches do not conclusively indicate overlaps. The problem is instead one of using matches to probabilistically classify overlap status.
### Mathematical Scores in Overlap Assessment
Biologists have used a variety of means (often in combination) to discern clone overlaps in DNA mapping projects. While many are biological, i.e. looking for shared markers, others are basically mathematical, usually adopting probabilistic and/or statistical approaches.
# Sulston Score Exposition
The Sulston Score is rooted in the concepts of Bernoulli and Binomial processes, as follows. Consider two clones, <math>\alpha</math> and <math>\beta</math>, having <math>m</math> and <math>n</math> measured fragment lengths, respectively, where <math>m \ge n</math>. That is, clone <math>\alpha</math> has at least as many fragments as clone <math>\beta</math>, but usually more. The Sulston score is the probability that at least <math>h</math> fragment lengths on clone <math>\beta</math> will be matched by any combination of lengths on <math>\alpha</math>. Intuitively, we see that, at most, there can be <math>n</math> matches. Thus, for a given comparison between two clones, one can measure the statistical significance of a match of <math>h</math> fragments, i.e. how likely it is that this match occurred simply as a result of random chance. Very low values would indicate a significant match that is highly unlikely to have arisen by pure chance, while higher values would suggest that the given match could be just a coincidence.
One of the basic assumptions is that fragments are uniformly distributed on a gel, i.e. a fragment has an equal likelihood of appearing anywhere on the gel. Since gel position is an indicator of fragment length, this assumption is equivalent to presuming that the fragment lengths are uniformly distributed. The measured location of any fragment <math>x</math>, has an associated error tolerance of <math>\pm t</math>, so that its true location is only known to lie within the segment <math>x \pm t</math>.
### Derivation
In what follows, let us refer to individual fragment lengths simply as lengths. Consider a specific length <math>j</math> on clone <math>\beta</math> and a specific length <math>i</math> on clone <math>\alpha</math>. These two lengths are arbitrarily selected from their respective sets <math>i \in \{1, 2, \dots, m\}</math> and <math>j \in \{1, 2, \dots, n\}</math>. We assume that the gel location of fragment <math>j</math> has been determined and we want
the probability of the event <math>E_{ij}</math> that the location of fragment <math>i</math> will match that of <math>j</math>. Geometrically, <math>i</math> will be declared to match <math>j</math> if it falls inside the window of size <math>2 t</math> around <math>j</math>. Since fragment <math>i</math> could occur anywhere in the gel of length <math>G</math>, we have <math>P \langle E_{ij} \rangle = 2 t / G</math>. The probability that <math>i</math> does not match <math>j</math> is simply the complement, i.e. <math>P \langle E_{i,j}^C \rangle = 1 - 2 t / G</math>, since it must either match or not match.
Now, let us expand this to compute the probability that no length on clone <math>\alpha</math> matches the single particular length <math>j</math> on clone <math>\beta</math>. This is simply the intersection of all individual trials <math>i \in \{1, 2, \dots, m\}</math> where the event <math>E_{i,j}^C</math> occurs, i.e. <math>P \langle E_{1,j}^C \cap E_{2,j}^C \cap \cdots \cap E_{m,j}^C \rangle</math>. This can be restated verbally as: length 1 on clone <math>\alpha</math> does not match length <math>j</math> on clone <math>\beta</math> and length 2 does not match length <math>j</math> and length 3 does not match, etc. Since each of these trials is assumed to be independent, the probability is simply
Of course, the actual event of interest is the complement: i.e. there is not "no matches". In other words, the probability of one or more matches is <math>p = 1 - \left(1 - 2 t / G\right)^m</math>. Formally, <math>p</math> is the probability that at least one band on clone <math>\alpha</math> matches band <math>j</math> on clone <math>\beta</math>.
This event is taken as a Bernoulli trial having a "success" (matching) probability of <math>p</math> for band <math>j</math>. However, we want to describe the process over all the bands on clone <math>\beta</math>. Since <math>p</math> is constant, the number of matches is distributed binomially. Given <math>h</math> observed matches, the Sulston score <math>S</math>is simply the probability of obtaining at least <math>h</math> matches by chance according to
where <math>C_{n,j}</math> are binomial coefficients.
# Mathematical Refinement
In a 2005 paper[2], Michael Wendl gave an example showing that the assumption of independent trials is not valid. So, although the traditional Sulston score does indeed represent a Probability distribution, it is not the distribution characteristic of the fingerprint problem. Wendl went on to give the general solution for this problem in terms of the Bell polynomials, showing the traditional score overpredicts P-values by orders of magnitude. (P-values are very small in this problem, so we are talking, for example, about probabilities on the order of 10e-14 versus 10e-12, the latter Sulston value being 2 orders of magnitude too high.) This solution provides a basis for determining when a problem has sufficient information content to be treated by the probabilistic approach and is also a general solution to the birthday problem of 2 types.
A disadvantage of the exact solution is that its evaluation is computationally intensive and, in fact, is not feasible for comparing large clones[2]. Some fast approximations for this problem have been proposed[3].
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https://www.wikidoc.org/index.php/Sulston_score
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41f50a7f369565a65137324d1d504f2b3126adf2
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wikidoc
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Sultamicillin
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Sultamicillin
# Overview
Sultamicillin is an oral form of the antibiotic combination (codrug or mutual prodrug) ampicillin/sulbactam. It contains esterified ampicillin and sulbactam and is marketed under a number of trade names, including Saltum from Morepen Lab and Unasyn from Pfizer.
The pharmacokinetic properties of sultamicillin are improved compared to a combination of ampicillin and sulbactam. Sultamicillin increases the absorption and decreases the chances of diarrhea and dysentery. The inclusion of sulbactam extends ampicillin's spectrum of action to beta-lactamase producing strains of bacteria. Oral sulbactam with parenteral form provides a regimen of continuous sulbactam therapy throughout the treatment, resulting in better clinical results.
# Chemical evaluation
Sultamicillin is a mutual prodrug of ampicillin and sulbactam. Ampicillin, a semi-synthetic orally active broad spectrum antibiotic, is linked via a methylene group with a beta-lactamase inhibitor. Sultamicillin is chemically oxymethyl penicillinate sulfone ester of ampicillin.
# Mechanism of action
After absorption, sultamicillin releases ampicillin and sulbactam into the system, so all the antibacterial efficacy of sultamicillin is due to ampicillin and sulbactam. Ampicillin exerts antibacterial activity against sensitive organisms by inhibiting biosynthesis of cell wall mucopeptide where as sulbactam irreversibly inhibits most important beta-lactamases that occur in resistant strains.
# Indications
Indications for sultamicillin include:
- Skin and soft tissue infections - furuncles, carbuncles, cellulitis, paronychia, impetigo contagiosa, diabetic foot ulcers and abscesses caused by Staphylococcus aureus and Streptococcus pyogenes.
- Upper respiratory tract infections - pharyngitis and tonsillitis caused by S. pyogenes and S. aureus. Acute and chronic sinusitis caused by S. aureus, S. pneumoniae, H. influenzae and S. progenies. Otis media, particularly suppurative otis media, with or without mastoiditis antrum.
- Lower respiratory tract infections - bacterial pneumonias, bronchitis, bronchiestasis caused by S. pneumoniae, H. influenzae, Staphylococcus aureus and S. progenies. Acute exacerbations of COPD.
- Urinary tract infections - pyelonephritis, cystitis caused by Escherichia coli, Proteus mirabilis, Klebsiella, Enterobacter and Staphylococcus aureus.
- Surgical infections - prophylaxis and treatment of surgical site infections, peri-operative prophylaxis in orthopaedic and cardiovascular surgery.
- Gynecological infections - Caused by beta-lactamase producing strains of E. coli and Bacteroides sp. (including B. fragilis).
- Infections of the gastrointestinal tract - Bacterial esophagitis, treatment of H. pylori infections as a part of MDT in ulcer management.
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Sultamicillin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sultamicillin is an oral form of the antibiotic combination (codrug or mutual prodrug) ampicillin/sulbactam. It contains esterified ampicillin and sulbactam and is marketed under a number of trade names, including Saltum from Morepen Lab and Unasyn from Pfizer.
The pharmacokinetic properties of sultamicillin are improved compared to a combination of ampicillin and sulbactam. Sultamicillin increases the absorption and decreases the chances of diarrhea and dysentery. The inclusion of sulbactam extends ampicillin's spectrum of action to beta-lactamase producing strains of bacteria. Oral sulbactam with parenteral form provides a regimen of continuous sulbactam therapy throughout the treatment, resulting in better clinical results.
# Chemical evaluation
Sultamicillin is a mutual prodrug of ampicillin and sulbactam. Ampicillin, a semi-synthetic orally active broad spectrum antibiotic, is linked via a methylene group with a beta-lactamase inhibitor. Sultamicillin is chemically oxymethyl penicillinate sulfone ester of ampicillin.
# Mechanism of action
After absorption, sultamicillin releases ampicillin and sulbactam into the system, so all the antibacterial efficacy of sultamicillin is due to ampicillin and sulbactam. Ampicillin exerts antibacterial activity against sensitive organisms by inhibiting biosynthesis of cell wall mucopeptide where as sulbactam irreversibly inhibits most important beta-lactamases that occur in resistant strains.
# Indications
Indications for sultamicillin include:
- Skin and soft tissue infections - furuncles, carbuncles, cellulitis, paronychia, impetigo contagiosa, diabetic foot ulcers and abscesses caused by Staphylococcus aureus and Streptococcus pyogenes.
- Upper respiratory tract infections - pharyngitis and tonsillitis caused by S. pyogenes and S. aureus. Acute and chronic sinusitis caused by S. aureus, S. pneumoniae, H. influenzae and S. progenies. Otis media, particularly suppurative otis media, with or without mastoiditis antrum.
- Lower respiratory tract infections - bacterial pneumonias, bronchitis, bronchiestasis caused by S. pneumoniae, H. influenzae, Staphylococcus aureus and S. progenies. Acute exacerbations of COPD.
- Urinary tract infections - pyelonephritis, cystitis caused by Escherichia coli, Proteus mirabilis, Klebsiella, Enterobacter and Staphylococcus aureus.
- Surgical infections - prophylaxis and treatment of surgical site infections, peri-operative prophylaxis in orthopaedic and cardiovascular surgery.
- Gynecological infections - Caused by beta-lactamase producing strains of E. coli and Bacteroides sp. (including B. fragilis).
- Infections of the gastrointestinal tract - Bacterial esophagitis, treatment of H. pylori infections as a part of MDT in ulcer management.
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https://www.wikidoc.org/index.php/Sultamicillin
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1d01588a435a7ea9aafa62982e4e8a4cf259b256
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wikidoc
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Sumatran Pine
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Sumatran Pine
The Sumatran Pine (Pinus merkusii) is a pine native to southeast Asia, mainly in the mountains of northern Sumatra, and with two outlying populations, on Mount Kerinci and Mount Talang in central Sumatra, and in the Philippines on Mindoro and the Zambales Mountains of western Luzon. The population in central Sumatra, between 1° 40' and 2° 06' S latitude, is the only natural occurrence of any pine south of the Equator. It generally occurs at moderate altitudes, mostly from 400-1500 m, but occasionally as low as 90 m and up to 2000 m.
It is a medium-sized to large tree, reaching 25-45 m tall and with a trunk diameter of up to 1 m. The bark is orange-red, thick and deeply fissured at the base of the trunk, and thin and flaky in the upper crown. The leaves ('needles') are in pairs, very slender, 15-20 cm long and less than 1 mm thick, green to yellowish green. The cones are narrow conic, 5-8 cm long and 2 cm broad at the base when closed, green at first, ripening glossy red-brown. They open to 4-5 cm broad at maturity to release the seeds. The seeds are 5-6 mm long, with a 15-20 mm wing, and are wind-dispersed.
Sumatran Pine is closely related to Tenasserim Pine Pinus latteri, which occurs further north in southeast Asia from Myanmar to Vietnam; some botanists treat the two as conspecific (under the name P. merkusii, which was described first), but the Tenasserim Pine differs in longer (18-27 cm) and stouter (over 1 mm thick) leaves and larger cones with thicker scales, the cones often remaining closed for some time after maturity. It is also related to the group of Mediterranean pines including Aleppo Pine and Turkish Pine, which share many features with it.
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Sumatran Pine
The Sumatran Pine (Pinus merkusii) is a pine native to southeast Asia, mainly in the mountains of northern Sumatra, and with two outlying populations, on Mount Kerinci and Mount Talang in central Sumatra, and in the Philippines on Mindoro and the Zambales Mountains of western Luzon. The population in central Sumatra, between 1° 40' and 2° 06' S latitude, is the only natural occurrence of any pine south of the Equator. It generally occurs at moderate altitudes, mostly from 400-1500 m, but occasionally as low as 90 m and up to 2000 m.
It is a medium-sized to large tree, reaching 25-45 m tall and with a trunk diameter of up to 1 m. The bark is orange-red, thick and deeply fissured at the base of the trunk, and thin and flaky in the upper crown. The leaves ('needles') are in pairs, very slender, 15-20 cm long and less than 1 mm thick, green to yellowish green. The cones are narrow conic, 5-8 cm long and 2 cm broad at the base when closed, green at first, ripening glossy red-brown. They open to 4-5 cm broad at maturity to release the seeds. The seeds are 5-6 mm long, with a 15-20 mm wing, and are wind-dispersed.
Sumatran Pine is closely related to Tenasserim Pine Pinus latteri, which occurs further north in southeast Asia from Myanmar to Vietnam; some botanists treat the two as conspecific (under the name P. merkusii, which was described first), but the Tenasserim Pine differs in longer (18-27 cm) and stouter (over 1 mm thick) leaves and larger cones with thicker scales, the cones often remaining closed for some time after maturity. It is also related to the group of Mediterranean pines including Aleppo Pine and Turkish Pine, which share many features with it.
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https://www.wikidoc.org/index.php/Sumatran_Pine
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088ad796077df5db42142e611d11cb144eeb4c9f
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wikidoc
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Sunflower oil
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Sunflower oil
Sunflower oil is the non-volatile oil expressed from sunflower (Helianthus annuus) seeds. Sunflower oil is commonly used in food as a frying oil, and in cosmetic formulations as an emollient.
# Composition
Sunflower oil contains predominantly linoleic acid in triglyceride form. The British Pharmacopoeia lists the following profile:
- Palmitic acid : 4 - 9%,
- Stearic acid : 1 - 7%,
- Oleic acid : 14 - 40%,
- Linoleic acid : 48 - 74%.
There are several types of sunflower oils produced, such as high linoleic, high oleic and mid oleic.
High linoleic sunflower oil typically has at least 69% linoleic acid. High oleic sunflower oil has at least 82% oleic acid. Variation in fatty acid profile is strongly influenced by both genetics and climate.
Sunflower oil also contains lecithin, tocopherols, carotenoids and waxes. Sunflower oil's properties are typical of a vegetable triglyceride oil. Sunflower oil is produced from oil type sunflower seeds. Sunflower oil is light in taste and appearance and has a high Vitamin E content. It is a combination of mono-unsaturated and polyunsaturated fats with low saturated fat levels.
# Physical properties
Sunflower oil is liquid at room temperature. The refined oil is clear and slightly amber-colored with a slightly fatty odor.
# Uses
As a frying oil, sunflower oil behaves as a typical vegetable triglyceride. In cosmetics, it has smoothing properties and is considered noncomedogenic. Only the high-oleic variety possesses shelf life sufficient for commercial cosmetic formulation. Sunflower oil's INCI name is Helianthus Annuus (Sunflower) Seed Oil.
# Health benefits
There are a variety of health benefits associated with the consumption of sunflower oil.
## Diet and cardiovascular benefits
Sunflower oil is high in the essential vitamin E and low in saturated fat. The two most common types of sunflower oil are linoleic and high oleic. Linoleic sunflower oil is a common cooking oil that has high levels of the essential fatty acids called polyunsaturated fat. It is also known for having a clean taste and low levels of trans fat. High oleic sunflower oils are classified as having monounsaturated levels of 80% and above. Newer versions of sunflower oil have been developed as a hybrid containing linoleic acid. They have monounsaturated levels lower than other oleic sunflower oils. The hybrid oil also has lower saturated fat levels than linoleic sunflower oil . Sunflower oil of any kind has been shown to have cardiovascular benefits as well. Diets combined with a low fat content and high levels of oleic acid have been suggested to lower cholesterol which, in turn, results in a smaller risk of heart disease . Sunflower oils fit this criteria. Studies of adults suggested that a balanced diet in which small quantities of saturated fats are replaced with sunflower oil has detectable cholesterol-reducing benefits. Research suggests that lower cholesterol levels can be caused by balances of polyunsaturated and monounsaturated fatty acids. Sunflower oil may help with this balance .
## Restaurant and food industry uses
Restaurants and food manufacturers are becoming aware of the health benefits of sunflower oil. The oil can be used in conditions with extremely high cooking temperatures . It may also help food stay fresher and healthier for longer periods of time . Food manufacturers are starting to use sunflower oil in an effort to lower the levels of trans fat in mass produced foods . A number of common snack foods currently contain sunflower oil, including Kettle Chips, Sun Chips, Sunflower Chips, Ruffles, Walkers and Lay's potato chips; the recipe of the latter was modified in late 2006 in order to include the oil.
## Sunflower oil as skin protection
Sunflower oil may also have suggested skin-health benefits. Sunflower oil, like other oils, can retain moisture in the skin. However, it may also provide a protective barrier that resists infection. Studies using sunflower oil have been conducted involving pre-term infants that are often susceptible to infection due to their underdeveloped skin. Research suggests that pre-term infants with low birth weight can benefit from sunflower oil skin treatments. Infections decreased by 41% in infants that received a daily skin treatment of sunflower oil. The sunflower oil provided a protective barrier against infection that was not otherwise present on the infant .
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Sunflower oil
Sunflower oil is the non-volatile oil expressed from sunflower (Helianthus annuus) seeds. Sunflower oil is commonly used in food as a frying oil, and in cosmetic formulations as an emollient.
# Composition
Sunflower oil contains predominantly linoleic acid in triglyceride form. The British Pharmacopoeia lists the following profile:[1]
- Palmitic acid : 4 - 9%,
- Stearic acid : 1 - 7%,
- Oleic acid : 14 - 40%,
- Linoleic acid : 48 - 74%.
There are several types of sunflower oils produced, such as high linoleic, high oleic and mid oleic.
High linoleic sunflower oil typically has at least 69% linoleic acid. High oleic sunflower oil has at least 82% oleic acid. Variation in fatty acid profile is strongly influenced by both genetics and climate.
Sunflower oil also contains lecithin, tocopherols, carotenoids and waxes. Sunflower oil's properties are typical of a vegetable triglyceride oil. Sunflower oil is produced from oil type sunflower seeds. Sunflower oil is light in taste and appearance and has a high Vitamin E content. It is a combination of mono-unsaturated and polyunsaturated fats with low saturated fat levels.
# Physical properties
Sunflower oil is liquid at room temperature. The refined oil is clear and slightly amber-colored with a slightly fatty odor.
# Uses
As a frying oil, sunflower oil behaves as a typical vegetable triglyceride. In cosmetics, it has smoothing properties and is considered noncomedogenic. Only the high-oleic variety possesses shelf life sufficient for commercial cosmetic formulation. Sunflower oil's INCI name is Helianthus Annuus (Sunflower) Seed Oil.
# Health benefits
There are a variety of health benefits associated with the consumption of sunflower oil.
## Diet and cardiovascular benefits
Sunflower oil is high in the essential vitamin E and low in saturated fat. The two most common types of sunflower oil are linoleic and high oleic. Linoleic sunflower oil is a common cooking oil that has high levels of the essential fatty acids called polyunsaturated fat. It is also known for having a clean taste and low levels of trans fat. High oleic sunflower oils are classified as having monounsaturated levels of 80% and above. Newer versions of sunflower oil have been developed as a hybrid containing linoleic acid. They have monounsaturated levels lower than other oleic sunflower oils. The hybrid oil also has lower saturated fat levels than linoleic sunflower oil [2]. Sunflower oil of any kind has been shown to have cardiovascular benefits as well. Diets combined with a low fat content and high levels of oleic acid have been suggested to lower cholesterol which, in turn, results in a smaller risk of heart disease [3]. Sunflower oils fit this criteria. Studies of adults suggested that a balanced diet in which small quantities of saturated fats are replaced with sunflower oil has detectable cholesterol-reducing benefits. Research suggests that lower cholesterol levels can be caused by balances of polyunsaturated and monounsaturated fatty acids. Sunflower oil may help with this balance [4].
## Restaurant and food industry uses
Restaurants and food manufacturers are becoming aware of the health benefits of sunflower oil. The oil can be used in conditions with extremely high cooking temperatures [4]. It may also help food stay fresher and healthier for longer periods of time [3]. Food manufacturers are starting to use sunflower oil in an effort to lower the levels of trans fat in mass produced foods [4]. A number of common snack foods currently contain sunflower oil, including Kettle Chips, Sun Chips, Sunflower Chips, Ruffles, Walkers and Lay's potato chips; the recipe of the latter was modified in late 2006 in order to include the oil.[5]
## Sunflower oil as skin protection
Sunflower oil may also have suggested skin-health benefits. Sunflower oil, like other oils, can retain moisture in the skin. However, it may also provide a protective barrier that resists infection. Studies using sunflower oil have been conducted involving pre-term infants that are often susceptible to infection due to their underdeveloped skin. Research suggests that pre-term infants with low birth weight can benefit from sunflower oil skin treatments. Infections decreased by 41% in infants that received a daily skin treatment of sunflower oil. The sunflower oil provided a protective barrier against infection that was not otherwise present on the infant [6].
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https://www.wikidoc.org/index.php/Sunflower_oil
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37453143fb8417c2bdc49a05b65a1f7a2f6be6a2
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wikidoc
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Superfetation
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Superfetation
Superfetation (also spelt superfoetation, based on a false etymology — see fetus) is the formation of a fetus while another fetus is already present in the uterus. When there are two separate instances of fertilisation during the same cycle, rather than different cycles, it is known as superfecundation.
Superfetation is claimed to be common in some species of animals, but is extremely rare in humans. It can occur only where there are two uteri, or where the menstrual cycle continues through pregnancy.
# In animals
Animals which have been claimed to be subject to superfetation include rodents (mice and rats), farm animals (horses and sheep), marsupials and primates (monkeys and humans). Superfetation has also been clearly demonstrated in poeciliid fish
# In humans
Reports of superfetation occurring long after the first impregnation have often been treated with suspicion and some have been clearly discredited. Other explanations have been given (and demonstrated) for different levels of development between twins. Artificially induced superfetation has, however, been demonstrated although only up to a short period after insemination.
In 2007, Ame and Lia Herrity, conceived 3 weeks apart, were born in the United Kingdom to Amelia Spence and George Herrity.
In May 2007, Harriet and Thomas Mullineux, also conceived 3 weeks apart, were born in Benfleet, Essex UK to Charlotte and Matt Mullineux,
## Hoaxes
Flavia d'Angelo, an Italian woman claiming to have become pregnant with triplets three months after initially getting pregnant, caused global media interest in 2001. However, it was later revealed to be a hoax.
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Superfetation
Superfetation (also spelt superfoetation, based on a false etymology — see fetus) is the formation of a fetus while another fetus is already present in the uterus. When there are two separate instances of fertilisation during the same cycle, rather than different cycles, it is known as superfecundation.
Superfetation is claimed to be common in some species of animals, but is extremely rare in humans. It can occur only where there are two uteri, or where the menstrual cycle continues through pregnancy.
# In animals
Animals which have been claimed to be subject to superfetation include rodents (mice and rats), farm animals (horses and sheep), marsupials and primates (monkeys and humans). Superfetation has also been clearly demonstrated in poeciliid fish [1]
# In humans
Reports of superfetation occurring long after the first impregnation have often been treated with suspicion and some have been clearly discredited. Other explanations have been given (and demonstrated) for different levels of development between twins. Artificially induced superfetation has, however, been demonstrated although only up to a short period after insemination.
In 2007, Ame and Lia Herrity, conceived 3 weeks apart, were born in the United Kingdom to Amelia Spence and George Herrity.[1]
In May 2007, Harriet and Thomas Mullineux, also conceived 3 weeks apart, were born in Benfleet, Essex UK to Charlotte and Matt Mullineux, [2]
## Hoaxes
Flavia d'Angelo, an Italian woman claiming to have become pregnant with triplets three months after initially getting pregnant, caused global media interest in 2001. [3] However, it was later revealed to be a hoax. [4]
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https://www.wikidoc.org/index.php/Superfetation
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e91f8c8cbe7786259bc6134e339eee28ec35ffa3
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wikidoc
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Superorganism
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Superorganism
A superorganism is an organism consisting of many organisms. This is usually meant to be a social unit of eusocial animals, where division of labour is highly specialised and where individuals are not able to survive by themselves for extended periods of time. Ants are the most well known example of such a superorganism. The technical definition of a superorganism is "a collection of agents which can act in concert to produce phenomena governed by the collective," phenomena being any activity "the hive wants" such as ants collecting food or bees choosing a new nest site.
The Gaia hypothesis of James Lovelock and the work of James Hutton, Vladimir Vernadsky and Guy Murchie, have suggested that the biosphere can be considered as a superorganism. However, strict ecological studies reveal little or no self control inside organism communities, and such communities usually easily go off balance or change into entirely different ones. This view is countered and balanced by Systems Theory and the dynamics of a complex system.
In cybernetics, particuarly biocybernetics, superorganisms are an important topic because they appear to represent a form of "distributed intelligence", in which many individual agents with limited intelligence and information are able to pool resources to accomplish a goal beyond the capabilities of the individuals. This concept has many implications for military and management applications, and is being actively researched.
# Problems and criticisms
The concept of a superorganism is in dispute, as many biologists maintain that in order for a social unit to be considered an organism by itself, the individuals should be in permanent physical connection to each other, and its evolution should be governed by selection to the whole society instead of individuals. While it's generally accepted that the society of eusocial animals is a unit of natural selection to at least some extent, most evolutionary scientists believe that the individuals are still the primary units of selection.
The question remains "What is to be considered the individual?". Some Darwinians like Richard Dawkins suggest that the individual selected is the selfish gene. Others believe it is the whole genome of an organism. E.O. Wilson has shown that with ant-colonies and other social insects it is the breeding entity of the colony that is selected, and not its individual members. This could apply to the bacterial members of a stromatolite, which, because of genetic sharing, in some way comprise a single gene pool. Gaian theorists like Lynn Margulis would argue this applies equally to the symbiogenesis of the bacterial underpinnings of the whole of the Earth.
It would appear, from computer simulations like Daisyworld that biological selection occurs at multiple levels simultaneously.
It is also opined that humans (as mirrors of the Universal Mind) are a superorganism that includes microorganisms such as bacteria and whose consciousness is constituted by an aggregate of processes. It is estimated that "the human intestinal microbiota is composed of 1013 to 1014 microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes as our own Our microbiome has significantly enriched metabolism of glycans, amino acids, and xenobiotics; methanogenesis; and 2-methyl-D-erythritol 4-phosphate pathway–mediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes." .
Timothy Leary suggested that there is really only one organism on Earth: the DNA. He described all species and physically independent lifeforms as limbs of this organism, and their ultimate purpose as growth beyond the planet. He also claimed that DNA had previously grown to settle on Earth, not originated here (see panspermia).
# Superorganic in social theory
Nineteenth century evolutionist Herbert Spencer coined the term super-organic to focus on social organization (the first chapter of his Principles of Sociology is entitled "Super-organic Evolution"), though this was apparently a distinction between the organic and the social, not an identity: Spencer explored the holistic nature of society as a social organism while distinguishing the ways in which society did not behave like an organism. For Spencer, the super-organic was an emergent property of interacting organisms, that is, human beings. And, as has been argued by D. C. Phillips, there is a "difference between emergence and reductionism."
Similarly, economist Carl Menger expanded upon the evolutionary nature of much social growth, but without ever abandoning methodological individualism. Many social institutions arose, Menger argued, not as "the result of socially teleological causes, but the unintended result of innumerable efforts of economic subjects pursuing 'individual' interests."
Spencer and Menger both argued that because it is individuals who choose and act, any social whole should be considered less than an organism, though Menger emphasized this more emphatically. Spencer used the organistic idea to engage in extended analysis of social structure, conceding that it was primarily an analogy. So, for Spencer, the idea of the super-organic best designated a distinct level of social reality above that of biology and psychology, and not a one-to-one identity with an organism.
Nevertheless, Spencer also argued that "every organism of appreciable size is a society," which has suggested to some that the issue may be terminological.
The term superorganic was adopted by anthropologist Alfred L. Kroeber in 1917.
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Superorganism
A superorganism is an organism consisting of many organisms. This is usually meant to be a social unit of eusocial animals, where division of labour is highly specialised and where individuals are not able to survive by themselves for extended periods of time. Ants are the most well known example of such a superorganism. The technical definition of a superorganism is "a collection of agents which can act in concert to produce phenomena governed by the collective,"[1] phenomena being any activity "the hive wants" such as ants collecting food or bees choosing a new nest site.
The Gaia hypothesis of James Lovelock[2] and the work of James Hutton, Vladimir Vernadsky and Guy Murchie, have suggested that the biosphere can be considered as a superorganism. However, strict ecological studies reveal little or no self control inside organism communities, and such communities usually easily go off balance or change into entirely different ones. This view is countered and balanced by Systems Theory and the dynamics of a complex system.
In cybernetics, particuarly biocybernetics, superorganisms are an important topic because they appear to represent a form of "distributed intelligence", in which many individual agents with limited intelligence and information are able to pool resources to accomplish a goal beyond the capabilities of the individuals. This concept has many implications for military and management applications, and is being actively researched.[3]
# Problems and criticisms
The concept of a superorganism is in dispute, as many biologists maintain that in order for a social unit to be considered an organism by itself, the individuals should be in permanent physical connection to each other, and its evolution should be governed by selection to the whole society instead of individuals. While it's generally accepted that the society of eusocial animals is a unit of natural selection to at least some extent, most evolutionary scientists believe that the individuals are still the primary units of selection.
The question remains "What is to be considered the individual?". Some Darwinians like Richard Dawkins suggest that the individual selected is the selfish gene.[4] Others believe it is the whole genome of an organism. E.O. Wilson has shown that with ant-colonies and other social insects it is the breeding entity of the colony that is selected, and not its individual members. This could apply to the bacterial members of a stromatolite, which, because of genetic sharing, in some way comprise a single gene pool. Gaian theorists like Lynn Margulis would argue this applies equally to the symbiogenesis of the bacterial underpinnings of the whole of the Earth.
It would appear, from computer simulations like Daisyworld that biological selection occurs at multiple levels simultaneously.
It is also opined that humans (as mirrors of the Universal Mind) are a superorganism that includes microorganisms such as bacteria and whose consciousness is constituted by an aggregate of processes. It is estimated that "the human intestinal microbiota is composed of 1013 to 1014 microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes as our own[...] Our microbiome has significantly enriched metabolism of glycans, amino acids, and xenobiotics; methanogenesis; and 2-methyl-D-erythritol 4-phosphate pathway–mediated biosynthesis of vitamins and isoprenoids. Thus, humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes." [5].
Timothy Leary suggested that there is really only one organism on Earth: the DNA. He described all species and physically independent lifeforms as limbs of this organism, and their ultimate purpose as growth beyond the planet. He also claimed that DNA had previously grown to settle on Earth, not originated here (see panspermia).
# Superorganic in social theory
Nineteenth century evolutionist Herbert Spencer coined the term super-organic to focus on social organization (the first chapter of his Principles of Sociology is entitled "Super-organic Evolution"[6]), though this was apparently a distinction between the organic and the social, not an identity: Spencer explored the holistic nature of society as a social organism while distinguishing the ways in which society did not behave like an organism.[7] For Spencer, the super-organic was an emergent property of interacting organisms, that is, human beings. And, as has been argued by D. C. Phillips, there is a "difference between emergence and reductionism."[8]
Similarly, economist Carl Menger expanded upon the evolutionary nature of much social growth, but without ever abandoning methodological individualism. Many social institutions arose, Menger argued, not as "the result of socially teleological causes, but the unintended result of innumerable efforts of economic subjects pursuing 'individual' interests."[9]
Spencer and Menger both argued that because it is individuals who choose and act, any social whole should be considered less than an organism, though Menger emphasized this more emphatically. Spencer used the organistic idea to engage in extended analysis of social structure, conceding that it was primarily an analogy. So, for Spencer, the idea of the super-organic best designated a distinct level of social reality above that of biology and psychology, and not a one-to-one identity with an organism.
Nevertheless, Spencer also argued that "every organism of appreciable size is a society," which has suggested to some that the issue may be terminological.[10]
The term superorganic was adopted by anthropologist Alfred L. Kroeber in 1917.[11]
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https://www.wikidoc.org/index.php/Superorganism
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6b7d79acc11b4cd56a34c53564931e86bb257db5
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wikidoc
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Support group
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Support group
# Overview
# Maintaining contact
Support groups maintain interpersonal contact among their members in a variety of ways. Most groups have traditionally met in person in group sizes that allowed conversational interaction. Support groups also maintain contact through printed newsletters, telephone chains, internet forums, and mailing lists. Some support groups are exclusively online.
Membership in some support groups is formally controlled, with admission requirements and membership fees. Other groups are "open" and allow anyone to drop in at an advertised meeting, for example, or to participate in an online forum.
# Self-help or Professionally run
A self-help support group is fully organized and managed by its members, usually volunteers. Alcoholics Anonymous and other twelve-step programs, typically facilitated by members, are one major type of self-help groups, that are also sometimes referred to as fellowships, peer support groups, mutual help groups, or mutual aid self-help groups.
Professionally run support groups are facilitated by a professional who does not share the problem of the members, such as a social worker, a psychologist, or a clergyperson. The facilitator controls discussions and provides other managerial service. Such professionally run groups are more often found in institutional settings, including hospitals, drug-treatment centers and correctional facilities. These types of support group may run for a limited time, and an attendance fee is sometimes charged.
# On-line support groups
Since at least 1982, the Internet has provided a new venue for support groups. Diverse remote networking formats have allowed the development of both synchronous groups, where individuals can exchange messages in real time, and asynchronous groups, where members who are not connected to a network at the same time can read and exchange messages. E-mail, Usenet and Internet bulletin boards have become popular methods of communication for self-help groups and among facilitated support groups.
Support groups have long offered companionship and information for people coping with diseases or disabilities, but on-line situationally oriented groups have expanded to offer support for people facing various life circumstances, especially those involving personal and cultural relationships. In 2006, Yahoo! listed more than 30,000 support groups focusing on a wide range of health-related topics within its hosted domains, though research suggests only several thousand of those groups may currently be active. The wide range of support groups now active on the Internet can make offer individuals support for an equally wide range of life circumstances. However, a researcher from the University College London says the lack of qualitative directories, and the fact that many support groups are not listed by search engines can make finding an appropriate group difficult.
Some people, however, feel that the internet still provides a wide range of benefits to self-help seekers through services other than Yahoo! Groups. Many self help groups can be found on message board services similar to BBSes which are not governed by any search engine and so may simply be harder to find.
The message boards are picked up by the search engines like Google, Yahoo and Alta Vista, just like any website. Especially if the board owner submit the board to the search engines. But after a while, topics, keywords and forums will be picked up anyway. Besides, both Google and Yahoo have directories with lists of support groups for different diseases. The Open Directory Project (ODP), also known as Dmoz, has directories with lists of support groups. The volunteer editors adds support groups to the lists even when the forums are not submitted. Google’s directory is using the ODP directory. It is not difficult to find an online support group, but it is hard to find a good one.
Marc D. Feldman, MD, of the University of Alabama at Birmingham's Center for Psychiatric Medicine, has warned about sympathy-seekers that invade Internet support groups. He calls it Munchausen by Internet. In these disorders, people cook up or induce fictitious illnesses in themselves or others in an effort to gain sympathy. And there's no doubt these storytellers can have an enormous impact on Internet support groups. Among other things, Feldman says, they can:
- Create a division between those who believe the tale and those who don't
- Cause some to leave the group
- Temporarily distract the group from its mission by forcing it to focus on the poser "Overwhelmingly, these support groups offer a tremendous benefit to people," he says. " as in other areas of our lives, we have to be informed."
# Other categories
In the case of a disease, an identity or a pre-disposition, for example, a support group will provide information, act as a clearing-house for experiences, and serve as a public relations voice for sufferers, other members, and their families. Compare Mental Health Stigma, depression, mood disorders, Mensa International and gay pride, for example.
In the case of alleged ex-cult members or personal addictions, on the other hand, a support group may veer more towards helping those involved to overcome or move "beyond" their condition/experience.
# History
Formal support groups may appear as a modern phenomenon, but they supplement traditional fraternal organizations such as Freemasonry in some respects, and may build on certain supportive functions (formerly) carried out in (extended) families.
# Support groups in the media
- The novel and movie Fight Club present a wry analysis of support groups and their function.
- In the Pixar film Finding Nemo, the two main characters encounter three different sharks that form a self-help support group to help each other swear off fish as food and change their image.
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Support group
# Overview
Template:Mind-body interventionsIn a support group, members provide each other with various types of nonprofessional, nonmaterial help for a particular shared burdensome characteristic. The help may take the form of providing relevant information, relating personal experiences, listening to others' experiences, providing sympathetic understanding and establishing social networks. A support group may also provide ancillary support, such as serving as a voice for the public or engaging in advocacy.
# Maintaining contact
Support groups maintain interpersonal contact among their members in a variety of ways. Most groups have traditionally met in person in group sizes that allowed conversational interaction. Support groups also maintain contact through printed newsletters, telephone chains, internet forums, and mailing lists. Some support groups are exclusively online.
Membership in some support groups is formally controlled, with admission requirements and membership fees. Other groups are "open" and allow anyone to drop in at an advertised meeting, for example, or to participate in an online forum.
# Self-help or Professionally run
A self-help support group is fully organized and managed by its members, usually volunteers. Alcoholics Anonymous and other twelve-step programs, typically facilitated by members, are one major type of self-help groups, that are also sometimes referred to as fellowships, peer support groups, mutual help groups, or mutual aid self-help groups.
Professionally run support groups are facilitated by a professional who does not share the problem of the members,[1] such as a social worker, a psychologist, or a clergyperson. The facilitator controls discussions and provides other managerial service. Such professionally run groups are more often found in institutional settings, including hospitals, drug-treatment centers and correctional facilities. These types of support group may run for a limited time, and an attendance fee is sometimes charged.[1]
# On-line support groups
Since at least 1982, the Internet has provided a new venue for support groups. Diverse remote networking formats have allowed the development of both synchronous groups, where individuals can exchange messages in real time, and asynchronous groups, where members who are not connected to a network at the same time can read and exchange messages. E-mail, Usenet and Internet bulletin boards have become popular methods of communication for self-help groups and among facilitated support groups.
Support groups have long offered companionship and information for people coping with diseases or disabilities, but on-line situationally oriented groups have expanded to offer support for people facing various life circumstances, especially those involving personal and cultural relationships. In 2006, Yahoo! listed more than 30,000 support groups focusing on a wide range of health-related topics within its hosted domains, though research suggests only several thousand of those groups may currently be active. The wide range of support groups now active on the Internet can make offer individuals support for an equally wide range of life circumstances. However, a researcher from the University College London says the lack of qualitative directories, and the fact that many support groups are not listed by search engines can make finding an appropriate group difficult. [1]
Some people, however, feel that the internet still provides a wide range of benefits to self-help seekers through services other than Yahoo! Groups. Many self help groups can be found on message board services similar to BBSes which are not governed by any search engine and so may simply be harder to find.
The message boards are picked up by the search engines like Google, Yahoo and Alta Vista, just like any website. Especially if the board owner submit the board to the search engines. But after a while, topics, keywords and forums will be picked up anyway. Besides, both Google and Yahoo have directories with lists of support groups for different diseases. The Open Directory Project (ODP), also known as Dmoz, has directories with lists of support groups. The volunteer editors adds support groups to the lists even when the forums are not submitted. Google’s directory is using the ODP directory. It is not difficult to find an online support group, but it is hard to find a good one.
Marc D. Feldman, MD, of the University of Alabama at Birmingham's Center for Psychiatric Medicine, has warned about sympathy-seekers that invade Internet support groups. He calls it Munchausen by Internet. In these disorders, people cook up or induce fictitious illnesses in themselves or others in an effort to gain sympathy. And there's no doubt these storytellers can have an enormous impact on Internet support groups. Among other things, Feldman says, they can:
- Create a division between those who believe the tale and those who don't
- Cause some to leave the group
- Temporarily distract the group from its mission by forcing it to focus on the poser "Overwhelmingly, these support groups offer a tremendous benefit to people," he says. "[But,] as in other areas of our lives, we have to be informed."
# Other categories
In the case of a disease, an identity or a pre-disposition, for example, a support group will provide information, act as a clearing-house for experiences, and serve as a public relations voice for sufferers, other members, and their families. Compare Mental Health Stigma, depression, mood disorders, Mensa International and gay pride, for example.
In the case of alleged ex-cult members or personal addictions, on the other hand, a support group may veer more towards helping those involved to overcome or move "beyond" their condition/experience.
# History
Formal support groups may appear as a modern phenomenon, but they supplement traditional fraternal organizations such as Freemasonry in some respects, and may build on certain supportive functions (formerly) carried out in (extended) families.
# Support groups in the media
- The novel and movie Fight Club present a wry analysis of support groups and their function.
- In the Pixar film Finding Nemo, the two main characters encounter three different sharks that form a self-help support group to help each other swear off fish as food and change their image.
# External links
- American Self-Help Group Clearinghouse (U.S.)
- Local Self-Help Group Clearinghouses (Worldwide)
- National Mental Health Consumers' Self-Help Clearinghouse (U.S.)
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https://www.wikidoc.org/index.php/Support_group
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41595c1ba71ee84587a5d936e4d96e6d512e14f2
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wikidoc
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Swish (slang)
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Swish (slang)
Swish is a derogatory term for effeminate behaviour and interests (camp), emphasized and sanctioned in pre-Stonewall gay male communities. This behaviour is also described as nelly. Wentworth and Flexner define swish as a noun meaning "a male homosexual, esp. one with obviously feminine traits".
Being swish includes sashaying and the use of limp wrists, falsetto voices, feminine pronouns, and superlatives (Sonenschein 1969; Tripp 197?, both cited in Levine 1998)—basically, everything up to the other side of camp, or drag.
"Extravagant language is common. Such expressions as 'Oh my word!' 'Good heavens!' and 'Oh, my dear!' are readily associated with other aspects of a feminine man. In describing ordinary experiences the male variant is likely to use such words as 'terrific,' 'amazing,' 'completely devoted,' 'horrible,' 'tremendous,' 'sublimely,' 'charming,' 'appalling,' 'vicious,' 'loathed,' and 'madly.' Exaggerations are made more conspicuous by placing undue or inappropriate emphasis on certain syllables and intonations which leave little doubt of the effeminacy of the speaker." (Henry, 1955, p. 291, cited in Levine 1998)
Though being butch was viewed as deviant and socially unacceptable by gay male society (Warren 1972, 1974; Helmer 1963, both cited in Levine 1998), being swish has since lost its mainstream gay status post-Stonewall, and in addition to being used occasionally by straight people is now most often derogatory even when used by gay men. Though it may be assumed that most post-Stonewall gay men view acting swish as internalized homophobia, a concession to straight stereotypes of gay men as failed men (or women); however, "clone"—the masculine, even macho, standard and ideal behaviour that replaced swish—adapted many camp elements such as dish.
Thus while clones view swish as harmfully embodying anti-gay stereotypes, being swish was a way of indicating and performing one's identity, indicating that anti-gay stereotypes were and are derived from gay identities. Further, one could turn one's swish on or off, as described by Martin Levine in Gay Macho:
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Swish (slang)
Template:LGBT
Swish is a derogatory term [1] for effeminate behaviour and interests (camp), emphasized and sanctioned[2] in pre-Stonewall gay male communities. This behaviour is also described as nelly. Wentworth and Flexner define swish as a noun meaning "a male homosexual, esp. one with obviously feminine traits".[3]
Being swish includes sashaying and the use of limp wrists, falsetto voices, feminine pronouns, and superlatives (Sonenschein 1969; Tripp 197?, both cited in Levine 1998)—basically, everything up to the other side of camp, or drag.
"Extravagant language is common. Such expressions as 'Oh my word!' 'Good heavens!' and 'Oh, my dear!' are readily associated with other aspects of a feminine man. In describing ordinary experiences the male variant is likely to use such words as 'terrific,' 'amazing,' 'completely devoted,' 'horrible,' 'tremendous,' 'sublimely,' 'charming,' 'appalling,' 'vicious,' 'loathed,' and 'madly.' Exaggerations are made more conspicuous by placing undue or inappropriate emphasis on certain syllables and intonations which leave little doubt of the effeminacy of the speaker." (Henry, 1955, p. 291, cited in Levine 1998)
Though being butch was viewed as deviant and socially unacceptable by gay male society (Warren 1972, 1974; Helmer 1963, both cited in Levine 1998), being swish has since lost its mainstream gay status post-Stonewall, and in addition to being used occasionally by straight people is now most often derogatory even when used by gay men. Though it may be assumed that most post-Stonewall gay men view acting swish as internalized homophobia, a concession to straight stereotypes of gay men as failed men (or women); however, "clone"—the masculine, even macho, standard and ideal behaviour that replaced swish—adapted many camp elements such as dish.
Thus while clones view swish as harmfully embodying anti-gay stereotypes, being swish was a way of indicating and performing one's identity, indicating that anti-gay stereotypes were and are derived from gay identities. Further, one could turn one's swish on or off, as described by Martin Levine in Gay Macho:
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https://www.wikidoc.org/index.php/Swish_(slang)
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b0db90937aa2de2d4192e194de49ef97891008bc
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wikidoc
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Symbiogenesis
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Symbiogenesis
Symbiogenesis is the merging of two separate organisms to form a single new organism. The idea originated with Konstantin Mereschkowsky in his 1926 book Symbiogenesis and the Origin of Species, which proposed that chloroplasts originate from cyanobacteria captured by a protozoan. Today both chloroplasts and mitochondria are believed to have such an origin; this is the endosymbiotic theory.
In Acquiring Genomes: A Theory of the Origins of Species, biologist Dr. Lynn Margulis argued that symbiogenesis is a primary force in evolution. According to her theory, acquisition and accumulation of random mutations are not sufficient to explain how inherited variations occur; rather, new organelles, bodies, organs, and species arise from symbiogenesis. Whereas the classical interpretation of evolution (the modern evolutionary synthesis) emphasizes competition as the main force behind evolution, Margulis emphasizes cooperation.
Many ecologists agree, but this idea has little support from other evolutionary biologists. They see little evidence that symbiogenesis has had a major impact on eukaryotic life, or that much of its diversification can be attributed to it. Other than the two examples of mitochondria and chloroplasts, there is no clear evidence of other major traits or transitions that can be attributed to symbiogenesis.
A fundamental principle of modern evolutionary theory is that mutations arise one at a time and either spread through the population or not, depending on whether they offer an individual fitness advantage. Nevertheless, this general case may not apply to all examples of evolutionary change. Indeed, genome mapping techniques have revealed that family trees of the major taxa appear to be extensively cross-linked - possibly due to lateral gene transfer.
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Symbiogenesis
Symbiogenesis is the merging of two separate organisms to form a single new organism. The idea originated with Konstantin Mereschkowsky in his 1926 book Symbiogenesis and the Origin of Species, which proposed that chloroplasts originate from cyanobacteria captured by a protozoan.[1] Today both chloroplasts and mitochondria are believed to have such an origin; this is the endosymbiotic theory.
In Acquiring Genomes: A Theory of the Origins of Species, biologist Dr. Lynn Margulis argued that symbiogenesis is a primary force in evolution. According to her theory, acquisition and accumulation of random mutations are not sufficient to explain how inherited variations occur; rather, new organelles, bodies, organs, and species arise from symbiogenesis.[2] Whereas the classical interpretation of evolution (the modern evolutionary synthesis) emphasizes competition as the main force behind evolution, Margulis emphasizes cooperation.[3]
Many ecologists agree, but this idea has little support from other evolutionary biologists. They see little evidence that symbiogenesis has had a major impact on eukaryotic life, or that much of its diversification can be attributed to it. Other than the two examples of mitochondria and chloroplasts, there is no clear evidence of other major traits or transitions that can be attributed to symbiogenesis.
A fundamental principle of modern evolutionary theory is that mutations arise one at a time and either spread through the population or not, depending on whether they offer an individual fitness advantage. Nevertheless, this general case may not apply to all examples of evolutionary change. Indeed, genome mapping techniques have revealed that family trees of the major taxa appear to be extensively cross-linked - possibly due to lateral gene transfer.[4]
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https://www.wikidoc.org/index.php/Symbiogenesis
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c8e6c2ea78c4f8ef6817e37c619423dc8a862558
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wikidoc
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Symphysiotomy
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Symphysiotomy
# Overview
Symphysiotomy is a surgical procedure in which the cartilage of the symphysis pubis is divided to widen the pelvis allowing childbirth when there is a mechanical problem.
# Introduction
Symphysiotomy was also advocated in 1597 by Severin Pineau after his description of a diastasis of the pubis on a hanged pregnant
woman . Thus symphysiotomies became a routine surgical procedure for women experiencing an obstructed labour. In the late 19th century after the risk of maternal death after caesarean section decreased due to improvement in techniques, hygiene and clinical practice the symphysiotomy was rarely used.
# Indications for the procedure
The most common indications are a trapped head of a breech baby, shoulder dystocia which does not resolve with routine manoeuvres and obstructed labour at full cervical dilation when there is no option of a caesarean section. Currently the procedure is rarely performed in developed countries, but is still routine in developing countries where caesarean section is not always an option.
# Surgical application
Symphysiotomy results in a temporary increase in pelvic diameter (up to 2 cm) by surgically dividing the ligaments of the symphysis under local anaesthesia. This procedure should be carried out only in combination with vacuum extraction. Symphysiotomy in combination with vacuum extraction can be a life-saving procedure in areas of the world where caesarean section is not feasible or immediately available. Symphysiotomy leaves no uterine scar and the risk of ruptured uterus in any future labour is not increased.
The procedure is not without risk, including urethral and bladder injury, infection, pain and long-term walking difficulty. Symphysiotomy should, therefore, be carried out only when there is no safe alternative. It is advised that this procedure should not be repeated due to the risk of the woman developing long term walking problems and continued pain.
Abduction of the thighs more than 45 degrees from the midline may cause tearing of the urethra and bladder.
- Give appropriate analgesic drugs.
- Apply elastic strapping across the front of the pelvis from one iliac crest to the other to stabilize the symphysis and reduce pain.
- Leave the catheter in the bladder for a minimum of 5 days.
- Encourage the woman to drink plenty of fluids to ensure a good urinary output.
- Encourage bed rest for 7 days after discharge from hospital.
- Encourage the woman to begin to walk with assistance when she is ready to do so.
If long-term walking difficulties and pain are reported (occur in 2% of cases), treat with physical therapy.
# Ireland and Symphysiotomy
Irish women who unknowingly and without consent underwent symphysiotomies during childbirth between the 1950s and 1980s say they were left them with severe side effects, including extreme pain, incontinence and depression. Irish obstetricians sought to establish this operation as an alternative to Caesarean sections because it was thought that women subjected to repeated Caesareans 'might be tempted to use contraception'.
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Symphysiotomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Symphysiotomy is a surgical procedure in which the cartilage of the symphysis pubis is divided to widen the pelvis allowing childbirth when there is a mechanical problem.
# Introduction
Symphysiotomy was also advocated in 1597 by Severin Pineau after his description of a diastasis of the pubis on a hanged pregnant
woman [1]. Thus symphysiotomies became a routine surgical procedure for women experiencing an obstructed labour. In the late 19th century [2] after the risk of maternal death after caesarean section decreased due to improvement in techniques, hygiene and clinical practice the symphysiotomy was rarely used.
# Indications for the procedure
The most common indications are a trapped head of a breech baby, shoulder dystocia which does not resolve with routine manoeuvres and obstructed labour at full cervical dilation when there is no option of a caesarean section. Currently the procedure is rarely performed in developed countries, but is still routine in developing countries where caesarean section is not always an option.[3]
# Surgical application
Symphysiotomy results in a temporary increase in pelvic diameter (up to 2 cm) by surgically dividing the ligaments of the symphysis under local anaesthesia. This procedure should be carried out only in combination with vacuum extraction. Symphysiotomy in combination with vacuum extraction can be a life-saving procedure in areas of the world where caesarean section is not feasible or immediately available. Symphysiotomy leaves no uterine scar and the risk of ruptured uterus in any future labour is not increased.[citation needed]
The procedure is not without risk, including urethral and bladder injury, infection, pain and long-term walking difficulty. Symphysiotomy should, therefore, be carried out only when there is no safe alternative.[citation needed] It is advised that this procedure should not be repeated due to the risk of the woman developing long term walking problems and continued pain.[citation needed]
Abduction of the thighs more than 45 degrees from the midline may cause tearing of the urethra and bladder.
- Give appropriate analgesic drugs.
- Apply elastic strapping across the front of the pelvis from one iliac crest to the other to stabilize the symphysis and reduce pain.
- Leave the catheter in the bladder for a minimum of 5 days.
- Encourage the woman to drink plenty of fluids to ensure a good urinary output.
- Encourage bed rest for 7 days after discharge from hospital.
- Encourage the woman to begin to walk with assistance when she is ready to do so.
If long-term walking difficulties and pain are reported (occur in 2% of cases), treat with physical therapy. [4]
# Ireland and Symphysiotomy
Irish women who unknowingly and without consent underwent symphysiotomies during childbirth between the 1950s and 1980s say they were left them with severe side effects, including extreme pain, incontinence and depression. Irish obstetricians sought to establish this operation as an alternative to Caesarean sections because it was thought that women subjected to repeated Caesareans 'might be tempted to use contraception'.[5]
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https://www.wikidoc.org/index.php/Symphysiotomy
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20357724ad4ad679bb5224f6029952aa7c18588c
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Synaptobrevin
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Synaptobrevin
Synaptobrevins (synaptobrevin isotypes 1-2) are small integral membrane proteins of secretory vesicles with molecular weight of 18 kilodalton (kDa) that are part of the vesicle-associated membrane protein (VAMP) family.
Synaptobrevin is one of the SNARE proteins involved in formation of the SNARE complexes. Out of four α-helices of the core SNARE complex one is contributed by synaptobrevin, one by syntaxin, and two by SNAP-25 (in neurons).
SNARE proteins are the key components of the molecular machinery that drives fusion of membranes in exocytosis. Their function however is subject to fine tuning by various regulatory protein collectively referred to as SNARE masters.
Because all proteins belonging to VAMP/synaptobrevin family share common structural feature, they have been classified as R-SNAREs. An alternative classification (v- and t-SNAREs) exists that takes into account origin of synaptobrevin-bearing organelle rather than their structural properties.
Synaptobrevin is degraded by Tetanospasmin, a protein derived from Clostridium tetani.
# References and notes
Baumert M, Maycox PR, Navone F, De Camilli P, Jahn R (1989). "Synaptobrevin: an integral membrane protein of 18,000 daltons present in small synaptic vesicles of rat brain". EMBO J. 8: 379–384.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Bock JB, Scheller RH (1999). "SNARE proteins mediate lipid bilayer fusion". PNAS. 96: 12227–12229.
Ernst JA, Brunger AT (2003). "High resolution structure, stability, and synaptotagmin binding of a truncated neuronal SNARE complex". J Biol Chem. 278: 8630–8636.
Fasshauer D, Sutton RB, Brunger AT, Jahn R (1998). "Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs". PNAS. 95: 15781–15786.CS1 maint: Multiple names: authors list (link)
Weber T, Zemelman BV, McNew JA, Westermann B, Gmachl M, Parlati F, Sollner TH, Rothman JE (1998). "SNAREpins: minimal machinery for membrane fusion". Cell. 92: 759–772.CS1 maint: Multiple names: authors list (link)
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Synaptobrevin
Synaptobrevins (synaptobrevin isotypes 1-2) are small integral membrane proteins of secretory vesicles with molecular weight of 18 kilodalton (kDa) that are part of the vesicle-associated membrane protein (VAMP) family.[1][2][3][4][5]
Synaptobrevin is one of the SNARE proteins involved in formation of the SNARE complexes. Out of four α-helices of the core SNARE complex one is contributed by synaptobrevin, one by syntaxin, and two by SNAP-25 (in neurons).
SNARE proteins are the key components of the molecular machinery that drives fusion of membranes in exocytosis. Their function however is subject to fine tuning by various regulatory protein collectively referred to as SNARE masters.
Because all proteins belonging to VAMP/synaptobrevin family share common structural feature, they have been classified as R-SNAREs. An alternative classification (v- and t-SNAREs) exists that takes into account origin of synaptobrevin-bearing organelle rather than their structural properties.
Synaptobrevin is degraded by Tetanospasmin, a protein derived from Clostridium tetani.
# References and notes
- ↑
Baumert M, Maycox PR, Navone F, De Camilli P, Jahn R (1989). "Synaptobrevin: an integral membrane protein of 18,000 daltons present in small synaptic vesicles of rat brain". EMBO J. 8: 379–384.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑
Bock JB, Scheller RH (1999). "SNARE proteins mediate lipid bilayer fusion". PNAS. 96: 12227–12229.
- ↑
Ernst JA, Brunger AT (2003). "High resolution structure, stability, and synaptotagmin binding of a truncated neuronal SNARE complex". J Biol Chem. 278: 8630–8636.
- ↑
Fasshauer D, Sutton RB, Brunger AT, Jahn R (1998). "Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs". PNAS. 95: 15781–15786.CS1 maint: Multiple names: authors list (link)
- ↑
Weber T, Zemelman BV, McNew JA, Westermann B, Gmachl M, Parlati F, Sollner TH, Rothman JE (1998). "SNAREpins: minimal machinery for membrane fusion". Cell. 92: 759–772.CS1 maint: Multiple names: authors list (link)
# External links
- Synaptobrevin at the US National Library of Medicine Medical Subject Headings (MeSH)
de:Synaptobrevin
Template:WikiDoc Sources
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https://www.wikidoc.org/index.php/Synaptobrevin
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e42782a65a6054b9c18e7cb86bdb67aa60444cda
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wikidoc
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Synaptophysin
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Synaptophysin
Synaptophysin, also known as the major synaptic vesicle protein p38, is a protein that in humans is encoded by the SYP gene.
# Genomics
The gene is located on the short arm of X chromosome (Xp11.23-p11.22). It is 12,406 bases in length and lies on the minus strand. The encoded protein has 313 amino acids with a predicted molecular weight of 33.845 kDa.
# Molecular biology
The protein is a synaptic vesicle glycoprotein with four transmembrane domains weighing 38kDa. It is present in neuroendocrine cells and in virtually all neurons in the brain and spinal cord that participate in synaptic transmission. It acts as a marker for neuroendocrine tumors, and its ubiquity at the synapse has led to the use of synaptophysin immunostaining for quantification of synapses.
The exact function of the protein is unknown: it interacts with the essential synaptic vesicle protein synaptobrevin, but when the synaptophysin gene is experimentally inactivated in animals, they still develop and function normally. Recent research has shown, however, that elimination of synaptophysin in mice creates behavioral changes such as increased exploratory behavior, impaired object novelty recognition, and reduced spatial learning.
# Clinical importance
This gene has been implicated in X linked intellectual disability.
Using immunohistochemistry, synaptophysin can be demonstrated in a range of neural and neuroendocrine tissues, including cells of the adrenal medulla and pancreatic islets. As a specific marker for these tissues, it can be used to identify tumours arising from them, such as neuroblastoma, retinoblastoma, phaeochromocytoma, carcinoid, small-cell carcinoma, medulloblastoma and medullary thyroid carcinoma, among others. Diagnostically, it is often used in combination with chromogranin A.
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Synaptophysin
Synaptophysin, also known as the major synaptic vesicle protein p38, is a protein that in humans is encoded by the SYP gene.[1][2]
# Genomics
The gene is located on the short arm of X chromosome (Xp11.23-p11.22). It is 12,406 bases in length and lies on the minus strand. The encoded protein has 313 amino acids with a predicted molecular weight of 33.845 kDa.
# Molecular biology
The protein is a synaptic vesicle glycoprotein with four transmembrane domains weighing 38kDa. It is present in neuroendocrine cells and in virtually all neurons in the brain and spinal cord that participate in synaptic transmission. It acts as a marker for neuroendocrine tumors, and its ubiquity at the synapse has led to the use of synaptophysin immunostaining for quantification of synapses.[3]
The exact function of the protein is unknown: it interacts with the essential synaptic vesicle protein synaptobrevin, but when the synaptophysin gene is experimentally inactivated in animals, they still develop and function normally.[4] Recent research has shown, however, that elimination of synaptophysin in mice creates behavioral changes such as increased exploratory behavior, impaired object novelty recognition, and reduced spatial learning.[5]
# Clinical importance
This gene has been implicated in X linked intellectual disability.[6]
Using immunohistochemistry, synaptophysin can be demonstrated in a range of neural and neuroendocrine tissues,[7] including cells of the adrenal medulla and pancreatic islets. As a specific marker for these tissues, it can be used to identify tumours arising from them, such as neuroblastoma, retinoblastoma, phaeochromocytoma, carcinoid, small-cell carcinoma, medulloblastoma and medullary thyroid carcinoma, among others. Diagnostically, it is often used in combination with chromogranin A.[8]
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https://www.wikidoc.org/index.php/Synaptophysin
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b6ab2f9ca0aca3f88856c267bd8151f03c2fdd8d
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wikidoc
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Synchondrosis
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Synchondrosis
# Overview
Where the connecting medium is cartilage, a joint is termed a synchondrosis.
This is a temporary form of joint, for the cartilage is converted into bone before adult life.
Such joints are found between the epiphyses and bodies of long bones, between the occipital and the sphenoid at, and for some years after, birth, and between the petrous portion of the temporal and the jugular process of the occipital.
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Synchondrosis
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Where the connecting medium is cartilage, a joint is termed a synchondrosis.
This is a temporary form of joint, for the cartilage is converted into bone before adult life. [1]
Such joints are found between the epiphyses and bodies of long bones, between the occipital and the sphenoid at, and for some years after, birth, and between the petrous portion of the temporal and the jugular process of the occipital.
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https://www.wikidoc.org/index.php/Synchondroses
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69c943659eb280a21c7b3624aff133062434b5ce
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Synchronicity
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Synchronicity
Synchronicity is the experience of two or more events which occur in a meaningful manner, but which are causally unrelated. In order to be synchronous, the events must be related to one another conceptually, and the chance that they would occur together by random chance must be very small.
# The concept of synchronicity
The idea of synchronicity is that the conceptual relationship of minds, defined by the relationship between ideas, is intricately structured in its own logical way and gives rise to relationships which have nothing to do with causal relationships in which a cause precedes an effect. Instead, causal relationships are understood as simultaneous — that is, the cause and effect occur at the same time. Synchronous events reveal an underlying pattern, a conceptual framework which encompasses, but is larger than, any of the systems which display the synchronicity. The suggestion of a larger framework is essential in order to satisfy the definition of synchronicity as originally developed by Swiss psychologist Carl Jung.
Carl Jung coined the word to describe what he called "temporally coincident occurrences of acausal events." Jung variously described synchronicity as an "'acausal connecting principle'" (i.e. a pattern of connection that cannot be explained by conventional, efficient causality), "meaningful coincidence" and "acausal parallelism". Jung introduced the concept in his 1952 paper "Synchronicity — An Acausal Connecting Principle", though he had been considering the concept for almost thirty years.
It was a principle that Jung felt gave conclusive evidence for his concepts of
archetypes and the collective unconscious , in that it was descriptive of a governing dynamic that underlay the whole of human experience and history — social, emotional, psychological, and spiritual.
Jung believed that many experiences perceived as coincidence were not merely due to chance but, instead, suggested the manifestation of parallel events or circumstances reflecting this governing dynamic.
One of Jung's favourite quotes on synchronicity was from Through the Looking-Glass by Lewis Carroll, in which the White Queen says to Alice: "It's a poor sort of memory that only works backwards".
Events that happen which appear at first to be coincidence but are later found to be causally related are termed Incoincident .
# Examples
- A well-known example of synchronicity is the true story of the French writer Émile Deschamps who in 1805 was treated to some plum pudding by the stranger Monsieur de Fortgibu. Ten years later, he encountered plum pudding on the menu of a Paris restaurant, and wanted to order some, but the waiter told him the last dish had already been served to another customer, who turned out to be de Fortgibu. Many years later in 1832 Émile Deschamps was at a diner, and was once again offered plum pudding. He recalled the earlier incident and told his friends that only de Fortgibu was missing to make the setting complete — and in the same instant the now senile de Fortgibu entered the room.
- A mother is working at preparing her dinner, and thinks "It would be nice to have some flowers here today", while her son is in the garden picking flowers for her dinner. The mother has never had flowers on the dinner table before, and the son has never brought flowers, but their close relationship leads them to both originally create the same idea at the same time.
- Simultaneous discovery, the creation of the same new idea at causally disconnected places by two persons at approximately the same time. It is very difficult to account for simultaneous discovery by random chance. If for example an American and a British musician, having never had anything to do with one another, arrived at the same musical concept, chord sequence, feel or lyrics at the same time in different places, this is an example of synchronicity. This is explained by reasons such as global culture, which is the larger framework required to fit the definition of synchronicity.
- During production of The Wizard of Oz, a coat bought from a second-hand store for the costume of Professor Marvel was later found to have belonged to L. Frank Baum, author of the children's book upon which the film is based.
- The Wizard of Oz and Pink Floyd are part of the alleged Dark Side of the Rainbow synchronicity.
# Study
A recent study within the Princeton Engineering Anomalies Research Lab (the PEAR lab), suggested that there is a small, though statistically measurable, link between human thought and patterns that occur in random data sets. There is no evidence as to whether this is caused by individuals unintentionally recognizing complex patterns and then moulding their thoughts towards an unconsciously known result or the thoughts of the individual are themselves affecting the random patterns in a manner of individuation. This study's results have not been replicated, and its methodologies are disputed. The PEAR lab closed at the end of February, 2007, after conducting 28 years of research on the relationships and interactions between Mind and Matter.
# Criticism
According to Occam's razor, positing an underlying mechanism for meaningfully interpreted correlations is an unsupported explanation for a "meaningful coincidence" which may be explained by simple coincidence. Jung and followers
believe that Synchronous events such as simultaneous discovery happen far more often than
random chance would allow, even after accounting for the sampling bias inherent in the
fact that meaningful coincidences are noticeable while meaningless coincidences are not.
# References in popular culture
- John Constantine, the main character in the Vertigo Comics series Hellblazer, is sometimes seen "riding the synchronicity highway," to meet certain goals or even just to one up those around him. This has the same effect as that described in this article, and it is one of John Constantine's more unusual tricks, and part of what makes him so dangerous. He is also seen doing this in Books of Magic, the graphic novel by Neil Gaiman.
- The phenomenon is also explored, though not named, in "The Red Notebook" by Paul Auster, and is considered a major theme of his entire bibliography, appearing in some form in almost every work.
- In the 1983 release Synchronicity by The Police (A&M Records), bassist Sting is reading a copy of Jung's Synchronicity on the front cover along with a negative/superimposed image of the actual text of the synchronicity hypothesis. A photo on the back cover also shows a close-up but mirrored and upside-down image of the book. There are two songs titled "Synchronicity I" and "Synchronicity II" included in the album. The latter song contrasts the dangerous breakdown of a desperate family man with the simultaneous emergence of a menacing something from the bottom of a dark Scottish loch. See The Police, Robert Aziz and marketing the A&M album, Synchronicity.
- In the 1976 film The Eagle Has Landed, the character Max Radl (Robert Duvall) asks a subordinate if he is familiar with the works of Jung, and then explains the theory of Synchronicity.
- The Dirk Gently series of books by Douglas Adams often plays on the synchronicity concept. The main character carries a "pocket I Ching" that also functions as a calculator, up to a point (see A suffusion of yellow).
- The concept of ta'veren in Robert Jordan's The Wheel of Time series functions similarly to synchronicity.
- In the film Repo Man Miller's famous Plate 'o' Shrimp theory is an exact representation of synchronicity.
- In a 2002 album Tenth Dimensions by metal artist Blaze, a lot of the songs refer to synchronicity, with some songs like "Stealing Time" directly using the word.
- In the film I ♥ Huckabees, a character hires existential detectives to solve his coincidence. They caution him: "Not all coincidences are meaningful!"
- In Philip K Dick's The Game Players of Titan, several characters possessing pre-cognitive abilities cite the acausal principle of synchronicity as an element which hampers their ability to accurately predict certain possible futures.
- In the D20 Modern roleplaying game Urban Arcana, Synchronicity is a magic spell that subtly rearranges reality, allowing the subject to avoid the minor inconveniences and hassles of everyday life. While the spell is in effect, buses and trains run on time, stoplights and crosswalk signals change in your favor just as you approach an intersection, and the flow of street traffic and pedestrians will allow you to proceed unimpeded, without hurry or delay. Waiters and clerks will approach as soon as they are wanted, and depart when you desire privacy. Taxi cabs, elevators, vacant parking spaces, and so forth will similarly be available wherever and whenever needed. This spell is particularly helpful when the subject is chasing someone or is trying to escape pursuers.
- In the television series Strange Luck, the main character Chance Harper spends his entire life experiencing unplanned synchronicity, which he takes advantage of by becoming a freelance photographer.
- The Dalai Lama quoted: "I am open to the guidance of synchronicity, and do not let expectations hinder my path."
- Terence McKenna used the term 'Cosmic giggle' to mean "a randomly roving zone of synchronicity and statistical anomaly. Should you be caught up in it, it will turn reality on its head. It is objective and subjective, simultaneously 'really there' and yet somehow is sustained by imagination and expectation...."
# Notes
- ↑ Roderick Main (2000). "Religion, Science, and Synchronicity". Harvest: Journal for Jungian Studies..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jung defined the collective
unconscious as akin to instincts in Archetypes and the Collective Unconscious.
- ↑ In Synchronicity in the final two pages of the Conclusion, Jung stated that not all coincidences are meaningful and further explained the creative causes of this phenomenon.
- ↑ Through the Looking-Glass, by Lewis Carroll, Ch. 5, Wool and Water. 'It's very good jam,' said the Queen.
'Well, I don't want any TO-DAY, at any rate.'
'You couldn't have it if you DID want it,' the Queen said.
'The rule is, jam to-morrow and jam yesterday--but never jam
to-day.'
'It MUST come sometimes to "jam to-day,"' Alice objected.
'No, it can't,' said the Queen. 'It's jam every OTHER day: to-day isn't any OTHER day, you know.'
'I don't understand you,' said Alice. 'It's dreadfully confusing!'
'That's the effect of living backwards,' the Queen said kindly: 'it always makes one a little giddy at first--'
'Living backwards!' Alice repeated in great astonishment. 'I never heard of such a thing!'
'--but there's one great advantage in it, that one's memory works both ways.'
'I'm sure MINE only works one way,' Alice remarked. 'I can't remember things before they happen.'
'It's a poor sort of memory that only works backwards,' the Queen remarked.
- ↑ Jung, C. G., Synchronicity: An Acausal Connecting Principle, from The Collected Works of C.G. Jung, vol. 8, page 15, Princeton/Bollingen, 1973
- ↑ "Snopes entry".
- ↑ Article on Wired.com
- ↑ From the wikiquote page on Repo Man:A lot o' people don't realize what's really going on. They view life as a bunch o' unconnected incidents 'n things. They don't realize that there's this, like, lattice o' coincidence that lays on top o' everything. Give you an example; show you what I mean: suppose you're thinkin' about a plate o' shrimp. Suddenly someone'll say, like, plate, or shrimp, or plate o' shrimp out of the blue, no explanation. No point in lookin' for one, either. It's all part of a cosmic unconsciousness.
- ↑ McKenna quoted by Alex Burns
# References and further reading
- Carl Jung (1972). Synchronicity — An Acausal Connecting Principle. Routledge and Kegan Paul. ISBN 0-7100-7397-6.
- Carl Jung (1977). Jung on Synchronicity and the Paranormal: Key Readings. Routledge. ISBN 0-415-15508-8.
- Carl Jung (1981). The Archetypes and the Collective Unconscious. Princeton University Press. ISBN 0-691-01833-2.
- Robert Aziz, C.G. Jung’s Psychology of Religion and Synchronicity (1990), currently in its 10th printing, is a refereed publication of The State University of New York Press. ISBN 0-7914-0166-9.
- Robert Aziz, Synchronicity and the Transformation of the Ethical in Jungian Psychology in Carl B. Becker, ed. Asian and Jungian Views of Ethics. Westport, CT: Greenwood, 1999. ISBN 0-313-30452-1.
- Robert Aziz, The Syndetic Paradigm:The Untrodden Path Beyond Freud and Jung (2007), a refereed publication of The State University of New York Press ISBN 13:978-0-7914-6982-8.
- Marie-Louise von Franz (1980). On Divination and Synchronicity: The Psychology of Meaningful Chance. Inner City Books. ISBN 0-919123-02-3.
- Joseph Jaworski (1996). Synchronicity: the inner path of leadership. Berrett-Koehler Publishers Inc. ISBN 1-881052-94-X.
- Arthur Koestler (1973). The Roots of Coincidence. Vintage. ISBN 0-394-71934-4.
- Victor Mansfield, (Physicist) (1995). Science, Synchronicity and Soul-Making. Open Court Publishing Company. ISBN 0-8126-9304-3.
- Elisabeth Mardorf, Das kann doch kein Zufall sein
- F. David Peat (1987). Synchronicity, The Bridge Between Matter and Mind. Bantam. ISBN 0-553-34676-8.
- Richard Wilhelm (1986). Lectures on the I Ching: Constancy and Change Bollingen edition. Princeton University Press; Reprint. ISBN 0-691-01872-3. Note especially the foreword by Carl Jung. (The I Ching is a type of oracle, or 'synchronicity computer', used for divination.)
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Synchronicity
Template:Otheruses4
Synchronicity is the experience of two or more events which occur in a meaningful manner, but which are causally unrelated. In order to be synchronous, the events must be related to one another conceptually, and the chance that they would occur together by random chance must be very small.
# The concept of synchronicity
The idea of synchronicity is that the conceptual relationship of minds, defined by the relationship between ideas, is intricately structured in its own logical way and gives rise to relationships which have nothing to do with causal relationships in which a cause precedes an effect. Instead, causal relationships are understood as simultaneous — that is, the cause and effect occur at the same time. Synchronous events reveal an underlying pattern, a conceptual framework which encompasses, but is larger than, any of the systems which display the synchronicity. The suggestion of a larger framework is essential in order to satisfy the definition of synchronicity as originally developed by Swiss psychologist Carl Jung.[citation needed]
Carl Jung coined the word to describe what he called "temporally coincident occurrences of acausal events." Jung variously described synchronicity as an "'acausal connecting principle'" (i.e. a pattern of connection that cannot be explained by conventional, efficient causality), "meaningful coincidence" and "acausal parallelism". Jung introduced the concept in his 1952 paper "Synchronicity — An Acausal Connecting Principle", though he had been considering the concept for almost thirty years.[1]
It was a principle that Jung felt gave conclusive evidence for his concepts of
archetypes and the collective unconscious [2], in that it was descriptive of a governing dynamic that underlay the whole of human experience and history — social, emotional, psychological, and spiritual.
Jung believed that many experiences perceived as coincidence were not merely due to chance but, instead, suggested the manifestation of parallel events or circumstances reflecting this governing dynamic. [3]
One of Jung's favourite quotes on synchronicity was from Through the Looking-Glass by Lewis Carroll, in which the White Queen says to Alice: "It's a poor sort of memory that only works backwards". [4]
Events that happen which appear at first to be coincidence but are later found to be causally related are termed Incoincident .
# Examples
- A well-known example of synchronicity is the true story of the French writer Émile Deschamps who in 1805 was treated to some plum pudding by the stranger Monsieur de Fortgibu. Ten years later, he encountered plum pudding on the menu of a Paris restaurant, and wanted to order some, but the waiter told him the last dish had already been served to another customer, who turned out to be de Fortgibu. Many years later in 1832 Émile Deschamps was at a diner, and was once again offered plum pudding. He recalled the earlier incident and told his friends that only de Fortgibu was missing to make the setting complete — and in the same instant the now senile de Fortgibu entered the room.[5]
- A mother is working at preparing her dinner, and thinks "It would be nice to have some flowers here today", while her son is in the garden picking flowers for her dinner. The mother has never had flowers on the dinner table before, and the son has never brought flowers, but their close relationship leads them to both originally create the same idea at the same time.
- Simultaneous discovery, the creation of the same new idea at causally disconnected places by two persons at approximately the same time. It is very difficult to account for simultaneous discovery by random chance.[citation needed] If for example an American and a British musician, having never had anything to do with one another, arrived at the same musical concept, chord sequence, feel or lyrics at the same time in different places, this is an example of synchronicity. This is explained by reasons such as global culture, which is the larger framework required to fit the definition of synchronicity.
- During production of The Wizard of Oz, a coat bought from a second-hand store for the costume of Professor Marvel was later found to have belonged to L. Frank Baum, author of the children's book upon which the film is based. [6]
- The Wizard of Oz and Pink Floyd are part of the alleged Dark Side of the Rainbow synchronicity.
# Study
A recent study within the Princeton Engineering Anomalies Research Lab (the PEAR lab), suggested that there is a small, though statistically measurable, link between human thought and patterns that occur in random data sets. There is no evidence as to whether this is caused by individuals unintentionally recognizing complex patterns and then moulding their thoughts towards an unconsciously known result or the thoughts of the individual are themselves affecting the random patterns in a manner of individuation. This study's results have not been replicated, and its methodologies are disputed.[7] The PEAR lab closed at the end of February, 2007, after conducting 28 years of research on the relationships and interactions between Mind and Matter.
# Criticism
According to Occam's razor, positing an underlying mechanism for meaningfully interpreted correlations is an unsupported explanation for a "meaningful coincidence" which may be explained by simple coincidence. Jung and followers
believe that Synchronous events such as simultaneous discovery happen far more often than
random chance would allow, even after accounting for the sampling bias inherent in the
fact that meaningful coincidences are noticeable while meaningless coincidences are not.
# References in popular culture
- John Constantine, the main character in the Vertigo Comics series Hellblazer, is sometimes seen "riding the synchronicity highway," to meet certain goals or even just to one up those around him. This has the same effect as that described in this article, and it is one of John Constantine's more unusual tricks, and part of what makes him so dangerous. He is also seen doing this in Books of Magic, the graphic novel by Neil Gaiman.
- The phenomenon is also explored, though not named, in "The Red Notebook" by Paul Auster, and is considered a major theme of his entire bibliography, appearing in some form in almost every work.
- In the 1983 release Synchronicity by The Police (A&M Records), bassist Sting is reading a copy of Jung's Synchronicity on the front cover along with a negative/superimposed image of the actual text of the synchronicity hypothesis. A photo on the back cover also shows a close-up but mirrored and upside-down image of the book. There are two songs titled "Synchronicity I" and "Synchronicity II" included in the album. The latter song contrasts the dangerous breakdown of a desperate family man with the simultaneous emergence of a menacing something from the bottom of a dark Scottish loch. See The Police, Robert Aziz and marketing the A&M album, Synchronicity.
- In the 1976 film The Eagle Has Landed, the character Max Radl (Robert Duvall) asks a subordinate if he is familiar with the works of Jung, and then explains the theory of Synchronicity.
- The Dirk Gently series of books by Douglas Adams often plays on the synchronicity concept. The main character carries a "pocket I Ching" that also functions as a calculator, up to a point (see A suffusion of yellow).
- The concept of ta'veren in Robert Jordan's The Wheel of Time series functions similarly to synchronicity.
- In the film Repo Man Miller's famous Plate 'o' Shrimp[8] theory is an exact representation of synchronicity.
- In a 2002 album Tenth Dimensions by metal artist Blaze, a lot of the songs refer to synchronicity, with some songs like "Stealing Time" directly using the word.
- In the film I ♥ Huckabees, a character hires existential detectives to solve his coincidence. They caution him: "Not all coincidences are meaningful!"
- In Philip K Dick's The Game Players of Titan, several characters possessing pre-cognitive abilities cite the acausal principle of synchronicity as an element which hampers their ability to accurately predict certain possible futures.
- In the D20 Modern roleplaying game Urban Arcana, Synchronicity is a magic spell that subtly rearranges reality, allowing the subject to avoid the minor inconveniences and hassles of everyday life. While the spell is in effect, buses and trains run on time, stoplights and crosswalk signals change in your favor just as you approach an intersection, and the flow of street traffic and pedestrians will allow you to proceed unimpeded, without hurry or delay. Waiters and clerks will approach as soon as they are wanted, and depart when you desire privacy. Taxi cabs, elevators, vacant parking spaces, and so forth will similarly be available wherever and whenever needed. This spell is particularly helpful when the subject is chasing someone or is trying to escape pursuers.
- In the television series Strange Luck, the main character Chance Harper spends his entire life experiencing unplanned synchronicity, which he takes advantage of by becoming a freelance photographer.
- The Dalai Lama quoted: "I am open to the guidance of synchronicity, and do not let expectations hinder my path."
- Terence McKenna used the term 'Cosmic giggle' to mean "a randomly roving zone of synchronicity and statistical anomaly. Should you be caught up in it, it will turn reality on its head. It is objective and subjective, simultaneously 'really there' and yet somehow is sustained by imagination and expectation...." [9]
# Notes
- ↑ Roderick Main (2000). "Religion, Science, and Synchronicity". Harvest: Journal for Jungian Studies..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jung defined the collective
unconscious as akin to instincts in Archetypes and the Collective Unconscious.
- ↑ In Synchronicity in the final two pages of the Conclusion, Jung stated that not all coincidences are meaningful and further explained the creative causes of this phenomenon.
- ↑ Through the Looking-Glass, by Lewis Carroll, Ch. 5, Wool and Water. 'It's very good jam,' said the Queen.
'Well, I don't want any TO-DAY, at any rate.'
'You couldn't have it if you DID want it,' the Queen said.
'The rule is, jam to-morrow and jam yesterday--but never jam
to-day.'
'It MUST come sometimes to "jam to-day,"' Alice objected.
'No, it can't,' said the Queen. 'It's jam every OTHER day: to-day isn't any OTHER day, you know.'
'I don't understand you,' said Alice. 'It's dreadfully confusing!'
'That's the effect of living backwards,' the Queen said kindly: 'it always makes one a little giddy at first--'
'Living backwards!' Alice repeated in great astonishment. 'I never heard of such a thing!'
'--but there's one great advantage in it, that one's memory works both ways.'
'I'm sure MINE only works one way,' Alice remarked. 'I can't remember things before they happen.'
'It's a poor sort of memory that only works backwards,' the Queen remarked.
- ↑ Jung, C. G., Synchronicity: An Acausal Connecting Principle, from The Collected Works of C.G. Jung, vol. 8, page 15, Princeton/Bollingen, 1973
- ↑ "Snopes entry".
- ↑ Article on Wired.com
- ↑ From the wikiquote page on Repo Man:A lot o' people don't realize what's really going on. They view life as a bunch o' unconnected incidents 'n things. They don't realize that there's this, like, lattice o' coincidence that lays on top o' everything. Give you an example; show you what I mean: suppose you're thinkin' about a plate o' shrimp. Suddenly someone'll say, like, plate, or shrimp, or plate o' shrimp out of the blue, no explanation. No point in lookin' for one, either. It's all part of a cosmic unconsciousness.
- ↑ McKenna quoted by Alex Burns
# References and further reading
- Carl Jung (1972). Synchronicity — An Acausal Connecting Principle. Routledge and Kegan Paul. ISBN 0-7100-7397-6.
- Carl Jung (1977). Jung on Synchronicity and the Paranormal: Key Readings. Routledge. ISBN 0-415-15508-8.
- Carl Jung (1981). The Archetypes and the Collective Unconscious. Princeton University Press. ISBN 0-691-01833-2.
- Robert Aziz, C.G. Jung’s Psychology of Religion and Synchronicity (1990), currently in its 10th printing, is a refereed publication of The State University of New York Press. ISBN 0-7914-0166-9.
- Robert Aziz, Synchronicity and the Transformation of the Ethical in Jungian Psychology in Carl B. Becker, ed. Asian and Jungian Views of Ethics. Westport, CT: Greenwood, 1999. ISBN 0-313-30452-1.
- Robert Aziz, The Syndetic Paradigm:The Untrodden Path Beyond Freud and Jung (2007), a refereed publication of The State University of New York Press ISBN 13:978-0-7914-6982-8.
- Marie-Louise von Franz (1980). On Divination and Synchronicity: The Psychology of Meaningful Chance. Inner City Books. ISBN 0-919123-02-3.
- Joseph Jaworski (1996). Synchronicity: the inner path of leadership. Berrett-Koehler Publishers Inc. ISBN 1-881052-94-X.
- Arthur Koestler (1973). The Roots of Coincidence. Vintage. ISBN 0-394-71934-4.
- Victor Mansfield, (Physicist) (1995). Science, Synchronicity and Soul-Making. Open Court Publishing Company. ISBN 0-8126-9304-3.
- Elisabeth Mardorf, Das kann doch kein Zufall sein [1]
- F. David Peat (1987). Synchronicity, The Bridge Between Matter and Mind. Bantam. ISBN 0-553-34676-8.
- Richard Wilhelm (1986). Lectures on the I Ching: Constancy and Change Bollingen edition. Princeton University Press; Reprint. ISBN 0-691-01872-3. Note especially the foreword by Carl Jung. (The I Ching is a type of oracle, or 'synchronicity computer', used for divination.)
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Syringomyelia
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Syringomyelia
# Overview
Syringomyelia is a spinal cord cavitation, which is a central dilation due to cystic degradation expands and destroyed the spinal cord. Caused by an injury, tumors or congenital malformation like hernia. The damage can Effect the brain and nerves, that leade to Bilateral loss of pain and temperature sensation in upper extremities. weakness, stiffness, hyperReflexives in lower extremities with hyposcoliosis. Each patient experiences a different combination of symptoms. These symptoms typically vary depending on the extent and, often more critically, on the location of the syrinx within the spinal cord.
# Historical Perspective
- In the 16th century, Estienne, a French anatomist, observed spinal cord cavitation for the first time.
- In 1545, Stephanus reported a case of spinal cord dilatation in one of his patients.
- In 1688, Brunner reported a liquor filled cavity with hydrocephalus in a pediatric case.
- In 1824, Olivier d'Angers coined the term syringomyelia.
- Also in 1824, Schuppel defined the fluid in the syrinx as a hydromyelia and proposed the pathogenesis as the persistence of the fetal central canal.
- In 1882, Otto von Kohler and Fredrich Schultz defined the clinical syndrome of syringomyelia.
- Between 1883 to 1891, Cleland and Hans Chiari associated syrinx formation with hyind brain herniation in what was subsequently named Chiari malformations types I to III.
- In 1959, Gardner described the waterhammer theory for pathogenesis of syringomyelia.
- In 1972, Ball and Dyan described the cavitation of the perivascular space as the source of syrinx formation.
- In 1980, Williams described the "suck and slosh" theory of syrinx formation.
- In 1994, Oldfield describes the piston effect of Chiari I malformation resulting in syringomyelia.
- In 2003, the Cisterna magna theory aimed to harmonize the Gardner, Williams, Oldfield and Ball&Dyan theories with neural imaging findings to propose an objective proposal of the pathogenesis of syringomyelia.
# Classification
Syringomyelia may be classified in various ways according to the anatomical features of the syrinx, or according to the underlying etiology of the disease.
## By Anatomy
Syringomyelia may be classified according to the anatomical description of the lesion (syrinx) as follows:
- Communicating vs. Non-communicating:
A communicating syringomyelia is one where the syrinx is continuous from the spinal cord, across the foramen magnum and the dilatation is continuous with the fourth ventricle
A non-communicating syringomyelia is characterized by absence of the continuity across the foramen magnum. It may present as isolated syringomyelia, or as isolated syringobulbia only affecting the brainstem with cranial nerve palsies.
- A communicating syringomyelia is one where the syrinx is continuous from the spinal cord, across the foramen magnum and the dilatation is continuous with the fourth ventricle
- A non-communicating syringomyelia is characterized by absence of the continuity across the foramen magnum. It may present as isolated syringomyelia, or as isolated syringobulbia only affecting the brainstem with cranial nerve palsies.
- Intracannalicular vs. Extracannalicular:
Intracannalicular synringomyelia originates within the central canal of the spinal cord.
Extracannalicular syringomyelia originates within the spinal cord parenchyma.
- Intracannalicular synringomyelia originates within the central canal of the spinal cord.
- Extracannalicular syringomyelia originates within the spinal cord parenchyma.
## By Etiology
Syringomyelia may be classified according to the underlying etiology or associated condition as follows:
- Congenital Malformations
- Post-infectious
- Post-traumatic
- Post-inflammatory
- Neoplastic
# Pathophysiology
## Pathogenesis
The exact pathogenesis of syringomyelia remains unknown. Several theories have been postulated about the development of a syrinx in the spinal cord. The underlying mechanisms of the disease involves disruption of CNS flow, subsequent formation of a syrinx, and enlargement of the lesion to impinge on the surrounding nerve fibers resulting in a symptomatic presentation.
- Congenital craniocervical abnormalities obstructing CSF flow from the ventricles to the central canal (e.g., arnold chiari malformation, scoliosis)
- Tumor or arachnoid cyst exhibiting a mass effect on the spinal cord
- Sequelae of spinal cord trauma results in abnormal obstruction of the central canal
- Sequelae of meningitis resulting in inflammation of the spinal cord meninges
- Sequelae of inflammatory conditions such as sarcoidosis, multiple sclerosis, seronegative spondyloarthropathies
- Gardner's hydrodynamic theory: Blockage of the foramen of Magendie at the obex results in a pulsatile "water-hammer" effect of the mass lesion on the spinal cord CSF. This pressure differential results in extravasation of fluid into the perivascular and extracellular spaces.
- William's theory: Increased intracranial pressure combined with decreased subarachnoid spinal pressure results in a "vaccuum-like" effect which further herniates the cerebellar tonsils through the foramen magnum. This results in sloshing of the subarachnoid CSF and causes extravasation of the CSF into the spinal cord parenchyma, thus creating a syrinx.
- Ball & Dyan theory: With the CSF pressure difference created by the lesion, fluid moves, collects, and expands within Robin Virchow's perivascular space.
- Oldfield's theory: The pulsatile waves of the CSF which occur during systole result in increased ICP. This increased pressure herniates the cerebellum to obstruct the subarachnoid space at the level of the foramen magnum. This pulsatile fluid wave against the surface of the spinal cord results in extravasation of fluid into the parenchyma and creates a syrinx.
- Cisterna Magna theory: This theory claims that the fluid storage capacity of the cisterna magna is the primary shock absorber of the CNS that allows the spinal cord parenchyma to remain protected from increases in intracranial pressure. Mass effect of any lesion "stiffens" the cisterna magna and results in decreased compliance of the space and increased transferrance of pressure to the spinal cord. This results in extravasation of fluid to the spinal cord parenchyma.
## Genetics
There is no genetic predilection for the development of syringomyelia. However, Chiari malformations which are the primary cause of syringomyelia have demonstrated a strong familial and genomic association.
# Causes
The most common cause of syringomyelia is Chiari I malformation. Other causes of syringomyelia may include:
## Common Causes
- Other congenital abnormalities (e.g., scoliosis, Chiari I and II malformations)
- Traumatic spinal cord injury
## Less Common Causes
- Infections (e.g., meningitis/arachnoiditis)
- Mass lesions or neoplasia (e.g., Ependymoma, hemangioblastoma, meningioma, or arachnoid cyst)
- Inflammatory conditions (e.g. multiple sclerosis, transverse myelitis, amyotrophic lateral sclerosis, sarcoidosis, other myelitis)
- Idiopathic
# Differentiating Syringomyelia from other diseases
Syringomyelia must be differentiated from other diseases which cause gait abnormalities, sensory and motor deficit, chronic pain syndromes, urinary and fecal incontinence, and cranial nerve palsies such as:
- Normopressure hydrocephalus
- ALS
- Meningitis
- Transverse Myelitis
- Cerebrovascular accidents
- Brain tumor
- Peripheral neuropathy
- Fibromyalgia
- Parkinsonism
- Cerebellar ataxia
- Multiple sclerosis
- Neurogenic bladder
- Spinal cord space occupying lesion (e.g., tumors, cysts, abscesses)
- Guillian Barre
- Chronic demyelinating polyneuropathy
# Risk Factors
The main risk factors associated with the development of syringomyelia are based on the underlying causes:
- Congenital Malformations: Chiari malformations, Klippel Feil syndrome, congenital scoliosis
- Post-infectious: Development of arachnoiditis and development of dural abscess.
- Post-traumatic: Increasing age at time of trauma , cervical and thoracic injuries compared with lumbar, displaced fractures, and spinal instrumentation without decompression.
- Post-inflammatory: Multiple sclerosis, neurosarcoidosis, Amyotrophic Lateral Sclerosis (ALS)
- Neoplastic: Ependymoma and hemangioblastoma are most strongly associated with development of syringomyelia.
# Screening
There is no recommended screening for syringomyelia.
# Epidemiology and Demographics
## Incidence
- More than 25% of patients with spinal cord injury progress to develop syringomyelia.
## Prevalence
Syringomyelia has a prevalence estimated at 8.4 cases per 100,000 people, or about 21,000 Americans, with symptoms usually beginning in young adulthood.
# Natural History, Complications, and Prognosis
## Natural History
The essential Course of disease in Syringomyelia is temperamental. Without treatment, syringomyelia may progress to develop the worsening of neurological deficit in cases of obstructive lesions. However, the disease has a slower progression in cases of mild disease.
## Complications
Complications that can develop as a result of syringomyelia are:
- Complex regional pain syndrome
- Scoliosis
- Diaphragmatic paralysis
- Spastic ataxia
- Obsturctive sleep apnea
- Central respiratory failure
- Horner's syndrome
- Skin ulceration
- Raynaud's syndrome
- Hemihypertrophy
- Upper motor neurone lesion
- Lower motor neurone lesion
- Charcot's joints
- Raynaud's phenomenon
## Prognosis
The prognosis of syringomyelia varies depending on factors such as cause, extent of neurological damage, presence of complications, and general health status of patient before undergoing surgical treatment.
- Patients with mild neurological deficit may respond better to surgical management.
- Early management of syringomyelia in cases of trauma is associated with decreased morbidity.
- The symptoms of 80% of patients usually end due to their response to surgical treatment, as well a mild cure.
- 20% of patients gets worse despite treatment in cases of advanced disease.
- Recurrence is not uncommon in syringomyelia.
# History and Symptoms
Specific areas of focus when obtaining the history such as onset, duration and progression of symptoms; history of trauma; associated conditions like multiple sclerosis, transverse myelitis, amyotrophic lateral sclerosis, sarcoidosis, congenital malformation, infection such as meningitis or neoplasia (ependymoma, meningioma, hemangioblastoma) may help diagnosing syringomyelia. Symptoms depends on the anatomical site of spinal cord involved.
# Physical Examination
The following includes how syringomyelia might be revealed :
# Imaging Findings
Imaging studies that may help diagnose syringomyelia, its cause and complications include:
## MRI
Spinal MRI may help to diagnose and follow up syringomyelia. It is characterized by the following findings:
- Presence of syrinx in the spinal cord, its extent, location and complications
- Enlargement of central canal of spinal cord
- Presence of syrinx in the brain stem (syringobulbia)
- Presence of assocaited congenital anomalies such as chiari malformation, klippel feil syndrome, spina bifida, tethered cord syndrome
- Presence of tumors such as ependymoma
- May be used for follow up post surgery
## CT
Syringomyelia may be diagnosed as an incidental finding on CT scan. However, delayed CT scan may have a diagnostic importance in early cases of syringomyelia without clinical manifestaions. Metrizimed CT scan using non-ionic contrast may be used to identify a syrinx in postinflammatory conditions (postinfectious and posthemorrhagic arachnoiditis). In addition, computed axial tomography (CT) scans of a patient's head may reveal the presence of tumors and other abnormalities such as hydrocephalus.
## X ray
There are no specific X ray findings associated with syringomyelia.
## Myelogram
Myelogram is rarely used to diagnose syringomyelia. It uses a contrast material combined with x ray or CT to image spinal cord in case of syringomyelia. However, CT metrimised myelography is more sensitive to diagnose syringomyelia as compared to conventional myelography.
# Other Diagnostic Studies
## Electromyography
EMG findings of syringomyelia include increased excitability of spinal motor neurons. However, the findings are non specific and does not hold diagnostic importance in case of syringomyelia.
## Lumbar Puncture
Role of lumbar puncture in syringomyelia is controversial since it may result in herniation in cases of Chiari malformation. However, it may be used by some clinicians as a diagnostic tool to look for CSF pressure and signs of inflammation based on individual patient assessment.
# Medical Therapy
Drugs have no curative value as a treatment for syringomyelia. The role of medical therapy in management of syringomyelia is for treatment of underlying conditions or management of associated symptoms.
## Treatment of Underlying Conditions
Radiation and chemotherapy may be utilized for management of an underlying spinal cord tumor.
Antibiotics may be used to treat an underlying infection (meningitis or encephalitis).
## Management of Symptoms
- Analgesics may be used to control pain.
- GABA inhibitors neurontin pregebalin may be used to control peripheral neuropathy.
- Drugs may be used for urinary or fecal incontinence or neurogenic bladder (e.g., oxybutynin, prazosin, loperamide, atropine)
In the absence of symptoms, syringomyelia is usually not treated. In addition, a physician may recommend not treating the condition in patients of advanced age or in cases where there is no progression of symptoms. Whether treated or not, many patients will be told to avoid activities that involve straining.
# Surgery
Surgery is not always required for syringomyelia. Indications for surgical management of syringomyelia include the following:
- Progressive neurological deterioration and worsening of symptoms
- Presence of tumor causing obstruction
- Congenital malformation(Chiari malformation)
- Traumatic injury to spinal cord
Surgical options used to treat syringomyelia include:
## Posterior fossa decompression
- Usually performed in Chiari malformation patients to expand the size of the posterior fossa and reverse tonsillar herniation resulting in relief of the obstructive lesion.
- This procedure may be combined with shunt, creating a large subarachanoid cistern to drain the syrinx or in conjunction with duroplasty in which dura is opened after bony removal of posterior occiput and posterior arch of C1 vertebra and a graft is sewed to dura effectively creating extra space in posterior fossa.
- Another procedure used along with posterior fossa decompression and duraplasty to help relieve obstruction is tonsillar resection or shrinkage.
## Shunt formation
Shunts are placed in order to drain the syrinx and alleviate symptoms such as headache and chronic pain syndromes. The choice of shunt is determined by the neurosurgeon; however, the following types of shunts may be performed:
Ventriculoperitoneal shunt
- Performed in patients with communicating syrinxes with hydrocephalus due to increased ventricular pressure.
- This surgery is more commonly associated with Chiari II malformations
Syringosubarachnoid shunt
- Performed more commonly in non-communicating syrinxes and is effective in rapidly reducing the size of the syrinx.
- This shunt drains the syrinx into the subarachnoid space, and the CSF is subsequently reabsorbed by the arachnoid villi.
Syringoperitoneal shunt
- Drainage of syrinx into the peritoneal cavity.
## Removal of obstruction
- In cases of tumors or arachnoid cysts as the underlying cause of the obstructive precursor lesion to syrinx formation, removal of said mass lesion may reverse the symptoms and reduce syrinx size.
## Surgical untethering and expansive duraplasty
- Performed in post-traumatic syringomyelia.
- This procedure involves establishing access to the spinal cord at the level of the injury, laminectomy, lysis of adhesions, entry into spinal cord at the site of syrinx and drainage of the syrinx into said space.
- Duroplasty is usually performed following this procedure, for regional structural support.
## Neuroendoscopic surgery
- Novel endoscopic procedure used for chiari malformation and syrinx drainage
- Minimally invasive
- Fast recovery
- Fewer complications
# Prevention
## Primary Prevention
There are no primary preventive measures associated with syringomyelia.
## Secondary Prevention
- Physiotherapy
- Prompt Surgery
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Syringomyelia
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2] Aysha Aslam, M.B.B.S[3] Eman Alademi, M.D.[4]
# Overview
Syringomyelia is a spinal cord cavitation, which is a central dilation due to cystic degradation expands and destroyed the spinal cord. Caused by an injury, tumors or congenital malformation like hernia. The damage can Effect the brain and nerves, that leade to Bilateral loss of pain and temperature sensation in upper extremities. weakness, stiffness, hyperReflexives in lower extremities with hyposcoliosis. Each patient experiences a different combination of symptoms. These symptoms typically vary depending on the extent and, often more critically, on the location of the syrinx within the spinal cord.
# Historical Perspective
- In the 16th century, Estienne, a French anatomist, observed spinal cord cavitation for the first time.[1][2]
- In 1545, Stephanus reported a case of spinal cord dilatation in one of his patients.[1][2]
- In 1688, Brunner reported a liquor filled cavity with hydrocephalus in a pediatric case.[1][2]
- In 1824, Olivier d'Angers coined the term syringomyelia.[1][2]
- Also in 1824, Schuppel defined the fluid in the syrinx as a hydromyelia and proposed the pathogenesis as the persistence of the fetal central canal.[1][2]
- In 1882, Otto von Kohler and Fredrich Schultz defined the clinical syndrome of syringomyelia.[1][2]
- Between 1883 to 1891, Cleland and Hans Chiari associated syrinx formation with hyind brain herniation in what was subsequently named Chiari malformations types I to III. [1][2]
- In 1959, Gardner described the waterhammer theory for pathogenesis of syringomyelia.[3]
- In 1972, Ball and Dyan described the cavitation of the perivascular space as the source of syrinx formation.[4]
- In 1980, Williams described the "suck and slosh" theory of syrinx formation.[5]
- In 1994, Oldfield describes the piston effect of Chiari I malformation resulting in syringomyelia.[6]
- In 2003, the Cisterna magna theory aimed to harmonize the Gardner, Williams, Oldfield and Ball&Dyan theories with neural imaging findings to propose an objective proposal of the pathogenesis of syringomyelia.[7]
# Classification
Syringomyelia may be classified in various ways according to the anatomical features of the syrinx, or according to the underlying etiology of the disease.[8]
## By Anatomy
Syringomyelia may be classified according to the anatomical description of the lesion (syrinx) as follows:[8]
- Communicating vs. Non-communicating:
A communicating syringomyelia is one where the syrinx is continuous from the spinal cord, across the foramen magnum and the dilatation is continuous with the fourth ventricle
A non-communicating syringomyelia is characterized by absence of the continuity across the foramen magnum. It may present as isolated syringomyelia, or as isolated syringobulbia only affecting the brainstem with cranial nerve palsies.
- A communicating syringomyelia is one where the syrinx is continuous from the spinal cord, across the foramen magnum and the dilatation is continuous with the fourth ventricle
- A non-communicating syringomyelia is characterized by absence of the continuity across the foramen magnum. It may present as isolated syringomyelia, or as isolated syringobulbia only affecting the brainstem with cranial nerve palsies.
- Intracannalicular vs. Extracannalicular:
Intracannalicular synringomyelia originates within the central canal of the spinal cord.
Extracannalicular syringomyelia originates within the spinal cord parenchyma.
- Intracannalicular synringomyelia originates within the central canal of the spinal cord.
- Extracannalicular syringomyelia originates within the spinal cord parenchyma.
## By Etiology
Syringomyelia may be classified according to the underlying etiology or associated condition as follows:[9][10][11]
- Congenital Malformations
- Post-infectious
- Post-traumatic
- Post-inflammatory
- Neoplastic
# Pathophysiology
## Pathogenesis
The exact pathogenesis of syringomyelia remains unknown. Several theories have been postulated about the development of a syrinx in the spinal cord. The underlying mechanisms of the disease involves disruption of CNS flow, subsequent formation of a syrinx, and enlargement of the lesion to impinge on the surrounding nerve fibers resulting in a symptomatic presentation.
- Congenital craniocervical abnormalities obstructing CSF flow from the ventricles to the central canal (e.g., arnold chiari malformation, scoliosis)
- Tumor or arachnoid cyst exhibiting a mass effect on the spinal cord
- Sequelae of spinal cord trauma results in abnormal obstruction of the central canal
- Sequelae of meningitis resulting in inflammation of the spinal cord meninges
- Sequelae of inflammatory conditions such as sarcoidosis, multiple sclerosis, seronegative spondyloarthropathies
- Gardner's hydrodynamic theory: Blockage of the foramen of Magendie at the obex results in a pulsatile "water-hammer" effect of the mass lesion on the spinal cord CSF. This pressure differential results in extravasation of fluid into the perivascular and extracellular spaces.[7][12][3]
- William's theory: Increased intracranial pressure combined with decreased subarachnoid spinal pressure results in a "vaccuum-like" effect which further herniates the cerebellar tonsils through the foramen magnum. This results in sloshing of the subarachnoid CSF and causes extravasation of the CSF into the spinal cord parenchyma, thus creating a syrinx.[7][5]
- Ball & Dyan theory: With the CSF pressure difference created by the lesion, fluid moves, collects, and expands within Robin Virchow's perivascular space.[4]
- Oldfield's theory: The pulsatile waves of the CSF which occur during systole result in increased ICP. This increased pressure herniates the cerebellum to obstruct the subarachnoid space at the level of the foramen magnum. This pulsatile fluid wave against the surface of the spinal cord results in extravasation of fluid into the parenchyma and creates a syrinx.[6]
- Cisterna Magna theory: This theory claims that the fluid storage capacity of the cisterna magna is the primary shock absorber of the CNS that allows the spinal cord parenchyma to remain protected from increases in intracranial pressure. Mass effect of any lesion "stiffens" the cisterna magna and results in decreased compliance of the space and increased transferrance of pressure to the spinal cord. This results in extravasation of fluid to the spinal cord parenchyma.[7]
## Genetics
There is no genetic predilection for the development of syringomyelia. However, Chiari malformations which are the primary cause of syringomyelia have demonstrated a strong familial and genomic association.[13][14][15][16][17][18]
# Causes
The most common cause of syringomyelia is Chiari I malformation[19]. Other causes of syringomyelia may include:
## Common Causes
- Other congenital abnormalities (e.g., scoliosis, Chiari I and II malformations)[20][19][21][22]
- Traumatic spinal cord injury[23]
## Less Common Causes
- Infections (e.g., meningitis/arachnoiditis)[24][25]
- Mass lesions or neoplasia (e.g., Ependymoma, hemangioblastoma, meningioma, or arachnoid cyst)[26][27][28][29]
- Inflammatory conditions (e.g. multiple sclerosis, transverse myelitis, amyotrophic lateral sclerosis, sarcoidosis, other myelitis)[30][31][32][33][34]
- Idiopathic [35][36]
# Differentiating Syringomyelia from other diseases
Syringomyelia must be differentiated from other diseases which cause gait abnormalities, sensory and motor deficit, chronic pain syndromes, urinary and fecal incontinence, and cranial nerve palsies such as:[37][38][39][40][41]
- Normopressure hydrocephalus
- ALS
- Meningitis
- Transverse Myelitis
- Cerebrovascular accidents
- Brain tumor
- Peripheral neuropathy
- Fibromyalgia
- Parkinsonism
- Cerebellar ataxia
- Multiple sclerosis
- Neurogenic bladder
- Spinal cord space occupying lesion (e.g., tumors, cysts, abscesses)
- Guillian Barre
- Chronic demyelinating polyneuropathy
# Risk Factors
The main risk factors associated with the development of syringomyelia are based on the underlying causes:
- Congenital Malformations: Chiari malformations, Klippel Feil syndrome, congenital scoliosis[19][21][42]
- Post-infectious: Development of arachnoiditis and development of dural abscess.[43]
- Post-traumatic: Increasing age at time of trauma , cervical and thoracic injuries compared with lumbar, displaced fractures, and spinal instrumentation without decompression.[44][45]
- Post-inflammatory: Multiple sclerosis, neurosarcoidosis, Amyotrophic Lateral Sclerosis (ALS)[30]
- Neoplastic: Ependymoma and hemangioblastoma are most strongly associated with development of syringomyelia.[46]
# Screening
There is no recommended screening for syringomyelia.
# Epidemiology and Demographics
## Incidence
- More than 25% of patients with spinal cord injury progress to develop syringomyelia.[47]
## Prevalence
Syringomyelia has a prevalence estimated at 8.4 cases per 100,000 people,[48] or about 21,000 Americans, with symptoms usually beginning in young adulthood.
# Natural History, Complications, and Prognosis
## Natural History
The essential Course of disease in Syringomyelia is temperamental. Without treatment, syringomyelia may progress to develop the worsening of neurological deficit in cases of obstructive lesions. However, the disease has a slower progression in cases of mild disease.[49][50][51]
## Complications
Complications that can develop as a result of syringomyelia are:[36][52][53][54][55][56][57][58][59][60][61]
- Complex regional pain syndrome
- Scoliosis
- Diaphragmatic paralysis
- Spastic ataxia
- Obsturctive sleep apnea
- Central respiratory failure
- Horner's syndrome
- Skin ulceration
- Raynaud's syndrome
- Hemihypertrophy
- Upper motor neurone lesion
- Lower motor neurone lesion
- Charcot's joints
- Raynaud's phenomenon
## Prognosis
The prognosis of syringomyelia varies depending on factors such as cause, extent of neurological damage, presence of complications, and general health status of patient before undergoing surgical treatment.[62][63][64]
- Patients with mild neurological deficit may respond better to surgical management.
- Early management of syringomyelia in cases of trauma is associated with decreased morbidity.
- The symptoms of 80% of patients usually end due to their response to surgical treatment, as well a mild cure.
- 20% of patients gets worse despite treatment in cases of advanced disease.
- Recurrence is not uncommon in syringomyelia.
# History and Symptoms
Specific areas of focus when obtaining the history such as onset, duration and progression of symptoms; history of trauma; associated conditions like multiple sclerosis, transverse myelitis, amyotrophic lateral sclerosis, sarcoidosis, congenital malformation, infection such as meningitis or neoplasia (ependymoma, meningioma, hemangioblastoma) may help diagnosing syringomyelia. Symptoms depends on the anatomical site of spinal cord involved.[65][66][67][68][69][70]
# Physical Examination
The following includes how syringomyelia might be revealed :[71][72][73][74][75][76]
# Imaging Findings
Imaging studies that may help diagnose syringomyelia, its cause and complications include:[77][78][79]
## MRI
Spinal MRI may help to diagnose and follow up syringomyelia. It is characterized by the following findings:[77][80][81][82][83]
- Presence of syrinx in the spinal cord, its extent, location and complications
- Enlargement of central canal of spinal cord
- Presence of syrinx in the brain stem (syringobulbia)
- Presence of assocaited congenital anomalies such as chiari malformation, klippel feil syndrome, spina bifida, tethered cord syndrome
- Presence of tumors such as ependymoma
- May be used for follow up post surgery
## CT
Syringomyelia may be diagnosed as an incidental finding on CT scan. However, delayed CT scan may have a diagnostic importance in early cases of syringomyelia without clinical manifestaions.[84][85] Metrizimed CT scan using non-ionic contrast may be used to identify a syrinx in postinflammatory conditions (postinfectious and posthemorrhagic arachnoiditis).[86][87] In addition, computed axial tomography (CT) scans of a patient's head may reveal the presence of tumors and other abnormalities such as hydrocephalus.
## X ray
There are no specific X ray findings associated with syringomyelia.
## Myelogram
Myelogram is rarely used to diagnose syringomyelia. It uses a contrast material combined with x ray or CT to image spinal cord in case of syringomyelia. However, CT metrimised myelography is more sensitive to diagnose syringomyelia as compared to conventional myelography.[87][88]
# Other Diagnostic Studies
## Electromyography
EMG findings of syringomyelia include increased excitability of spinal motor neurons. However, the findings are non specific and does not hold diagnostic importance in case of syringomyelia.[89][90]
## Lumbar Puncture
Role of lumbar puncture in syringomyelia is controversial since it may result in herniation in cases of Chiari malformation. However, it may be used by some clinicians as a diagnostic tool to look for CSF pressure and signs of inflammation based on individual patient assessment.[67]
# Medical Therapy
Drugs have no curative value as a treatment for syringomyelia. The role of medical therapy in management of syringomyelia is for treatment of underlying conditions or management of associated symptoms.
## Treatment of Underlying Conditions
Radiation and chemotherapy may be utilized for management of an underlying spinal cord tumor.
Antibiotics may be used to treat an underlying infection (meningitis or encephalitis).
## Management of Symptoms
- Analgesics may be used to control pain.
- GABA inhibitors neurontin pregebalin may be used to control peripheral neuropathy.
- Drugs may be used for urinary or fecal incontinence or neurogenic bladder (e.g., oxybutynin, prazosin, loperamide, atropine)[91]
In the absence of symptoms, syringomyelia is usually not treated. In addition, a physician may recommend not treating the condition in patients of advanced age or in cases where there is no progression of symptoms. Whether treated or not, many patients will be told to avoid activities that involve straining.
# Surgery
Surgery is not always required for syringomyelia. Indications for surgical management of syringomyelia include the following:[92][93]
- Progressive neurological deterioration and worsening of symptoms
- Presence of tumor causing obstruction
- Congenital malformation(Chiari malformation)
- Traumatic injury to spinal cord
Surgical options used to treat syringomyelia include:[94][95]
## Posterior fossa decompression
- Usually performed in Chiari malformation patients to expand the size of the posterior fossa and reverse tonsillar herniation resulting in relief of the obstructive lesion.[93][96]
- This procedure may be combined with shunt, creating a large subarachanoid cistern to drain the syrinx or in conjunction with duroplasty in which dura is opened after bony removal of posterior occiput and posterior arch of C1 vertebra and a graft is sewed to dura effectively creating extra space in posterior fossa.[96][97]
- Another procedure used along with posterior fossa decompression and duraplasty to help relieve obstruction is tonsillar resection or shrinkage.[98][99]
## Shunt formation
Shunts are placed in order to drain the syrinx and alleviate symptoms such as headache and chronic pain syndromes. The choice of shunt is determined by the neurosurgeon; however, the following types of shunts may be performed:[97][100][101]
Ventriculoperitoneal shunt
- Performed in patients with communicating syrinxes with hydrocephalus due to increased ventricular pressure.
- This surgery is more commonly associated with Chiari II malformations
Syringosubarachnoid shunt
- Performed more commonly in non-communicating syrinxes and is effective in rapidly reducing the size of the syrinx.
- This shunt drains the syrinx into the subarachnoid space, and the CSF is subsequently reabsorbed by the arachnoid villi.
Syringoperitoneal shunt
- Drainage of syrinx into the peritoneal cavity.
## Removal of obstruction
- In cases of tumors or arachnoid cysts as the underlying cause of the obstructive precursor lesion to syrinx formation, removal of said mass lesion may reverse the symptoms and reduce syrinx size.[102]
## Surgical untethering and expansive duraplasty
- Performed in post-traumatic syringomyelia.[67]
- This procedure involves establishing access to the spinal cord at the level of the injury, laminectomy, lysis of adhesions, entry into spinal cord at the site of syrinx and drainage of the syrinx into said space.[67]
- Duroplasty is usually performed following this procedure, for regional structural support.[67]
## Neuroendoscopic surgery
- Novel endoscopic procedure used for chiari malformation and syrinx drainage[103][104][105]
- Minimally invasive
- Fast recovery
- Fewer complications
# Prevention
## Primary Prevention
There are no primary preventive measures associated with syringomyelia.
## Secondary Prevention
- Physiotherapy
- Prompt Surgery
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https://www.wikidoc.org/index.php/Syringomyelia
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1dcb107206d16b32b68498aad8ab787036ad2acb
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wikidoc
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Systemic risk
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Systemic risk
In finance, systemic risk describes the likelihood of the collapse of a financial system, such as a general stock market crash or a joint breakdown of the banking system. As such, it is a type of "aggregate risk" as opposed to "idiosyncratic risk", which is specific to individual stocks or banks. Systemic risk should also be carefully distinguished from Non-systemic risk, which describes risks which the whole economy faces such as business cycles or wars.
In banking, banks hold capital to absorb credit risk (e.g. bad loans), market risk (e.g. interest rate risk) and operational risk (e.g. exposure to lawsuits). In recent years development of international derivative markets led to tendencies of banks to sell their credit risk through "credit risk derivatives", a trend that has become popular under the heading of "securitization".
In insurance it is difficult to obtain financial protection against "systemic risks" because of the inability of any counter-party to accept the risk. For example it is difficult to obtain insurance for life or property in the event of nuclear war. The essence of systematic risk is therefore the correlation of losses. "Systemic Risk" adds the important problem, that it is much more difficult to evaluate than "systematic risk". For example, while econometric estimates and expectation proxies in business cycle research led to a considerable improvement in forecasting recessions, data on "Systemic Risk" is often hard to obtain, since interdependencies and counter party risk on financial markets play a crucial role. If one bank goes bankrupt and sells all its assets, the drop in asset prices may induce liquidity problems of other banks, leading to a general banking panic.
One concern is the potential fragility of some financial markets. If the participants are trading at levels far above their capital bases, then the failure of one participant to settle trades may deprive others of liquidity, and through a domino effect expose the whole market to systemic risk.
# Diversification
Risks can be reduced in four main ways: Avoidance, Reduction, Retention and Transfer. Systematic risk is a risk of security that cannot be reduced through diversification. Also sometimes called market risk or un-diversifiable risk. Participants in the market, like hedge funds, can themselves be the source of an increase in systemic risk and transfer of risk to them may, paradoxically, increase the exposure to systemic risk.
# Regulation
One of the main reasons for regulation in the marketplace is to reduce systemic risk.
|
Systemic risk
In finance, systemic risk describes the likelihood of the collapse of a financial system[citation needed], such as a general stock market crash or a joint breakdown of the banking system. As such, it is a type of "aggregate risk" as opposed to "idiosyncratic risk", which is specific to individual stocks or banks. Systemic risk should also be carefully distinguished from Non-systemic risk, which describes risks which the whole economy faces such as business cycles or wars.
In banking, banks hold capital to absorb credit risk (e.g. bad loans), market risk (e.g. interest rate risk) and operational risk (e.g. exposure to lawsuits). In recent years development of international derivative markets led to tendencies of banks to sell their credit risk through "credit risk derivatives", a trend that has become popular under the heading of "securitization".
In insurance it is difficult to obtain financial protection against "systemic risks" because of the inability of any counter-party to accept the risk. For example it is difficult to obtain insurance for life or property in the event of nuclear war. The essence of systematic risk is therefore the correlation of losses. "Systemic Risk" adds the important problem, that it is much more difficult to evaluate than "systematic risk". For example, while econometric estimates and expectation proxies in business cycle research led to a considerable improvement in forecasting recessions, data on "Systemic Risk" is often hard to obtain, since interdependencies and counter party risk on financial markets play a crucial role. If one bank goes bankrupt and sells all its assets, the drop in asset prices may induce liquidity problems of other banks, leading to a general banking panic.
One concern is the potential fragility of some financial markets. If the participants are trading at levels far above their capital bases, then the failure of one participant to settle trades may deprive others of liquidity, and through a domino effect expose the whole market to systemic risk.
# Diversification
Risks can be reduced in four main ways: Avoidance, Reduction, Retention and Transfer. Systematic risk is a risk of security that cannot be reduced through diversification. Also sometimes called market risk or un-diversifiable risk. Participants in the market, like hedge funds, can themselves be the source of an increase in systemic risk[1] and transfer of risk to them may, paradoxically, increase the exposure to systemic risk.
# Regulation
One of the main reasons for regulation in the marketplace is to reduce systemic risk.
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https://www.wikidoc.org/index.php/Systemic_risk
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c81eecfee4223b3820ed8ce64e57a72ad653ef58
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wikidoc
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T-2 mycotoxin
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T-2 mycotoxin
T-2 (also known as "Yellow Rain"), a trichothecene mycotoxin, is a naturally-occurring mold byproduct of Fusarium spp fungus which is toxic to humans and animals. The clinical condition it causes is alimentary toxic aleukia and a host of symptoms on organs as diverse as the skin, airway, and stomach. It is the only mycotoxin known to have been used as a biological weapon, but ingestion may come from moldy whole grains.
# History
T-2 was discovered as a weapon by Russian scientists after a spring harvest delayed by World War II produced flour contaminated with Fusarium and distributed in bread. Many were sickened, some fatally. T-2 has also been suggested as a cause of the Plague of Athens (430 BC). T-2 is an infrequent contaminant in animal feed.
T-2 was proposed as a cause of Gulf War Syndrome for some United States troops exposed to a mortar shell shot by Iraqi forces during the Persian Gulf War and as the substance used to poison Viktor Yushchenko during his 2004 presidential election campaign (though doctors now believe it was dioxin).
## "Yellow Rain" incidents (1975-84)
The name yellow rain derives from a political incident in which the United States attempted to blame the Soviet Union for using chemical warfare agents. In the context of the late Cold War, this charge would have had very serious repercussions, including stalling efforts to get the United States Senate to ratify treaties.
The charges stemmed from events in Laos and Vietnam beginning in 1975, when the two communist governments, which were allied with and supported by the Soviet Union, retaliated against Hmong tribes, peoples who had sided with the United States during the Vietnam War. Refugees fled from what they described as chemical warfare attacks by low-flying aircraft; most of the reports were of a yellow, oily liquid that the Hmong dubbed "yellow rain". Those exposed suffered neurological and physical symptoms including seizures, blindness, and bleeding. Similar reports came from the Vietnamese invasion of Cambodia in 1978.
In 1981, after noting etiological similarities, U.S. chemical weapons experts matched samples taken from an alleged attack in Laos to trichothecene signatures, and hypothesized that T-2 was discovered accidentally through contamination and later weaponized. Secretary of State Alexander Haig announced in September 1981 that
In 1983, a now-declassified CIA report summarized the history of T-2 development in the Soviet Union, where it was referred to as lebeda, Russian for millet or animal feed, and weaponized for aerial delivery.
In 1987, these charges were disputed by Harvard biologist and biological weapons opponent Matthew Meselson and his team, who traveled to Laos and conducted a separate investigation. Meselson's team noted that trichothecene mycotoxins occur naturally in the region and questioned the witness testimony, suggesting an alternate hypothesis that the yellow rain was the harmless fecal matter of honeybees. The Meselson team offered the following as evidence: separate "yellow rain drops" which occurred on the same leaf, and which were "accepted as authentic", consisted largely of pollen; each drop contained a different mix of pollen grains, as one would expect if they came from different bees, and the grains showed properties characteristic of pollen processed by bees (the protein inside the pollen was gone, while the outer indigestible shell remained. Further, the pollen came from plant species typical of the area where the drop was collected.
The different composition is striking, as it implies that the Soviets would have had to have very sophisticated mixing apparatus, that could take pollen from local plants, treat it as done by bees, and then mix the pollen into different drops, such that different drops contain different pollens. In addition, many of the "native people" who made claims that they were attacked by chemical weapons could reasonably be seen as partial to the US.
The question of what exactly "Yellow Rain" was has never been fully resolved.
|
T-2 mycotoxin
T-2 (also known as "Yellow Rain"), a trichothecene mycotoxin, is a naturally-occurring mold byproduct of Fusarium spp fungus which is toxic to humans and animals. The clinical condition it causes is alimentary toxic aleukia and a host of symptoms on organs as diverse as the skin, airway, and stomach. It is the only mycotoxin known to have been used as a biological weapon, but ingestion may come from moldy whole grains.
# History
T-2 was discovered as a weapon by Russian scientists after a spring harvest delayed by World War II produced flour contaminated with Fusarium and distributed in bread. Many were sickened, some fatally. T-2 has also been suggested as a cause of the Plague of Athens (430 BC). T-2 is an infrequent contaminant in animal feed.
T-2 was proposed as a cause of Gulf War Syndrome for some United States troops exposed to a mortar shell shot by Iraqi forces during the Persian Gulf War and as the substance used to poison Viktor Yushchenko during his 2004 presidential election campaign (though doctors now believe it was dioxin).
## "Yellow Rain" incidents (1975-84)
The name yellow rain derives from a political incident in which the United States attempted to blame the Soviet Union for using chemical warfare agents. In the context of the late Cold War, this charge would have had very serious repercussions, including stalling efforts to get the United States Senate to ratify treaties.[dubious – discuss]
The charges stemmed from events in Laos and Vietnam beginning in 1975, when the two communist governments, which were allied with and supported by the Soviet Union, retaliated against Hmong tribes, peoples who had sided with the United States during the Vietnam War.[1] Refugees fled from what they described as chemical warfare attacks by low-flying aircraft; most of the reports were of a yellow, oily liquid that the Hmong dubbed "yellow rain". Those exposed suffered neurological and physical symptoms including seizures, blindness, and bleeding. Similar reports came from the Vietnamese invasion of Cambodia in 1978.
In 1981, after noting etiological similarities, U.S. chemical weapons experts matched samples taken from an alleged attack in Laos to trichothecene signatures, and hypothesized that T-2 was discovered accidentally through contamination and later weaponized. Secretary of State Alexander Haig announced in September 1981 that
In 1983, a now-declassified CIA report summarized the history of T-2 development in the Soviet Union, where it was referred to as lebeda, Russian for millet or animal feed, and weaponized for aerial delivery.
In 1987, these charges were disputed by Harvard biologist and biological weapons opponent Matthew Meselson and his team, who traveled to Laos and conducted a separate investigation. Meselson's team noted that trichothecene mycotoxins occur naturally in the region and questioned the witness testimony, suggesting an alternate hypothesis that the yellow rain was the harmless fecal matter of honeybees. The Meselson team offered the following as evidence: separate "yellow rain drops" which occurred on the same leaf, and which were "accepted as authentic", consisted largely of pollen; each drop contained a different mix of pollen grains, as one would expect if they came from different bees, and the grains showed properties characteristic of pollen processed by bees (the protein inside the pollen was gone, while the outer indigestible shell remained. Further, the pollen came from plant species typical of the area where the drop was collected.
The different composition is striking, as it implies that the Soviets would have had to have very sophisticated mixing apparatus, that could take pollen from local plants, treat it as done by bees, and then mix the pollen into different drops, such that different drops contain different pollens. In addition, many of the "native people" who made claims that they were attacked by chemical weapons could reasonably be seen as partial to the US.
The question of what exactly "Yellow Rain" was has never been fully resolved.
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https://www.wikidoc.org/index.php/T-2_mycotoxin
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a0ef3ac8725f984298a763b85a21a114b8bb468a
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wikidoc
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TES (protein)
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TES (protein)
'TES' (aka 'Testin') is the protein product of the TESS gene, located on chromosome 7 in Homo sapiens. TES is a 47 kDa protein composed of 421 amino acids found at focal adhesions and is thought to have a role in regulation of cell motility.
In addition to this, TES functions as a tumour suppressor
; the TESS gene is located within a fragile region of chromosome 7, and the promoter elements of the TESS gene have been shown to be susceptible to methylation - this prevents the expression of the TES protein.
# Domain Organisation
Tes is composed of the following domains:
The structures of the Cysteine rich domain and the PET domain are not known. LIM domains, however, are known as modulators of protein interactions
. LIM domain consist of 2 zinc fingers separated by 2 hydrophobic amino acids (generally a Phenylalanine and then a Leucine.
# Binding Partners
TES does not appear to be an enzyme; rather it is a protein that mediates/regulates cullular functions via Protein:protein interactions. Pull down experiments reveal that TES has putative interactions mediated by the indicated domain:
Garalov et al showed that the interaction between TES & zyxin were direct, using recombinant proteins expressed in E.coli.
Some of the potential binding partners (Zyxin, mENA) can be found in focal adhesion complexes; the range of binding partners indicates a potential role for TES in-between 'privileged' Actin polymerisation and focal adhesion contacts to the extracellular matrix. This tallies with the observation that GFP-tagged TES can be seen at focal adhesions.
# Conformational Change
Based on the observations that:
- Mammalian cell derived TES binding Zyxin
- E.coli produced recombinant TES (rTES) does not bind Zyxin
- An rTES construct composed of residues 201-421 (i.e, the linker and all 3 LIM domains) does bind Zyxin
- The above rTES construct binds an N-terminal rTES construct, consisting of the cysteine rich and PET domains - IE, the two halves of TES interact with each other.
Garalov et al propose that TES exists in two conformational states: A 'closed' state where the N & C halves of TES interact, obscuring the Zyxin binding site in LIM1, and an 'open' state where the Zyxin binding site is accessible and the two halves no-longer interact in the same fashion, if at all. The regulatory mechanism switching between the two states is not presently fully understood.
# Phenotype
In RNAi experiments, cells that had impaired TES expression showed an inability to correctly organise their focal adhesions and actin stress fibres.
In gene knockout experiments, transgenic mice lacking both copies of the TES gene displayed an increased susceptibility to tumour formation when challenged with a carcinogen. Mice retaining the TES gene were less susceptible: thus, TES is a tumour suppressor gene.
|
TES (protein)
'TES' (aka 'Testin') is the protein product of the TESS gene, located on chromosome 7[1] in Homo sapiens. TES is a 47 kDa protein composed of 421 amino acids found at focal adhesions and is thought to have a role in regulation of cell motility.
[2]
In addition to this, TES functions as a tumour suppressor
[3]; the TESS gene is located within a fragile region of chromosome 7, and the promoter elements of the TESS gene have been shown to be susceptible to methylation - this prevents the expression of the TES protein.
# Domain Organisation
Tes is composed of the following domains:
The structures of the Cysteine rich domain and the PET domain are not known. LIM domains, however, are known as modulators of protein interactions
[4]. LIM domain consist of 2 zinc fingers separated by 2 hydrophobic amino acids (generally a Phenylalanine and then a Leucine.
# Binding Partners
TES does not appear to be an enzyme; rather it is a protein that mediates/regulates cullular functions via Protein:protein interactions. Pull down experiments [5] reveal that TES has putative interactions mediated by the indicated domain:
Garalov et al showed that the interaction between TES & zyxin were direct, using recombinant proteins expressed in E.coli.
Some of the potential binding partners (Zyxin, mENA) can be found in focal adhesion complexes; the range of binding partners indicates a potential role for TES in-between 'privileged' Actin polymerisation and focal adhesion contacts to the extracellular matrix. This tallies with the observation that GFP-tagged TES can be seen at focal adhesions.
# Conformational Change
Based on the observations that:
- Mammalian cell derived TES binding Zyxin
- E.coli produced recombinant TES (rTES) does not bind Zyxin
- An rTES construct composed of residues 201-421 (i.e, the linker and all 3 LIM domains) does bind Zyxin
- The above rTES construct binds an N-terminal rTES construct, consisting of the cysteine rich and PET domains - IE, the two halves of TES interact with each other.
Garalov et al propose that TES exists in two conformational states: A 'closed' state where the N & C halves of TES interact, obscuring the Zyxin binding site in LIM1, and an 'open' state where the Zyxin binding site is accessible and the two halves no-longer interact in the same fashion, if at all. The regulatory mechanism switching between the two states is not presently fully understood.
# Phenotype
In RNAi experiments, cells that had impaired TES expression showed an inability to correctly organise their focal adhesions and actin stress fibres.
In gene knockout experiments, transgenic mice lacking both copies of the TES gene displayed an increased susceptibility to tumour formation when challenged with a carcinogen. Mice retaining the TES gene were less susceptible: thus, TES is a tumour suppressor gene.
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https://www.wikidoc.org/index.php/TES_(protein)
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6b2b63570ed26897e77cf8705dab3016989b07d8
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wikidoc
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TNF inhibitor
|
TNF inhibitor
# Overview
Tumor necrosis factor (TNF) promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis and refractory asthma. These disorders are sometimes treated by using a TNF inhibitor. This inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade) or adalimumab (Humira), or with a circulating receptor fusion protein such as etanercept (Enbrel).
Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are currently ongoing. A fourth anti-TNF biologic, certolizumab pegol, is expected to receive approval for human use in the near future.
In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent TB infection or disease. The anti-TNF monoclonal antibody biologics, Infliximab and adalimumab, and the fusion protein etanercept which are all currently Food and Drug Administration (FDA) approved for human use, have label warnings which state that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with these medications.
TNF or the effects of TNF are also inhibited by a number of natural compounds, including curcumin (a compound present in turmeric) and catechins (in green tea).
|
TNF inhibitor
# Overview
Tumor necrosis factor (TNF) promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis and refractory asthma. These disorders are sometimes treated by using a TNF inhibitor. This inhibition can be achieved with a monoclonal antibody such as infliximab (Remicade) or adalimumab (Humira), or with a circulating receptor fusion protein such as etanercept (Enbrel).
Clinical trials regarding the effectiveness of these drugs on hidradenitis suppurativa are currently ongoing. A fourth anti-TNF biologic, certolizumab pegol, is expected to receive approval for human use in the near future.
In patients with latent Mycobacterium tuberculosis infection, active tuberculosis (TB) may develop soon after the initiation of treatment with infliximab.[1] Before prescribing the drug, physicians should screen patients for latent TB infection or disease. The anti-TNF monoclonal antibody biologics, Infliximab and adalimumab, and the fusion protein etanercept which are all currently Food and Drug Administration (FDA) approved for human use, have label warnings which state that patients should be evaluated for latent TB infection and treatment should be initiated prior to starting therapy with these medications.
TNF or the effects of TNF are also inhibited by a number of natural compounds, including curcumin [2] [3] [4] [5] (a compound present in turmeric) and catechins (in green tea).
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https://www.wikidoc.org/index.php/TNF_inhibition
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4b7a6282b95eb525b191f6ca0ee904658aaaca83
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wikidoc
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Talin protein
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Talin protein
Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact and, in lymphocytes, at cell–cell contacts. Discovered in 1983 by Keith Burridge and colleagues, talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.
Also, talin-1 drives extravasation mechanism through engineered human microvasculature in microfluidic systems. Talin-1 is involved in each part of extravasation affecting adhesion, trans-endothelial migration and the invasion stages.
Integrin receptors are involved in the attachment of adherent cells to the extracellular matrix and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in the plasma membrane. Furthermore, in vitro binding studies suggest that integrins bind to talin, although with low affinity. Talin also binds with high affinity to vinculin, another cytoskeletal protein concentrated at points of cell adhesion. Finally, talin is a substrate for the calcium-ion activated protease, calpain II, which is also concentrated at points of cell–substratum contact.
Talin is a mechanosensitive protein. Its mechanical vulnerability and cellular position bridging integrin receptors and the actin cytoskeleton make it a fundamental protein in mechanotransduction. Mechanical stretching of talin promotes vinculin binding.
# Protein domains
Talin consists of a large C-terminal rod domain that contains bundles of alpha helices and an N-terminal FERM (band 4.1, ezrin, radixin, and moesin) domain with three subdomains: F1, F2, and F3. The F3 subdomain of the FERM domain contains the highest affinity integrin-binding site for integrin β tails and is sufficient to activate integrins.
## Middle domain
### Structure
Talin also has a middle domain, which has a structure consisting of five alpha helices that fold into a bundle. It contains a vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four.
### Function
Activation of the VBS leads to the recruitment of vinculin to form a complex with the integrins which aids stable cell adhesion. Formation of the complex between VBS and vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion' conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to bind actin.
Talin carries mechanical force (of 7-10 piconewton) during cell adhesion. It also allows cells to measure extracellular rigidity, since cells in which talin is prevented from forming mechanical linkages can no longer distinguish whether they are on a soft or rigid surface. The actin binding site2 is shown to be the major site for sensing the extracellular matrix rigidity.
Recently Kumar et al combined cellular electron cryo-tomography with FRET based tension measurements and find that the regions of high talin tension within focal adhesion have highly aligned and linear underlying filamentous actin structures while regions of low talin tension have less well-aligned actin filaments.
## Vinculin binding site
### Function
Vinculin binding sites are protein domains predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton.
### Structure
The consensus sequence for vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a secondary structure prediction of four amphipathic helices. The hydrophobic residues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.
# Activation of the integrin αIIbβ3
A structure–function analysis reported recently provides a cogent structural model (see top right) to explain talin-dependent integrin activation in three steps:
- The talin F3 domain (surface representation; colored by charge), freed from its autoinhibitory interactions in the full-length protein, becomes available for binding to the integrin.
- F3 engages the membrane-distal part of the β3-integrin tail (in red), which becomes ordered, but the α–β integrin interactions that hold the integrin in the low-affinity conformation remain intact.
- In a subsequent step, F3 engages the membrane-proximal portion of the β3 tail while maintaining its membrane–distal interactions.
# Human proteins containing this domain
TLN1; TLN2;
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Talin protein
Talin is a high-molecular-weight cytoskeletal protein concentrated at regions of cell–substratum contact[1] and, in lymphocytes, at cell–cell contacts.[2][3] Discovered in 1983 by Keith Burridge and colleagues,[1] talin is a ubiquitous cytosolic protein that is found in high concentrations in focal adhesions. It is capable of linking integrins to the actin cytoskeleton either directly or indirectly by interacting with vinculin and α-actinin.[4]
Also, talin-1 drives extravasation mechanism through engineered human microvasculature in microfluidic systems. Talin-1 is involved in each part of extravasation affecting adhesion, trans-endothelial migration and the invasion stages.[5]
Integrin receptors are involved in the attachment of adherent cells to the extracellular matrix[6][7] and of lymphocytes to other cells. In these situations, talin codistributes with concentrations of integrins in the plasma membrane.[8][9] Furthermore, in vitro binding studies suggest that integrins bind to talin, although with low affinity.[10] Talin also binds with high affinity to vinculin,[11] another cytoskeletal protein concentrated at points of cell adhesion.[12] Finally, talin is a substrate for the calcium-ion activated protease, calpain II,[13] which is also concentrated at points of cell–substratum contact.[14]
Talin is a mechanosensitive protein. Its mechanical vulnerability[15] and cellular position bridging integrin receptors and the actin cytoskeleton make it a fundamental protein in mechanotransduction. Mechanical stretching of talin promotes vinculin binding.[16]
# Protein domains
Talin consists of a large C-terminal rod domain that contains bundles of alpha helices and an N-terminal FERM (band 4.1, ezrin, radixin, and moesin) domain with three subdomains: F1, F2, and F3.[17][18][19][20] The F3 subdomain of the FERM domain contains the highest affinity integrin-binding site for integrin β tails and is sufficient to activate integrins.[21]
## Middle domain
### Structure
Talin also has a middle domain, which has a structure consisting of five alpha helices that fold into a bundle. It contains a vinculin binding site (VBS) composed of a hydrophobic surface spanning five turns of helix four.
### Function
Activation of the VBS leads to the recruitment of vinculin to form a complex with the integrins which aids stable cell adhesion. Formation of the complex between VBS and vinculin requires prior unfolding of this middle domain: once released from the talin hydrophobic core, the VBS helix is then available to induce the 'bundle conversion' conformational change within the vinculin head domain thereby displacing the intramolecular interaction with the vinculin tail, allowing vinculin to bind actin.[19]
Talin carries mechanical force (of 7-10 piconewton) during cell adhesion. It also allows cells to measure extracellular rigidity, since cells in which talin is prevented from forming mechanical linkages can no longer distinguish whether they are on a soft or rigid surface. The actin binding site2 is shown to be the major site for sensing the extracellular matrix rigidity.[22]
[23] Recently Kumar et al [24] combined cellular electron cryo-tomography with FRET based tension measurements and find that the regions of high talin tension within focal adhesion have highly aligned and linear underlying filamentous actin structures while regions of low talin tension have less well-aligned actin filaments.
## Vinculin binding site
### Function
Vinculin binding sites are protein domains predominantly found in talin and talin-like molecules, enabling binding of vinculin to talin, stabilising integrin-mediated cell-matrix junctions. Talin, in turn, links integrins to the actin cytoskeleton.
### Structure
The consensus sequence for vinculin binding sites is LxxAAxxVAxxVxxLIxxA, with a secondary structure prediction of four amphipathic helices. The hydrophobic residues that define the VBS are themselves 'masked' and are buried in the core of a series of helical bundles that make up the talin rod.[25]
# Activation of the integrin αIIbβ3
A structure–function analysis reported recently[26] provides a cogent structural model (see top right) to explain talin-dependent integrin activation in three steps:
- The talin F3 domain (surface representation; colored by charge), freed from its autoinhibitory interactions in the full-length protein, becomes available for binding to the integrin.
- F3 engages the membrane-distal part of the β3-integrin tail (in red), which becomes ordered, but the α–β integrin interactions that hold the integrin in the low-affinity conformation remain intact.
- In a subsequent step, F3 engages the membrane-proximal portion of the β3 tail while maintaining its membrane–distal interactions.
# Human proteins containing this domain
TLN1; TLN2;
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https://www.wikidoc.org/index.php/Talin
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87cd14c430b4770239dc03258166ee5ae9bcd80c
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wikidoc
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Tanning booth
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Tanning booth
# Overview
A tanning booth is a device that emits ultraviolet radiation, usually for the purpose of a cosmetic tan. They are very similar to a tanning bed, but the design is such that it is intended to be used while standing up, rather than lying down. Many persons prefer using a tanning booth rather than a tanning bed (or sunbed) for several reasons, but the main reason given is sanitation. This is because the user is always standing up in a booth, so there is little contact with the actual unit, unlike a traditional tanning bed. While there are many stories of people catching diseases from tanning beds due to prior users (herpes, etc.) this is more myth than fact. Tanning beds are usually cleaned using an FDA approved disinfectant which is very inexpensive, and the UV itself controls bacterial growth, and is a very effective sterilizing agent. Assuming the operator follows simple cleaning instructions, the risk is very minimal for either type of system.
Tanning booths generally use 160 watt VHO (Very High Output) or VHO-R (Very High Output with Reflector) lamps, but some less expensive systems use standard 100 watt HO (High Output) or RUVA (Reflector UVA) lamps. Many people confuse "VHO-R" and "VHR ", with the latter being a trademark of Cosmedico lamps for their versions of the VHO-R lamps. The average tanning booth has from 32 to 56 lamps and uses a 10 to 15 minute tanning session time.
# Comparing to tanning beds
Tanning booths are similar but distinct from tanning beds in that they are vertical rather than horizontal, but there are generally other difference as well. Most tanning booths use the higher watt VHO and VHO-R lamp, which consume 160 watts, while most tanning beds use 100W HO lamps, although there are many exceptions. Tanning booths are often said to give the user a better tan because it is easier to move while tanning, and most have handles above the head, which makes tanning under the arms and on the sides easier. Most booths do not have a reflector system behind the lamps because they use the VHO-R lamps, which have a more effective reflector built inside the lamp itself. This forces all the light to be focused out the front of the lamp, reducing lost UV from phase cancellation. This is where two opposing waves (in this case, UV) that are out of phase with each other partially cancelling each other out, resulting in a loss of net UV that reaches the user.
Another difference that is not as obvious is that there are no pressure points when tanning inside a booth. A person using a tanning bed is supported by the acrylic, and in these areas the blood flow is reduced. Melanin production is somewhat reduced in these areas leading to a tan that is not completely even. For most individuals, this isn't very obvious but certain individuals will experience circular areas with slight but noticeably less tan in those pressure areas. Most (but not all) tanning booths do not have acrylics and instead use a wire mesh to protect the user from the lamps. Although this results in a somewhat higher UV transmission, it does not offer the same protection that a solid acrylic sheet offers.
It is very common for tanning booths to have shorter exposure times than tanning beds. This is partially due to the more common use of the 160 watt lamps, which produce more UVA and UVB than a 100w lamp. Another factor is the choice of most manufacturers to use a higher UVB style lamp. Because the FDA regulates exposure time using a method that biases against UVB (for all tanning units), this reduces the average exposure time from the tradition 15 to 20 minutes found on most tanning beds, to 10 to 15 minutes, with some booths even lower. Tanning booths are subject to the same regulations as tanning beds, including posting the suggested time exposure in a conspicuous place on the tanning unit, and in the original owners manual.
# Common use
Tanning booths are not as common as tanning beds because they generally cost significantly more and because they are not as comfortable, as you tan standing up. This limits the adoption of tanning booths over tanning bed particularly in the residential market, where comfort and price are primary considerations for purchasing. There are no published statistics on the number of booths sold versus tanning beds, as all US tanning bed manufacturers are privately held companies and these numbers are considered proprietary. Anecdotal evidence would indicate that less than 10% of the tanning units in professional tanning salons are booths.
One reason professional salons may choose a booth over a bed is the amount of space required, as a booth requires significantly less square footage than a bed. Also, many booths have the option of a dressing room attached to the unit, which means the salon owner doesn't have to build a special room to house the unit, reducing their initial cost to install. This often offsets the higher cost of the unit.
# Potential risks
As with any device that emits ultraviolet, there are risks, especially with overexposure. Tanning booths are not safer than tanning beds, as the basic mechanics are the same. See sun tanning for a more complete list of the potential hazards associated with tanning indoors or out.
|
Tanning booth
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A tanning booth is a device that emits ultraviolet radiation, usually for the purpose of a cosmetic tan. They are very similar to a tanning bed, but the design is such that it is intended to be used while standing up, rather than lying down. Many persons prefer using a tanning booth rather than a tanning bed (or sunbed) for several reasons, but the main reason given is sanitation. This is because the user is always standing up in a booth, so there is little contact with the actual unit, unlike a traditional tanning bed. While there are many stories of people catching diseases from tanning beds[1] due to prior users (herpes, etc.) this is more myth than fact. Tanning beds are usually cleaned using an FDA approved disinfectant which is very inexpensive, and the UV itself controls bacterial growth, and is a very effective sterilizing agent. Assuming the operator follows simple cleaning instructions, the risk is very minimal for either type of system.
Tanning booths generally use 160 watt VHO (Very High Output) or VHO-R (Very High Output with Reflector) lamps, but some less expensive systems use standard 100 watt HO (High Output) or RUVA (Reflector UVA) lamps. Many people confuse "VHO-R" and "VHR ", with the latter being a trademark of Cosmedico lamps for their versions of the VHO-R lamps. The average tanning booth has from 32 to 56 lamps and uses a 10 to 15 minute tanning session time.
# Comparing to tanning beds
Tanning booths are similar but distinct from tanning beds in that they are vertical rather than horizontal, but there are generally other difference as well. Most tanning booths use the higher watt VHO and VHO-R lamp, which consume 160 watts, while most tanning beds use 100W HO lamps, although there are many exceptions. Tanning booths are often said to give the user a better tan because it is easier to move while tanning, and most have handles above the head, which makes tanning under the arms and on the sides easier. Most booths do not have a reflector system behind the lamps because they use the VHO-R lamps, which have a more effective reflector built inside the lamp itself. This forces all the light to be focused out the front of the lamp, reducing lost UV from phase cancellation. This is where two opposing waves (in this case, UV) that are out of phase with each other partially cancelling each other out, resulting in a loss of net UV that reaches the user.
Another difference that is not as obvious is that there are no pressure points when tanning inside a booth. A person using a tanning bed is supported by the acrylic, and in these areas the blood flow is reduced. Melanin production is somewhat reduced in these areas leading to a tan that is not completely even. For most individuals, this isn't very obvious but certain individuals will experience circular areas with slight but noticeably less tan in those pressure areas. Most (but not all) tanning booths do not have acrylics and instead use a wire mesh to protect the user from the lamps. Although this results in a somewhat higher UV transmission, it does not offer the same protection that a solid acrylic sheet offers.
It is very common for tanning booths to have shorter exposure times than tanning beds. This is partially due to the more common use of the 160 watt lamps, which produce more UVA and UVB than a 100w lamp. Another factor is the choice of most manufacturers to use a higher UVB style lamp. Because the FDA regulates exposure time using a method that biases against UVB (for all tanning units), this reduces the average exposure time from the tradition 15 to 20 minutes found on most tanning beds, to 10 to 15 minutes, with some booths even lower. Tanning booths are subject to the same regulations as tanning beds, including posting the suggested time exposure in a conspicuous place on the tanning unit, and in the original owners manual.
# Common use
Tanning booths are not as common as tanning beds because they generally cost significantly more and because they are not as comfortable, as you tan standing up. This limits the adoption of tanning booths over tanning bed particularly in the residential market, where comfort and price are primary considerations for purchasing. There are no published statistics on the number of booths sold versus tanning beds, as all US tanning bed manufacturers are privately held companies and these numbers are considered proprietary. Anecdotal evidence would indicate that less than 10% of the tanning units in professional tanning salons are booths.
One reason professional salons may choose a booth over a bed is the amount of space required, as a booth requires significantly less square footage than a bed. Also, many booths have the option of a dressing room attached to the unit, which means the salon owner doesn't have to build a special room to house the unit, reducing their initial cost to install. This often offsets the higher cost of the unit.
# Potential risks
As with any device that emits ultraviolet, there are risks, especially with overexposure. Tanning booths are not safer than tanning beds, as the basic mechanics are the same. See sun tanning for a more complete list of the potential hazards associated with tanning indoors or out.
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https://www.wikidoc.org/index.php/Tanning_booth
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9e3adf9b0c8a4eb12620796c1ded933079ba5e81
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wikidoc
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Tartaric acid
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Tartaric acid
# Overview
Tartaric acid is a white crystalline organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds, and is one of the main acids found in wine. It is added to other foods to give a sour taste, and is used as an antioxidant. Salts of tartaric acid are known as tartrates. It is a dihydroxy derivative of dicarboxylic acid.
Tartaric acid was first isolated from potassium tartrate, known to the ancients as tartar, c. 800 by the Persian alchemist Jabir ibn Hayyan, who was also responsible for numerous other basic chemical processes still in use today. The modern process was developed in 1769 by the Swedish chemist Carl Wilhelm Scheele. The chirality of tartaric acid was discovered in 1832 by Jean Baptiste Biot, who observed its ability to rotate polarized light. Louis Pasteur continued this research in 1847 by investigating the shapes of tartaric acid crystals, which he found to be asymmetric. Pasteur was the first to produce a pure sample of levotartaric acid.
# Stereochemistry
Naturally-occurring tartaric acid is chiral, meaning that it has molecules that are non-superimposable on their mirror-images. It is a useful raw material in organic chemistry for the synthesis of other chiral molecules. The naturally occurring form of the acid is L-(+)-tartaric acid or dextrotartaric acid.
The mirror-image (enantiomeric) form, levotartaric acid or D-(−)-tartaric acid, and the achiral form, mesotartaric acid, can be made artificially. Note, that the dextro and levo prefixes are not related to the D/L configuration (which is derived from the reference D- or L-glyceraldehyde), but to the orientation of the optical rotation, (+) = dextrorotatory, (−) = levorotatory. Sometimes, instead of capital letters, small italic d, l are used. They are abbreviations of dextro- and levo-, and nowadays should not be used. Levotartaric and dextrotartaric acid are enantiomers, mesotartaric acid is a diastereomer of both of them.
A rarely occurring optically inactive form of tartaric acid, DL-tartaric acid is a
1:1 mixture of the levo and dextro forms. It is distinct from mesotartaric acid and was called
racemic acid (from Latin racemus - "a bunch of grapes"). The word racemic later changed its meaning, becoming a general term for 1:1 enantiomeric mixtures - racemates.
# Derivatives
Important derivatives of tartaric acid include its salts, Cream of tartar (potassium bitartrate), Rochelle salt (potassium sodium tartrate, a mild laxative) and tartar emetic (antimony potassium tartrate).
Tartaric acid is a muscle toxin, which works by inhibiting the production of malic acid, and in high doses causes paralysis and death. The minimum recorded fatal dose for a human is about 7,5 grams/kg.
In spite of that, it is included in many foods, especially sour-tasting sweets. As a food additive, tartaric acid is used as an antioxidant with E number E334, tartrates are other additives serving as antioxidants or emulsifiers.
When cream of tartar is added to water, a suspension results which serves to clean copper coins very well. This is due to the fact that the tartrate solution can dissolve the layer of copper(II) oxide present on the surface of the coin. The resulting Copper(II)-tartrate complex that results is easily soluble in water.
# Tartaric acid in wine
Tartaric acid may be most immediately recognizable to wine drinkers as the source of "wine diamonds," the small potassium bitartrate crystals that sometimes form spontaneously on the cork. These "tartrates" are harmless, despite sometimes being mistaken for broken glass, and are prevented in many wines through cold stabilization. The tartrates that remain on the inside of aging barrels were at one time a major industrial source of potassium bitartrate.
However, tartaric acid plays an important role chemically, lowering the pH of fermenting "must" to a level where many undesirable spoilage bacteria cannot live, and acting as a preservative after fermentation. In the mouth, tartaric acid provides some of the tartness that is currently out of fashion in the wine world, although citric and malic acids also play a role. The modern practice of extended hang time, where grapes are allowed to sit on the vine nearly until they become raisins, can dramatically reduce the taste of tartaric acid in a wine, leaving it smoother but also potentially less compatible with food.
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Tartaric acid
# Overview
Tartaric acid is a white crystalline organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds, and is one of the main acids found in wine. It is added to other foods to give a sour taste, and is used as an antioxidant. Salts of tartaric acid are known as tartrates. It is a dihydroxy derivative of dicarboxylic acid.
Tartaric acid was first isolated from potassium tartrate, known to the ancients as tartar, c. 800 by the Persian alchemist Jabir ibn Hayyan, who was also responsible for numerous other basic chemical processes still in use today. The modern process was developed in 1769 by the Swedish chemist Carl Wilhelm Scheele. The chirality of tartaric acid was discovered in 1832 by Jean Baptiste Biot, who observed its ability to rotate polarized light. Louis Pasteur continued this research in 1847 by investigating the shapes of tartaric acid crystals, which he found to be asymmetric. Pasteur was the first to produce a pure sample of levotartaric acid.
# Stereochemistry
Naturally-occurring tartaric acid is chiral, meaning that it has molecules that are non-superimposable on their mirror-images. It is a useful raw material in organic chemistry for the synthesis of other chiral molecules. The naturally occurring form of the acid is L-(+)-tartaric acid or dextrotartaric acid.
The mirror-image (enantiomeric) form, levotartaric acid or D-(−)-tartaric acid, and the achiral form, mesotartaric acid, can be made artificially. Note, that the dextro and levo prefixes are not related to the D/L configuration (which is derived from the reference D- or L-glyceraldehyde), but to the orientation of the optical rotation, (+) = dextrorotatory, (−) = levorotatory. Sometimes, instead of capital letters, small italic d, l are used. They are abbreviations of dextro- and levo-, and nowadays should not be used. Levotartaric and dextrotartaric acid are enantiomers, mesotartaric acid is a diastereomer of both of them.
A rarely occurring optically inactive form of tartaric acid, DL-tartaric acid is a
1:1 mixture of the levo and dextro forms. It is distinct from mesotartaric acid and was called
racemic acid (from Latin racemus - "a bunch of grapes"). The word racemic later changed its meaning, becoming a general term for 1:1 enantiomeric mixtures - racemates.
# Derivatives
Important derivatives of tartaric acid include its salts, Cream of tartar (potassium bitartrate), Rochelle salt (potassium sodium tartrate, a mild laxative) and tartar emetic (antimony potassium tartrate).
Tartaric acid is a muscle toxin, which works by inhibiting the production of malic acid, and in high doses causes paralysis and death. The minimum recorded fatal dose for a human is about 7,5 grams/kg.
In spite of that, it is included in many foods, especially sour-tasting sweets. As a food additive, tartaric acid is used as an antioxidant with E number E334, tartrates are other additives serving as antioxidants or emulsifiers.
When cream of tartar is added to water, a suspension results which serves to clean copper coins very well. This is due to the fact that the tartrate solution can dissolve the layer of copper(II) oxide present on the surface of the coin. The resulting Copper(II)-tartrate complex that results is easily soluble in water.
# Tartaric acid in wine
Tartaric acid may be most immediately recognizable to wine drinkers as the source of "wine diamonds," the small potassium bitartrate crystals that sometimes form spontaneously on the cork. These "tartrates" are harmless, despite sometimes being mistaken for broken glass, and are prevented in many wines through cold stabilization. The tartrates that remain on the inside of aging barrels were at one time a major industrial source of potassium bitartrate.
However, tartaric acid plays an important role chemically, lowering the pH of fermenting "must" to a level where many undesirable spoilage bacteria cannot live, and acting as a preservative after fermentation. In the mouth, tartaric acid provides some of the tartness that is currently out of fashion in the wine world, although citric and malic acids also play a role. The modern practice of extended hang time, where grapes are allowed to sit on the vine nearly until they become raisins, can dramatically reduce the taste of tartaric acid in a wine, leaving it smoother but also potentially less compatible with food.
# External links
- "History of Tartaric Acid" from Linan Euro-China Co., Ltd.
bg:Винена киселина
ca:Àcid tàrtric
cs:Kyselina vinná
de:Weinsäure
el:Τρυγικό οξύ
eo:Tartrata acido
he:חומצה טרטרית
it:Acido tartarico
hu:Borkősav
nl:Wijnsteenzuur
lv:Vīnskābe
fi:Viinihappo
sk:Kyselina vínna
sv:Vinsyra
Template:WikiDoc Sources
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Task analysis
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Task analysis
Task analysis is the analysis of how a task is accomplished, including a detailed description of both manual and mental activities, task and element durations, task frequency, task allocation, task complexity, environmental conditions, necessary clothing and equipment, and any other unique factors involved in or required for one or more people to perform a given task. Task analysis emerged from research in applied behavior analysis and still has considerable research in that area.
Information from a task analysis can then be used for many purposes, such as personnel selection and training, tool or equipment design, procedure design (e.g., design of checklists or decision support systems) and automation.
The term "task" is often used interchangeably with activity or process. Task analysis often results in a hierarchical representation of what steps it takes to perform a task for which there is a goal and for which there is some lowest-level "action" that is performed. Task analysis is often performed by human factors professionals.
Task analysis may be of manual tasks, such as bricklaying, and be analyzed as time and motion studies using concepts from industrial engineering. Cognitive task analysis is applied to modern work environments such as supervisory control where little physical works occurs, but the tasks are more related to situation assessment, decision making, and response planning and execution.
Task analysis is also used in education. It is a model that is applied to classroom tasks to discover which curriculum components are well matched to the capabilities of students with learning disabilities and which task modification might be necessary. It discovers which tasks a person hasn't mastered, and the information processing demands of tasks that are easy or problematic. In behavior modification, it is a breakdown of a complex behavioral sequence into steps. This often serves as the basis for Chaining.
# Task analysis: data collection
The analyst will often directly observe tasks performed by practitioners (as in ethnographic studies) and may audio-tape and videotape actual task performance. A more controlled study may be done in a laboratory, as in experimental psychology, where the practitioner may work with a simulation of the real task environment. An analysis of actual work procedures, manuals, etc. is also valuable.
# Computational models of cognitive task performance
# Task analysis versus Work Domain Analysis
If task analysis is likened to a set of instructions on how to navigate from point A to point B, then work domain analysis (WDA) is like having a map of the terrain that includes Point A and Point B (see Lintern, 2005). WDA is broader and focuses on the environmental constraints and opportunities for behavior, as in Gibsonian ecological psychology and ecological interface design.
# Task analysis and documentation
Since the 1980s, a major change in technical documentation has been to emphasize the tasks performed with a system rather than documenting the system itself. (Hackos and Redish, 1998) In software documentation particularly, long printed technical manuals that exhaustively describe every function of the software are being replaced by online help organized into tasks. This is part of the new emphasis on usability and user-centered design rather than system/software/product design.
According to the historian of technical communication, R. John Brockmann, this task orientation in technical documentation began with publishing guidelines issued by IBM in the late 1980s. Later IBM studies led to John Carroll's theory of minimalism in the 1990s.
With the development of XML as a markup language suitable for both print and online documentation (replacing SGML with its focus on print), IBM developed the Darwin Information Typing Architecture XML standard in 2000. Now an OASIS standard, DITA has a strong emphasis on task analysis. Its three basic information types are Task, Concept, and Reference. Tasks are analyzed into steps, with a main goal of identifying steps that are reusable in multiple tasks.
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Task analysis
Task analysis is the analysis of how a task is accomplished, including a detailed description of both manual and mental activities, task and element durations, task frequency, task allocation, task complexity, environmental conditions, necessary clothing and equipment, and any other unique factors involved in or required for one or more people to perform a given task. Task analysis emerged from research in applied behavior analysis and still has considerable research in that area.
Information from a task analysis can then be used for many purposes, such as personnel selection and training, tool or equipment design, procedure design (e.g., design of checklists or decision support systems) and automation.
The term "task" is often used interchangeably with activity or process. Task analysis often results in a hierarchical representation of what steps it takes to perform a task for which there is a goal and for which there is some lowest-level "action" that is performed. Task analysis is often performed by human factors professionals.
Task analysis may be of manual tasks, such as bricklaying, and be analyzed as time and motion studies using concepts from industrial engineering. Cognitive task analysis is applied to modern work environments such as supervisory control where little physical works occurs, but the tasks are more related to situation assessment, decision making, and response planning and execution.
Task analysis is also used in education. It is a model that is applied to classroom tasks to discover which curriculum components are well matched to the capabilities of students with learning disabilities and which task modification might be necessary. It discovers which tasks a person hasn't mastered, and the information processing demands of tasks that are easy or problematic. In behavior modification, it is a breakdown of a complex behavioral sequence into steps. This often serves as the basis for Chaining.
# Task analysis: data collection
The analyst will often directly observe tasks performed by practitioners (as in ethnographic studies) and may audio-tape and videotape actual task performance. A more controlled study may be done in a laboratory, as in experimental psychology, where the practitioner may work with a simulation of the real task environment. An analysis of actual work procedures, manuals, etc. is also valuable.
# Computational models of cognitive task performance
# Task analysis versus Work Domain Analysis
If task analysis is likened to a set of instructions on how to navigate from point A to point B, then work domain analysis (WDA) is like having a map of the terrain that includes Point A and Point B (see Lintern, 2005). WDA is broader and focuses on the environmental constraints and opportunities for behavior, as in Gibsonian ecological psychology and ecological interface design.
# Task analysis and documentation
Since the 1980s, a major change in technical documentation has been to emphasize the tasks performed with a system rather than documenting the system itself. (Hackos and Redish, 1998) In software documentation particularly, long printed technical manuals that exhaustively describe every function of the software are being replaced by online help organized into tasks. This is part of the new emphasis on usability and user-centered design rather than system/software/product design.
According to the historian of technical communication, R. John Brockmann, this task orientation in technical documentation began with publishing guidelines issued by IBM in the late 1980s. Later IBM studies led to John Carroll's theory of minimalism in the 1990s.
With the development of XML as a markup language suitable for both print and online documentation (replacing SGML with its focus on print), IBM developed the Darwin Information Typing Architecture XML standard in 2000. Now an OASIS standard, DITA has a strong emphasis on task analysis. Its three basic information types are Task, Concept, and Reference. Tasks are analyzed into steps, with a main goal of identifying steps that are reusable in multiple tasks.
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https://www.wikidoc.org/index.php/Task_analysis
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0738c00d3806ce4d7ebfa41516b28067efcb5bcc
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wikidoc
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Taxus baccata
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Taxus baccata
Taxus baccata is a conifer native to western, central and southern Europe, northwest Africa, northern Iran and southwest Asia. Originally and still widely known in English as just Yew, the later discovery of other very similar related species has led to qualification as European Yew, Common Yew or English Yew where detail of which species of Taxus is required. The word yew is from Proto-Germanic *īwa-, possibly originally a loanword from Gaulish ivos, compare Irish ēo, Welsh ywen, French if; see Eihwaz for a discussion). Baccata is Latin for bearing berries.
# Description
It is a small to medium-sized evergreen tree, growing 10-20 m tall, exceptionally up to 28 m. It is relatively slow growing, but can be very long-lived, with the maximum recorded trunk diameter of 4 m probably only being reached in circa 2,000-4,000 years. The potential age of yews is impossible to determine accurately and is subject to much dispute. There is rarely any wood as old as the entire tree, while the boughs themselves often hollow with age, making ring counts impossible; there are unconfirmed claims as high as 5,000-9,500 years (Lewington & Parker 1999, p.71), but other evidence based on growth rates and archaeological work of surrounding structures suggests the oldest trees (such as the Fortingall Yew in Perthshire, Scotland) are more likely to be in the range of 2,000 years (Harte 1996, Kinmonth 2006). Even with this lower estimate, Taxus baccata is the longest living plant in Europe.
It has thin scaly brown bark. The leaves are lanceolate, flat, dark green, 1-4 cm long and 2-3 mm broad, arranged spirally on the stem, but with the leaf bases twisted to align the leaves in two flat rows either side of the stem except on erect leading shoots where the spiral arrangement is more obvious.
The seed cones are highly modified, each cone containing a single seed 4-7 mm long partly surrounded by a modified scale which develops into a soft, bright red berry-like structure called an aril, 8-15 mm long and wide and open at the end. The arils are mature 6-9 months after pollination, and with the seed contained are eaten by thrushes, waxwings and other birds, which disperse the hard seeds undamaged in their droppings; maturation of the arils is spread over 2-3 months, increasing the chances of successful seed dispersal. The male cones are globose, 3-6 mm diameter, and shed their pollen in early spring. It is mostly dioecious, but occasional individuals can be variably monoecious, or change sex with time.
All parts of the tree are highly toxic—except the bright red aril surrounding the seed, enabling ingestion and dispersal by birds—due to cyanide and the toxic alkaloid taxine. The plant remains toxic, even when wilted or dried. Symptoms include staggering gait, muscle tremors, convulsions, collapse, difficulty breathing, and eventually heart failure. However, death occurs so rapidly that many times the symptoms are missed. Horses may die from a mouthful of yew, and a 1/4 lb of the plant will kill an adult horse in 15 minutes. The tree should be fenced off or removed from pasture land to prevent grazing animals from consuming it.
# Uses and traditions
In the ancient Celtic world, the yew tree (*eburos) had extraordinary importance; a passage by Caesar narrates that Catuvolcus, chief of the Eburones, literally "farmers of the yew", poisoned himself with yew rather than submit to Rome (Gallic Wars 6: 31). Similarly, Florus notes that when the Cantabrians were under siege by the legate Gaius Furnius in 22 BC, most of them took their lives either by the sword or by fire or by a poison extracted ex arboribus taxeis, that is, from the yew tree (2: 33, 50-51). In a similar way, Orosius notes that when the Gallaecians were besieged at Mons Medullius, they preferred to die by their own swords or by the yew tree poison rather than surrender (6, 21, 1.).
The yew is often found in churchyards from England and Ireland to Galicia; some of these trees are exceptionally large (over 3 m diameter) and likely to be over 2,000 years old, long predating the churches they are beside and betokening an earlier sacred site. Many believe that the enormous sacred evergreen at the Temple at Uppsala was a yew. The Christian church commonly found it expedient to take over these existing sacred sites for churches. It is sometimes suggested that these were planted as a symbol of long life or trees of death. An explanation that the yews were planted to discourage farmers and drovers from letting their animals wander into the burial grounds, with the poisonous foliage being the disincentive, may be intentionally prosaic.
Yew is also associated with Wales and England because of the longbow, an early weapon of war, native to Northern Europe, and as the English longbow the basis for a mediaeval tactical system. Yew is the wood of choice for longbow making and the bows are constructed so that the heartwood of yew is on the inside of the bow while the sapwood is on the outside. This takes advantage of the natural properties of yew wood since the heartwood is able to withstand compression while the sapwood is elastic and allows the bow to stretch. Both tend to return to their original straightness when the arrow is released. Much yew is knotty and twisted, so unsuitable for bowmaking; most trunks do not give good staves and even in a good trunk much wood has to be discarded.
The trade of yew wood to England for longbows was such that it depleted the stocks of good-quality, mature yew over a huge area. The first documented import of yew bowstaves to England was in 1294. In 1350 there was a serious shortage, and Henry IV of England ordered his royal bowyer to enter private land and cut yew and other woods. In 1470 compulsory practice was renewed, and hazel, ash, and laburnum were specifically allowed for practice bows. Supplies still proved insufficient, until by the Statute of Westminster in 1472, every ship coming to an English port had to bring four bowstaves for every tun. Richard III of England increased this to ten for every tun. This stimulated a vast network of extraction and supply, which formed part of royal monopolies in southern Germany and Austria. In 1483, the price of bowstaves rose from two to eight pounds per hundred, and in 1510 the Venetians would only sell a hundred for sixteen pounds. In 1507 the Holy Roman Emperor asked the Duke of Bavaria to stop cutting yew, but the trade was profitable, and in 1532 the royal monopoly was granted for the usual quantity "if there are that many". In 1562, the Bavarian government sent a long plea to the Holy Roman Emperor asking him to stop the cutting of yew, and outlining the damage done to the forests by its selective extraction, which broke the canopy and allowed wind to destroy neighbouring trees. In 1568, despite a request from Saxony, no royal monopoly was granted because there was no yew to cut, and the next year Bavaria and Austria similarly failed to produce enough yew to justify a royal monopoly. Forestry records in this area in the 1600s do not mention yew, and it seems that no mature trees were to be had. The English tried to obtain supplies from the Baltic, but at this period bows were being replaced by guns in any case. .
Yews are widely used in landscaping and ornamental horticulture. Well over 200 cultivars of Taxus baccata have been named. The most popular of these are the "Irish Yew" (Taxus baccata 'Fastigiata'), a fastigiate cultivar of the European Yew selected from two trees found growing in Ireland, and the several cultivars with yellow leaves, collectively known as "Golden Yew". A special use of the yew is for topiary garden sculpture, a use not uncommon for many of the more elaborate gardens of England and Scotland.
The precursors of chemotherapy drug Paclitaxel can be derived from the leaves of European yew tree, which is a more renewable source than the bark of the endangered Pacific yew tree (Taxus brevifolia). This ended a point of conflict in the early 1990s; many environmentalists, including Al Gore, had opposed the harvesting of paclitaxel for cancer treatments. Docetaxel (another taxane) can then be obtained by semi-synthetic conversion from the precursors.
# Literary References
- In Shakesphere's Titus Andronicus, Act 2 Scene 3, Tamora the Goth queen exclaims: “ No sooner had they told this hellish tale\ But straight they told me they would bind me here\ Unto the body of a dismal yew”
- In Alexandre Dumas, père's novel, The Count of Monte Cristo, Edmond Dantès is imprisoned in the Château d'If, which literally translates to "Castle of the Yew." (If is a small island in France, and the name may or may not derive from the word which means yew.)
- John Keats refers to the yew in his "Ode on Melancholy", writing, "Make not your rosary of yew-berries, / Nor let the beetle, nor the death moth be / Your mournful Psyche, nor the downy owl / A partner in your sorrow's mysteries..." (lines 5-8).
- In the Irish myth "The Love of Chu Chulainn and Fand", the warrior and the goddess meet beneath a yew tree's head at every quarter moon.
- In J. R. R. Tolkien's The Silmarillion, Beleg Strongbow uses a bow made of yew.
- In Tolkien's The Hobbit, the eagle king complains of the men of Wilderland using bows made of yew to shoot at his people.
- In J. K. Rowling's Harry Potter series, Voldemort uses a wand made of yew.
- In Ursula LeGuin's Earthsea series, both the wizard Ged and the Master Summoner carry staves of yew.
- The murderer in Agatha Christie's mystery A Pocket Full of Rye uses taxine (taxol), a poison derived from yew, to kill the victim. The victim lives at Yewtree Lodge.
- Sylvia Plath poem from Ariel, "The Moon and the Yew Tree"
- George Bernard Shaw's Mrs. Warren's Profession uses a yew tree in the yard of Reverend Samuel Gardner.
- In Section V of Little Gidding from T.S. Eliot's Four Quartets (the last section of the poem), Eliot claims: "The moment of the rose and the moment of the yew-tree/ Are of equal duration."
- In the Warriors series, the poisonous deathberries are actually yew.
- In Zadie Smith's On Beauty, Carlene Kipps is buried behind a line of yews in Kensal Green Cemetery.
- A Yew tree is featured prominently in William Wordsworth's poems "Lines Left Upon a Seat in a Yew Tree" and "Yew-trees".
- The Yew is the subject of Swedish author Gunnar D Hansson's "lyrical monography" Idegransöarna (The Yew-tree Islands, 1994, untranslated to English). Hansson explores the yew in its uses (medicinal, lyrical, in place-names, etc) and its historical meaning. He speculates about the yew, and weaves a tale of prose poems, essays and lyrics, about the yew; the book takes the reader close to the yew in its relation to Hittites, Vikings, medicine, Robin Hood, Christmas, heathendom, etymology and mythology.
- The Great Chain of Being, which proposes a strict, hierarchical order for the beings (divine entities, animals, and plants) in the universe, designates the yew as the lowest form of tree among plants.
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Taxus baccata
Taxus baccata is a conifer native to western, central and southern Europe, northwest Africa, northern Iran and southwest Asia. Originally and still widely known in English as just Yew, the later discovery of other very similar related species has led to qualification as European Yew, Common Yew or English Yew where detail of which species of Taxus is required. The word yew is from Proto-Germanic *īwa-, possibly originally a loanword from Gaulish ivos, compare Irish ēo, Welsh ywen, French if; see Eihwaz for a discussion). Baccata is Latin for bearing berries.
# Description
It is a small to medium-sized evergreen tree, growing 10-20 m tall, exceptionally up to 28 m. It is relatively slow growing, but can be very long-lived, with the maximum recorded trunk diameter of 4 m probably only being reached in circa 2,000-4,000 years. The potential age of yews is impossible to determine accurately and is subject to much dispute. There is rarely any wood as old as the entire tree, while the boughs themselves often hollow with age, making ring counts impossible; there are unconfirmed claims as high as 5,000-9,500 years (Lewington & Parker 1999, p.71), but other evidence based on growth rates and archaeological work of surrounding structures suggests the oldest trees (such as the Fortingall Yew in Perthshire, Scotland) are more likely to be in the range of 2,000 years (Harte 1996, Kinmonth 2006). Even with this lower estimate, Taxus baccata is the longest living plant in Europe.
It has thin scaly brown bark. The leaves are lanceolate, flat, dark green, 1-4 cm long and 2-3 mm broad, arranged spirally on the stem, but with the leaf bases twisted to align the leaves in two flat rows either side of the stem except on erect leading shoots where the spiral arrangement is more obvious.
The seed cones are highly modified, each cone containing a single seed 4-7 mm long partly surrounded by a modified scale which develops into a soft, bright red berry-like structure called an aril, 8-15 mm long and wide and open at the end. The arils are mature 6-9 months after pollination, and with the seed contained are eaten by thrushes, waxwings and other birds, which disperse the hard seeds undamaged in their droppings; maturation of the arils is spread over 2-3 months, increasing the chances of successful seed dispersal. The male cones are globose, 3-6 mm diameter, and shed their pollen in early spring. It is mostly dioecious, but occasional individuals can be variably monoecious, or change sex with time.
All parts of the tree are highly toxic—except the bright red aril surrounding the seed, enabling ingestion and dispersal by birds—due to cyanide and the toxic alkaloid taxine. The plant remains toxic, even when wilted or dried. Symptoms include staggering gait, muscle tremors, convulsions, collapse, difficulty breathing, and eventually heart failure. However, death occurs so rapidly that many times the symptoms are missed. Horses may die from a mouthful of yew, and a 1/4 lb of the plant will kill an adult horse in 15 minutes. The tree should be fenced off or removed from pasture land to prevent grazing animals from consuming it.
# Uses and traditions
In the ancient Celtic world, the yew tree (*eburos) had extraordinary importance; a passage by Caesar narrates that Catuvolcus, chief of the Eburones, literally "farmers of the yew", poisoned himself with yew rather than submit to Rome (Gallic Wars 6: 31). Similarly, Florus notes that when the Cantabrians were under siege by the legate Gaius Furnius in 22 BC, most of them took their lives either by the sword or by fire or by a poison extracted ex arboribus taxeis, that is, from the yew tree (2: 33, 50-51). In a similar way, Orosius notes that when the Gallaecians were besieged at Mons Medullius, they preferred to die by their own swords or by the yew tree poison rather than surrender (6, 21, 1.).
The yew is often found in churchyards from England and Ireland to Galicia; some of these trees are exceptionally large (over 3 m diameter) and likely to be over 2,000 years old, long predating the churches they are beside and betokening an earlier sacred site. Many believe that the enormous sacred evergreen at the Temple at Uppsala was a yew. The Christian church commonly found it expedient to take over these existing sacred sites for churches. It is sometimes suggested that these were planted as a symbol of long life or trees of death. An explanation that the yews were planted to discourage farmers and drovers from letting their animals wander into the burial grounds, with the poisonous foliage being the disincentive, may be intentionally prosaic.
Yew is also associated with Wales and England because of the longbow, an early weapon of war, native to Northern Europe, and as the English longbow the basis for a mediaeval tactical system. Yew is the wood of choice for longbow making and the bows are constructed so that the heartwood of yew is on the inside of the bow while the sapwood is on the outside. This takes advantage of the natural properties of yew wood since the heartwood is able to withstand compression while the sapwood is elastic and allows the bow to stretch. Both tend to return to their original straightness when the arrow is released. Much yew is knotty and twisted, so unsuitable for bowmaking; most trunks do not give good staves and even in a good trunk much wood has to be discarded.
The trade of yew wood to England for longbows was such that it depleted the stocks of good-quality, mature yew over a huge area. The first documented import of yew bowstaves to England was in 1294. In 1350 there was a serious shortage, and Henry IV of England ordered his royal bowyer to enter private land and cut yew and other woods. In 1470 compulsory practice was renewed, and hazel, ash, and laburnum were specifically allowed for practice bows. Supplies still proved insufficient, until by the Statute of Westminster in 1472, every ship coming to an English port had to bring four bowstaves for every tun. Richard III of England increased this to ten for every tun. This stimulated a vast network of extraction and supply, which formed part of royal monopolies in southern Germany and Austria. In 1483, the price of bowstaves rose from two to eight pounds per hundred, and in 1510 the Venetians would only sell a hundred for sixteen pounds. In 1507 the Holy Roman Emperor asked the Duke of Bavaria to stop cutting yew, but the trade was profitable, and in 1532 the royal monopoly was granted for the usual quantity "if there are that many". In 1562, the Bavarian government sent a long plea to the Holy Roman Emperor asking him to stop the cutting of yew, and outlining the damage done to the forests by its selective extraction, which broke the canopy and allowed wind to destroy neighbouring trees. In 1568, despite a request from Saxony, no royal monopoly was granted because there was no yew to cut, and the next year Bavaria and Austria similarly failed to produce enough yew to justify a royal monopoly. Forestry records in this area in the 1600s do not mention yew, and it seems that no mature trees were to be had. The English tried to obtain supplies from the Baltic, but at this period bows were being replaced by guns in any case. [1].
Yews are widely used in landscaping and ornamental horticulture. Well over 200 cultivars of Taxus baccata have been named. The most popular of these are the "Irish Yew" (Taxus baccata 'Fastigiata'), a fastigiate cultivar of the European Yew selected from two trees found growing in Ireland, and the several cultivars with yellow leaves, collectively known as "Golden Yew". A special use of the yew is for topiary garden sculpture, a use not uncommon for many of the more elaborate gardens of England and Scotland.
The precursors of chemotherapy drug Paclitaxel can be derived from the leaves of European yew tree, which is a more renewable source than the bark of the endangered Pacific yew tree (Taxus brevifolia). This ended a point of conflict in the early 1990s; many environmentalists, including Al Gore, had opposed the harvesting of paclitaxel for cancer treatments. Docetaxel (another taxane) can then be obtained by semi-synthetic conversion from the precursors.
# Literary References
- In Shakesphere's Titus Andronicus, Act 2 Scene 3, Tamora the Goth queen exclaims: “ No sooner had they told this hellish tale\ But straight they told me they would bind me here\ Unto the body of a dismal yew”
- In Alexandre Dumas, père's novel, The Count of Monte Cristo, Edmond Dantès is imprisoned in the Château d'If, which literally translates to "Castle of the Yew." (If is a small island in France, and the name may or may not derive from the word which means yew.)
- John Keats refers to the yew in his "Ode on Melancholy", writing, "Make not your rosary of yew-berries, / Nor let the beetle, nor the death moth be / Your mournful Psyche, nor the downy owl / A partner in your sorrow's mysteries..." (lines 5-8).
- In the Irish myth "The Love of Chu Chulainn and Fand", the warrior and the goddess meet beneath a yew tree's head at every quarter moon.
- In J. R. R. Tolkien's The Silmarillion, Beleg Strongbow uses a bow made of yew.
- In Tolkien's The Hobbit, the eagle king complains of the men of Wilderland using bows made of yew to shoot at his people.
- In J. K. Rowling's Harry Potter series, Voldemort uses a wand made of yew.
- In Ursula LeGuin's Earthsea series, both the wizard Ged and the Master Summoner carry staves of yew.
- The murderer in Agatha Christie's mystery A Pocket Full of Rye uses taxine (taxol), a poison derived from yew, to kill the victim. The victim lives at Yewtree Lodge.
- Sylvia Plath poem from Ariel, "The Moon and the Yew Tree"
- George Bernard Shaw's Mrs. Warren's Profession uses a yew tree in the yard of Reverend Samuel Gardner.
- In Section V of Little Gidding from T.S. Eliot's Four Quartets (the last section of the poem), Eliot claims: "The moment of the rose and the moment of the yew-tree/ Are of equal duration."
- In the Warriors series, the poisonous deathberries are actually yew.
- In Zadie Smith's On Beauty, Carlene Kipps is buried behind a line of yews in Kensal Green Cemetery.
- A Yew tree is featured prominently in William Wordsworth's poems "Lines Left Upon a Seat in a Yew Tree" and "Yew-trees".
- The Yew is the subject of Swedish author Gunnar D Hansson's "lyrical monography" Idegransöarna (The Yew-tree Islands, 1994, untranslated to English). Hansson explores the yew in its uses (medicinal, lyrical, in place-names, etc) and its historical meaning. He speculates about the yew, and weaves a tale of prose poems, essays and lyrics, about the yew; the book takes the reader close to the yew in its relation to Hittites, Vikings, medicine, Robin Hood, Christmas, heathendom, etymology and mythology.
- The Great Chain of Being, which proposes a strict, hierarchical order for the beings (divine entities, animals, and plants) in the universe, designates the yew as the lowest form of tree among plants.
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https://www.wikidoc.org/index.php/Taxus_baccata
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f91bb159a5e89dfb710d79d2beb4d8b8fab4ccc4
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wikidoc
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Taylor series
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Taylor series
In mathematics, the Taylor series is a representation of a function as an infinite sum of terms calculated from the values of its derivatives at a single point. It may be regarded as the limit of the Taylor polynomials. Taylor series are named in honour of English mathematician Brook Taylor. If the series uses the derivatives at zero, the series is also called a Maclaurin series, named after Scottish mathematician Colin Maclaurin.
# Definition
The Taylor series of a real or complex function f(x) that is infinitely differentiable in a neighborhood of a real or complex number a, is the power series
which in a more compact form can be written as
where n! is the factorial of n and f (n)(a) denotes the nth derivative of f evaluated at the point a; the zeroth derivative of f is defined to be f itself and (x − a)0 and 0! are both defined to be 1.
Often f(x) is equal to its Taylor series evaluated at x for all x sufficiently close to a. This is the main reason why Taylor series are important.
In the particular case where a = 0, the series is also called a Maclaurin series.
# Examples
The Maclaurin series for any polynomial is the polynomial itself.
The Maclaurin series for (1-x)^{-1} is the geometric series
so the Taylor series for x^{-1} at a=1 is
By integrating the above Maclaurin series we find the Maclaurin series for -\ln(1 - x)\!, where \ln\! denotes the natural logarithm:
and the corresponding Taylor series for \ln(x)\! at a=1\! is
The Maclaurin series for the exponential function e^x at a=0 is
The above expansion holds because the derivative of e^x is also e^x and e^0 equals 1. This leaves the terms (x-0)^n in the numerator and n! in the denominator for each term in the infinite sum.
# Convergence
Taylor series need not in general be convergent series, but often they are.
The limit of a convergent Taylor series of a function f need not in general be equal to the function value f(x), but often it is. If f(x) is equal to its Taylor series in a neighborhood of a, it is said to be analytic in this neighborhood. If f(x) is equal to its Taylor series everywhere it is called entire. The exponential function e^x and the trigonometric functions sine and cosine are examples of entire functions. Examples of functions that are not entire include the logarithm, the trigonometric function tangent, and its inverse arctan. For these functions the Taylor series do not converge if x is far from a.
A Taylor series can be used to calculate the value of an entire function in every point, if the value of the function, and of all of its derivatives, are known at a single point. Uses of the Taylor series for entire functions include:
- The partial sums (the Taylor polynomials) of the series can be used as approximations of the entire function. These approximations are good if sufficiently many terms are included.
- The series representation simplifies many mathematical proofs.
Pictured on the right is an accurate approximation of sin(x) around the point a = 0. The pink curve is a polynomial of degree seven:
The error in this approximation is no more than \tfrac{|x|^9}{9!}\!. In particular, for |x|, the error is less than 0.000003.
In contrast, also shown is a picture of the function log(1+x) and some of its Taylor polynomials around a = 0. These approximations converge to the function only in the region -1 < x ≤ 1; outside of this region the higher-degree Taylor polynomials are worse approximations for the function. This is an example of Runge's phenomenon.
Taylor's theorem gives a variety of general bounds on the size of the error in R_{n}(x) incurred in approximating a function by its nth order Taylor polynomial.
# History
The Pythagorean philosopher Zeno considered the problem of summing an infinite series to achieve a finite result, but rejected it as an impossibility: the result was Zeno's paradox. Later, Aristotle proposed a philosophical resolution of the paradox, but the mathematical content was apparently unresolved until taken up by Democritus and then Archimedes. It was through Archimedes's method of exhaustion that an infinite number of progressive subdivisions could be performed to achieve a finite trigonometric result. Liu Hui independently employed a similar method a few centuries later.
In the 14th century, the earliest examples of the use of Taylor series and closely-related methods were given by Madhava of Sangamagrama. Though no record of his work survives, writings of later Indian mathematicians suggest that he found a number of special cases of the Taylor series, including those for the trigonometric functions of sine, cosine, tangent, and arctangent. The Kerala school of astronomy and mathematics further expanded his works with various series expansions and rational approximations until the 16th century.
In the 17th century, James Gregory also worked in this area and published several Maclaurin series. It was not until 1715 however that a general method for constructing these series for all functions for which they exist was finally provided by Brook Taylor, after whom the series are now named.
The Maclaurin series was named after Colin Maclaurin, a professor in Edinburgh, who published the special case of the Taylor result in the 18th century.
# Properties
If this series converges for every x in the interval (a − r, a + r) and the sum is equal to f(x), then the function f(x) is said to be analytic in the interval (a − r, a + r). If this is true for any r then the function is said to be an entire function. To check whether the series converges towards f(x), one normally uses estimates for the remainder term of Taylor's theorem. A function is analytic if and only if it can be represented as a power series; the coefficients in that power series are then necessarily the ones given in the above Taylor series formula.
The importance of such a power series representation is at least fourfold. First, differentiation and integration of power series can be performed term by term and is hence particularly easy. Second, an analytic function can be uniquely extended to a holomorphic function defined on an open disk in the complex plane, which makes the whole machinery of complex analysis available. Third, the (truncated) series can be used to compute function values approximately (often by recasting the polynomial into the Chebyshev form and evaluating it with the Clenshaw algorithm).
Fourth, algebraic operations can often be done much more readily on the power series representation; for instance the simplest proof of Euler's formula uses the Taylor series expansions for sine, cosine, and exponential functions. This result is of fundamental importance in such fields as harmonic analysis.
Note that there are examples of infinitely differentiable functions f(x) whose Taylor series converge, but are not equal to f(x). For instance, the function defined pointwise by f(x) = e−1/x² if x ≠ 0 and f(0) = 0 is an example of a non-analytic smooth function. All its derivatives at x = 0 are zero, so the Taylor series of f(x) at 0 is zero everywhere, even though the function is nonzero for every x ≠ 0. This particular pathology does not afflict Taylor series in complex analysis. There, the area of convergence of a Taylor series is always a disk in the complex plane (possibly with radius 0), and where the Taylor series converges, it converges to the function value. Notice that e−1/z² does not approach 0 as z approaches 0 along the imaginary axis, hence this function is not continuous as a function on the complex plane.
Since every sequence of real or complex numbers can appear as coefficients in the Taylor series of an infinitely differentiable function defined on the real line, the radius of convergence of a Taylor series can be zero. There are even infinitely differentiable functions defined on the real line whose Taylor series have a radius of convergence 0 everywhere.
Some functions cannot be written as Taylor series because they have a singularity; in these cases, one can often still achieve a series expansion if one allows also negative powers of the variable x; see Laurent series. For example, f(x) = e^{-1/x^2}\! can be written as a Laurent series.
The Parker-Sochacki method is a recent advance in finding Taylor series which are solutions to differential equations. This algorithm is an extension of the Picard iteration.
# List of Taylor series of some common functions
Several important Maclaurin series expansions follow. All these expansions are valid for complex arguments x\!.
Exponential function:
Natural logarithm:
Finite geometric series:
Infinite geometric series:
Variants of the infinite geometric series:
Square root:
Binomial series (includes the square root for α = 1/2 and the infinite geometric series for α = −1):
Trigonometric functions:
Hyperbolic functions:
Lambert's W function:
The numbers B_k\! appearing in the summation expansions of tan(x) and tanh(x) are the Bernoulli numbers. The E_k\! in the expansion of sec(x) are Euler numbers.
# Calculation of Taylor series
Several methods exist for the calculation of Taylor series of a large number of functions. One can attempt to use the Taylor series as-is and generalize the form of the coefficients, or one can use manipulations such as substitution, multiplication or division, addition or subtraction of standard Taylor series to construct the Taylor series of a function, by virtue of Taylor series being power series. In some cases, one can also derive the Taylor series by repeatedly applying integration by parts. Particularly convenient is the use of computer algebra systems to calculate Taylor series.
## First example
Compute the 7th degree Maclaurin polynomial for the function
First, rewrite the function as
We have for the natural logarithm (by using the big O notation)
and for the cosine function
The latter series expansion has a zero constant term, which enables us to substitute the second series into the first one and to easily omit terms of higher order than the 7th degree by using the big O notation:
&=\bigl(\cos x-1\bigr) - \frac12\bigl(\cos x-1\bigr)^2 + \frac13\bigl(\cos x-1\bigr)^3+ \mathcal{O}\bigl((\cos x-1)^4\bigr)\\&=\biggl(-\frac{x^2}2 + \frac{x^4}{24} - \frac{x^6}{720} +\mathcal{O}(x^8)\biggr)-\frac12\biggl(-\frac{x^2}2+\frac{x^4}{24}+\mathcal{O}(x^6)\biggr)^2+\frac13\biggl(-\frac{x^2}2+\mathcal{O}(x^4)\biggr)^3 + \mathcal{O}(x^8)\\ & =-\frac{x^2}2 + \frac{x^4}{24}-\frac{x^6}{720} - \frac{x^4}8 + \frac{x^6}{48} - \frac{x^6}{24} +\mathcal{O}(x^8)\\
& =- \frac{x^2}2 - \frac{x^4}{12} - \frac{x^6}{45}+\mathcal{O}(x^8). \end{align}\!
Since the cosine is an even function, the coefficients for all the odd powers x, x3, x5, x7, . . . have to be zero.
## Second example
Suppose we want the Taylor series at 0 of the function
We have for the exponential function
and, as in the first example,
Assume the power series is
Then multiplication with the denominator and substitution of the series of the cosine yields
&=\left(c_0 + c_1 x + c_2 x^2 + c_3 x^3 + c_4x^4 + \cdots\right)\left(1 - {x^2 \over 2!} + {x^4 \over 4!} - \cdots\right)\\&=c_0 - {c_0 \over 2}x^2 + {c_0 \over 4!}x^4 + c_1x - {c_1 \over 2}x^3 + {c_1 \over 4!}x^5 + c_2x^2 - {c_2 \over 2}x^4 + {c_2 \over 4!}x^6 + c_3x^3 - {c_3 \over 2}x^5 + {c_3 \over 4!}x^7 +\cdots \end{align}\!
Collecting the terms up to fourth order yields
Comparing coefficients with the above series of the exponential function yields the desired Taylor series
# Taylor series as definitions
Classically, algebraic functions are defined by an algebraic equation, and transcendental functions (including those discussed above) are defined by some property that holds for them, such as a differential equation. For example the exponential function is the function which is everywhere equal to its own derivative, and assumes the value 1 at the origin. However, one may equally well define an analytic function by its Taylor series.
Taylor series are used to define functions in diverse areas of mathematics. In particular, this is true in areas where the classical definitions of functions break down. For example, using Taylor series, one may define analytical functions of matrices and operators, such as the matrix exponential or matrix logarithm.
In other areas, such as formal analysis, it is more convenient to work directly with the power series themselves. Thus one may define a solution of a differential equation as a power series which, one hopes to prove, is the Taylor series of the desired solution.
# Taylor series in several variables
The Taylor series may also be generalized to functions of more than one variable with
\frac{\partial^{n_1}}{\partial x_1^{n_1}} \cdots \frac{\partial^{n_d}}{\partial x_d^{n_d}}
\frac{f(a_1,\cdots,a_d)}{n_1!\cdots n_d!}
(x_1-a_1)^{n_1}\cdots (x_d-a_d)^{n_d}\!.
For example, for a function that depends on two variables, x and y, the Taylor series to second order about the point (a, b) is:
where the subscripts denote the respective partial derivatives.
A second-order Taylor series expansion of a scalar-valued function of more than one variable can be compactly written as
where D f(\mathbf{a})\! is the gradient and D^2 f(\mathbf{a})\! is the Hessian matrix. Applying the multi-index notation the Taylor series for several variables becomes
in full analogy to the single variable case.
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Taylor series
In mathematics, the Taylor series is a representation of a function as an infinite sum of terms calculated from the values of its derivatives at a single point. It may be regarded as the limit of the Taylor polynomials. Taylor series are named in honour of English mathematician Brook Taylor. If the series uses the derivatives at zero, the series is also called a Maclaurin series, named after Scottish mathematician Colin Maclaurin.
# Definition
The Taylor series of a real or complex function f(x) that is infinitely differentiable in a neighborhood of a real or complex number a, is the power series
which in a more compact form can be written as
where n! is the factorial of n and f (n)(a) denotes the nth derivative of f evaluated at the point a; the zeroth derivative of f is defined to be f itself and (x − a)0 and 0! are both defined to be 1.
Often f(x) is equal to its Taylor series evaluated at x for all x sufficiently close to a. This is the main reason why Taylor series are important.
In the particular case where <math>a = 0</math>, the series is also called a Maclaurin series.
# Examples
The Maclaurin series for any polynomial is the polynomial itself.
The Maclaurin series for <math>(1-x)^{-1}</math> is the geometric series
so the Taylor series for <math>x^{-1}</math> at <math>a=1</math> is
By integrating the above Maclaurin series we find the Maclaurin series for <math>-\ln(1 - x)\!</math>, where <math>\ln\!</math> denotes the natural logarithm:
and the corresponding Taylor series for <math>\ln(x)\!</math> at <math>a=1\!</math> is
The Maclaurin series for the exponential function <math>e^x</math> at <math> a=0</math> is
The above expansion holds because the derivative of <math>e^x</math> is also <math>e^x</math> and <math>e^0</math> equals 1. This leaves the terms <math>(x-0)^n</math> in the numerator and n! in the denominator for each term in the infinite sum.
# Convergence
Taylor series need not in general be convergent series, but often they are.
The limit of a convergent Taylor series of a function <math>f</math> need not in general be equal to the function value <math>f(x)</math>, but often it is. If <math>f(x)</math> is equal to its Taylor series in a neighborhood of <math>a</math>, it is said to be analytic in this neighborhood. If <math>f(x)</math> is equal to its Taylor series everywhere it is called entire. The exponential function <math>e^x</math> and the trigonometric functions sine and cosine are examples of entire functions. Examples of functions that are not entire include the logarithm, the trigonometric function tangent, and its inverse arctan. For these functions the Taylor series do not converge if <math>x</math> is far from <math>a</math>.
A Taylor series can be used to calculate the value of an entire function in every point, if the value of the function, and of all of its derivatives, are known at a single point. Uses of the Taylor series for entire functions include:
- The partial sums (the Taylor polynomials) of the series can be used as approximations of the entire function. These approximations are good if sufficiently many terms are included.
- The series representation simplifies many mathematical proofs.
Pictured on the right is an accurate approximation of sin(x) around the point a = 0. The pink curve is a polynomial of degree seven:
The error in this approximation is no more than <math>\tfrac{|x|^9}{9!}\!</math>. In particular, for <math>|x|<1\!</math>, the error is less than 0.000003.
In contrast, also shown is a picture of the function log(1+x) and some of its Taylor polynomials around a = 0. These approximations converge to the function only in the region -1 < x ≤ 1; outside of this region the higher-degree Taylor polynomials are worse approximations for the function. This is an example of Runge's phenomenon.
Taylor's theorem gives a variety of general bounds on the size of the error in <math>R_{n}(x)</math> incurred in approximating a function by its nth order Taylor polynomial.
# History
The Pythagorean philosopher Zeno considered the problem of summing an infinite series to achieve a finite result, but rejected it as an impossibility: the result was Zeno's paradox. Later, Aristotle proposed a philosophical resolution of the paradox, but the mathematical content was apparently unresolved until taken up by Democritus and then Archimedes. It was through Archimedes's method of exhaustion that an infinite number of progressive subdivisions could be performed to achieve a finite trigonometric result.[1] Liu Hui independently employed a similar method a few centuries later.[2]
In the 14th century, the earliest examples of the use of Taylor series and closely-related methods were given by Madhava of Sangamagrama.[3] Though no record of his work survives, writings of later Indian mathematicians suggest that he found a number of special cases of the Taylor series, including those for the trigonometric functions of sine, cosine, tangent, and arctangent. The Kerala school of astronomy and mathematics further expanded his works with various series expansions and rational approximations until the 16th century.
In the 17th century, James Gregory also worked in this area and published several Maclaurin series. It was not until 1715 however that a general method for constructing these series for all functions for which they exist was finally provided by Brook Taylor[4], after whom the series are now named.
The Maclaurin series was named after Colin Maclaurin, a professor in Edinburgh, who published the special case of the Taylor result in the 18th century.
# Properties
If this series converges for every x in the interval (a − r, a + r) and the sum is equal to f(x), then the function f(x) is said to be analytic in the interval (a − r, a + r). If this is true for any r then the function is said to be an entire function. To check whether the series converges towards f(x), one normally uses estimates for the remainder term of Taylor's theorem. A function is analytic if and only if it can be represented as a power series; the coefficients in that power series are then necessarily the ones given in the above Taylor series formula.
The importance of such a power series representation is at least fourfold. First, differentiation and integration of power series can be performed term by term and is hence particularly easy. Second, an analytic function can be uniquely extended to a holomorphic function defined on an open disk in the complex plane, which makes the whole machinery of complex analysis available. Third, the (truncated) series can be used to compute function values approximately (often by recasting the polynomial into the Chebyshev form and evaluating it with the Clenshaw algorithm).
Fourth, algebraic operations can often be done much more readily on the power series representation; for instance the simplest proof of Euler's formula uses the Taylor series expansions for sine, cosine, and exponential functions. This result is of fundamental importance in such fields as harmonic analysis.
Note that there are examples of infinitely differentiable functions f(x) whose Taylor series converge, but are not equal to f(x). For instance, the function defined pointwise by f(x) = e−1/x² if x ≠ 0 and f(0) = 0 is an example of a non-analytic smooth function. All its derivatives at x = 0 are zero, so the Taylor series of f(x) at 0 is zero everywhere, even though the function is nonzero for every x ≠ 0. This particular pathology does not afflict Taylor series in complex analysis. There, the area of convergence of a Taylor series is always a disk in the complex plane (possibly with radius 0), and where the Taylor series converges, it converges to the function value. Notice that e−1/z² does not approach 0 as z approaches 0 along the imaginary axis, hence this function is not continuous as a function on the complex plane.
Since every sequence of real or complex numbers can appear as coefficients in the Taylor series of an infinitely differentiable function defined on the real line, the radius of convergence of a Taylor series can be zero.[5] There are even infinitely differentiable functions defined on the real line whose Taylor series have a radius of convergence 0 everywhere.[6]
Some functions cannot be written as Taylor series because they have a singularity; in these cases, one can often still achieve a series expansion if one allows also negative powers of the variable x; see Laurent series. For example, <math>f(x) = e^{-1/x^2}\!</math> can be written as a Laurent series.
The Parker-Sochacki method is a recent advance in finding Taylor series which are solutions to differential equations. This algorithm is an extension of the Picard iteration.
# List of Taylor series of some common functions
Several important Maclaurin series expansions follow. All these expansions are valid for complex arguments <math>x\!</math>.
Exponential function:
Natural logarithm:
Finite geometric series:
Infinite geometric series:
Variants of the infinite geometric series:
Square root:
Binomial series (includes the square root for α = 1/2 and the infinite geometric series for α = −1):
Trigonometric functions:
Hyperbolic functions:
Lambert's W function:
The numbers <math>B_k\!</math> appearing in the summation expansions of tan(x) and tanh(x) are the Bernoulli numbers. The <math>E_k\!</math> in the expansion of sec(x) are Euler numbers.
# Calculation of Taylor series
Several methods exist for the calculation of Taylor series of a large number of functions. One can attempt to use the Taylor series as-is and generalize the form of the coefficients, or one can use manipulations such as substitution, multiplication or division, addition or subtraction of standard Taylor series to construct the Taylor series of a function, by virtue of Taylor series being power series. In some cases, one can also derive the Taylor series by repeatedly applying integration by parts. Particularly convenient is the use of computer algebra systems to calculate Taylor series.
## First example
Compute the 7th degree Maclaurin polynomial for the function
First, rewrite the function as
We have for the natural logarithm (by using the big O notation)
and for the cosine function
The latter series expansion has a zero constant term, which enables us to substitute the second series into the first one and to easily omit terms of higher order than the 7th degree by using the big O notation:
&=\bigl(\cos x-1\bigr) - \frac12\bigl(\cos x-1\bigr)^2 + \frac13\bigl(\cos x-1\bigr)^3+ \mathcal{O}\bigl((\cos x-1)^4\bigr)\\&=\biggl(-\frac{x^2}2 + \frac{x^4}{24} - \frac{x^6}{720} +\mathcal{O}(x^8)\biggr)-\frac12\biggl(-\frac{x^2}2+\frac{x^4}{24}+\mathcal{O}(x^6)\biggr)^2+\frac13\biggl(-\frac{x^2}2+\mathcal{O}(x^4)\biggr)^3 + \mathcal{O}(x^8)\\ & =-\frac{x^2}2 + \frac{x^4}{24}-\frac{x^6}{720} - \frac{x^4}8 + \frac{x^6}{48} - \frac{x^6}{24} +\mathcal{O}(x^8)\\
& =- \frac{x^2}2 - \frac{x^4}{12} - \frac{x^6}{45}+\mathcal{O}(x^8). \end{align}\!</math>
Since the cosine is an even function, the coefficients for all the odd powers x, x3, x5, x7, . . . have to be zero.
## Second example
Suppose we want the Taylor series at 0 of the function
We have for the exponential function
and, as in the first example,
Assume the power series is
Then multiplication with the denominator and substitution of the series of the cosine yields
&=\left(c_0 + c_1 x + c_2 x^2 + c_3 x^3 + c_4x^4 + \cdots\right)\left(1 - {x^2 \over 2!} + {x^4 \over 4!} - \cdots\right)\\&=c_0 - {c_0 \over 2}x^2 + {c_0 \over 4!}x^4 + c_1x - {c_1 \over 2}x^3 + {c_1 \over 4!}x^5 + c_2x^2 - {c_2 \over 2}x^4 + {c_2 \over 4!}x^6 + c_3x^3 - {c_3 \over 2}x^5 + {c_3 \over 4!}x^7 +\cdots \end{align}\!</math>
Collecting the terms up to fourth order yields
Comparing coefficients with the above series of the exponential function yields the desired Taylor series
# Taylor series as definitions
Classically, algebraic functions are defined by an algebraic equation, and transcendental functions (including those discussed above) are defined by some property that holds for them, such as a differential equation. For example the exponential function is the function which is everywhere equal to its own derivative, and assumes the value 1 at the origin. However, one may equally well define an analytic function by its Taylor series.
Taylor series are used to define functions in diverse areas of mathematics. In particular, this is true in areas where the classical definitions of functions break down. For example, using Taylor series, one may define analytical functions of matrices and operators, such as the matrix exponential or matrix logarithm.
In other areas, such as formal analysis, it is more convenient to work directly with the power series themselves. Thus one may define a solution of a differential equation as a power series which, one hopes to prove, is the Taylor series of the desired solution.
# Taylor series in several variables
The Taylor series may also be generalized to functions of more than one variable with
\frac{\partial^{n_1}}{\partial x_1^{n_1}} \cdots \frac{\partial^{n_d}}{\partial x_d^{n_d}}
\frac{f(a_1,\cdots,a_d)}{n_1!\cdots n_d!}
(x_1-a_1)^{n_1}\cdots (x_d-a_d)^{n_d}\!</math>.
For example, for a function that depends on two variables, x and y, the Taylor series to second order about the point (a, b) is:
where the subscripts denote the respective partial derivatives.
A second-order Taylor series expansion of a scalar-valued function of more than one variable can be compactly written as
</math>
where <math>D f(\mathbf{a})\!</math> is the gradient and <math>D^2 f(\mathbf{a})\!</math> is the Hessian matrix. Applying the multi-index notation the Taylor series for several variables becomes
in full analogy to the single variable case.
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b1c57afae388d93272f822f99680b2e25cf18a0b
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Technetium-99
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Technetium-99
99Tc is an isotope of technetium which decays with a halflife of 211 thousand years, emitting soft beta rays but no gamma rays, and has a fission yield of 6.0507%.
The weak beta emission is stopped by the walls of laboratory glassware. Soft X-rays are emitted when the beta particles are stopped, but as long as the body is kept more than 30 cm away these should pose no problem. The primary hazard when working with technetium is inhalation of dust; such radioactive contamination in the lungs can pose a significant cancer risk.
As of 2005, technetium-99 is available to holders of an ORNL permit for US$83/g plus packing charges.
Due to its high fission yield and relatively high half-life, technetium-99 is one of the more significant components of nuclear waste. Measured in becquerels per amount of spent fuel, it is the dominant producer of radiation in the period from about 104 to 106 years after the creation of the nuclear waste. The next shortest-lived fission product is samarium-151 with a halflife of 90 years, though a number of actinides produced by neutron capture have halflives in the intermediate range.
An estimated 160 TBq (about 250 kg) of technetium-99 was released into the environment up to 1994 by atmospheric nuclear tests. The amount of technetium-99 from nuclear reactors released into the environment up to 1986 is estimated to be on the order of 1000 TBq (about 1600 kg), primarily by nuclear fuel reprocessing; most of this was discharged into the sea. In recent years, reprocessing methods have improved to reduce emissions, but as of 2005 the primary release of technetium-99 into the environment is by the Sellafield plant, which released an estimated 550 TBq (about 900 kg) from 1995-1999 into the Irish Sea. From 2000 onwards the amount has been limited by regulation to 90 TBq (about 140 kg) per year.
The long half-life of technetium-99 and its ability to form an anionic species makes it (along with 129I) a major concern when considering long-term disposal of high-level radioactive waste. In addition, many of the processes designed to remove fission products from medium-active process streams in reprocessing plants are designed to remove cationic species like caesium (e.g., 137Cs, 134Cs) and strontium (e.g., 90Sr). Hence the pertechnetate is able to escape through these treatment processes. Current disposal options favor burial in geologically stable rock. The primary danger with such a course is that the waste is likely to come into contact with water, which could leach radioactive contamination into the environment. The anionic pertechnetate and iodide are less able to absorb onto the surfaces of minerals so they are likely to be more mobile. By comparison plutonium, uranium, and caesium are much more able to bind to soil particles. For this reason, the environmental chemistry of technetium is an active area of research.
An alternative disposal method, transmutation, has been demonstrated at CERN for technetium-99. This transmutation process is one in which the technetium (99Tc as a metal target) is bombarded with neutrons to form the shortlived 100Tc (half life = 16 seconds) which decays by beta decay to ruthenium (100Ru).
Technetium-99m is a short-lived metastable nuclear isomer used in nuclear medicine.
|
Technetium-99
99Tc is an isotope of technetium which decays with a halflife of 211 thousand years, emitting soft beta rays but no gamma rays, and has a fission yield of 6.0507%.
The weak beta emission is stopped by the walls of laboratory glassware. Soft X-rays are emitted when the beta particles are stopped, but as long as the body is kept more than 30 cm away these should pose no problem. The primary hazard when working with technetium is inhalation of dust; such radioactive contamination in the lungs can pose a significant cancer risk.
As of 2005, technetium-99 is available to holders of an ORNL permit for US$83/g plus packing charges.[1]
Due to its high fission yield and relatively high half-life, technetium-99 is one of the more significant components of nuclear waste. Measured in becquerels per amount of spent fuel, it is the dominant producer of radiation in the period from about 104 to 106 years after the creation of the nuclear waste.[2] The next shortest-lived fission product is samarium-151 with a halflife of 90 years, though a number of actinides produced by neutron capture have halflives in the intermediate range.
An estimated 160 TBq (about 250 kg) of technetium-99 was released into the environment up to 1994 by atmospheric nuclear tests.[2] The amount of technetium-99 from nuclear reactors released into the environment up to 1986 is estimated to be on the order of 1000 TBq (about 1600 kg), primarily by nuclear fuel reprocessing; most of this was discharged into the sea. In recent years, reprocessing methods have improved to reduce emissions, but as of 2005 the primary release of technetium-99 into the environment is by the Sellafield plant, which released an estimated 550 TBq (about 900 kg) from 1995-1999 into the Irish Sea. From 2000 onwards the amount has been limited by regulation to 90 TBq (about 140 kg) per year.[3]
The long half-life of technetium-99 and its ability to form an anionic species makes it (along with 129I) a major concern when considering long-term disposal of high-level radioactive waste. In addition, many of the processes designed to remove fission products from medium-active process streams in reprocessing plants are designed to remove cationic species like caesium (e.g., 137Cs, 134Cs) and strontium (e.g., 90Sr). Hence the pertechnetate is able to escape through these treatment processes. Current disposal options favor burial in geologically stable rock. The primary danger with such a course is that the waste is likely to come into contact with water, which could leach radioactive contamination into the environment. The anionic pertechnetate and iodide are less able to absorb onto the surfaces of minerals so they are likely to be more mobile. By comparison plutonium, uranium, and caesium are much more able to bind to soil particles. For this reason, the environmental chemistry of technetium is an active area of research.
An alternative disposal method, transmutation, has been demonstrated at CERN for technetium-99. This transmutation process is one in which the technetium (99Tc as a metal target) is bombarded with neutrons to form the shortlived 100Tc (half life = 16 seconds) which decays by beta decay to ruthenium (100Ru).
Technetium-99m is a short-lived metastable nuclear isomer used in nuclear medicine.
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707b70e1de7341313eaa52ba053397a640bab3a6
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Teddy Grahams
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Teddy Grahams
Teddy Grahams are bear shaped graham cracker snacks created by Nabisco. Although they have had many incarnations since their 1988 release, including a cereal and the short lived Dizzy Grizzlies, the main flavors have always included cinnamon, honey, and chocolate. More recently, the chocolatey chip and oatmeal flavors have been introduced. Through the years Teddy Grahams have also maintained their classic shapes, bears with arms up and legs closed, and bears with legs open and arms down. At times Teddy Grahams have enjoyed a place in the spotlight, being used as a prop on Late Night with Conan O'Brien, were referenced on The Simpsons, and were even referred to in a Strong Bad email. The snack was also referenced in the song "Ridin' Rims" by Dem Franchize Boys.
# Nutritional information
Nabisco has always considered Teddy Grahams to be a healthy snack choice. However, these claims have come under attack. In a recent New York Times article, Eating Well, Marian Burros points out that Teddy Grahams use more bleached flour than actual whole wheat graham flour. In response, Nabisco increased the amount of whole grain flour used in the snack . The snacks also contain 0mg trans fat and are also considered a good source of calcium with a significant amount of iron. Additionally, according to Peta chocolate and cinnamon Teddy Grahams are vegan friendly.
# Advertising
Today it is rare to see advertisements for Teddy Grahams. The most recent could be seen on PBS. The simple ad featured a toddler eating Teddy Grahams and running around his house. But the most notable advertisements were for Teddy Graham “Breakfast Bears” Cereal and the limited edition Teddy Graham “Rockin’ Bears.” These commercials featured three rock star bears that played catchy rock music based on the latest Graham snacks.
Classic Jingles:
"We just want to eat, tasty teddy grahams.
Scrumptious bunch of bite sized bears, full of golden graham.
Oh let them be, your teddy grahams.
(Delicious graham snacks in honey, cinnamon and chocolate.)
Just want to eat those teddy grahams!"
"Wake up everybody! Wake up!
You’ve all been sound asleep woo, here’s breakfast bears to eat.
(Introducing Teddy Grahams breakfast bears cereal.)
Your dreams are over, its seven o’clock, graham cereals they can’t be beat.
(In honey, cinnamon, and chocolate, they’re scrumptious enough.
And they’re part of this nutritious breakfast, cause they’re bursting with wholesome graham goodness.)
Wake up to breakfast bears!"
"(New Teddy Grahams Rockin’ Bears!)
Tasting those Teddy Grahams!
We got new shapes to savor; we love to munch the snacks!
We got the graham, Teddy Grahams.
New Rockin’ Bears in vanilla and chocolate too, the rockin’ taste is just for you!
(New Teddy Grahams Rockin’ Bears, four new rockin’ shapes. On tour for a limited time only.) Woo Woo, tastin’ those Teddy Grahams!"
|
Teddy Grahams
Teddy Grahams are bear shaped graham cracker snacks created by Nabisco. Although they have had many incarnations since their 1988 release, including a cereal and the short lived Dizzy Grizzlies, the main flavors have always included cinnamon, honey, and chocolate. More recently, the chocolatey chip and oatmeal flavors have been introduced. Through the years Teddy Grahams have also maintained their classic shapes, bears with arms up and legs closed, and bears with legs open and arms down. At times Teddy Grahams have enjoyed a place in the spotlight, being used as a prop on Late Night with Conan O'Brien, were referenced on The Simpsons, and were even referred to in a Strong Bad email. The snack was also referenced in the song "Ridin' Rims" by Dem Franchize Boys.
# Nutritional information
Nabisco has always considered Teddy Grahams to be a healthy snack choice. However, these claims have come under attack. In a recent New York Times article, Eating Well, Marian Burros points out that Teddy Grahams use more bleached flour than actual whole wheat graham flour. In response, Nabisco increased the amount of whole grain flour used in the snack [1]. The snacks also contain 0mg trans fat and are also considered a good source of calcium with a significant amount of iron[2]. Additionally, according to Peta [3] chocolate and cinnamon Teddy Grahams are vegan friendly.
# Advertising
Today it is rare to see advertisements for Teddy Grahams. The most recent could be seen on PBS. The simple ad featured a toddler eating Teddy Grahams and running around his house. But the most notable advertisements were for Teddy Graham “Breakfast Bears” Cereal and the limited edition Teddy Graham “Rockin’ Bears.” These commercials featured three rock star bears that played catchy rock music based on the latest Graham snacks.
Classic Jingles:
"We just want to eat, tasty teddy grahams.
Scrumptious bunch of bite sized bears, full of golden graham.
Oh let them be, your teddy grahams.
(Delicious graham snacks in honey, cinnamon and chocolate.)
Just want to eat those teddy grahams!"
"Wake up everybody! Wake up!
You’ve all been sound asleep woo, here’s breakfast bears to eat.
(Introducing Teddy Grahams breakfast bears cereal.)
Your dreams are over, its seven o’clock, graham cereals they can’t be beat.
(In honey, cinnamon, and chocolate, they’re scrumptious enough.
And they’re part of this nutritious breakfast, cause they’re bursting with wholesome graham goodness.)
Wake up to breakfast bears!"
"(New Teddy Grahams Rockin’ Bears!)
Tasting those Teddy Grahams!
We got new shapes to savor; we love to munch the snacks!
We got the graham, Teddy Grahams.
New Rockin’ Bears in vanilla and chocolate too, the rockin’ taste is just for you!
(New Teddy Grahams Rockin’ Bears, four new rockin’ shapes. On tour for a limited time only.) Woo Woo, tastin’ those Teddy Grahams!"
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https://www.wikidoc.org/index.php/Teddy_Grahams
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8c2579222968330a08d7ff6b9ee499d9d7b601e0
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wikidoc
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Telithromycin
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Telithromycin
# Disclaimer
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# Black Box Warning
# Overview
Telithromycin is a antibiotic that is FDA approved for the treatment of community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant isolates ), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years old and above. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, vomiting, dizziness, headache, abnormal vision , blurred vision, diplopia, problem of visual accommodation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- KETEK tablets are indicated for the treatment of community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant isolates ), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years old and above.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of KETEK and other antibacterial drugs, KETEK should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- 3 MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2 nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
- The dose of KETEK tablets is 800 mg (2 tablets of 400 mg) taken orally once every 24 hours, for 7–10 days. KETEK tablets can be administered with or without food.
- KETEK may be administered without dosage adjustment in the presence of hepatic impairment.
- In the presence of severe renal impairment (CLCR < 30 mL/min), including patients who need dialysis, the dose should be reduced to KETEK 600 mg once daily. In patients undergoing hemodialysis, KETEK should be given after the dialysis session on dialysis days.
- In the presence of severe renal impairment (CLCR < 30 mL/min), with coexisting hepatic impairment, the dose should be reduced to KETEK 400 mg once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telithromycin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telithromycin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Telithromycin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telithromycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telithromycin in pediatric patients.
# Contraindications
- KETEK is contraindicated in patients with myasthenia gravis. Exacerbations of myasthenia gravis have been reported in patients and sometimes occurred within a few hours of the first dose of telithromycin. Reports have included fatal and life-threatening acute respiratory failure with a rapid onset and progression.
- KETEK is contraindicated in patients with previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibiotic.
- KETEK is contraindicated in patients with a history of hypersensitivity to telithromycin and/or any components of KETEK tablets, or any macrolide antibiotic.
- Concomitant administration of KETEK with cisapride or pimozide is contraindicated.
- Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment.
# Warnings
- Acute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with KETEK. These hepatic reactions included fulminant hepatitis and hepatic necrosis leading to liver transplant, and were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of a few doses of KETEK.
- Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of hepatitis must be advised to discontinue KETEK and immediately seek medical evaluation, which should include liver function tests. If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, KETEK should be permanently discontinued.
- Ketek must not be re-administered to patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibiotic.
- In addition, less severe hepatic dysfunction associated with increased liver enzymes, hepatitis and in some cases jaundice was reported with the use of KETEK. These events associated with less severe forms of liver toxicity were reversible.
- Telithromycin has the potential to prolong the QTc interval of the electrocardiogram in some patients. QTc prolongation may lead to an increased risk for ventricular arrhythmias, including torsades de pointes. Thus, telithromycin should be avoided in patients with congenital prolongation of the QTc interval, and in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (e.g., quinidine and procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.
- Cases of torsades de pointes have been reported post-marketing with KETEK. In clinical trials, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin treatment in 4780 patients in clinical trials, including 204 patients having a prolonged QTc at baseline.
- KETEK may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation. Visual disturbances included blurred vision, difficulty focusing, and diplopia. Most events were mild to moderate; however, severe cases have been reported.
- There have been post-marketing adverse event reports of transient loss of consciousness including some cases associated with vagal syndrome.
- Because of potential visual difficulties or loss of consciousness, patients should attempt to minimize activities such as driving a motor vehicle, operating heavy machinery or engaging in other hazardous activities during treatment with KETEK. If patients experience visual disorders or loss of consciousness while taking KETEK, patients should not drive a motor vehicle, operate heavy machinery or engage in other hazardous activities.
- Serious adverse reactions have been reported in patients taking KETEK concomitantly with CYP 3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP 3A4 (e.g., verapamil, amlodipine, diltiazem). (See PRECAUTIONS, DRUG INTERACTIONS.)
- Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong CYP 3A4 inhibitors. Telithromycin is a strong CYP 3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of telithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including KETEK, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
- In Phase III clinical trials, 4,780 patients (n=2702 in controlled trials) received daily oral doses of KETEK 800 mg once daily for 5 days or 7 to 10 days. Most adverse events were mild to moderate in severity. In the combined Phase III studies, discontinuation due to treatment-emergent adverse events occurred in 4.4% of KETEK-treated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the KETEK group were due to treatment-emergent adverse events in the gastrointestinal body system, primarily diarrhea (0.9% for KETEK vs. 0.7% for comparators), nausea (0.7% for KETEK vs. 0.5% for comparators).
- All and possibly related treatment-emergent adverse events (TEAEs) occurring in controlled clinical studies in ≥ 2.0% of all patients are included below:
- The following events judged by investigators to be at least possibly drug related were observed infrequently (≥ 0.2% and < 2%), in KETEK-treated patients in the controlled Phase III studies.
- Gastrointestinal system
- Abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis, watery stools.
- Liver and biliary system
- Abnormal liver function tests: increased transaminases, increased liver enzymes (e.g., ALT, AST) were usually asymptomatic and reversible. ALT elevations above 3 times the upper limit of normal were observed in 1.6%, and 1.7% of patients treated with KETEK and comparators, respectively. Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK, and was reversible.
- Nervous system
- Dry mouth, somnolence, insomnia, vertigo, increased sweating
- Body as a whole
- Abdominal pain, upper abdominal pain, fatigue
- Special senses
- Visual adverse events most often included blurred vision, diplopia, or difficulty focusing. Most events were mild to moderate; however, severe cases have been reported. Some patients discontinued therapy due to these adverse events. Visual adverse events were reported as having occurred after any dose during treatment, but most visual adverse events (65%) occurred following the first or second dose. Visual events lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some resolved on therapy while others continued to have symptoms until they completed the full course of treatment.
- Females and patients under 40 years old experienced a higher incidence of telithromycin-associated visual adverse events. (See CLINICAL STUDIES.)
- Urogenital system
- Vaginal candidiasis, vaginitis, vaginosis fungal
- Skin
- Rash
- Hematologic
- Increased platelet count
- Other possibly related clinically-relevant events occurring in <0.2% of patients treated with KETEK from the controlled Phase III studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with KETEK.
- Allergic
- Face edema, rare reports of severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis
- Cardiovascular
- Atrial arrhythmias, palpitations
- Gastrointestinal system
- Pancreatitis
- Liver and biliary system
- Hepatic dysfunction has been reported.
- Severe and in some cases fatal hepatotoxicity, including fulminant hepatitis, hepatic necrosis and hepatic failure have been reported in patients treated with KETEK. These hepatic reactions were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of only a few doses of KETEK. (See CONTRAINDICATIONS and WARNINGS.) Severe reactions, in some but not all cases, have been associated with serious underlying diseases or concomitant medications.
- Data from post-marketing reports and clinical trials show that most cases of hepatic dysfunction were mild to moderate. (See PRECAUTIONS, GENERAL.)
- Musculoskeletal
- Muscle cramps, rare reports of exacerbation of myasthenia gravis. Arthralgia, myalgia
- Nervous system
- Loss of consciousness, in some cases associated with vagal syndrome.
- Psychiatric disorders
- Confusion, hallucinations (mostly visual)
- Special senses
- Taste/smell perversion and/or loss
# Drug Interactions
- In vitro studies using a model compound have shown that telithromycin may act as an inhibitor for the hepatic uptake transporters OATP1B1 and OATP1B3. Although the clinical relevance of this finding is unknown, it is possible that concomitant administration of telithromycin with drugs that are substrates of OATP family members could result in increased plasma concentrations of the co-administered drug.
- Studies were performed to evaluate the effect of CYP 3A4 inhibitors on telithromycin and the effect of telithromycin on drugs that are substrates of CYP 3A4 and CYP 2D6. In addition, drug interaction studies were conducted with several other concomitantly prescribed drugs.
- A multiple-dose interaction study with itraconazole showed that Cmax of telithromycin was increased by 22% and AUC by 54%.
- A multiple-dose interaction study with ketoconazole showed that Cmax of telithromycin was increased by 51% and AUC by 95%.
- When telithromycin was given with 240 mL of grapefruit juice after an overnight fast to healthy subjects, the pharmacokinetics of telithromycin were not affected.
- Steady-state peak plasma concentrations of cisapride (an agent with the potential to increase QT interval) were increased by 95% when co-administered with repeated doses of telithromycin, resulting in significant increases in QTc.
- When simvastatin was co-administered with telithromycin, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in simvastatin AUC, a 15-fold increase in the simvastatin active metabolite Cmax, and a 12-fold increase in the simvastatin active metabolite AUC. (See PRECAUTIONS)
- In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4.0-fold increase in simvastatin AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. (See PRECAUTIONS)
- Concomitant administration of telithromycin with intravenous or oral midazolam resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam due to inhibition of CYP 3A4-dependent metabolism of midazolam.
- There was no pharmacokinetic effect on paroxetine when telithromycin was co-administered.
- When metoprolol was co-administered with telithromycin, there was an increase of approximately 38% on the Cmax and AUC of metoprolol, however, there was no effect on the elimination half-life of metoprolol. Telithromycin exposure is not modified with concomitant single-dose administration of metoprolol.
- The plasma peak and trough levels of digoxin were increased by 73% and 21%, respectively, in healthy volunteers when co-administered with telithromycin. However, trough plasma concentrations of digoxin (when equilibrium between plasma and tissue concentrations has been achieved) ranged from 0.74 to 2.17 ng/mL. There were no significant changes in ECG parameters and no signs of digoxin toxicity.
- When theophylline was co-administered with repeated doses of telithromycin, there was an increase of approximately 16% and 17% on the steady-state Cmax and AUC of theophylline. Co-administration of theophylline may worsen gastrointestinal side effects such as nausea and vomiting, especially in female patients. It is recommended that telithromycin should be taken with theophylline 1 hour apart to decrease the likelihood of gastrointestinal side effects.
- Telithromycin has been shown to decrease the Cmax and AUC of sotalol by 34% and 20%, respectively, due to decreased absorption.
- When co-administered with telithromycin in healthy subjects, there were no pharmacodynamic or pharmacokinetic effects on racemic warfarin.
- When oral contraceptives containing ethinyl estradiol and levonorgestrel were co-administered with telithromycin, the steady-state AUC of ethinyl estradiol did not change and the steady-state AUC of levonorgestrel was increased by 50%. The pharmacokinetic/pharmacodynamic study showed that telithromycin did not interfere with the antiovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.
- There was no clinically relevant pharmacokinetic interaction of ranitidine or antacids containing aluminum and magnesium hydroxide on telithromycin.
- During concomitant administration of rifampin and KETEK in repeated doses, Cmax and AUC of telithromycin were decreased by 79%, and 86%, respectively.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Telithromycin was not teratogenic in the rat or rabbit. Reproduction studies have been performed in rats and rabbits, with effect on pre-post natal development studied in the rat. At doses estimated to be 1.8 times (900 mg/m2) and 0.49 times (240 mg/m2) the daily human dose of 800 mg (492 mg/m2) in the rat and rabbit, respectively, no evidence of fetal terata was found. At doses higher than the 900 mg/m2 and 240 mg/m2 in rats and rabbits, respectively, maternal toxicity may have resulted in delayed fetal maturation. No adverse effects on prenatal and postnatal development of rat pups were observed at 1.5 times (750 mg/m2/d) the daily human dose.
- There are no adequate and well-controlled studies in pregnant women. Telithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Telithromycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Telithromycin during labor and delivery.
### Nursing Mothers
- Telithromycin is excreted in breast milk of rats. Telithromycin may also be excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KETEK is administered to a nursing mother.
### Pediatric Use
There is no FDA guidance on the use of Telithromycin with respect to pediatric patients.
### Geriatic Use
- In all Phase III clinical trials (n=4,780), KETEK was administered to 694 patients who were 65 years and older, including 231 patients who were 75 years and older. Efficacy and safety in elderly patients ≥ 65 years were generally similar to that observed in younger patients; however, greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is required based on age alone.
### Gender
- There was no significant difference between males and females in mean AUC, Cmax, and elimination half-life in two studies; one in 18 healthy young volunteers (18 to 40 years of age) and the other in 14 healthy elderly volunteers (65 to 92 years of age), given single and multiple once daily doses of 800 mg of KETEK.
### Race
There is no FDA guidance on the use of Telithromycin with respect to specific racial populations.
### Renal Impairment
- In a multiple-dose study, 36 subjects with varying degrees of renal impairment received 400 mg, 600 mg, or 800 mg KETEK once daily for 5 days. There was a 1.4-fold increase in Cmax,ss, and a 1.9-fold increase in AUC (0–24)ss at 800 mg multiple doses in the severely renally impaired group (CLCR < 30 mL/min) compared to healthy volunteers. Renal excretion may serve as a compensatory elimination pathway for telithromycin in situations where metabolic clearance is impaired. Patients with severe renal impairment are prone to conditions that may impair their metabolic clearance. Therefore, in the presence of severe renal impairment (CLCR < 30 mL/min), a reduced dosage of KETEK is recommended.
### Hepatic Impairment
- In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the Cmax, AUC and t1/2 of telithromycin were similar to those obtained in age- and sex-matched healthy subjects. In both studies, an increase in renal elimination was observed in hepatically impaired patients indicating that this pathway may compensate for some of the decrease in metabolic clearance. No dosage adjustment is recommended due to hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Telithromycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Telithromycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral.
- Intravenous.
### Monitoring
- Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly
- Patients concomitantly treated with statins should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis.
- Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and KETEK.
- Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and KETEK.
# IV Compatibility
There is limited information regarding IV Compatibility of Telithromycin in the drug label.
# Overdosage
- In the event of acute overdosage, the stomach should be emptied by gastric lavage. The patient should be carefully monitored (e.g., ECG, electrolytes) and given symptomatic and supportive treatment. Adequate hydration should be maintained. The effectiveness of hemodialysis in an overdose situation with KETEK is unknown.
# Pharmacology
There is limited information regarding Telithromycin Pharmacology in the drug label.
## Mechanism of Action
- Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g., Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the domain V binding site of telithromycin. Telithromycin may also inhibit the assembly of nascent ribosomal units.
- Staphylococcus aureus and Streptococcus pyogenes with the constitutive macrolide-lincosamide-streptogramin B (cMLSB) phenotype are resistant to telithromycin.
- Mutants of Streptococcus pneumoniae derived in the laboratory by serial passage in subinhibitory concentrations of telithromycin have demonstrated resistance based on L22 riboprotein mutations (telithromycin MICs are elevated but still within the susceptible range), one of two reported mutations affecting the L4 riboprotein, and production of K-peptide. The clinical significance of these laboratory mutants is not known.
- Telithromycin does not induce resistance through methylase gene expression in erythromycin-inducibly resistant bacteria, a function of its 3-keto moiety. Telithromycin has not been shown to induce resistance to itself.
- Telithromycin has been shown to be active against most strains of the following microorganisms.
- Aerobic gram-positive microorganisms
- Streptococcus pneumoniae (including multi-drug resistant isolates )
- Aerobic gram-negative microorganisms
- Haemophilus influenzae
- Moraxella catarrhalis
- Other microorganisms
- Chlamydophila (Chlamydia) pneumoniae
- Mycoplasma pneumoniae
- The following in vitro data are available, but their clinical significance is unknown.
- At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for telithromycin. However, the safety and efficacy of telithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Staphylococcus aureus (methicillin and erythromycin susceptible isolates only)
- Streptococcus pyogenes (erythromycin susceptible isolates only)
- Streptococci (Lancefield groups C and G)
- Legionella pneumophila
- 2 MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antimicrobials: penicillin, 2 nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
## Structure
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Telithromycin in the drug label.
## Pharmacokinetics
- Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 – 4 hours).
- It has an absolute bioavailability of 57% in both young and elderly subjects.
- The rate and extent of absorption are unaffected by food intake, thus KETEK tablets can be given without regard to food.
- In healthy adult subjects, peak plasma telithromycin concentrations of approximately 2 µg/mL are attained at a median of 1 hour after an 800-mg oral dose.
- Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with telithromycin 800 mg.
- Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.
- The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 1.
- Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 µg/mL at 6 hours, and remained at 14.1 µg/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 µg/mL 48 hours after the last dose.
- In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radio-labeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin.
- It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.
- The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Telithromycin in the drug label.
# Clinical Studies
- KETEK was studied in four randomized, double-blind, controlled studies and four open-label studies for the treatment of community-acquired pneumonia. Patients with mild to moderate CAP who were considered appropriate for oral outpatient treatment were enrolled in these trials. Patients with severe pneumonia were excluded based on any one of the following: ICU admission, need for parenteral antibiotics, respiratory rate > 30/minute, hypotension, altered mental status, < 90% oxygen saturation by pulse oximetry, or white blood cell count < 4000/mm3. Total number of clinically evaluable patients in the telithromycin group included 2016 patients.
- Clinical cure rates for patients with CAP due to Streptococcus pneumoniae were determined from patients in controlled and uncontrolled trials. Of 333 evaluable patients with CAP due to Streptococcus pneumoniae, 312 (93.7%) achieved clinical success. Only patients considered appropriate for oral outpatient therapy were included in these trials. More severely ill patients were not enrolled. Blood cultures were obtained in all patients participating in the clinical trials of mild to moderate community-acquired pneumonia. In a limited number of outpatients with incidental pneumococcal bacteremia treated with KETEK, a clinical cure rate of 88% (67/76) has been observed. KETEK is not indicated for the treatment of severe community-acquired pneumonia or suspected pneumococcal bacteremia.
- Clinical cure rates for patients with CAP due to multi-drug resistant Streptococcus pneumoniae (MDRSP*) were determined from patients in controlled and uncontrolled trials. Of 36 evaluable patients with CAP due to MDRSP, 33 (91.7%) achieved clinical success.
- MDRSP: Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
# How Supplied
- KETEK® 400 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "H3647" on one side and "400" on the other side. These are packaged in bottles as follows:
- Bottles of 60 :- (NDC 0088-2225-41)
- KETEK® 300 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "38AV" on one side and blank on the other side. These are packaged in bottles as follows:
- Bottles of 20 :- (NDC 0088-2223-20)
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Telithromycin in the drug label.
# Precautions with Alcohol
- Alcohol-Telithromycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KETEK®
# Look-Alike Drug Names
There is limited information regarding Telithromycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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Telithromycin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Telithromycin is a antibiotic that is FDA approved for the treatment of community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant isolates [MDRSP3]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years old and above. There is a Black Box Warning for this drug as shown here. Common adverse reactions include diarrhea, nausea, vomiting, dizziness, headache, abnormal vision , blurred vision, diplopia, problem of visual accommodation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- KETEK tablets are indicated for the treatment of community-acquired pneumonia (of mild to moderate severity) due to Streptococcus pneumoniae, (including multi-drug resistant isolates [MDRSP3]), Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, or Mycoplasma pneumoniae, for patients 18 years old and above.
- To reduce the development of drug-resistant bacteria and maintain the effectiveness of KETEK and other antibacterial drugs, KETEK should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
- 3 MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2 nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
- The dose of KETEK tablets is 800 mg (2 tablets of 400 mg) taken orally once every 24 hours, for 7–10 days. KETEK tablets can be administered with or without food.
- KETEK may be administered without dosage adjustment in the presence of hepatic impairment.
- In the presence of severe renal impairment (CLCR < 30 mL/min), including patients who need dialysis, the dose should be reduced to KETEK 600 mg once daily. In patients undergoing hemodialysis, KETEK should be given after the dialysis session on dialysis days.
- In the presence of severe renal impairment (CLCR < 30 mL/min), with coexisting hepatic impairment, the dose should be reduced to KETEK 400 mg once daily.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telithromycin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telithromycin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Telithromycin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telithromycin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telithromycin in pediatric patients.
# Contraindications
- KETEK is contraindicated in patients with myasthenia gravis. Exacerbations of myasthenia gravis have been reported in patients and sometimes occurred within a few hours of the first dose of telithromycin. Reports have included fatal and life-threatening acute respiratory failure with a rapid onset and progression.
- KETEK is contraindicated in patients with previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibiotic.
- KETEK is contraindicated in patients with a history of hypersensitivity to telithromycin and/or any components of KETEK tablets, or any macrolide antibiotic.
- Concomitant administration of KETEK with cisapride or pimozide is contraindicated.
- Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment.
# Warnings
- Acute hepatic failure and severe liver injury, in some cases fatal, have been reported in patients treated with KETEK. These hepatic reactions included fulminant hepatitis and hepatic necrosis leading to liver transplant, and were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of a few doses of KETEK.
- Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. Patients with signs or symptoms of hepatitis must be advised to discontinue KETEK and immediately seek medical evaluation, which should include liver function tests. If clinical hepatitis or transaminase elevations combined with other systemic symptoms occur, KETEK should be permanently discontinued.
- Ketek must not be re-administered to patients with a previous history of hepatitis and/or jaundice associated with the use of KETEK tablets, or any macrolide antibiotic.
- In addition, less severe hepatic dysfunction associated with increased liver enzymes, hepatitis and in some cases jaundice was reported with the use of KETEK. These events associated with less severe forms of liver toxicity were reversible.
- Telithromycin has the potential to prolong the QTc interval of the electrocardiogram in some patients. QTc prolongation may lead to an increased risk for ventricular arrhythmias, including torsades de pointes. Thus, telithromycin should be avoided in patients with congenital prolongation of the QTc interval, and in patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (e.g., quinidine and procainamide) or Class III (e.g., dofetilide) antiarrhythmic agents.
- Cases of torsades de pointes have been reported post-marketing with KETEK. In clinical trials, no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with telithromycin treatment in 4780 patients in clinical trials, including 204 patients having a prolonged QTc at baseline.
- KETEK may cause visual disturbances particularly in slowing the ability to accommodate and the ability to release accommodation. Visual disturbances included blurred vision, difficulty focusing, and diplopia. Most events were mild to moderate; however, severe cases have been reported.
- There have been post-marketing adverse event reports of transient loss of consciousness including some cases associated with vagal syndrome.
- Because of potential visual difficulties or loss of consciousness, patients should attempt to minimize activities such as driving a motor vehicle, operating heavy machinery or engaging in other hazardous activities during treatment with KETEK. If patients experience visual disorders or loss of consciousness while taking KETEK, patients should not drive a motor vehicle, operate heavy machinery or engage in other hazardous activities.
- Serious adverse reactions have been reported in patients taking KETEK concomitantly with CYP 3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP 3A4 (e.g., verapamil, amlodipine, diltiazem). (See PRECAUTIONS, DRUG INTERACTIONS.)
- Life-threatening and fatal drug interactions have been reported in patients treated with colchicine and strong CYP 3A4 inhibitors. Telithromycin is a strong CYP 3A4 inhibitor and this interaction may occur while using both drugs at their recommended doses. If co-administration of telithromycin and colchicine is necessary in patients with normal renal and hepatic function, the dose of colchicine should be reduced. Patients should be monitored for clinical symptoms of colchicine toxicity. Concomitant administration of KETEK and colchicine is contraindicated in patients with renal or hepatic impairment.
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including KETEK, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C difficile, and surgical evaluation should be instituted as clinically indicated.
# Adverse Reactions
## Clinical Trials Experience
- In Phase III clinical trials, 4,780 patients (n=2702 in controlled trials) received daily oral doses of KETEK 800 mg once daily for 5 days or 7 to 10 days. Most adverse events were mild to moderate in severity. In the combined Phase III studies, discontinuation due to treatment-emergent adverse events occurred in 4.4% of KETEK-treated patients and 4.3% of combined comparator-treated patients. Most discontinuations in the KETEK group were due to treatment-emergent adverse events in the gastrointestinal body system, primarily diarrhea (0.9% for KETEK vs. 0.7% for comparators), nausea (0.7% for KETEK vs. 0.5% for comparators).
- All and possibly related treatment-emergent adverse events (TEAEs) occurring in controlled clinical studies in ≥ 2.0% of all patients are included below:
- The following events judged by investigators to be at least possibly drug related were observed infrequently (≥ 0.2% and < 2%), in KETEK-treated patients in the controlled Phase III studies.
- Gastrointestinal system
- Abdominal distension, dyspepsia, gastrointestinal upset, flatulence, constipation, gastroenteritis, gastritis, anorexia, oral candidiasis, glossitis, stomatitis, watery stools.
- Liver and biliary system
- Abnormal liver function tests: increased transaminases, increased liver enzymes (e.g., ALT, AST) were usually asymptomatic and reversible. ALT elevations above 3 times the upper limit of normal were observed in 1.6%, and 1.7% of patients treated with KETEK and comparators, respectively. Hepatitis, with or without jaundice, occurred in 0.07% of patients treated with KETEK, and was reversible.
- Nervous system
- Dry mouth, somnolence, insomnia, vertigo, increased sweating
- Body as a whole
- Abdominal pain, upper abdominal pain, fatigue
- Special senses
- Visual adverse events most often included blurred vision, diplopia, or difficulty focusing. Most events were mild to moderate; however, severe cases have been reported. Some patients discontinued therapy due to these adverse events. Visual adverse events were reported as having occurred after any dose during treatment, but most visual adverse events (65%) occurred following the first or second dose. Visual events lasted several hours and recurred upon subsequent dosing in some patients. For patients who continued treatment, some resolved on therapy while others continued to have symptoms until they completed the full course of treatment.
- Females and patients under 40 years old experienced a higher incidence of telithromycin-associated visual adverse events. (See CLINICAL STUDIES.)
- Urogenital system
- Vaginal candidiasis, vaginitis, vaginosis fungal
- Skin
- Rash
- Hematologic
- Increased platelet count
- Other possibly related clinically-relevant events occurring in <0.2% of patients treated with KETEK from the controlled Phase III studies included: anxiety, bradycardia, eczema, elevated blood bilirubin, erythema multiforme, flushing, hypotension, increased blood alkaline phosphatase, increased eosinophil count, paresthesia, pruritus, urticaria.
## Postmarketing Experience
- In addition to adverse events reported from clinical trials, the following events have been reported from worldwide post-marketing experience with KETEK.
- Allergic
- Face edema, rare reports of severe allergic (hypersensitivity) reactions, including angioedema and anaphylaxis
- Cardiovascular
- Atrial arrhythmias, palpitations
- Gastrointestinal system
- Pancreatitis
- Liver and biliary system
- Hepatic dysfunction has been reported.
- Severe and in some cases fatal hepatotoxicity, including fulminant hepatitis, hepatic necrosis and hepatic failure have been reported in patients treated with KETEK. These hepatic reactions were observed during or immediately after treatment. In some of these cases, liver injury progressed rapidly and occurred after administration of only a few doses of KETEK. (See CONTRAINDICATIONS and WARNINGS.) Severe reactions, in some but not all cases, have been associated with serious underlying diseases or concomitant medications.
- Data from post-marketing reports and clinical trials show that most cases of hepatic dysfunction were mild to moderate. (See PRECAUTIONS, GENERAL.)
- Musculoskeletal
- Muscle cramps, rare reports of exacerbation of myasthenia gravis. Arthralgia, myalgia
- Nervous system
- Loss of consciousness, in some cases associated with vagal syndrome.
- Psychiatric disorders
- Confusion, hallucinations (mostly visual)
- Special senses
- Taste/smell perversion and/or loss
# Drug Interactions
- In vitro studies using a model compound have shown that telithromycin may act as an inhibitor for the hepatic uptake transporters OATP1B1 and OATP1B3. Although the clinical relevance of this finding is unknown, it is possible that concomitant administration of telithromycin with drugs that are substrates of OATP family members could result in increased plasma concentrations of the co-administered drug.
- Studies were performed to evaluate the effect of CYP 3A4 inhibitors on telithromycin and the effect of telithromycin on drugs that are substrates of CYP 3A4 and CYP 2D6. In addition, drug interaction studies were conducted with several other concomitantly prescribed drugs.
- A multiple-dose interaction study with itraconazole showed that Cmax of telithromycin was increased by 22% and AUC by 54%.
- A multiple-dose interaction study with ketoconazole showed that Cmax of telithromycin was increased by 51% and AUC by 95%.
- When telithromycin was given with 240 mL of grapefruit juice after an overnight fast to healthy subjects, the pharmacokinetics of telithromycin were not affected.
- Steady-state peak plasma concentrations of cisapride (an agent with the potential to increase QT interval) were increased by 95% when co-administered with repeated doses of telithromycin, resulting in significant increases in QTc.
- When simvastatin was co-administered with telithromycin, there was a 5.3-fold increase in simvastatin Cmax, an 8.9-fold increase in simvastatin AUC, a 15-fold increase in the simvastatin active metabolite Cmax, and a 12-fold increase in the simvastatin active metabolite AUC. (See PRECAUTIONS)
- In another study, when simvastatin and telithromycin were administered 12 hours apart, there was a 3.4-fold increase in simvastatin Cmax, a 4.0-fold increase in simvastatin AUC, a 3.2-fold increase in the active metabolite Cmax, and a 4.3-fold increase in the active metabolite AUC. (See PRECAUTIONS)
- Concomitant administration of telithromycin with intravenous or oral midazolam resulted in 2- and 6-fold increases, respectively, in the AUC of midazolam due to inhibition of CYP 3A4-dependent metabolism of midazolam.
- There was no pharmacokinetic effect on paroxetine when telithromycin was co-administered.
- When metoprolol was co-administered with telithromycin, there was an increase of approximately 38% on the Cmax and AUC of metoprolol, however, there was no effect on the elimination half-life of metoprolol. Telithromycin exposure is not modified with concomitant single-dose administration of metoprolol.
- The plasma peak and trough levels of digoxin were increased by 73% and 21%, respectively, in healthy volunteers when co-administered with telithromycin. However, trough plasma concentrations of digoxin (when equilibrium between plasma and tissue concentrations has been achieved) ranged from 0.74 to 2.17 ng/mL. There were no significant changes in ECG parameters and no signs of digoxin toxicity.
- When theophylline was co-administered with repeated doses of telithromycin, there was an increase of approximately 16% and 17% on the steady-state Cmax and AUC of theophylline. Co-administration of theophylline may worsen gastrointestinal side effects such as nausea and vomiting, especially in female patients. It is recommended that telithromycin should be taken with theophylline 1 hour apart to decrease the likelihood of gastrointestinal side effects.
- Telithromycin has been shown to decrease the Cmax and AUC of sotalol by 34% and 20%, respectively, due to decreased absorption.
- When co-administered with telithromycin in healthy subjects, there were no pharmacodynamic or pharmacokinetic effects on racemic warfarin.
- When oral contraceptives containing ethinyl estradiol and levonorgestrel were co-administered with telithromycin, the steady-state AUC of ethinyl estradiol did not change and the steady-state AUC of levonorgestrel was increased by 50%. The pharmacokinetic/pharmacodynamic study showed that telithromycin did not interfere with the antiovulatory effect of oral contraceptives containing ethinyl estradiol and levonorgestrel.
- There was no clinically relevant pharmacokinetic interaction of ranitidine or antacids containing aluminum and magnesium hydroxide on telithromycin.
- During concomitant administration of rifampin and KETEK in repeated doses, Cmax and AUC of telithromycin were decreased by 79%, and 86%, respectively.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Telithromycin was not teratogenic in the rat or rabbit. Reproduction studies have been performed in rats and rabbits, with effect on pre-post natal development studied in the rat. At doses estimated to be 1.8 times (900 mg/m2) and 0.49 times (240 mg/m2) the daily human dose of 800 mg (492 mg/m2) in the rat and rabbit, respectively, no evidence of fetal terata was found. At doses higher than the 900 mg/m2 and 240 mg/m2 in rats and rabbits, respectively, maternal toxicity may have resulted in delayed fetal maturation. No adverse effects on prenatal and postnatal development of rat pups were observed at 1.5 times (750 mg/m2/d) the daily human dose.
- There are no adequate and well-controlled studies in pregnant women. Telithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Telithromycin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Telithromycin during labor and delivery.
### Nursing Mothers
- Telithromycin is excreted in breast milk of rats. Telithromycin may also be excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when KETEK is administered to a nursing mother.
### Pediatric Use
There is no FDA guidance on the use of Telithromycin with respect to pediatric patients.
### Geriatic Use
- In all Phase III clinical trials (n=4,780), KETEK was administered to 694 patients who were 65 years and older, including 231 patients who were 75 years and older. Efficacy and safety in elderly patients ≥ 65 years were generally similar to that observed in younger patients; however, greater sensitivity of some older individuals cannot be ruled out. No dosage adjustment is required based on age alone.
### Gender
- There was no significant difference between males and females in mean AUC, Cmax, and elimination half-life in two studies; one in 18 healthy young volunteers (18 to 40 years of age) and the other in 14 healthy elderly volunteers (65 to 92 years of age), given single and multiple once daily doses of 800 mg of KETEK.
### Race
There is no FDA guidance on the use of Telithromycin with respect to specific racial populations.
### Renal Impairment
- In a multiple-dose study, 36 subjects with varying degrees of renal impairment received 400 mg, 600 mg, or 800 mg KETEK once daily for 5 days. There was a 1.4-fold increase in Cmax,ss, and a 1.9-fold increase in AUC (0–24)ss at 800 mg multiple doses in the severely renally impaired group (CLCR < 30 mL/min) compared to healthy volunteers. Renal excretion may serve as a compensatory elimination pathway for telithromycin in situations where metabolic clearance is impaired. Patients with severe renal impairment are prone to conditions that may impair their metabolic clearance. Therefore, in the presence of severe renal impairment (CLCR < 30 mL/min), a reduced dosage of KETEK is recommended.
### Hepatic Impairment
- In a single-dose study (800 mg) in 12 patients and a multiple-dose study (800 mg) in 13 patients with mild to severe hepatic insufficiency (Child Pugh Class A, B and C), the Cmax, AUC and t1/2 of telithromycin were similar to those obtained in age- and sex-matched healthy subjects. In both studies, an increase in renal elimination was observed in hepatically impaired patients indicating that this pathway may compensate for some of the decrease in metabolic clearance. No dosage adjustment is recommended due to hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Telithromycin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Telithromycin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral.
- Intravenous.
### Monitoring
- Physicians and patients should monitor for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly
- Patients concomitantly treated with statins should be carefully monitored for signs and symptoms of myopathy and rhabdomyolysis.
- Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and KETEK.
- Monitoring of digoxin side effects or serum levels should be considered during concomitant administration of digoxin and KETEK.
# IV Compatibility
There is limited information regarding IV Compatibility of Telithromycin in the drug label.
# Overdosage
- In the event of acute overdosage, the stomach should be emptied by gastric lavage. The patient should be carefully monitored (e.g., ECG, electrolytes) and given symptomatic and supportive treatment. Adequate hydration should be maintained. The effectiveness of hemodialysis in an overdose situation with KETEK is unknown.
# Pharmacology
There is limited information regarding Telithromycin Pharmacology in the drug label.
## Mechanism of Action
- Telithromycin blocks protein synthesis by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g., Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the domain V binding site of telithromycin. Telithromycin may also inhibit the assembly of nascent ribosomal units.
- Staphylococcus aureus and Streptococcus pyogenes with the constitutive macrolide-lincosamide-streptogramin B (cMLSB) phenotype are resistant to telithromycin.
- Mutants of Streptococcus pneumoniae derived in the laboratory by serial passage in subinhibitory concentrations of telithromycin have demonstrated resistance based on L22 riboprotein mutations (telithromycin MICs are elevated but still within the susceptible range), one of two reported mutations affecting the L4 riboprotein, and production of K-peptide. The clinical significance of these laboratory mutants is not known.
- Telithromycin does not induce resistance through methylase gene expression in erythromycin-inducibly resistant bacteria, a function of its 3-keto moiety. Telithromycin has not been shown to induce resistance to itself.
- Telithromycin has been shown to be active against most strains of the following microorganisms.
- Aerobic gram-positive microorganisms
- Streptococcus pneumoniae (including multi-drug resistant isolates [MDRSP2])
- Aerobic gram-negative microorganisms
- Haemophilus influenzae
- Moraxella catarrhalis
- Other microorganisms
- Chlamydophila (Chlamydia) pneumoniae
- Mycoplasma pneumoniae
- The following in vitro data are available, but their clinical significance is unknown.
- At least 90% of the following microorganisms exhibit in vitro minimum inhibitory concentrations (MICs) less than or equal to the susceptible breakpoint for telithromycin. However, the safety and efficacy of telithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
- Staphylococcus aureus (methicillin and erythromycin susceptible isolates only)
- Streptococcus pyogenes (erythromycin susceptible isolates only)
- Streptococci (Lancefield groups C and G)
- Legionella pneumophila
- 2 MDRSP=Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant S. pneumoniae), and are isolates resistant to two or more of the following antimicrobials: penicillin, 2 nd generation cephalosporins (e.g., cefuroxime), macrolides, tetracyclines, and trimethoprim/sulfamethoxazole.
## Structure
-
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Telithromycin in the drug label.
## Pharmacokinetics
- Following oral administration, telithromycin reached maximal concentration at about 1 hour (0.5 – 4 hours).
- It has an absolute bioavailability of 57% in both young and elderly subjects.
- The rate and extent of absorption are unaffected by food intake, thus KETEK tablets can be given without regard to food.
- In healthy adult subjects, peak plasma telithromycin concentrations of approximately 2 µg/mL are attained at a median of 1 hour after an 800-mg oral dose.
- Steady-state plasma concentrations are reached within 2 to 3 days of once daily dosing with telithromycin 800 mg.
- Following oral dosing, the mean terminal elimination half-life of telithromycin is 10 hours.
- The pharmacokinetics of telithromycin after administration of single and multiple (7 days) once daily 800-mg doses to healthy adult subjects are shown in Table 1.
- Telithromycin concentration in white blood cells exceeds the concentration in plasma and is eliminated more slowly from white blood cells than from plasma. Mean white blood cell concentrations of telithromycin peaked at 72.1 µg/mL at 6 hours, and remained at 14.1 µg/mL 24 hours after 5 days of repeated dosing of 600 mg once daily. After 10 days, repeated dosing of 600 mg once daily, white blood cell concentrations remained at 8.9 µg/mL 48 hours after the last dose.
- In total, metabolism accounts for approximately 70% of the dose. In plasma, the main circulating compound after administration of an 800-mg radio-labeled dose was parent compound, representing 56.7% of the total radioactivity. The main metabolite represented 12.6% of the AUC of telithromycin. Three other plasma metabolites were quantified, each representing 3% or less of the AUC of telithromycin.
- It is estimated that approximately 50% of its metabolism is mediated by CYP 450 3A4 and the remaining 50% is CYP 450-independent.
- The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Telithromycin in the drug label.
# Clinical Studies
- KETEK was studied in four randomized, double-blind, controlled studies and four open-label studies for the treatment of community-acquired pneumonia. Patients with mild to moderate CAP who were considered appropriate for oral outpatient treatment were enrolled in these trials. Patients with severe pneumonia were excluded based on any one of the following: ICU admission, need for parenteral antibiotics, respiratory rate > 30/minute, hypotension, altered mental status, < 90% oxygen saturation by pulse oximetry, or white blood cell count < 4000/mm3. Total number of clinically evaluable patients in the telithromycin group included 2016 patients.
- Clinical cure rates for patients with CAP due to Streptococcus pneumoniae were determined from patients in controlled and uncontrolled trials. Of 333 evaluable patients with CAP due to Streptococcus pneumoniae, 312 (93.7%) achieved clinical success. Only patients considered appropriate for oral outpatient therapy were included in these trials. More severely ill patients were not enrolled. Blood cultures were obtained in all patients participating in the clinical trials of mild to moderate community-acquired pneumonia. In a limited number of outpatients with incidental pneumococcal bacteremia treated with KETEK, a clinical cure rate of 88% (67/76) has been observed. KETEK is not indicated for the treatment of severe community-acquired pneumonia or suspected pneumococcal bacteremia.
- Clinical cure rates for patients with CAP due to multi-drug resistant Streptococcus pneumoniae (MDRSP*) were determined from patients in controlled and uncontrolled trials. Of 36 evaluable patients with CAP due to MDRSP, 33 (91.7%) achieved clinical success.
- MDRSP: Multi-drug resistant Streptococcus pneumoniae includes isolates known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are isolates resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
# How Supplied
- KETEK® 400 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "H3647" on one side and "400" on the other side. These are packaged in bottles as follows:
- Bottles of 60 :* (NDC 0088-2225-41)
- KETEK® 300 mg tablets are supplied as light-orange, oval, film-coated tablets, imprinted "38AV" on one side and blank on the other side. These are packaged in bottles as follows:
- Bottles of 20 :* (NDC 0088-2223-20)
## Storage
- Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Telithromycin in the drug label.
# Precautions with Alcohol
- Alcohol-Telithromycin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- KETEK®[1]
# Look-Alike Drug Names
There is limited information regarding Telithromycin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/Telithromycin
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Telluric acid
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Telluric acid
Telluric acid is a chemical compound with the formula Te(OH)6. It is a white solid made up of octahedral Te(OH)6 molecules and this structure persists in aqueous solution. There are two forms, rhombohedral and monoclinic, and both contain octahedral Te(OH)6 molecules.
Telluric acid is a weak acid,dibasic, forming tellurate salts with strong bases.
# Preparation
Telluric acid is formed by the oxidation of tellurium or tellurium dioxide with a powerful oxidising agent such as hydrogen peroxide, chromium trioxide or sodium peroxide.
Crystallisation of telluric acid solutions below 10°C gives Te(OH)6.4H2O.
It is oxidizing, as shown by the electrode potential for the reaction below, although it is kinetically slow in its oxidations.
# Properties and Reactions
The anhydrous acid is stable in air at 100°C but above this it dehydrates to form polymetatelluric acid, a white hygroscopic powder (approximate composition (H2TeO4)10), and allotelluric acid, an acid syrup of unknown structure (approximate composition (H2TeO4)3(H2O)4).
Strong heating at over 300°C produces the α- crystalline modification of tellurium trioxide, α-TeO3.
Reaction with diazomethane gives the hexamethyl ester, Te(OMe)6.
Telluric acid and its salts mostly contain hexacoordinate tellurium. This is true even for salts such as magnesium tellurate, MgTeO4, which is isostructural with magnesium molybdate and contains TeO6 octahedra.
# Metatelluric acid - H2TeO4,Tellurous acid - H2TeO3
Metatelluric acid, H2TeO4, the tellurium analogue of sulfuric acid, H2SO4, is unknown. Allotelluric acid of approximate composition H2TeO4)3(H2O)4, is not well characterised and may be a mixture of Te(OH)6 and (H2TeO4)n.
Tellurous acid, H2TeO3 is known but not well characterised.
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Telluric acid
Template:Chembox new
Telluric acid is a chemical compound with the formula Te(OH)6. It is a white solid made up of octahedral Te(OH)6 molecules and this structure persists in aqueous solution.[1] There are two forms, rhombohedral and monoclinic, and both contain octahedral Te(OH)6 molecules.[2]
Telluric acid is a weak acid,dibasic, forming tellurate salts with strong bases.[2][3]
# Preparation
Telluric acid is formed by the oxidation of tellurium or tellurium dioxide with a powerful oxidising agent such as hydrogen peroxide, chromium trioxide or sodium peroxide.[2]
Crystallisation of telluric acid solutions below 10°C gives Te(OH)6.4H2O.[1]
It is oxidizing, as shown by the electrode potential for the reaction below, although it is kinetically slow in its oxidations.[2]
# Properties and Reactions
The anhydrous acid is stable in air at 100°C but above this it dehydrates to form polymetatelluric acid, a white hygroscopic powder (approximate composition (H2TeO4)10), and allotelluric acid, an acid syrup of unknown structure (approximate composition (H2TeO4)3(H2O)4).[1]
Strong heating at over 300°C produces the α- crystalline modification of tellurium trioxide, α-TeO3.
[4]
Reaction with diazomethane gives the hexamethyl ester, Te(OMe)6.[1]
Telluric acid and its salts mostly contain hexacoordinate tellurium.[2] This is true even for salts such as magnesium tellurate, MgTeO4, which is isostructural with magnesium molybdate and contains TeO6 octahedra.[2]
# Metatelluric acid - H2TeO4,Tellurous acid - H2TeO3
Metatelluric acid, H2TeO4, the tellurium analogue of sulfuric acid, H2SO4, is unknown. Allotelluric acid of approximate composition H2TeO4)3(H2O)4, is not well characterised and may be a mixture of Te(OH)6 and (H2TeO4)n.[1]
Tellurous acid, H2TeO3 is known but not well characterised.
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https://www.wikidoc.org/index.php/Telluric_acid
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5bd36ad36c321f746b5371ccaf7454827241592d
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wikidoc
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Tenatoprazole
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Tenatoprazole
Tenatoprazole (rINN, also benatoprazole) is a novel proton pump inhibitor indicated for the treatment of reflux oesophagitis and peptic ulcer in Japan. Discovered by Mitsubishi Pharma, it is an imidazopyridine derivative and has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors. It is activated more slowly than other proton pump inhibitors but its inhibition is resistant to reversal. Tenatoprazole has an extended plasma half-life in comparison with all other proton pump inhibitors; this makes it more potent and effective in the treatment of nocturnal acid breakthrough than esomeprazole, one of the most popular proton pump inhibitors.
# Pharmacological action
Tenatoprazole is a prodrug of the proton pump inhibitor (PPI) class, which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach. This active species binds to luminally accessible cysteines of the gastric H+,K+ -ATPase resulting in disulfide formation and acid secretion inhibition. Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg(-1) of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg(-1) of the enzyme at 2 h after IV administration. The binding sites of tenatoprazole were in the TM5/6 region at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. Decay of tenatoprazole binding on the gastric H+,K+ -ATPase consisted of two components. One was relatively fast, with a half-life 3.9 h due to reversal of binding at cysteine 813, and the other was a plateau phase corresponding to ATPase turnover reflecting binding at cysteine 822 that also results in sustained inhibition in the presence of reducing agents in vitro. The stability of inhibition and the long plasma half-life of tenatoprazole should result in prolonged inhibition of acid secretion as compared to omeprazole. Further, the bioavailability of tenatoprazole was two-fold greater in the (S)-tenatoprazole sodium salt hydrate form as compared to the free form in dogs which is due to differences in the crystal structure and hydrophobic nature of the two forms.
Pharmacodynamic studies on the same subjects showed an increase of intragastric pH with tenatoprazole 40 mg daily for seven days significantly higher (p<0.05) than that observed with the same regimen of esomeprazole, the median pH being 4.6±0.9 and 4.2±0.8, respectively. In addition, the time spent above pH 4 during night-time after tenatoprazole administration was significantly longer than that observed with esomeprazole. The intragastric pH during the night was similarly higher (4.7±1.1 Units with tenatoprazole and 3.6±1.4 Units with esomeprazole, p<0.01). The better control of intragastric acidity achieved with tenatoprazole during the night was already evident from the first 24-hour of dosing.
A more recent pharmacodynamic and pharmacokinetic investigation did confirm and extended previous data showing the prolonged duration of acid suppression with tenatoprazole. The proportion of healthy volunteers spending at least 16 h above pH 4 in the 24 h period was remarkably higher with tenatoprazole than with esomeprazole (81.5% versus 34.5%, p3 and pH>4 were significantly higher with tenatoprazole, indicating a sustained control of intragastric acidity with this novel PPI compared to esomeprazole. After 7 days repeated dosing the maximal plasma concentration of tenatoprazole was almost six times higher than that of esomeprazole while AUC was 32 times higher. A significant correlation between AUC and percentage of time intragastric pH>4 was observed with tenatoprazole not only during but also after stopping treatment.
In summary, the available studies point out both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. Since this last compound provides – amongst the members of the class - the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing PPIs. Tenatoprazole (as well as its S-isomer) then appears a promising PPI for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.
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Tenatoprazole
Tenatoprazole (rINN, also benatoprazole) is a novel proton pump inhibitor indicated for the treatment of reflux oesophagitis and peptic ulcer in Japan. Discovered by Mitsubishi Pharma, it is an imidazopyridine derivative and has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors. It is activated more slowly than other proton pump inhibitors but its inhibition is resistant to reversal. Tenatoprazole has an extended plasma half-life in comparison with all other proton pump inhibitors; this makes it more potent and effective in the treatment of nocturnal acid breakthrough than esomeprazole, one of the most popular proton pump inhibitors.[1]
# Pharmacological action
Tenatoprazole is a prodrug of the proton pump inhibitor (PPI) class, which is converted to the active sulfenamide or sulfenic acid by acid in the secretory canaliculus of the stimulated parietal cell of the stomach. This active species binds to luminally accessible cysteines of the gastric H+,K+ -ATPase resulting in disulfide formation and acid secretion inhibition. Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg(-1) of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg(-1) of the enzyme at 2 h after IV administration. The binding sites of tenatoprazole were in the TM5/6 region at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. Decay of tenatoprazole binding on the gastric H+,K+ -ATPase consisted of two components. One was relatively fast, with a half-life 3.9 h due to reversal of binding at cysteine 813, and the other was a plateau phase corresponding to ATPase turnover reflecting binding at cysteine 822 that also results in sustained inhibition in the presence of reducing agents in vitro. The stability of inhibition and the long plasma half-life of tenatoprazole should result in prolonged inhibition of acid secretion as compared to omeprazole. Further, the bioavailability of tenatoprazole was two-fold greater in the (S)-tenatoprazole sodium salt hydrate form as compared to the free form in dogs which is due to differences in the crystal structure and hydrophobic nature of the two forms.
Pharmacodynamic studies on the same subjects showed an increase of intragastric pH with tenatoprazole 40 mg daily for seven days significantly higher (p<0.05) than that observed with the same regimen of esomeprazole, the median pH being 4.6±0.9 and 4.2±0.8, respectively. In addition, the time spent above pH 4 during night-time after tenatoprazole administration was significantly longer than that observed with esomeprazole. The intragastric pH during the night was similarly higher (4.7±1.1 Units with tenatoprazole and 3.6±1.4 Units with esomeprazole, p<0.01). The better control of intragastric acidity achieved with tenatoprazole during the night was already evident from the first 24-hour of dosing.
A more recent pharmacodynamic and pharmacokinetic investigation did confirm and extended previous data showing the prolonged duration of acid suppression with tenatoprazole. The proportion of healthy volunteers spending at least 16 h above pH 4 in the 24 h period was remarkably higher with tenatoprazole than with esomeprazole (81.5% versus 34.5%, p<0.001) while the proportion of subjects with NAB was lower (73.1% versus 93.1%, p=0.06), although the difference fell short of statistical significance. Even 3 days after treatment was discontinued, mean 24 h pH, and percentage of time at pH>3 and pH>4 were significantly higher with tenatoprazole, indicating a sustained control of intragastric acidity with this novel PPI compared to esomeprazole. After 7 days repeated dosing the maximal plasma concentration of tenatoprazole was almost six times higher than that of esomeprazole while AUC was 32 times higher. A significant correlation between AUC and percentage of time intragastric pH>4 was observed with tenatoprazole not only during but also after stopping treatment.
In summary, the available studies point out both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. Since this last compound provides – amongst the members of the class - the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing PPIs. Tenatoprazole (as well as its S-isomer) then appears a promising PPI for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.
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https://www.wikidoc.org/index.php/Tenatoprazole
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ec5008a2a21555ad814d362d24c9b890c7375cfc
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wikidoc
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Tenosynovitis
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Tenosynovitis
Synonyms and keywords: Tendon sheath inflammation; inflammation of the tendon sheath
# Overview
Tenosynovitis is the inflammation of the fluid-filled sheath (called the synovium) that surrounds a tendon. Symptoms of tenosynovitis include pain, swelling , and difficulty moving a particular joint where the inflammation occurs. When the condition causes the finger to "stick" in a flexed position, this is called "stenosing" tenosynovitis, which is commonly called "Trigger Finger."
When the finger tendon is inflamed, the synovium swells. Sometimes the tendon cannot slide easily through the synovium. When you straighten your finger, the tendon locks or sticks as it squeezes through the too-small synovium.
It usually occurs with tendinitis and it is related to stenosing tenosynovitis.
# Causes
Causes of trigger finger are unknown. Repeated use of hand tools can precede the condition, as well as arthritis or injury. Trigger Finger sometimes runs in families, and is generally seen more often in males than in females. The causes for children are even less known and have a recurrence rate of less than 1-5% after treatment.
(By organ system)
(In alphabetical order)
Other causes and associated conditions are:
- DeQuervain's syndrome
- Gonorrhea
- Pergolide
- Polymyalgia Rheumatica
- Trigger finger
# Diagnosis
## History and Symptoms
- Problems moving joints
- Pain, swelling and tenderness around a joint, particularly the hand, wrist, foot, and ankle
- Pain when moving the affected joint
## Physical Examination
A physical examination shows swelling over the involved tendon. The health care provider may touch or stretch the tendon or have you move the muscle to which it is attached to see whether you experience pain.
### Thumb
- Tenosynovitis nodular. Adapted from Dermatology Atlas.
- Tenosynovitis nodular. Adapted from Dermatology Atlas.
- Tenosynovitis nodular. Adapted from Dermatology Atlas.
- Tenosynovitis nodular. Adapted from Dermatology Atlas.
# Treatment
Possible treatments for tenosynovitis include cortisone injections (then a course of paracetomal and ibuprofen for pain) and an outpatient surgery to enlarge the synovium. The hand is splinted for a week or so.
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Tenosynovitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Associate Editor-In-Chief: M.Umer Tariq [3] Kiran Singh, M.D. [4]
Synonyms and keywords: Tendon sheath inflammation; inflammation of the tendon sheath
# Overview
Tenosynovitis is the inflammation of the fluid-filled sheath (called the synovium) that surrounds a tendon. Symptoms of tenosynovitis include pain, swelling , and difficulty moving a particular joint where the inflammation occurs. When the condition causes the finger to "stick" in a flexed position, this is called "stenosing" tenosynovitis, which is commonly called "Trigger Finger."
When the finger tendon is inflamed, the synovium swells. Sometimes the tendon cannot slide easily through the synovium. When you straighten your finger, the tendon locks or sticks as it squeezes through the too-small synovium.
It usually occurs with tendinitis and it is related to stenosing tenosynovitis.
# Causes
Causes of trigger finger are unknown. Repeated use of hand tools can precede the condition, as well as arthritis or injury. Trigger Finger sometimes runs in families, and is generally seen more often in males than in females. The causes for children are even less known and have a recurrence rate of less than 1-5% after treatment.
(By organ system)
(In alphabetical order)
Other causes and associated conditions are:
- DeQuervain's syndrome
- Gonorrhea
- Pergolide
- Polymyalgia Rheumatica
- Trigger finger
# Diagnosis
## History and Symptoms
- Problems moving joints
- Pain, swelling and tenderness around a joint, particularly the hand, wrist, foot, and ankle
- Pain when moving the affected joint
## Physical Examination
A physical examination shows swelling over the involved tendon. The health care provider may touch or stretch the tendon or have you move the muscle to which it is attached to see whether you experience pain. [1]
### Thumb
- Tenosynovitis nodular. Adapted from Dermatology Atlas.[2]
- Tenosynovitis nodular. Adapted from Dermatology Atlas.[2]
- Tenosynovitis nodular. Adapted from Dermatology Atlas.[2]
- Tenosynovitis nodular. Adapted from Dermatology Atlas.[2]
# Treatment
Possible treatments for tenosynovitis include cortisone injections (then a course of paracetomal and ibuprofen for pain) and an outpatient surgery to enlarge the synovium. The hand is splinted for a week or so.
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https://www.wikidoc.org/index.php/Tenosynovitis
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d47f258cf349825edf1e20436e45aad602d18601
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wikidoc
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Tequila agave
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Tequila agave
Blue Agave, the tequila agave of the Agave tequilana species, is an agave plant that is an important economic product of Jalisco state in Mexico due to its role as the base ingredient of tequila, a popular alcoholic drink.
The tequila agave grows natively in Jalisco, favoring the high altitudes of more than 1,500 m and sandy soil. Commercial and wild agaves have very different life cycles. Both start as a large succulent, with spiky fleshy leaves, which can grow to over two meters in length. Wild agaves sprout a shoot when about five years old which grows into a stem up to five metres and topped with yellow flowers. The flowers are pollinated by a native bat (Leptonycteris nivalis) and produce several thousand seeds per plant. The plant then dies. The shoots are removed when about a year old from commercial plants to allow the heart to grow larger. The plants are then reproduced by planting these shoots; this has led to a considerable loss of genetic diversity in cultivated blue agave. It is rare for one kept as a a houseplant to flower; nevertheless, a fifty year old blue agave in Boston has grown a 10 m (30 ft) stalk requiring a hole in the greenhouse roof and flowered sometime during the summer of 2006.
Tequila is produced by removing the heart of the plant in its twelfth year, normally weighing between 35-90 kg. This heart is stripped of leaves and heated to remove the sap, which is fermented and distilled. Other beverages like Mezcal and Pulque are also produced from Blue and other agaves by different methods (though still using the sap) and are regarded as more traditional.
Over 200 million Blue Agave plants are grown in several regions of Mexico, but in recent years the ability of farmers to meet demand has been in question. Through poor breeding practices, Blue Agave has lost resistance to fusarium fungus and several other diseases which currently render 25%-30% of the plants unusable for consumption.
Researchers from Mexico's University of Guadalajara believe blue agave contains compounds that may be useful in carrying drugs to the intestines to treat diseases such as Crohn's disease and colitis.
# TMA
Production of this important cash crop in Mexico has been hindered in the early 2000s by a number of rot-related problems, collectively referred to as TMA ("Tristeza y Muerte de Agave", the wilting and death of the agave). As of 2002, 23% or more of the plants produced in Jalisco were affected.
Part of the problem is a group of diseases spread by the larvae of the weevil Scyphophorus acupunctatus Gyll. (Coleoptera:Curculinidae). Also, the fungus Thielaviopsis paradoxa prevents younger plants from forming roots.
According to a 2004 study, additional pathogens, Erwinia carotovora, Enterobacter agglomerans, Pseudomonas mendocina, and Serratia sp. are responsible for continued rot.
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Tequila agave
Blue Agave, the tequila agave of the Agave tequilana species, is an agave plant that is an important economic product of Jalisco state in Mexico due to its role as the base ingredient of tequila, a popular alcoholic drink.
The tequila agave grows natively in Jalisco, favoring the high altitudes of more than 1,500 m and sandy soil. Commercial and wild agaves have very different life cycles. Both start as a large succulent, with spiky fleshy leaves, which can grow to over two meters in length. Wild agaves sprout a shoot when about five years old which grows into a stem up to five metres and topped with yellow flowers. The flowers are pollinated by a native bat (Leptonycteris nivalis) and produce several thousand seeds per plant. The plant then dies. The shoots are removed when about a year old from commercial plants to allow the heart to grow larger. The plants are then reproduced by planting these shoots; this has led to a considerable loss of genetic diversity in cultivated blue agave. It is rare for one kept as a a houseplant to flower; nevertheless, a fifty year old blue agave in Boston has grown a 10 m (30 ft) stalk requiring a hole in the greenhouse roof and flowered sometime during the summer of 2006.[1]
Tequila is produced by removing the heart of the plant in its twelfth year, normally weighing between 35-90 kg. This heart is stripped of leaves and heated to remove the sap, which is fermented and distilled. Other beverages like Mezcal and Pulque are also produced from Blue and other agaves by different methods (though still using the sap) and are regarded as more traditional.
Over 200 million Blue Agave plants are grown in several regions of Mexico, but in recent years the ability of farmers to meet demand has been in question. Through poor breeding practices, Blue Agave has lost resistance to fusarium fungus and several other diseases which currently render 25%-30% of the plants unusable for consumption.
Researchers from Mexico's University of Guadalajara believe blue agave contains compounds that may be useful in carrying drugs to the intestines to treat diseases such as Crohn's disease and colitis. [2]
# TMA
Production of this important cash crop in Mexico has been hindered in the early 2000s by a number of rot-related problems, collectively referred to as TMA ("Tristeza y Muerte de Agave", the wilting and death of the agave). As of 2002, 23% or more of the plants produced in Jalisco were affected.
Part of the problem is a group of diseases spread by the larvae of the weevil Scyphophorus acupunctatus Gyll. (Coleoptera:Curculinidae). Also, the fungus Thielaviopsis paradoxa prevents younger plants from forming roots.
According to a 2004 study, additional pathogens, Erwinia carotovora, Enterobacter agglomerans, Pseudomonas mendocina, and Serratia sp. are responsible for continued rot.[3]
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https://www.wikidoc.org/index.php/Tequila_agave
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34c1799c5bb44565ae751376e577dc23f58aa312
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wikidoc
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Teriflunomide
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Teriflunomide
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Teriflunomide is a pyrimidine synthesis inhibitor that is FDA approved for the treatment of patients with relapsing forms of multiple sclerosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, nausea, alopecia, increase in ALT.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
### Dosage
- The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.
### DOSAGE FORMS AND STRENGTHS
- AUBAGIO is available as 7 mg and 14 mg tablets.
- The 14 mg tablet is a pale blue to pastel blue, pentagonal film-coated tablet with the dose strength, "14" imprinted on one side and engraved with the corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.
- The 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with the corporate logo on other side. Each tablet contains 7 mg of teriflunomide.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriflunomide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriflunomide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Teriflunomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriflunomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriflunomide in pediatric patients.
# Contraindications
- Patients with severe hepatic impairment .
- AUBAGIO may cause fetal harm when administered to a pregnant woman.
- In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity.
- AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling
- Co-administration of teriflunomide with leflunomide is contraindicated.
# Warnings
- Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment .
- In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving AUBAGIO 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
- One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. AUBAGIO-induced liver injury in this patient could not be ruled out.
- Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue AUBAGIO and start an accelerated elimination procedure and monitor liver tests weekly until normalized. If AUBAGIO-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBAGIO therapy may be considered.
- There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman.
- Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO.
- Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk.
- Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures:
- If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.
- At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.
- Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.
- White Blood Cell (WBC) count decrease
- A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO compared to baseline. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8×109/L was observed in 10% and 12% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for AUBAGIO. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.
- Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.
- AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like AUBAGIO that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.
- In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.
- In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO.
- No clinical data are available on the efficacy and safety of live vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO.
- The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO.
- In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking AUBAGIO than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.4% (13 patients) and 1.9% (17 patients) of patients receiving 7 mg and 14 mg of AUBAGIO, respectively, compared with 0.4% receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with confirmed peripheral neuropathy (3 patients receiving AUBAGIO 7 mg and 5 patients receiving AUBAGIO 14 mg). Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment. Peripheral neuropathy also occurred in patients receiving leflunomide.
- Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure.
- Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for AUBAGIO . If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure.
- In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of AUBAGIO compared with 1.8% for placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO.
- Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for AUBAGIO. Interstitial lung disease may be fatal. Interstitial lung disease may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure.
- Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.
- In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are described elsewhere in the prescribing information:
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.
- Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively).
- Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established.
- In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance.
- In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Teriflunomide in the drug label.
# Drug Interactions
- Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required .
- Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.
- AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with AUBAGIO.
- Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required .
- Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required .
- Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking AUBAGIO
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).
- Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD.
- In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD.
- In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
- AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL).
- Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447 FREE
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teriflunomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Teriflunomide during labor and delivery.
### Nursing Mothers
- Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of AUBAGIO did not include patients over 65 years old.
### Gender
There is no FDA guidance on the use of Teriflunomide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Teriflunomide with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment
### Hepatic Impairment
- No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Teriflunomide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Teriflunomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO.
- Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection.
- Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection.
- Check blood pressure before start of AUBAGIO treatment and periodically thereafter
# IV Compatibility
There is limited information regarding IV Compatibility of Teriflunomide in the drug label.
# Overdosage
- There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.
- In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination
# Pharmacology
## Mechanism of Action
- Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.
## Structure
- AUBAGIO (teriflunomide) is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. Its molecular weight is 270.21, and the empirical formula is C12H9F3N2O2 with the following chemical structure:
## Pharmacodynamics
- In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).
## Pharmacokinetics
- Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
- Based on a population analysis of teriflunomide in healthy volunteers and MS patients, median t1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg.
- Median time to reach maximum plasma concentrations is between 1 to 4 hours post-dose following oral administration of teriflunomide.
- Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.
- Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.
- Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.
- Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.
- Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes.
- The Potential Effect of AUBAGIO on Other Drugs
- CYP2C8 Substrates
- There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose .
- CYP1A2 Substrates
- Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.
- OAT3 Substrates
- There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo.
- BCRP and OATP1B1/1B3 Substrates
- There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide , suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3).
- Oral Contraceptives
- There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide .
- Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).
- The Potential Effect of Other Drugs on AUBAGIO
- Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.
- Hepatic Impairment
- Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated.
- Renal Impairment
- Severe renal impairment had no impact on the pharmacokinetics of teriflunomide .
- Gender
- In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males.
- Race
- Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of non-white patients in the clinical trials.
## Nonclinical Toxicology
- No evidence of carcinogenicity was observed in lifetime carcinogenicity bioassays in mouse and rat. In mouse, teriflunomide was administered orally at doses up to 12 mg/kg/day for up to 95–104 weeks; plasma teriflunomide exposures (AUC) at the highest dose tested are approximately 3 times that in humans at the maximum recommended human dose (MRHD, 14 mg /day). In rat, teriflunomide was administered orally at doses up to 4 mg/kg/day for up to 97–104 weeks; plasma teriflunomide AUCs at the highest doses tested are less than that in humans at the MRHD.
- Teriflunomide was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and in in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive in an in vitro chromosomal aberration assay in human lymphocytes, with and without metabolic activation. Addition of uridine (to supplement the pyrimidine pool) reduced the magnitude of the clastogenic effect; however, teriflunomide was positive in the in vitro chromosomal aberration assay, even in the presence of uridine.
- 4-Trifluoromethylaniline (4-TFMA), a minor metabolite of teriflunomide, was positive in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and the in vitro chromosomal aberration assay in mammalian cells. 4-TFMA was negative in in vivo micronucleus and chromosomal aberration assays.
- Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a mg/m2 basis.
- Oral administration of teriflunomide (0, 0.84, 2.6, 8.6 mg/kg/day) to female rats, prior to and during mating (to untreated males) and continuing to gestation day 6, resulted in embryolethality, reduced fetal body weight, and/or malformations at all doses tested. Due to marked embryolethality at the highest dose tested, no fetuses were available for evaluation. The lowest dose tested is less than the MRHD on a mg/m2 basis.
# Clinical Studies
- Four randomized, controlled, double-blind clinical trials established the efficacy of AUBAGIO in patients with relapsing forms of multiple sclerosis.
- Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course, with or without progression, and to have experienced at least one relapse over the year preceding the trial or at least two relapses over the two years preceding the trial. Patients were required not to have received interferon-beta for at least four months, or any other multiple sclerosis medication for at least six months before entering the study, nor were these medications permitted during the study. Neurological evaluations were to be performed at screening, every 12 weeks until week 108, and after suspected relapses. MRI was to be performed at screening, and at Week 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR).
- In Study 1, 1088 patients were randomized to receive AUBAGIO 7 mg (n=366), AUBAGIO 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5. Patients had a mean age of 38 years, mean disease duration of 5 years, and mean EDSS at baseline of 2.7. A total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.
- There was a statistically significant reduction in ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg, compared to patients who received placebo (see Table 2). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.
- There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 2 and Figure 1).
- The effect of AUBAGIO on several magnetic resonance imaging (MRI) variables including the total lesion volume of T2 and hypointense T1 lesions, was assessed in Study 1. The change in total lesion volume from baseline was significantly lower in the AUBAGIO 7 mg and AUBAGIO 14 mg groups than in the placebo group. Patients in both AUBAGIO groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (see Table 2).
- Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course and to have experienced at least one relapse over the year preceding the trial, or at least two relapses over the two years preceding the trial. Patients were required not to have received any multiple sclerosis medication for at least three months before entering the trial, nor were these medications permitted during the trial. Neurological evaluations were to be performed at screening, every 12 weeks until completion, and after every suspected relapse. The primary end point was the ARR.
- A total of 1165 patients received AUBAGIO 7 mg (n=407), AUBAGIO 14 mg (n=370), or placebo (n=388). Patients had a mean age of 38 years, a mean disease duration of 5 years, and a mean EDSS at baseline of 2.7. A total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.
- There was a statistically significant reduction in the ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg compared to patients who received placebo (see Table 3). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.
- There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (See Table 3 and Figure 2).
- Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had a first clinical event consistent with acute demyelination occurring within 90 days of randomization with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of multiple sclerosis. A total of 614 patients received AUBAGIO 7 mg (n=203), AUBAGIO 14 mg (n=214), or placebo (n=197). Patients had a mean age of 32 years, EDSS at baseline of 1.7, and mean disease duration of two months. The proportion of patients free of relapse was greater in the AUBAGIO 7 mg (70.5%, p < 0.05) and AUBAGIO 14 mg (72.2%, p < 0.05) groups than in the placebo group (61.7%).
- The effect of AUBAGIO on MRI activity was also demonstrated in Study 4, a randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. A total of 179 patients were randomized to AUBAGIO 7 mg (n=61), AUBAGIO 14 mg (n=57), or placebo (n= 61). Baseline demographics were consistent across treatment groups. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with AUBAGIO 7 mg (1.06) and AUBAGIO 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0234 and p=0.0052, respectively).
# How Supplied
- AUBAGIO is available as 7 mg and 14 mg tablets.
- The 14 mg tablet is pale blue to pastel blue, pentagonal film-coated tablet with dose strength "14" imprinted on one side and engraved with corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.
- The 7 mg tablet is very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with corporate logo on other side. Each tablet contains 7 mg of teriflunomide.
## Storage
- Store at 68°F to 77°F (20°C to 25°C) with excursions permitted between 59°F and 86°F (15°C and 30°C).
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 58468-0210-2
Aubagio®
(teriflunomide)
Tablets
14 mg per Tablet
Rx only
Dispense with enclosed Medication Guide
28 tablets
genzyme
A SANOFI COMPANY
NDC 58468-0211-1
Aubagio®
(teriflunomide)
Tablets
7 mg per Tablet
Rx only
Dispense with enclosed Medication Guide
28 tablets
genzyme
A SANOFI COMPANY
### Ingredients and Appearance
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- A Medication Guide is required for distribution with AUBAGIO.
- Inform patients that AUBAGIO may increase liver enzymes and that their liver enzymes will be checked before starting AUBAGIO and for at least 6 months while they are taking AUBAGIO. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.
- Inform patients that based on animal studies, AUBAGIO may cause fetal harm.
- Advise women of childbearing potential of the need for effective contraception during AUBAGIO treatment and until completion of an accelerated elimination procedure. Advise them that an accelerated elimination procedure can be used at any time after the discontinuation of AUBAGIO.
- Instruct the patient that if she suspects or confirms pregnancy, she should immediately inform her physician. Inform the patients that an AUBAGIO pregnancy registry is available.
- Instruct men who are taking AUBAGIO and wish to father a child to discontinue AUBAGIO and use an accelerated elimination procedure. Instruct men taking AUBAGIO who do not wish to father a child that they and their female partners should use reliable contraception.
- Availability of an Accelerated Elimination Procedure
- Advise patients that AUBAGIO may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed.
- Inform patients that they may develop a lowering of their white blood cell counts and that their blood counts will be checked before starting AUBAGIO.
- Inform patients that they may be more likely to get infections when taking AUBAGIO and that they should contact their physician if they develop symptoms of infection, particularly in case of fever.
- Advise patients that the use of some vaccines should be avoided during treatment with AUBAGIO and for at least 6 months after discontinuation.
- Inform patients that they may develop peripheral neuropathy. Advise patients that they should contact their physician if they develop symptoms of peripheral neuropathy, such as numbness or tingling of hands or feet.
- Inform patients that AUBAGIO may increase blood pressure.
- Inform patients that it is not known whether this drug is present in human milk. Advise patients to discontinue breastfeeding or discontinue the drug.
### MEDICATION GUIDE
- Read this Medication Guide before you start using AUBAGIO and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.
- AUBAGIO may cause serious side effects, including:
- Liver problems: AUBAGIO may cause serious liver problems that may lead to death. Your risk of liver problems may be higher if you take other medicines that also affect your liver. Your doctor should do blood tests to check your liver:
- within 6 months before you start taking AUBAGIO
- 1 time a month for 6 months after you start taking AUBAGIO
- Call your doctor right away if you have any of the following symptoms of liver problems:
- nausea
- vomiting
- stomach pain
- loss of appetite
- tiredness
- your skin or the whites of your eyes turn yellow
- dark urine
- Harm to your unborn baby: AUBAGIO may cause harm to your unborn baby. Do not take AUBAGIO if you are pregnant. Do not take AUBAGIO unless you are using effective birth control.
- If you are a female, you should have a pregnancy test before you start taking AUBAGIO. Use effective birth control during your treatment with AUBAGIO.
- After stopping AUBAGIO, continue using effective birth control until you have blood tests to make sure your blood levels of AUBAGIO are low enough. If you become pregnant while taking AUBAGIO or within 2 years after you stop taking it, tell your doctor right away.
- AUBAGIO Pregnancy Registry. If you become pregnant while taking AUBAGIO or during the 2 years after you stop taking AUBAGIO, talk to your doctor about enrolling in the AUBAGIO Pregnancy Registry at 1-800-745-4447 FREE, option 2. The purpose of this registry is to collect information about your health and your baby's health.
- For men taking AUBAGIO:
- If your female partner plans to become pregnant, you should stop taking AUBAGIO and ask your doctor how to quickly lower the levels of AUBAGIO in your blood.
- If your female partner does not plan to become pregnant, you and your female partner should use effective birth control during your treatment with AUBAGIO. AUBAGIO remains in your blood after you stop taking it, so continue using effective birth control until AUBAGIO blood levels have been checked and they are low enough.
- AUBAGIO may stay in your blood for up to 2 years after you stop taking it. Your doctor can prescribe a medicine to help lower your blood levels of AUBAGIO more quickly. Talk to your doctor if you want more information about this.
- AUBAGIO is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS). AUBAGIO can decrease the number of MS flare-ups (relapses). AUBAGIO does not cure MS, but it can help slow down the physical problems that MS causes.
- It is not known if AUBAGIO is safe and effective in children.
- Do not take AUBAGIO if you:
- have severe liver problems
- are pregnant or are of childbearing age and not using effective birth control
- take a medicine called leflunomide
- Before you take AUBAGIO, tell your doctor if you:
- have liver or kidney problems
- have a fever or infection, or you are unable to fight infections
- have numbness or tingling in your hands or feet that is different from your MS symptoms
- have diabetes
- have had serious skin problems when taking other medicines
- have breathing problems
- have high blood pressure
- are breastfeeding or plan to breastfeed. It is not known if AUBAGIO passes into your breast milk. You and your doctor should decide if you will take AUBAGIO or breastfeed. You should not do both at the same time.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Using AUBAGIO and other medicines may affect each other causing serious side effects. AUBAGIO may affect the way other medicines work, and other medicines may affect how AUBAGIO works.
- Especially tell your doctor if you take medicines that could raise your chance of getting infections, including medicines used to treat cancer or to control your immune system.
- Ask your doctor or pharmacist for a list of these medicines if you are not sure.
- Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.
- Take AUBAGIO exactly as your doctor tells you to take it.
- Take AUBAGIO 1 time each day.
- Take AUBAGIO with or without food.
- AUBAGIO may cause serious side effects, including:
- See "What is the most important information I should know about AUBAGIO?"
- decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking AUBAGIO. When you have a low white blood cell count you:
- may have more frequent infections. You should have a skin test for TB (Tuberculosis) before you start taking AUBAGIO. Tell your doctor if you have any of these symptoms of an infection:
- fever
- tiredness
- body aches
- chills
- nausea
- vomiting
- should not receive certain vaccinations during your treatment with AUBAGIO and for 6 months after your treatment with AUBAGIO ends.
- numbness or tingling in your hands or feet that is different from your MS symptoms. You have a greater chance of getting peripheral neuropathy if you:
- are over 60 years of age
- take certain medicines that affect your nervous system
- have diabetes
- Tell your doctor if you have numbness or tingling in your hands or feet that is different from your MS.
- serious skin problems. Tell your doctor if you have any skin problems such as redness and peeling.
- new or worsening breathing problems. Tell your doctor if you have shortness of breath or coughing with or without fever.
- high blood pressure. Your doctor should check your blood pressure before you start taking AUBAGIO and while you are taking AUBAGIO.
- The most common side effects of AUBAGIO include:
- headache
- diarrhea
- nausea
- hair thinning or loss (alopecia)
- increases in the results of blood tests to check your liver function
- Tell your doctor if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of AUBAGIO. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-332-1088 FREE.
- Store AUBAGIO at room temperature between 68°F to 77°F (20°C to 25°C).
- Keep AUBAGIO and all medicines out of reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUBAGIO for a condition for which it was not prescribed. Do not give AUBAGIO to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about AUBAGIO. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AUBAGIO that is written for healthcare professionals.
- For more information, go to www.aubagio.com or call Genzyme Medical Information Services at 1-800-745-4447 FREE, option 2.
- Active ingredient: teriflunomide
- Inactive ingredients in 7 mg and 14 mg tablets: lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake.
- In addition, the 7 mg tablets also contain iron oxide yellow.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Teriflunomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aubagio®
# Look-Alike Drug Names
There is limited information regarding Teriflunomide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
|
Teriflunomide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Teriflunomide is a pyrimidine synthesis inhibitor that is FDA approved for the treatment of patients with relapsing forms of multiple sclerosis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, nausea, alopecia, increase in ALT.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.
### Dosage
- The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.
### DOSAGE FORMS AND STRENGTHS
- AUBAGIO is available as 7 mg and 14 mg tablets.
- The 14 mg tablet is a pale blue to pastel blue, pentagonal film-coated tablet with the dose strength, "14" imprinted on one side and engraved with the corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.
- The 7 mg tablet is a very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with the corporate logo on other side. Each tablet contains 7 mg of teriflunomide.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriflunomide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriflunomide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Teriflunomide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teriflunomide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teriflunomide in pediatric patients.
# Contraindications
- Patients with severe hepatic impairment .
- AUBAGIO may cause fetal harm when administered to a pregnant woman.
- In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity.
- AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling
- Co-administration of teriflunomide with leflunomide is contraindicated.
# Warnings
- Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment .
- In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving AUBAGIO 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment. Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.
- One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. AUBAGIO-induced liver injury in this patient could not be ruled out.
- Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue AUBAGIO and start an accelerated elimination procedure and monitor liver tests weekly until normalized. If AUBAGIO-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBAGIO therapy may be considered.
- There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman.
- Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception. Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO.
- Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk.
- Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures:
- If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.
- At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.
- Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.
- White Blood Cell (WBC) count decrease
- A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO compared to baseline. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8×109/L was observed in 10% and 12% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide. A similar risk would be expected for AUBAGIO. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.
- Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.
- AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like AUBAGIO that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.
- In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.
- In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection. AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown. For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO.
- No clinical data are available on the efficacy and safety of live vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO.
- The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO.
- In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking AUBAGIO than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.4% (13 patients) and 1.9% (17 patients) of patients receiving 7 mg and 14 mg of AUBAGIO, respectively, compared with 0.4% receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with confirmed peripheral neuropathy (3 patients receiving AUBAGIO 7 mg and 5 patients receiving AUBAGIO 14 mg). Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment. Peripheral neuropathy also occurred in patients receiving leflunomide.
- Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure.
- Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for AUBAGIO . If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure.
- In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of AUBAGIO compared with 1.8% for placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO.
- Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for AUBAGIO. Interstitial lung disease may be fatal. Interstitial lung disease may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure.
- Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.
- In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are described elsewhere in the prescribing information:
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.
- Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively).
- Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established.
- In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance.
- In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Teriflunomide in the drug label.
# Drug Interactions
- Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required .
- Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.
- AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with AUBAGIO.
- Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required .
- Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required .
- Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking AUBAGIO
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity. Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the no-effect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).
- Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD.
- In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity. Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD.
- In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
- AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL).
- Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447 FREE
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Teriflunomide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Teriflunomide during labor and delivery.
### Nursing Mothers
- Teriflunomide was detected in rat milk following a single oral dose of teriflunomide. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of AUBAGIO did not include patients over 65 years old.
### Gender
There is no FDA guidance on the use of Teriflunomide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Teriflunomide with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment
### Hepatic Impairment
- No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Teriflunomide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Teriflunomide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO.
- Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection.
- Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection.
- Check blood pressure before start of AUBAGIO treatment and periodically thereafter
# IV Compatibility
There is limited information regarding IV Compatibility of Teriflunomide in the drug label.
# Overdosage
- There is no experience regarding teriflunomide overdose or intoxication in humans. Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.
- In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination
# Pharmacology
## Mechanism of Action
- Teriflunomide, an immunomodulatory agent with anti-inflammatory properties, inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in de novo pyrimidine synthesis. The exact mechanism by which teriflunomide exerts its therapeutic effect in multiple sclerosis is unknown but may involve a reduction in the number of activated lymphocytes in CNS.
## Structure
- AUBAGIO (teriflunomide) is an oral de novo pyrimidine synthesis inhibitor of the DHO-DH enzyme, with the chemical name (Z)-2-Cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide. Its molecular weight is 270.21, and the empirical formula is C12H9F3N2O2 with the following chemical structure:
## Pharmacodynamics
- In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that teriflunomide caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).
## Pharmacokinetics
- Teriflunomide is the principal active metabolite of leflunomide and is responsible for leflunomide's activity in vivo. At recommended doses, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.
- Based on a population analysis of teriflunomide in healthy volunteers and MS patients, median t1/2 was approximately 18 and 19 days after repeated doses of 7 mg and 14 mg respectively. It takes approximately 3 months respectively to reach steady-state concentrations. The estimated AUC accumulation ratio is approximately 30 after repeated doses of 7 or 14 mg.
- Median time to reach maximum plasma concentrations is between 1 to 4 hours post-dose following oral administration of teriflunomide.
- Food does not have a clinically relevant effect on teriflunomide pharmacokinetics.
- Teriflunomide is extensively bound to plasma protein (>99%) and is mainly distributed in plasma. The volume of distribution is 11 L after a single intravenous (IV) administration.
- Teriflunomide is the major circulating moiety detected in plasma. The primary biotransformation pathway to minor metabolites of teriflunomide is hydrolysis, with oxidation being a minor pathway. Secondary pathways involve oxidation, N-acetylation and sulfate conjugation.
- Teriflunomide is eliminated mainly through direct biliary excretion of unchanged drug as well as renal excretion of metabolites. Over 21 days, 60.1% of the administered dose is excreted via feces (37.5%) and urine (22.6%). After an accelerated elimination procedure with cholestyramine, an additional 23.1% was recovered (mostly in feces). After a single IV administration, the total body clearance of teriflunomide is 30.5 mL/h.
- Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes.
- The Potential Effect of AUBAGIO on Other Drugs
- CYP2C8 Substrates
- There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, respectively), following repeated doses of teriflunomide and a single dose of 0.25 mg repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The magnitude of interaction could be higher at the recommended repaglinide dose [see Drug Interactions (7)].
- CYP1A2 Substrates
- Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% and 55%, respectively, suggesting that teriflunomide may be a weak inducer of CYP1A2 in vivo.
- OAT3 Substrates
- There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, respectively), following repeated doses of teriflunomide, suggesting that teriflunomide is an inhibitor of organic anion transporter 3 (OAT3) in vivo.
- BCRP and OATP1B1/1B3 Substrates
- There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, respectively), following repeated doses of teriflunomide , suggesting that teriflunomide is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3).
- Oral Contraceptives
- There was an increase in mean ethinylestradiol Cmax and AUC0–24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0–24 (1.33- and 1.41-fold, respectively) following repeated doses of teriflunomide .
- Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 substrate), and metoprolol (a CYP2D6 substrate).
- The Potential Effect of Other Drugs on AUBAGIO
- Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of teriflunomide.
- Hepatic Impairment
- Mild and moderate hepatic impairment had no impact on the pharmacokinetics of teriflunomide. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated.
- Renal Impairment
- Severe renal impairment had no impact on the pharmacokinetics of teriflunomide .
- Gender
- In a population analysis, the clearance rate for teriflunomide is 23% less in females than in males.
- Race
- Effect of race on the pharmacokinetics of teriflunomide cannot be adequately assessed due to a low number of non-white patients in the clinical trials.
## Nonclinical Toxicology
- No evidence of carcinogenicity was observed in lifetime carcinogenicity bioassays in mouse and rat. In mouse, teriflunomide was administered orally at doses up to 12 mg/kg/day for up to 95–104 weeks; plasma teriflunomide exposures (AUC) at the highest dose tested are approximately 3 times that in humans at the maximum recommended human dose (MRHD, 14 mg /day). In rat, teriflunomide was administered orally at doses up to 4 mg/kg/day for up to 97–104 weeks; plasma teriflunomide AUCs at the highest doses tested are less than that in humans at the MRHD.
- Teriflunomide was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and in in vivo micronucleus and chromosomal aberration assays. Teriflunomide was positive in an in vitro chromosomal aberration assay in human lymphocytes, with and without metabolic activation. Addition of uridine (to supplement the pyrimidine pool) reduced the magnitude of the clastogenic effect; however, teriflunomide was positive in the in vitro chromosomal aberration assay, even in the presence of uridine.
- 4-Trifluoromethylaniline (4-TFMA), a minor metabolite of teriflunomide, was positive in the in vitro bacterial reverse mutation (Ames) assay, the in vitro HPRT assay, and the in vitro chromosomal aberration assay in mammalian cells. 4-TFMA was negative in in vivo micronucleus and chromosomal aberration assays.
- Oral administration of teriflunomide (0, 1, 3, 10 mg/kg/day) to male rats prior to and during mating (to untreated females) resulted in no adverse effects on fertility; however, reduced epididymal sperm count was observed at the mid and high doses tested. The no-effect dose for reproductive toxicity in male rats (1 mg/kg) is less than the MRHD on a mg/m2 basis.
- Oral administration of teriflunomide (0, 0.84, 2.6, 8.6 mg/kg/day) to female rats, prior to and during mating (to untreated males) and continuing to gestation day 6, resulted in embryolethality, reduced fetal body weight, and/or malformations at all doses tested. Due to marked embryolethality at the highest dose tested, no fetuses were available for evaluation. The lowest dose tested is less than the MRHD on a mg/m2 basis.
# Clinical Studies
- Four randomized, controlled, double-blind clinical trials established the efficacy of AUBAGIO in patients with relapsing forms of multiple sclerosis.
- Study 1 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 26 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course, with or without progression, and to have experienced at least one relapse over the year preceding the trial or at least two relapses over the two years preceding the trial. Patients were required not to have received interferon-beta for at least four months, or any other multiple sclerosis medication for at least six months before entering the study, nor were these medications permitted during the study. Neurological evaluations were to be performed at screening, every 12 weeks until week 108, and after suspected relapses. MRI was to be performed at screening, and at Week 24, 48, 72, and 108. The primary endpoint was the annualized relapse rate (ARR).
- In Study 1, 1088 patients were randomized to receive AUBAGIO 7 mg (n=366), AUBAGIO 14 mg (n=359), or placebo (n=363). At entry, patients had an Expanded Disability Status Scale (EDSS) score ≤5.5. Patients had a mean age of 38 years, mean disease duration of 5 years, and mean EDSS at baseline of 2.7. A total of 91% of patients had relapsing remitting multiple sclerosis, and 9% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 635, 627, and 631 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 75%, 73%, and 71% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.
- There was a statistically significant reduction in ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg, compared to patients who received placebo (see Table 2). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.
- There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (see Table 2 and Figure 1).
- The effect of AUBAGIO on several magnetic resonance imaging (MRI) variables including the total lesion volume of T2 and hypointense T1 lesions, was assessed in Study 1. The change in total lesion volume from baseline was significantly lower in the AUBAGIO 7 mg and AUBAGIO 14 mg groups than in the placebo group. Patients in both AUBAGIO groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (see Table 2).
- Study 2 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 40 months in patients with relapsing forms of multiple sclerosis. Patients were required to have a diagnosis of multiple sclerosis exhibiting a relapsing clinical course and to have experienced at least one relapse over the year preceding the trial, or at least two relapses over the two years preceding the trial. Patients were required not to have received any multiple sclerosis medication for at least three months before entering the trial, nor were these medications permitted during the trial. Neurological evaluations were to be performed at screening, every 12 weeks until completion, and after every suspected relapse. The primary end point was the ARR.
- A total of 1165 patients received AUBAGIO 7 mg (n=407), AUBAGIO 14 mg (n=370), or placebo (n=388). Patients had a mean age of 38 years, a mean disease duration of 5 years, and a mean EDSS at baseline of 2.7. A total of 98% of patients had relapsing remitting multiple sclerosis, and 2% had a progressive form of multiple sclerosis with relapses. The mean duration of treatment was 552, 567, and 571 days for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively. The percentage of patients who completed the study treatment period was 67%, 66%, and 68% for AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo, respectively.
- There was a statistically significant reduction in the ARR for patients who received AUBAGIO 7 mg or AUBAGIO 14 mg compared to patients who received placebo (see Table 3). There was a consistent reduction of the ARR noted in subgroups defined by sex, age group, prior multiple sclerosis therapy, and baseline disease activity.
- There was a statistically significant reduction in the relative risk of disability progression at week 108 sustained for 12 weeks (as measured by at least a 1-point increase from baseline EDSS ≤ 5.5 or a 0.5 point increase for those with a baseline EDSS > 5.5) in the AUBAGIO 14 mg group compared to placebo (See Table 3 and Figure 2).
- Study 3 was a double-blind, placebo-controlled clinical trial that evaluated once daily doses of AUBAGIO 7 mg and AUBAGIO 14 mg for up to 108 weeks in patients with relapsing multiple sclerosis. Patients were required to have had a first clinical event consistent with acute demyelination occurring within 90 days of randomization with 2 or more T2 lesions at least 3 mm in diameter that were characteristic of multiple sclerosis. A total of 614 patients received AUBAGIO 7 mg (n=203), AUBAGIO 14 mg (n=214), or placebo (n=197). Patients had a mean age of 32 years, EDSS at baseline of 1.7, and mean disease duration of two months. The proportion of patients free of relapse was greater in the AUBAGIO 7 mg (70.5%, p < 0.05) and AUBAGIO 14 mg (72.2%, p < 0.05) groups than in the placebo group (61.7%).
- The effect of AUBAGIO on MRI activity was also demonstrated in Study 4, a randomized, double-blind, placebo-controlled clinical trial of multiple sclerosis patients with relapse. In Study 4, MRI was to be performed at baseline, 6 weeks, 12 weeks, 18 weeks, 24 weeks, 30 weeks, and 36 weeks after treatment initiation. A total of 179 patients were randomized to AUBAGIO 7 mg (n=61), AUBAGIO 14 mg (n=57), or placebo (n= 61). Baseline demographics were consistent across treatment groups. The primary endpoint was the average number of unique active lesions/MRI scan during treatment. The mean number of unique active lesions per brain MRI scan during the 36-week treatment period was lower in patients treated with AUBAGIO 7 mg (1.06) and AUBAGIO 14 mg (0.98) as compared to placebo (2.69), the difference being statistically significant for both (p=0.0234 and p=0.0052, respectively).
# How Supplied
- AUBAGIO is available as 7 mg and 14 mg tablets.
- The 14 mg tablet is pale blue to pastel blue, pentagonal film-coated tablet with dose strength "14" imprinted on one side and engraved with corporate logo on the other side. Each tablet contains 14 mg of teriflunomide.
- The 7 mg tablet is very light greenish-bluish grey to pale greenish-blue, hexagonal film-coated tablet with dose strength "7" imprinted on one side and engraved with corporate logo on other side. Each tablet contains 7 mg of teriflunomide.
## Storage
- Store at 68°F to 77°F (20°C to 25°C) with excursions permitted between 59°F and 86°F (15°C and 30°C).
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 58468-0210-2
Aubagio®
(teriflunomide)
Tablets
14 mg per Tablet
Rx only
Dispense with enclosed Medication Guide
28 tablets
genzyme
A SANOFI COMPANY
NDC 58468-0211-1
Aubagio®
(teriflunomide)
Tablets
7 mg per Tablet
Rx only
Dispense with enclosed Medication Guide
28 tablets
genzyme
A SANOFI COMPANY
### Ingredients and Appearance
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Medication Guide).
- A Medication Guide is required for distribution with AUBAGIO.
- Inform patients that AUBAGIO may increase liver enzymes and that their liver enzymes will be checked before starting AUBAGIO and for at least 6 months while they are taking AUBAGIO. Advise patients that they should contact their physician if they have any unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.
- Inform patients that based on animal studies, AUBAGIO may cause fetal harm.
- Advise women of childbearing potential of the need for effective contraception during AUBAGIO treatment and until completion of an accelerated elimination procedure. Advise them that an accelerated elimination procedure can be used at any time after the discontinuation of AUBAGIO.
- Instruct the patient that if she suspects or confirms pregnancy, she should immediately inform her physician. Inform the patients that an AUBAGIO pregnancy registry is available.
- Instruct men who are taking AUBAGIO and wish to father a child to discontinue AUBAGIO and use an accelerated elimination procedure. Instruct men taking AUBAGIO who do not wish to father a child that they and their female partners should use reliable contraception.
- Availability of an Accelerated Elimination Procedure
- Advise patients that AUBAGIO may stay in the blood for up to 2 years after the last dose and that an accelerated elimination procedure may be used if needed.
- Inform patients that they may develop a lowering of their white blood cell counts and that their blood counts will be checked before starting AUBAGIO.
- Inform patients that they may be more likely to get infections when taking AUBAGIO and that they should contact their physician if they develop symptoms of infection, particularly in case of fever.
- Advise patients that the use of some vaccines should be avoided during treatment with AUBAGIO and for at least 6 months after discontinuation.
- Inform patients that they may develop peripheral neuropathy. Advise patients that they should contact their physician if they develop symptoms of peripheral neuropathy, such as numbness or tingling of hands or feet.
- Inform patients that AUBAGIO may increase blood pressure.
- Inform patients that it is not known whether this drug is present in human milk. Advise patients to discontinue breastfeeding or discontinue the drug.
### MEDICATION GUIDE
- Read this Medication Guide before you start using AUBAGIO and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.
- AUBAGIO may cause serious side effects, including:
- Liver problems: AUBAGIO may cause serious liver problems that may lead to death. Your risk of liver problems may be higher if you take other medicines that also affect your liver. Your doctor should do blood tests to check your liver:
- within 6 months before you start taking AUBAGIO
- 1 time a month for 6 months after you start taking AUBAGIO
- Call your doctor right away if you have any of the following symptoms of liver problems:
- nausea
- vomiting
- stomach pain
- loss of appetite
- tiredness
- your skin or the whites of your eyes turn yellow
- dark urine
- Harm to your unborn baby: AUBAGIO may cause harm to your unborn baby. Do not take AUBAGIO if you are pregnant. Do not take AUBAGIO unless you are using effective birth control.
- If you are a female, you should have a pregnancy test before you start taking AUBAGIO. Use effective birth control during your treatment with AUBAGIO.
- After stopping AUBAGIO, continue using effective birth control until you have blood tests to make sure your blood levels of AUBAGIO are low enough. If you become pregnant while taking AUBAGIO or within 2 years after you stop taking it, tell your doctor right away.
- AUBAGIO Pregnancy Registry. If you become pregnant while taking AUBAGIO or during the 2 years after you stop taking AUBAGIO, talk to your doctor about enrolling in the AUBAGIO Pregnancy Registry at 1-800-745-4447 FREE, option 2. The purpose of this registry is to collect information about your health and your baby's health.
- For men taking AUBAGIO:
- If your female partner plans to become pregnant, you should stop taking AUBAGIO and ask your doctor how to quickly lower the levels of AUBAGIO in your blood.
- If your female partner does not plan to become pregnant, you and your female partner should use effective birth control during your treatment with AUBAGIO. AUBAGIO remains in your blood after you stop taking it, so continue using effective birth control until AUBAGIO blood levels have been checked and they are low enough.
- AUBAGIO may stay in your blood for up to 2 years after you stop taking it. Your doctor can prescribe a medicine to help lower your blood levels of AUBAGIO more quickly. Talk to your doctor if you want more information about this.
- AUBAGIO is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS). AUBAGIO can decrease the number of MS flare-ups (relapses). AUBAGIO does not cure MS, but it can help slow down the physical problems that MS causes.
- It is not known if AUBAGIO is safe and effective in children.
- Do not take AUBAGIO if you:
- have severe liver problems
- are pregnant or are of childbearing age and not using effective birth control
- take a medicine called leflunomide
- Before you take AUBAGIO, tell your doctor if you:
- have liver or kidney problems
- have a fever or infection, or you are unable to fight infections
- have numbness or tingling in your hands or feet that is different from your MS symptoms
- have diabetes
- have had serious skin problems when taking other medicines
- have breathing problems
- have high blood pressure
- are breastfeeding or plan to breastfeed. It is not known if AUBAGIO passes into your breast milk. You and your doctor should decide if you will take AUBAGIO or breastfeed. You should not do both at the same time.
- Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
- Using AUBAGIO and other medicines may affect each other causing serious side effects. AUBAGIO may affect the way other medicines work, and other medicines may affect how AUBAGIO works.
- Especially tell your doctor if you take medicines that could raise your chance of getting infections, including medicines used to treat cancer or to control your immune system.
- Ask your doctor or pharmacist for a list of these medicines if you are not sure.
- Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.
- Take AUBAGIO exactly as your doctor tells you to take it.
- Take AUBAGIO 1 time each day.
- Take AUBAGIO with or without food.
- AUBAGIO may cause serious side effects, including:
- See "What is the most important information I should know about AUBAGIO?"
- decreases in your white blood cell count. Your white blood cell counts should be checked before you start taking AUBAGIO. When you have a low white blood cell count you:
- may have more frequent infections. You should have a skin test for TB (Tuberculosis) before you start taking AUBAGIO. Tell your doctor if you have any of these symptoms of an infection:
- fever
- tiredness
- body aches
- chills
- nausea
- vomiting
- should not receive certain vaccinations during your treatment with AUBAGIO and for 6 months after your treatment with AUBAGIO ends.
- numbness or tingling in your hands or feet that is different from your MS symptoms. You have a greater chance of getting peripheral neuropathy if you:
- are over 60 years of age
- take certain medicines that affect your nervous system
- have diabetes
- Tell your doctor if you have numbness or tingling in your hands or feet that is different from your MS.
- serious skin problems. Tell your doctor if you have any skin problems such as redness and peeling.
- new or worsening breathing problems. Tell your doctor if you have shortness of breath or coughing with or without fever.
- high blood pressure. Your doctor should check your blood pressure before you start taking AUBAGIO and while you are taking AUBAGIO.
- The most common side effects of AUBAGIO include:
- headache
- diarrhea
- nausea
- hair thinning or loss (alopecia)
- increases in the results of blood tests to check your liver function
- Tell your doctor if you have any side effect that bothers you or that does not go away.
- These are not all the possible side effects of AUBAGIO. For more information, ask your doctor or pharmacist.
- Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-332-1088 FREE.
- Store AUBAGIO at room temperature between 68°F to 77°F (20°C to 25°C).
- Keep AUBAGIO and all medicines out of reach of children.
- Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUBAGIO for a condition for which it was not prescribed. Do not give AUBAGIO to other people, even if they have the same symptoms you have. It may harm them.
- This Medication Guide summarizes the most important information about AUBAGIO. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about AUBAGIO that is written for healthcare professionals.
- For more information, go to www.aubagio.com or call Genzyme Medical Information Services at 1-800-745-4447 FREE, option 2.
- Active ingredient: teriflunomide
- Inactive ingredients in 7 mg and 14 mg tablets: lactose monohydrate, corn starch, hydroxypropylcellulose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hypromellose, titanium dioxide, talc, polyethylene glycol and indigo carmine aluminum lake.
- In addition, the 7 mg tablets also contain iron oxide yellow.
- This Medication Guide has been approved by the U.S. Food and Drug Administration.
# Precautions with Alcohol
- Alcohol-Teriflunomide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aubagio®[1]
# Look-Alike Drug Names
There is limited information regarding Teriflunomide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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Ternary logic
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Ternary logic
A ternary, three-valued or trivalent logic is a term to describe any of several multi-valued logic systems in which there are three truth values indicating true, false and some third value. This is contrasted with the more commonly known bivalent logics (such as boolean logic) which provide only for true and false.
# Definitions
## Representation of values
As with bivalent logic, truth values in ternary logic may be represented numerically using various representations of the ternary numeral system. A few of the more common examples are:
- 1 for true, 2 for false, and 0 for unknown, irrelevant, or both.
- 0 for false, 1 for true, with the third value being non-integer symbol such as # or ½.
- Balanced ternary uses -1 for false, 1 for true and 0 for the third value; these values may also be simplified to -, +, and 0, respectively.
This article mainly illustrates a system of ternary propositional logic using the truth values {false, unknown, and true}, and extends conventional boolean connectives to a trivalent context. Ternary predicate logics exist as well; these may have readings of the quantifier different from classical (binary) predicate logic, and may include alternative quantifiers as well.
# Basic truth table
Below is a truth table showing the results of some logic operations for a true/false/unknown state system.
In this truth table, the UNKNOWN state can be metaphorically thought of as a sealed box containing either an unambiguously TRUE or unambiguously FALSE value. The knowledge of whether any particular UNKNOWN state secretly represents TRUE or FALSE at any moment in time is not available. However, certain logical operations can yield an unambiguous result, even if they involve at least one UNKNOWN operand. For example, since TRUE OR TRUE equals TRUE, and TRUE OR FALSE also equals TRUE, one can infer that TRUE OR UNKNOWN equals TRUE, as well. In this example, since either bivalent state could be underlying the UNKNOWN state, but either state also yields the same result, a definitive TRUE results in all three cases.
# Ternary logic in database applications
The database structural query language SQL implements ternary logic as a means of handling NULL field content. SQL uses NULL to represent missing data in a database. If a field contains no defined value, SQL assumes this means that an actual value exists, but that value is not currently recorded in the database. Note that a missing value is not the same as either a numeric value of zero, or a string value of zero length. Comparing anything to NULL—even another NULL—results in an UNKNOWN truth state (which happens to also be represented by a NULL value). For example, the SQL expression "City = 'Paris'" resolves to FALSE for a record with "Chicago" in the City field, but it resolves to UNKNOWN for a record with a NULL City field. In other words, to SQL, an undefined field represents potentially any possible value: a missing city might or might not represent Paris.
Using ternary logic, SQL can then account for the UNKNOWN truth state in evaluating boolean expressions. Consider the expression "City = 'Paris' OR Balance < 0.0". This expression resolves to TRUE for any record whose Balance field contains a negative number. Likewise, this expression is TRUE for any record with 'Paris' in its City field. The expression resolves to FALSE only for a record whose City field explicitly contains a string other than 'Paris', and whose Balance field explicitly contains a non-negative number. In any other case, the expression resolves to UNKNOWN. This is because a missing City value might be missing the string 'Paris', and a missing Balance might be missing a negative number. However, regardless of missing data, a boolean OR operation is FALSE only when both of its operands are also FALSE, so not all missing data leads to an UNKNOWN resolution.
In SQL Data Manipulation Language, a truth state of TRUE for an expression (e.g. in a WHERE clause) initiates an action on a row (e.g. return the row), while a truth state of UNKNOWN or FALSE does not. In this way, ternary logic is implemented in SQL, while behaving as binary logic to the SQL user.
SQL Check Constraints behave differently, however. Only a truth state of FALSE results in a violation of a check constraint. A truth state of TRUE or UNKNOWN indicates a row has been successfully validated against the check constraint.
An in-depth discussion of the SQL implementation of ternary logic is available in the article on Null.
## Truth table for AND operator
# Electronics
Digital electronics theory supports four distinct logic values:
- 1 or High, also H, usually representing TRUE.
- 0 or Low, also L, usually representing FALSE.
- X representing "Unknown", "Don't Know", or "Don't Care".
- Z representing "High Impedance", or a disconnected input.
The "X" value does not exist in real-world circuits, it is merely a placeholder used in simulators and for design purposes. Some simulators support representation of the "Z" value, others do not. The "Z" value does exist in real-world circuits but only as an output state.
## Use of "X" value in simulation
Many hardware description language (HDL) simulation tools, such as verilog and VHDL, support an unknown value like that shown above during simulation of digital electronics. The unknown value may be the result of a design error, which the designer can correct before synthesis into an actual circuit. The unknown also represents uninitialised memory values and circuit inputs before the simulation has asserted what the real input value should be.
HDL synthesis tools usually produce circuits that operate only on binary logic.
## Use of "X" value in digital design
When designing a digital circuit, some conditions may be outside the scope of the purpose that the circuit will perform. Thus, the designer does not care what happens under those conditions. In addition, the situation occurs that inputs to a circuit are masked by other signals so the value of that input has no effect on circuit behaviour.
In these situations, it is traditional to use "X" as a placeholder to indicate "Don't Care" when building truth tables. This is especially common in state machine design and Karnaugh map simplification. The "X" values provide additional degrees of freedom to the final circuit design, generally resulting in a simplified and smaller circuit.
Once the circuit design is complete and a real circuit is constructed, the "X" values will no longer exist. They will become some tangible "0" or "1" value but could be either depending on the final design optimisation.
## Use of "Z" value for high impedance
Some digital devices support a form of three-state logic on their outputs only. The three states are "0", "1", and "Z".
Commonly referred to as tristate logic (a trademark of National Semiconductor), it comprises the usual true and false states, with a third transparent high impedance state (or 'off-state') which effectively disconnects the logic output. This provides an effective way to connect several logic outputs to a single input, where all but one are put into the high impedance state, allowing the remaining output to operate in the normal binary sense. This is commonly used to connect banks of computer memory and other similar devices to a common data bus; a large number of devices can communicate over the same channel simply by ensuring only one is enabled at a time.
It is important to note that while outputs can have one of three states, yet inputs can only recognise two. Hence the kind of relations shown in the table above do not occur. Although it could be argued that the high-impedance state is effectively an "unknown", there is absolutely no provision in the vast majority of normal electronics to interpret a high-impedance state as a state in itself. Inputs can only detect "0" and "1".
When a digital input is left disconnected (i.e. when it is given a high impedance signal), the digital value interpreted by the input depends on the type of technology used. TTL technology will reliably default to a "1" state. On the other hand CMOS technology will temporarily hold the previous state seen on that input (due to the capacitance of the gate input). Over time, leakage current causes the CMOS input to drift in a random direction, possibly causing the input state to flip. Disconnected inputs on CMOS devices can pickup noise, they can cause oscillation, the supply current may dramatically increase (crowbar power) or the device may completely destroy itself.
## Exotic ternary-logic devices
True ternary logic can be implemented in electronics, although the complexity of design has thus far made it uneconomical to pursue commercially and interest has been primarily confined to research, since 'normal' binary logic is very much cheaper to implement and in most cases can easily be configured to emulate ternary systems. However, there are useful applications in fuzzy logic and error correction, and several true ternary logic devices have been manufactured (see external links).
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Ternary logic
A ternary, three-valued or trivalent logic is a term to describe any of several multi-valued logic systems in which there are three truth values indicating true, false and some third value. This is contrasted with the more commonly known bivalent logics (such as boolean logic) which provide only for true and false.
# Definitions
## Representation of values
As with bivalent logic, truth values in ternary logic may be represented numerically using various representations of the ternary numeral system. A few of the more common examples are:
- 1 for true, 2 for false, and 0 for unknown, irrelevant, or both.[1]
- 0 for false, 1 for true, with the third value being non-integer symbol such as # or ½.[2]
- Balanced ternary uses -1 for false, 1 for true and 0 for the third value; these values may also be simplified to -, +, and 0, respectively.[3]
This article mainly illustrates a system of ternary propositional logic using the truth values {false, unknown, and true}, and extends conventional boolean connectives to a trivalent context. Ternary predicate logics exist as well[citation needed]; these may have readings of the quantifier different from classical (binary) predicate logic, and may include alternative quantifiers as well.
# Basic truth table
Below is a truth table showing the results of some logic operations for a true/false/unknown state system.
In this truth table, the UNKNOWN state can be metaphorically thought of as a sealed box containing either an unambiguously TRUE or unambiguously FALSE value. The knowledge of whether any particular UNKNOWN state secretly represents TRUE or FALSE at any moment in time is not available. However, certain logical operations can yield an unambiguous result, even if they involve at least one UNKNOWN operand. For example, since TRUE OR TRUE equals TRUE, and TRUE OR FALSE also equals TRUE, one can infer that TRUE OR UNKNOWN equals TRUE, as well. In this example, since either bivalent state could be underlying the UNKNOWN state, but either state also yields the same result, a definitive TRUE results in all three cases.
# Ternary logic in database applications
The database structural query language SQL implements ternary logic as a means of handling NULL field content. SQL uses NULL to represent missing data in a database. If a field contains no defined value, SQL assumes this means that an actual value exists, but that value is not currently recorded in the database. Note that a missing value is not the same as either a numeric value of zero, or a string value of zero length. Comparing anything to NULL—even another NULL—results in an UNKNOWN truth state (which happens to also be represented by a NULL value). For example, the SQL expression "City = 'Paris'" resolves to FALSE for a record with "Chicago" in the City field, but it resolves to UNKNOWN for a record with a NULL City field. In other words, to SQL, an undefined field represents potentially any possible value: a missing city might or might not represent Paris.
Using ternary logic, SQL can then account for the UNKNOWN truth state in evaluating boolean expressions. Consider the expression "City = 'Paris' OR Balance < 0.0". This expression resolves to TRUE for any record whose Balance field contains a negative number. Likewise, this expression is TRUE for any record with 'Paris' in its City field. The expression resolves to FALSE only for a record whose City field explicitly contains a string other than 'Paris', and whose Balance field explicitly contains a non-negative number. In any other case, the expression resolves to UNKNOWN. This is because a missing City value might be missing the string 'Paris', and a missing Balance might be missing a negative number. However, regardless of missing data, a boolean OR operation is FALSE only when both of its operands are also FALSE, so not all missing data leads to an UNKNOWN resolution.
In SQL Data Manipulation Language, a truth state of TRUE for an expression (e.g. in a WHERE clause) initiates an action on a row (e.g. return the row), while a truth state of UNKNOWN or FALSE does not.[4] In this way, ternary logic is implemented in SQL, while behaving as binary logic to the SQL user.
SQL Check Constraints behave differently, however. Only a truth state of FALSE results in a violation of a check constraint. A truth state of TRUE or UNKNOWN indicates a row has been successfully validated against the check constraint[5].
An in-depth discussion of the SQL implementation of ternary logic is available in the article on Null.
## Truth table for AND operator
# Electronics
Digital electronics theory supports four distinct logic values:
- 1 or High, also H, usually representing TRUE.
- 0 or Low, also L, usually representing FALSE.
- X representing "Unknown", "Don't Know", or "Don't Care".
- Z representing "High Impedance", or a disconnected input.
The "X" value does not exist in real-world circuits, it is merely a placeholder used in simulators and for design purposes. Some simulators support representation of the "Z" value, others do not. The "Z" value does exist in real-world circuits but only as an output state.
## Use of "X" value in simulation
Many hardware description language (HDL) simulation tools, such as verilog and VHDL, support an unknown value like that shown above during simulation of digital electronics. The unknown value may be the result of a design error, which the designer can correct before synthesis into an actual circuit. The unknown also represents uninitialised memory values and circuit inputs before the simulation has asserted what the real input value should be.
HDL synthesis tools usually produce circuits that operate only on binary logic.
## Use of "X" value in digital design
When designing a digital circuit, some conditions may be outside the scope of the purpose that the circuit will perform. Thus, the designer does not care what happens under those conditions. In addition, the situation occurs that inputs to a circuit are masked by other signals so the value of that input has no effect on circuit behaviour.
In these situations, it is traditional to use "X" as a placeholder to indicate "Don't Care" when building truth tables. This is especially common in state machine design and Karnaugh map simplification. The "X" values provide additional degrees of freedom to the final circuit design, generally resulting in a simplified and smaller circuit.[6]
Once the circuit design is complete and a real circuit is constructed, the "X" values will no longer exist. They will become some tangible "0" or "1" value but could be either depending on the final design optimisation.
## Use of "Z" value for high impedance
Some digital devices support a form of three-state logic on their outputs only. The three states are "0", "1", and "Z".
Commonly referred to as tristate [7] logic (a trademark of National Semiconductor), it comprises the usual true and false states, with a third transparent high impedance state (or 'off-state') which effectively disconnects the logic output. This provides an effective way to connect several logic outputs to a single input, where all but one are put into the high impedance state, allowing the remaining output to operate in the normal binary sense. This is commonly used to connect banks of computer memory and other similar devices to a common data bus; a large number of devices can communicate over the same channel simply by ensuring only one is enabled at a time.
It is important to note that while outputs can have one of three states, yet inputs can only recognise two. Hence the kind of relations shown in the table above do not occur. Although it could be argued that the high-impedance state is effectively an "unknown", there is absolutely no provision in the vast majority of normal electronics to interpret a high-impedance state as a state in itself. Inputs can only detect "0" and "1".
When a digital input is left disconnected (i.e. when it is given a high impedance signal), the digital value interpreted by the input depends on the type of technology used. TTL technology will reliably default to a "1" state. On the other hand CMOS technology will temporarily hold the previous state seen on that input (due to the capacitance of the gate input). Over time, leakage current causes the CMOS input to drift in a random direction, possibly causing the input state to flip. Disconnected inputs on CMOS devices can pickup noise, they can cause oscillation, the supply current may dramatically increase (crowbar power) or the device may completely destroy itself.
## Exotic ternary-logic devices
True ternary logic can be implemented in electronics, although the complexity of design has thus far made it uneconomical to pursue commercially and interest has been primarily confined to research, since 'normal' binary logic is very much cheaper to implement and in most cases can easily be configured to emulate ternary systems. However, there are useful applications in fuzzy logic and error correction, and several true ternary logic devices have been manufactured (see external links).
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678a1b626411319798c4f50a904bd4f553bbca78
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Terry's nails
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Terry's nails
# Overview
Terry's nails is a physical finding in which fingernails and/or toenails appear white with a characteristic "ground glass" appearance, with no lunula.
# Pathophysiology
## Associated Conditions
It frequently occurs in the setting of the following conditions.
- Aging
- Cancer
- Cirrhosis
- Congestive heart failure
- Diabetes mellitus
- Hepatic failure
- Hyperthyroidism
- Malnutrition
Eighty percent of patients with severe liver disease have Terry's nails.
# Causes
## Common Causes
The condition is thought to be due to a decrease in vascularity and an increase in connective tissue within the nail bed.
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Terry's nails
Template:DiseaseDisorder infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Terry's nails is a physical finding in which fingernails and/or toenails appear white with a characteristic "ground glass" appearance, with no lunula.
# Pathophysiology
## Associated Conditions
It frequently occurs in the setting of the following conditions.
- Aging
- Cancer
- Cirrhosis
- Congestive heart failure
- Diabetes mellitus
- Hepatic failure
- Hyperthyroidism
- Malnutrition
Eighty percent of patients with severe liver disease have Terry's nails.
# Causes
## Common Causes
The condition is thought to be due to a decrease in vascularity and an increase in connective tissue within the nail bed.
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https://www.wikidoc.org/index.php/Terry%27s_nails
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f8b3cd77734cf02b24b6cd1e145540fd16aaf03b
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wikidoc
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Tetrabenazine
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Tetrabenazine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Tetrabenazine is a central nervous system agent that is FDA approved for the treatment of chorea associated with Huntington's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Sedation,somnolence, fatigue, insomnia, depression, akathisia, anxiety, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Treatment of chorea associated with Huntington's disease.
# Dosage
General Dosing Considerations
- The chronic daily dose of tetrabenazine used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to identify a dose of tetrabenazine that reduces chorea and is tolerated. tetrabenazine can be administered without regard to food.
Individualization of Dose
- The dose of Tetrabenazine should be individualized.
Dosing Recommendations Up to 50 mg per day
- The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. tetrabenazine should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants).
Dosing Recommendations Above 50 mg per day
- Patients who require doses of tetrabenazine greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of tetrabenazine should then be individualized accordingly to their status as PMs or EMs.
Extensive and Intermediate CYP2D6 Metabolizers
- Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of tetrabenazine above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse events such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants).
Poor CYP2D6 Metabolizers
- In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg.
CYP2D6 Inhibitors
Strong CYP2D6 Inhibitors
- Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ, therefore, the total dose of tetrabenazine should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg.
Patients with Hepatic Impairment
- Because the safety and efficacy of the increased exposure to tetrabenazine and other circulating metabolites are unknown, it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment.
Discontinuation of Treatment
- Treatment with tetrabenazine can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of tetrabenazine.
Resumption of Treatment
- Following treatment interruption of greater than five (5) days, tetrabenazine therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tetrabenazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tetrabenazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tetrabenazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tetrabenazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tetrabenazine in pediatric patients.
# Contraindications
- Tetrabenazine is contraindicated in patients who are actively suicidal, or in patients with untreated or inadequately treated depression.
- Tetrabenazine is contraindicated in patients with impaired hepatic function.
- Tetrabenazine is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.
- Tetrabenazine is contraindicated in patients taking reserpine. At least 20 days should elapse after stopping reserpine before starting tetrabenazine.
# Warnings
Clinical Worsening and Adverse Effects
- Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, tetrabenazine was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown. Therefore, proper use of the drug requires attention to all facets of the underlying disease process over time.
- Prescribers should periodically re-evaluate the need for tetrabenazine in their patients by assessing the beneficial effect on chorea and possible adverse effects, including depression, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness and disability. It may be difficult to distinguish between drug-induced side-effects and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for tetrabenazine.
Dosing of Tetrabenazine
- Proper dosing of tetrabenazine involves titration of therapy to determine an individualized dose for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is tolerated. Some adverse effects such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism and akathisia may be dose-dependent and may resolve or lessen with dosage adjustment or specific treatment. If the adverse effect does not resolve or decrease, consider discontinuing tetrabenazine.
- Doses above 50 mg should not be given without CYP2D6 genotyping patients to determine if they are poor metabolizers.
Risk of Depression and Suicidality
- Patients with Huntington's disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). tetrabenazine increases the risk for suicidality in patients with HD. All patients treated with tetrabenazine should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine.
- In a 12-week, double-blind placebo-controlled study in patients with chorea associated with Huntington's disease, 10 of 54 patients (19%) treated with tetrabenazine were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received tetrabenazine for up to 48 weeks; in the second study, 75 patients received tetrabenazine for up to 80 weeks), the rate of depression/worsening depression was 35%.
- In all of the HD chorea studies of tetrabenazine (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.
- Clinicians should be alert to the heightened risk of suicide in patients with Huntington's disease regardless of depression indices. Reported rates of completed suicide among individuals with Huntington's disease range from 3-13% and over 25% of patients attempt suicide at some point in their illness.
- Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with tetrabenazine and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately.
Laboratory Tests'
- Before prescribing a daily dose of tetrabenazine that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of tetrabenazine.
- Patients who are PMs of tetrabenazine will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient's CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg.
Risk of Neuroleptic Malignant Syndrome (NMS)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine and other drugs that reduce dopaminergic transmission. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection), and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
- The management of NMS should include (1) immediate discontinuation of tetrabenazine and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- Recurrence of NMS has been reported. If treatment with tetrabenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence.
Risk of Akathisia, Restlessness, and Agitation
- In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine-treated patients and 0% of placebo-treated patients. In an 80-week open-label study, akathisia was observed in 20% of tetrabenazine-treated patients. akathisia was not observed in a 48-week open-label study. Patients receiving tetrabenazine should be monitored for the presence of akathisia. Patients receiving Tetrabenazine should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine dose should be reduced; however, some patients may require discontinuation of therapy.
Risk of Parkinsonism
- Tetrabenazine can cause parkinsonism. In a 12-week double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15% of tetrabenazine-treated patients compared to 0% of placebo-treated patients. In 48-week and 80-week open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of tetrabenazine-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between this drug-induced side-effect and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington's disease. If a patient develops parkinsonism during treatment with tetrabenazine, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.
Risk of Dysphagia
- Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of tetrabenazine-treated patients and 3% of placebo-treated patients. In 48-week and 80-week open-label studies, dysphagia was observed in 10% and 8% of tetrabenazine-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.
Risk of Sedation and Somnolence
- Sedation is the most common dose-limiting adverse effect of tetrabenazine. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence was observed in 17/54 (31%) tetrabenazine-treated patients and in 1 (3%) placebo-treated patient. Sedation was the reason upward titration of tetrabenazine was stopped and/or the dose of tetrabenazine was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of tetrabenazine resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/somnolence was observed in 17% and 57% of tetrabenazine-treated patients, respectively. In some patients, sedation occurred at doses that were lower than recommended doses.
- Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine and know how the drug affects them.
Interaction with Alcohol
- Patients should be advised that the concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Risk of QTc Prolongation
- Tetrabenazine causes a small increase (about 8 msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. The use of tetrabenazine should be avoided in combination with other drugs that are known to prolong QTc, including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval.
- Tetrabenazine should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval .
Concomitant Use of Neuroleptic Drugs, Reserpine and MAOIs
Neuroleptic Drugs
- Patients taking neuroleptic (antipsychotic) drugs (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) were excluded from clinical studies during the tetrabenazine development program. Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists .
Reserpine
- Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. The physician should wait for chorea to reemerge before administering tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting tetrabenazine. Tetrabenazine and reserpine should not be used concomitantly.
Monoamine Oxidase Inhibitors (MAOIs)
- Tetrabenazine is contraindicated in patients taking MAOIs. tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI .
Risk of Hypotension and Orthostatic Hypotension
- Tetrabenazine induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of tetrabenazine-treated patients (vs. none on placebo) in the 12-week controlled trial; however, blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.
Risk of Hyperprolactinemia
- Tetrabenazine elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if tetrabenazine is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the tetrabenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine.
Risk of Tardive Dyskinesia (TD)
- A potentially irreversible syndrome of involuntary, dyskinetic movements may develop in patients treated with neuroleptic drugs. In an animal model of orofacial dyskinesias, acute administration of reserpine, a monoamine depletor, has been shown to produce vacuous chewing in rats. Although the pathophysiology of tardive dyskinesia remains incompletely understood, the most commonly accepted hypothesis of the mechanism is that prolonged post-synaptic dopamine receptor blockade leads to supersensitivity to dopamine. Neither reserpine nor tetrabenazine, which are dopamine depletors, have been reported to cause clear tardive dyskinesia in humans, but as pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine, and tetrabenazine can cause the extrapyramidal symptoms also known to be associated with neuroleptics (e.g., parkinsonism and akathisia), physicians should be aware of the possible risk of tardive dyskinesia. If signs and symptoms of TD appear in a patient treated with tetrabenazine, drug discontinuation should be considered.
Use in Patients with Concomitant Illnesses
- Clinical experience with tetrabenazine in patients with systemic illnesses is limited.
Depression and Suicidality
- Tetrabenazine may increase the risk for depression or suicidality in patients with a history of depression or suicidal behavior or in patients with diseases, conditions, or treatments that cause depression or suicidality. Tetrabenazine is contraindicated in patients with untreated or inadequately treated depression or who are actively suicidal.
Hepatic Disease
- Tetrabenazine is contraindicated in patients with hepatic impairment.
Heart Disease
- Tetrabenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials.
Binding to Melanin-Containing Tissues
- Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye was conducted in the chronic toxicity study in dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.
- The clinical relevance of tetrabenazine's binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects
# Adverse Reactions
## Clinical Trials Experience
- The following risks are discussed in greater detail in other sections of the labeling:
- Depression and suicidality
- Akathisia, restlessness and agitation
- Parkinsonism
- Dysphagia
- Sedation and somnolence
Commonly Observed Adverse Reactions in Controlled Clinical Trials
- The most common adverse reactions from Table 1 occurring in over 10% of tetrabenazine-treated patients, and at least 5% greater than placebo, were sedation/somnolence (31%), fatigue (22%), insomnia (22%), depression (19%), akathisia (19%), and nausea (13%).
Clinical Studies Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- During its development, tetrabenazine was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine varied greatly, and included single and multiple dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients.
- In a randomized, 12-week, placebo-controlled clinical trial of HD subjects, adverse reactions (ARs) were more common in the tetrabenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received tetrabenazine experienced one or more ARs at any time during the study. The ARs most commonly reported (over 10%, and at least 5% greater than placebo) were sedation/somnolence (31% vs. 3% on placebo), fatigue (22% vs. 13% on placebo), insomnia (22% vs. 0% on placebo), depression (19% vs. 0% on placebo), akathisia (19% vs. 0% on placebo), and nausea (13% vs. 7% on placebo).
Adverse Reactions Occurring in ≥4% Patients
- The number and percentage of the most commonly reported AEs that occurred at any time during the study in ≥4% of tetrabenazine-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1 in decreasing order of frequency within body systems for the tetrabenazine group.
- Dose escalation was discontinued or dosage of study drug was reduced because of one or more ARs in 28 of 54 (52%) patients randomized to tetrabenazine . These ARs consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AR and are, therefore, counted more than once.
Adverse Reactions Due to Extrapyramidal Symptoms (EPS)
- The following table describes the incidence of events considered to be extrapyramidal adverse reactions.
- Patients may have had events in more than one category.
Laboratory Tests
- No clinically significant changes in laboratory parameters were reported in clinical trials with tetrabenazine. In controlled clinical trials, tetrabenazine caused a small mean increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), laboratory values as compared to placebo.
Vital Signs
- In controlled clinical trials, tetrabenazine did not affect blood pressure, pulse, and body weight. Orthostatic blood pressure was not consistently measured in the tetrabenazine clinical trials.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tetrabenazine in the drug label.
# Drug Interactions
Strong CYP2D6 Inhibitors
- In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYPD6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in tetrabenazine dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of tetrabenazine. The daily dose of tetrabenazine should not exceed 50 mg per day and the maximum single dose of tetrabenazine should not exceed 25 mg in patients taking strong CYP2D6 inhibitors.
Reserpine
- Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting tetrabenazine. Tetrabenazine and reserpine should not be used concomitantly.
Monoamine Oxidase Inhibitors (MAOIs)
- Tetrabenazine is contraindicated in patients taking MAOIs. Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI .
Alcohol
- Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Drugs that Cause QTc Prolongation
- Since tetrabenazine causes a small increase in QTc prolongation (about 8 msec), the concomitant use with other drugs that are known to cause QTc prolongation should be avoided including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetrabenazine should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
Neuroleptic Drugs
- Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists, including antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. Tetrabenazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tetrabenazine had no clear effects on embryo-fetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose of 100 mg/day on a mg/m2 basis). Tetrabenazine had no effects on embryo-fetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m2 basis). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately addressed the potential effects of tetrabenazine on embryo-fetal development in humans.
- When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on a mg/m2 basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, this study may not have adequately assessed the potential effects of tetrabenazine on the offspring of women exposed in utero and via lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tetrabenazine in women who are pregnant.
### Labor and Delivery
- The effect of tetrabenazine on labor and delivery in humans is unknown.
### Nursing Mothers
- It is not known whether tetrabenazine or its metabolites are excreted in human milk.
- Since many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from tetrabenazine, a decision should be made whether to discontinue nursing or to discontinue tetrabenazine, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of tetrabenazine in children have not been established.
### Geriatic Use
- The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.
### Gender
- There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
### Race
There is no FDA guidance on the use of Tetrabenazine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tetrabenazine in patients with renal impairment.
### Hepatic Impairment
- The use of tetrabenazine in patients with liver disease is contraindicated.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Tetrabenazine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Tetrabenazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Tetrabenazine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tetrabenazine in the drug label.
# Overdosage
Human Experience
- Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with tetrabenazine have been reported in the literature. The dose of tetrabenazine in these patients ranged from 100 mg to 1 g. Adverse reactions associated with tetrabenazine overdose included acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.
Management of Overdose
- Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR®).
# Pharmacology
## Mechanism of Action
- The precise mechanism by which tetrabenazine exerts its anti-chorea effects is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α- and β-HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).
## Structure
- XENAZINE (tetrabenazine) is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43; the pKa is 6.51. Tetrabenazine is a hexahydro-dimethoxy-benzoquinolizine derivative and has the following chemical name: cis rac –1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzoquinolizin-2-one.
- The empirical formula C19H27NO3 is represented by the following structural formula:
- Tetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.
- Each XENAZINE (tetrabenazine) Tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient.
- XENAZINE (tetrabenazine) Tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose, magnesium stearate, maize starch, and talc. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient.
- XENAZINE (tetrabenazine) is supplied as a yellowish-buff scored tablet containing 25 mg of XENAZINE or as a white non-scored tablet containing 12.5 mg of XENAZINE.
## Pharmacodynamics
QTc Prolongation
- The effect of a single 25 or 50 mg dose of tetrabenazine on the QT interval was studied in a randomized, double-blind, placebo controlled crossover study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, tetrabenazine caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of tetrabenazine does not further increase the effect on the QTc interval. Effects at higher exposures to either tetrabenazine or its metabolites have not been evaluated.
Melanin Binding
- Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.
## Pharmacokinetics
Absorption
- Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
Food Effects
- The effects of food on the bioavailability of tetrabenazine were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ. Tetrabenazine can, therefore, be administered without regard to meals.
Distribution
- Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.
- The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.
Metabolism
- After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-α-DHTBZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ.
- The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
- Neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.
- No in vitro metabolism studies have been conducted to evaluate the potential of the 9-desmethyl-β-DHTBZ metabolite to interact with other drugs. The activity of this metabolite relative to the parent drug is unknown.
Elimination
- After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
'Specific Populations''
Pediatric Patient
- The pharmacokinetics of tetrabenazine and its primary metabolites have not been studied in pediatric subjects.
Geriatric Patient
- The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.
Gender
- There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
Race
- Racial differences in the pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied.
Patients with Renal Impairment
- The effect of renal insufficiency on the pharmacokinetics of tetrabenazine and its primary metabolites has not been studied.
Patients with Hepatic Impairment
- The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmax in hepatically impaired subjects was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment.
Patients Who Are Poor or Extensive CYP2D6 Metabolizers
- Patients should be genotyped for drug metabolizing enzyme, CYP2D6, prior to treatment with daily doses of tetrabenazine over 50 mg.
Poor Metabolizers
- Although the pharmacokinetics of tetrabenazine and its metabolites in subjects who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively). Patients who are PMs should not be given doses greater than 50 mg per day and the maximum recommended single dose is 25 mg.
Extensive or Intermediate CYP2D6 Metabolizers
- In patients who express the enzyme, CYP2D6, (extensive or intermediate metabolizers), the maximum recommended daily dose is 100 mg per day, with a maximum recommended single dose of 37.5 mg.
## Nonclinical Toxicology
# Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15 and 30 mg/kg/day for 26 weeks. When compared to humans receiving a 50 mg dose of tetrabenazine, mice dosed with a 30 mg/kg dose of tetrabenazine produce about one sixth the levels of 9-desmethyl-beta-DHTBZ, a major human metabolite. Therefore, this study may not have adequately characterized the potential of tetrabenazine to be carcinogenic in people.
Mutagenesis
- Tetrabenazine and metabolites α-HTBZ and β-HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus tests were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats.
- Because the bioactivation system used in the in vitro studies was hepatic S9 fraction prepared from rat, a species that, when dosed with tetrabenazine, does not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of tetrabenazine to be mutagenic in humans. Furthermore, since the mouse produces very low levels of this metabolite when dosed with tetrabenazine, the in vivo study may not have adequately assessed the potential of tetrabenazine to be mutagenic in humans.
Impairment of Fertility
- Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis).
- No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (doses of 5, 15 or 30 mg/kg/day; up to 3 times the MRHD on a mg/m2 basis) prior to and throughout mating with untreated females.
- Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of XENAZINE to impair fertility in humans.
# Clinical Studies
Study 1
- The efficacy of tetrabenazine as a treatment for the chorea of Huntington's disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of HD. The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5-week maintenance period followed by a 1-week washout. The dose of tetrabenazine was started at 12.5 mg per day and titrated upward at weekly intervals in 12.5 mg increments until satisfactory control of chorea was achieved, until intolerable side effects occurred, or until a maximal dose of 100 mg per day was reached.
- The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.
- As shown in Figure 1, Total Chorea Scores for subjects in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of subjects receiving tetrabenazine returned to baseline.
- Figure 2 illustrates the cumulative percentages of patients from the tetrabenazine and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the X axis. The left-ward shift of the curve (toward greater improvement) for tetrabenazine-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. Thus, for example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of tetrabenazine-treated patients. The percentage of patients achieving reductions of at least 10, 6, and 3-points from baseline to Week 12 are shown in the inset table.
- Figure 2. Cumulative Percentage of Patients with Specified Changes from Baseline in Total Chorea Score. The Percentages of Randomized Patients within each treatment group who completed Study 1 were: Placebo 97%, Tetrabenazine 91%.
Study 2
- A second controlled study was performed in patients who had been treated with open-label tetrabenazine for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of tetrabenazine at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared.Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study 1 (about 3.5 units).
- A Physician-rated Clinical Global Impression (CGI) favored tetrabenazine statistically. In general, measures of functional capacity and cognition showed no difference between tetrabenazine and placebo. However, one functional measure (Part 4 of the UHDRS), a 25-item scale assessing the capacity for patients to perform certain activities of daily living, showed a decrement for patients treated with tetrabenazine compared to placebo, a difference that was nominally statistically significant. A 3-item cognitive battery specifically developed to assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed a decrement for patients treated with tetrabenazine compared to placebo, but the difference was not statistically significant.
# How Supplied
There is limited information regarding Tetrabenazine How Supplied in the drug label.
## Storage
There is limited information regarding Tetrabenazine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians are advised to discuss the following issues with patients and their families:
Risk of Suicidality
- Patients and their families should be told that tetrabenazine may increase the risk of suicidal thinking and behaviors. Patients and their families should be encouraged to be alert to the emergence of suicidal ideation and should report it immediately to the patient's physician.
Risk of Depression
- Patients and their families should be told that tetrabenazine may cause depression or may worsen pre-existing depression. They should be encouraged to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and should report such symptoms promptly to the patient's physician.
Dosing of Tetrabenazine
- Patients and their families should be told that the dose of tetrabenazine will be titrated up slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician and the tetrabenazine dose may need to be reduced or discontinued.
Risk of Sedation and Somnolence
- Patients should be told that tetrabenazine may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Patients should be advised that until they learn how they respond to tetrabenazine, they should be careful doing activities that require them to be alert, such as driving a car or operating machinery.
Interaction with Alcohol
- Patients and their families should be advised that alcohol may potentiate the sedation induced by tetrabenazine.
Usage in Pregnancy
- Patients and their families should be advised to notify the physician if the patient becomes pregnant or intends to become pregnant during tetrabenazine therapy, or is breast-feeding or intending to breast-feed an infant during therapy.
General Advice
- Patients and their families should be advised to notify the physician of all medications the patient is taking and to consult with the physician before starting any new medications.
# Precautions with Alcohol
- Alcohol-Tetrabenazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XENAZINE
# Look-Alike Drug Names
There is limited information regarding Tetrabenazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
|
Tetrabenazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Black Box Warning
# Overview
Tetrabenazine is a central nervous system agent that is FDA approved for the treatment of chorea associated with Huntington's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Sedation,somnolence, fatigue, insomnia, depression, akathisia, anxiety, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Treatment of chorea associated with Huntington's disease.
# Dosage
General Dosing Considerations
- The chronic daily dose of tetrabenazine used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to identify a dose of tetrabenazine that reduces chorea and is tolerated. tetrabenazine can be administered without regard to food.
Individualization of Dose
- The dose of Tetrabenazine should be individualized.
Dosing Recommendations Up to 50 mg per day
- The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. tetrabenazine should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants).
Dosing Recommendations Above 50 mg per day
- Patients who require doses of tetrabenazine greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of tetrabenazine should then be individualized accordingly to their status as PMs or EMs.
Extensive and Intermediate CYP2D6 Metabolizers
- Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of tetrabenazine above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If adverse events such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants).
Poor CYP2D6 Metabolizers
- In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg, and the recommended daily dose should not exceed a maximum of 50 mg.
CYP2D6 Inhibitors
Strong CYP2D6 Inhibitors
- Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g., fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ, therefore, the total dose of tetrabenazine should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg.
Patients with Hepatic Impairment
- Because the safety and efficacy of the increased exposure to tetrabenazine and other circulating metabolites are unknown, it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment.
Discontinuation of Treatment
- Treatment with tetrabenazine can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of tetrabenazine.
Resumption of Treatment
- Following treatment interruption of greater than five (5) days, tetrabenazine therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tetrabenazine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tetrabenazine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tetrabenazine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tetrabenazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tetrabenazine in pediatric patients.
# Contraindications
- Tetrabenazine is contraindicated in patients who are actively suicidal, or in patients with untreated or inadequately treated depression.
- Tetrabenazine is contraindicated in patients with impaired hepatic function.
- Tetrabenazine is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.
- Tetrabenazine is contraindicated in patients taking reserpine. At least 20 days should elapse after stopping reserpine before starting tetrabenazine.
# Warnings
Clinical Worsening and Adverse Effects
- Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, tetrabenazine was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown. Therefore, proper use of the drug requires attention to all facets of the underlying disease process over time.
- Prescribers should periodically re-evaluate the need for tetrabenazine in their patients by assessing the beneficial effect on chorea and possible adverse effects, including depression, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness and disability. It may be difficult to distinguish between drug-induced side-effects and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for tetrabenazine.
Dosing of Tetrabenazine
- Proper dosing of tetrabenazine involves titration of therapy to determine an individualized dose for each patient. When first prescribed, tetrabenazine therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is tolerated. Some adverse effects such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism and akathisia may be dose-dependent and may resolve or lessen with dosage adjustment or specific treatment. If the adverse effect does not resolve or decrease, consider discontinuing tetrabenazine.
- Doses above 50 mg should not be given without CYP2D6 genotyping patients to determine if they are poor metabolizers.
Risk of Depression and Suicidality
- Patients with Huntington's disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). tetrabenazine increases the risk for suicidality in patients with HD. All patients treated with tetrabenazine should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine.
- In a 12-week, double-blind placebo-controlled study in patients with chorea associated with Huntington's disease, 10 of 54 patients (19%) treated with tetrabenazine were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients. In two open-label studies (in one study, 29 patients received tetrabenazine for up to 48 weeks; in the second study, 75 patients received tetrabenazine for up to 80 weeks), the rate of depression/worsening depression was 35%.
- In all of the HD chorea studies of tetrabenazine (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.
- Clinicians should be alert to the heightened risk of suicide in patients with Huntington's disease regardless of depression indices. Reported rates of completed suicide among individuals with Huntington's disease range from 3-13% and over 25% of patients attempt suicide at some point in their illness.
- Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with tetrabenazine and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately.
Laboratory Tests'
- Before prescribing a daily dose of tetrabenazine that is greater than 50 mg per day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of tetrabenazine.
- Patients who are PMs of tetrabenazine will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient's CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg.
Risk of Neuroleptic Malignant Syndrome (NMS)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine and other drugs that reduce dopaminergic transmission. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection), and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.
- The management of NMS should include (1) immediate discontinuation of tetrabenazine and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.
- Recurrence of NMS has been reported. If treatment with tetrabenazine is needed after recovery from NMS, patients should be monitored for signs of recurrence.
Risk of Akathisia, Restlessness, and Agitation
- In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine-treated patients and 0% of placebo-treated patients. In an 80-week open-label study, akathisia was observed in 20% of tetrabenazine-treated patients. akathisia was not observed in a 48-week open-label study. Patients receiving tetrabenazine should be monitored for the presence of akathisia. Patients receiving Tetrabenazine should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine dose should be reduced; however, some patients may require discontinuation of therapy.
Risk of Parkinsonism
- Tetrabenazine can cause parkinsonism. In a 12-week double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15% of tetrabenazine-treated patients compared to 0% of placebo-treated patients. In 48-week and 80-week open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of tetrabenazine-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between this drug-induced side-effect and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington's disease. If a patient develops parkinsonism during treatment with tetrabenazine, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.
Risk of Dysphagia
- Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of tetrabenazine-treated patients and 3% of placebo-treated patients. In 48-week and 80-week open-label studies, dysphagia was observed in 10% and 8% of tetrabenazine-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.
Risk of Sedation and Somnolence
- Sedation is the most common dose-limiting adverse effect of tetrabenazine. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence was observed in 17/54 (31%) tetrabenazine-treated patients and in 1 (3%) placebo-treated patient. Sedation was the reason upward titration of tetrabenazine was stopped and/or the dose of tetrabenazine was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of tetrabenazine resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/somnolence was observed in 17% and 57% of tetrabenazine-treated patients, respectively. In some patients, sedation occurred at doses that were lower than recommended doses.
- Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine and know how the drug affects them.
Interaction with Alcohol
- Patients should be advised that the concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Risk of QTc Prolongation
- Tetrabenazine causes a small increase (about 8 msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases. The use of tetrabenazine should be avoided in combination with other drugs that are known to prolong QTc, including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval.
- Tetrabenazine should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval .
Concomitant Use of Neuroleptic Drugs, Reserpine and MAOIs
Neuroleptic Drugs
- Patients taking neuroleptic (antipsychotic) drugs (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) were excluded from clinical studies during the tetrabenazine development program. Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists .
Reserpine
- Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. The physician should wait for chorea to reemerge before administering tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting tetrabenazine. Tetrabenazine and reserpine should not be used concomitantly.
Monoamine Oxidase Inhibitors (MAOIs)
- Tetrabenazine is contraindicated in patients taking MAOIs. tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI .
Risk of Hypotension and Orthostatic Hypotension
- Tetrabenazine induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of tetrabenazine-treated patients (vs. none on placebo) in the 12-week controlled trial; however, blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.
Risk of Hyperprolactinemia
- Tetrabenazine elevates serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if tetrabenazine is being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the tetrabenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine.
Risk of Tardive Dyskinesia (TD)
- A potentially irreversible syndrome of involuntary, dyskinetic movements may develop in patients treated with neuroleptic drugs. In an animal model of orofacial dyskinesias, acute administration of reserpine, a monoamine depletor, has been shown to produce vacuous chewing in rats. Although the pathophysiology of tardive dyskinesia remains incompletely understood, the most commonly accepted hypothesis of the mechanism is that prolonged post-synaptic dopamine receptor blockade leads to supersensitivity to dopamine. Neither reserpine nor tetrabenazine, which are dopamine depletors, have been reported to cause clear tardive dyskinesia in humans, but as pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine, and tetrabenazine can cause the extrapyramidal symptoms also known to be associated with neuroleptics (e.g., parkinsonism and akathisia), physicians should be aware of the possible risk of tardive dyskinesia. If signs and symptoms of TD appear in a patient treated with tetrabenazine, drug discontinuation should be considered.
Use in Patients with Concomitant Illnesses
- Clinical experience with tetrabenazine in patients with systemic illnesses is limited.
Depression and Suicidality
- Tetrabenazine may increase the risk for depression or suicidality in patients with a history of depression or suicidal behavior or in patients with diseases, conditions, or treatments that cause depression or suicidality. Tetrabenazine is contraindicated in patients with untreated or inadequately treated depression or who are actively suicidal.
Hepatic Disease
- Tetrabenazine is contraindicated in patients with hepatic impairment.
Heart Disease
- Tetrabenazine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials.
Binding to Melanin-Containing Tissues
- Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye was conducted in the chronic toxicity study in dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.
- The clinical relevance of tetrabenazine's binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects
# Adverse Reactions
## Clinical Trials Experience
- The following risks are discussed in greater detail in other sections of the labeling:
- Depression and suicidality
- Akathisia, restlessness and agitation
- Parkinsonism
- Dysphagia
- Sedation and somnolence
Commonly Observed Adverse Reactions in Controlled Clinical Trials
- The most common adverse reactions from Table 1 occurring in over 10% of tetrabenazine-treated patients, and at least 5% greater than placebo, were sedation/somnolence (31%), fatigue (22%), insomnia (22%), depression (19%), akathisia (19%), and nausea (13%).
Clinical Studies Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- During its development, tetrabenazine was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine varied greatly, and included single and multiple dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients.
- In a randomized, 12-week, placebo-controlled clinical trial of HD subjects, adverse reactions (ARs) were more common in the tetrabenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received tetrabenazine experienced one or more ARs at any time during the study. The ARs most commonly reported (over 10%, and at least 5% greater than placebo) were sedation/somnolence (31% vs. 3% on placebo), fatigue (22% vs. 13% on placebo), insomnia (22% vs. 0% on placebo), depression (19% vs. 0% on placebo), akathisia (19% vs. 0% on placebo), and nausea (13% vs. 7% on placebo).
Adverse Reactions Occurring in ≥4% Patients
- The number and percentage of the most commonly reported AEs that occurred at any time during the study in ≥4% of tetrabenazine-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1 in decreasing order of frequency within body systems for the tetrabenazine group.
- Dose escalation was discontinued or dosage of study drug was reduced because of one or more ARs in 28 of 54 (52%) patients randomized to tetrabenazine . These ARs consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AR and are, therefore, counted more than once.
Adverse Reactions Due to Extrapyramidal Symptoms (EPS)
- The following table describes the incidence of events considered to be extrapyramidal adverse reactions.
- Patients may have had events in more than one category.
Laboratory Tests
- No clinically significant changes in laboratory parameters were reported in clinical trials with tetrabenazine. In controlled clinical trials, tetrabenazine caused a small mean increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), laboratory values as compared to placebo.
Vital Signs
- In controlled clinical trials, tetrabenazine did not affect blood pressure, pulse, and body weight. Orthostatic blood pressure was not consistently measured in the tetrabenazine clinical trials.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tetrabenazine in the drug label.
# Drug Interactions
Strong CYP2D6 Inhibitors
- In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYPD6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in tetrabenazine dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of tetrabenazine. The daily dose of tetrabenazine should not exceed 50 mg per day and the maximum single dose of tetrabenazine should not exceed 25 mg in patients taking strong CYP2D6 inhibitors.
Reserpine
- Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting tetrabenazine. Tetrabenazine and reserpine should not be used concomitantly.
Monoamine Oxidase Inhibitors (MAOIs)
- Tetrabenazine is contraindicated in patients taking MAOIs. Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI .
Alcohol
- Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Drugs that Cause QTc Prolongation
- Since tetrabenazine causes a small increase in QTc prolongation (about 8 msec), the concomitant use with other drugs that are known to cause QTc prolongation should be avoided including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide), and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetrabenazine should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
Neuroleptic Drugs
- Adverse reactions associated with tetrabenazine, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists, including antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. Tetrabenazine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tetrabenazine had no clear effects on embryo-fetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [MRHD] of 100 mg/day on a mg/m2 basis). Tetrabenazine had no effects on embryo-fetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m2 basis). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately addressed the potential effects of tetrabenazine on embryo-fetal development in humans.
- When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on a mg/m2 basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, this study may not have adequately assessed the potential effects of tetrabenazine on the offspring of women exposed in utero and via lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tetrabenazine in women who are pregnant.
### Labor and Delivery
- The effect of tetrabenazine on labor and delivery in humans is unknown.
### Nursing Mothers
- It is not known whether tetrabenazine or its metabolites are excreted in human milk.
- Since many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from tetrabenazine, a decision should be made whether to discontinue nursing or to discontinue tetrabenazine, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of tetrabenazine in children have not been established.
### Geriatic Use
- The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.
### Gender
- There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
### Race
There is no FDA guidance on the use of Tetrabenazine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tetrabenazine in patients with renal impairment.
### Hepatic Impairment
- The use of tetrabenazine in patients with liver disease is contraindicated.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Tetrabenazine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Tetrabenazine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Tetrabenazine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tetrabenazine in the drug label.
# Overdosage
Human Experience
- Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with tetrabenazine have been reported in the literature. The dose of tetrabenazine in these patients ranged from 100 mg to 1 g. Adverse reactions associated with tetrabenazine overdose included acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.
Management of Overdose
- Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR®).
# Pharmacology
## Mechanism of Action
- The precise mechanism by which tetrabenazine exerts its anti-chorea effects is unknown but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2) (Ki ≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α- and β-HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).
## Structure
- XENAZINE (tetrabenazine) is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43; the pKa is 6.51. Tetrabenazine is a hexahydro-dimethoxy-benzoquinolizine derivative and has the following chemical name: cis rac –1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.
- The empirical formula C19H27NO3 is represented by the following structural formula:
- Tetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.
- Each XENAZINE (tetrabenazine) Tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient.
- XENAZINE (tetrabenazine) Tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose, magnesium stearate, maize starch, and talc. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient.
- XENAZINE (tetrabenazine) is supplied as a yellowish-buff scored tablet containing 25 mg of XENAZINE or as a white non-scored tablet containing 12.5 mg of XENAZINE.
## Pharmacodynamics
QTc Prolongation
- The effect of a single 25 or 50 mg dose of tetrabenazine on the QT interval was studied in a randomized, double-blind, placebo controlled crossover study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, tetrabenazine caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of tetrabenazine does not further increase the effect on the QTc interval. Effects at higher exposures to either tetrabenazine or its metabolites have not been evaluated.
Melanin Binding
- Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.
## Pharmacokinetics
Absorption
- Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.
Food Effects
- The effects of food on the bioavailability of tetrabenazine were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ. Tetrabenazine can, therefore, be administered without regard to meals.
Distribution
- Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.
- The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.
Metabolism
- After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-α-DHTBZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ.
- The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.
- Neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.
- No in vitro metabolism studies have been conducted to evaluate the potential of the 9-desmethyl-β-DHTBZ metabolite to interact with other drugs. The activity of this metabolite relative to the parent drug is unknown.
Elimination
- After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.
'Specific Populations''
Pediatric Patient
- The pharmacokinetics of tetrabenazine and its primary metabolites have not been studied in pediatric subjects.
Geriatric Patient
- The pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.
Gender
- There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.
Race
- Racial differences in the pharmacokinetics of tetrabenazine and its primary metabolites have not been formally studied.
Patients with Renal Impairment
- The effect of renal insufficiency on the pharmacokinetics of tetrabenazine and its primary metabolites has not been studied.
Patients with Hepatic Impairment
- The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmax in hepatically impaired subjects was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment.
Patients Who Are Poor or Extensive CYP2D6 Metabolizers
- Patients should be genotyped for drug metabolizing enzyme, CYP2D6, prior to treatment with daily doses of tetrabenazine over 50 mg.
Poor Metabolizers
- Although the pharmacokinetics of tetrabenazine and its metabolites in subjects who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively). Patients who are PMs should not be given doses greater than 50 mg per day and the maximum recommended single dose is 25 mg.
Extensive or Intermediate CYP2D6 Metabolizers
- In patients who express the enzyme, CYP2D6, (extensive [EMs] or intermediate [IMs] metabolizers), the maximum recommended daily dose is 100 mg per day, with a maximum recommended single dose of 37.5 mg.
## Nonclinical Toxicology
# Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15 and 30 mg/kg/day for 26 weeks. When compared to humans receiving a 50 mg dose of tetrabenazine, mice dosed with a 30 mg/kg dose of tetrabenazine produce about one sixth the levels of 9-desmethyl-beta-DHTBZ, a major human metabolite. Therefore, this study may not have adequately characterized the potential of tetrabenazine to be carcinogenic in people.
Mutagenesis
- Tetrabenazine and metabolites α-HTBZ and β-HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus tests were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats.
- Because the bioactivation system used in the in vitro studies was hepatic S9 fraction prepared from rat, a species that, when dosed with tetrabenazine, does not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of tetrabenazine to be mutagenic in humans. Furthermore, since the mouse produces very low levels of this metabolite when dosed with tetrabenazine, the in vivo study may not have adequately assessed the potential of tetrabenazine to be mutagenic in humans.
Impairment of Fertility
- Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis).
- No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (doses of 5, 15 or 30 mg/kg/day; up to 3 times the MRHD on a mg/m2 basis) prior to and throughout mating with untreated females.
- Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of XENAZINE to impair fertility in humans.
# Clinical Studies
Study 1
- The efficacy of tetrabenazine as a treatment for the chorea of Huntington's disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of HD. The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5-week maintenance period followed by a 1-week washout. The dose of tetrabenazine was started at 12.5 mg per day and titrated upward at weekly intervals in 12.5 mg increments until satisfactory control of chorea was achieved, until intolerable side effects occurred, or until a maximal dose of 100 mg per day was reached.
- The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington's Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.
- As shown in Figure 1, Total Chorea Scores for subjects in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of subjects receiving tetrabenazine returned to baseline.
- Figure 2 illustrates the cumulative percentages of patients from the tetrabenazine and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the X axis. The left-ward shift of the curve (toward greater improvement) for tetrabenazine-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. Thus, for example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of tetrabenazine-treated patients. The percentage of patients achieving reductions of at least 10, 6, and 3-points from baseline to Week 12 are shown in the inset table.
- Figure 2. Cumulative Percentage of Patients with Specified Changes from Baseline in Total Chorea Score. The Percentages of Randomized Patients within each treatment group who completed Study 1 were: Placebo 97%, Tetrabenazine 91%.
Study 2
- A second controlled study was performed in patients who had been treated with open-label tetrabenazine for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of tetrabenazine at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared.Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study 1 (about 3.5 units).
- A Physician-rated Clinical Global Impression (CGI) favored tetrabenazine statistically. In general, measures of functional capacity and cognition showed no difference between tetrabenazine and placebo. However, one functional measure (Part 4 of the UHDRS), a 25-item scale assessing the capacity for patients to perform certain activities of daily living, showed a decrement for patients treated with tetrabenazine compared to placebo, a difference that was nominally statistically significant. A 3-item cognitive battery specifically developed to assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed a decrement for patients treated with tetrabenazine compared to placebo, but the difference was not statistically significant.
# How Supplied
There is limited information regarding Tetrabenazine How Supplied in the drug label.
## Storage
There is limited information regarding Tetrabenazine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Physicians are advised to discuss the following issues with patients and their families:
Risk of Suicidality
- Patients and their families should be told that tetrabenazine may increase the risk of suicidal thinking and behaviors. Patients and their families should be encouraged to be alert to the emergence of suicidal ideation and should report it immediately to the patient's physician.
Risk of Depression
- Patients and their families should be told that tetrabenazine may cause depression or may worsen pre-existing depression. They should be encouraged to be alert to the emergence of sadness, worsening of depression, withdrawal, insomnia, irritability, hostility (aggressiveness), akathisia (psychomotor restlessness), anxiety, agitation, or panic attacks and should report such symptoms promptly to the patient's physician.
Dosing of Tetrabenazine
- Patients and their families should be told that the dose of tetrabenazine will be titrated up slowly to the dose that is best for each patient. Sedation, akathisia, parkinsonism, depression, and difficulty swallowing may occur. Such symptoms should be promptly reported to the physician and the tetrabenazine dose may need to be reduced or discontinued.
Risk of Sedation and Somnolence
- Patients should be told that tetrabenazine may induce sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Patients should be advised that until they learn how they respond to tetrabenazine, they should be careful doing activities that require them to be alert, such as driving a car or operating machinery.
Interaction with Alcohol
- Patients and their families should be advised that alcohol may potentiate the sedation induced by tetrabenazine.
Usage in Pregnancy
- Patients and their families should be advised to notify the physician if the patient becomes pregnant or intends to become pregnant during tetrabenazine therapy, or is breast-feeding or intending to breast-feed an infant during therapy.
General Advice
- Patients and their families should be advised to notify the physician of all medications the patient is taking and to consult with the physician before starting any new medications.
# Precautions with Alcohol
- Alcohol-Tetrabenazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XENAZINE
# Look-Alike Drug Names
There is limited information regarding Tetrabenazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price
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https://www.wikidoc.org/index.php/Tetrabenazine
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Tetrachromacy
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Tetrachromacy
Tetrachromacy is the condition of possessing four independent channels for conveying color information, or possessing four different cones. Organisms with tetrachromacy are called tetrachromats. For these organisms, the perceptual effect of any arbitrarily chosen light from its visible spectrum can be matched by a mixture of no fewer than four different pure spectral lights.
# Description
The normal explanation of tetrachromacy is that the organism's retina contains four types of higher-intensity light receptors (called cone cells in vertebrates as opposed to rod cells which are lower intensity light receptors) with different absorption spectra. This means the animal may see wavelengths beyond those of a typical human being's eyesight, and may be able to distinguish colors that to a human are identical.
The zebrafish (Danio rerio) is an example of a tetrachromat, containing cone cells sensitive for red, green, blue, and ultraviolet light.
Tetrachromacy is expected to occur in several species of birds, fish, amphibians, reptiles, arachnids and insects.
# Possibility of human tetrachromats
Humans and closely related primates normally have three types of cone cells and are therefore trichromats (animals with three different cones). However, at low light intensities the rod cells may contribute to color vision, giving a small region of tetrachromacy in the color space. It has been suggested that women who are carriers for variant cone pigments might be born as full tetrachromats, having four different simultaneously functioning kinds of cones to pick up different colors. One study suggested that 2–3% of the world's women might have the kind of fourth cone that lies between the standard red and green cones, giving, theoretically, a significant increase in color differentiation. However, another study suggests that as many as 50% of women and 8% of men may have four photopigments.
Further studies will need to be conducted to verify tetrachromacy in humans. Two possible tetrachromats have been identified: "Mrs. M," an English social worker, was located in a study conducted in 1993, and an unidentified physician, also in England. Variation in cone pigment genes is widespread in most human populations, but the most prevalent and pronounced tetrachromacy would derive from female carriers of major red-green pigment anomalies, usually classed as forms of "color blindness" (protanomaly or deuteranomaly). The biological basis for this phenomenon is X-inactivation.
# Difficulties
It is possible that some humans could have four rather than three color receptors. Preliminary visual processing occurs within the nerves of the eye. It is not known how these nerves would respond to a new color channel, if they could handle it separately or would just lump it in with an existing channel. Visual information leaves the eye by way of the optic nerve. It is not known if the optic nerve has the spare capacity to handle a new color channel. A variety of final image processing takes place in the brain. It is not known how the various areas of the brain would respond if presented with a new color channel.
# Historical remarks
According to Lord Rayleigh in 1871, "Sir John Herschel even thinks that our inability to resolve yellow leaves it doubtful whether our vision is trichromatic or tetrachromatic..."
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Tetrachromacy
Tetrachromacy is the condition of possessing four independent channels for conveying color information, or possessing four different cones. Organisms with tetrachromacy are called tetrachromats. For these organisms, the perceptual effect of any arbitrarily chosen light from its visible spectrum can be matched by a mixture of no fewer than four different pure spectral lights.
# Description
The normal explanation of tetrachromacy is that the organism's retina contains four types of higher-intensity light receptors (called cone cells in vertebrates as opposed to rod cells which are lower intensity light receptors) with different absorption spectra. This means the animal may see wavelengths beyond those of a typical human being's eyesight, and may be able to distinguish colors that to a human are identical.
The zebrafish (Danio rerio) is an example of a tetrachromat, containing cone cells sensitive for red, green, blue, and ultraviolet light.[1]
Tetrachromacy is expected to occur in several species of birds, fish, amphibians, reptiles, arachnids and insects.
# Possibility of human tetrachromats
Humans and closely related primates normally have three types of cone cells and are therefore trichromats (animals with three different cones). However, at low light intensities the rod cells may contribute to color vision, giving a small region of tetrachromacy in the color space.[citation needed] It has been suggested that women who are carriers for variant cone pigments might be born as full tetrachromats, having four different simultaneously functioning kinds of cones to pick up different colors.[2] One study suggested that 2–3% of the world's women might have the kind of fourth cone that lies between the standard red and green cones, giving, theoretically, a significant increase in color differentiation.[3] However, another study suggests that as many as 50% of women and 8% of men may have four photopigments.[2]
Further studies will need to be conducted to verify tetrachromacy in humans. Two possible tetrachromats have been identified: "Mrs. M," an English social worker, was located in a study conducted in 1993,[4] and an unidentified physician, also in England.[3] Variation in cone pigment genes is widespread in most human populations, but the most prevalent and pronounced tetrachromacy would derive from female carriers of major red-green pigment anomalies, usually classed as forms of "color blindness" (protanomaly or deuteranomaly). The biological basis for this phenomenon is X-inactivation.
# Difficulties
It is possible that some humans could have four rather than three color receptors. Preliminary visual processing occurs within the nerves of the eye. It is not known how these nerves would respond to a new color channel, if they could handle it separately or would just lump it in with an existing channel. Visual information leaves the eye by way of the optic nerve. It is not known if the optic nerve has the spare capacity to handle a new color channel. A variety of final image processing takes place in the brain. It is not known how the various areas of the brain would respond if presented with a new color channel.
# Historical remarks
According to Lord Rayleigh in 1871, "Sir John Herschel even thinks that our inability to resolve yellow leaves it doubtful whether our vision is trichromatic or tetrachromatic..."[5]
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Thermodynamic
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Thermodynamic
Thermodynamics (from the Greek θερμη, therme, meaning "heat" and δυναμις, dunamis, meaning "power") is a branch of physics and of chemistry that studies the effects of changes in temperature, pressure, and volume on physical systems at the macroscopic scale by analysing the collective motion of their particles using statistics. Roughly, heat means "energy in transit" and dynamics relates to "movement"; thus, in essence thermodynamics studies the movement of energy and how energy instills movement. Historically, thermodynamics developed out of need to increase the efficiency of early steam engines.
The starting point for most thermodynamic considerations are the laws of thermodynamics, which postulate that energy can be exchanged between physical systems as heat or work. They also postulate the existence of a quantity named entropy, which can be defined for any system. In thermodynamics, interactions between large ensembles of objects are studied and categorized. Central to this are the concepts of system and surroundings. A system is composed of particles, whose average motions define its properties, which in turn are related to one another through equations of state. Properties can be combined to express internal energy and thermodynamic potentials, which are useful for determining conditions for equilibrium and spontaneous processes.
With these tools, thermodynamics describes how systems respond to changes in their surroundings. This can be applied to a wide variety of topics in science and engineering, such as engines, phase transitions, chemical reactions, transport phenomena, and even black holes. The results of thermodynamics are essential for other fields of physics and for chemistry, chemical engineering, aerospace engineering, mechanical engineering, cell biology, biomedical engineering, and materials science to name a few.
# History
A brief history of thermodynamics begins with Otto von Guericke who in 1650 built and designed the world's first vacuum pump and created the world's first ever vacuum (known as the Magdeburg hemispheres). He was driven to make a vacuum in order to disprove Aristotle's long-held supposition that 'nature abhors a vacuum'. Shortly thereafter, Irish physicist and chemist Robert Boyle had learned of Guericke's designs and in 1656, in coordination with English scientist Robert Hooke, built an air pump. Using this pump, Boyle and Hooke noticed a correlation between pressure, temperature, and volume. In time, Boyle's Law was formulated, which states that pressure and volume are inversely proportional. Then, in 1679, based on these concepts, an associate of Boyle's named Denis Papin built a bone digester, which was a closed vessel with a tightly fitting lid that confined steam until a high pressure was generated.
Later designs implemented a steam release valve that kept the machine from exploding. By watching the valve rhythmically move up and down, Papin conceived of the idea of a piston and a cylinder engine. He did not, however, follow through with his design. Nevertheless, in 1697, based on Papin's designs, engineer Thomas Savery built the first engine. Although these early engines were crude and inefficient, they attracted the attention of the leading scientists of the time. One such scientist was Sadi Carnot, the "father of thermodynamics", who in 1824 published Reflections on the Motive Power of Fire, a discourse on heat, power, and engine efficiency. The paper outlined the basic energetic relations between the Carnot engine, the Carnot cycle, and Motive power. This marks the start of thermodynamics as a modern science.
The term thermodynamics was coined by James Joule in 1858 to designate the science of relations between heat and power. By 1849, "thermo-dynamics", as a functional term, was used in William Thomson's paper An Account of Carnot's Theory of the Motive Power of Heat. The first thermodynamic textbook was written in 1859 by William Rankine, originally trained as a physicist and a civil and mechanical engineering professor at the University of Glasgow.
# The laws of thermodynamics
In thermodynamics, there are four laws of very general validity, and as such they do not depend on the details of the interactions or the systems being studied. Hence, they can be applied to systems about which one knows nothing other than the balance of energy and matter transfer. Examples of this include Einstein's prediction of spontaneous emission around the turn of the 20th century and current research into the thermodynamics of black holes.
The four laws are:
- Zeroth law of thermodynamics, stating that thermodynamic equilibrium is an equivalence relation.
- First law of thermodynamics, about the conservation of energy
- Second law of thermodynamics, about entropy
- Third law of thermodynamics, about absolute zero temperature
- Onsager reciprocal relations (sometimes called the Fourth Law of Thermodynamics)
# Thermodynamic potentials
As can be derived from the energy balance equation ( or Burks' equation) on a thermodynamic system there exist energetic quantities called thermodynamic potentials, being the quantitative measure of the stored energy in the system. The five most well known potentials are:
Other thermodynamic potentials can be obtained through Legendre transformation. Potentials are used to measure energy changes in systems as they evolve from an initial state to a final state. The potential used depends on the constraints of the system, such as constant temperature or pressure. Internal energy is the internal energy of the system, enthalpy is the internal energy of the system plus the energy related to pressure-volume work, and Helmholtz and Gibbs energy are the energies available in a system to do useful work when the temperature and volume or the pressure and temperature are fixed, respectively.
# Classical thermodynamics
Classical thermodynamics is the original early 1800s variation of thermodynamics concerned with thermodynamic states, and properties as energy, work, and heat, and with the laws of thermodynamics, all lacking an atomic interpretation. In precursory form, classical thermodynamics derives from chemist Robert Boyle’s 1662 postulate that the pressure P of a given quantity of gas varies inversely as its volume V at constant temperature; i.e. in equation form: PV = k, a constant. From here, a semblance of a thermo-science began to develop with the construction of the first successful atmospheric steam engines in England by Thomas Savery in 1697 and Thomas Newcomen in 1712. The first and second laws of thermodynamics emerged simultaneously in the 1850s, primarily out of the works of William Rankine, Rudolf Clausius, and William Thomson (Lord Kelvin).
# Statistical thermodynamics
With the development of atomic and molecular theories in the late 1800s and early 1900s, thermodynamics was given a molecular interpretation. This field is called statistical thermodynamics, which can be thought of as a bridge between macroscopic and microscopic properties of systems. Essentially, statistical thermodynamics is an approach to thermodynamics situated upon statistical mechanics, which focuses on the derivation of macroscopic results from first principles. It can be opposed to its historical predecessor phenomenological thermodynamics, which gives scientific descriptions of phenomena with avoidance of microscopic details. The statistical approach is to derive all macroscopic properties (temperature, volume, pressure, energy, entropy, etc.) from the properties of moving constituent particles and the interactions between them (including quantum phenomena). It was found to be very successful and thus is commonly used.
# Chemical thermodynamics
Chemical thermodynamics is the study of the interrelation of heat with chemical reactions or with a physical change of state within the confines of the laws of thermodynamics. During the years 1873-76 the American mathematical physicist Josiah Willard Gibbs published a series of three papers, the most famous being On the Equilibrium of Heterogeneous Substances, in which he showed how thermodynamic processes could be graphically analyzed, by studying the energy, entropy, volume, temperature and pressure of the thermodynamic system, in such a manner to determine if a process would occur spontaneously. During the early 20th century, chemists such as Gilbert N. Lewis, Merle Randall, and E. A. Guggenheim began to apply the mathematical methods of Gibbs to the analysis of chemical processes.
# Thermodynamic systems
An important concept in thermodynamics is the “system”. Everything in the universe except the system is known as surroundings. A system is the region of the universe under study. A system is separated from the remainder of the universe by a boundary which may be imaginary or not, but which by convention delimits a finite volume. The possible exchanges of work, heat, or matter between the system and the surroundings take place across this boundary. Boundaries are of four types: fixed, moveable, real, and imaginary.
Basically, the “boundary” is simply an imaginary dotted line drawn around a volume of something when there is going to be a change in the internal energy of that something. Anything that passes across the boundary that effects a change in the internal energy of the something needs to be accounted for in the energy balance equation. That something can be the volumetric region surrounding a single atom resonating energy, such as Max Planck defined in 1900; it can be a body of steam or air in a steam engine, such as Sadi Carnot defined in 1824; it can be the body of a tropical cyclone, such as Kerry Emanuel theorized in 1986 in the field of atmospheric thermodynamics; it could also be just one nuclide (i.e. a system of quarks) as some are theorizing presently in quantum thermodynamics.
For an engine, a fixed boundary means the piston is locked at its position; as such, a constant volume process occurs. In that same engine, a moveable boundary allows the piston to move in and out. For closed systems, boundaries are real while for open system boundaries are often imaginary. There are five dominant classes of systems:
- Isolated Systems – matter and energy may not cross the boundary
- Adiabatic Systems – heat must not cross the boundary
- Diathermic Systems - heat may cross boundary
- Closed Systems – matter may not cross the boundary
- Open Systems – heat, work, and matter may cross the boundary (often called a control volume in this case)
As time passes in an isolated system, internal differences in the system tend to even out and pressures and temperatures tend to equalize, as do density differences. A system in which all equalizing processes have gone practically to completion, is considered to be in a state of thermodynamic equilibrium.
In thermodynamic equilibrium, a system's properties are, by definition, unchanging in time. Systems in equilibrium are much simpler and easier to understand than systems which are not in equilibrium. Often, when analysing a thermodynamic process, it can be assumed that each intermediate state in the process is at equilibrium. This will also considerably simplify the situation. Thermodynamic processes which develop so slowly as to allow each intermediate step to be an equilibrium state are said to be reversible processes.
# Thermodynamic parameters
The central concept of thermodynamics is that of energy, the ability to do work. As stipulated by the first law, the total energy of the system and its surroundings is conserved. It may be transferred into a body by heating, compression, or addition of matter, and extracted from a body either by cooling, expansion, or extraction of matter. For comparison, in mechanics, energy transfer results from a force which causes displacement, the product of the two being the amount of energy transferred. In a similar way, thermodynamic systems can be thought of as transferring energy as the result of a generalized force causing a generalized displacement, with the product of the two being the amount of energy transferred. These thermodynamic force-displacement pairs are known as conjugate variables. The most common conjugate thermodynamic variables are pressure-volume (mechanical parameters), temperature-entropy (thermal parameters), and chemical potential-particle number (material parameters).
# Thermodynamic instruments
There are two types of thermodynamic instruments, the meter and the reservoir. A thermodynamic meter is any device which measures any parameter of a thermodynamic system. In some cases, the thermodynamic parameter is actually defined in terms of an idealized measuring instrument. For example, the zeroth law states that if two bodies are in thermal equilibrium with a third body, they are also in thermal equilibrium with each other. This principle, as noted by James Maxwell in 1872, asserts that it is possible to measure temperature. An idealized thermometer is a sample of an ideal gas at constant pressure. From the ideal gas law PV=nRT, the volume of such a sample can be used as an indicator of temperature; in this manner it defines temperature. Although pressure is defined mechanically, a pressure-measuring device, called a barometer may also be constructed from a sample of an ideal gas held at a constant temperature. A calorimeter is a device which is used to measure and define the internal energy of a system.
A thermodynamic reservoir is a system which is so large that it does not appreciably alter its state parameters when brought into contact with the test system. It is used to impose a particular value of a state parameter upon the system. For example, a pressure reservoir is a system at a particular pressure, which imposes that pressure upon any test system that it is mechanically connected to. The earth's atmosphere is often used as a pressure reservoir.
It is important that these two types of instruments are distinct. A meter does not perform its task accurately if it behaves like a reservoir of the state variable it is trying to measure. If, for example, a thermometer were to act as a temperature reservoir it would alter the temperature of the system being measured, and the reading would be incorrect. Ideal meters have no effect on the state variables of the system they are measuring.
# Thermodynamic states
When a system is at equilibrium under a given set of conditions, it is said to be in a definite state. The state of the system can be described by a number of intensive variables and extensive variables. The properties of the system can be described by an equation of state which specifies the relationship between these variables. State may be thought of as the instantaneous quantitative description of a system with a set number of variables held constant
# Thermodynamic processes
A thermodynamic process may be defined as the energetic evolution of a thermodynamic system proceeding from an initial state to a final state. Typically, each thermodynamic process is distinguished from other processes, in energetic character, according to what parameters, as temperature, pressure, or volume, etc., are held fixed. Furthermore, it is useful to group these processes into pairs, in which each variable held constant is one member of a conjugate pair. The seven most common thermodynamic processes are shown below:
- An isobaric process occurs at constant pressure.
- An isochoric process, or isometric/isovolumetric process, occurs at constant volume.
- An isothermal process occurs at a constant temperature.
- An adiabatic process occurs without loss or gain of heat.
- An isentropic process (reversible adiabatic process) occurs at a constant entropy.
- An isenthalpic process occurs at a constant enthalpy.
- A steady state process occurs without a change in the internal energy of a system.
# Quotes & humor
- Attributed to Arnold Sommerfeld:
- Sir Arthur Eddington in The Nature of the Physical World:
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Thermodynamic
Thermodynamics (from the Greek θερμη, therme, meaning "heat"[1] and δυναμις, dunamis, meaning "power") is a branch of physics and of chemistry that studies the effects of changes in temperature, pressure, and volume on physical systems at the macroscopic scale by analysing the collective motion of their particles using statistics.[2][3] Roughly, heat means "energy in transit" and dynamics relates to "movement"; thus, in essence thermodynamics studies the movement of energy and how energy instills movement. Historically, thermodynamics developed out of need to increase the efficiency of early steam engines.[4]
The starting point for most thermodynamic considerations are the laws of thermodynamics, which postulate that energy can be exchanged between physical systems as heat or work.[5] They also postulate the existence of a quantity named entropy, which can be defined for any system.[6] In thermodynamics, interactions between large ensembles of objects are studied and categorized. Central to this are the concepts of system and surroundings. A system is composed of particles, whose average motions define its properties, which in turn are related to one another through equations of state. Properties can be combined to express internal energy and thermodynamic potentials, which are useful for determining conditions for equilibrium and spontaneous processes.
With these tools, thermodynamics describes how systems respond to changes in their surroundings. This can be applied to a wide variety of topics in science and engineering, such as engines, phase transitions, chemical reactions, transport phenomena, and even black holes. The results of thermodynamics are essential for other fields of physics and for chemistry, chemical engineering, aerospace engineering, mechanical engineering, cell biology, biomedical engineering, and materials science to name a few.[7][8]
# History
A brief history of thermodynamics begins with Otto von Guericke who in 1650 built and designed the world's first vacuum pump and created the world's first ever vacuum (known as the Magdeburg hemispheres). He was driven to make a vacuum in order to disprove Aristotle's long-held supposition that 'nature abhors a vacuum'. Shortly thereafter, Irish physicist and chemist Robert Boyle had learned of Guericke's designs and in 1656, in coordination with English scientist Robert Hooke, built an air pump.[9] Using this pump, Boyle and Hooke noticed a correlation between pressure, temperature, and volume. In time, Boyle's Law was formulated, which states that pressure and volume are inversely proportional. Then, in 1679, based on these concepts, an associate of Boyle's named Denis Papin built a bone digester, which was a closed vessel with a tightly fitting lid that confined steam until a high pressure was generated.
Later designs implemented a steam release valve that kept the machine from exploding. By watching the valve rhythmically move up and down, Papin conceived of the idea of a piston and a cylinder engine. He did not, however, follow through with his design. Nevertheless, in 1697, based on Papin's designs, engineer Thomas Savery built the first engine. Although these early engines were crude and inefficient, they attracted the attention of the leading scientists of the time. One such scientist was Sadi Carnot, the "father of thermodynamics", who in 1824 published Reflections on the Motive Power of Fire, a discourse on heat, power, and engine efficiency. The paper outlined the basic energetic relations between the Carnot engine, the Carnot cycle, and Motive power. This marks the start of thermodynamics as a modern science.[2]
The term thermodynamics was coined by James Joule in 1858 to designate the science of relations between heat and power.[2] By 1849, "thermo-dynamics", as a functional term, was used in William Thomson's paper An Account of Carnot's Theory of the Motive Power of Heat.[10] The first thermodynamic textbook was written in 1859 by William Rankine, originally trained as a physicist and a civil and mechanical engineering professor at the University of Glasgow.[11]
# The laws of thermodynamics
In thermodynamics, there are four laws of very general validity, and as such they do not depend on the details of the interactions or the systems being studied. Hence, they can be applied to systems about which one knows nothing other than the balance of energy and matter transfer. Examples of this include Einstein's prediction of spontaneous emission around the turn of the 20th century and current research into the thermodynamics of black holes.
The four laws are:
- Zeroth law of thermodynamics, stating that thermodynamic equilibrium is an equivalence relation.
- First law of thermodynamics, about the conservation of energy
- Second law of thermodynamics, about entropy
- Third law of thermodynamics, about absolute zero temperature
- Onsager reciprocal relations (sometimes called the Fourth Law of Thermodynamics)
# Thermodynamic potentials
As can be derived from the energy balance equation ( or Burks' equation) on a thermodynamic system there exist energetic quantities called thermodynamic potentials, being the quantitative measure of the stored energy in the system. The five most well known potentials are:
Other thermodynamic potentials can be obtained through Legendre transformation. Potentials are used to measure energy changes in systems as they evolve from an initial state to a final state. The potential used depends on the constraints of the system, such as constant temperature or pressure. Internal energy is the internal energy of the system, enthalpy is the internal energy of the system plus the energy related to pressure-volume work, and Helmholtz and Gibbs energy are the energies available in a system to do useful work when the temperature and volume or the pressure and temperature are fixed, respectively.
# Classical thermodynamics
Classical thermodynamics is the original early 1800s variation of thermodynamics concerned with thermodynamic states, and properties as energy, work, and heat, and with the laws of thermodynamics, all lacking an atomic interpretation. In precursory form, classical thermodynamics derives from chemist Robert Boyle’s 1662 postulate that the pressure P of a given quantity of gas varies inversely as its volume V at constant temperature; i.e. in equation form: PV = k, a constant. From here, a semblance of a thermo-science began to develop with the construction of the first successful atmospheric steam engines in England by Thomas Savery in 1697 and Thomas Newcomen in 1712. The first and second laws of thermodynamics emerged simultaneously in the 1850s, primarily out of the works of William Rankine, Rudolf Clausius, and William Thomson (Lord Kelvin).
# Statistical thermodynamics
With the development of atomic and molecular theories in the late 1800s and early 1900s, thermodynamics was given a molecular interpretation. This field is called statistical thermodynamics, which can be thought of as a bridge between macroscopic and microscopic properties of systems. Essentially, statistical thermodynamics is an approach to thermodynamics situated upon statistical mechanics, which focuses on the derivation of macroscopic results from first principles. It can be opposed to its historical predecessor phenomenological thermodynamics, which gives scientific descriptions of phenomena with avoidance of microscopic details. The statistical approach is to derive all macroscopic properties (temperature, volume, pressure, energy, entropy, etc.) from the properties of moving constituent particles and the interactions between them (including quantum phenomena). It was found to be very successful and thus is commonly used.
# Chemical thermodynamics
Chemical thermodynamics is the study of the interrelation of heat with chemical reactions or with a physical change of state within the confines of the laws of thermodynamics. During the years 1873-76 the American mathematical physicist Josiah Willard Gibbs published a series of three papers, the most famous being On the Equilibrium of Heterogeneous Substances, in which he showed how thermodynamic processes could be graphically analyzed, by studying the energy, entropy, volume, temperature and pressure of the thermodynamic system, in such a manner to determine if a process would occur spontaneously.[12] During the early 20th century, chemists such as Gilbert N. Lewis, Merle Randall, and E. A. Guggenheim began to apply the mathematical methods of Gibbs to the analysis of chemical processes.[13]
# Thermodynamic systems
An important concept in thermodynamics is the “system”. Everything in the universe except the system is known as surroundings. A system is the region of the universe under study. A system is separated from the remainder of the universe by a boundary which may be imaginary or not, but which by convention delimits a finite volume. The possible exchanges of work, heat, or matter between the system and the surroundings take place across this boundary. Boundaries are of four types: fixed, moveable, real, and imaginary.
Basically, the “boundary” is simply an imaginary dotted line drawn around a volume of something when there is going to be a change in the internal energy of that something. Anything that passes across the boundary that effects a change in the internal energy of the something needs to be accounted for in the energy balance equation. That something can be the volumetric region surrounding a single atom resonating energy, such as Max Planck defined in 1900; it can be a body of steam or air in a steam engine, such as Sadi Carnot defined in 1824; it can be the body of a tropical cyclone, such as Kerry Emanuel theorized in 1986 in the field of atmospheric thermodynamics; it could also be just one nuclide (i.e. a system of quarks) as some are theorizing presently in quantum thermodynamics.
For an engine, a fixed boundary means the piston is locked at its position; as such, a constant volume process occurs. In that same engine, a moveable boundary allows the piston to move in and out. For closed systems, boundaries are real while for open system boundaries are often imaginary. There are five dominant classes of systems:
- Isolated Systems – matter and energy may not cross the boundary
- Adiabatic Systems – heat must not cross the boundary
- Diathermic Systems - heat may cross boundary
- Closed Systems – matter may not cross the boundary
- Open Systems – heat, work, and matter may cross the boundary (often called a control volume in this case)
As time passes in an isolated system, internal differences in the system tend to even out and pressures and temperatures tend to equalize, as do density differences. A system in which all equalizing processes have gone practically to completion, is considered to be in a state of thermodynamic equilibrium.
In thermodynamic equilibrium, a system's properties are, by definition, unchanging in time. Systems in equilibrium are much simpler and easier to understand than systems which are not in equilibrium. Often, when analysing a thermodynamic process, it can be assumed that each intermediate state in the process is at equilibrium. This will also considerably simplify the situation. Thermodynamic processes which develop so slowly as to allow each intermediate step to be an equilibrium state are said to be reversible processes.
# Thermodynamic parameters
The central concept of thermodynamics is that of energy, the ability to do work. As stipulated by the first law, the total energy of the system and its surroundings is conserved. It may be transferred into a body by heating, compression, or addition of matter, and extracted from a body either by cooling, expansion, or extraction of matter. For comparison, in mechanics, energy transfer results from a force which causes displacement, the product of the two being the amount of energy transferred. In a similar way, thermodynamic systems can be thought of as transferring energy as the result of a generalized force causing a generalized displacement, with the product of the two being the amount of energy transferred. These thermodynamic force-displacement pairs are known as conjugate variables. The most common conjugate thermodynamic variables are pressure-volume (mechanical parameters), temperature-entropy (thermal parameters), and chemical potential-particle number (material parameters).
# Thermodynamic instruments
There are two types of thermodynamic instruments, the meter and the reservoir. A thermodynamic meter is any device which measures any parameter of a thermodynamic system. In some cases, the thermodynamic parameter is actually defined in terms of an idealized measuring instrument. For example, the zeroth law states that if two bodies are in thermal equilibrium with a third body, they are also in thermal equilibrium with each other. This principle, as noted by James Maxwell in 1872, asserts that it is possible to measure temperature. An idealized thermometer is a sample of an ideal gas at constant pressure. From the ideal gas law PV=nRT, the volume of such a sample can be used as an indicator of temperature; in this manner it defines temperature. Although pressure is defined mechanically, a pressure-measuring device, called a barometer may also be constructed from a sample of an ideal gas held at a constant temperature. A calorimeter is a device which is used to measure and define the internal energy of a system.
A thermodynamic reservoir is a system which is so large that it does not appreciably alter its state parameters when brought into contact with the test system. It is used to impose a particular value of a state parameter upon the system. For example, a pressure reservoir is a system at a particular pressure, which imposes that pressure upon any test system that it is mechanically connected to. The earth's atmosphere is often used as a pressure reservoir.
It is important that these two types of instruments are distinct. A meter does not perform its task accurately if it behaves like a reservoir of the state variable it is trying to measure. If, for example, a thermometer were to act as a temperature reservoir it would alter the temperature of the system being measured, and the reading would be incorrect. Ideal meters have no effect on the state variables of the system they are measuring.
# Thermodynamic states
When a system is at equilibrium under a given set of conditions, it is said to be in a definite state. The state of the system can be described by a number of intensive variables and extensive variables. The properties of the system can be described by an equation of state which specifies the relationship between these variables. State may be thought of as the instantaneous quantitative description of a system with a set number of variables held constant
# Thermodynamic processes
A thermodynamic process may be defined as the energetic evolution of a thermodynamic system proceeding from an initial state to a final state. Typically, each thermodynamic process is distinguished from other processes, in energetic character, according to what parameters, as temperature, pressure, or volume, etc., are held fixed. Furthermore, it is useful to group these processes into pairs, in which each variable held constant is one member of a conjugate pair. The seven most common thermodynamic processes are shown below:
- An isobaric process occurs at constant pressure.
- An isochoric process, or isometric/isovolumetric process, occurs at constant volume.
- An isothermal process occurs at a constant temperature.
- An adiabatic process occurs without loss or gain of heat.
- An isentropic process (reversible adiabatic process) occurs at a constant entropy.
- An isenthalpic process occurs at a constant enthalpy.
- A steady state process occurs without a change in the internal energy of a system.
# Quotes & humor
- Attributed to Arnold Sommerfeld:
- Sir Arthur Eddington in The Nature of the Physical World:
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Thiabendazole
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Thiabendazole
# Overview
Tiabendazole (INN, BAN), thiabendazole (AAN, USAN), TBZ and the trade names Mintezol, Tresaderm, and Arbotect) is a fungicide and parasiticide.
# Uses
## Fungicide
It is used primarily to control mold, blight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.
Use in treatment of aspergillosis has been reported.
## Parasiticide
As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis), hookworms, and other helminth species which attack wild animals, livestock and humans.
## Angiogenesis inhibitor
Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells
# Pharmacodynamics
TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.
# Other
Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as lead, mercury, or antimony poisoning.
In dogs and cats, thiabendazole is used to treat ear infections.
Thiabendazole is also used as a food additive, a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU, Australia and New Zealand.
# Safety
The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below Template:LD50 level). Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur. Carcinogenic effects have been shown at higher doses.
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Thiabendazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tiabendazole (INN, BAN), thiabendazole (AAN, USAN), TBZ and the trade names Mintezol, Tresaderm, and Arbotect) is a fungicide and parasiticide.
# Uses
## Fungicide
It is used primarily to control mold, blight, and other fungal diseases in fruits (e.g. oranges) and vegetables; it is also used as a prophylactic treatment for Dutch elm disease.
Use in treatment of aspergillosis has been reported.[1]
## Parasiticide
As an antiparasitic, it is able to control roundworms (such as those causing strongyloidiasis),[2] hookworms, and other helminth species which attack wild animals, livestock and humans.[3]
## Angiogenesis inhibitor
Genes responsible for the maintenance of cell walls in yeast have been shown to be responsible for angiogenesis in vertebrates. Tiabendazole serves to block angiogenesis in both frog embryos and human cells. It has also been shown to serve as a vascular disrupting agent to reduce newly established blood vessels. Tiabendazole has been shown to effectively do this in certain cancer cells [4]
# Pharmacodynamics
TBZ works by inhibition of the mitochondrial, helminth-specific enzyme, fumarate reductase, with possible interaction with endogenous quinone.[5]
# Other
Medicinally, thiabendazole is also a chelating agent, which means it is used medicinally to bind metals in cases of metal poisoning, such as lead, mercury, or antimony poisoning.
In dogs and cats, thiabendazole is used to treat ear infections.
Thiabendazole is also used as a food additive,[6][7] a preservative with E number E233 (INS number 233). For example, it is applied to bananas to ensure freshness, and is a common ingredient in the waxes applied to the skins of citrus fruits. It is not approved as a food additive in the EU,[8] Australia and New Zealand.[9]
# Safety
The substance appears to have a slight toxicity in higher doses, with effects such as liver and intestinal disorders at high exposure in test animals (just below Template:LD50 level).[citation needed] Some reproductive disorders and decreasing weaning weight have been observed, also at high exposure. Effects on humans from use as a drug include nausea, vomiting, loss of appetite, diarrhea, dizziness, drowsiness, or headache; very rarely also ringing in the ears, vision changes, stomach pain, yellowing eyes and skin, dark urine, fever, fatigue, increased thirst and change in the amount of urine occur.[citation needed] Carcinogenic effects have been shown at higher doses.[10]
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e22da43b357166b8e073e343026f1ff784992ee0
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Thiamphenicol
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Thiamphenicol
# Overview
Thiamphenicol (also known as thiophenicol and dextrosulphenidol) is an antibiotic. It is the methyl-sulfonyl analogue of chloramphenicol and has a similar spectrum of activity, but is 2.5 to 5 times as potent. Like chloramphenicol, it is insoluble in water, but highly soluble in lipids. It is used in many countries as a veterinary antibiotic, but is available in China, Morocco and Italy for use in humans. Its main advantage over chloramphenicol is that it has never been associated with aplastic anaemia.
Thiamphenicol is also widely used in Brazil, particularly for the treatment of sexually transmitted infections and pelvic inflammatory disease.
Unlike chloramphenicol, thiamphenicol is not readily metabolized in cattle, poultry, sheep, or humans, but is predominantly excreted unchanged. In pigs and rats the drug is excreted both as parent drug and as thiamphenicol glucuronate (FAO, 1997).
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Thiamphenicol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Thiamphenicol (also known as thiophenicol and dextrosulphenidol) is an antibiotic. It is the methyl-sulfonyl analogue of chloramphenicol and has a similar spectrum of activity, but is 2.5 to 5 times as potent. Like chloramphenicol, it is insoluble in water, but highly soluble in lipids. It is used in many countries as a veterinary antibiotic, but is available in China, Morocco and Italy for use in humans. Its main advantage over chloramphenicol is that it has never been associated with aplastic anaemia.
Thiamphenicol is also widely used in Brazil, particularly for the treatment of sexually transmitted infections and pelvic inflammatory disease.[1]
Unlike chloramphenicol, thiamphenicol is not readily metabolized in cattle, poultry, sheep, or humans, but is predominantly excreted unchanged. In pigs and rats the drug is excreted both as parent drug and as thiamphenicol glucuronate (FAO, 1997).
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1fcbe648ed5cd1e1703af70796262dd042dcc070
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Thioacetazone
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Thioacetazone
Thioacetazone(INN and BAN) is also called thiocetazone, thiacetazone, thiosemicarbazone, benzothiozane or amithiozone(USAN); abbreviated T.
Thioacetazone is used in the treatment of tuberculosis; it has only weak activity against Mycobacterium tuberculosis and is only useful in preventing resistance to more powerful drugs like isoniazid and rifampicin. It is never used on its own to treat tuberculosis; it is used in a similar way to ethambutol. Thioacetazone is the only anti-TB drug that is ineffective when given intermittently.
There is no advantage to using thioacetazone if the regimen used already contains ethambutol, but many countries in sub-Saharan Africa still use thioacetazone because it is extremely cheap. Use of thioacetazone is declining because it can cause severe (sometimes fatal) skin reactions in HIV positive patients.
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Thioacetazone
Thioacetazone(INN and BAN) is also called thiocetazone, thiacetazone, thiosemicarbazone, benzothiozane or amithiozone(USAN); abbreviated T.
Thioacetazone is used in the treatment of tuberculosis; it has only weak activity against Mycobacterium tuberculosis and is only useful in preventing resistance to more powerful drugs like isoniazid and rifampicin. It is never used on its own to treat tuberculosis; it is used in a similar way to ethambutol. Thioacetazone is the only anti-TB drug that is ineffective when given intermittently.
There is no advantage to using thioacetazone if the regimen used already contains ethambutol, but many countries in sub-Saharan Africa still use thioacetazone because it is extremely cheap. Use of thioacetazone is declining because it can cause severe (sometimes fatal) skin reactions in HIV positive patients.[1][2]
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https://www.wikidoc.org/index.php/Thioacetazone
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26b95b89fcff85e599e70c40a266681d625f328f
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Thomas Willis
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Thomas Willis
Thomas Willis (January 27, 1621 – November 11, 1675) was an English doctor who played an important part in the history of the science of anatomy, neurology and psychiatry. He was a co-founder of the Royal Society (1662).
Born in Great Bedwyn, Wiltshire, Willis worked as a physician in Westminster, London, and from 1660 until his death was Sedleian Professor of Natural Philosophy at Oxford. He was a pioneer in research into the anatomy of the brain, nervous system and muscles. The "circle of Willis", a part of the brain, was his discovery.
His anatomy of the brain and nerves, as described in his Cerebri anatomi of 1664, is so minute and elaborate, and abounds so much in new information, that it presents an enormous contrast with the vague and meagre efforts of his predecessors. This work was not the result of his own personal and unaided exertions; he acknowledged his debt to Sir Christopher Wren and Thomas Millington, and his fellow anatomist Richard Lower. This work coined the term neurology.
In 1667 he published 'Pathologicae cerebri, et nervosi generis specimen', an important work on the pathology and neurophysiology of the brain. In it he developed a new theory of the cause of epilepsy and other convulsive diseases, and contributed to the development of psychiatry. In 1672 he published the earliest English work on medical psychology, 'Two Discourses concerning The Soul of Brutes, Which is that of the Vital and Sensitive of Man'.
Willis was the first to number the cranial nerves in the order in which they are now usually enumerated by anatomists. His observation of the connexion of the eighth pair with the slender nerve which issues from the beginning of the spinal cord is known to all. He remarked the parallel lines of the mesolobe, afterwards minutely described by Félix Vicq-d'Azyr. He seems to have recognized the communication of the convoluted surface of the brain and that between the lateral cavities beneath the fornix. He described the corpora striata and optic thalami; the four orbicular eminences, with the bridge, which he first named annular protuberance; and the white mammillary eminences, behind the infundibulum. In the cerebellum he remarks the arborescent arrangement of the white and grey matter, and gives a good account of the internal carotids, and the communications which they make with the branches of the basilar artery.
# Sources
- Encyclopedia Britannica
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Thomas Willis
Thomas Willis (January 27, 1621 – November 11, 1675) was an English doctor who played an important part in the history of the science of anatomy, neurology and psychiatry. He was a co-founder of the Royal Society (1662).
Born in Great Bedwyn, Wiltshire, Willis worked as a physician in Westminster, London, and from 1660 until his death was Sedleian Professor of Natural Philosophy at Oxford. He was a pioneer in research into the anatomy of the brain, nervous system and muscles. The "circle of Willis", a part of the brain, was his discovery.
His anatomy of the brain and nerves, as described in his Cerebri anatomi of 1664, is so minute and elaborate, and abounds so much in new information, that it presents an enormous contrast with the vague and meagre efforts of his predecessors. This work was not the result of his own personal and unaided exertions; he acknowledged his debt to Sir Christopher Wren and Thomas Millington, and his fellow anatomist Richard Lower. This work coined the term neurology.
In 1667 he published 'Pathologicae cerebri, et nervosi generis specimen', an important work on the pathology and neurophysiology of the brain. In it he developed a new theory of the cause of epilepsy and other convulsive diseases, and contributed to the development of psychiatry. In 1672 he published the earliest English work on medical psychology, 'Two Discourses concerning The Soul of Brutes, Which is that of the Vital and Sensitive of Man'.[1]
Willis was the first to number the cranial nerves in the order in which they are now usually enumerated by anatomists. His observation of the connexion of the eighth pair with the slender nerve which issues from the beginning of the spinal cord is known to all. He remarked the parallel lines of the mesolobe, afterwards minutely described by Félix Vicq-d'Azyr. He seems to have recognized the communication of the convoluted surface of the brain and that between the lateral cavities beneath the fornix. He described the corpora striata and optic thalami; the four orbicular eminences, with the bridge, which he first named annular protuberance; and the white mammillary eminences, behind the infundibulum. In the cerebellum he remarks the arborescent arrangement of the white and grey matter, and gives a good account of the internal carotids, and the communications which they make with the branches of the basilar artery.
# Sources
- Encyclopedia Britannica
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Thoracic duct
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Thoracic duct
In human anatomy, the thoracic duct is an important part of the lymphatic system—it is the largest lymphatic vessel in the body.
It collects most of the lymph in the body (except that from the right arm and the right side of the chest, neck and head, which is collected by the right lymphatic duct) and drains into the systemic (blood) circulation at the left subclavian vein.
# Location and direction of flow
In adults, the thoracic duct is typically 38-45cm in length and an average diameter of about 5mm. It usually starts from the level of the second lumbar vertebra and extends to the root of the neck.
It originates in the abdomen from the confluence of the right and left lumbar trunk and the intestinal trunk, forming a significant pathway upward called the cisterna chyli.
It extends vertically in the chest and curves posteriorly to the left carotid artery and left jugular vein at the C7 vertebral level to empty into the junction of the left subclavian vein and left jugular vein, below the clavicle, near the shoulders.
It traverses the diaphragm at the aortic aperture and ascends the posterior mediastinum between the descending thoracic aorta (to its left) and the azygos vein (to its right).
# Volume, mechanism, and direction of flow
In adults, the thoracic duct transports up to 4 L of lymph per day.
The lymph transport in the thoracic duct is mainly caused by the action of breathing, aided by the duct's smooth muscle and by internal one way valves which prevent the lymph from flowing back down again.
There are also two valves at the junction of the duct with the left subclavian vein, to prevent the flow of venous blood into the duct.
# Clinical significance
When the thoracic duct is blocked or damaged a large amount of lymph can quickly accumulate in the pleural cavity, this situation is called chylothorax.
The first sign of a malignancy (especially an intraabdominal one) may be an enlarged Virchow's node, a lymph node in the left supraclavicular area, in the vicinity where the thoracic duct empties into the left subclavian vein.
# Nomenclature
It is also known under various other names including the alimentary duct, chyliferous duct, duct of Pecquet, the left lymphatic duct and Van Hoorne's canal.
# Additional images
- Transverse section of thorax, showing relations of pulmonary artery.
- The arch of the aorta, and its branches.
- Deep lymph nodes and vessels of the thorax and abdomen (diagrammatic).
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
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Thoracic duct
Template:Infobox Lymph
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In human anatomy, the thoracic duct is an important part of the lymphatic system—it is the largest lymphatic vessel in the body.
It collects most of the lymph in the body (except that from the right arm and the right side of the chest, neck and head, which is collected by the right lymphatic duct) and drains into the systemic (blood) circulation at the left subclavian vein.
# Location and direction of flow
In adults, the thoracic duct is typically 38-45cm in length and an average diameter of about 5mm. It usually starts from the level of the second lumbar vertebra and extends to the root of the neck.
It originates in the abdomen from the confluence of the right and left lumbar trunk and the intestinal trunk, forming a significant pathway upward called the cisterna chyli.
It extends vertically in the chest and curves posteriorly to the left carotid artery and left jugular vein at the C7 vertebral level to empty into the junction of the left subclavian vein and left jugular vein, below the clavicle, near the shoulders.
It traverses the diaphragm at the aortic aperture and ascends the posterior mediastinum between the descending thoracic aorta (to its left) and the azygos vein (to its right).
# Volume, mechanism, and direction of flow
In adults, the thoracic duct transports up to 4 L of lymph per day.
The lymph transport in the thoracic duct is mainly caused by the action of breathing, aided by the duct's smooth muscle and by internal one way valves which prevent the lymph from flowing back down again.
There are also two valves at the junction of the duct with the left subclavian vein, to prevent the flow of venous blood into the duct.
# Clinical significance
When the thoracic duct is blocked or damaged a large amount of lymph can quickly accumulate in the pleural cavity, this situation is called chylothorax.
The first sign of a malignancy (especially an intraabdominal one) may be an enlarged Virchow's node, a lymph node in the left supraclavicular area, in the vicinity where the thoracic duct empties into the left subclavian vein.
# Nomenclature
It is also known under various other names including the alimentary duct, chyliferous duct, duct of Pecquet, the left lymphatic duct and Van Hoorne's canal. [1]
# Additional images
- Transverse section of thorax, showing relations of pulmonary artery.
- The arch of the aorta, and its branches.
- Deep lymph nodes and vessels of the thorax and abdomen (diagrammatic).
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
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Thou (length)
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Thou (length)
A thou, also known as a mil, is a unit of length equal to 0.001 inches (a "milli-inch" or a "thousandth of one inch"). It is sometimes used in engineering and in the specification of:
- the thickness of items such as paper, film, foil, wires, paint coatings, latex gloves, plastic sheeting, and fibers; and
- manufacturing dimensions and tolerances.
As the metric system became more common in the States, use of the term mil began to decline among technical users due to the possible confusion with millimeters. However, the mil is still in common use in the United States for the thickness of plastic sheeting or bags.
Internationally, use of the thou is now generally deprecated in favour of the use of SI units of length such as the micrometre. In the United States, the mil/thou is still in use extensively in certain industries such as in the manufacture of printed circuit boards (PCBs).
The plural of thou is also thou, e.g. a measurement of one hundredth of an inch is described as "10 thou". The th in thou is pronounced as in thousand, Template:IPAEng, unlike the pronoun thou, Template:IPA, where the th is pronounced as in that.
The plural of mil is mils.
There is a related measurement for area known as the circular mil, based on a circle having a diameter of one mil. Because of this relationship, a mil and a circular mil might be easily confused.
# Equivalence to other units of length
1 thou is equal to:
- 0.001 international inches (1 international inch is equal to 1,000 thou)
- 0.0254 mm, or 25.4 μm (1 millimetre is about equal to 39.37 thou)
# Notes
- ↑ Mil at How Many? A Dictionary of Units of Measurement by Russ Rowlett
- ↑ Thou at How Many? A Dictionary of Units of Measurement by Russ Rowlett
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Thou (length)
Template:Unit of length
A thou, also known as a mil, is a unit of length equal to 0.001 inches (a "milli-inch" or a "thousandth of one inch"). It is sometimes used in engineering and in the specification of:
- the thickness of items such as paper, film, foil, wires, paint coatings, latex gloves, plastic sheeting, and fibers; and
- manufacturing dimensions and tolerances.
As the metric system became more common in the States, use of the term mil began to decline among technical users due to the possible confusion with millimeters.[1][2] However, the mil is still in common use in the United States for the thickness of plastic sheeting or bags.
Internationally, use of the thou is now generally deprecated in favour of the use of SI units of length such as the micrometre. In the United States, the mil/thou is still in use extensively in certain industries such as in the manufacture of printed circuit boards (PCBs).
The plural of thou is also thou, e.g. a measurement of one hundredth of an inch is described as "10 thou". The th in thou is pronounced as in thousand, Template:IPAEng, unlike the pronoun thou, Template:IPA, where the th is pronounced as in that.
The plural of mil is mils.
There is a related measurement for area known as the circular mil, based on a circle having a diameter of one mil. Because of this relationship, a mil and a circular mil might be easily confused.
# Equivalence to other units of length
1 thou is equal to:
- 0.001 international inches (1 international inch is equal to 1,000 thou)
- 0.0254 mm, or 25.4 μm (1 millimetre is about equal to 39.37 thou)
# Notes
- ↑ Mil at How Many? A Dictionary of Units of Measurement by Russ Rowlett
- ↑ Thou at How Many? A Dictionary of Units of Measurement by Russ Rowlett
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ku:Mil
nl:Mil (lengtemaat)
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Tissue factor
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Tissue factor
Tissue factor, also called platelet tissue factor, factor III, or CD142 is a protein encoded by the F3 gene, present in subendothelial tissue and leukocytes. Its role in the clotting process is the initiation of thrombin formation from the zymogen prothrombin. Thromboplastin defines the cascade that leads to the activation of factor X - the tissue factor pathway. In doing so it has replaced the previously named extrinsic pathway in order to eliminate ambiguity.
# Function
The F3 gene encodes coagulation factor III which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces. There are 3 distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described. In addition to the membrane-bound tissue factor, soluble form of tissue factor was also found which results from alternatively spliced tissue factor mRNA transcripts, in which exon 5 is absent and exon 4 is spliced directly to exon 6.
## Coagulation
TF is the cell surface receptor for the serine protease factor VIIa.
The best known function of tissue factor is its role in blood coagulation. The complex of TF with factor VIIa catalyzes the conversion of the inactive protease factor X into the active protease factor Xa.
Together with factor VIIa, tissue factor forms the tissue factor or extrinsic pathway of coagulation. This is opposed to the intrinsic (amplification) pathway which involves both activated factor IX and factor VIII. Both pathways lead to the activation of factor X (the common pathway) which combines with activated factor V in the presence of calcium and phospholipid to produce thrombin (thromboplastin activity).
## Cytokine signaling
TF is related to a protein family known as the cytokine receptor class II family. The members of this receptor family are activated by cytokines. Cytokines are small proteins that can influence the behavior of white blood cells. Binding of VIIa to TF has also been found to start signaling processes inside the cell. The signaling function of TF/VIIa plays a role in angiogenesis and apoptosis. Pro-inflammatory and pro-angiogenic responses are activated by TF/VIIa mediated cleavage by the protease-activated receptor 2 (PAR2). EphB2 and EphA2 of the Eph tyrosine kinase receptor (RTK) family can also be cleaved by TF/VIIa.
# Structure
Tissue factor belongs to the cytokine receptor protein superfamily and consists of three domains:
- an extracellular domain, which consists of two fibronectin type III modules whose hydrophobic cores merge in the domain-domain interface. This serves as a (probably rigid) template for factor VIIa binding.
- a transmembrane domain.
- a cytosolic domain of 21 amino acids length inside the cell which is involved in the signaling function of TF.
Note that one of factor VIIa's domains, GLA domain, binds in the presence of calcium to negatively charged phospholipids, and this binding greatly enhances factor VIIa binding to tissue factor.
# Tissue distribution
Some cells release TF in response to blood vessel damage (see next paragraph) and some do only in response to inflammatory mediators (endothelial cells/macrophages).
TF is expressed by cells which are normally not exposed to flowing blood such as sub-endothelial cells (e.g. smooth muscle cells) and cells surrounding blood vessels (e.g. fibroblasts). This can change when the blood vessel is damaged by for example physical injury or rupture of atherosclerotic plaques. Exposure of TF expressing cells during injury allows the complex formation of TF with factor VII. Factor VII and TF form an equal molar complex in the presence of calcium ions and this leads to the activation of factor VII on a membrane surface.
The inner surface of the blood vessel consists of endothelial cells. Endothelial cells do not express TF except when they are exposed to inflammatory molecules such as tumor necrosis factor-alpha (TNF-alpha). Another cell type that expresses TF on the cell surface in inflammatory conditions is the monocyte (a white blood cell).
# Thromboplastin
Historically, thromboplastin was a lab reagent, usually derived from placental sources, used to assay prothrombin times (PT time). Thromboplastin, by itself, could activate the extrinsic coagulation pathway. When manipulated in the laboratory, a derivative could be created called partial thromboplastin, which was used to measure the intrinsic pathway. This test is called the aPTT, or activated partial thromboplastin time. It was not until much later that the subcomponents of thromboplastin and partial thromboplastin were identified. Thromboplastin contains phospholipids as well as tissue factor, both of which needed in the activation of the extrinsic pathway, whereas partial thromboplastin does not contain tissue factor. Tissue factor is not needed to activate the intrinsic pathway.
# Interactions
Tissue factor has been shown to interact with Factor VII.
# Additional images
- Tissue factor
- Blood plasma after the addition of tissue factor
Blood plasma after the addition of tissue factor
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Tissue factor
Tissue factor, also called platelet tissue factor, factor III, or CD142 is a protein encoded by the F3 gene, present in subendothelial tissue and leukocytes. Its role in the clotting process is the initiation of thrombin formation from the zymogen prothrombin. Thromboplastin defines the cascade that leads to the activation of factor X - the tissue factor pathway. In doing so it has replaced the previously named extrinsic pathway in order to eliminate ambiguity.
# Function
The F3 gene encodes coagulation factor III which is a cell surface glycoprotein. This factor enables cells to initiate the blood coagulation cascades, and it functions as the high-affinity receptor for the coagulation factor VII. The resulting complex provides a catalytic event that is responsible for initiation of the coagulation protease cascades by specific limited proteolysis. Unlike the other cofactors of these protease cascades, which circulate as nonfunctional precursors, this factor is a potent initiator that is fully functional when expressed on cell surfaces. There are 3 distinct domains of this factor: extracellular, transmembrane, and cytoplasmic. This protein is the only one in the coagulation pathway for which a congenital deficiency has not been described.[1] In addition to the membrane-bound tissue factor, soluble form of tissue factor was also found which results from alternatively spliced tissue factor mRNA transcripts, in which exon 5 is absent and exon 4 is spliced directly to exon 6.[2][3]
## Coagulation
TF is the cell surface receptor for the serine protease factor VIIa.
The best known function of tissue factor is its role in blood coagulation. The complex of TF with factor VIIa catalyzes the conversion of the inactive protease factor X into the active protease factor Xa.
Together with factor VIIa, tissue factor forms the tissue factor or extrinsic pathway of coagulation. This is opposed to the intrinsic (amplification) pathway which involves both activated factor IX and factor VIII. Both pathways lead to the activation of factor X (the common pathway) which combines with activated factor V in the presence of calcium and phospholipid to produce thrombin (thromboplastin activity).
## Cytokine signaling
TF is related to a protein family known as the cytokine receptor class II family. The members of this receptor family are activated by cytokines. Cytokines are small proteins that can influence the behavior of white blood cells. Binding of VIIa to TF has also been found to start signaling processes inside the cell. The signaling function of TF/VIIa plays a role in angiogenesis and apoptosis. Pro-inflammatory and pro-angiogenic responses are activated by TF/VIIa mediated cleavage by the protease-activated receptor 2 (PAR2).[4] EphB2 and EphA2 of the Eph tyrosine kinase receptor (RTK) family can also be cleaved by TF/VIIa.[5]
# Structure
Tissue factor belongs to the cytokine receptor protein superfamily and consists of three domains:[6]
- an extracellular domain, which consists of two fibronectin type III modules whose hydrophobic cores merge in the domain-domain interface. This serves as a (probably rigid) template for factor VIIa binding.
- a transmembrane domain.
- a cytosolic domain of 21 amino acids length inside the cell which is involved in the signaling function of TF.
Note that one of factor VIIa's domains, GLA domain, binds in the presence of calcium to negatively charged phospholipids, and this binding greatly enhances factor VIIa binding to tissue factor.
# Tissue distribution
Some cells release TF in response to blood vessel damage (see next paragraph) and some do only in response to inflammatory mediators (endothelial cells/macrophages).
TF is expressed by cells which are normally not exposed to flowing blood such as sub-endothelial cells (e.g. smooth muscle cells) and cells surrounding blood vessels (e.g. fibroblasts). This can change when the blood vessel is damaged by for example physical injury or rupture of atherosclerotic plaques. Exposure of TF expressing cells during injury allows the complex formation of TF with factor VII. Factor VII and TF form an equal molar complex in the presence of calcium ions and this leads to the activation of factor VII on a membrane surface.
The inner surface of the blood vessel consists of endothelial cells. Endothelial cells do not express TF except when they are exposed to inflammatory molecules such as tumor necrosis factor-alpha (TNF-alpha). Another cell type that expresses TF on the cell surface in inflammatory conditions is the monocyte (a white blood cell).
# Thromboplastin
Historically, thromboplastin was a lab reagent, usually derived from placental sources, used to assay prothrombin times (PT time). Thromboplastin, by itself, could activate the extrinsic coagulation pathway. When manipulated in the laboratory, a derivative could be created called partial thromboplastin, which was used to measure the intrinsic pathway. This test is called the aPTT, or activated partial thromboplastin time. It was not until much later that the subcomponents of thromboplastin and partial thromboplastin were identified. Thromboplastin contains phospholipids as well as tissue factor, both of which needed in the activation of the extrinsic pathway, whereas partial thromboplastin does not contain tissue factor. Tissue factor is not needed to activate the intrinsic pathway.
# Interactions
Tissue factor has been shown to interact with Factor VII.[7][8]
# Additional images
- Tissue factor
- Blood plasma after the addition of tissue factor
Blood plasma after the addition of tissue factor
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Thumb sucking
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Thumb sucking
# Overview
Thumb sucking is the act of putting the thumb into the mouth and rhythmically repeating sucking contact for a prolonged duration. It can also be accomplished with any piece of skin within reach (such as the big toe) and is considered to be soothing and therapeutic for the person. Thumb sucking is generally associated with babies and young children.
Children suck on objects (including pacifiers) to soothe themselves; sucking is one of a baby’s natural reflexes and completely typical for babies and young children.
Although some adults do suck their thumbs it is rarely performed in public, which leads many to believe that adults do not suck their thumbs at all. The private act of thumb sucking by adults is due to the fear of embarrassment or shyness. There are some stigmas attached to thumb sucking in public for adults.
Thumb sucking can start as early as 15 weeks of growth in the uterus or within months of being born. Prior to 12 weeks, the fetus has webbed digits. Most thumb-suckers stop gradually by the age of five years. Rarely does it continue into adulthood. It is not uncommon for thumb-suckers to suck both thumbs or their fingers. Finger sucking is synonymous with thumb sucking in effect and treatment, but less common.
# Dental problems
Thumb-sucking can cause problems for dental development. To prevent their children from sucking their thumbs some parents put hot sauce or sour potions on their child's thumbs — although this is not a procedure encouraged by the American Dental Association: or the Association of Pediatric Dentists . During the 1950s, parents could get a series of sharp prongs known as "hay-rakes" cemented to a child's teeth to discourage sucking.
Most children stop sucking on thumbs, pacifiers or other objects on their own between two and four years of age. No harm is done to their teeth or jaws until permanent teeth start to erupt. The only time it might cause concern is if it goes on beyond 6 to 8 years of age. At this time, it may affect the shape of the oral cavity or dentition.
Tips from the American Dental Association :
- Praise children for not sucking, instead of scolding them when they do.
- If a child is sucking their thumb when feeling insecure or needing comfort, focus instead on correcting the cause of the anxiety and provide comfort to your child.
- If a child is sucking on their thumb because of boredom, try getting a child's attention with a fun activity.
- Involve older children in the selection of a means to cease thumb sucking.
- The pediatric dentist can offer encouragement to a child and explain what could happen to their teeth if they do not stop sucking.
- Only if these tips are ineffective, remind the child of their habit by bandaging the thumb or putting a sock/glove on the hand at night.
Summary of Best Practices Recommendations:
- American Academy of Pediatrics : Most children suck their thumbs or fingers at some time in their early life. The only time it might cause concern is if it goes on beyond 6 to 8 years of age or affects the shape of the child's mouth and the position of teeth.
- American Dental Association : Children suck on objects as a natural reflex; however, during and after the eruption of the permanent teeth, such sucking may cause problems with the skeletal development of the mouth and alignment of the teeth.
# Thumb sucking and sexuality
Sigmund Freud considered thumb sucking a form of sexual expression and used it to study infantile sexuality. Passionate sucking can consume all of a child's attention, leading either to sleep or even in some cases to a motor reaction in a kind of orgasm. Furthermore, the rubbing of certain sensitive parts of the body (such as the genitals) is often combined with sucking. In this way children can move from thumb sucking to masturbation.
In 1919, in issue 20 of Neurologisches Zentralblatt Dr. Galant published the confession of a young woman who had not given up this activity as a child in which she described the satisfaction derived from it as analogous to sexual satisfaction.
# Media references
- The 2005 movie Thumbsucker by director Mike Mills focuses on a 17 year old teenager who has the habit of sucking his thumb. It was based on a 1999 novel of the same name by Walter Kirn.
- Walt Disney Studio's 1973 film Robin Hood portrays Prince John as an adult thumb sucker.
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Thumb sucking
# Overview
Thumb sucking is the act of putting the thumb into the mouth and rhythmically repeating sucking contact for a prolonged duration. It can also be accomplished with any piece of skin within reach (such as the big toe) and is considered to be soothing and therapeutic for the person. Thumb sucking is generally associated with babies and young children.
Children suck on objects (including pacifiers) to soothe themselves; sucking is one of a baby’s natural reflexes and completely typical for babies and young children.
Although some adults do suck their thumbs it is rarely performed in public, which leads many to believe that adults do not suck their thumbs at all. The private act of thumb sucking by adults is due to the fear of embarrassment or shyness. There are some stigmas attached to thumb sucking in public for adults.
Thumb sucking can start as early as 15 weeks of growth in the uterus or within months of being born. Prior to 12 weeks, the fetus has webbed digits. Most thumb-suckers stop gradually by the age of five years. Rarely does it continue into adulthood. It is not uncommon for thumb-suckers to suck both thumbs or their fingers. Finger sucking is synonymous with thumb sucking in effect and treatment, but less common.
# Dental problems
Thumb-sucking can cause problems for dental development. To prevent their children from sucking their thumbs some parents put hot sauce or sour potions on their child's thumbs — although this is not a procedure encouraged by the American Dental Association[1]: or the Association of Pediatric Dentists [2]. During the 1950s, parents could get a series of sharp prongs known as "hay-rakes" cemented to a child's teeth to discourage sucking.
Most children stop sucking on thumbs, pacifiers or other objects on their own between two and four years of age. No harm is done to their teeth or jaws until permanent teeth start to erupt. The only time it might cause concern is if it goes on beyond 6 to 8 years of age. At this time, it may affect the shape of the oral cavity or dentition.
Tips from the American Dental Association [3]:
- Praise children for not sucking, instead of scolding them when they do.
- If a child is sucking their thumb when feeling insecure or needing comfort, focus instead on correcting the cause of the anxiety and provide comfort to your child.
- If a child is sucking on their thumb because of boredom, try getting a child's attention with a fun activity.
- Involve older children in the selection of a means to cease thumb sucking.
- The pediatric dentist can offer encouragement to a child and explain what could happen to their teeth if they do not stop sucking.
- Only if these tips are ineffective, remind the child of their habit by bandaging the thumb or putting a sock/glove on the hand at night.
Summary of Best Practices Recommendations:
- American Academy of Pediatrics [4]: Most children suck their thumbs or fingers at some time in their early life. The only time it might cause concern is if it goes on beyond 6 to 8 years of age or affects the shape of the child's mouth and the position of teeth.
- American Dental Association [5]: Children suck on objects as a natural reflex; however, during and after the eruption of the permanent teeth, such sucking may cause problems with the skeletal development of the mouth and alignment of the teeth.
# Thumb sucking and sexuality
Sigmund Freud considered thumb sucking a form of sexual expression and used it to study infantile sexuality. Passionate sucking can consume all of a child's attention, leading either to sleep or even in some cases to a motor reaction in a kind of orgasm. Furthermore, the rubbing of certain sensitive parts of the body (such as the genitals) is often combined with sucking. In this way children can move from thumb sucking to masturbation.[3]
In 1919, in issue 20 of Neurologisches Zentralblatt Dr. Galant published the confession of a young woman who had not given up this activity as a child in which she described the satisfaction derived from it as analogous to sexual satisfaction.[3]
# Media references
- The 2005 movie Thumbsucker by director Mike Mills focuses on a 17 year old teenager who has the habit of sucking his thumb. It was based on a 1999 novel of the same name by Walter Kirn.
- Walt Disney Studio's 1973 film Robin Hood portrays Prince John as an adult thumb sucker.
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Thyroid gland
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Thyroid gland
# Overview
The thyroid is one of the largest endocrine glands in the body. This gland is found in the neck just below the Adam's apple. The thyroid controls how quickly the body burns energy, makes proteins, and how sensitive the body should be to other hormones.
The thyroid participates in these processes by producing thyroid hormones, principally thyroxine (T4) and triiodothyronine (T3). These hormones regulate the rate of metabolism and affect the growth and rate of function of many other systems in the body. Iodine is an essential component of both T3 and T4. The thyroid also produces the hormone calcitonin, which plays a role in calcium homeostasis.
The thyroid is controlled by the hypothalamus and pituitary. The gland gets its name from the Greek word for "shield", after its shape, a double-lobed structure. Hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid) are the most common problems of the thyroid gland. Specialists are called Thyroidologists.
# Anatomy
The thyroid is situated on the anterior side of the neck, starting at the oblique line on the thyroid cartilage (just below the laryngeal prominence or Adam's apple), and extending to the 6th Tracheal ring (C-shaped cartilagenous ring of the trachea). It is inappropriate to demarcate the gland's upper and lower border with vertebral levels as it moves position in relation to these during swallowing. It lies over the trachea and is covered by layers of pretracheal fascia (allowing it to move), muscle and skin.
The thyroid is one of the larger endocrine glands - 10-20 grams in adults - and butterfly-shaped. The wings correspond to the lobes and the body to the isthmus of the thyroid. The isthmus overlies tracheal rings 2, 3 and 4. The thyroid may enlarge substantially during pregnancy and when affected by a variety of diseases.
## Embryologic development
The thyroid is derived from the third branchial pouch. In the fetus, at 3-4 weeks of gestation, the thyroid gland appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue between the tuberculum impar and the copula linguae at a point latter indicated by the foramen cecum.
Subsequently the thyroid descends in front of the pharyngeal gut as a bilobed diverticulum through the thyroglossal duct. Over the next few weeks, it migrates to the base of the neck. During migration, the thyroid remains connected to the tongue by a narrow canal, the thyroglossal duct.
Follicles of the thyroid begin to make colloid in the 11th week and thyroxine by the 18th week.
## Histology
At a histological level, there are three primary features of the thyroid:
# Physiology
The primary function of the thyroid is production of the hormones thyroxine (T4), triiodothyronine (T3), and calcitonin. Up to 80% of the T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. T3 is about ten times more active than T4.
## T3 and T4 production and action
Thyroxine is synthesised by the follicular cells from free tyrosine and on the tyrosine residues of the protein called thyroglobulin (TG). Iodine is captured with the "iodine trap" by the hydrogen peroxide generated by the enzyme thyroid peroxidase (TPO) and linked to the 3' and 5' sites of the benzene ring of the tyrosine residues on TG, and on free tyrosine. Upon stimulation by the thyroid-stimulating hormone (TSH), the follicular cells reabsorb TG and proteolytically cleave the iodinated tyrosines from TG, forming T4 and T3 (in T3, one iodine is absent compared to T4), and releasing them into the blood. Deiodinase enzymes convert T4 to T3. Thyroid hormone that is secreted from the gland is about 90% T4 and about 10% T3.
Cells of the brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a particularly crucial role in brain development during pregnancy. A transport protein (OATP1C1) has been identified that seems to be important for T4 transport across the blood brain barrier. A second transport protein (MCT8) is important for T3 transport across brain cell membranes.
In the blood, T4 and T3 are partially bound to thyroxine-binding globulin, transthyretin and albumin. Only a very small fraction of the circulating hormone is free (unbound) - T4 0.03% and T3 0.3%. Only the free fraction has hormonal activity. As with the steroid hormones and retinoic acid, thyroid hormones cross the cell membrane and bind to intracellular receptors (α1, α2, β1 and β2), which act alone, in pairs or together with the retinoid X-receptor as transcription factors to modulate DNA transcription.
## T3 and T4 regulation
The production of thyroxine and triiodothyronine is regulated by thyroid-stimulating hormone (TSH), released by the anterior pituitary. The thyroid and thyrotropes form a negative feedback loop: TSH production is suppressed when the T4 levels are high, and vice versa. The TSH production itself is modulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold (in which an accelerated metabolism would generate more heat). TSH production is blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones (estrogen and testosterone), and excessively high blood iodide concentration.
## Calcitonin
An additional hormone produced by the thyroid contributes to the regulation of blood calcium levels. Parafollicular cells produce calcitonin in response to hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to the effects of parathyroid hormone (PTH). However, calcitonin seems far less essential than PTH, as calcium metabolism remains clinically normal after removal of the thyroid, but not the parathyroids.
It may be used diagnostically as a tumor marker for a form of thyroid cancer (medullary thyroid adenocarcinoma), in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g. swollen lymph nodes) to establish whether they are metastasis of the original cancer.
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.
## Significance of iodine
In areas of the world where iodine (essential for the production of thyroxine, which contains four iodine atoms) is lacking in the diet, the thyroid gland can be considerably enlarged, resulting in the swollen necks of endemic goitre.
Thyroxine is critical to the regulation of metabolism and growth throughout the animal kingdom. Among amphibians, for example, administering a thyroid-blocking agent such as propylthiouracil (PTU) can prevent tadpoles from metamorphosing into frogs; conversely, administering thyroxine will trigger metamorphosis.
In humans, children born with thyroid hormone deficiency will have physical growth and development problems, and brain development can also be severely impaired, in the condition referred to as cretinism. Newborn children in many developed countries are now routinely tested for thyroid hormone deficiency as part of newborn screening by analysis of a drop of blood. Children with thyroid hormone deficiency are treated by supplementation with synthetic thyroxine, which enables them to grow and develop normally.
Because of the thyroid's selective uptake and concentration of what is a fairly rare element, it is sensitive to the effects of various radioactive isotopes of iodine produced by nuclear fission. In the event of large accidental releases of such material into the environment, the uptake of radioactive iodine isotopes by the thyroid can, in theory, be blocked by saturating the uptake mechanism with a large surplus of non-radioactive iodine, taken in the form of potassium iodide tablets. While biological researchers making compounds labelled with iodine isotopes do this, in the wider world such preventive measures are usually not stockpiled before an accident, nor are they distributed adequately afterward. One consequence of the Chernobyl disaster was an increase in thyroid cancers in children in the years following the accident.
The use of iodised salt is an efficient way to add iodine to the diet. It has eliminated endemic cretinism in most developed countries, and some governments have made the iodination of flour mandatory. Potassium iodide and Sodium iodide are the most active forms of supplemental iodine.
# Diseases
## Hyper- and hypofunction (affects about 2% of the population)
- Hypothyroidism (underactivity)
Hashimoto's thyroiditis / thyroiditis
Ord's thyroiditis
Postoperative hypothyroidism
Postpartum thyroiditis
Silent thyroiditis
Acute thyroiditis
Iatrogenic hypothyroidism
- Hashimoto's thyroiditis / thyroiditis
- Ord's thyroiditis
- Postoperative hypothyroidism
- Postpartum thyroiditis
- Silent thyroiditis
- Acute thyroiditis
- Iatrogenic hypothyroidism
- Hyperthyroidism (overactivity)
Thyroid storm
Graves-Basedow disease
Toxic thyroid nodule
Toxic nodular struma (Plummer's disease)
Hashitoxicosis
Iatrogenic hyperthyroidism
De Quervain thyroiditis (inflammation starting as hyperthyroidism, can end as hypothyroidism)
- Thyroid storm
- Graves-Basedow disease
- Toxic thyroid nodule
- Toxic nodular struma (Plummer's disease)
- Hashitoxicosis
- Iatrogenic hyperthyroidism
- De Quervain thyroiditis (inflammation starting as hyperthyroidism, can end as hypothyroidism)
## Anatomical problems
- Goitre
Endemic goitre
Diffuse goitre
Multinodular goitre
- Endemic goitre
- Diffuse goitre
- Multinodular goitre
- Lingual thyroid
- Thyroglossal duct cyst
## Tumors
- Thyroid adenoma
- Thyroid cancer
Papillary
Follicular
Medullary
Anaplastic
- Papillary
- Follicular
- Medullary
- Anaplastic
- Lymphomas and metastasis from elsewhere (rare)
## Deficiencies
- Cretinism
Medication linked to thyroid disease includes amiodarone, lithium salts, some types of interferon and IL-2.
# Diagnosis
## Blood tests
- The measurement of thyroid-stimulating hormone (TSH) levels is often used by doctors as a screening test. Elevated TSH levels can signify an inadequate hormone production, while suppressed levels can point at excessive unregulated production of hormone.
- If TSH is abnormal, decreased levels of thyroid hormones T4 and T3 may be present; these may be determined to confirm this.
- Autoantibodies may be detected in various disease states (anti-TG, anti-TPO, TSH receptor stimulating antibodies).
- There are two cancer markers for thyroid derived cancers. Thyroglobulin (TG) for well differentiated papillary or follcular adenocarcinoma, and the rare medullary thyroid cancer has calcitonin as the marker.
- Very infrequently, TBG and transthyretin levels may be abnormal; these are not routinely tested.
## Ultrasound
Nodules of the thyroid may or may not be cancer. Medical ultrasonography can help determine their nature because some of the characteristics of benign and malignant nodules differ. The main characteristics of a thyroid nodule on high frequency thyroid ultrasound are as follows:
Ultrasonography is not always able to separate benign from malignant nodules with complete certainty. In suspicious cases, a tissue sample is often obtained by biopsy for microscopic examination.
## Radioiodine scanning and uptake
Thyroid scintigraphy, imaging of the thyroid with the aid of radioactive iodine, usually iodine-123 (123I), is performed in the nuclear medicine department of a hospital or clinic. Radioiodine collects in the thyroid gland before being excreted in the urine. While in the thyroid the radioactive emissions can be detected by a camera, producing a rough image of the shape (a radiodine scan) and tissue activity (a radioiodine uptake) of the thyroid gland.
A normal radioiodine scan shows even uptake and activity throughout the gland. Irregularity can reflect an abnormally shaped or abnormally located gland, or it can indicate that a portion of the gland is overactive or underactive, different from the rest. For example, a nodule that is overactive ("hot") to the point of suppressing the activity of the rest of the gland is usually a thyrotoxic adenoma, a surgically curable form of hyperthyroidism that is hardly ever malignant. In contrast, finding that a substantial section of the thyroid is inactive ("cold") may indicate an area of non-functioning tissue such as thyroid cancer.
The amount of radioactivity can be counted as an indicator of the metabolic activity of the gland. A normal quantitation of radioiodine uptake demonstrates that about 8 to 35% of the administered dose can be detected in the thyroid 24 hours later. Overactivity or underactivity of the gland as may occur with hypothyroidism or hyperthyroidism is usually reflected in decreased or increased radioiondine uptake. Different patterns may occur with different causes of hypo- or hyperthyroidism.
## Biopsy
A medical biopsy refers to the obtaining of a tissue sample for examination under the microscope or other testing, usually to distinguish cancer from noncancerous conditions. Thyroid tissue may be obtained for biopsy by fine needle aspiration or by surgery.
Needle aspiration has the advantage of being a brief, safe, outpatient procedure that is safer and less expensive than surgery and does not leave a visible scar. Needle biopsies became widely used in the 1980s, but it was recognized that accuracy of identification of cancer was good but not perfect. The accuracy of the diagnosis depends on obtaining tissue from all of the suspicious areas of an abnormal thyroid gland. The reliability of needle aspiration is increased when sampling can be guided by ultrasound, and over the last 15 years, this has become the preferred method for thyroid biopsy in North America.
# Treatment
## Medical treatment
Levothyroxine is a stereoisomer of thyroxine which is degraded much slower and can be administered once daily in patients with hypothyroidism.
Graves' disease may be treated with the thioamide drugs propylthiouracil, carbimazole or methimazole, or rarely with Lugol's solution. Hyperthyroidism as well as thyroid tumors may be treated with radioactive iodine.
Percutaneous Ethanol Injections, PEI, for therapy of recurrent thyroid cysts, and metastatic thyroid cancer lymph nodes, as an alternative to the usual surgical method.
## Surgery
Thyroid surgery is performed for a variety of reasons. A nodule or lobe of the thyroid is sometimes removed for biopsy or for the presence of an autonomously functioning adenoma causing hyperthyroidism. A large majority of the thyroid may be removed, a subtotal thyroidectomy, to treat the hyperthyroidism of Graves' disease, or to remove a goitre that is unsightly or impinges on vital structures. A complete thyroidectomy of the entire thyroid, including associated lymph nodes, is the preferred treatment for thyroid cancer. Removal of the bulk of the thyroid gland usually produces hypothyroidism, unless the person takes thyroid hormone replacement.
If the thyroid gland must be removed surgically, care must be taken to avoid damage to adjacent structures, the parathyroid glands and the recurrent laryngeal nerve. Both are susceptible to accidental removal and/or injury during thyroid surgery. The parathyroid glands produce parathyroid hormone (PTH), a hormone needed to maintain adequate amounts of calcium in the blood. Removal results in hypoparathyroidism and a need for supplemental calcium and vitamin D each day. The recurrent laryngeal nerves provide motor control for all external muscles of the larynx except for the cricothyroid muscle, also runs along the posterior thyroid. Accidental laceration of either of the two or both recurrent laryngeal nerves may cause paralysis of the vocal cords and their associated muscles, changing the voice quality.
## Radioiodine therapy
Large goiters that cause symptoms, but do not harbor cancer, after evaluation, and biopsy of suspicious nodules can be treated by an alternative therapy with radioiodine. The iodine uptake can be high in countries with iodine deficiency, but low in iodine sufficient countries. The 1999 release of rhTSH thyrogen in the USA, can boost the uptakes to 50-60% allowing the therapy with iodine 131. The gland shrinks by 50-60%, but can cause hypothyroidism, and rarely pain syndrome cause by radiation thyroiditis that is short lived and treated by steroids.
# History
There are several findings that evidence a great interest for thyroid disorders just in the Medieval Medical School of Salerno (XII Century). Rogerius Salernitanus, the Salernitan surgeon and author of "Post mundi fabricam" (around 1180) was considered at that time the surgical text par excellence all over Europe. In the chapter "De bocio" of his magnus opum he describes several pharmacological and surgical cures, some of which nowadays are reappraised quite scientifically effective.
In modern times, the thyroid was first identified by the anatomist Thomas Wharton (whose name is also eponymised in Wharton's duct of the submandibular gland) in 1656.
Thyroid hormone (or thyroxin) was only identified in the 19th century.
# Additional images
- Section of the neck at about the level of the sixth cervical vertebra.
- Muscles of the neck. Anterior view.
- The arch of the aorta, and its branches.
- Superficial dissection of the right side of the neck, showing the carotid and subclavian arteries.
- Diagram showing common arrangement of thyroid veins.
- Sagittal section of nose mouth, pharynx, and larynx.
- Muscles of the pharynx, viewed from behind, together with the associated vessels and nerves.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- Section of thyroid gland of sheep. X 160.
- The thymus of a full-term fetus, exposed in situ.
- Thyoid histology
|
Thyroid gland
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The thyroid is one of the largest endocrine glands in the body. This gland is found in the neck just below the Adam's apple. The thyroid controls how quickly the body burns energy, makes proteins, and how sensitive the body should be to other hormones.
The thyroid participates in these processes by producing thyroid hormones, principally thyroxine (T4) and triiodothyronine (T3). These hormones regulate the rate of metabolism and affect the growth and rate of function of many other systems in the body. Iodine is an essential component of both T3 and T4. The thyroid also produces the hormone calcitonin, which plays a role in calcium homeostasis.
The thyroid is controlled by the hypothalamus and pituitary. The gland gets its name from the Greek word for "shield", after its shape, a double-lobed structure. Hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid) are the most common problems of the thyroid gland. Specialists are called Thyroidologists.
# Anatomy
The thyroid is situated on the anterior side of the neck, starting at the oblique line on the thyroid cartilage (just below the laryngeal prominence or Adam's apple), and extending to the 6th Tracheal ring (C-shaped cartilagenous ring of the trachea). It is inappropriate to demarcate the gland's upper and lower border with vertebral levels as it moves position in relation to these during swallowing. It lies over the trachea and is covered by layers of pretracheal fascia (allowing it to move), muscle and skin.
The thyroid is one of the larger endocrine glands - 10-20 grams in adults - and butterfly-shaped. The wings correspond to the lobes and the body to the isthmus of the thyroid. The isthmus overlies tracheal rings 2, 3 and 4. The thyroid may enlarge substantially during pregnancy and when affected by a variety of diseases.
## Embryologic development
The thyroid is derived from the third branchial pouch. In the fetus, at 3-4 weeks of gestation, the thyroid gland appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue between the tuberculum impar and the copula linguae at a point latter indicated by the foramen cecum.
Subsequently the thyroid descends in front of the pharyngeal gut as a bilobed diverticulum through the thyroglossal duct. Over the next few weeks, it migrates to the base of the neck. During migration, the thyroid remains connected to the tongue by a narrow canal, the thyroglossal duct.
Follicles of the thyroid begin to make colloid in the 11th week and thyroxine by the 18th week.
## Histology
At a histological level, there are three primary features of the thyroid:
# Physiology
The primary function of the thyroid is production of the hormones thyroxine (T4), triiodothyronine (T3), and calcitonin. Up to 80% of the T4 is converted to T3 by peripheral organs such as the liver, kidney and spleen. T3 is about ten times more active than T4.[1]
## T3 and T4 production and action
Thyroxine is synthesised by the follicular cells from free tyrosine and on the tyrosine residues of the protein called thyroglobulin (TG). Iodine is captured with the "iodine trap" by the hydrogen peroxide generated by the enzyme thyroid peroxidase (TPO)[2] and linked to the 3' and 5' sites of the benzene ring of the tyrosine residues on TG, and on free tyrosine. Upon stimulation by the thyroid-stimulating hormone (TSH), the follicular cells reabsorb TG and proteolytically cleave the iodinated tyrosines from TG, forming T4 and T3 (in T3, one iodine is absent compared to T4), and releasing them into the blood. Deiodinase enzymes convert T4 to T3.[3] Thyroid hormone that is secreted from the gland is about 90% T4 and about 10% T3.[1]
Cells of the brain are a major target for the thyroid hormones T3 and T4. Thyroid hormones play a particularly crucial role in brain development during pregnancy.[4] A transport protein (OATP1C1) has been identified that seems to be important for T4 transport across the blood brain barrier.[5] A second transport protein (MCT8) is important for T3 transport across brain cell membranes.[5]
In the blood, T4 and T3 are partially bound to thyroxine-binding globulin, transthyretin and albumin. Only a very small fraction of the circulating hormone is free (unbound) - T4 0.03% and T3 0.3%. Only the free fraction has hormonal activity. As with the steroid hormones and retinoic acid, thyroid hormones cross the cell membrane and bind to intracellular receptors (α1, α2, β1 and β2), which act alone, in pairs or together with the retinoid X-receptor as transcription factors to modulate DNA transcription[2].
## T3 and T4 regulation
The production of thyroxine and triiodothyronine is regulated by thyroid-stimulating hormone (TSH), released by the anterior pituitary. The thyroid and thyrotropes form a negative feedback loop: TSH production is suppressed when the T4 levels are high, and vice versa. The TSH production itself is modulated by thyrotropin-releasing hormone (TRH), which is produced by the hypothalamus and secreted at an increased rate in situations such as cold (in which an accelerated metabolism would generate more heat). TSH production is blunted by somatostatin (SRIH), rising levels of glucocorticoids and sex hormones (estrogen and testosterone), and excessively high blood iodide concentration.
## Calcitonin
An additional hormone produced by the thyroid contributes to the regulation of blood calcium levels. Parafollicular cells produce calcitonin in response to hypercalcemia. Calcitonin stimulates movement of calcium into bone, in opposition to the effects of parathyroid hormone (PTH). However, calcitonin seems far less essential than PTH, as calcium metabolism remains clinically normal after removal of the thyroid, but not the parathyroids.
It may be used diagnostically as a tumor marker for a form of thyroid cancer (medullary thyroid adenocarcinoma), in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy samples from suspicious lesions (e.g. swollen lymph nodes) to establish whether they are metastasis of the original cancer.
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.
## Significance of iodine
In areas of the world where iodine (essential for the production of thyroxine, which contains four iodine atoms) is lacking in the diet, the thyroid gland can be considerably enlarged, resulting in the swollen necks of endemic goitre.
Thyroxine is critical to the regulation of metabolism and growth throughout the animal kingdom. Among amphibians, for example, administering a thyroid-blocking agent such as propylthiouracil (PTU) can prevent tadpoles from metamorphosing into frogs; conversely, administering thyroxine will trigger metamorphosis.
In humans, children born with thyroid hormone deficiency will have physical growth and development problems, and brain development can also be severely impaired, in the condition referred to as cretinism. Newborn children in many developed countries are now routinely tested for thyroid hormone deficiency as part of newborn screening by analysis of a drop of blood. Children with thyroid hormone deficiency are treated by supplementation with synthetic thyroxine, which enables them to grow and develop normally.
Because of the thyroid's selective uptake and concentration of what is a fairly rare element, it is sensitive to the effects of various radioactive isotopes of iodine produced by nuclear fission. In the event of large accidental releases of such material into the environment, the uptake of radioactive iodine isotopes by the thyroid can, in theory, be blocked by saturating the uptake mechanism with a large surplus of non-radioactive iodine, taken in the form of potassium iodide tablets. While biological researchers making compounds labelled with iodine isotopes do this, in the wider world such preventive measures are usually not stockpiled before an accident, nor are they distributed adequately afterward. One consequence of the Chernobyl disaster was an increase in thyroid cancers in children in the years following the accident. [3]
The use of iodised salt is an efficient way to add iodine to the diet. It has eliminated endemic cretinism in most developed countries, and some governments have made the iodination of flour mandatory. Potassium iodide and Sodium iodide are the most active forms of supplemental iodine.
# Diseases
## Hyper- and hypofunction (affects about 2% of the population)
- Hypothyroidism (underactivity)
Hashimoto's thyroiditis / thyroiditis
Ord's thyroiditis
Postoperative hypothyroidism
Postpartum thyroiditis
Silent thyroiditis
Acute thyroiditis
Iatrogenic hypothyroidism
- Hashimoto's thyroiditis / thyroiditis
- Ord's thyroiditis
- Postoperative hypothyroidism
- Postpartum thyroiditis
- Silent thyroiditis
- Acute thyroiditis
- Iatrogenic hypothyroidism
- Hyperthyroidism (overactivity)
Thyroid storm
Graves-Basedow disease
Toxic thyroid nodule
Toxic nodular struma (Plummer's disease)
Hashitoxicosis
Iatrogenic hyperthyroidism
De Quervain thyroiditis (inflammation starting as hyperthyroidism, can end as hypothyroidism)
- Thyroid storm
- Graves-Basedow disease
- Toxic thyroid nodule
- Toxic nodular struma (Plummer's disease)
- Hashitoxicosis
- Iatrogenic hyperthyroidism
- De Quervain thyroiditis (inflammation starting as hyperthyroidism, can end as hypothyroidism)
## Anatomical problems
- Goitre
Endemic goitre
Diffuse goitre
Multinodular goitre
- Endemic goitre
- Diffuse goitre
- Multinodular goitre
- Lingual thyroid
- Thyroglossal duct cyst
## Tumors
- Thyroid adenoma
- Thyroid cancer
Papillary
Follicular
Medullary
Anaplastic
- Papillary
- Follicular
- Medullary
- Anaplastic
- Lymphomas and metastasis from elsewhere (rare)
## Deficiencies
- Cretinism
Medication linked to thyroid disease includes amiodarone, lithium salts, some types of interferon and IL-2.
# Diagnosis
## Blood tests
- The measurement of thyroid-stimulating hormone (TSH) levels is often used by doctors as a screening test. Elevated TSH levels can signify an inadequate hormone production, while suppressed levels can point at excessive unregulated production of hormone.
- If TSH is abnormal, decreased levels of thyroid hormones T4 and T3 may be present; these may be determined to confirm this.
- Autoantibodies may be detected in various disease states (anti-TG, anti-TPO, TSH receptor stimulating antibodies).
- There are two cancer markers for thyroid derived cancers. Thyroglobulin (TG) for well differentiated papillary or follcular adenocarcinoma, and the rare medullary thyroid cancer has calcitonin as the marker.
- Very infrequently, TBG and transthyretin levels may be abnormal; these are not routinely tested.
## Ultrasound
Nodules of the thyroid may or may not be cancer. Medical ultrasonography can help determine their nature because some of the characteristics of benign and malignant nodules differ. The main characteristics of a thyroid nodule on high frequency thyroid ultrasound are as follows:
Ultrasonography is not always able to separate benign from malignant nodules with complete certainty. In suspicious cases, a tissue sample is often obtained by biopsy for microscopic examination.
## Radioiodine scanning and uptake
Thyroid scintigraphy, imaging of the thyroid with the aid of radioactive iodine, usually iodine-123 (123I), is performed in the nuclear medicine department of a hospital or clinic. Radioiodine collects in the thyroid gland before being excreted in the urine. While in the thyroid the radioactive emissions can be detected by a camera, producing a rough image of the shape (a radiodine scan) and tissue activity (a radioiodine uptake) of the thyroid gland.
A normal radioiodine scan shows even uptake and activity throughout the gland. Irregularity can reflect an abnormally shaped or abnormally located gland, or it can indicate that a portion of the gland is overactive or underactive, different from the rest. For example, a nodule that is overactive ("hot") to the point of suppressing the activity of the rest of the gland is usually a thyrotoxic adenoma, a surgically curable form of hyperthyroidism that is hardly ever malignant. In contrast, finding that a substantial section of the thyroid is inactive ("cold") may indicate an area of non-functioning tissue such as thyroid cancer.
The amount of radioactivity can be counted as an indicator of the metabolic activity of the gland. A normal quantitation of radioiodine uptake demonstrates that about 8 to 35% of the administered dose can be detected in the thyroid 24 hours later. Overactivity or underactivity of the gland as may occur with hypothyroidism or hyperthyroidism is usually reflected in decreased or increased radioiondine uptake. Different patterns may occur with different causes of hypo- or hyperthyroidism.
## Biopsy
A medical biopsy refers to the obtaining of a tissue sample for examination under the microscope or other testing, usually to distinguish cancer from noncancerous conditions. Thyroid tissue may be obtained for biopsy by fine needle aspiration or by surgery.
Needle aspiration has the advantage of being a brief, safe, outpatient procedure that is safer and less expensive than surgery and does not leave a visible scar. Needle biopsies became widely used in the 1980s, but it was recognized that accuracy of identification of cancer was good but not perfect. The accuracy of the diagnosis depends on obtaining tissue from all of the suspicious areas of an abnormal thyroid gland. The reliability of needle aspiration is increased when sampling can be guided by ultrasound, and over the last 15 years, this has become the preferred method for thyroid biopsy in North America.
# Treatment
## Medical treatment
Levothyroxine is a stereoisomer of thyroxine which is degraded much slower and can be administered once daily in patients with hypothyroidism.
Graves' disease may be treated with the thioamide drugs propylthiouracil, carbimazole or methimazole, or rarely with Lugol's solution. Hyperthyroidism as well as thyroid tumors may be treated with radioactive iodine.
Percutaneous Ethanol Injections, PEI, for therapy of recurrent thyroid cysts, and metastatic thyroid cancer lymph nodes, as an alternative to the usual surgical method.
## Surgery
Thyroid surgery is performed for a variety of reasons. A nodule or lobe of the thyroid is sometimes removed for biopsy or for the presence of an autonomously functioning adenoma causing hyperthyroidism. A large majority of the thyroid may be removed, a subtotal thyroidectomy, to treat the hyperthyroidism of Graves' disease, or to remove a goitre that is unsightly or impinges on vital structures. A complete thyroidectomy of the entire thyroid, including associated lymph nodes, is the preferred treatment for thyroid cancer. Removal of the bulk of the thyroid gland usually produces hypothyroidism, unless the person takes thyroid hormone replacement.
If the thyroid gland must be removed surgically, care must be taken to avoid damage to adjacent structures, the parathyroid glands and the recurrent laryngeal nerve. Both are susceptible to accidental removal and/or injury during thyroid surgery. The parathyroid glands produce parathyroid hormone (PTH), a hormone needed to maintain adequate amounts of calcium in the blood. Removal results in hypoparathyroidism and a need for supplemental calcium and vitamin D each day. The recurrent laryngeal nerves provide motor control for all external muscles of the larynx except for the cricothyroid muscle, also runs along the posterior thyroid. Accidental laceration of either of the two or both recurrent laryngeal nerves may cause paralysis of the vocal cords and their associated muscles, changing the voice quality.
## Radioiodine therapy
Large goiters that cause symptoms, but do not harbor cancer, after evaluation, and biopsy of suspicious nodules can be treated by an alternative therapy with radioiodine. The iodine uptake can be high in countries with iodine deficiency, but low in iodine sufficient countries. The 1999 release of rhTSH thyrogen in the USA, can boost the uptakes to 50-60% allowing the therapy with iodine 131. The gland shrinks by 50-60%, but can cause hypothyroidism, and rarely pain syndrome cause by radiation thyroiditis that is short lived and treated by steroids.
# History
There are several findings that evidence a great interest for thyroid disorders just in the Medieval Medical School of Salerno (XII Century). Rogerius Salernitanus, the Salernitan surgeon and author of "Post mundi fabricam" (around 1180) was considered at that time the surgical text par excellence all over Europe. In the chapter "De bocio" of his magnus opum he describes several pharmacological and surgical cures, some of which nowadays are reappraised quite scientifically effective.[6]
In modern times, the thyroid was first identified by the anatomist Thomas Wharton (whose name is also eponymised in Wharton's duct of the submandibular gland) in 1656.[7]
Thyroid hormone (or thyroxin) was only identified in the 19th century.
# Additional images
-
- Section of the neck at about the level of the sixth cervical vertebra.
- Muscles of the neck. Anterior view.
- The arch of the aorta, and its branches.
- Superficial dissection of the right side of the neck, showing the carotid and subclavian arteries.
- Diagram showing common arrangement of thyroid veins.
- Sagittal section of nose mouth, pharynx, and larynx.
- Muscles of the pharynx, viewed from behind, together with the associated vessels and nerves.
- The position and relation of the esophagus in the cervical region and in the posterior mediastinum. Seen from behind.
- Section of thyroid gland of sheep. X 160.
- The thymus of a full-term fetus, exposed in situ.
- Thyoid histology
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https://www.wikidoc.org/index.php/Thyroid_Gland
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4ad93a9ebe9b5e612af52fe022c82480a19c716b
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wikidoc
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Thyroid storm
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Thyroid storm
For patient information, click Thyroid storm
Synonyms and keywords: Thyrotoxic storm, accelerated hyperthyroidism, hyperthyroid storm
# Overview
An unusual but life threatening condition develops in patients with hyperthyroidism either due to poorly controlled pre existing hyperthyroidism or due to medical conditions that precipitate a crisis situation called thyroid storm. There develops a hypermetabolic state that leads to its development. It is mainly a clinical diagnosis and warrants prompt treatment.
# Historical Perspective
# Classification
# Pathophysiology
Thyroid storm is a state of decompensation of the hyperthyroid gland. It could be either due to increased levels of thyroid hormones, increased responsiveness to catecholamines, enhanced response to thyroid hormones at the cellular level, presence of unique catecholamine like substance in hyperthyroidism or due to direct sympathomimetic effect of thyroid hormone due to its structural similarity to catecholamines . The exact cause is not clear. Also, it has been found that it is only the free T4 and T3 that are high. The levels of total T4 and T3 are fairly similar to those found in hyperthyroidism. For a hyperthyroid patient just being intolerant to heat and exhibiting diaphoresis, thyroid storm makes one hyperpyrexic. The enhanced metabolism is translated into increased oxygen and energy consumption. Similarly, moderate tachycardia of hyperthyroidism enhances to hypertension , arrhythmias and possibly high output heart failure. Irritable and restless patient of hyperthyroidism now has agitation, delirium, seizures and could progress to coma. The exact cause behind this heightened effect is unclear.
## Genetics
## Associated Conditions
## Gross Pathology
## Microscopic Pathology
# Causes
## Common Causes
- Any surgery
- Direct trauma to the gland
- Recent infection
- Withdrawal or non compliance with antithyroid medication
- Medical stressors like myocardial infarction
- Acute iodine load
- Parturition
## Causes by Organ System
## Causes in Alphabetical Order
- Iodixanol
Make sure that each diagnosis is linked to a page.
# Differentiating thyroid storm from other Diseases
# Epidemiology and Demographics
The frequency of thyroid storm is unknown in children. In a national survey in Japan, incidence of thyroid storm in hospitalized patient was found to be 0.20 per 100,000 per year. If the diagnosis is promptly made and early management initiated, the adult mortality rate is less than 20% contrary to a rate of 90% if patient left untreated.
## Age
Children aged 10-15 years account for greater than 2/3rd cases of thyrotoxicosis. Hence, thyroid storm is more common in adolescents though it can occur in any age group.
## Gender
Hyperthyroidism is 3-5 times more common in females than males. Incidence of thyroid storm is presumed to be higher in females but no clear data is available.
## Race
## Developed Countries
## Developing Countries
# Risk Factors
# Screening
# Natural History, Complications and Prognosis
Congestive heart failure and pulmonary edema can develop rapidly and lead to death.
# Diagnosis
## History
The patient may be a known case of hyperthyroidism or may present initially with severe symptoms of thyroid storm.
## Symptoms
Hyperpyrexia ie. temperature > 104'F, tachycardia > 140/min or Atrial fibrillation and delirium or agitation are typical features of thyroid storm.
Other features include -
- General- profuse sweating, poor feeding, weight loss, respiratory distress, fatigue.
- Cardiovascular- pulmonary edema, hypotension, arrhythmia and death from cardiovascular collapse.
- Gastrointestinal- severe nausea, vomiting, diarrhea, abdominal pain, hepatic failure, unexplained jaundice.
- CNS- agitation, anxiety, delirium, psychosis, stupor, seizures and coma.
Burch and Wartofsky introduced a scoring system for identification of thyroid storm. They used criteria like thermoregulatory dysfunction, cardiovascular dysfunction, central nervous system effects, heart failure, gastro-intestinal-hepatic dysfunction and precipitant history. A score >45 is highly suggestive of thyroid storm while score <25 makes it unlikely. A score of 25-44 is suggestive of an impending storm.
## Past Medical History
## Family History
## Social History
### Occupational
### Alcohol
The frequency and amount of alcohol consumption should be characterized.
### Drug Use
### Smoking
## Allergies
## Physical Examination
### Appearance of the Patient
The patient has features of hyperthyroidism like profuse sweating and orbital signs like lid lag etc. The patient would be in a state of agitation or confusion or maybe seizing or could present with coma.
### Vital Signs
Thyroid storm is characterized by high fever (>38.5'C or 101.3'F). This may progress to hyperpyrexia (>40'C or 104'F). There could be hypotension or hypertension with a wide pulse pressure. The tachycardia in thyroid storm is out of proportion to the fever. The patient may have heart rate upto 140/min and may progress to atrial fibrillation.
### Skin
There will be typical features of hyperthyroidism like warm and moist skin.
### Head
### Eyes
The eye signs are similar to those found in hyperthyroidism like exophthalmos, lid retraction, lid lag, wide palpebral fissure, staring expression, inability to keep eyeballs converged.
### Ear
### Nose
### Throat
A palpable goiter may be felt in the neck.
### Heart
There would be signs of right sided heart failure like edema, hepatomegaly, ascites, rales, etc. Thyroid storm is associated with supraventricular tachycardia , though ventricular tachycardia can also occur.
### Lungs
### Abdomen
### Extremities
### Neurologic
The patient would be in altered mental status ranging from agitation, confusion, seizures, stupor and coma. There could be tremors and some pyramidal signs.
### Genitals
### Other
## Laboratory Findings
The diagnosis of thyroid storm is mainly clinical and if suspected, immediate treatment should begin without waiting for laboratory results. The laboratory findings are similar to hyperthyroidism and are as follows-
- Thyroid function test- elevated free T3 and T4 and may or may not have decreased TSH. There is increased T3 resin uptake and elevated 24 hr iodine uptake.
- Complete blood count- mild leukocytosis with shift to left.
- Liver function test- non specific abnormalities like increase in alanine transaminase(ALT), aspartate transaminase(AST), lactate dehydrogenase(LDH), alkaline phosphatase(ALP) , Creatine Kinase and serum bilirubin.
### Electrolyte and Biomarker Studies
### Electrocardiogram
One could find narrow complex QRS suggestive of supraventricular tachycardia or 3 or more ventricular beats at a rate of 110-250/minute suggestive of ventricular tachycardia. Of the supraventricular tachycardia, atrial fibrillation is the most common one characterized by absent P waves, unorganized electrical activity in their place and irregular R-R interval.
### Chest X Ray
Features of cardiomegaly may be found which are suggestive of congestive heart failure. There could also be features of pulmonary edema like increased fluid in alveolar walls, Kerley B lines , increased vascularity in the peri hilum region (classical bat wing appearance) suggestive of pulmonary edema.
### CT
In view of features like agitation, confusion, delirium etc, a CT scan of head may be needed to rule out intracranial causes.
### MRI
### Echocardiography or Ultrasound
### Other Imaging Findings
## Other Diagnostic Studies
# Treatment
## Pharmacotherapy
The main aims of medical therapy are as follows-
- Reduce effects of thyroid hormone on peripheral tissues.
- Decrease further synthesis of thyroid hormone
- Decrease release of hormone
- Prevent further TH secretion and peripheral conversion of T4 to T3.
The medications used to accomplish the above aims are described as follows (in order of the aims)-
Beta blockers block peripheral conversion of T4 to T3. Exercise caution while using in patients with congestive heart failure and cardiomyopathy. They are known to precipitate cardiac arrest in patients with cardiomyopathy.
- Propanolol- nonselective beta adrenergic antagonist, used widely.
- Esmolol- beta 1 specific antagonist with a short duration of action.
Propylthiouracil is the drug of choice for thyroid storm that prevents organification, trapping of iodide to iodine and also peripheral conversion of T4 to T3. It is available only as per oral medication and hence comatosed patients may need to be given via nasogastric tube. It causes more rapid decrease in T3 levels than methimazole.
Methimazole has similar mechanism of action as propylthiouracil except it does not inhibit peripheral conversion. It is more potent than propylthiouracil. It is also only available as per oral formulation. It has longer duration of action, used in non life threatening situations. It is less hepatotoxic therefore all patients started on propylthiouracil should be started on methimazole before discharge.
Few patients may be one unable to take antithyroids due to side effects like agranulocytosis, hepatotoxicity and/or allergy. Thyroid storm has been found to develop in patients upon discontinuation of antithyroids. In that case, on should go for a week course of steroid, Lugols iodine, beta blockers and proceed with thyroidectomy on the 8th day.
Lugol solution has 100 mg potassium iodide and 50 mg iodine. It also inhibits peripheral conversion of T4 to T3 within hours. It has to be given in thyroid storm but atleast 1 hour after antithyroid administration. This is done so that there is no chance that iodine be used to make new thyroid hormones. By giving antithyroids first all synthesis steps will be blocked and iodine then would be an added bonus in blocking release of already formed hormones. Side effects of iodine are direct injury to esophagus.
The 4th aim is fulfilled by both glucocorticoids and iodine contrast agents.
- Steroids have been found to be associated with improved survival. They also effect the autoimmune process in case of crisis due to Graves disease. Preferred steroid is hydrocortisone.
- Iodinated contrast agents are presently not available in the US due to doubts on their efficacy. As was with iodine, these are also given an hour after antithyroids.
- Lithium- given to block release of thyroid hormone but its toxic to liver.
- Plasmaphereis- has been tried when other therapies failed.
### Acute Pharmacotherapies
### Chronic Pharmacotherapies
## Surgery and Device Based Therapy
### Indications for Surgery
### Pre-Operative Assessment
### Post-Operative Management
### Transplantation
## Primary Prevention
## Secondary Prevention
## Cost-Effectiveness of Therapy
## Future or Investigational Therapies
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Thyroid storm
For patient information, click Thyroid storm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Thyrotoxic storm, accelerated hyperthyroidism, hyperthyroid storm
# Overview
An unusual but life threatening condition develops in patients with hyperthyroidism either due to poorly controlled pre existing hyperthyroidism or due to medical conditions that precipitate a crisis situation called thyroid storm. There develops a hypermetabolic state that leads to its development. It is mainly a clinical diagnosis and warrants prompt treatment.
# Historical Perspective
# Classification
# Pathophysiology
Thyroid storm is a state of decompensation of the hyperthyroid gland. It could be either due to increased levels of thyroid hormones, increased responsiveness to catecholamines, enhanced response to thyroid hormones at the cellular level, presence of unique catecholamine like substance in hyperthyroidism or due to direct sympathomimetic effect of thyroid hormone due to its structural similarity to catecholamines . The exact cause is not clear. Also, it has been found that it is only the free T4 and T3 that are high. The levels of total T4 and T3 are fairly similar to those found in hyperthyroidism. For a hyperthyroid patient just being intolerant to heat and exhibiting diaphoresis, thyroid storm makes one hyperpyrexic. The enhanced metabolism is translated into increased oxygen and energy consumption. Similarly, moderate tachycardia of hyperthyroidism enhances to hypertension , arrhythmias and possibly high output heart failure. Irritable and restless patient of hyperthyroidism now has agitation, delirium, seizures and could progress to coma. The exact cause behind this heightened effect is unclear.
## Genetics
## Associated Conditions
## Gross Pathology
## Microscopic Pathology
# Causes
## Common Causes
- Any surgery
- Direct trauma to the gland
- Recent infection
- Withdrawal or non compliance with antithyroid medication
- Medical stressors like myocardial infarction
- Acute iodine load
- Parturition
## Causes by Organ System
## Causes in Alphabetical Order
- Iodixanol
Make sure that each diagnosis is linked to a page.
# Differentiating thyroid storm from other Diseases
# Epidemiology and Demographics
The frequency of thyroid storm is unknown in children. In a national survey in Japan, incidence of thyroid storm in hospitalized patient was found to be 0.20 per 100,000 per year. If the diagnosis is promptly made and early management initiated, the adult mortality rate is less than 20% contrary to a rate of 90% if patient left untreated.
## Age
Children aged 10-15 years account for greater than 2/3rd cases of thyrotoxicosis. Hence, thyroid storm is more common in adolescents though it can occur in any age group.
## Gender
Hyperthyroidism is 3-5 times more common in females than males. Incidence of thyroid storm is presumed to be higher in females but no clear data is available.
## Race
## Developed Countries
## Developing Countries
# Risk Factors
# Screening
# Natural History, Complications and Prognosis
Congestive heart failure and pulmonary edema can develop rapidly and lead to death.
# Diagnosis
## History
The patient may be a known case of hyperthyroidism or may present initially with severe symptoms of thyroid storm.
## Symptoms
Hyperpyrexia ie. temperature > 104'F, tachycardia > 140/min or Atrial fibrillation and delirium or agitation are typical features of thyroid storm.
Other features include -
- General- profuse sweating, poor feeding, weight loss, respiratory distress, fatigue.
- Cardiovascular- pulmonary edema, hypotension, arrhythmia and death from cardiovascular collapse.
- Gastrointestinal- severe nausea, vomiting, diarrhea, abdominal pain, hepatic failure, unexplained jaundice.
- CNS- agitation, anxiety, delirium, psychosis, stupor, seizures and coma.
Burch and Wartofsky introduced a scoring system for identification of thyroid storm. They used criteria like thermoregulatory dysfunction, cardiovascular dysfunction, central nervous system effects, heart failure, gastro-intestinal-hepatic dysfunction and precipitant history. A score >45 is highly suggestive of thyroid storm while score <25 makes it unlikely. A score of 25-44 is suggestive of an impending storm.
## Past Medical History
## Family History
## Social History
### Occupational
### Alcohol
The frequency and amount of alcohol consumption should be characterized.
### Drug Use
### Smoking
## Allergies
## Physical Examination
### Appearance of the Patient
The patient has features of hyperthyroidism like profuse sweating and orbital signs like lid lag etc. The patient would be in a state of agitation or confusion or maybe seizing or could present with coma.
### Vital Signs
Thyroid storm is characterized by high fever (>38.5'C or 101.3'F). This may progress to hyperpyrexia (>40'C or 104'F). There could be hypotension or hypertension with a wide pulse pressure. The tachycardia in thyroid storm is out of proportion to the fever. The patient may have heart rate upto 140/min and may progress to atrial fibrillation.
### Skin
There will be typical features of hyperthyroidism like warm and moist skin.
### Head
### Eyes
The eye signs are similar to those found in hyperthyroidism like exophthalmos, lid retraction, lid lag, wide palpebral fissure, staring expression, inability to keep eyeballs converged.
### Ear
### Nose
### Throat
A palpable goiter may be felt in the neck.
### Heart
There would be signs of right sided heart failure like edema, hepatomegaly, ascites, rales, etc. Thyroid storm is associated with supraventricular tachycardia , though ventricular tachycardia can also occur.
### Lungs
### Abdomen
### Extremities
### Neurologic
The patient would be in altered mental status ranging from agitation, confusion, seizures, stupor and coma. There could be tremors and some pyramidal signs.
### Genitals
### Other
## Laboratory Findings
The diagnosis of thyroid storm is mainly clinical and if suspected, immediate treatment should begin without waiting for laboratory results. The laboratory findings are similar to hyperthyroidism and are as follows-
- Thyroid function test- elevated free T3 and T4 and may or may not have decreased TSH. There is increased T3 resin uptake and elevated 24 hr iodine uptake.
- Complete blood count- mild leukocytosis with shift to left.
- Liver function test- non specific abnormalities like increase in alanine transaminase(ALT), aspartate transaminase(AST), lactate dehydrogenase(LDH), alkaline phosphatase(ALP) , Creatine Kinase and serum bilirubin.
### Electrolyte and Biomarker Studies
### Electrocardiogram
One could find narrow complex QRS suggestive of supraventricular tachycardia or 3 or more ventricular beats at a rate of 110-250/minute suggestive of ventricular tachycardia. Of the supraventricular tachycardia, atrial fibrillation is the most common one characterized by absent P waves, unorganized electrical activity in their place and irregular R-R interval.
### Chest X Ray
Features of cardiomegaly may be found which are suggestive of congestive heart failure. There could also be features of pulmonary edema like increased fluid in alveolar walls, Kerley B lines , increased vascularity in the peri hilum region (classical bat wing appearance) suggestive of pulmonary edema.
### CT
In view of features like agitation, confusion, delirium etc, a CT scan of head may be needed to rule out intracranial causes.
### MRI
### Echocardiography or Ultrasound
### Other Imaging Findings
## Other Diagnostic Studies
# Treatment
## Pharmacotherapy
The main aims of medical therapy are as follows-
- Reduce effects of thyroid hormone on peripheral tissues.
- Decrease further synthesis of thyroid hormone
- Decrease release of hormone
- Prevent further TH secretion and peripheral conversion of T4 to T3.
The medications used to accomplish the above aims are described as follows (in order of the aims)-
Beta blockers block peripheral conversion of T4 to T3. Exercise caution while using in patients with congestive heart failure and cardiomyopathy. They are known to precipitate cardiac arrest in patients with cardiomyopathy.
- Propanolol- nonselective beta adrenergic antagonist, used widely.
- Esmolol- beta 1 specific antagonist with a short duration of action.
Propylthiouracil is the drug of choice for thyroid storm that prevents organification, trapping of iodide to iodine and also peripheral conversion of T4 to T3. It is available only as per oral medication and hence comatosed patients may need to be given via nasogastric tube. It causes more rapid decrease in T3 levels than methimazole.
Methimazole has similar mechanism of action as propylthiouracil except it does not inhibit peripheral conversion. It is more potent than propylthiouracil. It is also only available as per oral formulation. It has longer duration of action, used in non life threatening situations. It is less hepatotoxic therefore all patients started on propylthiouracil should be started on methimazole before discharge.
Few patients may be one unable to take antithyroids due to side effects like agranulocytosis, hepatotoxicity and/or allergy. Thyroid storm has been found to develop in patients upon discontinuation of antithyroids. In that case, on should go for a week course of steroid, Lugols iodine, beta blockers and proceed with thyroidectomy on the 8th day.
Lugol solution has 100 mg potassium iodide and 50 mg iodine. It also inhibits peripheral conversion of T4 to T3 within hours. It has to be given in thyroid storm but atleast 1 hour after antithyroid administration. This is done so that there is no chance that iodine be used to make new thyroid hormones. By giving antithyroids first all synthesis steps will be blocked and iodine then would be an added bonus in blocking release of already formed hormones. Side effects of iodine are direct injury to esophagus.
The 4th aim is fulfilled by both glucocorticoids and iodine contrast agents.
- Steroids have been found to be associated with improved survival. They also effect the autoimmune process in case of crisis due to Graves disease. Preferred steroid is hydrocortisone.
- Iodinated contrast agents are presently not available in the US due to doubts on their efficacy. As was with iodine, these are also given an hour after antithyroids.
- Lithium- given to block release of thyroid hormone but its toxic to liver.
- Plasmaphereis- has been tried when other therapies failed.
### Acute Pharmacotherapies
### Chronic Pharmacotherapies
## Surgery and Device Based Therapy
### Indications for Surgery
### Pre-Operative Assessment
### Post-Operative Management
### Transplantation
## Primary Prevention
## Secondary Prevention
## Cost-Effectiveness of Therapy
## Future or Investigational Therapies
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Tienilic acid
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Tienilic acid
# Overview
Tienilic acid (INN and BAN) or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.
Criminal charges were brought against SmithKline executives with regard to hiding data related to toxicity while gaining FDA approval. The company pleaded guilty to 14 counts of failure to report adverse reactions and 20 counts of selling a misbranded drug.
Tienilic acid was found to act as a suicide substrate at the cytochrome P450 enzymes involved in drug metabolism. Unfortunately, the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophene sulfoxide which proved highly electrophilic. This encouraged a Michael reaction leading to alkylation of a thiol group in the enzyme's active site. Loss of water from the thiophene sulfoxide restored the thiophene ring and resulted in tienilic acid being covalently linked to the enzyme, thus inhibiting the enzyme irreversibly.
The above explanation is a hypothesis. It is still not known (after 15 years) if the reactive intermediate which inactivates the CYP2C9 is the thiophene sulfoxide or the thiophene epoxide. The target on the protein is also not known (could be multiple). However tienilic acid is a good mechanism based inhibitor of CYP2C9 and seems to inactivate it stoichiometrically. Progress in proteomics may one day give the answer.
Recent studies indicate that in fact the primary metabolite of tienilic acid (5-OH tienilic acid) cannot be derived from a thiophene-S-oxide intermediate as was previously hypothesized. It was determined to be derived from a thiophene epoxide intermediate and this reactive intermediate is then likely a cause for the covalent binding to as well as mechanism-based inactivation of CYP2C9.
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Tienilic acid
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tienilic acid (INN and BAN) or ticrynafen (USAN) is a loop diuretic drug with uric acid-lowering (uricosuric) action, formerly marketed for the treatment of hypertension. It was approved by FDA on May 2, 1979, and withdrawn in 1982, after case reports in the United States indicated a link between the use of ticrynafen and hepatitis.
Criminal charges were brought against SmithKline executives with regard to hiding data related to toxicity while gaining FDA approval. The company pleaded guilty to 14 counts of failure to report adverse reactions and 20 counts of selling a misbranded drug.[1]
Tienilic acid was found to act as a suicide substrate at the cytochrome P450 enzymes involved in drug metabolism. Unfortunately, the metabolic reaction carried out by these enzymes converted tienilic acid to a thiophene sulfoxide which proved highly electrophilic. This encouraged a Michael reaction leading to alkylation of a thiol group in the enzyme's active site. Loss of water from the thiophene sulfoxide restored the thiophene ring and resulted in tienilic acid being covalently linked to the enzyme, thus inhibiting the enzyme irreversibly.
The above explanation is a hypothesis. It is still not known (after 15 years) if the reactive intermediate which inactivates the CYP2C9 is the thiophene sulfoxide or the thiophene epoxide. The target on the protein is also not known (could be multiple). However tienilic acid is a good mechanism based inhibitor of CYP2C9 and seems to inactivate it stoichiometrically. Progress in proteomics may one day give the answer.
Recent studies indicate that in fact the primary metabolite of tienilic acid (5-OH tienilic acid) cannot be derived from a thiophene-S-oxide intermediate as was previously hypothesized. It was determined to be derived from a thiophene epoxide intermediate and this reactive intermediate is then likely a cause for the covalent binding to as well as mechanism-based inactivation of CYP2C9.
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https://www.wikidoc.org/index.php/Tienilic_acid
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Tildrakizumab
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Tildrakizumab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Tildrakizumab is a interleukin-23 antagonist that is FDA approved for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Common adverse reactions include upper respiratory infections, injection site reactions, and diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tildrakizumab is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
- Tildrakizumab is administered by subcutaneous injection. The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter. Each syringe contains 1 mL of 100 mg/mL tildrakizumab-asmn.
- Injection: 100 mg/mL solution in a single-dose prefilled syringe. Tildrakizumab is a clear to slightly opalescent, colorless to slightly yellow solution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tildrakizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Tildrakizumab is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients.
# Warnings
- Cases of angioedema and urticaria occurred in tildrakizumab treated subjects in clinical trials. If a serious hypersensitivity reaction occurs, discontinue tildrakizumab immediately and initiate appropriate therapy.
- Tildrakizumab may increase the risk of infection. Although infections were slightly more common in the tildrakizumab group (23%), the difference in frequency of infections between the tildrakizumab group and the placebo group was less than 1% during the placebo-controlled period. However, subjects with active infections or a history of recurrent infections were not included in clinical trials. Upper respiratory infections occurred more frequently in the tildrakizumab group than in the placebo group.
- The rates of serious infections for the tildrakizumab group and the placebo group were ≤0.3%. Treatment with tildrakizumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
- In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing tildrakizumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and consider discontinuation of tildrakizumab until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with tildrakizumab. Initiate treatment of latent TB prior to administering tildrakizumab. In clinical trials, of 55 subjects with latent TB who were concurrently treated with tildrakizumab and appropriate TB prophylaxis, no subjects developed active TB (during the mean follow-up of 56.5 weeks). One other subject developed TB while receiving tildrakizumab. Monitor patients for signs and symptoms of active TB during and after tildrakizumab treatment. Consider antiTB therapy prior to initiation of tildrakizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer tildrakizumab to patients with active TB infection.
- Prior to initiating therapy with tildrakizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid the use of live vaccines in patients treated with tildrakizumab. No data are available on the response to live or inactive vaccines.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In clinical trials, a total of 1994 subjects with plaque psoriasis were treated with tildrakizumab, of which 1083 subjects were treated with tildrakizumab 100 mg. Of these, 672 subjects were exposed for at least 12 months, 587 for 18 months, and 469 for 24 months.
- Data from three placebo-controlled trials (Trials 1, 2, and 3) in 705 subjects (mean age 46 years, 71% males, 81% white) were pooled to evaluate the safety of tildrakizumab (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 12 weeks ).
- In the placebo-controlled period of Trials 1, 2, and 3 in the 100 mg group, adverse events occurred in 48.2% of subjects in the tildrakizumab group compared to 53.8% of subjects in the placebo group. The rates of serious adverse events were 1.4% in the tildrakizumab group and 1.7% in the placebo group.
- Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the tildrakizumab group than in the placebo group.
- During the placebo-controlled period of Trials 1, 2, and 3, adverse reactions that occurred at rates less than 1% but greater than 0.1% in the tildrakizumab group and at a higher rate than in the placebo group included dizziness and pain in extremity.
Hypersensitivity Reactions
- Cases of angioedema and urticaria occurred in tildrakizumab-treated subjects in clinical trials.
Infections
- Infections were slightly more common in the tildrakizumab group. The difference in frequency of infections between the tildrakizumab group (23%) and the placebo group was less than 1% during the placebo-controlled period. The most common (≥1%) infections were upper respiratory infections. The rates of severe infections for the tildrakizumab group and the placebo group were ≤0.3%.
Safety Through Week 52/64
- Through Week 52 (Trials 1 and 3) and Week 64 (Trial 2), no new adverse reactions were identified with tildrakizumab use and the frequency of the adverse reactions was similar to that observed during the placebo-controlled period.
- As with all therapeutic proteins there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to tildrakizumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.
- Up to Week 64, approximately 6.5% of subjects treated with tildrakizumab 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all subjects receiving tildrakizumab) had antibodies that were classified as neutralizing. Development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and reduced efficacy.
## Postmarketing Experience
There is limited information regarding Tildrakizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Live Vaccinations
- Avoid use of live vaccines in patients treated with tildrakizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Limited available data with tildrakizumab use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Human IgG is known to cross the placental barrier; therefore, tildrakizumab may be transferred from the mother to the fetus. An embryofetal developmental study conducted with tildrakizumab in pregnant monkeys revealed no treatment-related effects to the developing fetus when tildrakizumab was administered subcutaneously during organogenesis to near parturition at doses up to 159 times the maximum recommended human dose (MRHD). When dosing was continued until parturition, a small increase in neonatal death was observed at 59 times the MRHD. The clinical significance of this nonclinical finding is unknown.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- In an embryofetal developmental study, subcutaneous doses up to 300 mg/kg tildrakizumab were administered to pregnant cynomolgus monkeys once every two weeks during organogenesis to gestation day 118 (22 days from parturition). No maternal or embryofetal toxicities were observed at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys.
- In a pre- and postnatal developmental study, subcutaneous doses up to 100 mg/kg tildrakizumab were administered to pregnant cynomolgus monkeys once every two weeks from gestation day 50 to parturition. Neonatal deaths occurred in the offspring of one control monkey, two monkeys at 10 mg/kg dose (6 times the MRHD based on AUC comparison), and four monkeys at 100 mg/kg dose (59 times the MRHD based on AUC comparison). The clinical significance of these nonclinical findings is unknown. No tildrakizumab-related adverse effects were noted in the remaining infants from birth through 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tildrakizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tildrakizumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of tildrakizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. Tildrakizumab was detected in the milk of monkeys.
- The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tildrakizumab and any potential adverse effects on the breastfed child from tildrakizumab or from the underlying maternal condition.
- Very low levels of tildrakizumab were detected in breast milk of monkeys in the pre- and postnatal developmental study described in 8.1. The mean tildrakizumab concentrations in milk were approximately 0.09 – 0.2% of that in serum on postpartum days 28 and 91.
### Pediatric Use
- Safety and effectiveness of tildrakizumab in pediatric patients (<18 years of age) have not been established.
### Geriatic Use
- A total of 1083 subjects were exposed to tildrakizumab 100 mg during Phase 2 and 3 trials. A total of 92 subjects were 65 years or older, and 17 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Tildrakizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tildrakizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tildrakizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tildrakizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tildrakizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tildrakizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with tildrakizumab.
- Tildrakizumab should only be administered by a healthcare provider. Administer tildrakizumab subcutaneously. Each pre-filled syringe is for single-dose only. Inject the full amount (1 mL), which provides 100 mg of tildrakizumab per syringe. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regularly scheduled interval.
- Before injection, remove tildrakizumab carton from the refrigerator, and let the prefilled syringe (in the tildrakizumab carton with the lid closed) sit at room temperature for 30 minutes. *Follow the instructions on the tildrakizumab carton to remove the prefilled syringe correctly, and remove only when ready to inject. Do not pull off the needle cover until you are ready to inject.
- Inspect tildrakizumab visually for particulate matter and discoloration prior to administration. Tildrakizumab is a clear to slightly opalescent, colorless to slightly yellow solution. Do not use if the liquid contains visible particles or the syringe is damaged. Air bubbles may be present; there is no need to remove them.
- Choose an injection site with clear skin and easy access (such as abdomen, thighs, or upper arm). Do not administer 2 inches around the navel or where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis. Also do not inject into scars, stretch marks, or blood vessels.
- While holding the body of the syringe, pull the needle cover straight off (do not twist) and
discard.
- Inject tildrakizumab subcutaneously as recommended.
- Press down the blue plunger until it can go no further. This activates the safety mechanism that will ensure full retraction of the needle after the injection is given.
- Remove the needle from the skin entirely before letting go of the blue plunger. After the blue plunger is released, the safely lock will draw the needle inside the needle guard.
- Discard of any unused portion. Dispose of used syringe.
### Monitoring
- An improvement in signs and symptoms of moderate-to-severe plaque psoriasis is indicative of efficacy.
- Tuberculosis (TB) screening: Prior to initiation.
- Signs and symptoms of active TB: During and after treatment.
# IV Compatibility
There is limited information regarding the compatibility of Tildrakizumab and IV administrations.
# Overdosage
- In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
- Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.
## Structure
There is limited information regarding Tildrakizumab Structure in the drug label.
## Pharmacodynamics
- No formal pharmacodynamics studies have been conducted with tildrakizumab.
## Pharmacokinetics
- Tildrakizumab pharmacokinetics increases proportionally over a dose range from 50 mg to 200 mg (0.5 to 2 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of tildrakizumab at Weeks 0, 4, and every 12 weeks thereafter. At the 100 mg dose at Week 16, the mean (± SD) steady-state trough concentrations ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%).
- The absolute bioavailability of tildrakizumab was estimated to be 73-80% following subcutaneous injection. The peak concentration (Cmax) was reached by approximately 6 days.
- The geometric mean (CV%) volume of distribution is 10.8 L (24%).
- The geometric mean (CV%) systemic clearance was 0.32 L/day (38%) and the half-life was approximately 23 days (23%).
Metabolism
- The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
- No clinically significant differences in the pharmacokinetics of tildrakizumab were observed based on age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of tildrakizumab.
Body Weight
- Tildrakizumab concentrations were lower in subjects with higher body weight.
Cytochrome P450 Substrates
- The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of tildrakizumab.
- No effects on fertility parameters were observed in male or female cynomolgus monkeys that were administered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once every two weeks for 3 months (133 or 155 times the MRHD, respectively, based on AUC comparison). The monkeys were not mated to evaluate fertility.
# Clinical Studies
- In two multicenter, randomized, double-blind, placebo-controlled trials (Trial 2 and Trial 3 ), 926 subjects were treated with tildrakizumab 100 mg (N=616) or placebo (N=310). Subjects had a Physician Global Assessment (PGA) score of ≥3 (moderate) on a 5-point scale of overall disease severity, Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum body surface area (BSA) involvement of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.
- In both trials, subjects were randomized to either placebo or tildrakizumab (100 mg at Week 0, Week 4 and every twelve weeks thereafter ) up to 64 weeks.
- Trials 2 and 3 assessed the changes from baseline to Week 12 in the two co-primary endpoints:
- PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score.
- PGA of 0 (“cleared”) or 1 (“minimal”), the proportion of subjects with a PGA of 0 or 1 and at least a 2-point improvement.
- Other evaluated outcomes in Trials 2 and 3 included the proportion of subjects who achieved a reduction from baseline in PASI score of at least 90% (PASI 90) and a reduction of 100% in PASI score (PASI 100) at Week 12 and maintenance of efficacy up to Week 64.
- In both trials, subjects in the tildrakizumab 100 mg and placebo treatment groups were predominantly men (69%) and White (80%), with a mean age of 46 years. At baseline, these subjects had a median affected BSA of 27%, a median PASI score of 17.8, and approximately 33% had a PGA score of 4 (“marked”) or 5 (“severe”). Approximately 34% had received prior phototherapy, 39% had received prior conventional systemic therapy, and 18% had received prior biologic therapy for the treatment of psoriasis. Approximately 16% of subjects had a history of psoriatic arthritis.
- The results of Trials 2 and 3 are presented in Table 2.
- Examination of age, gender, race, and previous treatment with a biologic did not identify differences in response to tildrakizumab among these subgroups at Week 12.
- In Trial 2, subjects originally randomized to tildrakizumab and who were responders at Week 28 (i.e., PASI 75) were re-randomized to an additional 36 weeks of either maintaining the same dose of tildrakizumab Q12W (every twelve weeks) or placebo.
- At Week 28, 229 (74%) subjects treated with tildrakizumab 100 mg were PASI 75 responders. At Week 64, 84% of subjects who continued on tildrakizumab 100 mg Q12W maintained PASI 75 compared to 22% of subjects who were re-randomized to placebo. In addition, for subjects who were re-randomized and also had a PGA score of 0 or 1 at Week 28, 69% of subjects who continued on tildrakizumab 100 mg Q12W maintained this response (PGA 0 or 1) at Week 64 compared to 14% of subjects who were rerandomized to placebo.
- For PASI 75 responders at Week 28 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to loss of PASI 75 was approximately 20 weeks.
- In addition, for subjects who were re-randomized to placebo and also had a PGA score of 0 or 1 at Week 28, the median time to loss of PGA score of 0 or 1 was approximately 16 weeks.
# How Supplied
- Tildrakizumab Injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution. Tildrakizumab is supplied as one single-dose prefilled syringe per carton that delivers 1 mL of a 100 mg/mL solution.
- NDC 0006-4241-00
- Each prefilled syringe is equipped with a passive needle guard and a needle cover.
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Tildrakizumab can be kept at room temperature at 25°C (77°F) for up to 30 days in the original carton to protect from light. Once stored at room temperature, do not place back in the refrigerator. If not used within 30 days, discard tildrakizumab. Do not store tildrakizumab above 25°C (77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling.
- Instruct patients and/or caregivers to read the Medication Guide before starting tildrakizumab therapy and to reread the Medication Guide each time the prescription is renewed. Advise patients of the potential benefits and risks of tildrakizumab.
- Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.
- Instruct patients of the importance of communicating any history of infections to the doctor and contacting their doctor if they develop any symptoms of infection
# Precautions with Alcohol
Alcohol-Tildrakizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Ilumya
# Look-Alike Drug Names
There is limited information regarding Tildrakizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price
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Tildrakizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Tildrakizumab is a interleukin-23 antagonist that is FDA approved for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Common adverse reactions include upper respiratory infections, injection site reactions, and diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tildrakizumab is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
- Tildrakizumab is administered by subcutaneous injection. The recommended dose is 100 mg at Weeks 0, 4, and every twelve weeks thereafter. Each syringe contains 1 mL of 100 mg/mL tildrakizumab-asmn.
- Injection: 100 mg/mL solution in a single-dose prefilled syringe. Tildrakizumab is a clear to slightly opalescent, colorless to slightly yellow solution.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tildrakizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tildrakizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Tildrakizumab is contraindicated in patients with a previous serious hypersensitivity reaction to tildrakizumab or to any of the excipients.
# Warnings
- Cases of angioedema and urticaria occurred in tildrakizumab treated subjects in clinical trials. If a serious hypersensitivity reaction occurs, discontinue tildrakizumab immediately and initiate appropriate therapy.
- Tildrakizumab may increase the risk of infection. Although infections were slightly more common in the tildrakizumab group (23%), the difference in frequency of infections between the tildrakizumab group and the placebo group was less than 1% during the placebo-controlled period. However, subjects with active infections or a history of recurrent infections were not included in clinical trials. Upper respiratory infections occurred more frequently in the tildrakizumab group than in the placebo group.
- The rates of serious infections for the tildrakizumab group and the placebo group were ≤0.3%. Treatment with tildrakizumab should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated.
- In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing tildrakizumab. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and consider discontinuation of tildrakizumab until the infection resolves.
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with tildrakizumab. Initiate treatment of latent TB prior to administering tildrakizumab. In clinical trials, of 55 subjects with latent TB who were concurrently treated with tildrakizumab and appropriate TB prophylaxis, no subjects developed active TB (during the mean follow-up of 56.5 weeks). One other subject developed TB while receiving tildrakizumab. Monitor patients for signs and symptoms of active TB during and after tildrakizumab treatment. Consider antiTB therapy prior to initiation of tildrakizumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Do not administer tildrakizumab to patients with active TB infection.
- Prior to initiating therapy with tildrakizumab, consider completion of all age appropriate immunizations according to current immunization guidelines. Avoid the use of live vaccines in patients treated with tildrakizumab. No data are available on the response to live or inactive vaccines.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In clinical trials, a total of 1994 subjects with plaque psoriasis were treated with tildrakizumab, of which 1083 subjects were treated with tildrakizumab 100 mg. Of these, 672 subjects were exposed for at least 12 months, 587 for 18 months, and 469 for 24 months.
- Data from three placebo-controlled trials (Trials 1, 2, and 3) in 705 subjects (mean age 46 years, 71% males, 81% white) were pooled to evaluate the safety of tildrakizumab (100 mg administered subcutaneously at Weeks 0 and 4, followed by every 12 weeks [Q12W]).
- In the placebo-controlled period of Trials 1, 2, and 3 in the 100 mg group, adverse events occurred in 48.2% of subjects in the tildrakizumab group compared to 53.8% of subjects in the placebo group. The rates of serious adverse events were 1.4% in the tildrakizumab group and 1.7% in the placebo group.
- Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the tildrakizumab group than in the placebo group.
- During the placebo-controlled period of Trials 1, 2, and 3, adverse reactions that occurred at rates less than 1% but greater than 0.1% in the tildrakizumab group and at a higher rate than in the placebo group included dizziness and pain in extremity.
Hypersensitivity Reactions
- Cases of angioedema and urticaria occurred in tildrakizumab-treated subjects in clinical trials.
Infections
- Infections were slightly more common in the tildrakizumab group. The difference in frequency of infections between the tildrakizumab group (23%) and the placebo group was less than 1% during the placebo-controlled period. The most common (≥1%) infections were upper respiratory infections. The rates of severe infections for the tildrakizumab group and the placebo group were ≤0.3%.
Safety Through Week 52/64
- Through Week 52 (Trials 1 and 3) and Week 64 (Trial 2), no new adverse reactions were identified with tildrakizumab use and the frequency of the adverse reactions was similar to that observed during the placebo-controlled period.
- As with all therapeutic proteins there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to tildrakizumab in the studies described below with the incidences of antibodies in other studies or to other products may be misleading.
- Up to Week 64, approximately 6.5% of subjects treated with tildrakizumab 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all subjects receiving tildrakizumab) had antibodies that were classified as neutralizing. Development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and reduced efficacy.
## Postmarketing Experience
There is limited information regarding Tildrakizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Live Vaccinations
- Avoid use of live vaccines in patients treated with tildrakizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Limited available data with tildrakizumab use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. Human IgG is known to cross the placental barrier; therefore, tildrakizumab may be transferred from the mother to the fetus. An embryofetal developmental study conducted with tildrakizumab in pregnant monkeys revealed no treatment-related effects to the developing fetus when tildrakizumab was administered subcutaneously during organogenesis to near parturition at doses up to 159 times the maximum recommended human dose (MRHD). When dosing was continued until parturition, a small increase in neonatal death was observed at 59 times the MRHD. The clinical significance of this nonclinical finding is unknown.
- All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- In an embryofetal developmental study, subcutaneous doses up to 300 mg/kg tildrakizumab were administered to pregnant cynomolgus monkeys once every two weeks during organogenesis to gestation day 118 (22 days from parturition). No maternal or embryofetal toxicities were observed at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys.
- In a pre- and postnatal developmental study, subcutaneous doses up to 100 mg/kg tildrakizumab were administered to pregnant cynomolgus monkeys once every two weeks from gestation day 50 to parturition. Neonatal deaths occurred in the offspring of one control monkey, two monkeys at 10 mg/kg dose (6 times the MRHD based on AUC comparison), and four monkeys at 100 mg/kg dose (59 times the MRHD based on AUC comparison). The clinical significance of these nonclinical findings is unknown. No tildrakizumab-related adverse effects were noted in the remaining infants from birth through 6 months of age.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tildrakizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tildrakizumab during labor and delivery.
### Nursing Mothers
- There are no data on the presence of tildrakizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG is known to be present in human milk. Tildrakizumab was detected in the milk of monkeys.
- The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tildrakizumab and any potential adverse effects on the breastfed child from tildrakizumab or from the underlying maternal condition.
- Very low levels of tildrakizumab were detected in breast milk of monkeys in the pre- and postnatal developmental study described in 8.1. The mean tildrakizumab concentrations in milk were approximately 0.09 – 0.2% of that in serum on postpartum days 28 and 91.
### Pediatric Use
- Safety and effectiveness of tildrakizumab in pediatric patients (<18 years of age) have not been established.
### Geriatic Use
- A total of 1083 subjects were exposed to tildrakizumab 100 mg during Phase 2 and 3 trials. A total of 92 subjects were 65 years or older, and 17 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Tildrakizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tildrakizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tildrakizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tildrakizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tildrakizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tildrakizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with tildrakizumab.
- Tildrakizumab should only be administered by a healthcare provider. Administer tildrakizumab subcutaneously. Each pre-filled syringe is for single-dose only. Inject the full amount (1 mL), which provides 100 mg of tildrakizumab per syringe. If a dose is missed, administer the dose as soon as possible. Thereafter, resume dosing at the regularly scheduled interval.
- Before injection, remove tildrakizumab carton from the refrigerator, and let the prefilled syringe (in the tildrakizumab carton with the lid closed) sit at room temperature for 30 minutes. *Follow the instructions on the tildrakizumab carton to remove the prefilled syringe correctly, and remove only when ready to inject. Do not pull off the needle cover until you are ready to inject.
- Inspect tildrakizumab visually for particulate matter and discoloration prior to administration. Tildrakizumab is a clear to slightly opalescent, colorless to slightly yellow solution. Do not use if the liquid contains visible particles or the syringe is damaged. Air bubbles may be present; there is no need to remove them.
- Choose an injection site with clear skin and easy access (such as abdomen, thighs, or upper arm). Do not administer 2 inches around the navel or where the skin is tender, bruised, erythematous, indurated, or affected by psoriasis. Also do not inject into scars, stretch marks, or blood vessels.
- While holding the body of the syringe, pull the needle cover straight off (do not twist) and
discard.
- Inject tildrakizumab subcutaneously as recommended.
- Press down the blue plunger until it can go no further. This activates the safety mechanism that will ensure full retraction of the needle after the injection is given.
- Remove the needle from the skin entirely before letting go of the blue plunger. After the blue plunger is released, the safely lock will draw the needle inside the needle guard.
- Discard of any unused portion. Dispose of used syringe.
### Monitoring
- An improvement in signs and symptoms of moderate-to-severe plaque psoriasis is indicative of efficacy.
- Tuberculosis (TB) screening: Prior to initiation.
- Signs and symptoms of active TB: During and after treatment.
# IV Compatibility
There is limited information regarding the compatibility of Tildrakizumab and IV administrations.
# Overdosage
- In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and administer appropriate symptomatic treatment immediately.
# Pharmacology
## Mechanism of Action
- Tildrakizumab is a humanized IgG1/k monoclonal antibody that selectively binds to the p19 subunit of IL-23 and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines.
## Structure
There is limited information regarding Tildrakizumab Structure in the drug label.
## Pharmacodynamics
- No formal pharmacodynamics studies have been conducted with tildrakizumab.
## Pharmacokinetics
- Tildrakizumab pharmacokinetics increases proportionally over a dose range from 50 mg to 200 mg (0.5 to 2 times the approved recommended dosage) following subcutaneous administration in subjects with plaque psoriasis. Steady-state concentrations were achieved by Week 16 following subcutaneous administration of tildrakizumab at Weeks 0, 4, and every 12 weeks thereafter. At the 100 mg dose at Week 16, the mean (± SD) steady-state trough concentrations ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%).
- The absolute bioavailability of tildrakizumab was estimated to be 73-80% following subcutaneous injection. The peak concentration (Cmax) was reached by approximately 6 days.
- The geometric mean (CV%) volume of distribution is 10.8 L (24%).
- The geometric mean (CV%) systemic clearance was 0.32 L/day (38%) and the half-life was approximately 23 days (23%).
Metabolism
- The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG.
- No clinically significant differences in the pharmacokinetics of tildrakizumab were observed based on age (≥18 years). No specific studies have been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of tildrakizumab.
Body Weight
- Tildrakizumab concentrations were lower in subjects with higher body weight.
Cytochrome P450 Substrates
- The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of tildrakizumab.
- No effects on fertility parameters were observed in male or female cynomolgus monkeys that were administered tildrakizumab at subcutaneous or intravenous doses up to 140 mg/kg once every two weeks for 3 months (133 or 155 times the MRHD, respectively, based on AUC comparison). The monkeys were not mated to evaluate fertility.
# Clinical Studies
- In two multicenter, randomized, double-blind, placebo-controlled trials (Trial 2 [NCT01722331] and Trial 3 [NCT01729754]), 926 subjects were treated with tildrakizumab 100 mg (N=616) or placebo (N=310). Subjects had a Physician Global Assessment (PGA) score of ≥3 (moderate) on a 5-point scale of overall disease severity, Psoriasis Area and Severity Index (PASI) score ≥12, and a minimum body surface area (BSA) involvement of 10%. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded.
- In both trials, subjects were randomized to either placebo or tildrakizumab (100 mg at Week 0, Week 4 and every twelve weeks thereafter [Q12W]) up to 64 weeks.
- Trials 2 and 3 assessed the changes from baseline to Week 12 in the two co-primary endpoints:
- PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score.
- PGA of 0 (“cleared”) or 1 (“minimal”), the proportion of subjects with a PGA of 0 or 1 and at least a 2-point improvement.
- Other evaluated outcomes in Trials 2 and 3 included the proportion of subjects who achieved a reduction from baseline in PASI score of at least 90% (PASI 90) and a reduction of 100% in PASI score (PASI 100) at Week 12 and maintenance of efficacy up to Week 64.
- In both trials, subjects in the tildrakizumab 100 mg and placebo treatment groups were predominantly men (69%) and White (80%), with a mean age of 46 years. At baseline, these subjects had a median affected BSA of 27%, a median PASI score of 17.8, and approximately 33% had a PGA score of 4 (“marked”) or 5 (“severe”). Approximately 34% had received prior phototherapy, 39% had received prior conventional systemic therapy, and 18% had received prior biologic therapy for the treatment of psoriasis. Approximately 16% of subjects had a history of psoriatic arthritis.
- The results of Trials 2 and 3 are presented in Table 2.
- Examination of age, gender, race, and previous treatment with a biologic did not identify differences in response to tildrakizumab among these subgroups at Week 12.
- In Trial 2, subjects originally randomized to tildrakizumab and who were responders at Week 28 (i.e., PASI 75) were re-randomized to an additional 36 weeks of either maintaining the same dose of tildrakizumab Q12W (every twelve weeks) or placebo.
- At Week 28, 229 (74%) subjects treated with tildrakizumab 100 mg were PASI 75 responders. At Week 64, 84% of subjects who continued on tildrakizumab 100 mg Q12W maintained PASI 75 compared to 22% of subjects who were re-randomized to placebo. In addition, for subjects who were re-randomized and also had a PGA score of 0 or 1 at Week 28, 69% of subjects who continued on tildrakizumab 100 mg Q12W maintained this response (PGA 0 or 1) at Week 64 compared to 14% of subjects who were rerandomized to placebo.
- For PASI 75 responders at Week 28 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to loss of PASI 75 was approximately 20 weeks.
- In addition, for subjects who were re-randomized to placebo and also had a PGA score of 0 or 1 at Week 28, the median time to loss of PGA score of 0 or 1 was approximately 16 weeks.
# How Supplied
- Tildrakizumab Injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution. Tildrakizumab is supplied as one single-dose prefilled syringe per carton that delivers 1 mL of a 100 mg/mL solution.
- NDC 0006-4241-00
- Each prefilled syringe is equipped with a passive needle guard and a needle cover.
## Storage
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light until the time of use. Do not freeze. Do not shake. Tildrakizumab can be kept at room temperature at 25°C (77°F) for up to 30 days in the original carton to protect from light. Once stored at room temperature, do not place back in the refrigerator. If not used within 30 days, discard tildrakizumab. Do not store tildrakizumab above 25°C (77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling.
- Instruct patients and/or caregivers to read the Medication Guide before starting tildrakizumab therapy and to reread the Medication Guide each time the prescription is renewed. Advise patients of the potential benefits and risks of tildrakizumab.
- Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions.
- Instruct patients of the importance of communicating any history of infections to the doctor and contacting their doctor if they develop any symptoms of infection
# Precautions with Alcohol
Alcohol-Tildrakizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Ilumya
# Look-Alike Drug Names
There is limited information regarding Tildrakizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price
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https://www.wikidoc.org/index.php/Tildrakizumab
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3fd0d7df66bdd06c33bc516e15eb90b42b2a2628
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wikidoc
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Timothy-grass
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Timothy-grass
Timothy-grass (Phleum pratense), is an abundant perennial grass native to most of Europe except for the Mediterranean region. It grows to 50–150 cm tall, with leaves up to 45 cm long and 1 cm broad. The flowerhead is 7–15 cm long and 8–10 mm broad, with densely packed spikelets.
Timothy-grass can be confused with Meadow Foxtail (Alopecurus pratensis) and Purple-stem Cat's-tail (Phleum phleoides).
There are two subspecies:
- Phleum pratense subsp. pratense. Larger, to 150 cm tall. Widespread.
- Phleum pratense subsp. bertolonii. Smaller, to 70 cm tall. Calcareous grassland.
# Cultivation and uses
Timothy-grass was unintentionally introduced to North America by early settlers, and was first described in 1711 by John Herd from plants growing in New Hampshire. Herd named the grass "herd grass" but a farmer named Timothy Hanson began to promote cultivation of it as a hay about 1720, and the grass has been known by its present name since then.
It is commonly grown for cattle feed and, in particular, as hay for horses. It is relatively high in fibre, especially when cut late. It is considered part of the standard mix for grass hay and provides quality nutrition for horses. Timothy hay is a staple food for domestic pet rabbits, guinea pigs, and degus, often making up the bulk of their diet. The caterpillars of some Lepidoptera use it as a foodplant, e.g. the Essex Skipper (Thymelicus lineola).
Its pollen is a common allergen; It has recently been used in small amounts as part of a new hay fever vaccine Grazax, which is designed to recondition the body's immune system so it no longer responds to pollen.
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Timothy-grass
Timothy-grass (Phleum pratense), is an abundant perennial grass native to most of Europe except for the Mediterranean region. It grows to 50–150 cm tall, with leaves up to 45 cm long and 1 cm broad. The flowerhead is 7–15 cm long and 8–10 mm broad, with densely packed spikelets.
Timothy-grass can be confused with Meadow Foxtail (Alopecurus pratensis) and Purple-stem Cat's-tail (Phleum phleoides).
There are two subspecies:
- Phleum pratense subsp. pratense. Larger, to 150 cm tall. Widespread.
- Phleum pratense subsp. bertolonii. Smaller, to 70 cm tall. Calcareous grassland.
## Cultivation and uses
Timothy-grass was unintentionally introduced to North America by early settlers, and was first described in 1711 by John Herd from plants growing in New Hampshire. Herd named the grass "herd grass" but a farmer named Timothy Hanson began to promote cultivation of it as a hay about 1720, and the grass has been known by its present name since then.
It is commonly grown for cattle feed and, in particular, as hay for horses. It is relatively high in fibre, especially when cut late. It is considered part of the standard mix for grass hay and provides quality nutrition for horses. Timothy hay is a staple food for domestic pet rabbits, guinea pigs, and degus, often making up the bulk of their diet. The caterpillars of some Lepidoptera use it as a foodplant, e.g. the Essex Skipper (Thymelicus lineola).
Its pollen is a common allergen; It has recently been used in small amounts as part of a new hay fever vaccine Grazax, which is designed to recondition the body's immune system so it no longer responds to pollen.
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https://www.wikidoc.org/index.php/Timothy-grass
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4ce08bba742a9b6824630a68842751b205587481
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wikidoc
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Tinea capitis
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Tinea capitis
# Overview
Tinea capitis (also known as "Herpes tonsurans", "Ringworm of the hair," "Ringworm of the scalp," "Scalp ringworm", and "Tinea tonsurans") is a superficial fungal infection (dermatophytosis) of the scalp. The disease is primarily caused by dermatophytes in the Trichophyton and Microsporum genera that invade the hair shaft. The clinical presentation is typically single or multiple patches of hair loss, sometimes with a 'black dot' pattern (often with broken-off hairs), that may be accompanied by inflammation, scaling, pustules, and itching. Uncommon in adults, tinea capitis is predominantly seen in pre-pubertal children, more often boys than girls.
At least eight species of dermatophytes are associated with tinea capitis. Cases of Trichophyton infection predominate from Central America to the United States and in parts of Western Europe. Infections from Microsporum species are mainly in South America, Southern and Central Europe, Africa and the Middle East. The disease is infectious and can be transmitted by humans, animals, or objects that harbor the fungus. The fungus can also exist in a carrier state on the scalp, without clinical symptomatology. Treatment of tinea capitis requires an oral antifungal agent; griseofulvin is the most commonly used drug, but other newer antimycotic drugs, such as terbinafine, itraconazole, and fluconazole have started to gain acceptance.
# Symptoms
It may appear as thickened, scaly, and sometimes boggy swellings, or as expanding raised red rings (ringworm). Common symptoms are severe itching of the scalp, dandruff, and bald patches where the fungus has rooted itself in the skin. It often presents identically to dandruff or seborrheic dermatitis. The highest incidence in the United States of America is in American boys of school age.
There are three type of tinea capitis, microsporosis, trichophytosis, and favus; these are based on the causative microorganism, and the nature of the symptoms. In microsporosis, the lesion is a small red papule around a hair shaft that later becomes scaly; eventually the hairs break off 1–3 mm above the scalp. This disease used to be caused primarily by microsporum audouinii, but in Europe, M. canis is more frequently the causative fungus. The source of this fungus is typically sick cats and kittens; it may be spread through person to person contact, or by sharing contaminated brushes and combs. In the United States, Trichophytosis is usually caused by Trichophyton tonsurans, while T. violaceum is more common in Eastern Europe, Africa, and India. This fungus causes dry, non-inflammatory patches that tend to be angular in shape. When the hairs break off at the opening of the follicle, black dots remain. Favus is caused by T. schoenlenii, and is endemic in South Africa and the Middle East. It is characterized by a number of yellowish, circular, cup-shaped crusts (scutula) grouped in patches like a piece of honeycomb, each about the size of a split pea, with a hair projecting in the center. These increase in size and become crusted over, so that the characteristic lesion can only be seen around the edge of the scab.
# Diagnosis
Tiniea capitis may be difficult to distinguish from other skin diseases that cause scaling, such as psoriasis and seborrhoeic dermatitis; the basis for the diagnosis is positive microscopic examination and microbial culture of epilated hairs. Wood's lamp examination will reveal bright green to yellow-green fluorescence of hairs infected by M. canis, M. audouinii, M. rivalieri, and M. ferrugineum and a dull green or blue-white color of hairs infected by T. schoenleinii. Individuals with M. canis infection trichoscopy will show characteristic small comma hairs. Histopathology of scalp biopsy shows fungi sparsely distributed in the stratum corneum and hyphae extending down the hair follicle, placed on the surface of the hair shaft. These findings are occasionally associated with inflammatory tissue reaction in the local tissue.
## Physical Examination
### Skin
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
- Tinea capitis. Adapted from Dermatology Atlas.
# Treatment
The treatment of choice by dermatologists is a safe and inexpensive oral medication, griseofulvin, a secondary metabolite of the fungus Penicillium griseofulvin. This compound is fungistatic (inhibiting the growth or reproduction of fungi) and works by affecting the microtubular system of fungi, interfering with the mitotic spindle and cytoplasmic microtubules. The recommended pediatric dosage is 10 mg/kg/day for 6–8 weeks, although this may be increased to 20 mg/kg/d for those infected by T. tonsurans, or those who fail to respond to the initial 6 weeks of treatment. Unlike other fungal skin infections that may be treated with topical therapies like creams applied directly to the afflicted area, griseofulvin must be taken orally to be effective; this allows the drug to penetrate the hair shaft where the fungus lives. The effective therapy rate of this treatment is generally high, in the range of 88–100%.
Other oral antifungal treatments for tinea capitis also frequently reported in the literature include terbinafine, itraconazole, and fluconazole; these drugs have the advantage of shorter treatment durations than griseofulvin. However, concern has been raised about the possibility of rare side effects like liver toxicity or interactions with other drugs; furthermore, the newer drug treatments tend to be more expensive than griseofulvin.
On September 28, 2007, the U.S. Food and Drug Administration stated that Lamisil (Terbinafine hydrochloride, by Novartis AG) is a new treatment approved for use by children aged 4 years and older. The antifungal granules can be sprinkled on a child's food to treat the infection. Lamisil carries hepatotoxic risk, and can cause a metallic taste in the mouth.
## Antimicrobial Regimen
- Tinea capitis
- Preferred regimen (1): Griseofulvin 10-20 mg/kg/day for minimum 6 weeks
- Preferred regimen (2): Itraconazole 4-6 mg/kg pulsed dose weekly
- Preferred regimen (3): Terbinafine if 40 kg: 250 mg/day
# Pathophysiology
From the site of inoculation, the fungus grows down into the stratum corneum, where it invades keratin. Dermatophytes are unique in that they produce keratinase, which enables them to use keratin as a nutrient source. Infected hairs become brittle, and after three weeks, the clinical presentation of broken hairs is evident.
There are three types of infection:
Ectothrix: Characterized by the growth of fungal spores (arthroconidia) on the exterior of the hair shaft. Infected hairs usually fluoresce greenish-yellow under a Wood lamp. Associated with Microsporum canis, Microsporum gypseum, Trichophyton equinum, and Trichophyton verrucosum.
Endothrix: Similar to ectothrix, but characterized by arthroconidia restricted to the hair shaft, and restricted to anthropophilic bacteria. The cuticle of the hair remains intact and clinically this type does not have florescence. Associated with Trichophyton tonsurans and Trichophyton violaceum, which are anthropophilic.
Favus: Causes crusting on the surface of the skin, combined with hair loss. Associated with Trichophyton schoenleini.
# Epidemiology
Tinea capitis caused by species of Microsporum and Trichophyton is a contagious disease that is endemic in many countries. Affecting primarily pre-pubertal children between 6 and 10 years, it is more common in males than females; rarely does the disease persist past age sixteen. Because spread is thought to occur through direct contact with afflicted individuals, large outbreaks have been known to occur in schools and other places where children are in close quarters; however, indirect spread through contamination with infected objects (fomites) may also be a factor in the spread of infection. In the USA, tinea capitis is thought to occur in 3-8% of the pediatric population; up to one-third of households with contact with an infected person may harbor the disease without showing any symptoms.
The fungal species responsible for causing tinea capitis vary according to the geographical region, and may also change over time. For example, Microsporum audouinii was the predominant etiological agent in North America and Europe until the 1950s, but now Trichophyton tonsurans is more common in the USA, and becoming more common in Europe and the United Kingdom. This shift is thought to be due to the widespread use of griseofulvin, which is more effective against M. audounii than T. tonsurans; also, changes in immigration patterns and increases in international travel have likely spread T. tonsurans to new areas. Another fungal species that has increased in prevalence is Trichophyton violaceum, especially in urban populations of the United Kingdom and Europe.
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Tinea capitis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Tinea capitis (also known as "Herpes tonsurans",[1] "Ringworm of the hair,"[1] "Ringworm of the scalp,"[1] "Scalp ringworm",[2] and "Tinea tonsurans"[1]) is a superficial fungal infection (dermatophytosis) of the scalp.[3] The disease is primarily caused by dermatophytes in the Trichophyton and Microsporum genera that invade the hair shaft. The clinical presentation is typically single or multiple patches of hair loss, sometimes with a 'black dot' pattern (often with broken-off hairs), that may be accompanied by inflammation, scaling, pustules, and itching. Uncommon in adults, tinea capitis is predominantly seen in pre-pubertal children, more often boys than girls.
At least eight species of dermatophytes are associated with tinea capitis. Cases of Trichophyton infection predominate from Central America to the United States and in parts of Western Europe. Infections from Microsporum species are mainly in South America, Southern and Central Europe, Africa and the Middle East. The disease is infectious and can be transmitted by humans, animals, or objects that harbor the fungus. The fungus can also exist in a carrier state on the scalp, without clinical symptomatology. Treatment of tinea capitis requires an oral antifungal agent; griseofulvin is the most commonly used drug, but other newer antimycotic drugs, such as terbinafine, itraconazole, and fluconazole have started to gain acceptance.
# Symptoms
It may appear as thickened, scaly, and sometimes boggy swellings, or as expanding raised red rings (ringworm). Common symptoms are severe itching of the scalp, dandruff, and bald patches where the fungus has rooted itself in the skin. It often presents identically to dandruff or seborrheic dermatitis. The highest incidence in the United States of America is in American boys of school age.[4]
There are three type of tinea capitis, microsporosis, trichophytosis, and favus; these are based on the causative microorganism, and the nature of the symptoms. In microsporosis, the lesion is a small red papule around a hair shaft that later becomes scaly; eventually the hairs break off 1–3 mm above the scalp. This disease used to be caused primarily by microsporum audouinii, but in Europe, M. canis is more frequently the causative fungus. The source of this fungus is typically sick cats and kittens; it may be spread through person to person contact, or by sharing contaminated brushes and combs. In the United States, Trichophytosis is usually caused by Trichophyton tonsurans, while T. violaceum is more common in Eastern Europe, Africa, and India. This fungus causes dry, non-inflammatory patches that tend to be angular in shape. When the hairs break off at the opening of the follicle, black dots remain. Favus is caused by T. schoenlenii, and is endemic in South Africa and the Middle East. It is characterized by a number of yellowish, circular, cup-shaped crusts (scutula) grouped in patches like a piece of honeycomb, each about the size of a split pea, with a hair projecting in the center. These increase in size and become crusted over, so that the characteristic lesion can only be seen around the edge of the scab.[5]
# Diagnosis
Tiniea capitis may be difficult to distinguish from other skin diseases that cause scaling, such as psoriasis and seborrhoeic dermatitis; the basis for the diagnosis is positive microscopic examination and microbial culture of epilated hairs.[6] Wood's lamp examination will reveal bright green to yellow-green fluorescence of hairs infected by M. canis, M. audouinii, M. rivalieri, and M. ferrugineum and a dull green or blue-white color of hairs infected by T. schoenleinii.[7] Individuals with M. canis infection trichoscopy will show characteristic small comma hairs.[8] Histopathology of scalp biopsy shows fungi sparsely distributed in the stratum corneum and hyphae extending down the hair follicle, placed on the surface of the hair shaft. These findings are occasionally associated with inflammatory tissue reaction in the local tissue.[9]
## Physical Examination
### Skin
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
- Tinea capitis. Adapted from Dermatology Atlas.[10]
# Treatment
The treatment of choice by dermatologists is a safe and inexpensive oral medication, griseofulvin, a secondary metabolite of the fungus Penicillium griseofulvin. This compound is fungistatic (inhibiting the growth or reproduction of fungi) and works by affecting the microtubular system of fungi, interfering with the mitotic spindle and cytoplasmic microtubules. The recommended pediatric dosage is 10 mg/kg/day for 6–8 weeks, although this may be increased to 20 mg/kg/d for those infected by T. tonsurans, or those who fail to respond to the initial 6 weeks of treatment.[11] Unlike other fungal skin infections that may be treated with topical therapies like creams applied directly to the afflicted area, griseofulvin must be taken orally to be effective; this allows the drug to penetrate the hair shaft where the fungus lives. The effective therapy rate of this treatment is generally high, in the range of 88–100%.[12]
Other oral antifungal treatments for tinea capitis also frequently reported in the literature include terbinafine, itraconazole, and fluconazole; these drugs have the advantage of shorter treatment durations than griseofulvin.[13] However, concern has been raised about the possibility of rare side effects like liver toxicity or interactions with other drugs; furthermore, the newer drug treatments tend to be more expensive than griseofulvin.[14]
On September 28, 2007, the U.S. Food and Drug Administration stated that Lamisil (Terbinafine hydrochloride, by Novartis AG) is a new treatment approved for use by children aged 4 years and older. The antifungal granules can be sprinkled on a child's food to treat the infection.[15] Lamisil carries hepatotoxic risk, and can cause a metallic taste in the mouth.
## Antimicrobial Regimen
- Tinea capitis[16]
- Preferred regimen (1): Griseofulvin 10-20 mg/kg/day for minimum 6 weeks
- Preferred regimen (2): Itraconazole 4-6 mg/kg pulsed dose weekly
- Preferred regimen (3): Terbinafine if <20 kg: 62.5 mg/day, if 20-40 kg: 125 mg/day, if >40 kg: 250 mg/day
# Pathophysiology
From the site of inoculation, the fungus grows down into the stratum corneum, where it invades keratin. Dermatophytes are unique in that they produce keratinase, which enables them to use keratin as a nutrient source.[17] Infected hairs become brittle, and after three weeks, the clinical presentation of broken hairs is evident.[18]
There are three types of infection:
Ectothrix: Characterized by the growth of fungal spores (arthroconidia) on the exterior of the hair shaft. Infected hairs usually fluoresce greenish-yellow under a Wood lamp. Associated with Microsporum canis, Microsporum gypseum, Trichophyton equinum, and Trichophyton verrucosum.
Endothrix: Similar to ectothrix, but characterized by arthroconidia restricted to the hair shaft, and restricted to anthropophilic bacteria. The cuticle of the hair remains intact and clinically this type does not have florescence. Associated with Trichophyton tonsurans and Trichophyton violaceum, which are anthropophilic.
Favus: Causes crusting on the surface of the skin, combined with hair loss. Associated with Trichophyton schoenleini.[19]
# Epidemiology
Tinea capitis caused by species of Microsporum and Trichophyton is a contagious disease that is endemic in many countries. Affecting primarily pre-pubertal children between 6 and 10 years, it is more common in males than females; rarely does the disease persist past age sixteen.[20] Because spread is thought to occur through direct contact with afflicted individuals, large outbreaks have been known to occur in schools and other places where children are in close quarters; however, indirect spread through contamination with infected objects (fomites) may also be a factor in the spread of infection. In the USA, tinea capitis is thought to occur in 3-8% of the pediatric population; up to one-third of households with contact with an infected person may harbor the disease without showing any symptoms.[21]
The fungal species responsible for causing tinea capitis vary according to the geographical region, and may also change over time. For example, Microsporum audouinii was the predominant etiological agent in North America and Europe until the 1950s, but now Trichophyton tonsurans is more common in the USA, and becoming more common in Europe and the United Kingdom. This shift is thought to be due to the widespread use of griseofulvin, which is more effective against M. audounii than T. tonsurans; also, changes in immigration patterns and increases in international travel have likely spread T. tonsurans to new areas.[22] Another fungal species that has increased in prevalence is Trichophyton violaceum, especially in urban populations of the United Kingdom and Europe.[22]
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https://www.wikidoc.org/index.php/Tinea_Capitis
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06ba13f12cb84c8cc0e1cf405cd4de0ee7f2043b
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wikidoc
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Token economy
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Token economy
A token economy is a system of behavior modification based on the principles of operant conditioning. Contingency management systems are often employed by those who practice applied behavior analysis. It is one approach to a contingency management program. Specifically, the original proposal for such a system emphasized reinforcing positive behavior by awarding "tokens" for meeting positive behavioral goals. The first therapeutic use of a token system was by Avendano y Carderera in 1859, who described a "ticket" for rewarding good behavior in children. The system as popularized in a year-long study conducted by Teodoro Ayllon in Florida was primarily geared towards changing adolescent behavior. Ayllon's study included only adolescent males.
Ayllon's tokens themselves were not reinforcers; tokens were accumulated and "spent" in order to obtain a reinforcer. "Patients earn tokens, which they can exchange for privileges, such as time watching television or walks on the hospital grounds, by completing assigned duties (such as making their beds) or even just by engaging in appropriate conversations with others" (Nolen-Hoeksema's Abnormal Psychology, p.409). Early during the program, a participant would be required to spend all of his or her tokens daily to emphasize the reinforcement activity early, and as time passed and success was made, participants would be allowed (or required) to accumulate their tokens over the course of longer time periods. This, as a variable-rate scheduling system, helped prevent extinction of the behavior after the program's termination.
# Proceeding
The following must be defined:
- Desired behavior(Transparency)
- A large number of rewards
- What is a token
- How are tokens allocated
- How are the token earnings changing while approaching the goals
- How many tokens will be earned achieving the desired behavior
- How many tokens are necessary to get rewards (or maybe to do be allowed to do something). Earning and exchange of tokens have to be in a well-balanced proportion.
If the desired behavior is achieved, the token program must be faded out.
# Advantages of token economy
- tokens are flexible
- tokens can be used for several needs and therefore saturation is improbable
- there is no delay giving tokens after the desired behavior has been shown
- it does not matter who gives the tokens (an automat is also possible)
- mostly the token economy is well-regulated thus it is easy for therapists to decide whether they have to give a token or not
# Requirements of token economy
- it is very important to observe the rules (nobody must give them awards otherwise the token economy will be corrupted)
- 10% - 20% of clients do not respond to token economies
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Token economy
Template:Psychology (sidebar)
A token economy is a system of behavior modification based on the principles of operant conditioning. Contingency management systems are often employed by those who practice applied behavior analysis. It is one approach to a contingency management program. Specifically, the original proposal for such a system emphasized reinforcing positive behavior by awarding "tokens" for meeting positive behavioral goals. The first therapeutic use of a token system was by Avendano y Carderera in 1859, who described a "ticket" for rewarding good behavior in children.[1] The system as popularized in a year-long study conducted by Teodoro Ayllon in Florida was primarily geared towards changing adolescent behavior. Ayllon's study included only adolescent males.
Ayllon's tokens themselves were not reinforcers; tokens were accumulated and "spent" in order to obtain a reinforcer. "Patients earn tokens, which they can exchange for privileges, such as time watching television or walks on the hospital grounds, by completing assigned duties (such as making their beds) or even just by engaging in appropriate conversations with others" (Nolen-Hoeksema's Abnormal Psychology, p.409). Early during the program, a participant would be required to spend all of his or her tokens daily to emphasize the reinforcement activity early, and as time passed and success was made, participants would be allowed (or required) to accumulate their tokens over the course of longer time periods. This, as a variable-rate scheduling system, helped prevent extinction of the behavior after the program's termination.
## Proceeding
The following must be defined:
- Desired behavior(Transparency)
- A large number of rewards
- What is a token
- How are tokens allocated
- How are the token earnings changing while approaching the goals
- How many tokens will be earned achieving the desired behavior
- How many tokens are necessary to get rewards (or maybe to do be allowed to do something). Earning and exchange of tokens have to be in a well-balanced proportion.
If the desired behavior is achieved, the token program must be faded out.
## Advantages of token economy
- tokens are flexible
- tokens can be used for several needs and therefore saturation is improbable
- there is no delay giving tokens after the desired behavior has been shown
- it does not matter who gives the tokens (an automat is also possible)
- mostly the token economy is well-regulated thus it is easy for therapists to decide whether they have to give a token or not
## Requirements of token economy
- it is very important to observe the rules (nobody must give them awards otherwise the token economy will be corrupted)
- 10% - 20% of clients do not respond to token economies
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https://www.wikidoc.org/index.php/Token_economy
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d647bdcb5bebd860fec3d657705b98d0ede1d916
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wikidoc
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Tonsil stones
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Tonsil stones
# Overview
Tonsil Stones are a formation combined of food debris, excess phloem, and the remains of white blood cells. The reason why they form in the tonsils is because the tonsil, especially at a young age, is meant to trap foreign debris entering the mouth. It's essentially a protector for your body. White blood cells are your body's normal defense against a multitude of things entering your body but in this case they attack debris in the tonsil, building thicker and thicker and eventually creating a tonsillolith. Tonsil Stones hide in the holes in your tonsils which are technically known as "tonsil crypts".
# Symptoms
Some typical symptoms of having tonsil stones are chronic bad breath, the feeling of something stuck in your throat that you can't get out, and feeling like you have to brush your teeth more than three times a day, (never feeling like your breath is fresh). Of course if you look in the mirror and you see white things sticking out of your tonsils, or if you cough up little white chunks, they're both a sure sign of having tonsil stones. While harmless in nature they're nothing more than annoyance and they don't have any physical negative effects on your body.
# Risk Factors and Promoters
Some foods that aggravate and promote tonsil stone growth are, dairy products (especially milk), high protein meats like fish, sugars and acidic things like coffee
# Treatement
There are a variety of ways that one can remove a tonsil stone. The most common is using any form of applying pressure to the side of the tonsil to push the tonsil stone out of the crypt. Some use a waterpik to do this, some use a qtip or even just their finger. Be careful of your gag reflex in all cases.
# Commercial Products to Prevent Tonsil Stones
While there's many commercial products out there that claim to be effective at combating tonsil stone growth, there's only a handful that actually work well. Some of the brands out there that sell products for this are profresh, breathrx, therabreath, oramd, smartmouth, to name a few.
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Tonsil stones
# Overview
Tonsil Stones are a formation combined of food debris, excess phloem, and the remains of white blood cells. The reason why they form in the tonsils is because the tonsil, especially at a young age, is meant to trap foreign debris entering the mouth. It's essentially a protector for your body. White blood cells are your body's normal defense against a multitude of things entering your body but in this case they attack debris in the tonsil, building thicker and thicker and eventually creating a tonsillolith. Tonsil Stones hide in the holes in your tonsils which are technically known as "tonsil crypts".
# Symptoms
Some typical symptoms of having tonsil stones are chronic bad breath, the feeling of something stuck in your throat that you can't get out, and feeling like you have to brush your teeth more than three times a day, (never feeling like your breath is fresh). Of course if you look in the mirror and you see white things sticking out of your tonsils, or if you cough up little white chunks, they're both a sure sign of having tonsil stones. While harmless in nature they're nothing more than annoyance and they don't have any physical negative effects on your body.
# Risk Factors and Promoters
Some foods that aggravate and promote tonsil stone growth are, dairy products (especially milk), high protein meats like fish, sugars and acidic things like coffee
# Treatement
There are a variety of ways that one can remove a tonsil stone. The most common is using any form of applying pressure to the side of the tonsil to push the tonsil stone out of the crypt. Some use a waterpik to do this, some use a qtip or even just their finger. Be careful of your gag reflex in all cases.
# Commercial Products to Prevent Tonsil Stones
While there's many commercial products out there that claim to be effective at combating tonsil stone growth, there's only a handful that actually work well. Some of the brands out there that sell products for this are profresh, breathrx, therabreath, oramd, smartmouth, to name a few.
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https://www.wikidoc.org/index.php/Tonsil_stones
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75fb7acb031f03f5ae256470e77393564a35a011
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wikidoc
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Tonsillectomy
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Tonsillectomy
# Overview
A tonsillectomy is a surgical procedure in which the tonsils are removed. Sometimes the adenoids are removed at the same time.
# Reasons for tonsillectomy
Tonsillectomy may be performed when the patient:
- Experiences frequent bouts of acute tonsillitis. The number requiring tonsillectomy varies with the severity of the episodes. One case, even severe, is generally not enough for most surgeons to decide tonsillectomy is necessary.
- Has chronic tonsillitis, consisting of persistent, moderate-to-severe throat pain.
- Has multiple bouts of peritonsillar abscess.
- Has sleep apnea (stopping or obstructing breathing at night due to enlarged tonsils or adenoids)
- Difficulty eating or swallowing due to enlarged tonsils
# Common Causes and Demographics
Infections requiring tonsillectomy are often a result of Streptococcus ("strep throat"), but some may be due to other bacteria, such as Staphylococcus, or viruses. However, the etiology of the condition is largely irrelevant in determining whether tonsillectomy is required .
Most tonsillectomies are performed on children, although many are also performed on teenagers and adults. The number of tonsillectomies in the United States has dropped significantly from several million in the 1970s to approximately 600,000 in the late 1990s. This has been due in part to more stringent guidelines for tonsillectomy and adenoidectomy (see tonsillitis and adenoid). Still, debate about the usefulness of tonsillectomies continues. Not surprisingly, the otolaryngology literature is usually pro-tonsillectomy, whereas the pediatric literature has the opposing view. Enlarged tonsils are being removed more often among adults and children for sleep apnea (airway obstruction while sleeping), snoring, and upper airway obstruction. Children who have sleep apnea can do poorly in school, are tired and fatigued during the day, and have some links to ADHD .
Tonsillectomy in adults is more painful than in children, although each patient will have a different experience. In adults it can be extremely painful often referred to as more painful than child birth. Post-operative recovery can take from 10 up to 20 days, during which narcotic analgesics are typically prescribed. Most surgeons advise eating soft foods after having your tonsils removed. Some believe that dairy products tend to coat the throat and therefore discourage their use. Spicy and acidic foods are irritating, and should be avoided. Proper hydration is also very important during this time, since dehydration can increase throat pain, leading to a vicious cycle of poor fluid intake. At some point, most commonly 7-11 days after the surgery (but occasionally as long as two weeks (14 days) after), bleeding can occur when scabs begin sloughing off from the surgical sites. The overall risk of bleeding is approximately 1-2% higher in adults .
Approximately 3% of adult patients develop significant bleeding at this time. The bleeding might naturally stop quickly, or else mild intervention (e.g., gargling cold water) could be needed. Otherwise, a surgeon must repair the bleeding immediately by cauterization, which presents all the risks associated with emergency surgery (most having to do with the administration of anesthesia on a patient whose stomach is not empty). Various procedures are available to remove tonsils, each with different advantages and disadvantages. Children and teenagers sometimes exhibit a noticeable change in voice after the operation .
# Methods of tonsil removal
The first report of tonsillectomy was made by the Roman encyclopedist Celsus in 30 AD. He described scraping the tonsils and tearing them out or picking them up with a hook and excising them with a scalpel. Today, the scalpel is still the preferred surgical instrument of many ear, nose, and throat specialists. However, there are other procedures available – the choice may be dictated by the extent of the procedure (complete tonsil removal versus partial tonsillectomy) and other considerations such as pain and post-operative bleeding. A quick review of each procedure follows:
- Dissection and snare method: Removal of the tonsils by use of a forceps and scissors with wire loop called 'snare' is the most common method practiced by otolaryngologists today. The procedure requires the patient to undergo general anesthesia; the tonsils are completely removed with minimal post-operative bleeding.
- Electrocautery: Electrocautery burns the tonsillar tissue and assists in reducing blood loss through cauterization. Research has shown that the heat of electrocautery (400 C) results in thermal injury to surrounding tissue. This may result in more discomfort during the postoperative period.
- Harmonic scalpel: This medical device uses ultrasonic energy to vibrate its blade at 55,000 cycles per second. Invisible to the naked eye, the vibration transfers energy to the tissue, providing simultaneous cutting and coagulation. The temperature of the surrounding tissue reaches 80 C. Proponents of this procedure assert that the end result is precise cutting with minimal thermal damage.
- Radiofrequency ablation: Monopolar radiofrequency thermal ablation transfers radiofrequency energy to the tonsil tissue through probes inserted in the tonsil. The procedure can be performed in an office setting under light sedation or local anesthesia. After the treatment is performed, scarring occurs within the tonsil causing it to decrease in size over a period of several weeks. The treatment can be performed several times. The advantages of this technique are minimal discomfort, ease of operations, and immediate return to work or school. Tonsillar tissue remains after the procedure but is less prominent. This procedure is recommended for treating enlarged tonsils and not chronic or recurrent tonsillitis.
- Thermal Welding: A new technology which uses pure thermal energy to seal and divide the tissue. The resulting absence of thermal spread means that the temperature of surrounding tissue is only 2-3 degrees C higher than normal body temperature. Clinical papers show patients with minimal post-operative pain (no requirement for narcotic pain-killers), zero edema (swelling) plus almost no incidence of bleeding. Hospitals in the US are advertising this procedure as "Painless Tonsillectomy". Also known as Tissue Welding.
- Carbon dioxide laser: Laser tonsil ablation (LTA) finds the otolaryngologist employing a hand-held CO2 or KTP laser to vaporize and remove tonsil tissue. This technique reduces tonsil volume and eliminates recesses in the tonsils that collect chronic and recurrent infections. This procedure is recommended for chronic recurrent tonsillitis, chronic sore throats, severe halitosis, or airway obstruction caused by enlarged tonsils. The LTA is performed in 15 to 20 minutes in an office setting under local anesthesia. The patient leaves the office with minimal discomfort and returns to school or work the next day. Post-tonsillectomy bleeding may occur in two to five percent of patients. Previous research studies state that laser technology provides significantly less pain during the post-operative recovery of children, resulting in less sleep disturbance, decreased morbidity, and less need for medications. On the other hand, some believe that children are adverse to outpatient procedures without sedation.
- Microdebrider: The microdebrider is a powered rotary shaving device with continuous suction often used during sinus surgery. It is made up of a cannula or tube, connected to a hand piece, which in turn is connected to a motor with foot control and a suction device.The endoscopic microdebrider is used in performing a partial tonsillectomy, by partially shaving the tonsils. This procedure entails eliminating the obstructive portion of the tonsil while preserving the tonsillar capsule. A natural biologic dressing is left in place over the pharyngeal muscles, preventing injury, inflammation, and infection. The procedure results in less post-operative pain, a more rapid recovery, and perhaps fewer delayed complications. However, the partial tonsillectomy is suggested for enlarged tonsils – not those that incur repeated infections.
- Bipolar Radiofrequency Ablation (Coblation): This procedure produces an ionized saline layer that disrupts molecular bonds without using heat. As the energy is transferred to the tissue, ionic dissociation occurs. This mechanism can be used to remove all or only part of the tonsil. It is done under general anesthesia in the operating room and can be used for enlarged tonsils and chronic or recurrent infections. This causes removal of tissue with a thermal effect of 45-85 C. It has been claimed that this technique results in less pain, faster healing, and less post operative care . However, review of 21 studies gives conflicting results about levels of pain, and its comparative safety has yet to be confirmed .
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Tonsillectomy
# Overview
A tonsillectomy is a surgical procedure in which the tonsils are removed. Sometimes the adenoids are removed at the same time.
# Reasons for tonsillectomy
Tonsillectomy may be performed when the patient:
- Experiences frequent bouts of acute tonsillitis. The number requiring tonsillectomy varies with the severity of the episodes. One case, even severe, is generally not enough for most surgeons to decide tonsillectomy is necessary.
- Has chronic tonsillitis, consisting of persistent, moderate-to-severe throat pain.
- Has multiple bouts of peritonsillar abscess.
- Has sleep apnea (stopping or obstructing breathing at night due to enlarged tonsils or adenoids)
- Difficulty eating or swallowing due to enlarged tonsils
# Common Causes and Demographics
Infections requiring tonsillectomy are often a result of Streptococcus ("strep throat"), but some may be due to other bacteria, such as Staphylococcus, or viruses. However, the etiology of the condition is largely irrelevant in determining whether tonsillectomy is required [1].
Most tonsillectomies are performed on children, although many are also performed on teenagers and adults. The number of tonsillectomies in the United States has dropped significantly from several million in the 1970s to approximately 600,000 in the late 1990s. This has been due in part to more stringent guidelines for tonsillectomy and adenoidectomy (see tonsillitis and adenoid). Still, debate about the usefulness of tonsillectomies continues. Not surprisingly, the otolaryngology literature is usually pro-tonsillectomy, whereas the pediatric literature has the opposing view. Enlarged tonsils are being removed more often among adults and children for sleep apnea (airway obstruction while sleeping), snoring, and upper airway obstruction. Children who have sleep apnea can do poorly in school, are tired and fatigued during the day, and have some links to ADHD [2] [3].
Tonsillectomy in adults is more painful than in children, although each patient will have a different experience. In adults it can be extremely painful often referred to as more painful than child birth. Post-operative recovery can take from 10 up to 20 days, during which narcotic analgesics are typically prescribed. Most surgeons advise eating soft foods after having your tonsils removed. Some believe that dairy products tend to coat the throat and therefore discourage their use. Spicy and acidic foods are irritating, and should be avoided. Proper hydration is also very important during this time, since dehydration can increase throat pain, leading to a vicious cycle of poor fluid intake. At some point, most commonly 7-11 days after the surgery (but occasionally as long as two weeks (14 days) after), bleeding can occur when scabs begin sloughing off from the surgical sites. The overall risk of bleeding is approximately 1-2% higher in adults [4].
Approximately 3% of adult patients develop significant bleeding at this time. The bleeding might naturally stop quickly, or else mild intervention (e.g., gargling cold water) could be needed. Otherwise, a surgeon must repair the bleeding immediately by cauterization, which presents all the risks associated with emergency surgery (most having to do with the administration of anesthesia on a patient whose stomach is not empty). Various procedures are available to remove tonsils, each with different advantages and disadvantages. Children and teenagers sometimes exhibit a noticeable change in voice [5] after the operation [6] [7].
# Methods of tonsil removal
The first report of tonsillectomy was made by the Roman encyclopedist Celsus in 30 AD. He described scraping the tonsils and tearing them out or picking them up with a hook and excising them with a scalpel. Today, the scalpel is still the preferred surgical instrument of many ear, nose, and throat specialists. However, there are other procedures available – the choice may be dictated by the extent of the procedure (complete tonsil removal versus partial tonsillectomy) and other considerations such as pain and post-operative bleeding. A quick review of each procedure follows:
- Dissection and snare method: Removal of the tonsils by use of a forceps and scissors with wire loop called 'snare' is the most common method practiced by otolaryngologists today. The procedure requires the patient to undergo general anesthesia; the tonsils are completely removed with minimal post-operative bleeding.
- Electrocautery: Electrocautery burns the tonsillar tissue and assists in reducing blood loss through cauterization. Research has shown that the heat of electrocautery (400 C) results in thermal injury to surrounding tissue. This may result in more discomfort during the postoperative period.
- Harmonic scalpel: This medical device uses ultrasonic energy to vibrate its blade at 55,000 cycles per second. Invisible to the naked eye, the vibration transfers energy to the tissue, providing simultaneous cutting and coagulation. The temperature of the surrounding tissue reaches 80 C. Proponents of this procedure assert that the end result is precise cutting with minimal thermal damage.
- Radiofrequency ablation: Monopolar radiofrequency thermal ablation transfers radiofrequency energy to the tonsil tissue through probes inserted in the tonsil. The procedure can be performed in an office setting under light sedation or local anesthesia. After the treatment is performed, scarring occurs within the tonsil causing it to decrease in size over a period of several weeks. The treatment can be performed several times. The advantages of this technique are minimal discomfort, ease of operations, and immediate return to work or school. Tonsillar tissue remains after the procedure but is less prominent. This procedure is recommended for treating enlarged tonsils and not chronic or recurrent tonsillitis.
- Thermal Welding: A new technology which uses pure thermal energy to seal and divide the tissue. The resulting absence of thermal spread means that the temperature of surrounding tissue is only 2-3 degrees C higher than normal body temperature. Clinical papers show patients with minimal post-operative pain (no requirement for narcotic pain-killers), zero edema (swelling) plus almost no incidence of bleeding. Hospitals in the US are advertising this procedure as "Painless Tonsillectomy". Also known as Tissue Welding.
- Carbon dioxide laser: Laser tonsil ablation (LTA) finds the otolaryngologist employing a hand-held CO2 or KTP laser to vaporize and remove tonsil tissue. This technique reduces tonsil volume and eliminates recesses in the tonsils that collect chronic and recurrent infections. This procedure is recommended for chronic recurrent tonsillitis, chronic sore throats, severe halitosis, or airway obstruction caused by enlarged tonsils. The LTA is performed in 15 to 20 minutes in an office setting under local anesthesia. The patient leaves the office with minimal discomfort and returns to school or work the next day. Post-tonsillectomy bleeding may occur in two to five percent of patients. Previous research studies state that laser technology provides significantly less pain during the post-operative recovery of children, resulting in less sleep disturbance, decreased morbidity, and less need for medications. On the other hand, some believe that children are adverse to outpatient procedures without sedation.
- Microdebrider: The microdebrider is a powered rotary shaving device with continuous suction often used during sinus surgery. It is made up of a cannula or tube, connected to a hand piece, which in turn is connected to a motor with foot control and a suction device.The endoscopic microdebrider is used in performing a partial tonsillectomy, by partially shaving the tonsils. This procedure entails eliminating the obstructive portion of the tonsil while preserving the tonsillar capsule. A natural biologic dressing is left in place over the pharyngeal muscles, preventing injury, inflammation, and infection. The procedure results in less post-operative pain, a more rapid recovery, and perhaps fewer delayed complications. However, the partial tonsillectomy is suggested for enlarged tonsils – not those that incur repeated infections.
- Bipolar Radiofrequency Ablation (Coblation): This procedure produces an ionized saline layer that disrupts molecular bonds without using heat. As the energy is transferred to the tissue, ionic dissociation occurs. This mechanism can be used to remove all or only part of the tonsil. It is done under general anesthesia in the operating room and can be used for enlarged tonsils and chronic or recurrent infections. This causes removal of tissue with a thermal effect of 45-85 C. It has been claimed that this technique results in less pain, faster healing, and less post operative care [8]. However, review of 21 studies gives conflicting results about levels of pain, and its comparative safety has yet to be confirmed [9].
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https://www.wikidoc.org/index.php/Tonsilectomy
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f838d29b24f4dbce440105189eae9daf1e21d3b7
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wikidoc
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Tortilla Wall
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Tortilla Wall
The Tortilla Wall is a term given to a 14 mile (22.5 kilometer) section of United States border fence between the Otay Mesa Border Crossing in San Diego, California and the Pacific Ocean. This "San Diego wall" was completed in the early 1990s. While there are other walls at various points along the border, the Tortilla Wall is the longest to date.
The Tortilla Wall is marked with graffiti, crosses, photos and remembrances of individuals who have died trying to illegally cross into the United States.
# Effectiveness
The effectiveness of the wall has been significant according to U.S. Congressional testimony
"...apprehensions along the region with a security fence dropped from 202,000 in 1992 to 9,000 in 1994."
The building of the tortilla wall is generally considered by Mexicans to be an unfriendly gesture. It is a symbol of the controversial immigration issue. It is argued that the wall simply forces illegal border crossings to be moved to the more dangerous area of the Arizona desert.
# The Future of the Tortilla Wall
In 2006, the U.S. Congress voted The Secure Fence Act of 2006 which authorized spending $1.2 billion to build 700 miles (1,100 km) of additional fencing on the southern border facing Mexico. Additional fencing would lend some plausibility that the Tortilla Wall will continue to have support on the U.S. side.
# Anecdotal Wall Stories
Tunnels under the wall are still a popular way to cross the border. Some tunnels are quite sophisticated. One such tunnel created by smugglers ran from Tijuana to San Diego, was a half mile long, and included a concrete floor as well as electricity. Other tunnels have included steel rails, while other tunnels are simply dirt passageways or connect to sewer or drain systems.
As a stunt, a circus cannon was placed on the south side of the wall and an acrobat was blasted over the wall into the Border Field State Park in the U.S. He had his passport with him.
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Tortilla Wall
Template:Mergeto
The Tortilla Wall is a term given to a 14 mile (22.5 kilometer) section of United States border fence between the Otay Mesa Border Crossing in San Diego, California and the Pacific Ocean. This "San Diego wall" was completed in the early 1990s. While there are other walls at various points along the border, the Tortilla Wall is the longest to date.
The Tortilla Wall is marked with graffiti, crosses, photos and remembrances of individuals who have died trying to illegally cross into the United States.
# Effectiveness
The effectiveness of the wall has been significant according to U.S. Congressional testimony
"...apprehensions along the region with a security fence dropped from 202,000 in 1992 to 9,000 in 1994."
The building of the tortilla wall is generally considered by Mexicans to be an unfriendly gesture.[citation needed] It is a symbol of the controversial immigration issue. It is argued that the wall simply forces illegal border crossings to be moved to the more dangerous area of the Arizona desert.[citation needed]
# The Future of the Tortilla Wall
In 2006, the U.S. Congress voted The Secure Fence Act of 2006 which authorized spending $1.2 billion to build 700 miles (1,100 km) of additional fencing on the southern border facing Mexico. Additional fencing would lend some plausibility that the Tortilla Wall will continue to have support on the U.S. side.
# Anecdotal Wall Stories
Tunnels under the wall are still a popular way to cross the border. Some tunnels are quite sophisticated. One such tunnel created by smugglers ran from Tijuana to San Diego, was a half mile long, and included a concrete floor as well as electricity.[1] Other tunnels have included steel rails, while other tunnels are simply dirt passageways or connect to sewer or drain systems.[2]
As a stunt, a circus cannon was placed on the south side of the wall and an acrobat was blasted over the wall into the Border Field State Park in the U.S. He had his passport with him.[3]
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https://www.wikidoc.org/index.php/Tortilla_Wall
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f90fe5cf7f659765661cc435c0a518736fd8fb67
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wikidoc
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Toxicodendron
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Toxicodendron
Toxicodendron is a genus of woody trees, shrubs and vines in the Anacardiaceae or Sumac Family. All members of the genus produce the skin-irritating oil urushiol, which can cause a severe allergic reaction; hence the scientific name which means "poison tree".
Members of this genus are sometimes included in the genus Rhus, although recent molecular evidence points to keeping Toxicodendron as a separate monophyletic genus.
They have pinnately compound, alternate leaves and whitish or grayish drupes. The best known members of the genus in North America are poison ivy, practically ubiquitous throughout most of eastern North America, and poison oak, similiarly ubiquitous throughout much of the western part of the continent.
The plants are quite variable in appearance. The leaves may have smooth, toothed or lobed edges, and all three types of leaf edge may be present in a single plant. The plants grow as creeping vines, climbing vines, shrubs, or, in the case of Lacquer Tree and Poison Sumac, as trees. While leaves of Poison ivy and poison oaks usually have three leaflets, sometimes there are five or, occasionally, even seven leaflets. Leaves of Poison Sumac have 7-13 leaflets, and of Lacquer Tree, 7-19 leaflets.
The common names come from similar appearances to other species that are not closely related and to the allergic response to the urushiol. Poison oak is not an oak (Quercus, family Fagaceae), but this common name comes from the leaves' resemblance to white oak (Quercus alba) leaves, while Poison ivy is not an ivy (Hedera, family Araliaceae), but has a superficially similar growth form. Both Poison oak and Poison ivy are members of the sumac family, Anacardiaceae. Technically, the plants do not contain a poison; they contain a potent allergen.
The resins of certain species native to Japan, China and other Asian countries, such as T. vernicifluum (Lacquer Tree) and T. succedaneum (Wax Tree), are used to make lacquer, and, as a byproduct of lacquer manufacture, their berries are used to make japan wax.
# Avoidance, treatment, and safety
For specific information on prevention and treatment of Toxicodendron rashes, see Urushiol-induced contact dermatitis.
# Species of Toxicodendron
- Western Poison oak (Toxicodendron diversilobum or Rhus diversiloba) is found throughout much of western North America, ranging from the Pacific coast into the Sierra Nevada and Cascade mountain ranges between southern British Columbia and into Baja California. It is extremely common in that region, where it is the predominant species of the genus. Indeed, it is California's most prevalent woody shrub. Extremely variable, it grows as a dense shrub in open sunlight, or as a climbing vine in shaded areas. Like poison ivy, it reproduces by creeping rootstocks or by seeds. The leaves are divided into three leaflets, 35-100 mm long, with scalloped, toothed, or lobed edges. Californians learn to recognize it by the rhyme "leaves of three, let it be". The leaves may be red, yellow, green, or some combination of those colors, depending on various factors, such as the time of year.
- Asian Poison ivy (Toxicodendron orientale or Rhus orientale) is very similar to the American Poison ivy, and replaces it throughout east Asia (so similar that some texts treat it as just a variety of the American species).
- Potanin's Lacquer Tree or Chinese Varnish Tree (Toxicodendron potaninii or Rhus potaninii) from central China, is similar to T. vernicifluum but with (usually) fewer leaflets per leaf. Growing up to 20 m tall, like T. vernicifluum it is used for lacquer production. The leaves have 7-9 leaflets.
- Poison ivy (Toxicodendron radicans or Rhus radicans) is extremely common in some areas of North America. In the United States it grows in all states except Alaska, Hawaii, and California, but it is much less common than Poison oak in western North America. It also grows in Central America. Appearing as a creeping vine, a climbing vine, or a shrub, it reproduces both by creeping rootstocks and by seeds. The appearance varies. Leaves, arranged in an alternate pattern, usually in groups of three, are from 20 to 50 mm long, pointed at the tip, and may be toothed, smooth, or lobed, but never serrated. Leaves may be shiny or dull, and the color varies with the season. Vines grow almost straight up rather than wrapping around their support, and can grow to 8-10 m in height. In some cases, Poison ivy may entirely engulf the supporting structure, and vines may extend outward like limbs, so that it appears to be a Poison ivy "tree".
- Western Poison ivy (Toxicodendron rydbergii or Rhus rydbergii) is found in northern parts of the eastern United States. It also exists in the western United States and Canada, but is much less common than Poison oak. It may grow as a vine or a shrub. It was once considered a subspecies of Poison ivy. It does sometimes hybridize with the climbing species. Western Poison ivy is found in much of western and central United States and Canada, although not on the West Coast. In the eastern United States it is rarely found south of New England.
- Wax Tree (Toxicodendron succedaneum or Rhus succedanea), a native of Asia, although it has been planted elsewhere, most notably Australia and New Zealand. It is a large shrub or tree, up to 8 m tall, somewhat similar to a sumac tree. Because of its beautiful autumn foliage, it has been planted outside of Asia as an ornamental plant, often by gardeners who were apparently unaware of the dangers of allergic reactions. It is now officially classified as a noxious weed in Australia and New Zealand. The fatty-acid methyl ester of the kernel oil meets all of the major biodiesel requirements in the USA (ASTM D 6751-02, ASTM PS 121-99), Germany (DIN V 51606) and European Union (EN 14214).
- Atlantic Poison oak (Toxicodendron pubescens or Rhus toxicarium) grows mostly in sandy soils in eastern parts of the United States. Growing as a shrub, its leaves are in groups of three. Leaves are typically rounded or lobed, and are densely haired. Although it is often confused with the more common poison ivy, even in the scientific literature, Atlantic Poison oak has small clumps of hair on the veins on the underside of the leaves, while Poison ivy does not.
- Lacquer Tree or Varnish Tree (Toxicodendron vernicifluum or Rhus verniciflua) grows in Asia, especially China and Japan. Growing up to 20 m tall, its sap produces an extremely durable lacquer. The leaves have 7-19 leaflets (most often 11-13). The sap contains the allergenic oil, urushiol. Urushiol gets its name from this species which in Japanese is called Urushi. Other names for this species include Japanese lacquer tree, Japanese Varnish Tree and Japanese Sumac (Note: the term "varnish tree" is also occasionally applied to the Candlenut, Aleurites moluccana, a southeast Asian tree unrelated to Toxicodendron).
- Poison Sumac (Toxicodendron vernix or Rhus vernix) is a tall shrub or a small tree, from 2-7 m tall. It is found in swampy, open areas and reproduces by seeds. The leaves have between 7-13 untoothed leaflets, in a feather-compound arrangement. In terms of its potential to cause urushiol-induced contact dermatitis, poison sumac is far more virulent than other Toxicodendron species, even more virulent than poison ivy and poison oak. According to some botanists, poison sumac (Toxicodendron vernix) is the most toxic plant species in the United States (Frankel, 1991).
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Toxicodendron
Toxicodendron is a genus of woody trees, shrubs and vines in the Anacardiaceae or Sumac Family. All members of the genus produce the skin-irritating oil urushiol, which can cause a severe allergic reaction; hence the scientific name which means "poison tree".
Members of this genus are sometimes included in the genus Rhus, although recent molecular evidence points to keeping Toxicodendron as a separate monophyletic genus.[1]
They have pinnately compound, alternate leaves and whitish or grayish drupes. The best known members of the genus in North America are poison ivy, practically ubiquitous throughout most of eastern North America, and poison oak, similiarly ubiquitous throughout much of the western part of the continent.
The plants are quite variable in appearance. The leaves may have smooth, toothed or lobed edges, and all three types of leaf edge may be present in a single plant. The plants grow as creeping vines, climbing vines, shrubs, or, in the case of Lacquer Tree and Poison Sumac, as trees. While leaves of Poison ivy and poison oaks usually have three leaflets, sometimes there are five or, occasionally, even seven leaflets. Leaves of Poison Sumac have 7-13 leaflets, and of Lacquer Tree, 7-19 leaflets.
The common names come from similar appearances to other species that are not closely related and to the allergic response to the urushiol. Poison oak is not an oak (Quercus, family Fagaceae), but this common name comes from the leaves' resemblance to white oak (Quercus alba) leaves, while Poison ivy is not an ivy (Hedera, family Araliaceae), but has a superficially similar growth form. Both Poison oak and Poison ivy are members of the sumac family, Anacardiaceae. Technically, the plants do not contain a poison; they contain a potent allergen.
The resins of certain species native to Japan, China and other Asian countries, such as T. vernicifluum (Lacquer Tree) and T. succedaneum (Wax Tree), are used to make lacquer, and, as a byproduct of lacquer manufacture, their berries are used to make japan wax.
# Avoidance, treatment, and safety
For specific information on prevention and treatment of Toxicodendron rashes, see Urushiol-induced contact dermatitis.
# Species of Toxicodendron
- Western Poison oak (Toxicodendron diversilobum or Rhus diversiloba) is found throughout much of western North America, ranging from the Pacific coast into the Sierra Nevada and Cascade mountain ranges between southern British Columbia and into Baja California. It is extremely common in that region, where it is the predominant species of the genus. Indeed, it is California's most prevalent woody shrub.[2] Extremely variable, it grows as a dense shrub in open sunlight, or as a climbing vine in shaded areas. Like poison ivy, it reproduces by creeping rootstocks or by seeds. The leaves are divided into three leaflets, 35-100 mm long, with scalloped, toothed, or lobed edges. Californians learn to recognize it by the rhyme "leaves of three, let it be". The leaves may be red, yellow, green, or some combination of those colors, depending on various factors, such as the time of year.
- Asian Poison ivy (Toxicodendron orientale or Rhus orientale) is very similar to the American Poison ivy, and replaces it throughout east Asia (so similar that some texts treat it as just a variety of the American species).
- Potanin's Lacquer Tree or Chinese Varnish Tree (Toxicodendron potaninii or Rhus potaninii) from central China, is similar to T. vernicifluum but with (usually) fewer leaflets per leaf. Growing up to 20 m tall, like T. vernicifluum it is used for lacquer production. The leaves have 7-9 leaflets.
- Poison ivy (Toxicodendron radicans or Rhus radicans) is extremely common in some areas of North America. In the United States it grows in all states except Alaska, Hawaii, and California, but it is much less common than Poison oak in western North America. It also grows in Central America. Appearing as a creeping vine, a climbing vine, or a shrub, it reproduces both by creeping rootstocks and by seeds. The appearance varies. Leaves, arranged in an alternate pattern, usually in groups of three, are from 20 to 50 mm long, pointed at the tip, and may be toothed, smooth, or lobed, but never serrated. Leaves may be shiny or dull, and the color varies with the season. Vines grow almost straight up rather than wrapping around their support, and can grow to 8-10 m in height. In some cases, Poison ivy may entirely engulf the supporting structure, and vines may extend outward like limbs, so that it appears to be a Poison ivy "tree".
- Western Poison ivy (Toxicodendron rydbergii or Rhus rydbergii) is found in northern parts of the eastern United States. It also exists in the western United States and Canada, but is much less common than Poison oak. It may grow as a vine or a shrub. It was once considered a subspecies of Poison ivy. It does sometimes hybridize with the climbing species. Western Poison ivy is found in much of western and central United States and Canada, although not on the West Coast. In the eastern United States it is rarely found south of New England.
- Wax Tree (Toxicodendron succedaneum or Rhus succedanea), a native of Asia, although it has been planted elsewhere, most notably Australia and New Zealand. It is a large shrub or tree, up to 8 m tall, somewhat similar to a sumac tree. Because of its beautiful autumn foliage, it has been planted outside of Asia as an ornamental plant, often by gardeners who were apparently unaware of the dangers of allergic reactions. It is now officially classified as a noxious weed in Australia and New Zealand. The fatty-acid methyl ester of the kernel oil meets all of the major biodiesel requirements in the USA (ASTM D 6751-02, ASTM PS 121-99), Germany (DIN V 51606) and European Union (EN 14214). [3]
- Atlantic Poison oak (Toxicodendron pubescens or Rhus toxicarium) grows mostly in sandy soils in eastern parts of the United States. Growing as a shrub, its leaves are in groups of three. Leaves are typically rounded or lobed, and are densely haired. Although it is often confused with the more common poison ivy, even in the scientific literature[4], Atlantic Poison oak has small clumps of hair on the veins on the underside of the leaves, while Poison ivy does not.
- Lacquer Tree or Varnish Tree (Toxicodendron vernicifluum or Rhus verniciflua) grows in Asia, especially China and Japan. Growing up to 20 m tall, its sap produces an extremely durable lacquer. The leaves have 7-19 leaflets (most often 11-13). The sap contains the allergenic oil, urushiol. Urushiol gets its name from this species which in Japanese is called Urushi. Other names for this species include Japanese lacquer tree, Japanese Varnish Tree and Japanese Sumac (Note: the term "varnish tree" is also occasionally applied to the Candlenut, Aleurites moluccana, a southeast Asian tree unrelated to Toxicodendron).
- Poison Sumac (Toxicodendron vernix or Rhus vernix) is a tall shrub or a small tree, from 2-7 m tall. It is found in swampy, open areas and reproduces by seeds. The leaves have between 7-13 untoothed leaflets, in a feather-compound arrangement.[5] In terms of its potential to cause urushiol-induced contact dermatitis, poison sumac is far more virulent than other Toxicodendron species, even more virulent than poison ivy and poison oak. According to some botanists, poison sumac (Toxicodendron vernix) is the most toxic plant species in the United States (Frankel, 1991).
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https://www.wikidoc.org/index.php/Toxicodendron
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3591182d7ec6f1a9d6fb72b46cd0a3c98f12884c
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wikidoc
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Transaldolase
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Transaldolase
Transaldolase is an enzyme (EC 2.2.1.2) of the non-oxidative phase of the pentose phosphate pathway. In humans, transaldolase is encoded by the TALDO1 gene.
The following chemical reaction is catalyzed by transaldolase:
- sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate \rightleftharpoons erythrose 4-phosphate + fructose 6-phosphate
# Clinical significance
The pentose phosphate pathway has two metabolic functions: (1) generation of nicotinamide adenine dinucleotide phosphate (reduced NADPH), for reductive biosynthesis, and (2) formation of ribose, which is an essential component of ATP, DNA, and RNA. Transaldolase links the pentose phosphate pathway to glycolysis. In patients with deficiency of transaldolase, there's an accumulation of erythritol (from erythrose 4-phosphate), D-arabitol, and ribitol.
The deletion in 3 base pairs in the TALDO1 gene results in the absence of serine at position 171 of the transaldolase protein, which is part of a highly conserved region, suggesting that the mutation causes the transaldolase deficiency that is found in erythrocytes and lymphoblasts. The deletion of this amino acid can lead to liver cirrhosis and hepatosplenomegaly (enlarged spleen and liver) during early infancy. Transaldolase is also a target of autoimmunity in patients with multiple sclerosis.
# Structure
Transaldolase is a single domain composed of 337 amino acids. The core structure is an α/β barrel, similar to other class I aldolases, made up of eight parallel β-sheets and seven α-helices. There are also seven additional α-helices that are not part of the barrel. Hydrophobic amino acids are located between the β-sheets in the barrel and the surrounding α-helices to contribute to packing, such as the area containing Leu-168, Phe-170, Phe-189, Gly-311, and Phe-315. In the crystal, human transaldolase forms a dimer, with the two subunits connected by 18 residues in each subunit. See mechanism to the left for details.
The active site, located in the center of the barrel, contains three key residues: lysine-142, glutamate-106, and aspartate-27. The lysine holds the sugar in place while the glutamate and aspartate act as proton donors and acceptors.
# Mechanism of catalysis
The residue of lysine-142 in the active site of transaldolase forms a Schiff base with the keto group in sedoheptulose-7-phosphate after deprotonation by another active site residue, glutamate-106. The reaction mechanism is similar to the reverse reaction catalyzed by aldolase: The bond joining carbons 3 and 4 is broken, leaving dihydroxyacetone joined to the enzyme via a Schiff base. This cleavage reaction generates the unusual aldose sugar erythrose-4-phosphate. Then transaldolase catalyzes the condensation of glyceraldehyde-3-phosphate with the Schiff base of dihydroxyacetone, yielding enzyme-bound fructose 6-phosphate. Hydrolysis of the Schiff base liberates free fructose 6-phosphate, one of the products of the pentose phosphate pathway.
- Reaction scheme for the conversion of sedoheptulose-7-phosphate to fructose-6-phosphate.
Reaction scheme for the conversion of sedoheptulose-7-phosphate to fructose-6-phosphate.
- The pentose phosphate pathway adapted from (Verhoeven, 2001)
The pentose phosphate pathway adapted from (Verhoeven, 2001)
|
Transaldolase
Transaldolase is an enzyme (EC 2.2.1.2) of the non-oxidative phase of the pentose phosphate pathway. In humans, transaldolase is encoded by the TALDO1 gene.[3][4]
The following chemical reaction is catalyzed by transaldolase:
- sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate <math>\rightleftharpoons</math> erythrose 4-phosphate + fructose 6-phosphate
# Clinical significance
The pentose phosphate pathway has two metabolic functions: (1) generation of nicotinamide adenine dinucleotide phosphate (reduced NADPH), for reductive biosynthesis, and (2) formation of ribose, which is an essential component of ATP, DNA, and RNA. Transaldolase links the pentose phosphate pathway to glycolysis. In patients with deficiency of transaldolase, there's an accumulation of erythritol (from erythrose 4-phosphate), D-arabitol, and ribitol.[5][6]
The deletion in 3 base pairs in the TALDO1 gene results in the absence of serine at position 171 of the transaldolase protein, which is part of a highly conserved region, suggesting that the mutation causes the transaldolase deficiency that is found in erythrocytes and lymphoblasts.[5] The deletion of this amino acid can lead to liver cirrhosis and hepatosplenomegaly (enlarged spleen and liver) during early infancy. Transaldolase is also a target of autoimmunity in patients with multiple sclerosis.[7]
# Structure
Transaldolase is a single domain composed of 337 amino acids. The core structure is an α/β barrel, similar to other class I aldolases, made up of eight parallel β-sheets and seven α-helices. There are also seven additional α-helices that are not part of the barrel. Hydrophobic amino acids are located between the β-sheets in the barrel and the surrounding α-helices to contribute to packing, such as the area containing Leu-168, Phe-170, Phe-189, Gly-311, and Phe-315. In the crystal, human transaldolase forms a dimer, with the two subunits connected by 18 residues in each subunit. See mechanism to the left for details.
The active site, located in the center of the barrel, contains three key residues: lysine-142, glutamate-106, and aspartate-27. The lysine holds the sugar in place while the glutamate and aspartate act as proton donors and acceptors.[1]
# Mechanism of catalysis
The residue of lysine-142 in the active site of transaldolase forms a Schiff base with the keto group in sedoheptulose-7-phosphate after deprotonation by another active site residue, glutamate-106. The reaction mechanism is similar to the reverse reaction catalyzed by aldolase: The bond joining carbons 3 and 4 is broken, leaving dihydroxyacetone joined to the enzyme via a Schiff base. This cleavage reaction generates the unusual aldose sugar erythrose-4-phosphate. Then transaldolase catalyzes the condensation of glyceraldehyde-3-phosphate with the Schiff base of dihydroxyacetone, yielding enzyme-bound fructose 6-phosphate. Hydrolysis of the Schiff base liberates free fructose 6-phosphate, one of the products of the pentose phosphate pathway.
- Reaction scheme for the conversion of sedoheptulose-7-phosphate to fructose-6-phosphate.[8]
Reaction scheme for the conversion of sedoheptulose-7-phosphate to fructose-6-phosphate.[8]
- The pentose phosphate pathway adapted from (Verhoeven, 2001)[5]
The pentose phosphate pathway adapted from (Verhoeven, 2001)[5]
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https://www.wikidoc.org/index.php/Transaldolase
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6a48db677e92c3522944fb6b0257f86c4268050a
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wikidoc
|
Transcriptome
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Transcriptome
# Overview
The transcriptome is the set of all messenger RNA (mRNA) molecules, or "transcripts", produced in one or a population of cells. The term can be applied to the total set of transcripts in a given organism, or to the specific subset of transcripts present in a particular cell type. Unlike the genome, which is roughly fixed for a given cell line (excluding mutations), the transcriptome can vary with external environmental conditions. Because it includes all mRNA transcripts in the cell, the transcriptome reflects the genes that are being actively expressed at any given time, with the exception of mRNA degradation phenomena such as transcriptional attenuation. The study of transcriptomics examines the expression level of mRNAs in a given cell population, often using high-throughput techniques based on DNA microarray technology.
# Applications and analysis
The transcriptomes of stem cells and cancer cells are of particular interest to researchers who seek to understand the processes of cellular differentiation and carcinogenesis. A number of organism-specific transcriptome databases have been constructed and annotated to aid in the identification of genes that are differentially expressed in distinct cell populations or subtypes; however, the analysis of relative mRNA expression levels can be complicated by the fact that relatively small changes in mRNA expression can produce large changes in the total amount of the corresponding protein present in the cell. One analysis method, known as Gene Set Enrichment Analysis, identifies coregulated gene networks rather than individual genes that are up- or down-regulated in different cell populations.
# mRNA regulation
Although microarray studies can reveal the relative amounts of different mRNAs in the cell, levels of mRNA are not directly proportional to the expression level of the proteins they code for. The number of protein molecules synthesized using a given mRNA molecule as a template is highly dependent on translation-initiation features of the mRNA sequence; in particular, the ability of the translation initiation sequence is a key determinant in the recruiting of ribosomes for protein translation. The complete protein complement of a cell or organism is known as the proteome.
A study of 158,807 mouse transcripts revealed that 4520 of these transcripts form antisense partners that are base pair complementary to the exons of genes. These results raise the possibility that significant numbers of "antisense RNA-coding genes" might participate in the regulation of the levels of expression of protein-coding mRNAs.
|
Transcriptome
# Overview
The transcriptome is the set of all messenger RNA (mRNA) molecules, or "transcripts", produced in one or a population of cells. The term can be applied to the total set of transcripts in a given organism, or to the specific subset of transcripts present in a particular cell type. Unlike the genome, which is roughly fixed for a given cell line (excluding mutations), the transcriptome can vary with external environmental conditions. Because it includes all mRNA transcripts in the cell, the transcriptome reflects the genes that are being actively expressed at any given time, with the exception of mRNA degradation phenomena such as transcriptional attenuation. The study of transcriptomics examines the expression level of mRNAs in a given cell population, often using high-throughput techniques based on DNA microarray technology.
# Applications and analysis
The transcriptomes of stem cells and cancer cells are of particular interest to researchers who seek to understand the processes of cellular differentiation and carcinogenesis. A number of organism-specific transcriptome databases have been constructed and annotated to aid in the identification of genes that are differentially expressed in distinct cell populations or subtypes; however, the analysis of relative mRNA expression levels can be complicated by the fact that relatively small changes in mRNA expression can produce large changes in the total amount of the corresponding protein present in the cell. One analysis method, known as Gene Set Enrichment Analysis, identifies coregulated gene networks rather than individual genes that are up- or down-regulated in different cell populations[1].
# mRNA regulation
Although microarray studies can reveal the relative amounts of different mRNAs in the cell, levels of mRNA are not directly proportional to the expression level of the proteins they code for. The number of protein molecules synthesized using a given mRNA molecule as a template is highly dependent on translation-initiation features of the mRNA sequence; in particular, the ability of the translation initiation sequence is a key determinant in the recruiting of ribosomes for protein translation. The complete protein complement of a cell or organism is known as the proteome.
A study of 158,807 mouse transcripts revealed that 4520 of these transcripts form antisense partners that are base pair complementary to the exons of genes[2]. These results raise the possibility that significant numbers of "antisense RNA-coding genes" might participate in the regulation of the levels of expression of protein-coding mRNAs.
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https://www.wikidoc.org/index.php/Transcriptome
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d025c385890acc657ff5ed460bb54e2d9aaa5236
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wikidoc
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Transketolase
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Transketolase
Transketolase encoded by the TKT gene is an enzyme of both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. It catalyzes two important reactions, which operate in opposite directions in these two pathways. In the first reaction of the non-oxidative pentose phosphate pathway, the cofactor thiamine diphosphate accepts a 2-carbon fragment from a 5-carbon ketose (D-xylulose-5-P), then transfers this fragment to a 5-carbon aldose (D-ribose-5-P) to form a 7-carbon ketose (sedoheptulose-7-P). The abstraction of two carbons from D-xylulose-5-P yields the 3-carbon aldose glyceraldehyde-3-P. In the Calvin cycle, transketolase catalyzes the reverse reaction, the conversion of sedoheptulose-7-P and glyceraldehyde-3-P to pentoses, the aldose D-ribose-5-P and the ketose D-xylulose-5-P.
The second reaction catalyzed by transketolase in the pentose phosphate pathway involves the same thiamine diphosphate-mediated transfer of a 2-carbon fragment from D-xylulose-5-P to the aldose erythrose-4-phosphate, affording fructose 6-phosphate and glyceraldehyde-3-P. Again, in the Calvin cycle exactly the same reaction occurs, but in the opposite direction. Moreover, in the Calvin cycle this is the first reaction catalyzed by transketolase, rather than the second.
In mammals, transketolase connects the pentose phosphate pathway to glycolysis, feeding excess sugar phosphates into the main carbohydrate metabolic pathways. Its presence is necessary for the production of NADPH, especially in tissues actively engaged in biosyntheses, such as fatty acid synthesis by the liver and mammary glands, and for steroid synthesis by the liver and adrenal glands. Thiamine diphosphate is an essential cofactor, along with calcium.
Transketolase is abundantly expressed in the mammalian cornea by the stromal keratocytes and epithelial cells and is reputed to be one of the corneal crystallins.
# Species distribution
Transketolase is widely expressed in a wide range of organisms including bacteria, plants, and mammals. The following human genes encode proteins with transketolase activity:
- TKT (transketolase)
- TKTL1 (transketolase-like protein 1)
- TKTL2 (transketolase-like protein 2)
# Structure
The entrance to the active site for this enzyme is made up mainly of several arginine, histidine, serine, and aspartate side-chains, with a glutamate side-chain playing a secondary role. These side-chains, to be specific Arg359, Arg528, His469, and Ser386, are conserved within each transketolase enzyme and interact with the phosphate group of the donor and acceptor substrates. Because the substrate channel is so narrow, the donor and acceptor substrates cannot be bound simultaneously. Also, the substrates conform into a slightly extended form upon binding in the active site to accommodate this narrow channel.
Although this enzyme is able to bind numerous types of substrates, such as phosphorylated and nonphosphorylated monosaccharides including the keto and aldosugars fructose, ribose, etc., it has a high specificity for the stereoconfiguration of the hydroxyl groups of the sugars. These hydroxyl groups at C-3 and C-4 of the ketose donor must be in the D-threo configuration in order to correctly correspond to the C-1 and C-2 positions on the aldose acceptor. Also they stabilize the substrate in the active site by interacting with the Asp477, His30, and His263 residues. Disruption of this configuration, both the placement of hydroxyl groups or their stereochemistry, would consequently alter the H-bonding between the residues and substrates thus causing a lower affinity for the substrates.
In the first half of this pathway, His263 is used to effectively abstract the C3 hydroxyl proton, which thus allows a 2-carbon segment to be cleaved from fructose 6-phosphate. The cofactor necessary for this step to occur is thiamin pyrophosphate (TPP). The binding of TPP to the enzyme incurs no major conformational change to the enzyme; instead, the enzyme has two flexible loops at the active site that make TPP accessible and binding possible. Thus, this allows the active site to have a "closed" conformation rather than a large conformational change. Later in the pathway, His263 is used as a proton donor for the substrate acceptor-TPP complex, which can then generate erythrose-4-phosphate.
The histidine and aspartate side-chains are used to effectively stabilize the substrate within the active site and also participate in deprotonation of the substrate. To be specific, the His 263 and His30 side-chains form hydrogen bonds to the aldehyde end of the substrate, which is deepest into the substrate channel, and Asp477 forms hydrogen bonds with the alpha hydroxyl group on the substrate, where it works to effectively bind the substrate and check for proper stereochemistry. It is also thought that Asp477 could have important catalytic effects because of its orientation in the middle of the active site and its interactions with the alpha hydroxyl group of the substrate. Glu418, which is located in the deepest region of the active site, plays a critical role in stabilizing the TPP cofactor. To be specific, it is involved in the cofactor-assisted proton abstraction from the substrate molecule.
The phosphate group of the substrate also plays an important role in stabilizing the substrate upon its entrance into the active site. The tight ionic and polar interactions between this phosphate group and the residues Arg359, Arg528, His469, and Ser386 collectively work to stabilize the substrate by forming H-bonds to the oxygen atoms of the phosphate. The ionic nature is found in the salt bridge formed from Arg359 to the phosphate group.
# Mechanism
The catalysis of this mechanism is initiated by the deprotonation of TPP at the thiazolium ring. This carbanion then binds to the carbonyl of the donor substrate thus cleaving the bond between C-2 and C-3. This keto fragment remains covalently bound to the C-2 carbon of TPP. The donor substrate is then released, and the acceptor substrate enters the active site where the fragment, which is bound to the intermediate α-β-dihydroxyethyl thiamin diphosphate, is then transferred to the acceptor.
Mechanism of fructose-6-phosphate to xylulose-5-phosphate in transketolase active site
File:R Groups in Transketolase Mechanism.png
Experiments have also been conducted that test the effect replacing alanine for the amino acids at the entrance to the active site, Arg359, Arg528, and His469, which interact with the phosphate group of the substrate. This replacement creates a mutant enzyme with impaired catalytic activity.
# Role in disease
Transketolase activity is decreased in deficiency of thiamine, which in general is due to malnutrition. Several diseases are associated with thiamine deficiency, including beriberi, Biotin-Thiamine-Responsive Basal Ganglia Disease, Wernicke-Korsakoff syndrome, and others (see thiamine for a comprehensive listing).
In Wernicke-Korsakoff syndrome, while no mutations could be demonstrated, there is an indication that thiamine deficiency leads to Wernicke-Korsakoff syndrome only in those whose transketolase has a reduced affinity for thiamine. In this way, the activity of transketolase is greatly hindered, and, as a consequence, the entire pentose phosphate pathway is inhibited.
# Diagnostic use
Red blood cell transketolase activity is reduced in deficiency of thiamine (vitamin B1), and may be used in the diagnosis of Wernicke's encephalopathy and other B1-deficiency syndromes if the diagnosis is in doubt. Apart from the baseline enzyme activity (which may be normal even in deficiency states), acceleration of enzyme activity after the addition of thiamine pyrophosphate may be diagnostic of thiamine deficiency (0-15% normal, 15-25% deficiency, >25% severe deficiency).
|
Transketolase
Transketolase encoded by the TKT gene is an enzyme of both the pentose phosphate pathway in all organisms and the Calvin cycle of photosynthesis. It catalyzes two important reactions, which operate in opposite directions in these two pathways. In the first reaction of the non-oxidative pentose phosphate pathway, the cofactor thiamine diphosphate accepts a 2-carbon fragment from a 5-carbon ketose (D-xylulose-5-P), then transfers this fragment to a 5-carbon aldose (D-ribose-5-P) to form a 7-carbon ketose (sedoheptulose-7-P). The abstraction of two carbons from D-xylulose-5-P yields the 3-carbon aldose glyceraldehyde-3-P. In the Calvin cycle, transketolase catalyzes the reverse reaction, the conversion of sedoheptulose-7-P and glyceraldehyde-3-P to pentoses, the aldose D-ribose-5-P and the ketose D-xylulose-5-P.
The second reaction catalyzed by transketolase in the pentose phosphate pathway involves the same thiamine diphosphate-mediated transfer of a 2-carbon fragment from D-xylulose-5-P to the aldose erythrose-4-phosphate, affording fructose 6-phosphate and glyceraldehyde-3-P. Again, in the Calvin cycle exactly the same reaction occurs, but in the opposite direction. Moreover, in the Calvin cycle this is the first reaction catalyzed by transketolase, rather than the second.
In mammals, transketolase connects the pentose phosphate pathway to glycolysis, feeding excess sugar phosphates into the main carbohydrate metabolic pathways. Its presence is necessary for the production of NADPH, especially in tissues actively engaged in biosyntheses, such as fatty acid synthesis by the liver and mammary glands, and for steroid synthesis by the liver and adrenal glands. Thiamine diphosphate is an essential cofactor, along with calcium.
Transketolase is abundantly expressed in the mammalian cornea by the stromal keratocytes and epithelial cells and is reputed to be one of the corneal crystallins.[1]
# Species distribution
Transketolase is widely expressed in a wide range of organisms including bacteria, plants, and mammals. The following human genes encode proteins with transketolase activity:
- TKT (transketolase)
- TKTL1 (transketolase-like protein 1)
- TKTL2 (transketolase-like protein 2)
# Structure
The entrance to the active site for this enzyme is made up mainly of several arginine, histidine, serine, and aspartate side-chains, with a glutamate side-chain playing a secondary role. These side-chains, to be specific Arg359, Arg528, His469, and Ser386, are conserved within each transketolase enzyme and interact with the phosphate group of the donor and acceptor substrates. Because the substrate channel is so narrow, the donor and acceptor substrates cannot be bound simultaneously. Also, the substrates conform into a slightly extended form upon binding in the active site to accommodate this narrow channel.
Although this enzyme is able to bind numerous types of substrates, such as phosphorylated and nonphosphorylated monosaccharides including the keto and aldosugars fructose, ribose, etc., it has a high specificity for the stereoconfiguration of the hydroxyl groups of the sugars. These hydroxyl groups at C-3 and C-4 of the ketose donor must be in the D-threo configuration in order to correctly correspond to the C-1 and C-2 positions on the aldose acceptor.[2] Also they stabilize the substrate in the active site by interacting with the Asp477, His30, and His263 residues. Disruption of this configuration, both the placement of hydroxyl groups or their stereochemistry, would consequently alter the H-bonding between the residues and substrates thus causing a lower affinity for the substrates.
In the first half of this pathway, His263 is used to effectively abstract the C3 hydroxyl proton, which thus allows a 2-carbon segment to be cleaved from fructose 6-phosphate.[3] The cofactor necessary for this step to occur is thiamin pyrophosphate (TPP). The binding of TPP to the enzyme incurs no major conformational change to the enzyme; instead, the enzyme has two flexible loops at the active site that make TPP accessible and binding possible.[2] Thus, this allows the active site to have a "closed" conformation rather than a large conformational change. Later in the pathway, His263 is used as a proton donor for the substrate acceptor-TPP complex, which can then generate erythrose-4-phosphate.
The histidine and aspartate side-chains are used to effectively stabilize the substrate within the active site and also participate in deprotonation of the substrate. To be specific, the His 263 and His30 side-chains form hydrogen bonds to the aldehyde end of the substrate, which is deepest into the substrate channel, and Asp477 forms hydrogen bonds with the alpha hydroxyl group on the substrate, where it works to effectively bind the substrate and check for proper stereochemistry. It is also thought that Asp477 could have important catalytic effects because of its orientation in the middle of the active site and its interactions with the alpha hydroxyl group of the substrate. Glu418, which is located in the deepest region of the active site, plays a critical role in stabilizing the TPP cofactor. To be specific, it is involved in the cofactor-assisted proton abstraction from the substrate molecule.[2]
The phosphate group of the substrate also plays an important role in stabilizing the substrate upon its entrance into the active site. The tight ionic and polar interactions between this phosphate group and the residues Arg359, Arg528, His469, and Ser386 collectively work to stabilize the substrate by forming H-bonds to the oxygen atoms of the phosphate.[2] The ionic nature is found in the salt bridge formed from Arg359 to the phosphate group.
# Mechanism
The catalysis of this mechanism is initiated by the deprotonation of TPP at the thiazolium ring. This carbanion then binds to the carbonyl of the donor substrate thus cleaving the bond between C-2 and C-3. This keto fragment remains covalently bound to the C-2 carbon of TPP. The donor substrate is then released, and the acceptor substrate enters the active site where the fragment, which is bound to the intermediate α-β-dihydroxyethyl thiamin diphosphate, is then transferred to the acceptor.[2]
Mechanism of fructose-6-phosphate to xylulose-5-phosphate in transketolase active site
File:R Groups in Transketolase Mechanism.png
Experiments have also been conducted that test the effect replacing alanine for the amino acids at the entrance to the active site, Arg359, Arg528, and His469, which interact with the phosphate group of the substrate. This replacement creates a mutant enzyme with impaired catalytic activity.[2]
# Role in disease
Transketolase activity is decreased in deficiency of thiamine, which in general is due to malnutrition. Several diseases are associated with thiamine deficiency, including beriberi, Biotin-Thiamine-Responsive Basal Ganglia Disease,[4] Wernicke-Korsakoff syndrome, and others (see thiamine for a comprehensive listing).
In Wernicke-Korsakoff syndrome, while no mutations could be demonstrated,[5] there is an indication that thiamine deficiency leads to Wernicke-Korsakoff syndrome only in those whose transketolase has a reduced affinity for thiamine.[6] In this way, the activity of transketolase is greatly hindered, and, as a consequence, the entire pentose phosphate pathway is inhibited.[7]
# Diagnostic use
Red blood cell transketolase activity is reduced in deficiency of thiamine (vitamin B1), and may be used in the diagnosis of Wernicke's encephalopathy and other B1-deficiency syndromes if the diagnosis is in doubt.[8] Apart from the baseline enzyme activity (which may be normal even in deficiency states), acceleration of enzyme activity after the addition of thiamine pyrophosphate may be diagnostic of thiamine deficiency (0-15% normal, 15-25% deficiency, >25% severe deficiency).[9]
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https://www.wikidoc.org/index.php/Transketolase
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