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c582594c7e26aefca529c8e25a1ad5a6e8b2ec8d	wikidoc	Free surface	Free surface In physics a free surface is the surface of a body that is subject to neither perpendicular normal stress nor parallel shear stress, such as the boundary between two homogenous fluids, for example liquid water and the air in the Earth's atmosphere. Unlike liquids, gases cannot form a free surface on their own. A liquid in a gravitational field will form a free surface if unconfined from above. Under mechanical equilibrium this free surface must be perpendicular to the forces acting on the liquid; if not there would be a force along the surface, and the liquid would flow in that direction. Thus, on the surface of the Earth, all free surfaces of liquids are horizontal unless disturbed (except near solids dipping into them, where surface tension distorts the surface locally). In a free liquid at rest, that is one subject to internal attractive forces only and not affected by outside forces such as a gravitational field, its free surface will assume the shape with the least surface area for its volume — a perfect sphere. This can be demonstrated experimentally by observing a large globule of oil placed below the surface of a mixture of water and alcohol having the same density so the oil has neutral buoyancy. # Waves If the free surface of a liquid is disturbed, waves are produced on the surface. These waves are not elastic waves due to any elastic force; they are gravity waves caused by the force of gravity tending to bring the surface of the disturbed liquid back to its horizontal level, but due to momentum, it overshoots. Thus it oscillates and spreads the disturbance to the neighboring portions of the surface. The velocity of the surface waves varies as the square root of the wavelength if the liquid is deep; therefore long waves on the sea go faster than short ones. Very minute waves or ripples are not due to gravity but to capillary action, and have properties different from those of the longer ocean surface waves, because the surface is increased in area by the ripples and the capillary forces are in this case large compared with the gravitational forces. # Rotation If a liquid is contained in a cylindrical vessel and is rotating around a vertical axis coinciding with the axis of the cylinder, the free surface will assume a parabolic surface of revolution known as a paraboloid. The free surface at each point is at a right angle to the force acting at it, which is the resultant of the force of gravity and the centrifugal force from the motion of each point in a circle. If a free liquid is rotating about an axis, the free surface will take the shape of an oblate spheroid: the approximate shape of the Earth due to its equatorial bulge. # Related terms - In hydrodynamics, the free surface is defined mathematically by the the free-surface condition: - In fluid dynamics, a free-surface vortex, also known as a potential vortex or whirlpool, forms in an irrotational flow, for example when a bathtub is drained. - In naval architecture and marine safety, the free surface effect occurs when liquids or granular materials under a free surface in partially filled tanks or holds shift when the vessel heels. - In hydraulic engineering a free-surface jet is one where the entrainment of the fluid outside the jet is minimal, as opposed to submerged jet where the entrainment effect is significant. A liquid jet in air approximates a free surface jet. - In fluid mechanics a free surface flow, also called open channel flow, is the gravity driven flow of a fluid under a free surface, typically water flowing under air in the atmosphere.	Free surface In physics a free surface is the surface of a body that is subject to neither perpendicular normal stress nor parallel shear stress,[1] such as the boundary between two homogenous fluids,[2] for example liquid water and the air in the Earth's atmosphere. Unlike liquids, gases cannot form a free surface on their own.[3] A liquid in a gravitational field will form a free surface if unconfined from above.[3] Under mechanical equilibrium this free surface must be perpendicular to the forces acting on the liquid; if not there would be a force along the surface, and the liquid would flow in that direction.[4] Thus, on the surface of the Earth, all free surfaces of liquids are horizontal unless disturbed (except near solids dipping into them, where surface tension distorts the surface locally).[4] In a free liquid at rest, that is one subject to internal attractive forces only and not affected by outside forces such as a gravitational field, its free surface will assume the shape with the least surface area for its volume — a perfect sphere. This can be demonstrated experimentally by observing a large globule of oil placed below the surface of a mixture of water and alcohol having the same density so the oil has neutral buoyancy.[5][6] # Waves If the free surface of a liquid is disturbed, waves are produced on the surface. These waves are not elastic waves due to any elastic force; they are gravity waves caused by the force of gravity tending to bring the surface of the disturbed liquid back to its horizontal level, but due to momentum, it overshoots. Thus it oscillates and spreads the disturbance to the neighboring portions of the surface.[4] The velocity of the surface waves varies as the square root of the wavelength if the liquid is deep; therefore long waves on the sea go faster than short ones.[4] Very minute waves or ripples are not due to gravity but to capillary action, and have properties different from those of the longer ocean surface waves,[4] because the surface is increased in area by the ripples and the capillary forces are in this case large compared with the gravitational forces.[7] # Rotation If a liquid is contained in a cylindrical vessel and is rotating around a vertical axis coinciding with the axis of the cylinder, the free surface will assume a parabolic surface of revolution known as a paraboloid. The free surface at each point is at a right angle to the force acting at it, which is the resultant of the force of gravity and the centrifugal force from the motion of each point in a circle.[4] If a free liquid is rotating about an axis, the free surface will take the shape of an oblate spheroid: the approximate shape of the Earth due to its equatorial bulge.[8] # Related terms - In hydrodynamics, the free surface is defined mathematically by the the free-surface condition:[9] </math> - In fluid dynamics, a free-surface vortex, also known as a potential vortex or whirlpool, forms in an irrotational flow,[10] for example when a bathtub is drained.[11] - In naval architecture and marine safety, the free surface effect occurs when liquids or granular materials under a free surface in partially filled tanks or holds shift when the vessel heels.[12] - In hydraulic engineering a free-surface jet is one where the entrainment of the fluid outside the jet is minimal, as opposed to submerged jet where the entrainment effect is significant. A liquid jet in air approximates a free surface jet.[13] - In fluid mechanics a free surface flow, also called open channel flow, is the gravity driven flow of a fluid under a free surface, typically water flowing under air in the atmosphere.[3]	https://www.wikidoc.org/index.php/Free_surface
0055aad7e0ba7ff94187053239adf8ea7f5d4f08	wikidoc	Fritz London	Fritz London Fritz Wolfgang London (March 7, 1900–March 30, 1954) was a German-born American theoretical physicist. London's early work with Heitler on chemical bonding is now treated in any textbook -n physical chemistry. This paper was the first to properly explain the bonding in a homonuclear molecule as H2. It is no coincidence that the Heitler-London work appeared shortly after the introduction of quantum mechanics by Heisenberg and Schrödinger, because quantum mechanics was crucial in their explanation of the covalent bond. Another necessary ingredient was the realization that electrons are indistinguishable, as expressed in the Pauli principle. Other early work of London was in the area of intermolecular forces. He coined the expression "dispersion effect" for the attraction between two rare gas atoms at large (say about 1 nanometer) distance from each other. Nowadays this attraction is often referred to as "London force". In 1930 he gave (together with R. Eisenschitz) a unified treatment of the interaction between two noble gas atoms that attract each other at large distance, but at short distance are repellent. Eisenschitz and London showed that this repulsion is a consequence of enforcing the electronic wavefunction to be antisymmetric under electron permutations. This antisymmetry is required by the Pauli principle and the fact that electrons are fermions. For atoms and nonpolar molecules, the London dispersion force is the only intermolecular forces and are responsible for the existence of the liquid and solid states. For polar molecules, this force is one part of the van der Waals force, along with forces between the permanent molecular dipole moments. London was the first theoretical physicist to make the fundamental, and at the time controversial, suggestion that superfluidity is intrinsically related to the Einstein condensation of bosons, a phenomenon now known as Bose–Einstein condensation (BEC). However, note that Bose, whose contribution was to recognize that the statistics of massless photons could also be applied to massive particles, did not contribute to the theory of the condensation of bosons. London was also one of the early authors (including Schrödinger) to have properly understood the principle of local gauge invariance (Weyl) in the context of the then new quantum mechanics. London was born in Breslau, Germany (now Wroclaw, Poland). After Hitler's Nazi Party passed the 1933 racial laws, London lost his position at the University of Berlin. He took visiting positions in England and France, and eventually emigrated to the United States in 1939. In 1945, he became a naturalized citizen. He died in Durham, North Carolina. London was in his later life a professor at Duke University. He was awarded the Lorentz Medal in 1953. # Bibliography - Gavroglu, Kostas Fritz London: A Scientific Biography (Cambridge, 2005)	Fritz London Template:Infobox Scientist Fritz Wolfgang London (March 7, 1900–March 30, 1954) was a German-born American theoretical physicist. London's early work with Heitler [1] on chemical bonding is now treated in any textbook on physical chemistry. This paper was the first to properly explain the bonding in a homonuclear molecule as H2. It is no coincidence that the Heitler-London work appeared shortly after the introduction of quantum mechanics by Heisenberg and Schrödinger, because quantum mechanics was crucial in their explanation of the covalent bond. Another necessary ingredient was the realization that electrons are indistinguishable, as expressed in the Pauli principle. Other early work of London was in the area of intermolecular forces. He coined the expression "dispersion effect" for the attraction between two rare gas atoms at large (say about 1 nanometer) distance from each other. Nowadays this attraction is often referred to as "London force". In 1930 he gave (together with R. Eisenschitz)[2] a unified treatment of the interaction between two noble gas atoms that attract each other at large distance, but at short distance are repellent. Eisenschitz and London showed that this repulsion is a consequence of enforcing the electronic wavefunction to be antisymmetric under electron permutations. This antisymmetry is required by the Pauli principle and the fact that electrons are fermions. For atoms and nonpolar molecules, the London dispersion force is the only intermolecular forces and are responsible for the existence of the liquid and solid states. For polar molecules, this force is one part of the van der Waals force, along with forces between the permanent molecular dipole moments. London was the first theoretical physicist to make the fundamental, and at the time controversial, suggestion that superfluidity is intrinsically related to the Einstein condensation of bosons, a phenomenon now known as Bose–Einstein condensation (BEC). However, note that Bose, whose contribution was to recognize that the statistics of massless photons could also be applied to massive particles, did not contribute to the theory of the condensation of bosons. London was also one of the early authors (including Schrödinger) to have properly understood the principle of local gauge invariance (Weyl) in the context of the then new quantum mechanics. London was born in Breslau, Germany (now Wroclaw, Poland). After Hitler's Nazi Party passed the 1933 racial laws, London lost his position at the University of Berlin. He took visiting positions in England and France, and eventually emigrated to the United States in 1939. In 1945, he became a naturalized citizen. He died in Durham, North Carolina. London was in his later life a professor at Duke University. He was awarded the Lorentz Medal in 1953. # Bibliography - Gavroglu, Kostas Fritz London: A Scientific Biography (Cambridge, 2005)	https://www.wikidoc.org/index.php/Fritz_London
06941ddf51a2ef43a4334f2cd294f55de55d4302	wikidoc	Frontal bone	Frontal bone # Overview The frontal bone is a bone in the human skull that resembles a cockleshell in form, and consists of two portions: - a vertical portion, the squama frontalis, corresponding with the region of the forehead. - an orbital or horizontal portion, the pars orbitalis, which enters into the formation of the roofs of the orbital and nasal cavities. # Borders The border of the squama temporalis is thick, strongly serrated, bevelled at the expense of the inner table above, where it rests upon the parietal bones, and at the expense of the outer table on either side, where it receives the lateral pressure of those bones; this border is continued below into a triangular, rough surface, which articulates with the great wing of the sphenoid. The posterior borders of the orbital plates are thin and serrated, and articulate with the small wings of the sphenoid. # Structure The squama and the zygomatic processes are very thick, consisting of diploic tissue contained between two compact laminæ; the diploic tissue is absent in the regions occupied by the frontal air sinuses. The orbital portion is thin, translucent, and composed entirely of compact bone; hence the facility with which instruments can penetrate the cranium through this part of the orbit; when the frontal sinuses are exceptionally large they may extend backward for a considerable distance into the orbital portion, which in such cases also consists of only two tables. # Additional images - The seven bones which articulate to form the orbit. - Facial bones. - Cranial bones - Sphenoid bone visible center right. - Side view of the skull. - The skull from the front. - Medial wall of left orbit. - Floor of the skull. - Sagittal section of skull.	Frontal bone Template:Infobox Bone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The frontal bone is a bone in the human skull that resembles a cockleshell in form, and consists of two portions: - a vertical portion, the squama frontalis, corresponding with the region of the forehead. - an orbital or horizontal portion, the pars orbitalis, which enters into the formation of the roofs of the orbital and nasal cavities. # Borders The border of the squama temporalis is thick, strongly serrated, bevelled at the expense of the inner table above, where it rests upon the parietal bones, and at the expense of the outer table on either side, where it receives the lateral pressure of those bones; this border is continued below into a triangular, rough surface, which articulates with the great wing of the sphenoid. The posterior borders of the orbital plates are thin and serrated, and articulate with the small wings of the sphenoid. # Structure The squama and the zygomatic processes are very thick, consisting of diploic tissue contained between two compact laminæ; the diploic tissue is absent in the regions occupied by the frontal air sinuses. The orbital portion is thin, translucent, and composed entirely of compact bone; hence the facility with which instruments can penetrate the cranium through this part of the orbit; when the frontal sinuses are exceptionally large they may extend backward for a considerable distance into the orbital portion, which in such cases also consists of only two tables. # Additional images - The seven bones which articulate to form the orbit. - Facial bones. - Cranial bones - Sphenoid bone visible center right. - Side view of the skull. - - The skull from the front. - Medial wall of left orbit. - Floor of the skull. - Sagittal section of skull.	https://www.wikidoc.org/index.php/Frontal_bone
4e72f75f304fc2a300e51b861e35c65305a6c0e3	wikidoc	Frontal lobe	Frontal lobe # Overview The frontal lobe is an area in the brain of mammals. Located at the front of each cerebral hemisphere, frontal lobes are positioned in front of (anterior to) the parietal lobes. The temporal lobes are located beneath and behind the frontal lobes. In the human brain, the precentral gyrus and the related cortical tissue that folds into the central sulcus comprise the primary motor cortex, which controls voluntary movements of specific body parts associated with areas of the gyrus. The frontal lobes have been found to play a part in impulse control, judgment, language production, working memory, motor function, sexual behavior, socialization, and spontaneity. The frontal lobes assist in planning, coordinating, controlling, and executing behavior. People who have damaged frontal lobes may experience problems with these aspects of cognitive function, being at times impulsive; impaired in their ability to plan and execute complex sequences of actions; perhaps persisting with one course of action or pattern of behavior when a change would be appropriate (perseveration). Cognitive maturity associated with adulthood is marked by related maturation of cerebral fibers in the frontal lobes between late teenager years and early adult years. The frontal lobe reaches full maturity around age 25. Research by Arthur Toga, UCLA, found increased myelin in the frontal lobe white matter of young adults compared to that of teens, whereas gray matter in parietal and temporal lobes was more fully matured by teen years. Typical onset of schizophrenia in early adult years correlates with poorly myelinated and thus inefficient connections between cells in the fore-brain. A report from the National Institute of Mental Health says a gene variant that reduces dopamine activity in the prefrontal cortex is related to poorer performance and inefficient functioning of that brain region during working memory tasks, and to slightly increased risk for schizophrenia. Dopamine-sensitive neurons in the cerebral cortex are found primarily in the frontal lobes. The dopamine system is associated with pleasure, long-term memory, planning and drive. Dopamine tends to limit and select sensory information arriving from the thalamus to the fore-brain. Poor regulation of dopamine pathways has been associated with schizophrenia. The so-called executive functions of the frontal lobes involve the ability to recognize future consequences resulting from current actions, to choose between good and bad actions (or better and best), override and suppress unacceptable social responses, and determine similarities and differences between things or events. The frontal lobes also play an important part in retaining longer term memories which are not task-based. These are often memories with associated emotions, derived from input from the brain's limbic system, and modified by the higher frontal lobe centers to generally fit socially acceptable norms (see executive functions above). The frontal lobes have rich neuronal input from both the alert centers in the brain-stem, and from the limbic regions. Psychological tests that measure frontal lobe function include Finger tapping, Wisconsin Card Sorting Task, and measures of verbal and figural fluency . # Psychosurgery In the early 20th century, a medical treatment for mental illness, first developed by Portuguese neurologist Egas Moniz, involved damaging the pathways connecting the frontal lobe to the limbic system. Frontal lobotomy (sometimes called frontal leucotomy) successfully reduced distress but at the cost of often blunting the subject's emotions, volition and personality. The indiscriminate use of this psychosurgical procedure, combined with the severe side effects and dangerous nature of the operation gained it a bad reputation and the frontal lobotomy has largely died out as a psychiatric treatment. More precise psychosurgical procedures are still occasionally used, although are now very rare occurrences. They may include procedures such as the anterior capsulotomy (bilateral thermal lesions of the anterior limbs of the internal capsule) or the bilateral cingulotomy (bilateral they are one lesions of the anterior cingulate gyri) and might be used to treat otherwise untreatable obsessional disorders or clinical depression. # Additional images - Lobes - Base of brain. - Drawing to illustrate the relations of the brain to the skull.	Frontal lobe Template:Infobox Brain Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The frontal lobe is an area in the brain of mammals. Located at the front of each cerebral hemisphere, frontal lobes are positioned in front of (anterior to) the parietal lobes. The temporal lobes are located beneath and behind the frontal lobes. In the human brain, the precentral gyrus and the related cortical tissue that folds into the central sulcus comprise the primary motor cortex, which controls voluntary movements of specific body parts associated with areas of the gyrus. The frontal lobes have been found to play a part in impulse control, judgment, language production, working memory, motor function, sexual behavior, socialization, and spontaneity. The frontal lobes assist in planning, coordinating, controlling, and executing behavior. People who have damaged frontal lobes may experience problems with these aspects of cognitive function, being at times impulsive; impaired in their ability to plan and execute complex sequences of actions; perhaps persisting with one course of action or pattern of behavior when a change would be appropriate (perseveration). Cognitive maturity associated with adulthood is marked by related maturation of cerebral fibers in the frontal lobes between late teenager years and early adult years. The frontal lobe reaches full maturity around age 25. Research by Arthur Toga, UCLA, found increased myelin in the frontal lobe white matter of young adults compared to that of teens, whereas gray matter in parietal and temporal lobes was more fully matured by teen years. Typical onset of schizophrenia in early adult years correlates with poorly myelinated and thus inefficient connections between cells in the fore-brain. A report from the National Institute of Mental Health says a gene variant that reduces dopamine activity in the prefrontal cortex is related to poorer performance and inefficient functioning of that brain region during working memory tasks, and to slightly increased risk for schizophrenia. Dopamine-sensitive neurons in the cerebral cortex are found primarily in the frontal lobes. The dopamine system is associated with pleasure, long-term memory, planning and drive. Dopamine tends to limit and select sensory information arriving from the thalamus to the fore-brain. Poor regulation of dopamine pathways has been associated with schizophrenia. The so-called executive functions of the frontal lobes involve the ability to recognize future consequences resulting from current actions, to choose between good and bad actions (or better and best), override and suppress unacceptable social responses, and determine similarities and differences between things or events. The frontal lobes also play an important part in retaining longer term memories which are not task-based. These are often memories with associated emotions, derived from input from the brain's limbic system, and modified by the higher frontal lobe centers to generally fit socially acceptable norms (see executive functions above). The frontal lobes have rich neuronal input from both the alert centers in the brain-stem, and from the limbic regions. Psychological tests that measure frontal lobe function include Finger tapping, Wisconsin Card Sorting Task, and measures of verbal and figural fluency [1]. # Psychosurgery In the early 20th century, a medical treatment for mental illness, first developed by Portuguese neurologist Egas Moniz, involved damaging the pathways connecting the frontal lobe to the limbic system. Frontal lobotomy (sometimes called frontal leucotomy) successfully reduced distress but at the cost of often blunting the subject's emotions, volition and personality. The indiscriminate use of this psychosurgical procedure, combined with the severe side effects and dangerous nature of the operation gained it a bad reputation and the frontal lobotomy has largely died out as a psychiatric treatment. More precise psychosurgical procedures are still occasionally used, although are now very rare occurrences. They may include procedures such as the anterior capsulotomy (bilateral thermal lesions of the anterior limbs of the internal capsule) or the bilateral cingulotomy (bilateral they are one lesions of the anterior cingulate gyri) and might be used to treat otherwise untreatable obsessional disorders or clinical depression. # Additional images - Lobes - Base of brain. - Drawing to illustrate the relations of the brain to the skull.	https://www.wikidoc.org/index.php/Frontal_cortex
e729e83bf135e07aa61aea1383464f5efcd7f2cd	wikidoc	Frontal vein	Frontal vein The frontal vein begins on the forehead in a venous plexus which communicates with the frontal branches of the superficial temporal vein. The veins converge to form a single trunk, which runs downward near the middle line of the forehead parallel with the vein of the opposite side. The two veins are joined, at the root of the nose, by a transverse branch, called the nasal arch, which receives some small veins from the dorsum of the nose. At the root of the nose the veins diverge, and, each at the medial angle of the orbit, joins the supraorbital vein, to form the angular vein. Occasionally the frontal veins join to form a single trunk, which bifurcates at the root of the nose into the two angular veins.	Frontal vein Template:Infobox Vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The frontal vein begins on the forehead in a venous plexus which communicates with the frontal branches of the superficial temporal vein. The veins converge to form a single trunk, which runs downward near the middle line of the forehead parallel with the vein of the opposite side. The two veins are joined, at the root of the nose, by a transverse branch, called the nasal arch, which receives some small veins from the dorsum of the nose. At the root of the nose the veins diverge, and, each at the medial angle of the orbit, joins the supraorbital vein, to form the angular vein. Occasionally the frontal veins join to form a single trunk, which bifurcates at the root of the nose into the two angular veins. # External links - Diagram at stchas.edu Template:Gray's Template:VeinsHeadNeck Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Frontal_vein
b387cc6fb642b17e0f6116a4eed6a196e789b6b0	wikidoc	Frovatriptan	Frovatriptan # 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 Frovatriptan is a serotonin (5-HT1B/1D) receptor agonist that is FDA approved for the {{{indicationType}}} of acute treatment of migraine with or without aura in adults. Common adverse reactions include dizziness, headache, paresthesia, dry mouth, dyspepsia, fatigue, hot or cold sensation, chest pain, skeletal pain, and flushing. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose is a single tablet of FROVA (frovatriptan 2.5 mg) taken orally with fluids. - If the migraine recurs after initial relief, a second tablet may be taken, providing there is an interval of at least 2 hours between doses. The total daily dose of FROVA should not exceed 3 tablets (3 x 2.5 mg per 24 hour period). - There is no evidence that a second dose of FROVA is effective in patients who do not respond to a first dose of the drug for the same headache. - The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Frovatriptan in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 6-day course of frovatriptan 2.5 mg once daily. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Frovatriptan in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Frovatriptan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Frovatriptan in pediatric patients. # Contraindications - FROVA is contraindicated in patients with: - Ischemic coronary artery disease (CAD) (e.g. angina pectoris, history of myocardial infarction, or documented silent ischemia), or coronary artery vasospasm, including Prinzmetal’s angina. - Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke. - Peripheral vascular disease. - Ischemic bowel disease. - Uncontrolled hypertension. - Recent use (i.e., within 24 hours) of another 5-HT1 agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide. - Hypersensitivity to FROVA (angioedema and anaphylaxis seen). # Warnings ### Precautions - Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina - FROVA is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of FROVA. Some of these reactions occurred in patients without known CAD. FROVA may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. - Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving FROVA. Do not administer FROVA if there is evidence of CAD or coronary artery vasospasm. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first FROVA dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following FROVA administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of FROVA. - Arrhythmias - Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue FROVA if these disturbances occur. FROVA is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - Chest, Throat, Neck, and Jaw Pain/Tightness/Pressure - Sensations of pain, tightness, pressure, and heaviness have been reported in the chest, throat, neck, and jaw after treatment with FROVA and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of FROVA is contraindicated in patients with CAD and those with Prinzmetal’s angina. - Cerebrovascular Events - Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. - Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. FROVA is contraindicated in patients with a history of stroke or TIA. - Other Vasospasm Reactions - FROVA, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before using FROVA. - Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established. - Medication Overuse Headache - Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. - Serotonin Syndrome - Serotonin syndrome may occur with FROVA, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue FROVA if serotonin syndrome is suspected. - Increase in Blood Pressure - Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with FROVA. FROVA is contraindicated in patients with uncontrolled hypertension. - Anaphylactic/Anaphylactoid Reactions - There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving FROVA. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. FROVA is contraindicated in patients with a history of hypersensitivity reaction to FROVA. # 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. - FROVA was evaluated in four randomized, double-blind, placebo-controlled, short-term trials. These trials involved 2392 patients (1554 on FROVA 2.5 mg and 838 on placebo). In these short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 - 69).The treatment-emergent adverse events that occurred most frequently following administration of FROVA 2.5 mg (i.e., in at least 2% of patients), and at an incidence ≥1% greater than with placebo, were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation, dyspepsia, skeletal pain, and chest pain. In a long term, open-label study where 496 patients were allowed to treat multiple migraine attacks with FROVA 2.5 mg for up to 1 year, 5% of patients (n=26) discontinued due to treatment-emergent adverse events. - Table 1 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with FROVA 2.5 mg at an incidence of ≥2% and more often than on placebo, in the four placebo-controlled trials. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these incidence estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. - Table 1 - Treatment-Emergent Adverse Events Reported within 48 Hours (Incidence ≥ 2% and Greater Than Placebo) of - Patients in Four Pooled Placebo-Controlled Migraine Trials - The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The incidence of adverse events in placebo-controlled clinical trials was not affected by gender, age or concomitant medications commonly used by migraine patients. There were insufficient data to assess the impact of race on the incidence of adverse events. - Other Events Observed in Association with the Administration of FROVA - The incidence of frequently reported adverse events in four placebo-controlled trials are presented below. Events are further classified within body system categories. Frequent adverse events are those occurring in at least 1/100 patients. - Central and peripheral nervous system: dysesthesia and hypoesthesia. - Gastrointestinal: vomiting, abdominal pain and diarrhea. - Body as a whole: pain. - Psychiatric: insomnia and anxiety. - Respiratory: sinusitis and rhinitis. - Vision disorders: vision abnormal. - Skin and appendages: sweating increased. - Hearing and vestibular disorders: tinnitus. - Heart rate and rhythm: palpitation. ## Postmarketing Experience - The following adverse reactions were identified during post approval use of FROVA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Central and peripheral nervous system: Seizure. # Drug Interactions - Ergot-containing Drugs - Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and FROVA within 24 hours of each other is contraindicated. - 5-HT1B/1D Agonists - Because their vasospastic effects may be additive, co-administration of FROVA and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. - Selective Serotonin Reuptake Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome - Cases of serotonin syndrome have been reported during combined use of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled trials in pregnant women; therefore, frovatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - When pregnant rats were administered frovatriptan during the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day (equivalent to 130, 650 and 1300 times the maximum recommended human dose of 7.5 mg/day on a mg/m2 basis) there were dose related increases in incidences of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters. A no-effect dose for renal effects was not established. This signifies a syndrome of related effects on a specific organ in the developing embryo in all treated groups, which is consistent with a slight delay in fetal maturation. This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups. Reduced fetal weights and an increased incidence of embryolethality were observed in treated rats; an increase in embryolethality occurred in both the embryo-fetal developmental study and in the prenatal-postnatal developmental study. No increase in embryolethality was observed at the lowest dose level studied (100 mg/kg/day, equivalent to 130 times the MRHD on a mg/m2 basis). When pregnant rabbits were dosed throughout organogenesis at oral doses up to 80 mg/kg/day (equivalent to 210 times the MRHD on a mg/m2 basis), no effects on fetal development were observed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Frovatriptan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Frovatriptan during labor and delivery. ### Nursing Mothers - It is not known whether frovatriptan 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 FROVA, 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. - In rats, oral dosing with frovatriptan resulted in levels of frovatriptan and/or its metabolites in milk up to four times higher than in plasma. ### Pediatric Use - The safety and effectiveness in pediatric patients have not been established. Therefore, FROVA is not recommended for use in patients under 18 years of age. There are no additional adverse reactions identified in pediatric patients based on postmarketing experience that were not previously identified in adults. ### Geriatic Use - Mean blood concentrations of frovatriptan in elderly patients were 1.5- to 2-times higher than those seen in younger adults. No dosage adjustment is necessary. ### Gender There is no FDA guidance on the use of Frovatriptan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Frovatriptan with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Frovatriptan in patients with renal impairment. ### Hepatic Impairment - No dosage adjustment is necessary when FROVA is given to patients with mild to moderate hepatic impairment. - There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment. Because a greater than two-fold increase in AUC is predicted in patients with severe hepatic impairment, there is a greater potential for adverse events in these patients, and FROVA should therefore be used with caution in that population. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Frovatriptan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Frovatriptan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Frovatriptan in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Frovatriptan in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The elimination half-life of frovatriptan is 26 hours. Therefore, monitoring of patients after overdose with frovatriptan should continue for at least 48 hours or while symptoms or signs persist. ### Management - There is no specific antidote to frovatriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of frovatriptan. ## Chronic Overdose There is limited information regarding Chronic Overdose of Frovatriptan in the drug label. # Pharmacology ## Mechanism of Action - Frovatriptan binds with high affinity to 5-HT1B/1D receptors. The therapeutic activity of FROVA is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. ## Structure - FROVA (frovatriptan succinate) tablets contain frovatriptan succinate, a selective 5-hydroxy-tryptamine1 (5-HT1B/1D) receptor subtype agonist (triptan), as the active ingredient. Frovatriptan succinate is chemically designated as R-(+) 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate and it has the following structure: - The empirical formula is C14H17N3O.C4H6O4.H2O, representing a molecular weight of 379.4. Frovatriptan succinate is a white to off-white powder that is soluble in water. - Each FROVA tablet for oral administration contains 3.91 mg frovatriptan succinate, equivalent to 2.5 mg of frovatriptan base. Each tablet also contains the inactive ingredients lactose NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, sodium starch glycolate NF, magnesium stearate NF, hypromellose USP, polyethylene glycol 3000 USP, triacetin USP, and titanium dioxide USP. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Frovatriptan in the drug label. ## Pharmacokinetics - The pharmacokinetics of frovatriptan are similar in migraine patients and healthy subjects. - Absorption - Mean maximum blood concentrations (Cmax) in patients are achieved approximately 2 - 4 hours after administration of a single oral dose of frovatriptan 2.5 mg. The absolute bioavailability of an oral dose of frovatriptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of frovatriptan, but delays tmax by one hour. - Distribution - Binding of frovatriptan to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%, resulting in a blood: plasma ratio of about 2:1 in both males and females. The mean steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3.0 L/kg in females. - Metabolism - In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. - Elimination - After an intravenous dose, mean clearance of frovatriptan was 220 and 130 mL/min in males and females, respectively. Renal clearance accounted for about 40% (82 mL/min) and 45% (60 mL/min) of total clearance in males and females, respectively. The mean terminal elimination half-life of frovatriptan in both males and females is approximately 26 hours. - Special Populations - Hepatic Impairment - The AUC of frovatriptan in patients with mild (Child-Pugh 5-6) to moderate (Child-Pugh 7-9) hepatic impairment was about twice that of young, healthy subjects, but within the range observed in healthy elderly subjects and was considerably lower than the values attained with higher doses of frovatriptan (up to 40 mg), which were not associated with any serious adverse effects. There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment. - Renal Impairment - The pharmacokinetics of frovatriptan following a single oral dose of 2.5 mg was not different in patients with renal impairment (5 males and 6 females, creatinine clearance 16 - 73 mL/min) compared to subjects with normal renal function. - Age - Mean AUC of frovatriptan was 1.5- to 2-fold higher in healthy elderly subjects (age 65 – 77 years) compared to those in healthy younger subjects (age 21 - 37 years). There was no difference in tmax or t1/2 between the two populations. - Sex - There was no difference in the mean terminal elimination half-life of frovatriptan in males and females. Bioavailability was higher, and systemic exposure to frovatriptan was approximately 2-fold greater, in females than males, irrespective of age. - Race - The effect of race on the pharmacokinetics of frovatriptan has not been examined. - Drug Interaction Studies - Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 (isozymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in vitro at concentrations up to 250 to 500- fold higher than the highest blood concentrations observed in man at a dose of 2.5 mg. No induction of drug metabolizing enzymes was observed following multiple dosing of frovatriptan to rats or on addition to human hepatocytes in vitro. Although no clinical trials have been performed, it is unlikely that frovatriptan will affect the metabolism of co-administered drugs metabolized by these mechanisms. - Oral Contraceptives - Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives compared to those not taking oral contraceptives. - Ergotamine - The AUC and Cmax of frovatriptan (2 x 2.5 mg dose) were reduced by approximately 25% when co-administered with ergotamine tartrate. - Propranolol - Propranolol increased the AUC of frovatriptan 2.5 mg in males by 60% and in females by 29%. The Cmax of frovatriptan was increased 23% in males and 16% in females in the presence of propranolol. The tmax as well as half-life of frovatriptan, though slightly longer in the females, were not affected by concomitant administration of propranolol. - Moclobemide - The pharmacokinetic profile of frovatriptan was unaffected when a single oral dose of frovatriptan 2.5 mg was administered to healthy female subjects receiving the MAO-A inhibitor, moclobemide, at an oral dose of 150 mg bid for 8 days. ## Nonclinical Toxicology - Carcinogenesis - The carcinogenic potential of orally administered frovatriptan was evaluated in an 84-week study in mice (4, 13, and 40 mg/kg/day), a 104-week study in rats (8.5, 27 and 85 mg/kg/day), and a 26-week study in p53(+/-) transgenic mice (20, 62.5, 200, and 400 mg/kg/day). Although a maximum tolerated dose was not achieved in the 84-week mouse study and in female rats, plasma exposures at the highest doses studied were higher than that achieved in humans at the maximum recommended human dose (MRHD) of 7.5 mg/day. There were no increases in tumor incidence in the 84-week mouse study at doses producing plasma exposures (AUC) 140 times that in humans at the MRHD. In the rat study, there was a statistically significant increase in the incidence of pituitary adenomas in males only at 85 mg/kg/day, a dose associated with a plasma AUC 250 times that in humans at the MRHD. In the 26-week p53(+/-) transgenic mouse study, the incidence of subcutaneous sarcomas was increased in females at doses of 200 and 400 mg/kg/day. - These sarcomas were associated with subcutaneously implanted animal identification transponders, and are not considered to be relevant to humans. There were no other increases in tumor incidence of any type in any dose group. - Mutagenesis - Frovatriptan was clastogenic in human lymphocyte cultures, in the absence of metabolic activation. In the bacterial reverse mutation assay (Ames test), frovatriptan produced an equivocal response in the absence of metabolic activation. Frovatriptan was negative in an in vitro mouse lymphoma tk assay and an in vivo mouse bone marrow micronucleus test. - Impairment of Fertility - Male and female rats were dosed orally with frovatriptan prior to and during mating and in females up to implantation, at doses of 100, 500, and 1000 mg/kg/day (equivalent to approximately 130, 650, and 1300 times the MRHD on a mg/m2 basis). At all dose levels, there was an increase in the number of females that mated on the first day of pairing compared to control animals. This occurred in conjunction with a prolongation of the estrous cycle. In addition, females had a decreased mean number of corpora lutea, and consequently a lower number of live fetuses per litter, which suggested a partial impairment of ovulation. There were no other fertility-related effects. # Clinical Studies - The efficacy of FROVA in the acute treatment of migraine headaches was demonstrated in four randomized, double-blind, placebo-controlled, short-term outpatient trials. In these trials, patients received doses of frovatriptan from 0.5 mg to 40 mg. In these controlled short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 - 69). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed for up to 24 hours after dosing. The associated symptoms nausea, vomiting, photophobia and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post dose. In two of the trials a second dose of FROVA was provided after the initial treatment, to treat recurrence of the headache within 24 hours. Other medication, excluding other 5-HT1 agonists and ergotamine containing compounds, was permitted from 2 hours after the first dose of FROVA. The frequency and time to use of additional medications were also recorded. - In all four placebo-controlled trials, the percentage of patients achieving a headache response 2 hours after treatment was significantly greater for those taking FROVA 2.5 mg compared to those taking placebo (Table 2). - Lower doses of frovatriptan (1 mg or 0.5 mg) were not effective at 2 hours. Higher doses (5 mg to 40 mg) of frovatriptan showed no added benefit over 2.5 mg but did cause a greater incidence of adverse events. - Table 2 - Percentage of Patients with Headache Response (Mild or No Headache) 2 Hours Following Treatmenta - The estimated probability of achieving an initial headache response by 2 hours following treatment is depicted in Figure 1. - Figure 1 - Estimated Probability of Achieving Initial Headache Response Within 2 Hours - Figure 1 shows a Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with FROVA 2.5 mg or placebo. The probabilities displayed are based on pooled data from the four placebo-controlled trials described in Table 2. Patients who did not achieve a response were censored at 24 hours. - In patients with migraine-associated nausea, photophobia and phonophobia at baseline there was a decreased incidence of these symptoms in FROVA treated patients compared to placebo. - The estimated probability of patients taking a second dose or other medication for their migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. - Figure 2 - Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine - Over the 24 Hours Following the Initial Dose of Study Treatment - Figure 2 is a Kaplan-Meier plot showing the probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study medication based on the data from the four placebo-controlled trials described in Table 2. The plot includes those patients who had a response to the initial dose and those who did not. The protocols did not permit remedication within 2 hours of the initial dose. - Efficacy was unaffected by a history of aura; gender; age, or concomitant medications commonly used by migraine patients. # How Supplied - FROVA tablets, containing 2.5 mg of frovatriptan (base) as the succinate salt, are available as round, white, film-coated tablets debossed with 2.5 on one side and “E” on the other side. The tablets are available in: - Blister card of 9 tablets, 1 blister card per carton (NDC 63481-025-09) - Store FROVA tablets at controlled room temperature, 25°C (77°F) excursions permitted to 15 - 30°C (59°F - 86°F). Protect from moisture. ## Storage There is limited information regarding Frovatriptan Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events - Inform patients that FROVA may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions. - Anaphylactic/Anaphylactoid Reactions - Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving FROVA. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. - Medication Overuse Headache - Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary). - Serotonin Syndrome - Inform patients about the risk of serotonin syndrome with the use of FROVA or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors. - Pregnancy - Inform patients that FROVA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. - Nursing Mothers - Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed. # Precautions with Alcohol - Alcohol-Frovatriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FROVA® # Look-Alike Drug Names There is limited information regarding Frovatriptan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Frovatriptan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, 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. # Overview Frovatriptan is a serotonin (5-HT1B/1D) receptor agonist that is FDA approved for the {{{indicationType}}} of acute treatment of migraine with or without aura in adults. Common adverse reactions include dizziness, headache, paresthesia, dry mouth, dyspepsia, fatigue, hot or cold sensation, chest pain, skeletal pain, and flushing. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose is a single tablet of FROVA (frovatriptan 2.5 mg) taken orally with fluids. - If the migraine recurs after initial relief, a second tablet may be taken, providing there is an interval of at least 2 hours between doses. The total daily dose of FROVA should not exceed 3 tablets (3 x 2.5 mg per 24 hour period). - There is no evidence that a second dose of FROVA is effective in patients who do not respond to a first dose of the drug for the same headache. - The safety of treating an average of more than 4 migraine attacks in a 30-day period has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Frovatriptan in adult patients. ### Non–Guideline-Supported Use - Dosing Information - 6-day course of frovatriptan 2.5 mg once daily.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Frovatriptan in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Frovatriptan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Frovatriptan in pediatric patients. # Contraindications - FROVA is contraindicated in patients with: - Ischemic coronary artery disease (CAD) (e.g. angina pectoris, history of myocardial infarction, or documented silent ischemia), or coronary artery vasospasm, including Prinzmetal’s angina. - Wolff-Parkinson-White Syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - History of stroke, transient ischemic attack (TIA), or history of hemiplegic or basilar migraine because these patients are at a higher risk of stroke. - Peripheral vascular disease. - Ischemic bowel disease. - Uncontrolled hypertension. - Recent use (i.e., within 24 hours) of another 5-HT1 agonist, an ergotamine containing or ergot-type medication such as dihydroergotamine (DHE) or methysergide. - Hypersensitivity to FROVA (angioedema and anaphylaxis seen). # Warnings ### Precautions - Myocardial Ischemia, Myocardial Infarction, and Prinzmetal’s Angina - FROVA is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of FROVA. Some of these reactions occurred in patients without known CAD. FROVA may cause coronary artery vasospasm (Prinzmetal’s angina), even in patients without a history of CAD. - Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving FROVA. Do not administer FROVA if there is evidence of CAD or coronary artery vasospasm. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administrating the first FROVA dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following FROVA administration. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of FROVA. - Arrhythmias - Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue FROVA if these disturbances occur. FROVA is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - Chest, Throat, Neck, and Jaw Pain/Tightness/Pressure - Sensations of pain, tightness, pressure, and heaviness have been reported in the chest, throat, neck, and jaw after treatment with FROVA and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. The use of FROVA is contraindicated in patients with CAD and those with Prinzmetal’s angina. - Cerebrovascular Events - Cerebral hemorrhage, subarachnoid hemorrhage, stroke and other cerebrovascular events have been reported in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. - Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. FROVA is contraindicated in patients with a history of stroke or TIA. - Other Vasospasm Reactions - FROVA, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud’s syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before using FROVA. - Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established. - Medication Overuse Headache - Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. - Serotonin Syndrome - Serotonin syndrome may occur with FROVA, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue FROVA if serotonin syndrome is suspected. - Increase in Blood Pressure - Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with FROVA. FROVA is contraindicated in patients with uncontrolled hypertension. - Anaphylactic/Anaphylactoid Reactions - There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving FROVA. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. FROVA is contraindicated in patients with a history of hypersensitivity reaction to FROVA. # 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. - FROVA was evaluated in four randomized, double-blind, placebo-controlled, short-term trials. These trials involved 2392 patients (1554 on FROVA 2.5 mg and 838 on placebo). In these short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 - 69).The treatment-emergent adverse events that occurred most frequently following administration of FROVA 2.5 mg (i.e., in at least 2% of patients), and at an incidence ≥1% greater than with placebo, were dizziness, paresthesia, headache, dry mouth, fatigue, flushing, hot or cold sensation, dyspepsia, skeletal pain, and chest pain. In a long term, open-label study where 496 patients were allowed to treat multiple migraine attacks with FROVA 2.5 mg for up to 1 year, 5% of patients (n=26) discontinued due to treatment-emergent adverse events. - Table 1 lists treatment-emergent adverse events reported within 48 hours of drug administration that occurred with FROVA 2.5 mg at an incidence of ≥2% and more often than on placebo, in the four placebo-controlled trials. The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these incidence estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. - Table 1 - Treatment-Emergent Adverse Events Reported within 48 Hours (Incidence ≥ 2% and Greater Than Placebo) of - Patients in Four Pooled Placebo-Controlled Migraine Trials - The incidence of adverse events in clinical trials did not increase when up to 3 doses were used within 24 hours. The incidence of adverse events in placebo-controlled clinical trials was not affected by gender, age or concomitant medications commonly used by migraine patients. There were insufficient data to assess the impact of race on the incidence of adverse events. - Other Events Observed in Association with the Administration of FROVA - The incidence of frequently reported adverse events in four placebo-controlled trials are presented below. Events are further classified within body system categories. Frequent adverse events are those occurring in at least 1/100 patients. - Central and peripheral nervous system: dysesthesia and hypoesthesia. - Gastrointestinal: vomiting, abdominal pain and diarrhea. - Body as a whole: pain. - Psychiatric: insomnia and anxiety. - Respiratory: sinusitis and rhinitis. - Vision disorders: vision abnormal. - Skin and appendages: sweating increased. - Hearing and vestibular disorders: tinnitus. - Heart rate and rhythm: palpitation. ## Postmarketing Experience - The following adverse reactions were identified during post approval use of FROVA. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Central and peripheral nervous system: Seizure. # Drug Interactions - Ergot-containing Drugs - Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and FROVA within 24 hours of each other is contraindicated. - 5-HT1B/1D Agonists - Because their vasospastic effects may be additive, co-administration of FROVA and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. - Selective Serotonin Reuptake Inhibitors / Serotonin Norepinephrine Reuptake Inhibitors and Serotonin Syndrome - Cases of serotonin syndrome have been reported during combined use of triptans and SSRIs, SNRIs, TCAs, and MAO inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled trials in pregnant women; therefore, frovatriptan should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - When pregnant rats were administered frovatriptan during the period of organogenesis at oral doses of 100, 500 and 1000 mg/kg/day (equivalent to 130, 650 and 1300 times the maximum recommended human dose [MRHD] of 7.5 mg/day on a mg/m2 basis) there were dose related increases in incidences of fetuses with dilated ureters, unilateral and bilateral pelvic cavitation, hydronephrosis, and hydroureters. A no-effect dose for renal effects was not established. This signifies a syndrome of related effects on a specific organ in the developing embryo in all treated groups, which is consistent with a slight delay in fetal maturation. This delay was also indicated by a treatment related increased incidence of incomplete ossification of the sternebrae, skull and nasal bones in all treated groups. Reduced fetal weights and an increased incidence of embryolethality were observed in treated rats; an increase in embryolethality occurred in both the embryo-fetal developmental study and in the prenatal-postnatal developmental study. No increase in embryolethality was observed at the lowest dose level studied (100 mg/kg/day, equivalent to 130 times the MRHD on a mg/m2 basis). When pregnant rabbits were dosed throughout organogenesis at oral doses up to 80 mg/kg/day (equivalent to 210 times the MRHD on a mg/m2 basis), no effects on fetal development were observed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Frovatriptan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Frovatriptan during labor and delivery. ### Nursing Mothers - It is not known whether frovatriptan 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 FROVA, 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. - In rats, oral dosing with frovatriptan resulted in levels of frovatriptan and/or its metabolites in milk up to four times higher than in plasma. ### Pediatric Use - The safety and effectiveness in pediatric patients have not been established. Therefore, FROVA is not recommended for use in patients under 18 years of age. There are no additional adverse reactions identified in pediatric patients based on postmarketing experience that were not previously identified in adults. ### Geriatic Use - Mean blood concentrations of frovatriptan in elderly patients were 1.5- to 2-times higher than those seen in younger adults. No dosage adjustment is necessary. ### Gender There is no FDA guidance on the use of Frovatriptan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Frovatriptan with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Frovatriptan in patients with renal impairment. ### Hepatic Impairment - No dosage adjustment is necessary when FROVA is given to patients with mild to moderate hepatic impairment. - There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment. Because a greater than two-fold increase in AUC is predicted in patients with severe hepatic impairment, there is a greater potential for adverse events in these patients, and FROVA should therefore be used with caution in that population. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Frovatriptan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Frovatriptan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Frovatriptan in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Frovatriptan in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The elimination half-life of frovatriptan is 26 hours. Therefore, monitoring of patients after overdose with frovatriptan should continue for at least 48 hours or while symptoms or signs persist. ### Management - There is no specific antidote to frovatriptan. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of frovatriptan. ## Chronic Overdose There is limited information regarding Chronic Overdose of Frovatriptan in the drug label. # Pharmacology ## Mechanism of Action - Frovatriptan binds with high affinity to 5-HT1B/1D receptors. The therapeutic activity of FROVA is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. ## Structure - FROVA (frovatriptan succinate) tablets contain frovatriptan succinate, a selective 5-hydroxy-tryptamine1 (5-HT1B/1D) receptor subtype agonist (triptan), as the active ingredient. Frovatriptan succinate is chemically designated as R-(+) 3-methylamino-6-carboxamido-1,2,3,4-tetrahydrocarbazole monosuccinate monohydrate and it has the following structure: - The empirical formula is C14H17N3O.C4H6O4.H2O, representing a molecular weight of 379.4. Frovatriptan succinate is a white to off-white powder that is soluble in water. - Each FROVA tablet for oral administration contains 3.91 mg frovatriptan succinate, equivalent to 2.5 mg of frovatriptan base. Each tablet also contains the inactive ingredients lactose NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, sodium starch glycolate NF, magnesium stearate NF, hypromellose USP, polyethylene glycol 3000 USP, triacetin USP, and titanium dioxide USP. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Frovatriptan in the drug label. ## Pharmacokinetics - The pharmacokinetics of frovatriptan are similar in migraine patients and healthy subjects. - Absorption - Mean maximum blood concentrations (Cmax) in patients are achieved approximately 2 - 4 hours after administration of a single oral dose of frovatriptan 2.5 mg. The absolute bioavailability of an oral dose of frovatriptan 2.5 mg in healthy subjects is about 20% in males and 30% in females. Food has no significant effect on the bioavailability of frovatriptan, but delays tmax by one hour. - Distribution - Binding of frovatriptan to serum proteins is low (approximately 15%). Reversible binding to blood cells at equilibrium is approximately 60%, resulting in a blood: plasma ratio of about 2:1 in both males and females. The mean steady state volume of distribution of frovatriptan following intravenous administration of 0.8 mg is 4.2 L/kg in males and 3.0 L/kg in females. - Metabolism - In vitro, cytochrome P450 1A2 appears to be the principal enzyme involved in the metabolism of frovatriptan. Following administration of a single oral dose of radiolabeled frovatriptan 2.5 mg to healthy male and female subjects, 32% of the dose was recovered in urine and 62% in feces. Radiolabeled compounds excreted in urine were unchanged frovatriptan, hydroxylated frovatriptan, N-acetyl desmethyl frovatriptan, hydroxylated N-acetyl desmethyl frovatriptan and desmethyl frovatriptan, together with several other minor metabolites. Desmethyl frovatriptan has lower affinity for 5-HT1B/1D receptors compared to the parent compound. The N-acetyl desmethyl metabolite has no significant affinity for 5-HT receptors. The activity of the other metabolites is unknown. - Elimination - After an intravenous dose, mean clearance of frovatriptan was 220 and 130 mL/min in males and females, respectively. Renal clearance accounted for about 40% (82 mL/min) and 45% (60 mL/min) of total clearance in males and females, respectively. The mean terminal elimination half-life of frovatriptan in both males and females is approximately 26 hours. - Special Populations - Hepatic Impairment - The AUC of frovatriptan in patients with mild (Child-Pugh 5-6) to moderate (Child-Pugh 7-9) hepatic impairment was about twice that of young, healthy subjects, but within the range observed in healthy elderly subjects and was considerably lower than the values attained with higher doses of frovatriptan (up to 40 mg), which were not associated with any serious adverse effects. There is no clinical or pharmacokinetic experience with FROVA in patients with severe hepatic impairment. - Renal Impairment - The pharmacokinetics of frovatriptan following a single oral dose of 2.5 mg was not different in patients with renal impairment (5 males and 6 females, creatinine clearance 16 - 73 mL/min) compared to subjects with normal renal function. - Age - Mean AUC of frovatriptan was 1.5- to 2-fold higher in healthy elderly subjects (age 65 – 77 years) compared to those in healthy younger subjects (age 21 - 37 years). There was no difference in tmax or t1/2 between the two populations. - Sex - There was no difference in the mean terminal elimination half-life of frovatriptan in males and females. Bioavailability was higher, and systemic exposure to frovatriptan was approximately 2-fold greater, in females than males, irrespective of age. - Race - The effect of race on the pharmacokinetics of frovatriptan has not been examined. - Drug Interaction Studies - Frovatriptan is not an inhibitor of human monoamine oxidase (MAO) enzymes or cytochrome P450 (isozymes 1A2, 2C9, 2C19, 2D6, 2E1, 3A4) in vitro at concentrations up to 250 to 500- fold higher than the highest blood concentrations observed in man at a dose of 2.5 mg. No induction of drug metabolizing enzymes was observed following multiple dosing of frovatriptan to rats or on addition to human hepatocytes in vitro. Although no clinical trials have been performed, it is unlikely that frovatriptan will affect the metabolism of co-administered drugs metabolized by these mechanisms. - Oral Contraceptives - Retrospective analysis of pharmacokinetic data from females across trials indicated that the mean Cmax and AUC of frovatriptan are 30% higher in those subjects taking oral contraceptives compared to those not taking oral contraceptives. - Ergotamine - The AUC and Cmax of frovatriptan (2 x 2.5 mg dose) were reduced by approximately 25% when co-administered with ergotamine tartrate. - Propranolol - Propranolol increased the AUC of frovatriptan 2.5 mg in males by 60% and in females by 29%. The Cmax of frovatriptan was increased 23% in males and 16% in females in the presence of propranolol. The tmax as well as half-life of frovatriptan, though slightly longer in the females, were not affected by concomitant administration of propranolol. - Moclobemide - The pharmacokinetic profile of frovatriptan was unaffected when a single oral dose of frovatriptan 2.5 mg was administered to healthy female subjects receiving the MAO-A inhibitor, moclobemide, at an oral dose of 150 mg bid for 8 days. ## Nonclinical Toxicology - Carcinogenesis - The carcinogenic potential of orally administered frovatriptan was evaluated in an 84-week study in mice (4, 13, and 40 mg/kg/day), a 104-week study in rats (8.5, 27 and 85 mg/kg/day), and a 26-week study in p53(+/-) transgenic mice (20, 62.5, 200, and 400 mg/kg/day). Although a maximum tolerated dose was not achieved in the 84-week mouse study and in female rats, plasma exposures at the highest doses studied were higher than that achieved in humans at the maximum recommended human dose (MRHD) of 7.5 mg/day. There were no increases in tumor incidence in the 84-week mouse study at doses producing plasma exposures (AUC) 140 times that in humans at the MRHD. In the rat study, there was a statistically significant increase in the incidence of pituitary adenomas in males only at 85 mg/kg/day, a dose associated with a plasma AUC 250 times that in humans at the MRHD. In the 26-week p53(+/-) transgenic mouse study, the incidence of subcutaneous sarcomas was increased in females at doses of 200 and 400 mg/kg/day. - These sarcomas were associated with subcutaneously implanted animal identification transponders, and are not considered to be relevant to humans. There were no other increases in tumor incidence of any type in any dose group. - Mutagenesis - Frovatriptan was clastogenic in human lymphocyte cultures, in the absence of metabolic activation. In the bacterial reverse mutation assay (Ames test), frovatriptan produced an equivocal response in the absence of metabolic activation. Frovatriptan was negative in an in vitro mouse lymphoma tk assay and an in vivo mouse bone marrow micronucleus test. - Impairment of Fertility - Male and female rats were dosed orally with frovatriptan prior to and during mating and in females up to implantation, at doses of 100, 500, and 1000 mg/kg/day (equivalent to approximately 130, 650, and 1300 times the MRHD on a mg/m2 basis). At all dose levels, there was an increase in the number of females that mated on the first day of pairing compared to control animals. This occurred in conjunction with a prolongation of the estrous cycle. In addition, females had a decreased mean number of corpora lutea, and consequently a lower number of live fetuses per litter, which suggested a partial impairment of ovulation. There were no other fertility-related effects. # Clinical Studies - The efficacy of FROVA in the acute treatment of migraine headaches was demonstrated in four randomized, double-blind, placebo-controlled, short-term outpatient trials. In these trials, patients received doses of frovatriptan from 0.5 mg to 40 mg. In these controlled short-term trials, patients were predominately female (88%) and Caucasian (94%) with a mean age of 42 years (range 18 - 69). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed for up to 24 hours after dosing. The associated symptoms nausea, vomiting, photophobia and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours post dose. In two of the trials a second dose of FROVA was provided after the initial treatment, to treat recurrence of the headache within 24 hours. Other medication, excluding other 5-HT1 agonists and ergotamine containing compounds, was permitted from 2 hours after the first dose of FROVA. The frequency and time to use of additional medications were also recorded. - In all four placebo-controlled trials, the percentage of patients achieving a headache response 2 hours after treatment was significantly greater for those taking FROVA 2.5 mg compared to those taking placebo (Table 2). - Lower doses of frovatriptan (1 mg or 0.5 mg) were not effective at 2 hours. Higher doses (5 mg to 40 mg) of frovatriptan showed no added benefit over 2.5 mg but did cause a greater incidence of adverse events. - Table 2 - Percentage of Patients with Headache Response (Mild or No Headache) 2 Hours Following Treatmenta - The estimated probability of achieving an initial headache response by 2 hours following treatment is depicted in Figure 1. - Figure 1 - Estimated Probability of Achieving Initial Headache Response Within 2 Hours - Figure 1 shows a Kaplan-Meier plot of the probability over time of obtaining headache response (no or mild pain) following treatment with FROVA 2.5 mg or placebo. The probabilities displayed are based on pooled data from the four placebo-controlled trials described in Table 2. Patients who did not achieve a response were censored at 24 hours. - In patients with migraine-associated nausea, photophobia and phonophobia at baseline there was a decreased incidence of these symptoms in FROVA treated patients compared to placebo. - The estimated probability of patients taking a second dose or other medication for their migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. - Figure 2 - Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine - Over the 24 Hours Following the Initial Dose of Study Treatment - Figure 2 is a Kaplan-Meier plot showing the probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study medication based on the data from the four placebo-controlled trials described in Table 2. The plot includes those patients who had a response to the initial dose and those who did not. The protocols did not permit remedication within 2 hours of the initial dose. - Efficacy was unaffected by a history of aura; gender; age, or concomitant medications commonly used by migraine patients. # How Supplied - FROVA tablets, containing 2.5 mg of frovatriptan (base) as the succinate salt, are available as round, white, film-coated tablets debossed with 2.5 on one side and “E” on the other side. The tablets are available in: - Blister card of 9 tablets, 1 blister card per carton (NDC 63481-025-09) - Store FROVA tablets at controlled room temperature, 25°C (77°F) excursions permitted to 15 - 30°C (59°F - 86°F). Protect from moisture. ## Storage There is limited information regarding Frovatriptan Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Myocardial Ischemia and/or Infarction, Prinzmetal’s Angina, Other Vasospastic Reactions, and Cerebrovascular Events - Inform patients that FROVA may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions. - Anaphylactic/Anaphylactoid Reactions - Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving FROVA. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. - Medication Overuse Headache - Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary). - Serotonin Syndrome - Inform patients about the risk of serotonin syndrome with the use of FROVA or other triptans, particularly during combined use with SSRIs, SNRIs, TCAs, and MAO inhibitors. - Pregnancy - Inform patients that FROVA should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. - Nursing Mothers - Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed. # Precautions with Alcohol - Alcohol-Frovatriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - FROVA®[2] # Look-Alike Drug Names There is limited information regarding Frovatriptan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Frova
ce17228aec5446bd2fd8a6752d312ccffd31ed20	wikidoc	Fructokinase	Fructokinase Fructokinase (/fructokinase/ ), also known as D-fructokinase or D-fructose (D-mannose) kinase, is an enzyme of the liver, intestine, and kidney cortex. Fructokinase, with a length of approximately 2.6 angstroms, is in a family of enzymes called transferases, meaning that this enzyme transfers phosphorus containing groups; it is also considered a phosphotransferase, since it uses an alcohol group as an acceptor. Fructokinase specifically catalyzes the transfer of a phosphate group from ATP (the substrate) to fructose as the initial step in its utilization. The main role of fructokinase is in carbohydrate metabolism, more specifically, sucrose and starch metabolism. The reaction equation is as follows: ATP + D-fructose = ADP + D-fructose 6-phosphate. # Role in Plants and Bacteria Fructokinase has been characterized from various organisms such as pea (Pisum sativum) seeds, avocado (Persera americana) fruit, and maize (Zea mays) kernels, and many more. Specifically, fructokinase may also regulate starch synthesis in conjunction with SS, sucrose synthase, which first metabolizes sink tissue in plant tissues such as in potatoes. There are also two divergent fructokinase genes that are differentially expressed and which also have different enzymatic properties such as those found in tomatoes. In tomatoes, fructokinase 1 (Frk 1) mRNA is expressed at a constant level during fruit development. However, fructokinase 2 (Frk 2) mRNA has a high expression level in young tomato fruit but then decreases during the later stages of fruit development. Frk 2 has a higher affinity for fructose than Frk 1 but Frk 2 activity is inhibited by high levels of fructose, whereas Frk 1 activity is not. # Role in Animals and Humans In human liver, purified fructokinase, when coupled with aldolase, has been discovered to contribute to an alternative mechanism to produce oxalate from xylitol. In coupled sequence, fructokinase and aldolase produce glycolaldehyde, a precursor to oxalate, from D-xylulose via D-xylulose 1-phosphate. In rat liver cells (hepatocytes), GTP is also a substrate of fructokinase. It can be used at a substantial rate by fructokinase. In these isolated hepatocytes, in vivo, when the concentration of ATP falls to about 1 millimole in a short time interval, GTP becomes an important substrate under these specific conditions. ATP + D-Fructose = ADP + D-Fructose 6-phosphate # Diseases Fructosuria or hepatic fructokinase deficiency is a rare but benign inherited metabolic disorder. This condition is caused by a deficiency of fructokinase in the liver. Affected individuals usually display a large blood fructose concentration after the ingestion of fructose, sucrose or sorbitol. The disease is mainly characterized by the detection of the abnormal excretion of fructose in the urine through a urinalysis. Fructokinase is needed for the synthesis of glycogen, the body's form of stored energy, from fructose. The presence of fructose in the blood and urine may lead to an incorrect diagnosis of diabetes mellitus. Symptoms that may lead to the eventual diagnosis of fructosuria are hepatic fructokinase deficiency, levulosuria and ketohexokinase deficiency.	Fructokinase Fructokinase (/fruc•to•ki•nase/ [-ki´nas]), also known as D-fructokinase or D-fructose (D-mannose) kinase,[1] is an enzyme of the liver, intestine, and kidney cortex. Fructokinase, with a length of approximately 2.6 angstroms, is in a family of enzymes called transferases, meaning that this enzyme transfers phosphorus containing groups; it is also considered a phosphotransferase, since it uses an alcohol group as an acceptor.[1] Fructokinase specifically catalyzes the transfer of a phosphate group from ATP (the substrate) to fructose as the initial step in its utilization.[1] The main role of fructokinase is in carbohydrate metabolism, more specifically, sucrose and starch metabolism. The reaction equation is as follows: ATP + D-fructose = ADP + D-fructose 6-phosphate. # Role in Plants and Bacteria Fructokinase has been characterized from various organisms such as pea (Pisum sativum) seeds, avocado (Persera americana) fruit, and maize (Zea mays) kernels, and many more.[2] Specifically, fructokinase may also regulate starch synthesis in conjunction with SS, sucrose synthase, which first metabolizes sink tissue in plant tissues such as in potatoes.[2] There are also two divergent fructokinase genes that are differentially expressed and which also have different enzymatic properties such as those found in tomatoes. In tomatoes, fructokinase 1 (Frk 1) mRNA is expressed at a constant level during fruit development. However, fructokinase 2 (Frk 2) mRNA has a high expression level in young tomato fruit but then decreases during the later stages of fruit development. Frk 2 has a higher affinity for fructose than Frk 1 but Frk 2 activity is inhibited by high levels of fructose, whereas Frk 1 activity is not. # Role in Animals and Humans In human liver, purified fructokinase, when coupled with aldolase, has been discovered to contribute to an alternative mechanism to produce oxalate from xylitol. In coupled sequence, fructokinase and aldolase produce glycolaldehyde, a precursor to oxalate, from D-xylulose via D-xylulose 1-phosphate.[3] In rat liver cells (hepatocytes), GTP is also a substrate of fructokinase. It can be used at a substantial rate by fructokinase. In these isolated hepatocytes, in vivo, when the concentration of ATP falls to about 1 millimole in a short time interval, GTP becomes an important substrate under these specific conditions.[4] ATP + D-Fructose = ADP + D-Fructose 6-phosphate[5] # Diseases Fructosuria or hepatic fructokinase deficiency is a rare but benign inherited metabolic disorder.[6] This condition is caused by a deficiency of fructokinase in the liver. Affected individuals usually display a large blood fructose concentration after the ingestion of fructose, sucrose or sorbitol.[7] The disease is mainly characterized by the detection of the abnormal excretion of fructose in the urine through a urinalysis. Fructokinase is needed for the synthesis of glycogen, the body's form of stored energy, from fructose. The presence of fructose in the blood and urine may lead to an incorrect diagnosis of diabetes mellitus. Symptoms that may lead to the eventual diagnosis of fructosuria are hepatic fructokinase deficiency, levulosuria and ketohexokinase deficiency.	https://www.wikidoc.org/index.php/Fructokinase
d56fe0e36effc4446680b091c21f95a9a2e0396e	wikidoc	Fructosamine	Fructosamine # Overview Fructosamine is a compound which can be considered as the result of a reaction between fructose and ammonia or an amine (with a molecule of water being released). A fructosamine is also formed when carbonyl group of glucose reacts with an amino group of a protein, as the double bond to oxygen moves from the end carbon atom to the next carbon atom and water is released. Fructosamines formed from blood proteins such as serum albumin are known as Glycated Serum Protein (GSP) or Glycated Albumin, and are used to identify the plasma glucose concentration over time and so assess diabetic control. # Indications More commonly diabetics have their glucose control assessed with the Glycosylated hemoglobin measurement that assesses average glucose levels over the preceding 6 weeks; as reflected by the permanent glycosylation of a small fraction of the hemoglobin molecules in their blood. However, this is not appropriate where there has been a recent change in diet or treatment within 6 weeks, nor if there are abnormalities of red blood cell aging process or mix of hemoglobin subtypes (predominantly HbA in normal adults). Hence people with recent blood loss or hemolytic anemia, or hemoglobinopathy such as sickle-cell disease are not suitable for some glycosylated hemoglobin methods that do not account for higher-turnover hemoglobin. Fructosamine is used in these circumstances, as it also reflects an average of blood glucose levels, but over a shorter period of 2 to 3 weeks. Fructosamine is also of use in conditions, such as pregnancy, in which hormonal changes cause greater short-term fluctuation in glucose concentrations. # Interpretation of Results There is no standard reference range available for this test. The reference values depends upon the factors of patient age, gender, sample population and test method. Hence each laboratory reports will include their specific reference range for the test. An increase in fructosamine in lab testing results usually means an increase in glucose in the blood. Approximately each change of 3.3 mmol (60 mg/dl) in average blood sugar levels will give rise to changes of 2% HbA1c and 75 µmol fructosamine values. # Related Chapters - Diabetes mellitus	Fructosamine Template:Diabetes Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Fructosamine is a compound which can be considered as the result of a reaction between fructose and ammonia or an amine (with a molecule of water being released). A fructosamine is also formed when carbonyl group of glucose reacts with an amino group of a protein, as the double bond to oxygen moves from the end carbon atom to the next carbon atom and water is released. Fructosamines formed from blood proteins such as serum albumin are known as Glycated Serum Protein (GSP) or Glycated Albumin, and are used to identify the plasma glucose concentration over time and so assess diabetic control.[1] # Indications More commonly diabetics have their glucose control assessed with the Glycosylated hemoglobin measurement that assesses average glucose levels over the preceding 6 weeks; as reflected by the permanent glycosylation of a small fraction of the hemoglobin molecules in their blood. However, this is not appropriate where there has been a recent change in diet or treatment within 6 weeks, nor if there are abnormalities of red blood cell aging process or mix of hemoglobin subtypes (predominantly HbA in normal adults). Hence people with recent blood loss or hemolytic anemia, or hemoglobinopathy such as sickle-cell disease are not suitable for some glycosylated hemoglobin methods that do not account for higher-turnover hemoglobin. Fructosamine is used in these circumstances, as it also reflects an average of blood glucose levels, but over a shorter period of 2 to 3 weeks. Fructosamine is also of use in conditions, such as pregnancy, in which hormonal changes cause greater short-term fluctuation in glucose concentrations. # Interpretation of Results There is no standard reference range available for this test. The reference values depends upon the factors of patient age, gender, sample population and test method. Hence each laboratory reports will include their specific reference range for the test. An increase in fructosamine in lab testing results usually means an increase in glucose in the blood. Approximately each change of 3.3 mmol (60 mg/dl) in average blood sugar levels will give rise to changes of 2% HbA1c and 75 µmol fructosamine values.[2] # Related Chapters - Diabetes mellitus	https://www.wikidoc.org/index.php/Fructosamine
542524d0fec5b43042e92e5b2e0ea483a2679b81	wikidoc	Fusidic acid	Fusidic acid Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. # Pharmacology Fusidic acid works by interfering with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G (EF-G) from the ribosome. Fusidic acid is only effective on gram-positive bacteria such as Staphylococcus species and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed "bacteriostatic". Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is not licensed for use in the US, but, as sodium fusidate, it is approved for use under prescription in the UK, Europe Australia and New Zealand. # Uses Fusidic acid is active in vitro against Staphylococcus aureus, most coagulase-negative staphylococci, Corynebacterium species, most clostridium species. Fusidic acid has no useful activity against streptococci, enterococci or most Gram-negative bacteria (except Neisseria, Moraxella, Legionella pneumophila and Bacteroides fragilis). Fusidic acid is active in vitro and clinically against Mycobacterium leprae but has only marginal activity against Mycobacterium tuberculosis. The most important use of fusidic acid clinically is its activity against Methicillin Resistant Staphylococcus Aureus, a sometimes-fatal 'hospital-acquired 'superbug'. Many strains of MRSA remain sensitive to fusidic acid, but because there is a low genetic barrier to resistance (a single point mutation is all that is required), fusidic acid must never be used on its own to treat MRSA and should be combined with another antimicrobial such as rifampicin. Fusidic acid is often found in topical skin and eye preparations (e.g., Fusibet®), a use which has been contested. # Dosing Fusidic acid should not be used on its own to treat Staph. aureus infections. The use of topical preparations (skin creams and eye ointments) containing fusidic acid is strongly associated with the development of resistance, and there are voicing agitating against the continued use of fusidic acid monotherapy in the community. Topical preparations used in Europe often contain fusidic acid and gentamicin in combination, which helps to prevent the development of resistance. Depending on the reason for which sodium fusidate is prescribed the adult dose can be 250 mg twice a day and or up to 750 mg three times a day. (Skin conditions normally need the smaller dose). It is available in tablet and suspension form. There is an intravenous preparation available but it is irritant to veins, causing phlebitis. Most people absorb the drug extremely well after taking it orally so, if a patient can swallow, there is not much need to administer it intravenously, including endocarditis (infection of the heart chambers). ## Pregnancy caution 'There is inadequate evidence of safety in human pregnancy. Animal studies and many years of clinical experience suggest that fusidic acid is devoid of teratogenic effects (birth defects)...fusidic acid can cross the placental barrier. ## Side Effects - 'Fucidin®) Tablets and Suspension can occasionally cause liver upsets which can produce jaundice (yellowing of a patient's skin and the whites of his or her eyes). This condition will almost always get better after you finish taking Fucidin®) Tablets or Suspension. Other related side effects include dark urine, lighter-than-usual feces. These, too should normalize when the course of treatment is completed.' - Patients taking the drug should tell their doctors if they notice that their urine is 'very dark', their feces is 'very pale' or if their skin or the whites of their eyes becomes yellow, the Australian data sheet for patients adds. # Resistance Because the drug is not licensed for use in the US, and there are therefore no Clinical and Laboratory Standards Institute standard definitions of fusidic acid resistance. In the UK and Australia, susceptibility is defined as an MIC of 0.25mg/l or 0.5mg/l or less. Resistance is defined as an MIC of 2mg/l or more. In laboratories using disc diffusion methods, susceptibility for a 2.5µg disc is defined as a zone of 22 mm or more, and resistance is defined as a zone of 17 mm or less; intermediate values are defined as intermediate resistance. Mechanisms of resistance have only been extensively studied in Staphylococcus aureus. The most important mechanism is the development of point mutations in fusA, the chromosomal gene which codes for EF-G. The mutation alters EF-G so that fusidic acid is no longer able to bind to it. Resistance is readily acquired when fusidic acid is used alone and commonly develops during the course of treatment, but resistance does not occur when fusidic acid is used in combination with other antibiotics. For this reason, fusidic acid should not be used on its own to treat Staph. aureus infections. Some bacteria also mediate resistance via the fusB gene, which is carried on a plasmid; the mechanism by which fusB causes resistance is unknown. # Interactions Fusidic acid must not be used with quinolones, with which they are antagonistic. When combined with rifampicin, the action of fusidic acid is additive or synergistic. It is delivered as an ointment, a cream, eye drops or in tablet form. # Trade names and preparations - Fusidin (of Leo in Canada) - Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India) - Fucidine (of Leo in France) - Fucithalmic (of Leo in UK and Denmark) - Fucicort (topical mixture with hydrocortisone) - Fucibet (topical mixture with betamethasone)	Fusidic acid Fusidic acid is a bacteriostatic antibiotic that is often used topically in creams and eyedrops, but may also be given systemically as tablets or injections. # Pharmacology Fusidic acid works by interfering with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G (EF-G) from the ribosome. Fusidic acid is only effective on gram-positive bacteria such as Staphylococcus species and Corynebacterium species. Fusidic acid inhibits bacterial replication and does not kill the bacteria, and is therefore termed "bacteriostatic". Fusidic acid is a true antibiotic, derived from the fungus Fusidium coccineum and was developed by Leo Laboratories in Ballerup, Denmark and released for clinical use in the 1960s. It has also been isolated from Mucor ramannianus and Isaria kogana. The drug is not licensed for use in the US, but, as sodium fusidate, it is approved for use under prescription in the UK, Europe Australia and New Zealand. # Uses Fusidic acid is active in vitro against Staphylococcus aureus, most coagulase-negative staphylococci, Corynebacterium species, most clostridium species. Fusidic acid has no useful activity against streptococci, enterococci or most Gram-negative bacteria (except Neisseria, Moraxella, Legionella pneumophila and Bacteroides fragilis). Fusidic acid is active in vitro and clinically against Mycobacterium leprae but has only marginal activity against Mycobacterium tuberculosis. The most important use of fusidic acid clinically is its activity against Methicillin Resistant Staphylococcus Aureus, a sometimes-fatal 'hospital-acquired 'superbug'.[1] Many strains of MRSA remain sensitive to fusidic acid, but because there is a low genetic barrier to resistance (a single point mutation is all that is required), fusidic acid must never be used on its own to treat MRSA and should be combined with another antimicrobial such as rifampicin. Fusidic acid is often found in topical skin and eye preparations (e.g., Fusibet®), a use which has been contested.[2] # Dosing Fusidic acid should not be used on its own to treat Staph. aureus infections. The use of topical preparations (skin creams and eye ointments) containing fusidic acid is strongly associated with the development of resistance,[3] and there are voicing agitating against the continued use of fusidic acid monotherapy in the community.[2] Topical preparations used in Europe often contain fusidic acid and gentamicin in combination, which helps to prevent the development of resistance. Depending on the reason for which sodium fusidate is prescribed the adult dose can be 250 mg twice a day and or up to 750 mg three times a day. (Skin conditions normally need the smaller dose). It is available in tablet and suspension form.[4] There is an intravenous preparation available but it is irritant to veins, causing phlebitis. Most people absorb the drug extremely well after taking it orally so, if a patient can swallow, there is not much need to administer it intravenously, including endocarditis (infection of the heart chambers). ## Pregnancy caution 'There is inadequate evidence of safety in human pregnancy. Animal studies and many years of clinical experience suggest that fusidic acid is devoid of teratogenic effects (birth defects)...fusidic acid can cross the placental barrier.[5] ## Side Effects - 'Fucidin®) Tablets and Suspension can occasionally cause liver upsets which can produce jaundice (yellowing of a patient's skin and the whites of his or her eyes). This condition will almost always get better after you finish taking Fucidin®) Tablets or Suspension. Other related side effects include dark urine, lighter-than-usual feces. These, too should normalize when the course of treatment is completed.'[6] - Patients taking the drug should tell their doctors if they notice that their urine is 'very dark', their feces is 'very pale' or if their skin or the whites of their eyes becomes yellow, the Australian data sheet for patients adds. # Resistance Because the drug is not licensed for use in the US, and there are therefore no Clinical and Laboratory Standards Institute standard definitions of fusidic acid resistance. In the UK and Australia, susceptibility is defined as an MIC of 0.25mg/l or 0.5mg/l or less. Resistance is defined as an MIC of 2mg/l or more. In laboratories using disc diffusion methods, susceptibility for a 2.5µg disc is defined as a zone of 22 mm or more, and resistance is defined as a zone of 17 mm or less; intermediate values are defined as intermediate resistance. Mechanisms of resistance have only been extensively studied in Staphylococcus aureus. The most important mechanism is the development of point mutations in fusA, the chromosomal gene which codes for EF-G. The mutation alters EF-G so that fusidic acid is no longer able to bind to it.[7][8] Resistance is readily acquired when fusidic acid is used alone and commonly develops during the course of treatment, but resistance does not occur when fusidic acid is used in combination with other antibiotics.[9] For this reason, fusidic acid should not be used on its own to treat Staph. aureus infections. Some bacteria also mediate resistance via the fusB gene, which is carried on a plasmid; the mechanism by which fusB causes resistance is unknown. # Interactions Fusidic acid must not be used with quinolones, with which they are antagonistic. When combined with rifampicin, the action of fusidic acid is additive or synergistic.[10] It is delivered as an ointment, a cream, eye drops or in tablet form. # Trade names and preparations - Fusidin (of Leo in Canada) - Fucidin (of Leo in UK/ Leo-Ranbaxy-Croslands in India) - Fucidine (of Leo in France) - Fucithalmic (of Leo in UK and Denmark) - Fucicort (topical mixture with hydrocortisone) - Fucibet (topical mixture with betamethasone)	https://www.wikidoc.org/index.php/Fucidin
2117635addcdad8542525b572e63b97af663c988	wikidoc	Fundus (eye)	Fundus (eye) The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula, and posterior pole. The fundus can be viewed with an ophthalmoscope. The term may also be inclusive of Bruch's membrane and the choroid. The eye's fundus is the only part of the human body where the microcirculation can be observed directly. The diameter of the blood vessels around the optic disc is about 150 μm, and an ophthalmoscope allows observation of blood vessels with diameters as small as 10 μm. # Diagnosis Medical signs that can be detected from observation of eye fundus include haemorrhages, exudates, cotton wool spots, blood vessel abnormalities (tortuosity, pulsation and new vessels) and pigmentation. ## Physical Examination ### Eyes - Normal Fundus - Example of eye fundus image - Diabetic Fundus with hemorrhages	Fundus (eye) The fundus of the eye is the interior surface of the eye, opposite the lens, and includes the retina, optic disc, macula, and posterior pole.[1] The fundus can be viewed with an ophthalmoscope.[1] The term may also be inclusive of Bruch's membrane and the choroid. The eye's fundus is the only part of the human body where the microcirculation can be observed directly.[2] The diameter of the blood vessels around the optic disc is about 150 μm, and an ophthalmoscope allows observation of blood vessels with diameters as small as 10 μm.[2] # Diagnosis Medical signs that can be detected from observation of eye fundus include haemorrhages, exudates, cotton wool spots, blood vessel abnormalities (tortuosity, pulsation and new vessels) and pigmentation.[3] ## Physical Examination ### Eyes - Normal Fundus[4] - Example of eye fundus image - Diabetic Fundus with hemorrhages[5]	https://www.wikidoc.org/index.php/Fundus_(eye)
6184b163b732569aa997418e87c62f2e1d80f2a5	wikidoc	Funeral home	Funeral home A funeral home, or mortuary, is a business that provides burial and funeral services for the deceased and their families. These services may include a prepared wake and funeral, and the provision of a chapel for the funeral. # Services Funeral homes arrange services in accordance with the wishes of families and the deceased. The funeral home often takes care of the necessary paperwork, permits, and other details, such as making arrangements with the cemetery, and providing obituaries to the news media. There are a few common types of services in the United States of America. A traditional funeral service consists of a viewing (sometimes referred to as a wake), a funeral service at the church of the deceased (or at the mortuary chapel), and a graveside committal service. Direct cremation consists of the mortuary receiving the remains of the deceased, filing the necessary paperwork (according to state laws), and completing the cremation process. Direct/immediate Burial is when the family of the deceased forgoes a funeral ceremony and solely wishes their loved one to be buried in a timely manner. Forwarding or receiving of remains to or from another mortuary consists of preparing the body for shipment in a casket strapped into an airtray or a combination unit. This is used when the cemetery in which the deceased is to be buried lies in another state or country. When the deceased are brought to the funeral home, they are sometimes embalmed to delay decomposition. The typical embalming procedure involves replacement of the blood of the decedent with a mixture of preservative chemicals and dyes, aspiration of the internal organs, and the setting of the person's features. The use of makeup to make a person look more lifelike is often employed. If the deceased was disfigured from an accident or illness, the embalmer can sometimes utilize restorative techniques to make the corpse presentable for an open casket service. If the embalmer is unable to do so, or if the family requests otherwise, the funeral home can perform a closed casket service. The funeral home often sets aside one or more large areas for families to gather at a visitation. This area may contain a space to display the deceased in their casket for visitors to pay their respects. Funeral services and memorial services may also take place at the funeral home. Many funeral homes also offer prearrangement services for those who wish to prepare their own funeral services before death. Because of the increasing popularity of cremation, there are more funeral homes with crematoriums. Funeral homes without facilities on-site often contract the work out to other firms. Some funeral homes are family owned and operated. Others are part of larger corporations; however, unlike those in other industries, these corporations often act anonymously to appear as if they are family owned. One of the largest corporations is Service Corporation International. # Funeral homes in popular culture - The television series Six Feet Under portrayed a fictional funeral home. - The television series Family Plots showed the operations of an actual Californian funeral home. The show lasted for two seasons before it was canceled. - In the movie My Girl Harry Sultenfuss (Dan Aykroyd) ran a mortuary from his home. - In the Lifetime tv movie Wisegal, Frank Russo, the mafia captain, owns a Funeral Home as a front	Funeral home A funeral home, or mortuary, is a business that provides burial and funeral services for the deceased and their families. These services may include a prepared wake and funeral, and the provision of a chapel for the funeral. # Services Funeral homes arrange services in accordance with the wishes of families and the deceased. The funeral home often takes care of the necessary paperwork, permits, and other details, such as making arrangements with the cemetery, and providing obituaries to the news media. There are a few common types of services in the United States of America. A traditional funeral service consists of a viewing (sometimes referred to as a wake), a funeral service at the church of the deceased (or at the mortuary chapel), and a graveside committal service. Direct cremation consists of the mortuary receiving the remains of the deceased, filing the necessary paperwork (according to state laws), and completing the cremation process. Direct/immediate Burial is when the family of the deceased forgoes a funeral ceremony and solely wishes their loved one to be buried in a timely manner. Forwarding or receiving of remains to or from another mortuary consists of preparing the body for shipment in a casket strapped into an airtray or a combination unit. This is used when the cemetery in which the deceased is to be buried lies in another state or country. When the deceased are brought to the funeral home, they are sometimes embalmed to delay decomposition. The typical embalming procedure involves replacement of the blood of the decedent with a mixture of preservative chemicals and dyes, aspiration of the internal organs, and the setting of the person's features. The use of makeup to make a person look more lifelike is often employed. If the deceased was disfigured from an accident or illness, the embalmer can sometimes utilize restorative techniques to make the corpse presentable for an open casket service. If the embalmer is unable to do so, or if the family requests otherwise, the funeral home can perform a closed casket service. The funeral home often sets aside one or more large areas for families to gather at a visitation. This area may contain a space to display the deceased in their casket for visitors to pay their respects. Funeral services and memorial services may also take place at the funeral home. Many funeral homes also offer prearrangement services for those who wish to prepare their own funeral services before death. Because of the increasing popularity of cremation, there are more funeral homes with crematoriums.[citation needed] Funeral homes without facilities on-site often contract the work out to other firms. Some funeral homes are family owned and operated. Others are part of larger corporations; however, unlike those in other industries, these corporations often act anonymously to appear as if they are family owned. [1] One of the largest corporations is Service Corporation International. # Funeral homes in popular culture - The television series Six Feet Under portrayed a fictional funeral home. - The television series Family Plots showed the operations of an actual Californian funeral home. The show lasted for two seasons before it was canceled. - In the movie My Girl Harry Sultenfuss (Dan Aykroyd) ran a mortuary from his home. - In the Lifetime tv movie Wisegal, Frank Russo, the mafia captain, owns a Funeral Home as a front	https://www.wikidoc.org/index.php/Funeral_home
3bf546b8de28ac99dd8602a8b6e17b30662923cb	wikidoc	Fungal prion	Fungal prion Fungal prions have been investigated, leading to a deeper understanding of disease-forming mammalian prions. Prion-like proteins are found naturally in some plants and non-mammalian animals. Some of these are not associated with any disease state and may possibly even have a useful role. Because of this, scientists reasoned that such proteins could give some sort of evolutionary advantage to their host. This was suggested to be the case in a species of fungus, Podospora anserina. Genetically compatible colonies of this fungus can merge together and share cellular contents such as nutrients and cytoplasm. A natural system of protective "incompatibility" proteins exists to prevent promiscuous sharing between unrelated colonies. One such protein, called HET-S, adopts a prion-like form in order to function properly . The prion form of HET-S spreads rapidly throughout the cellular network of a colony and can convert the non-prion form of the protein to a prion state after compatible colonies have merged . However, when an incompatible colony tries to merge with a prion-containing colony, the prion causes the "invader" cells to die, ensuring that only related colonies obtain the benefit of sharing resources. # Sup35p & Ure2p In 1965, Brian Cox, a geneticist working with the yeast Saccharomyces cerevisiae, described a genetic trait (termed PSI+) with an unusual pattern of inheritance. The initial discovery of PSI+ was made in a strain auxotrophic for adenine due to a nonsense mutation Despite many years of effort, Cox could not identify a conventional mutation that was responsible for the PSI+ trait. In 1994, yeast geneticist Reed Wickner correctly hypothesized that PSI+ as well as another mysterious heritable trait, URE3, resulted from prion forms of certain normal cellular proteins . It was soon noticed that heat shock proteins (which help other proteins fold properly) were intimately tied to the inheritance and transmission of PSI+ and many other yeast prions. Since then, researchers have unravelled how the proteins that code for PSI+ and URE3 can convert between prion and non-prion forms, as well as the consequences of having intracellular prions. When exposed to certain adverse conditions, PSI+ cells actually fare better than their prion-free siblings ; this finding suggests that, in some proteins, the ability to adopt a prion form may result from positive evolutionary selection . It has been speculated that the ability to convert between prion infected and prion-free forms enables yeast to quickly and reversibly adapt in variable environments. Nevertheless, Wickner maintains that URE3 and PSI+ are diseases . Further investigation found that PSI+ is the misfolded form of Sup35, which is an important factor for translation termination during protein synthesis . It is believed that causes suppression of nonsense mutations by sequestering functional Sup35 in non-functional aggregates, thereby allowing stop codon readthrough. , in turn, is the misfolded form of the protein Rnq1. However, the normal function of this protein is unknown to date. It is of note that for the induction of most variants of , the presence of is required. Though reasons for this are poorly understood, it is suggested that aggregates may act as “seeds” for the polymerization of . Two modified versions of Sup35 have been created that can induce PSI+ in the absence of when overexpressed. One version was created by digestion of the gene with BalI, which results in a protein consisting of only the M and N portions of Sup35 . The other is a fusion of Sup35NM with HPR, a human membrane receptor protein. Laboratories commonly identify by growth of a strain auxotrophic for adenine on media lacking adenine, similar to that used by Cox et al. These strains cannot synthesize adenine due to a nonsense mutation in one of the enzymes involved in biosynthetic pathway. When the strain is grown on yeast-extract/dextrose/peptone media (YPD), the blocked pathway results in buildup of a red-colored intermediate compound, which is exported from the cell due to its toxicity. Hence, color is an alternative method of identifying -- strains are white or pinkish in color, and strains are red. A third method of identifying is by the presence of Sup35 in the pelleted fraction of cellular lysate. # Classification As of 2003, the following proteins in Saccharomyces cerevisiae had been identified or postulated as prions: - Sup35p, forming the element; - Ure2p, forming the element; - Rnq1p, forming the element (also known as ) - A fifth prion protein, forming the element remains to be identified.	Fungal prion Fungal prions have been investigated, leading to a deeper understanding of disease-forming mammalian prions. Prion-like proteins are found naturally in some plants and non-mammalian animals. Some of these are not associated with any disease state and may possibly even have a useful role[1]. Because of this, scientists reasoned that such proteins could give some sort of evolutionary advantage to their host. This was suggested to be the case in a species of fungus, Podospora anserina. Genetically compatible colonies of this fungus can merge together and share cellular contents such as nutrients and cytoplasm. A natural system of protective "incompatibility" proteins exists to prevent promiscuous sharing between unrelated colonies. One such protein, called HET-S, adopts a prion-like form in order to function properly [2]. The prion form of HET-S spreads rapidly throughout the cellular network of a colony and can convert the non-prion form of the protein to a prion state after compatible colonies have merged [3]. However, when an incompatible colony tries to merge with a prion-containing colony, the prion causes the "invader" cells to die, ensuring that only related colonies obtain the benefit of sharing resources. # Sup35p & Ure2p In 1965, Brian Cox, a geneticist working with the yeast Saccharomyces cerevisiae, described a genetic trait (termed PSI+) with an unusual pattern of inheritance. The initial discovery of PSI+ was made in a strain auxotrophic for adenine due to a nonsense mutation [1] Despite many years of effort, Cox could not identify a conventional mutation that was responsible for the PSI+ trait. In 1994, yeast geneticist Reed Wickner correctly hypothesized that PSI+ as well as another mysterious heritable trait, URE3, resulted from prion forms of certain normal cellular proteins [4]. It was soon noticed that heat shock proteins (which help other proteins fold properly) were intimately tied to the inheritance and transmission of PSI+ and many other yeast prions. Since then, researchers have unravelled how the proteins that code for PSI+ and URE3 can convert between prion and non-prion forms, as well as the consequences of having intracellular prions. When exposed to certain adverse conditions, PSI+ cells actually fare better than their prion-free siblings [5]; this finding suggests that, in some proteins, the ability to adopt a prion form may result from positive evolutionary selection [6]. It has been speculated that the ability to convert between prion infected and prion-free forms enables yeast to quickly and reversibly adapt in variable environments. Nevertheless, Wickner maintains that URE3 and PSI+ are diseases [7]. Further investigation found that PSI+ is the misfolded form of Sup35, which is an important factor for translation termination during protein synthesis [2]. It is believed that [PSI+] causes suppression of nonsense mutations by sequestering functional Sup35 in non-functional aggregates, thereby allowing stop codon readthrough. [PIN+], in turn, is the misfolded form of the protein Rnq1. However, the normal function of this protein is unknown to date. It is of note that for the induction of most variants of [PSI+], the presence of [PIN+] is required. Though reasons for this are poorly understood, it is suggested that [PIN+] aggregates may act as “seeds” for the polymerization of [PSI+] [3]. Two modified versions of Sup35 have been created that can induce PSI+ in the absence of [PIN+] when overexpressed. One version was created by digestion of the gene with BalI, which results in a protein consisting of only the M and N portions of Sup35 [4]. The other is a fusion of Sup35NM with HPR, a human membrane receptor protein. Laboratories commonly identify [PSI+] by growth of a strain auxotrophic for adenine on media lacking adenine, similar to that used by Cox et al. These strains cannot synthesize adenine due to a nonsense mutation in one of the enzymes involved in biosynthetic pathway. When the strain is grown on yeast-extract/dextrose/peptone media (YPD), the blocked pathway results in buildup of a red-colored intermediate compound, which is exported from the cell due to its toxicity. Hence, color is an alternative method of identifying [PSI+] -- [PSI+] strains are white or pinkish in color, and [psi-] strains are red. A third method of identifying [PSI+] is by the presence of Sup35 in the pelleted fraction of cellular lysate. # Classification As of 2003, the following proteins in Saccharomyces cerevisiae had been identified or postulated as prions: - Sup35p, forming the [PSI+] element; - Ure2p, forming the [URE3] element; - Rnq1p, forming the [RNQ+] element (also known as [PIN+]) - A fifth prion protein, forming the [ISP+] element remains to be identified.	https://www.wikidoc.org/index.php/Fungal_prion
8c84bd80c2db6ed68111581706890dc2fc7ec972	wikidoc	Furazolidine	Furazolidine # Overview Furazolidone is a nitrofuran antibacterial. It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M. Diafuron, medaron # Uses Furazolidone has been used in human and veterinary medicine. It has a broad spectrum of activity being active against - Gram positive Clostridium perfringens Corynebacterium pyogenes Streptococci Staphylococci - Clostridium perfringens - Corynebacterium pyogenes - Streptococci - Staphylococci - Gram negative Escherichia coli Salmonella dublin Salmonella typhimurium - Escherichia coli - Salmonella dublin - Salmonella typhimurium - Protozoa Giardia lamblia Eimeria species Histomonas meleagridis - Giardia lamblia - Eimeria species - Histomonas meleagridis ## Use in humans In humans it has used to treat diarrhoea and enteritis caused by bacteria or protozoan infections. It has been used to treat traveler's diarrhoea, cholera and bacteremic salmonellosis. Use in treating Helicobacter pylori infections has also been proposed. Furazolidone is also used for giardiasis (due to Giardia lamblia), though it is not a first line treatment. As for all medicines the most recent local recommendations for its use should be always be followed. The usual dose is: - Adult: 100 mg 4 times daily. Usual duration: 2-5 days, up to 7 days in some patients or 10 days for giardiasis. - Child: 1.25 mg/kg 4 times daily, usually given for 2-5 days or up to 10 days for giardiasis. ## Use in animals As a veterinary medicine, furazolidone has been used with some success to treat salmonids for Myxobolus cerebralis infections. It has also been used in aquaculture. Since furazolidone is a nitrofuran antibiotic, its use in food animals is currently prohibited by the FDA under the Animal Medicinal Drug Use Clarification Act, 1994. ## Use in laboratory It is used to differentiate micrococci and staphylococci. # Mechanism It is believed to work by crosslinking of DNA. # Side effects Furazolidone is no longer available in the US. Though an effective antibiotic when all others fail, against extremely drug resistant infections, it has many side effects, and as with other nitrofurans generally, minimum inhibitory concentrations also produce systemic toxicity (tremors, convulsions, peripheral neuritis, gastrointestinal disturbances, depression of spermatogenesis.) Nitrofurans are recognized by FDA as mutagens/carcinogens, and can no longer be used since 1991.	Furazolidine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Furazolidone is a nitrofuran antibacterial. It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M. Diafuron, medaron # Uses Furazolidone has been used in human and veterinary medicine. It has a broad spectrum of activity being active against - Gram positive Clostridium perfringens Corynebacterium pyogenes Streptococci Staphylococci - Clostridium perfringens - Corynebacterium pyogenes - Streptococci - Staphylococci - Gram negative Escherichia coli Salmonella dublin Salmonella typhimurium - Escherichia coli - Salmonella dublin - Salmonella typhimurium - Protozoa Giardia lamblia Eimeria species Histomonas meleagridis - Giardia lamblia - Eimeria species - Histomonas meleagridis ## Use in humans In humans it has used to treat diarrhoea and enteritis caused by bacteria or protozoan infections. It has been used to treat traveler's diarrhoea, cholera and bacteremic salmonellosis. Use in treating Helicobacter pylori infections has also been proposed.[1] Furazolidone is also used for giardiasis (due to Giardia lamblia), though it is not a first line treatment.[2] As for all medicines the most recent local recommendations for its use should be always be followed. The usual dose is: - Adult: 100 mg 4 times daily. Usual duration: 2-5 days, up to 7 days in some patients or 10 days for giardiasis. - Child: 1.25 mg/kg 4 times daily, usually given for 2-5 days or up to 10 days for giardiasis. ## Use in animals As a veterinary medicine, furazolidone has been used with some success to treat salmonids for Myxobolus cerebralis infections. It has also been used in aquaculture.[3] Since furazolidone is a nitrofuran antibiotic, its use in food animals is currently prohibited by the FDA under the Animal Medicinal Drug Use Clarification Act, 1994.[4] ## Use in laboratory It is used to differentiate micrococci and staphylococci. # Mechanism It is believed to work by crosslinking of DNA.[5] # Side effects Furazolidone is no longer available in the US. Though an effective antibiotic when all others fail, against extremely drug resistant infections, it has many side effects, and as with other nitrofurans generally, minimum inhibitory concentrations also produce systemic toxicity (tremors, convulsions, peripheral neuritis, gastrointestinal disturbances, depression of spermatogenesis.) Nitrofurans are recognized by FDA as mutagens/carcinogens, and can no longer be used since 1991.[6]	https://www.wikidoc.org/index.php/Furazolidine
6721ec7e62d6849d5ce4923cb1f41a913eb581fc	wikidoc	Furazolidone	Furazolidone # Overview Furazolidone is a nitrofuran antibacterial. It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M. Diafuron, medaron # Uses Furazolidone has been used in human and veterinary medicine. It has a broad spectrum of activity being active against - Gram positive Clostridium perfringens Corynebacterium pyogenes Streptococci Staphylococci - Clostridium perfringens - Corynebacterium pyogenes - Streptococci - Staphylococci - Gram negative Escherichia coli Salmonella dublin Salmonella typhimurium - Escherichia coli - Salmonella dublin - Salmonella typhimurium - Protozoa Giardia lamblia Eimeria species Histomonas meleagridis - Giardia lamblia - Eimeria species - Histomonas meleagridis ## Use in humans In humans it has used to treat diarrhoea and enteritis caused by bacteria or protozoan infections. It has been used to treat traveler's diarrhoea, cholera and bacteremic salmonellosis. Use in treating Helicobacter pylori infections has also been proposed. Furazolidone is also used for giardiasis (due to Giardia lamblia), though it is not a first line treatment. As for all medicines the most recent local recommendations for its use should be always be followed. The usual dose is: - Adult: 100 mg 4 times daily. Usual duration: 2-5 days, up to 7 days in some patients or 10 days for giardiasis. - Child: 1.25 mg/kg 4 times daily, usually given for 2-5 days or up to 10 days for giardiasis. ## Use in animals As a veterinary medicine, furazolidone has been used with some success to treat salmonids for Myxobolus cerebralis infections. It has also been used in aquaculture. Since furazolidone is a nitrofuran antibiotic, its use in food animals is currently prohibited by the FDA under the Animal Medicinal Drug Use Clarification Act, 1994. ## Use in laboratory It is used to differentiate micrococci and staphylococci. # Mechanism It is believed to work by crosslinking of DNA. # Side effects Furazolidone is no longer available in the US. Though an effective antibiotic when all others fail, against extremely drug resistant infections, it has many side effects, and as with other nitrofurans generally, minimum inhibitory concentrations also produce systemic toxicity (tremors, convulsions, peripheral neuritis, gastrointestinal disturbances, depression of spermatogenesis.) Nitrofurans are recognized by FDA as mutagens/carcinogens, and can no longer be used since 1991.	Furazolidone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Furazolidone is a nitrofuran antibacterial. It is marketed by Roberts Laboratories under the brand name Furoxone and by GlaxoSmithKline as Dependal-M. Diafuron, medaron # Uses Furazolidone has been used in human and veterinary medicine. It has a broad spectrum of activity being active against - Gram positive Clostridium perfringens Corynebacterium pyogenes Streptococci Staphylococci - Clostridium perfringens - Corynebacterium pyogenes - Streptococci - Staphylococci - Gram negative Escherichia coli Salmonella dublin Salmonella typhimurium - Escherichia coli - Salmonella dublin - Salmonella typhimurium - Protozoa Giardia lamblia Eimeria species Histomonas meleagridis - Giardia lamblia - Eimeria species - Histomonas meleagridis ## Use in humans In humans it has used to treat diarrhoea and enteritis caused by bacteria or protozoan infections. It has been used to treat traveler's diarrhoea, cholera and bacteremic salmonellosis. Use in treating Helicobacter pylori infections has also been proposed.[1] Furazolidone is also used for giardiasis (due to Giardia lamblia), though it is not a first line treatment.[2] As for all medicines the most recent local recommendations for its use should be always be followed. The usual dose is: - Adult: 100 mg 4 times daily. Usual duration: 2-5 days, up to 7 days in some patients or 10 days for giardiasis. - Child: 1.25 mg/kg 4 times daily, usually given for 2-5 days or up to 10 days for giardiasis. ## Use in animals As a veterinary medicine, furazolidone has been used with some success to treat salmonids for Myxobolus cerebralis infections. It has also been used in aquaculture.[3] Since furazolidone is a nitrofuran antibiotic, its use in food animals is currently prohibited by the FDA under the Animal Medicinal Drug Use Clarification Act, 1994.[4] ## Use in laboratory It is used to differentiate micrococci and staphylococci. # Mechanism It is believed to work by crosslinking of DNA.[5] # Side effects Furazolidone is no longer available in the US. Though an effective antibiotic when all others fail, against extremely drug resistant infections, it has many side effects, and as with other nitrofurans generally, minimum inhibitory concentrations also produce systemic toxicity (tremors, convulsions, peripheral neuritis, gastrointestinal disturbances, depression of spermatogenesis.) Nitrofurans are recognized by FDA as mutagens/carcinogens, and can no longer be used since 1991.[6]	https://www.wikidoc.org/index.php/Furazolidone
e3db33d28bd94057f1eddcbc516044db42aa9bb0	wikidoc	GDP deflator	GDP deflator In economics, the GDP deflator (implicit price deflator for GDP) is a measure of the change in prices of all new, domestically produced, final goods and services in an economy. GDP stands for gross domestic product, the total value of all final goods and services produced within that economy during a specified period. # Calculation ## Measurement in national accounts In most systems of national accounts the GDP deflator measures the difference between the real (or chain volume measure) GDP and the nominal (or current price) GDP. The formula used to calculate the deflator is: Dividing the nominal GDP by the GDP deflator would then give the figure for real GDP, hence deflating the nominal GDP into a real measure. It is often useful to consider implicit price deflators for certain subcategories of GDP, such as computer hardware. In this case, it is useful to think of the price deflator as the ratio of the current-year price of a good to its price in some base year. The price in the base year is normalized to 100. For example, for computer hardware, we could define a "unit" to be a computer with a specific level of processing power, memory, hard drive space and so on. A price deflator of 200 means that the current-year price of this computing power is twice its base-year price - price inflation. A price deflator of 50 means that the current-year price is half the base year price - price deflation. Unlike some price indexes, the GDP deflator is not based on a fixed basket of goods and services. The basket is allowed to change with people's consumption and investment patterns. (Specifically, for GDP, the "basket" in each year is the set of all goods that were produced domestically, weighted by the market value of the total consumption of each good.) Therefore, new expenditure patterns are allowed to show up in the deflator as people respond to changing prices. The advantage of this approach is that the GDP deflator reflects up to date expenditure patterns. For instance, if the price of chicken increases relative to the price of beef, people would likely spend more money on beef as a substitute for chicken. A fixed market basket measurement would miss this change. In practice, the difference between the deflator and a price index like the CPI is often relatively small. On the other hand, with governments in developed countries increasingly utilizing price indexes for everything from fiscal and monetary planning to payments to social program recipients, the even small differences between inflation measures can shift budget revenues and expenses by millions or billions of dollars. ## United States The GDP and GDP deflator are calculated by the Bureau of Economic Analysis (BEA). ## United Kingdom The GDP and GDP deflator series are published by HM Treasury # Hedonics A hedonic regression for a specific good relates the expected price of the good to its characteristics. For example, a hedonic model for a computer relates a computer's price to the value of its processor speed, memory, hard drive capacity, and so on. Hedonic regressions can be used to create hedonic price indices. These can vary over time as the price structure of the underlying characteristics change. In recent years, some commentators have expressed concern that the national accounts may overstate spending on computer hardware because of the way the hedonic price index and implicit price deflator are used. It is well-known that the prices of a unit of processor speed, a unit of memory, and a unit of hard drive capacity have declined very quickly since 1995. Therefore, the current-year (say, 2003) price deflator for an entire computer - using the hedonic method - is less than one relative to a base year of 1995. This means that when nominal spending on computer hardware is divided by the deflator to give real spending on computers, the number rises. (The "deflator" here is actually an inflator!) From the second quarter of 2000 through the fourth quarter of 2003, the government estimated that real tech spending rose from $446 billion to $557 billion, when nominal spending only increased to $488 billion. Some analysts feel that this overstates the "true" spending on computers by $72 billion. However, it is also true that this extra $72 billion captures the increase in value and utility of the computers that were purchased in 2003 as compared to 2000, due to the former's superior quality and capability for the same nominal price as the latter.	GDP deflator In economics, the GDP deflator (implicit price deflator for GDP) is a measure of the change in prices of all new, domestically produced, final goods and services in an economy. GDP stands for gross domestic product, the total value of all final goods and services produced within that economy during a specified period. . # Calculation ## Measurement in national accounts In most systems of national accounts the GDP deflator measures the difference between the real (or chain volume measure) GDP and the nominal (or current price) GDP. The formula used to calculate the deflator is: Dividing the nominal GDP by the GDP deflator would then give the figure for real GDP, hence deflating the nominal GDP into a real measure. It is often useful to consider implicit price deflators for certain subcategories of GDP, such as computer hardware. In this case, it is useful to think of the price deflator as the ratio of the current-year price of a good to its price in some base year. The price in the base year is normalized to 100. For example, for computer hardware, we could define a "unit" to be a computer with a specific level of processing power, memory, hard drive space and so on. A price deflator of 200 means that the current-year price of this computing power is twice its base-year price - price inflation. A price deflator of 50 means that the current-year price is half the base year price - price deflation. Unlike some price indexes, the GDP deflator is not based on a fixed basket of goods and services. The basket is allowed to change with people's consumption and investment patterns. (Specifically, for GDP, the "basket" in each year is the set of all goods that were produced domestically, weighted by the market value of the total consumption of each good.) Therefore, new expenditure patterns are allowed to show up in the deflator as people respond to changing prices. The advantage of this approach is that the GDP deflator reflects up to date expenditure patterns. For instance, if the price of chicken increases relative to the price of beef, people would likely spend more money on beef as a substitute for chicken. A fixed market basket measurement would miss this change. In practice, the difference between the deflator and a price index like the CPI is often relatively small. On the other hand, with governments in developed countries increasingly utilizing price indexes for everything from fiscal and monetary planning to payments to social program recipients, the even small differences between inflation measures can shift budget revenues and expenses by millions or billions of dollars. ## United States The GDP and GDP deflator are calculated by the Bureau of Economic Analysis (BEA). ## United Kingdom The GDP and GDP deflator series are published by HM Treasury [1] # Hedonics A hedonic regression for a specific good relates the expected price of the good to its characteristics. For example, a hedonic model for a computer relates a computer's price to the value of its processor speed, memory, hard drive capacity, and so on. Hedonic regressions can be used to create hedonic price indices. These can vary over time as the price structure of the underlying characteristics change. In recent years, some commentators have expressed concern that the national accounts may overstate spending on computer hardware because of the way the hedonic price index and implicit price deflator are used. It is well-known that the prices of a unit of processor speed, a unit of memory, and a unit of hard drive capacity have declined very quickly since 1995. Therefore, the current-year (say, 2003) price deflator for an entire computer - using the hedonic method - is less than one relative to a base year of 1995. This means that when nominal spending on computer hardware is divided by the deflator to give real spending on computers, the number rises. (The "deflator" here is actually an inflator!) From the second quarter of 2000 through the fourth quarter of 2003, the government estimated that real tech spending rose from $446 billion to $557 billion, when nominal spending only increased to $488 billion. Some analysts feel that this overstates the "true" spending on computers by $72 billion.[citation needed] However, it is also true that this extra $72 billion captures the increase in value and utility of the computers that were purchased in 2003 as compared to 2000, due to the former's superior quality and capability for the same nominal price as the latter.	https://www.wikidoc.org/index.php/GDP_deflator
50eb715c33508583c7c1aba316693a5f937e28c1	wikidoc	GHB receptor	GHB receptor The γ-hydroxybutyrate (GHB) receptor (GHBR), originally identified as GPR172A, is a G protein-coupled receptor (GPCR) that binds the neurotransmitter and psychoactive drug γ-hydroxybutyric acid (GHB). # History The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted. The rat GHB receptor was first cloned and characterised in 2003 followed by the human receptor in 2007. # Function The function of the GHB receptor appears to be quite different from that of the GABAB receptor. It shares no sequence homology with GABAB, and administration of mixed GHB/GABAB receptor agonists along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses, thought to be mediated through increased Na+/K+ current and increased release of dopamine and glutamate. # Ligands ## Agonists - 1,4-Butanediol - 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA) - 4-(p-Chlorobenzyl)-GHB - γ-Butyrolactone (GBL) - γ-Hydroxybutyric acid (GHB) - γ-Hydroxyvaleric acid (GHV; 4-methyl-GHB) - γ-Valerolactone (GVL) - trans-Hydroxycrotonic acid (T-HCA) - Aceburic acid - NCS-356 (4-(4-chlorophenyl)-4-hydroxy-but-2-enoic acid, CAS# 430440-66-7) - NCS-435 (4-(p-methoxybenzyl)-GHB) - UMB66 - UMB68 - UMB72 - UMB86 ## Antagonists - Gabazine (SR-95531) - NCS-382 ## Unknown/unclear - (R)-4--GHB]] - Amisulpride - Levosulpiride - Prochlorperazine - Sulpiride - Sultopride	GHB receptor The γ-hydroxybutyrate (GHB) receptor (GHBR), originally identified as GPR172A, is a G protein-coupled receptor (GPCR) that binds the neurotransmitter and psychoactive drug γ-hydroxybutyric acid (GHB). # History The existence of a specific GHB receptor was predicted by observing the action of GHB and related compounds that primarily act on the GABAB receptor, but also exhibit a range of effects which were found not to be produced by GABAB activity, and so were suspected of being produced by a novel and at the time unidentified receptor target. Following the discovery of the "orphan" G-protein coupled receptor GPR172A, it was subsequently found to be the GHB receptor whose existence had been previously predicted.[1] The rat GHB receptor was first cloned and characterised in 2003[2] followed by the human receptor in 2007.[3] # Function The function of the GHB receptor appears to be quite different from that of the GABAB receptor. It shares no sequence homology with GABAB, and administration of mixed GHB/GABAB receptor agonists along with a selective GABAB antagonist or selective agonists for the GHB receptor which are not agonists at GABAB, do not produce a sedative effect, instead causing a stimulant effect followed by convulsions at higher doses, thought to be mediated through increased Na+/K+ current and increased release of dopamine and glutamate.[4][5][6][7][8][9] # Ligands ## Agonists - 1,4-Butanediol - 3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA) - 4-(p-Chlorobenzyl)-GHB - γ-Butyrolactone (GBL) - γ-Hydroxybutyric acid (GHB) - γ-Hydroxyvaleric acid (GHV; 4-methyl-GHB) - γ-Valerolactone (GVL) - trans-Hydroxycrotonic acid (T-HCA) - Aceburic acid - NCS-356 (4-(4-chlorophenyl)-4-hydroxy-but-2-enoic acid, CAS# 430440-66-7) - NCS-435 (4-(p-methoxybenzyl)-GHB) - UMB66 - UMB68 - UMB72 - UMB86[10] ## Antagonists - Gabazine (SR-95531)[11] - NCS-382 ## Unknown/unclear - (R)-4-[4′-(2-Iodobenzyloxy)phenyl]-GHB]][12] - Amisulpride - Levosulpiride - Prochlorperazine - Sulpiride - Sultopride	https://www.wikidoc.org/index.php/GHB_receptor
a4aebb0e39d9ed0db6d5b118cf9bc23376a66acb	wikidoc	Somatostatin	Somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion. Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 amino acids (shown in infobox to right), the other consisting of 28 amino acids. Among the vertebrates, there exist six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5 and SS6. Zebrafish have all six. The six different genes, along with the five different somatostatin receptors, allow somatostatin to possess a large range of functions. Humans have only one somatostatin gene, SST. # Nomenclature Synonyms of "somatostatin" include: - growth hormone–inhibiting hormone (GHIH) - growth hormone release–inhibiting hormone (GHRIH) - somatotropin release–inhibiting factor (SRIF) - somatotropin release–inhibiting hormone (SRIH) # Production ## Digestive system Somatostatin is secreted by delta cells at several locations in the digestive system, namely the pyloric antrum, the duodenum and the pancreatic islets. Somatostatin released in the pyloric antrum travels via the portal venous system to the heart, then enters the systemic circulation to reach the locations where it will exert its inhibitory effects. In addition, somatostatin release from delta cells can act in a paracrine manner. In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion. Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin, secretin and histamine which effectively slows down the digestive process. ## Brain Somatostatin is produced by neuroendocrine neurons of the ventromedial nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamohypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone. Somatostatin is also produced by several other populations that project centrally, i.e., to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, populations of somatostatin neurons occur in the arcuate nucleus, the hippocampus, and the brainstem nucleus of the solitary tract. # Actions Somatostatin is classified as an inhibitory hormone, and is induced by low pH.. Its actions are spread to different parts of the body. Somatostatin release is inhibited by the Vagus nerve. ## Anterior pituitary In the anterior pituitary gland, the effects of somatostatin are: - Inhibit the release of growth hormone (GH) (thus opposing the effects of growth hormone–releasing hormone (GHRH)) - Inhibit the release of thyroid-stimulating hormone (TSH) - Inhibit adenylyl cyclase in parietal cells - Inhibits the release of prolactin (PRL) ## Gastrointestinal system - Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones Gastrin Cholecystokinin (CCK) Secretin Motilin Vasoactive intestinal peptide (VIP) Gastric inhibitory polypeptide (GIP) Enteroglucagon - Gastrin - Cholecystokinin (CCK) - Secretin - Motilin - Vasoactive intestinal peptide (VIP) - Gastric inhibitory polypeptide (GIP) - Enteroglucagon - Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine - Suppresses the release of pancreatic hormones Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit insulin release. Inhibits the release of glucagon - Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit insulin release. - Inhibits the release of glucagon - Suppresses the exocrine secretory action of the pancreas # Synthetic substitutes Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone, and has a much longer half-life (about 90 minutes, compared to 2–3 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome and acromegaly. It is also finding increased use in polycystic diseases of the liver and kidney. Lanreotide (Somatuline, Ipsen Pharmaceuticals)is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analog of somatostatin, like octreotide. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration on August 30, 2007. # Evolutionary history Six somatostatin genes have been discovered in vertebrates. The current proposed history as to how these six genes arose is based on the three whole-genome duplication events that took place in vertebrate evolution along with local duplications in teleost fish. An ancestral somatostatin gene was duplicated during the first whole-genome duplication event (1R) to create SS1 and SS2. These two genes were duplicated during the second whole-genome duplication event (2R) to create four new somatostatin genes:SS1, SS2, SS3, and one gene that was lost during the evolution of vertebrates. Tetrapods retained SS1 (also known as SS-14 and SS-28) and SS2 (also known as cortistatin) after the split in the Sarcopterygii and Actinopterygii lineage split. In teleost fish, SS1, SS2, and SS3 were duplicated during the third whole-genome duplication event (3R) to create SS1, SS2, SS4, SS5, and two genes that were lost during the evolution of teleost fish. SS1 and SS2 went through local duplications to give rise to SS6 and SS3.	Somatostatin Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion.[1] Somatostatin has two active forms produced by the alternative cleavage of a single preproprotein: one consisting of 14 amino acids (shown in infobox to right), the other consisting of 28 amino acids.[2][3] Among the vertebrates, there exist six different somatostatin genes that have been named SS1, SS2, SS3, SS4, SS5 and SS6.[4] Zebrafish have all six.[4] The six different genes, along with the five different somatostatin receptors, allow somatostatin to possess a large range of functions.[5] Humans have only one somatostatin gene, SST.[6][7][8] # Nomenclature Synonyms of "somatostatin" include: - growth hormone–inhibiting hormone (GHIH) - growth hormone release–inhibiting hormone (GHRIH) - somatotropin release–inhibiting factor (SRIF) - somatotropin release–inhibiting hormone (SRIH) # Production ## Digestive system Somatostatin is secreted by delta cells at several locations in the digestive system, namely the pyloric antrum, the duodenum and the pancreatic islets.[9] Somatostatin released in the pyloric antrum travels via the portal venous system to the heart, then enters the systemic circulation to reach the locations where it will exert its inhibitory effects. In addition, somatostatin release from delta cells can act in a paracrine manner.[9] In the stomach, somatostatin acts directly on the acid-producing parietal cells via a G-protein coupled receptor (which inhibits adenylate cyclase, thus effectively antagonising the stimulatory effect of histamine) to reduce acid secretion.[9] Somatostatin can also indirectly decrease stomach acid production by preventing the release of other hormones, including gastrin, secretin and histamine which effectively slows down the digestive process. ## Brain Somatostatin is produced by neuroendocrine neurons of the ventromedial nucleus of the hypothalamus. These neurons project to the median eminence, where somatostatin is released from neurosecretory nerve endings into the hypothalamohypophysial system through neuron axons. Somatostatin is then carried to the anterior pituitary gland, where it inhibits the secretion of growth hormone from somatotrope cells. The somatostatin neurons in the periventricular nucleus mediate negative feedback effects of growth hormone on its own release; the somatostatin neurons respond to high circulating concentrations of growth hormone and somatomedins by increasing the release of somatostatin, so reducing the rate of secretion of growth hormone. Somatostatin is also produced by several other populations that project centrally, i.e., to other areas of the brain, and somatostatin receptors are expressed at many different sites in the brain. In particular, populations of somatostatin neurons occur in the arcuate nucleus,[citation needed] the hippocampus,[citation needed] and the brainstem nucleus of the solitary tract.[citation needed] # Actions Somatostatin is classified as an inhibitory hormone,[2] and is induced by low pH.[citation needed]. Its actions are spread to different parts of the body. Somatostatin release is inhibited by the Vagus nerve.[10] ## Anterior pituitary In the anterior pituitary gland, the effects of somatostatin are: - Inhibit the release of growth hormone (GH)[11] (thus opposing the effects of growth hormone–releasing hormone (GHRH)) - Inhibit the release of thyroid-stimulating hormone (TSH)[12] - Inhibit adenylyl cyclase in parietal cells - Inhibits the release of prolactin (PRL) ## Gastrointestinal system - Somatostatin is homologous with cortistatin (see somatostatin family) and suppresses the release of gastrointestinal hormones Gastrin Cholecystokinin (CCK) Secretin Motilin Vasoactive intestinal peptide (VIP) Gastric inhibitory polypeptide (GIP) Enteroglucagon - Gastrin - Cholecystokinin (CCK) - Secretin - Motilin - Vasoactive intestinal peptide (VIP) - Gastric inhibitory polypeptide (GIP) - Enteroglucagon - Decreases the rate of gastric emptying, and reduces smooth muscle contractions and blood flow within the intestine[11] - Suppresses the release of pancreatic hormones Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit insulin release.[13][14] Inhibits the release of glucagon[13] - Somatostatin release is triggered by the beta cell peptide urocortin3 (Ucn3) to inhibit insulin release.[13][14] - Inhibits the release of glucagon[13] - Suppresses the exocrine secretory action of the pancreas # Synthetic substitutes Octreotide (brand name Sandostatin, Novartis Pharmaceuticals) is an octapeptide that mimics natural somatostatin pharmacologically, though is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone, and has a much longer half-life (about 90 minutes, compared to 2–3 minutes for somatostatin). Since it is absorbed poorly from the gut, it is administered parenterally (subcutaneously, intramuscularly, or intravenously). It is indicated for symptomatic treatment of carcinoid syndrome and acromegaly. It is also finding increased use in polycystic diseases of the liver and kidney. Lanreotide (Somatuline, Ipsen Pharmaceuticals)is a medication used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome. It is a long-acting analog of somatostatin, like octreotide. It is available in several countries, including the United Kingdom, Australia, and Canada, and was approved for sale in the United States by the Food and Drug Administration on August 30, 2007. # Evolutionary history Six somatostatin genes have been discovered in vertebrates. The current proposed history as to how these six genes arose is based on the three whole-genome duplication events that took place in vertebrate evolution along with local duplications in teleost fish. An ancestral somatostatin gene was duplicated during the first whole-genome duplication event (1R) to create SS1 and SS2. These two genes were duplicated during the second whole-genome duplication event (2R) to create four new somatostatin genes:SS1, SS2, SS3, and one gene that was lost during the evolution of vertebrates. Tetrapods retained SS1 (also known as SS-14 and SS-28) and SS2 (also known as cortistatin) after the split in the Sarcopterygii and Actinopterygii lineage split. In teleost fish, SS1, SS2, and SS3 were duplicated during the third whole-genome duplication event (3R) to create SS1, SS2, SS4, SS5, and two genes that were lost during the evolution of teleost fish. SS1 and SS2 went through local duplications to give rise to SS6 and SS3.[4]	https://www.wikidoc.org/index.php/GHIH
6d867a92cc476934818cec63d0d325ab6d012d7d	wikidoc	Gadofosveset	Gadofosveset - Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. - The risk for NSF appears highest among patients with: - chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or - acute kidney injury. - Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. - For patients at highest risk for NSF, do not exceed the recommended ABLAVAR dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration. - ABLAVAR is indicated for use as a contrast agent in magnetic resonance angiography (MRA) to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected peripheral vascular disease. - Administer ABLAVAR as an intravenous bolus injection, manually or by power injection, at a dose of 0.12 mL/kg body weight (0.03 mmol/kg) over a period of time up to 30 seconds followed by a 25-30 mL normal saline flush. (See Table 1 for weight-adjusted dose volumes). - Inspect the ABLAVAR vial visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. - ABLAVAR is intended for single use only and should be used immediately upon opening. Discard any unused portion of the ABLAVAR vial. - Do not mix intravenous medications or parenteral nutrition solutions with ABLAVAR. Do not administer any other medications in the same intravenous line simultaneously with ABLAVAR. - Nephrogenic Systemic Fibrosis (NSF) - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 – 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ABLAVAR administration to Lantheus Medical Imaging, Inc. (1-978-667-9531)/(1-800-362-2668) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ABLAVAR dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - Hypersensitivity Reactions - ABLAVAR may cause anaphylactoid and/or anaphylactic reactions, including life-threatening or fatal reactions. In clinical trials, anaphylactoid and/or anaphylactic reactions occurred in two of 1676 subjects. If anaphylactic or anaphylactoid reactions occur, stop ABLAVAR Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after ABLAVAR administration. Have trained personnel and emergency resuscitative equipment available prior to and during ABLAVAR administration. If such a reaction occurs stop ABLAVAR and immediately begin appropriate therapy. - Acute Renal Failure - In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred with the use of other gadolinium agents. The risk of renal failure may increase with increasing dose of gadolinium contrast. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction. No reports of acute renal failure were observed in clinical trials of ABLAVAR. - QTc Prolongation and Risk for Arrhythmias - linical trials, a small increase (2.8 msec) in the average change from baseline in QTc was observed at 45 minutes following ABLAVAR administration; no increase was observed at 24 and 72 hours. A QTc change of 30 to 60 msec from baseline was observed in 39/702 (6%) patients at 45 min following ABLAVAR administration. At this time point, 3/702 (0.4%) patients experienced a QTc increase of > 60 msec. These QTc prolongations were not associated with arrhythmias or symptoms. In patients at high risk for arrhythmias due to QT prolongation (e.g., concomitant medications, underlying cardiac conditions) consider obtaining baseline electrocardiograms to help assess the risks for ABLAVAR administration. If ABLAVAR is administered to these patients, consider follow-up electrocardiograms and risk reduction measures (e.g., patient counseling or intensive electrocardiography monitoring) until most ABLAVAR has been eliminated from the blood. In patients with normal renal function, most ABLAVAR was eliminated from the blood by 72 hours following injection. - In all clinical trials evaluating ABLAVAR with MRA, a total of 1,676 (1379 patients and 297 healthy subjects) were exposed to various doses ABLAVAR. The mean age of the 1379 patients who received ABLAVAR was 63 years (range 18 to 91 years); 66% (903) were men and 34% (476) were women. In this population, there were 80% (1100) Caucasian, 8% (107) Black, 12% (159) Hispanic, 1% (7) Asian, and < 1% (6) patients of other racial or ethnic groups. Table 2 shows the most common adverse reactions (≥1%) experienced by subjects receiving ABLAVAR at a dose of 0.03 mmol/kg. - In a clinical trial of 10 patients receiving a stable dose of warfarin, a single dose of ABLAVAR (0.05 mmol/kg) did not alter the anticoagulant activity of warfarin as measured by the International Normalized Ratio (INR). - There are no adequate and well-controlled studies of ABLAVAR in pregnant women. In animal studies, pregnant rabbits treated with gadofosveset trisodium at doses 3 times the human dose (based on body surface area) experienced higher rates of fetal loss and resorptions. Because animal reproduction studies are not always predictive of human response, only use ABLAVAR during pregnancy if the diagnostic benefit justifies the potential risks to the fetus. - In reproductive studies, pregnant rats and rabbits received gadofosveset trisodium at various doses up to approximately 11 (rats) and 21.5 (rabbits) times the human dose (based on body surface area). The highest dose resulted in maternal toxicity in both species. In rabbits that received gadofosveset trisodium at 3 times the human dose (based on body surface area), increased post-implantation loss, resorptions, and dead fetuses were observed. Fetal anomalies were not observed in the rat or rabbit offspring. Because pregnant animals received repeated daily doses of ABLAVAR, their overall exposure was significantly higher than that achieved with a single dose administered to humans. There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadofosveset in women who are pregnant. - In animal studies, less than 1% of gadofosveset at doses up to 0.3 mmol/kg was secreted in the milk of lactating rats. - ABLAVAR Injection has been administered to humans up to a dose of 0.15 mmol/kg (5 times the clinical dose). No ABLAVAR overdoses were reported in clinical trials. In the event of an overdose, direct treatment toward the support of all vital functions and prompt institution of symptomatic therapy. Gadofosveset has been shown to be removed by hemodialysis using a high flux dialysis procedure. # Chronic Overdose There is limited information regarding Chronic Overdose of Gadofosveset in the drug label.	Gadofosveset - Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. - The risk for NSF appears highest among patients with: - chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or - acute kidney injury. - Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing. - For patients at highest risk for NSF, do not exceed the recommended ABLAVAR dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration. - ABLAVAR is indicated for use as a contrast agent in magnetic resonance angiography (MRA) to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected peripheral vascular disease. - Administer ABLAVAR as an intravenous bolus injection, manually or by power injection, at a dose of 0.12 mL/kg body weight (0.03 mmol/kg) over a period of time up to 30 seconds followed by a 25-30 mL normal saline flush. (See Table 1 for weight-adjusted dose volumes). - Inspect the ABLAVAR vial visually for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or particulate matter is present. - ABLAVAR is intended for single use only and should be used immediately upon opening. Discard any unused portion of the ABLAVAR vial. - Do not mix intravenous medications or parenteral nutrition solutions with ABLAVAR. Do not administer any other medications in the same intravenous line simultaneously with ABLAVAR. - Nephrogenic Systemic Fibrosis (NSF) - Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30-59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 – 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following ABLAVAR administration to Lantheus Medical Imaging, Inc. (1-978-667-9531)/(1-800-362-2668) or FDA (1-800-FDA-1088 or www.fda.gov/medwatch). - Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (e.g., age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. - Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and the degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administered to a patient. For patients at highest risk for NSF, do not exceed the recommended ABLAVAR dose and allow a sufficient period of time for elimination of the drug prior to re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent's elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. - Hypersensitivity Reactions - ABLAVAR may cause anaphylactoid and/or anaphylactic reactions, including life-threatening or fatal reactions. In clinical trials, anaphylactoid and/or anaphylactic reactions occurred in two of 1676 subjects. If anaphylactic or anaphylactoid reactions occur, stop ABLAVAR Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after ABLAVAR administration. Have trained personnel and emergency resuscitative equipment available prior to and during ABLAVAR administration. If such a reaction occurs stop ABLAVAR and immediately begin appropriate therapy. - Acute Renal Failure - In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred with the use of other gadolinium agents. The risk of renal failure may increase with increasing dose of gadolinium contrast. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. Consider follow-up renal function assessments for patients with a history of renal dysfunction. No reports of acute renal failure were observed in clinical trials of ABLAVAR. - QTc Prolongation and Risk for Arrhythmias - linical trials, a small increase (2.8 msec) in the average change from baseline in QTc was observed at 45 minutes following ABLAVAR administration; no increase was observed at 24 and 72 hours. A QTc change of 30 to 60 msec from baseline was observed in 39/702 (6%) patients at 45 min following ABLAVAR administration. At this time point, 3/702 (0.4%) patients experienced a QTc increase of > 60 msec. These QTc prolongations were not associated with arrhythmias or symptoms. In patients at high risk for arrhythmias due to QT prolongation (e.g., concomitant medications, underlying cardiac conditions) consider obtaining baseline electrocardiograms to help assess the risks for ABLAVAR administration. If ABLAVAR is administered to these patients, consider follow-up electrocardiograms and risk reduction measures (e.g., patient counseling or intensive electrocardiography monitoring) until most ABLAVAR has been eliminated from the blood. In patients with normal renal function, most ABLAVAR was eliminated from the blood by 72 hours following injection. - In all clinical trials evaluating ABLAVAR with MRA, a total of 1,676 (1379 patients and 297 healthy subjects) were exposed to various doses ABLAVAR. The mean age of the 1379 patients who received ABLAVAR was 63 years (range 18 to 91 years); 66% (903) were men and 34% (476) were women. In this population, there were 80% (1100) Caucasian, 8% (107) Black, 12% (159) Hispanic, 1% (7) Asian, and < 1% (6) patients of other racial or ethnic groups. Table 2 shows the most common adverse reactions (≥1%) experienced by subjects receiving ABLAVAR at a dose of 0.03 mmol/kg. - In a clinical trial of 10 patients receiving a stable dose of warfarin, a single dose of ABLAVAR (0.05 mmol/kg) did not alter the anticoagulant activity of warfarin as measured by the International Normalized Ratio (INR). - There are no adequate and well-controlled studies of ABLAVAR in pregnant women. In animal studies, pregnant rabbits treated with gadofosveset trisodium at doses 3 times the human dose (based on body surface area) experienced higher rates of fetal loss and resorptions. Because animal reproduction studies are not always predictive of human response, only use ABLAVAR during pregnancy if the diagnostic benefit justifies the potential risks to the fetus. - In reproductive studies, pregnant rats and rabbits received gadofosveset trisodium at various doses up to approximately 11 (rats) and 21.5 (rabbits) times the human dose (based on body surface area). The highest dose resulted in maternal toxicity in both species. In rabbits that received gadofosveset trisodium at 3 times the human dose (based on body surface area), increased post-implantation loss, resorptions, and dead fetuses were observed. Fetal anomalies were not observed in the rat or rabbit offspring. Because pregnant animals received repeated daily doses of ABLAVAR, their overall exposure was significantly higher than that achieved with a single dose administered to humans. There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadofosveset in women who are pregnant. - In animal studies, less than 1% of gadofosveset at doses up to 0.3 mmol/kg was secreted in the milk of lactating rats. - ABLAVAR Injection has been administered to humans up to a dose of 0.15 mmol/kg (5 times the clinical dose). No ABLAVAR overdoses were reported in clinical trials. In the event of an overdose, direct treatment toward the support of all vital functions and prompt institution of symptomatic therapy. Gadofosveset has been shown to be removed by hemodialysis using a high flux dialysis procedure. ## Chronic Overdose There is limited information regarding Chronic Overdose of Gadofosveset in the drug label.	https://www.wikidoc.org/index.php/Gadofosveset
b811f8c258ebb44121dac5e9e2374df811f7a0e4	wikidoc	Gale Pollock	Gale Pollock Major General Gale S. Pollock has served as the Deputy Surgeon General of the United States Army since October 2006, and also as chief of the Army Nurse Corps. She became acting Surgeon General of the United States Army on 20 March 2007 following the retirement of her predecessor, Kevin C. Kiley, due to fallout from the Walter Reed Army Medical Center neglect scandal. She is the first woman and the first non-physician to hold the position. She has 30 years of service in the Army and is a Certified Registered Nurse Anesthetist. Note that the Surgeon General of the United States Army is a different office than the Surgeon General of the United States. # Education Pollock received a Bachelor of Science degree in Nursing from the University of Maryland, Baltimore. She attended the U.S. Army Nurse Anesthesia Program and is a Certified Registered Nurse Anesthetist (CRNA). She received her Master of Business Administration from Boston University, a Master's in Healthcare Administration from Baylor University, a Master's in National Security and Strategy from the National Defense University, and an honorary Doctorate of Public Service from the University of Maryland. She is also a Fellow in The American College of Healthcare Executives (FACHE). Pollock's military education includes the Department of Defense CAPSTONE Program; the Senior Service College at the Industrial College of the Armed Forces; the Air War College; the Interagency Institute for Federal Health Care Executives; the Military Health System CAPSTONE program; the Principles of Advanced Nurse Administrators; and the NATO Staff Officer Course. # Military career Pollock's last position was Commanding General of Tripler Army Medical Center of the Pacific Regional Medical Command. She was also and Lead Agent of TRICARE Pacific in Honolulu, Hawaii. Her past military assignments include Special Assistant to the Surgeon General for Information Management and Health Policy; Commander, Martin Army Community Hospital, Fort Benning, Ga.; Commander, U.S. Army Medical Activity, Fort Drum, N.Y.; Staff Officer, Strategic Initiatives Command Group for the Army Surgeon General; Department of Defense Healthcare Advisor to the Congressional Commission on Service Members and Veterans Transition Assistance; Health Fitness Advisor at the National Defense University; Senior Policy Analyst in Health Affairs, DoD; and Chief, Anesthesia Nursing Service at Walter Reed Army Medical Center, Washington, D.C. # Awards Pollock's awards and decorations include the Distinguished Service Medal, Legion of Merit (with 2 oak leaf clusters), the Defense Meritorious Service Medal, the Meritorious Service Medal (with 4 oak leaf clusters), the Joint Service Commendation Medal, the Army Commendation Medal, and the Army Achievement Medal. She also earned the Expert Field Medical Badge, and the Parachutist Badge. She received the Army Staff Identification Badge for her work at the Pentagon and earned the German Armed Forces Military Efficiency Badge (Leistungsabzeichen) in gold. # Criticism According to ABC News and The Nation journalist Joshua Kors, Pollock covered up a scandal involving personality disorder discharges from the military. . Pollock released a memo claiming that her office had conducted a careful review of a series of personality disorder discharges from Fort Carson, Colorado. According to Kors the review was "a sham". According to Kors, Pollock's office did not contact a single soldier, and merely checked with officials who made the official diagnoses at Ft. Carson and asked if they got it right the first time. When the officials naturally said yes, Pollock's office closed the review. Pollock's actions have been criticized by the Iraq War Veterans Organization and Veterans for America. # Citations # Reference - Article adapted from official public domain military biography released by the United States Army.	Gale Pollock Template:Infobox Military Person Major General Gale S. Pollock has served as the Deputy Surgeon General of the United States Army since October 2006, and also as chief of the Army Nurse Corps. She became acting Surgeon General of the United States Army on 20 March 2007 following the retirement of her predecessor, Kevin C. Kiley, due to fallout from the Walter Reed Army Medical Center neglect scandal.[1] She is the first woman and the first non-physician to hold the position. She has 30 years of service in the Army and is a Certified Registered Nurse Anesthetist.[2] Note that the Surgeon General of the United States Army is a different office than the Surgeon General of the United States. # Education Pollock received a Bachelor of Science degree in Nursing from the University of Maryland, Baltimore. She attended the U.S. Army Nurse Anesthesia Program and is a Certified Registered Nurse Anesthetist (CRNA). She received her Master of Business Administration from Boston University, a Master's in Healthcare Administration from Baylor University, a Master's in National Security and Strategy from the National Defense University, and an honorary Doctorate of Public Service from the University of Maryland. She is also a Fellow in The American College of Healthcare Executives (FACHE). Pollock's military education includes the Department of Defense CAPSTONE Program; the Senior Service College at the Industrial College of the Armed Forces; the Air War College; the Interagency Institute for Federal Health Care Executives; the Military Health System CAPSTONE program; the Principles of Advanced Nurse Administrators; and the NATO Staff Officer Course. # Military career Pollock's last position was Commanding General of Tripler Army Medical Center of the Pacific Regional Medical Command. She was also and Lead Agent of TRICARE Pacific in Honolulu, Hawaii. Her past military assignments include Special Assistant to the Surgeon General for Information Management and Health Policy; Commander, Martin Army Community Hospital, Fort Benning, Ga.; Commander, U.S. Army Medical Activity, Fort Drum, N.Y.; Staff Officer, Strategic Initiatives Command Group for the Army Surgeon General; Department of Defense Healthcare Advisor to the Congressional Commission on Service Members and Veterans Transition Assistance; Health Fitness Advisor at the National Defense University; Senior Policy Analyst in Health Affairs, DoD; and Chief, Anesthesia Nursing Service at Walter Reed Army Medical Center, Washington, D.C. # Awards Pollock's awards and decorations include the Distinguished Service Medal, Legion of Merit (with 2 oak leaf clusters), the Defense Meritorious Service Medal, the Meritorious Service Medal (with 4 oak leaf clusters), the Joint Service Commendation Medal, the Army Commendation Medal, and the Army Achievement Medal. She also earned the Expert Field Medical Badge, and the Parachutist Badge. She received the Army Staff Identification Badge for her work at the Pentagon and earned the German Armed Forces Military Efficiency Badge (Leistungsabzeichen) in gold. # Criticism According to ABC News and The Nation journalist Joshua Kors, Pollock covered up a scandal involving personality disorder discharges from the military. [3]. Pollock released a memo claiming that her office had conducted a careful review of a series of personality disorder discharges from Fort Carson, Colorado. According to Kors the review was "a sham".[4] According to Kors, Pollock's office did not contact a single soldier, and merely checked with officials who made the official diagnoses at Ft. Carson and asked if they got it right the first time. [5]When the officials naturally said yes, Pollock's office closed the review. [6][7] Pollock's actions have been criticized by the Iraq War Veterans Organization[8][9] and Veterans for America[10]. # Citations - ↑ http://www.army.mil/-newsreleases/2007/03/12/2216-army-surgeon-general-submits-retirement-request/ - ↑ http://www.washingtonpost.com/wp-dyn/content/article/2007/03/12/AR2007031200544_2.html - ↑ http://www.pbs.org/now/news/veterans-benefits.html - ↑ http://www.pbs.org/now/news/veterans-benefits.html - ↑ http://www.pbs.org/now/news/veterans-benefits.html - ↑ http://www.pbs.org/now/news/veterans-benefits.html - ↑ http://www.tbrnews.org/Archives/a2663.htm - ↑ http://www.scoop.co.nz/stories/HL0704/S00027.htm - ↑ http://www.politicalaffairs.net/article/view/5069/1/46 - ↑ http://www.scoop.co.nz/stories/HL0704/S00027.htm # Reference - Article adapted from official public domain military biography released by the United States Army. # External links - Official Army Medicine Command (USAMEDCOM) / The Surgeon General site - Interview with Major General Gale S. Pollock when she was U.S. Army Deputy Surgeon General - PDF of Gale Pollock's statement before the House Armed Services Committee, 27 March 2007 - The Nation report from Joshua Kors criticizing Pollock's review of PDD's at Ft. Carson hosted by senate.gov Template:Start Template:Incumbent succession box Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gale_Pollock
7547f026b85648250910b8b835150a7d8d23dd8a	wikidoc	Neural crest	Neural crest # Overview The neural crest, a transient component of the ectoderm, is located in between the neural tube and the epidermis (or the free margins of the neural folds) of an embryo during neural tube formation. Neural crest cells quickly migrate during or shortly after neurulation, an embryological event marked by neural tube closure. It has been referred to as the fourth germ layer, due to its great importance. The neural crest can give rise to neurons and glia of the peripheral nervous system (PNS); some skeletal elements, tendons and smooth muscle; chondrocytes, osteocytes, melanocytes, chromaffin cells, and supporting cells and hormone producing cells in certain organs. # Clinical significance Diseases due to defects in the neural crest induction, formation or migration are referred to as neurocristopathies, and genes that cause some of these like piebaldism and Hirschprung's disease have been cloned in mice models. # History and Nomenclature In 1868 His described Neural Crest as "zwischenstrang"- a strip of cells lying between the dorsal ectoderm and the neural tube. From this time till almost 1950s most of the work on this structure was done on amphibian embryos, eg a 1950 comprehensive review in a monograph by the Swedish embryologist Sven Hörstadius. Newth (who also studied it in fishes) in 1951 described it as such by "a remarkable embryonic structure" and till another decade its origin still remained an enigma! In 1960s with the invent of cell labeling with tritiated thymidine by Chibon and Weston gave rise to a major breakthrough in this field through amphibian and avian studies. But this was a transient method of cell labeling and the field had to wait till the chick-quail transfer studies were devised for a definitive confirmation of those results. These extensive works in 1970s was reviewed extensively in "the Neural Crest" by Nicole Le Douarin first published in 1982 (and second ed in 1999). The nomenclature of these cells derives from amphibian and avian studies which demonstrate migration from the neural crest which forms on the rostral region of the neurulating ectoderm in the trilaminar disc. In humans, the cells actually migrate from the lateral margins of the neural tube however the use of 'crest cells' in this regard is retained. # Induction Cells fated to become neural crest tissue are induced by BMP, Wnt and FGF signaling to express the proteins Fox3D, RhoB and Slug, and to lose expression of E-cadherin. - RhoB is likely to signal cytoskeletal changes required for migration. - Slug is a repressor that leads to an activation of factors that dissociate tight junctions. # Categories There are several main categories of neural crest based upon function: ## Cranial neural crest - The cranial neural crest arises in the anterior and populates the face and the pharyngeal arches giving rise to bones, cartilage, nerves and connective tissue. - Into the pharyngeal arches and play an inductive in thymus development. - Into the pharyngeal arches and form the parafollicular cell or ultimobranchial bodies of the thyroid gland. - Into the pharyngeal arches and play an inductive role in parathyroid gland development. - Facial ectomesenchyme of the pharyngeal arches forming skeletal muscle, bone, and cartilage in the face. - Odontoblasts (dentin-producing cells) of the teeth. - Into the optic vesicle and the developing eye and contributes to many anterior eye elements such the cornea, sclera, and ciliary muscle. It also contributes to the attaching skeletal muscles of the eye. - Into the otic placode and participates in the inner ear development. - Sensory ganglia of the fifth, seventh, ninth and tenth cranial nerves. ## Vagal and sacral neural crest - The vagal and sacral neural crest arises in the neck and tail and populates the gut, forming the parasympathetic neurons that regulates peristalsis and control blood vessel dilation. - Walls of the viscera to become enteric ganglia. ## Trunk neural crest - The trunk neural crest lies between the vagal and sacral neural crest and gives rise to two groups of cells. One group migrates dorsolateral and populates the skin, forming pigment cells and the other migrates ventrolateral through the anterior sclerotome to become the epinephrine-producing cells of the adrenal gland and the neurons of the sympathetic nervous system. Some cells remain in the sclerotome to form the dorsal root ganglia - Proximal to the spinal cord and line up symmetrically to form the dorsal root ganglia. - Into the skin to form melanocytes and Merkel cells. - Chromaffin cells of the adrenal medulla. - Near the vertebral column and become sympathetic chain ganglia. ## Cardiac neural crest - The cardiac neural crest overlaps the vagal neural crest and migrates to populate the pharyngeal arches 3, 4 and 6 (producing structures in the head) and to the heart, forming connective tissue that separates the great vessels of the heart. - Into the pharyngeal arches and Truncus arteriosus (embryology), forming the aorticopulmonary septum and the smooth muscle of great arteries. - Anterior of the aorta to become the four pre-aortic ganglia (celiac ganglion, superior mesenteric ganglion, inferior mesenteric ganglion and aortical renal ganglia) # Migration Neural crest cells require extracellular matrix to migrate through interactions between integrins and fibronectin and laminin. Migration is directed by inhibitory and attractive signals from cells. Ephrin is an inhibitory ligand in posterior sclerotome that affects ventral pathway trunk neural crest cells and causes them to migrate through the anterior sclerotome instead. Thrombospondin promotes migration through the anterior sclerotome. Another signal, stem cell factor is involved in specifying the destination of migration. If expressed in the wrong locations, pigment cells migrate to that site and proliferate there. # Plasticity Neural crest cells show varying degrees of plasticity. Some trunk neural crest cells are pluripotent. Cranial neural crest cells can give rise to trunk neural crest cells if transplanted. However, heart neural crest cells are committed before migration. Individual neural crest cells can take on a new fate, however groups of neural crest cells cannot.	Neural crest Template:Infobox Embryology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The neural crest, a transient component of the ectoderm, is located in between the neural tube and the epidermis (or the free margins of the neural folds) of an embryo during neural tube formation. Neural crest cells quickly migrate during or shortly after neurulation, an embryological event marked by neural tube closure. It has been referred to as the fourth germ layer, due to its great importance. The neural crest can give rise to neurons and glia of the peripheral nervous system (PNS); some skeletal elements, tendons and smooth muscle; chondrocytes, osteocytes, melanocytes, chromaffin cells, and supporting cells and hormone producing cells in certain organs. # Clinical significance Diseases due to defects in the neural crest induction, formation or migration are referred to as neurocristopathies, and genes that cause some of these like piebaldism and Hirschprung's disease have been cloned in mice models. # History and Nomenclature In 1868 His described Neural Crest as "zwischenstrang"- a strip of cells lying between the dorsal ectoderm and the neural tube.[1] From this time till almost 1950s most of the work on this structure was done on amphibian embryos, eg a 1950 comprehensive review in a monograph by the Swedish embryologist Sven Hörstadius.[2] Newth (who also studied it in fishes)[3] in 1951 described it as such by "a remarkable embryonic structure" and till another decade its origin still remained an enigma! In 1960s with the invent of cell labeling with tritiated thymidine by Chibon[4] and Weston[5] gave rise to a major breakthrough in this field through amphibian and avian studies. But this was a transient method of cell labeling and the field had to wait till the chick-quail transfer studies were devised for a definitive confirmation of those results. These extensive works in 1970s was reviewed extensively in "the Neural Crest" by Nicole Le Douarin first published in 1982 (and second ed in 1999).[6] The nomenclature of these cells derives from amphibian and avian studies which demonstrate migration from the neural crest which forms on the rostral region of the neurulating ectoderm in the trilaminar disc. In humans, the cells actually migrate from the lateral margins of the neural tube however the use of 'crest cells' in this regard is retained. # Induction Cells fated to become neural crest tissue are induced by BMP, Wnt and FGF signaling to express the proteins Fox3D, RhoB and Slug, and to lose expression of E-cadherin. - RhoB is likely to signal cytoskeletal changes required for migration. [7] - Slug is a repressor[8] that leads to an activation of factors that dissociate tight junctions. # Categories There are several main categories of neural crest based upon function:[9] ## Cranial neural crest - The cranial neural crest arises in the anterior and populates the face and the pharyngeal arches giving rise to bones, cartilage, nerves and connective tissue. - Into the pharyngeal arches and play an inductive in thymus development. - Into the pharyngeal arches and form the parafollicular cell or ultimobranchial bodies of the thyroid gland. - Into the pharyngeal arches and play an inductive role in parathyroid gland development. - Facial ectomesenchyme of the pharyngeal arches forming skeletal muscle, bone, and cartilage in the face. - Odontoblasts (dentin-producing cells) of the teeth. - Into the optic vesicle and the developing eye and contributes to many anterior eye elements such the cornea, sclera, and ciliary muscle. It also contributes to the attaching skeletal muscles of the eye. - Into the otic placode and participates in the inner ear development. - Sensory ganglia of the fifth, seventh, ninth and tenth cranial nerves. ## Vagal and sacral neural crest - The vagal and sacral neural crest arises in the neck and tail and populates the gut, forming the parasympathetic neurons that regulates peristalsis and control blood vessel dilation. - Walls of the viscera to become enteric ganglia. ## Trunk neural crest - The trunk neural crest lies between the vagal and sacral neural crest and gives rise to two groups of cells. One group migrates dorsolateral and populates the skin, forming pigment cells and the other migrates ventrolateral through the anterior sclerotome to become the epinephrine-producing cells of the adrenal gland and the neurons of the sympathetic nervous system. Some cells remain in the sclerotome to form the dorsal root ganglia - Proximal to the spinal cord and line up symmetrically to form the dorsal root ganglia. - Into the skin to form melanocytes and Merkel cells. - Chromaffin cells of the adrenal medulla. - Near the vertebral column and become sympathetic chain ganglia. ## Cardiac neural crest - The cardiac neural crest overlaps the vagal neural crest and migrates to populate the pharyngeal arches 3, 4 and 6 (producing structures in the head) and to the heart, forming connective tissue that separates the great vessels of the heart. - Into the pharyngeal arches and Truncus arteriosus (embryology), forming the aorticopulmonary septum and the smooth muscle of great arteries. - Anterior of the aorta to become the four pre-aortic ganglia (celiac ganglion, superior mesenteric ganglion, inferior mesenteric ganglion and aortical renal ganglia) # Migration Neural crest cells require extracellular matrix to migrate through interactions between integrins and fibronectin and laminin. Migration is directed by inhibitory and attractive signals from cells. Ephrin is an inhibitory ligand in posterior sclerotome that affects ventral pathway trunk neural crest cells and causes them to migrate through the anterior sclerotome instead. Thrombospondin promotes migration through the anterior sclerotome. Another signal, stem cell factor is involved in specifying the destination of migration. If expressed in the wrong locations, pigment cells migrate to that site and proliferate there. # Plasticity Neural crest cells show varying degrees of plasticity. Some trunk neural crest cells are pluripotent. Cranial neural crest cells can give rise to trunk neural crest cells if transplanted. However, heart neural crest cells are committed before migration. Individual neural crest cells can take on a new fate, however groups of neural crest cells cannot.	https://www.wikidoc.org/index.php/Ganglion_ridge
099f9ea5423514dce9d1b691243577e7de56b93e	wikidoc	Respirometer	Respirometer A respirometer is a device used to measure the rate of respiration of a living organism by measuring its rate of exchange of oxygen and carbon dioxide. They allow investigation into how factors such as age or the effect of light affect the rate of respiration. A simple respirometer designed to measure oxygen uptake or CO2 release consists of a sealed container with the living specimen together with a substance to absorb the carbon dioxide given off during respiration, such as soda lime pellets or cotton wads soaked with potassium hydroxide. The oxygen uptake is detected by displacement of manometric fluid in a thin glass U-tube connected to the container. When the organism takes in oxygen it gives off an equal volume of carbon dioxide. As this is absorbed by the soda lime, air is sucked in from the U-tube to keep the pressure constant, displacing the liquid. The rate of change gives a direct and reasonably accurate reading for the organism's rate of respiration. As changes in temperature or pressure can also affect the displacement of the manometric fluid, a second respirometer identical to the first except with a dead specimen (or something with the same mass as the specimen in place of the organism) is sometimes set up. Subtracting the displacement of the second respirometer from the first allows for control of these factors.	Respirometer Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A respirometer is a device used to measure the rate of respiration of a living organism by measuring its rate of exchange of oxygen and carbon dioxide. They allow investigation into how factors such as age or the effect of light affect the rate of respiration. A simple respirometer designed to measure oxygen uptake or CO2 release consists of a sealed container with the living specimen together with a substance to absorb the carbon dioxide given off during respiration, such as soda lime pellets or cotton wads soaked with potassium hydroxide. The oxygen uptake is detected by displacement of manometric fluid in a thin glass U-tube connected to the container. When the organism takes in oxygen it gives off an equal volume of carbon dioxide. As this is absorbed by the soda lime, air is sucked in from the U-tube to keep the pressure constant, displacing the liquid. The rate of change gives a direct and reasonably accurate reading for the organism's rate of respiration. As changes in temperature or pressure can also affect the displacement of the manometric fluid, a second respirometer identical to the first except with a dead specimen (or something with the same mass as the specimen in place of the organism) is sometimes set up. Subtracting the displacement of the second respirometer from the first allows for control of these factors.	https://www.wikidoc.org/index.php/Ganong%27s_Respirometer
9b872ecad284ebe92c7f1605f612848ab3af899e	wikidoc	Gap junction	Gap junction # Overview A gap junction or nexus is a junction between certain animal cell-types that allows different molecules and ions, mostly small intracellular signaling molecules (intracellular mediators), to pass freely between cells. The junction connects the cytoplasm of cells. One gap junction is composed of two connexons (or hemichannels) which connect across the intercellular space. They are analogous to the plasmodesmata that join plant cells. # Structure In vertebrates, gap junction hemichannels are primarily homo- or hetero-hexamers of connexin proteins. Invertebrate gap junctions comprise proteins from the hypothetical innexin family. However, the recently characterized pannexin family, functionally similar but genetically distinct from connexins and expressed in both vertebrates and invertebrates, probably encompasses the innexins. At gap junctions, the intercellular spaces narrows from 25 nm to 3 nm and unit connexons in the membrane of each cell are lined up with one another. Gap junctions formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels but it is not yet known how. Generally, the genes coding for gap junctions are classified in one of three groups, based on sequence similarity: A, B and C (for example, GJA1, GJC1). However, genes do not code directly for the expression of gap junctions; genes can only produce the proteins which make up gap junctions (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3). # Levels of organization - DNA to RNA to Connexin protein. - One connexin protein has four transmembrane domains - 6 Connexins create one Connexon (hemichannel). When different connexins join together to form one connexon, it is called a heteromeric connexon - Two hemichannels, joined together across a cell membrane comprise a Gap Junction. - Several gap junctions (hundreds) assemble into a macromolecular complex called a plaque. # Properties - Allows for direct electrical communication between cells, although different connexin subunits can impart different single channel conductances, from about 30 pS to 500 pS. - Allows for chemical communication between cells, through the transmission of small second messengers, such as IP3 and Ca2+, although different connexin subunits can impart different selectivity for particular small molecules. - Generally allows molecules smaller than 1,000 Daltons to pass through, although different connexin subunits can impart different pore sizes and different charge selectivity. Large biomolecules, for example, nucleic acid and protein, are not allowed to be shared. # Areas of electrical coupling ## Heart Gap junctions are particularly important in the cardiac muscle: the signal to contract is passed efficiently through the gap junctions, allowing the heart muscle cells to contract in tandem. However, gap junctions are now known to be expressed in virtually all tissues of the body, with the exception of mobile cell types such as sperm or erythrocytes. Several human genetic disorders are now associated with mutations in gap junction genes. Many of those affect the skin, because this tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation. ## Neurons Few locations have been discovered where there is siginificant coupling between neurons in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the vestibular nucleus, the nucleus of trigeminal nerve, the inferior olivary nucleus, and the Ventral Tegmental Area. There has been some observation of weak neuron to glial cell coupling in the locus coeruleus, and in the cerebellum between Purkinje neurons and Bergmann glial cells. It now seems that astrocytes are strongly coupled by gap junctions. Experimental data show strong gap junction expression in astrocytes. Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease and multiple sclerosis. Connexin proteins expressed in neurons include: - mCX26 - mCX43 - mCX36 - mCX56.6 - mCX57 - mCX45 ### Retina Neurons within the retina show extensive coupling, both within populations of one cell type, and between different cell types.	Gap junction Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A gap junction or nexus is a junction between certain animal cell-types that allows different molecules and ions, mostly small intracellular signaling molecules (intracellular mediators), to pass freely between cells. The junction connects the cytoplasm of cells. One gap junction is composed of two connexons (or hemichannels) which connect across the intercellular space. They are analogous to the plasmodesmata that join plant cells[1]. # Structure In vertebrates, gap junction hemichannels are primarily homo- or hetero-hexamers of connexin proteins. Invertebrate gap junctions comprise proteins from the hypothetical innexin family. However, the recently characterized pannexin family, functionally similar but genetically distinct from connexins and expressed in both vertebrates and invertebrates, probably encompasses the innexins. At gap junctions, the intercellular spaces narrows from 25 nm to 3 nm and unit connexons in the membrane of each cell are lined up with one another. Gap junctions formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels but it is not yet known how. Generally, the genes coding for gap junctions are classified in one of three groups, based on sequence similarity: A, B and C (for example, GJA1, GJC1). However, genes do not code directly for the expression of gap junctions; genes can only produce the proteins which make up gap junctions (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3). # Levels of organization - DNA to RNA to Connexin protein. - One connexin protein has four transmembrane domains - 6 Connexins create one Connexon (hemichannel). When different connexins join together to form one connexon, it is called a heteromeric connexon - Two hemichannels, joined together across a cell membrane comprise a Gap Junction. - Several gap junctions (hundreds) assemble into a macromolecular complex called a plaque. # Properties - Allows for direct electrical communication between cells, although different connexin subunits can impart different single channel conductances, from about 30 pS to 500 pS. - Allows for chemical communication between cells, through the transmission of small second messengers, such as IP3 and Ca2+[1], although different connexin subunits can impart different selectivity for particular small molecules. - Generally allows molecules smaller than 1,000 Daltons to pass through, although different connexin subunits can impart different pore sizes and different charge selectivity. Large biomolecules, for example, nucleic acid and protein, are not allowed to be shared. # Areas of electrical coupling ## Heart Gap junctions are particularly important in the cardiac muscle: the signal to contract is passed efficiently through the gap junctions, allowing the heart muscle cells to contract in tandem. However, gap junctions are now known to be expressed in virtually all tissues of the body, with the exception of mobile cell types such as sperm or erythrocytes. Several human genetic disorders are now associated with mutations in gap junction genes. Many of those affect the skin, because this tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation. ## Neurons Few locations have been discovered where there is siginificant coupling between neurons in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the vestibular nucleus, the nucleus of trigeminal nerve, the inferior olivary nucleus, and the Ventral Tegmental Area. There has been some observation of weak neuron to glial cell coupling in the locus coeruleus, and in the cerebellum between Purkinje neurons and Bergmann glial cells. It now seems that astrocytes are strongly coupled by gap junctions. Experimental data show strong gap junction expression in astrocytes. Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease and multiple sclerosis. Connexin proteins expressed in neurons include: - mCX26 - mCX43 - mCX36 - mCX56.6 - mCX57 - mCX45 ### Retina Neurons within the retina show extensive coupling, both within populations of one cell type, and between different cell types.	https://www.wikidoc.org/index.php/Gap_junction
b6036f8321586538ae08be4c351c80d21fc2c4e3	wikidoc	Gas constant	Gas constant # Overview The gas constant (also known as the molar, universal, or ideal gas constant, usually denoted by symbol R) is a physical constant which is featured in a large number of fundamental equations in the physical sciences, such as the ideal gas law and the Nernst equation. It is equivalent to the Boltzmann constant, but expressed in units of energy (i.e. the pressure-volume product) per kelvin per mole (rather than energy per kelvin per particle). Its value is: The two digits in parentheses are the uncertainty (standard deviation) in the last two digits of the value. The gas constant occurs in the simplest equation of state, the ideal gas law, as follows: where: The gas constant has the same units as specific entropy. ## Relationship with the Boltzmann constant The Boltzmann constant kB (often abbreviated k) may be used in place of the gas constant by working in pure particle count, N, rather than number of moles, n, since where N_A is Avogadro's number. For example, the ideal gas law in terms of Boltzmann's constant is PV=Nk_BT\,\!. ## Specific gas constant The specific gas constant of a gas or a mixture of gases (\bar{R}) is given by the universal gas constant, divided by the molar mass (M) of the gas/mixture. It is common to represent the specific gas constant by the symbol R. In such cases the context and/or units of R should make it clear as to which gas constant is being referred to. For example, the equation for the speed of sound is usually written in terms of the specific gas constant. The specific gas constant of dry air is # US Standard Atmosphere The US Standard Atmosphere, 1976 (USSA1976) defines the Universal Gas Constant as: The USSA1976 does recognize, however, that this value is not consistent with the cited values for the Avogadro constant and the Boltzmann constant. This disparity is not a significant departure from accuracy, and USSA1976 uses this value of R for all the calculations of the standard atmosphere. When using the ISO value of R, the calculated pressure increases by only 0.62 pascals at 11,000 meters (the equivalent of a difference of only 0.174 meters – or 6.8 inches) and an increase of 0.292 pascals at 20,000 meters (the equivalent of a difference of only 0.338 meters – or 13.2 inches).	Gas constant # Overview The gas constant (also known as the molar, universal, or ideal gas constant, usually denoted by symbol R) is a physical constant which is featured in a large number of fundamental equations in the physical sciences, such as the ideal gas law and the Nernst equation. It is equivalent to the Boltzmann constant, but expressed in units of energy (i.e. the pressure-volume product) per kelvin per mole (rather than energy per kelvin per particle). Its value is: The two digits in parentheses are the uncertainty (standard deviation) in the last two digits of the value. The gas constant occurs in the simplest equation of state, the ideal gas law, as follows: where: The gas constant has the same units as specific entropy. ## Relationship with the Boltzmann constant The Boltzmann constant kB (often abbreviated k) may be used in place of the gas constant by working in pure particle count, N, rather than number of moles, n, since where <math>N_A</math> is Avogadro's number. For example, the ideal gas law in terms of Boltzmann's constant is <math>PV=Nk_BT\,\!</math>. ## Specific gas constant The specific gas constant of a gas or a mixture of gases (<math>\bar{R}</math>) is given by the universal gas constant, divided by the molar mass (<math>M</math>) of the gas/mixture. It is common to represent the specific gas constant by the symbol <math>R</math>. In such cases the context and/or units of <math>R</math> should make it clear as to which gas constant is being referred to. For example, the equation for the speed of sound is usually written in terms of the specific gas constant. The specific gas constant of dry air is # US Standard Atmosphere The US Standard Atmosphere, 1976 (USSA1976) defines the Universal Gas Constant as:[1][2] The USSA1976 does recognize, however, that this value is not consistent with the cited values for the Avogadro constant and the Boltzmann constant.[2] This disparity is not a significant departure from accuracy, and USSA1976 uses this value of R for all the calculations of the standard atmosphere. When using the ISO value of R, the calculated pressure increases by only 0.62 pascals at 11,000 meters (the equivalent of a difference of only 0.174 meters – or 6.8 inches) and an increase of 0.292 pascals at 20,000 meters (the equivalent of a difference of only 0.338 meters – or 13.2 inches).	https://www.wikidoc.org/index.php/Gas_constant
02c072112b3b59030ec196543de2922e729e1ccc	wikidoc	Gastric acid	Gastric acid # Overview Gastric acid is, together with several enzymes and intrinsic factor, one of the main secretions of the stomach. Chemically it is an acid solution consisting mainly of hydrochloric acid (HCl), and small quantities of potassium chloride (KCl) and sodium chloride (NaCl). # Physiology Gastric acid is produced by parietal cells (also called oxyntic cells) in the stomach. Its secretion is a complex and relatively energetically expensive process. Parietal cells contain an extensive secretory network (called canaliculi) from which the gastric acid is secreted into the lumen of the stomach. These cells are part of epithelial fundic glands in the gastric mucosa. The pH of gastric acid is 2 to 3 in the human stomach lumen, the acidity being maintained by the proton pump H+/K+ ATPase. The parietal cell releases bicarbonate into the blood stream in the process, which causes the temporary rise of pH in the blood, known as alkaline tide. The resulting highly acidic environment in the stomach lumen causes proteins from food to lose their characteristic folded structure (or denature). This exposes the protein's peptide bonds.The chief cells of the stomach secrete enzymes for protein breakdown (inactive pepsinogen and renin). The gastric acid activates pepsinogen into pepsin - this enzyme then helps digestion by breaking the bonds linking amino acids, a process known as proteolysis. In addition, many microorganisms have their growth inhibited by such an acidic environment which is helpful to prevent infection. ### Secretion The gastric acid secretion happens in several steps. Chloride and hydrogen ions are secreted separately from the cytoplasm of parietal cells and get combined into HCl only in their canaliculi. Gastric acid is then secreted into the lumen of the oxyntic gland and gradually reaches the main stomach lumen. The highest concentration that it reaches in the stomach is 160 mM in the canaliculi. This is about 3 million times that of arterial blood, but almost exactly isotonic with other bodily fluids. The lowest pH of the secreted acid is about 0.8, but the acid gets diluted in the stomach lumen to the pH between 2 and 3. At first, negative chloride ions and sodium ions get secreted actively from the cytoplasm of the parietal cell into the lumen of the canaliculus. This creates a negative potential of -40 mV (millivolts)to -70 mV across the membrane that enables the diffusion of potassium ions and a small number of sodium ions from the cytoplasm into the canaliculus. Another step is the production of hydrogen ions in the cytoplasm of parietal cells. The enzyme carbonic anhydrase catalyses the reaction between carbon dioxide and water, in which carbonic acid is produced. This acid immediately dissociates into hydrogen ions and hydrogen carbonate ions. The hydrogen ions leave the cell by the aid of H+/K+ ATPase antiporter. At the same time sodium ions are actively reabsorbed. This means the largest amount of secreted K+ and Na+ ions return into the cytoplasm. In the canaliculus, secreted hydrogen and chloride ions combine into HCl and are then secreted into the lumen of the oxyntic gland. There are three phases in the secretion of gastric acid: 1. The cephalic phase: 30% of the total gastric acid to be produced is stimulated by anticipation of eating and the smell or taste of food 2. The gastric phase: 60% of the acid secreted is stimulated by the distention of the stomach with food. Plus, digestion produces proteins, which causes even more gastrin production 3. The intestinal phase: the remaining 10% of acid is secreted when chyme enters the small intestine, and is stimulated by small intestine distention. ## Regulation of secretion Gastric acid production is regulated by both the autonomic nervous system and several hormones. The parasympathetic nervous system, via the vagus nerve, and the hormone gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal cells and indirectly, through the stimulation of the secretion of the hormone histamine from enterochromaffine-like cells (ELC). Vasoactive intestinal peptide, cholecystokinin, and secretin all inhibit production. The production of gastric acid in the stomach is tightly regulated by positive regulators and negative feedback mechanisms. Four types of cells are involved in this process: parietal cells, G cells, D cells and enterochromaffine-like cells. Besides this, the endings of the vagus nerve (X) and the intramural nervous plecus in the digestive tract influence the secretion significantly. Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine and gastrin-releasing peptide. Their action is both direct on parietal cells and mediated through the secretion of gastrin from G cells and histamine from enterochromaffine-like cells. Gastrin acts on parietal cells directly and indirectly too, by stimulating the release of histamine. The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach. Its release is stimulated by gastrin and acetylcholine and inhibited by somatostatin. ### Neutralization In the duodenum, gastric acid is neutralized by sodium bicarbonate. This also blocks gastric enzymes that have their optima in the acid range of pH. The secretion of sodium bicarbonate from the pancreas is stimulated by secretin. This polypeptide hormone gets activated and secreted from so-called S cells in the mucosa of the duodenum and jejunum when the pH in duodenum falls below 4.5 to 5.0. The neutralization is described by the equation: The carbonic acid instantly dissociates into carbon dioxide and water, then gets eliminated through urine. ### Safety mechanisms There are several safety mechanisms that prevent the damage of gastric epithelium. Nonetheless, when due to different reasons these fail (e.g. because of excess acid production), this can lead to heartburn or peptic ulcers. # Role in disease In hypochlorhydria and achlorhydria, there is low or no gastric acid in the stomach, potentially leading to problems as the disinfectant properties of the gastric lumen are decreased. In such conditions, there is greater risk of infections of the digestive tract (such as infection with Vibrio or Helicobacter bacteria). In Zollinger-Ellison syndrome and hypercalcemia, there are increased gastrin levels, leading to excess gastric acid production, which can cause gastric ulcers. In diseases featuring excess vomiting, patients develop hypochloremic metabolic alkalosis (decreased blood acidity by H+ and chlorine depletion). # Pharmacology The proton pump enzyme is the target of proton pump inhibitors, used to increase gastric pH in diseases which feature excess acid. H2 antagonists indirectly decrease gastric acid production. Antacids neutralize existing acid.	Gastric acid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gastric acid is, together with several enzymes and intrinsic factor, one of the main secretions of the stomach. Chemically it is an acid solution consisting mainly of hydrochloric acid (HCl), and small quantities of potassium chloride (KCl) and sodium chloride (NaCl). # Physiology Gastric acid is produced by parietal cells (also called oxyntic cells) in the stomach. Its secretion is a complex and relatively energetically expensive process. Parietal cells contain an extensive secretory network (called canaliculi) from which the gastric acid is secreted into the lumen of the stomach. These cells are part of epithelial fundic glands in the gastric mucosa. The pH of gastric acid is 2 to 3 in the human stomach lumen, the acidity being maintained by the proton pump H+/K+ ATPase. The parietal cell releases bicarbonate into the blood stream in the process, which causes the temporary rise of pH in the blood, known as alkaline tide. The resulting highly acidic environment in the stomach lumen causes proteins from food to lose their characteristic folded structure (or denature). This exposes the protein's peptide bonds.The chief cells of the stomach secrete enzymes for protein breakdown (inactive pepsinogen and renin). The gastric acid activates pepsinogen into pepsin - this enzyme then helps digestion by breaking the bonds linking amino acids, a process known as proteolysis. In addition, many microorganisms have their growth inhibited by such an acidic environment which is helpful to prevent infection. ### Secretion The gastric acid secretion happens in several steps. Chloride and hydrogen ions are secreted separately from the cytoplasm of parietal cells and get combined into HCl only in their canaliculi. Gastric acid is then secreted into the lumen of the oxyntic gland and gradually reaches the main stomach lumen. The highest concentration that it reaches in the stomach is 160 mM in the canaliculi. This is about 3 million times that of arterial blood, but almost exactly isotonic with other bodily fluids. The lowest pH of the secreted acid is about 0.8, but the acid gets diluted in the stomach lumen to the pH between 2 and 3. At first, negative chloride ions and sodium ions get secreted actively from the cytoplasm of the parietal cell into the lumen of the canaliculus. This creates a negative potential of -40 mV (millivolts)to -70 mV across the membrane that enables the diffusion of potassium ions and a small number of sodium ions from the cytoplasm into the canaliculus. Another step is the production of hydrogen ions in the cytoplasm of parietal cells. The enzyme carbonic anhydrase catalyses the reaction between carbon dioxide and water, in which carbonic acid is produced. This acid immediately dissociates into hydrogen ions and hydrogen carbonate ions. The hydrogen ions leave the cell by the aid of H+/K+ ATPase antiporter. At the same time sodium ions are actively reabsorbed. This means the largest amount of secreted K+ and Na+ ions return into the cytoplasm. In the canaliculus, secreted hydrogen and chloride ions combine into HCl and are then secreted into the lumen of the oxyntic gland. There are three phases in the secretion of gastric acid: 1. The cephalic phase: 30% of the total gastric acid to be produced is stimulated by anticipation of eating and the smell or taste of food 2. The gastric phase: 60% of the acid secreted is stimulated by the distention of the stomach with food. Plus, digestion produces proteins, which causes even more gastrin production 3. The intestinal phase: the remaining 10% of acid is secreted when chyme enters the small intestine, and is stimulated by small intestine distention. ## Regulation of secretion Gastric acid production is regulated by both the autonomic nervous system and several hormones. The parasympathetic nervous system, via the vagus nerve, and the hormone gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal cells and indirectly, through the stimulation of the secretion of the hormone histamine from enterochromaffine-like cells (ELC). Vasoactive intestinal peptide, cholecystokinin, and secretin all inhibit production. The production of gastric acid in the stomach is tightly regulated by positive regulators and negative feedback mechanisms. Four types of cells are involved in this process: parietal cells, G cells, D cells and enterochromaffine-like cells. Besides this, the endings of the vagus nerve (X) and the intramural nervous plecus in the digestive tract influence the secretion significantly. Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine and gastrin-releasing peptide. Their action is both direct on parietal cells and mediated through the secretion of gastrin from G cells and histamine from enterochromaffine-like cells. Gastrin acts on parietal cells directly and indirectly too, by stimulating the release of histamine. The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach. Its release is stimulated by gastrin and acetylcholine and inhibited by somatostatin. ### Neutralization In the duodenum, gastric acid is neutralized by sodium bicarbonate. This also blocks gastric enzymes that have their optima in the acid range of pH. The secretion of sodium bicarbonate from the pancreas is stimulated by secretin. This polypeptide hormone gets activated and secreted from so-called S cells in the mucosa of the duodenum and jejunum when the pH in duodenum falls below 4.5 to 5.0. The neutralization is described by the equation: The carbonic acid instantly dissociates into carbon dioxide and water, then gets eliminated through urine. ### Safety mechanisms There are several safety mechanisms that prevent the damage of gastric epithelium. Nonetheless, when due to different reasons these fail (e.g. because of excess acid production), this can lead to heartburn or peptic ulcers. # Role in disease In hypochlorhydria and achlorhydria, there is low or no gastric acid in the stomach, potentially leading to problems as the disinfectant properties of the gastric lumen are decreased. In such conditions, there is greater risk of infections of the digestive tract (such as infection with Vibrio or Helicobacter bacteria). In Zollinger-Ellison syndrome and hypercalcemia, there are increased gastrin levels, leading to excess gastric acid production, which can cause gastric ulcers. In diseases featuring excess vomiting, patients develop hypochloremic metabolic alkalosis (decreased blood acidity by H+ and chlorine depletion). # Pharmacology The proton pump enzyme is the target of proton pump inhibitors, used to increase gastric pH in diseases which feature excess acid. H2 antagonists indirectly decrease gastric acid production. Antacids neutralize existing acid. # External links - Template:McGrawHillAnimation	https://www.wikidoc.org/index.php/Gastric_acid
b3aacfce06a5f4a286586b622e1dce38675b5962	wikidoc	Gatifloxacin	Gatifloxacin # 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 Gatifloxacin is an anti-infective agent that is FDA approved for the treatment of bacterial conjunctivitis caused by susceptible strains of haemophilus influenzae, staphylococcus aureus, staphylococcus epidermidis, streptococcus mitis group, streptococcus oralis, and Streptococcus pneumoniae. Common adverse reactions include worsening of conjunctivitis, eye irritation, dysgeusia, and eye pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Gatifloxacin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Gatifloxacin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Gatifloxacin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Gatifloxacin in pediatric patients. # Contraindications - None # Warnings Topical Ophthalmic Use Only - ZYMAXID® solution should not be introduced directly into the anterior chamber of the eye. Growth of Resistant Organisms with Prolonged Use - As with other anti-infectives, prolonged use of ZYMAXID® (gatifloxacin ophthalmic solution) 0.5% may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and where appropriate, fluorescein staining. Avoidance of Contact Lens Wear - Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis or during the course of therapy with ZYMAXID®. # Adverse Reactions ## Clinical Trials Experience Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - In clinical studies with ZYMAXID®, the most frequently reported adverse reactions occurring in ≥ 1% of patients in the gatifloxacin study population (N=717) were: worsening of the conjunctivitis, eye irritation, dysgeusia, and eye pain. - Additional adverse events reported with other formulations of gatifloxacin ophthalmic solution include chemosis, conjunctival hemorrhage, dry eye, eye discharge, eyelid edema, headache, increased lacrimation, keratitis, papillary conjunctivitis, and reduced visual acuity. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Gatifloxacin in the drug label. # Drug Interactions - Specific drug interaction studies have not been conducted with ZYMAXID® ophthalmic solution. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Teratogenic Effects: There were no teratogenic effects observed in rats or rabbits following oral gatifloxacin doses up to 50 mg/kg/day (approximately 1000-fold higher than the maximum recommended ophthalmic dose). However, skeletal/craniofacial malformations or delayed ossification, atrial enlargement, and reduced fetal weight were observed in fetuses from rats given ≥150 mg/kg/day (approximately 3000-fold higher than the maximum recommended ophthalmic dose). In a perinatal/postnatal study, increased late post-implantation loss and neonatal/perinatal mortalities were observed at 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose). - Because there are no adequate and well-controlled studies in pregnant women, ZYMAXID® solution 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 Gatifloxacin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Gatifloxacin during labor and delivery. ### Nursing Mothers - Gatifloxacin is excreted in the breast milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZYMAXID® is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of ZYMAXID® in infants below one year of age have not been established. ZYMAXID® has been demonstrated in clinical trials to be safe and effective for the treatment of bacterial conjunctivitis in pediatric patients one year or older. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender - There is no FDA guidance on the use of Gatifloxacin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Gatifloxacin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Gatifloxacin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Gatifloxacin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Gatifloxacin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Gatifloxacin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7. ### DOSAGE FORMS AND STRENGTHS - Five (5) mL bottle containing 2.5 mL of a 0.5% sterile topical ophthalmic solution. ### Monitoring - There is limited information regarding Monitoring of Gatifloxacin in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Gatifloxacin in the drug label. # Overdosage There is limited information regarding Gatifloxacin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Gatifloxacin is a fluoroquinolone antibacterial. ## Structure - ZYMAXID® sterile ophthalmic solution is an 8-methoxyfluoroquinolone anti-infective for the treatment of bacterial conjunctivitis. Its chemical name is (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, sesquihydrate. Its molecular formula is C19H22FN3O4 · 1½H2O, and its molecular weight is 402.42. Its chemical structure is: - ZYMAXID® is a clear, pale yellow, sterile, preserved aqueous solution with an osmolality of 260-330 mOsm/kg and a pH of 5.1-5.7. - ZYMAXID® contains Active: gatifloxacin 0.5% (5 mg/mL); Inactives: benzalkonium chloride 0.005%; edetate disodium; purified water; and sodium chloride. May contain hydrochloric acid and/or sodium hydroxide to adjust pH. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Gatifloxacin in the drug label. ## Pharmacokinetics - Gatifloxacin ophthalmic solution 0.3% or 0.5% was administered to one eye of 6 healthy male subjects each in an escalated dosing regimen starting with a single 2 drop dose, then 2 drops 4 times daily for 7 days, and finally 2 drops 8 times daily for 3 days. At all time points, serum gatifloxacin levels were below the lower limit of quantification (5 ng/mL) in all subjects. ### Microbiology - Gatifloxacin is an 8-methoxyfluoroquinolone with a 3-methylpiperazinyl substituent at C7. The antibacterial action of gatifloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. The mechanism of action of fluoroquinolones including gatifloxacin is different from that of aminoglycoside, macrolide, and tetracycline antibiotics. Therefore, gatifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to gatifloxacin. There is no cross-resistance between gatifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic gatifloxacin and some other fluoroquinolones. - Resistance to gatifloxacin in vitro develops via multiple-step mutations. Resistance to gatifloxacin in vitro occurs at a general frequency of 1 x 10-7 to 10-10. - Gatifloxacin has been shown to be active against most isolates of the following organisms both microbiologically and clinically, in conjunctival infections as described in the INDICATIONS AND USAGE, Section 1. - Aerobic Gram-Positive Bacteria: - Staphylococcus aureus - Staphylococcus epidermidis - Streptococcus mitis group* - Streptococcus oralis* - Streptococcus pneumoniae - Aerobic Gram-Negative Bacteria: - Haemophilus influenzae - Efficacy for this organism was studied in fewer than 10 infections. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - There was no increase in neoplasms among B6C3F1 mice given gatifloxacin in the diet for 18 months at doses averaging 81 mg/kg/day in males and 90 mg/kg/day in females. These doses are approximately 1600-fold and 1800-fold higher, respectively, than the maximum recommended ophthalmic dose of 0.05 mg/kg/day in a 50 kg human. - There was no increase in neoplasms among Fischer 344 rats given gatifloxacin in the diet for 2 years at doses averaging 47 mg/kg/day in males and 139 mg/kg/day in females (900- and 2800-fold higher, respectively, than the maximum recommended ophthalmic dose). A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in males treated with a high dose of approximately 2000-fold higher than the maximum recommended ophthalmic dose. Fischer 344 rats have a high spontaneous background rate of LGL leukemia and the incidence in high-dose males only slightly exceeded the historical control range established for this strain. - In genetic toxicity tests, gatifloxacin was positive in 1 of 5 strains used in bacterial reverse mutation assays: Salmonella strain TA102. Gatifloxacin was positive in in vitro mammalian cell mutation and chromosome aberration assays. Gatifloxacin was positive in in vitro unscheduled DNA synthesis in rat hepatocytes but not human leukocytes. Gatifloxacin was negative in in vivo micronucleus tests in mice, cytogenetics test in rats, and DNA repair test in rats. The findings may be due to the inhibitory effects of high concentrations on eukaryotic type II DNA topoisomerase. - There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose for ZYMAXID®). # Clinical Studies - In two randomized, double-masked, multicenter clinical trials, where patients 1-89 years of age were dosed for 5 days, ZYMAXID® solution was clinically superior to its vehicle on day 6 in patients with conjunctivitis and positive conjunctival cultures. Clinical outcomes for the trials demonstrated clinical success (resolution of conjunctival hyperaemia and conjunctival discharge) of 58% (193/333) for the gatifloxacin-treated groups versus 45% (148/325) for the vehicle-treated groups. Microbiological outcomes for the same clinical trials demonstrated a statistically superior eradication rate for causative pathogens of 90% (301/333) for gatifloxacin versus 70% (228/325) for vehicle. Please note that microbiological eradication does not always correlate with clinical outcome in anti-infective trials. # How Supplied - ZYMAXID® (gatifloxacin ophthalmic solution) 0.5% is supplied sterile in a white, low density polyethylene (LDPE) bottle with a controlled dropper tip, and a tan, high impact polystyrene (HIPS) cap in the following size: - 2.5 mL in 5 mL bottle: NDC 0023-3615-25 ## Storage - Store at 15°-25°C (59°-77°F). Protect from freezing. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Avoiding Contamination of the Product - Patients should be instructed to avoid contaminating the applicator tip with material from the eye, fingers, or other source. Avoidance of Contact Lens Wear - Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis. # Precautions with Alcohol - Alcohol-Gatifloxacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Tequin, Tequin Teq-Paqs, Zymar, Zymaxid. # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Gatifloxacin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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. # Overview Gatifloxacin is an anti-infective agent that is FDA approved for the treatment of bacterial conjunctivitis caused by susceptible strains of haemophilus influenzae, staphylococcus aureus, staphylococcus epidermidis, streptococcus mitis group, streptococcus oralis, and Streptococcus pneumoniae. Common adverse reactions include worsening of conjunctivitis, eye irritation, dysgeusia, and eye pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Gatifloxacin in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Gatifloxacin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Gatifloxacin in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Gatifloxacin in pediatric patients. # Contraindications - None # Warnings Topical Ophthalmic Use Only - ZYMAXID® solution should not be introduced directly into the anterior chamber of the eye. Growth of Resistant Organisms with Prolonged Use - As with other anti-infectives, prolonged use of ZYMAXID® (gatifloxacin ophthalmic solution) 0.5% may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit lamp biomicroscopy and where appropriate, fluorescein staining. Avoidance of Contact Lens Wear - Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis or during the course of therapy with ZYMAXID®. # Adverse Reactions ## Clinical Trials Experience Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - In clinical studies with ZYMAXID®, the most frequently reported adverse reactions occurring in ≥ 1% of patients in the gatifloxacin study population (N=717) were: worsening of the conjunctivitis, eye irritation, dysgeusia, and eye pain. - Additional adverse events reported with other formulations of gatifloxacin ophthalmic solution include chemosis, conjunctival hemorrhage, dry eye, eye discharge, eyelid edema, headache, increased lacrimation, keratitis, papillary conjunctivitis, and reduced visual acuity. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Gatifloxacin in the drug label. # Drug Interactions - Specific drug interaction studies have not been conducted with ZYMAXID® ophthalmic solution. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Teratogenic Effects: There were no teratogenic effects observed in rats or rabbits following oral gatifloxacin doses up to 50 mg/kg/day (approximately 1000-fold higher than the maximum recommended ophthalmic dose). However, skeletal/craniofacial malformations or delayed ossification, atrial enlargement, and reduced fetal weight were observed in fetuses from rats given ≥150 mg/kg/day (approximately 3000-fold higher than the maximum recommended ophthalmic dose). In a perinatal/postnatal study, increased late post-implantation loss and neonatal/perinatal mortalities were observed at 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose). - Because there are no adequate and well-controlled studies in pregnant women, ZYMAXID® solution 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 Gatifloxacin in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Gatifloxacin during labor and delivery. ### Nursing Mothers - Gatifloxacin is excreted in the breast milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZYMAXID® is administered to a nursing woman. ### Pediatric Use - The safety and effectiveness of ZYMAXID® in infants below one year of age have not been established. ZYMAXID® has been demonstrated in clinical trials to be safe and effective for the treatment of bacterial conjunctivitis in pediatric patients one year or older. ### Geriatic Use - No overall differences in safety or effectiveness have been observed between elderly and younger patients. ### Gender - There is no FDA guidance on the use of Gatifloxacin with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Gatifloxacin with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Gatifloxacin in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Gatifloxacin in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Gatifloxacin in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Gatifloxacin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Patients 1 year of age or older: Instill one drop every two hours in the affected eye(s) while awake, up to 8 times on Day 1. Instill one drop two to four times daily in the affected eye(s) while awake on Days 2 through 7. ### DOSAGE FORMS AND STRENGTHS - Five (5) mL bottle containing 2.5 mL of a 0.5% sterile topical ophthalmic solution. ### Monitoring - There is limited information regarding Monitoring of Gatifloxacin in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Gatifloxacin in the drug label. # Overdosage There is limited information regarding Gatifloxacin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Gatifloxacin is a fluoroquinolone antibacterial. ## Structure - ZYMAXID® sterile ophthalmic solution is an 8-methoxyfluoroquinolone anti-infective for the treatment of bacterial conjunctivitis. Its chemical name is (±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, sesquihydrate. Its molecular formula is C19H22FN3O4 · 1½H2O, and its molecular weight is 402.42. Its chemical structure is: - ZYMAXID® is a clear, pale yellow, sterile, preserved aqueous solution with an osmolality of 260-330 mOsm/kg and a pH of 5.1-5.7. - ZYMAXID® contains Active: gatifloxacin 0.5% (5 mg/mL); Inactives: benzalkonium chloride 0.005%; edetate disodium; purified water; and sodium chloride. May contain hydrochloric acid and/or sodium hydroxide to adjust pH. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Gatifloxacin in the drug label. ## Pharmacokinetics - Gatifloxacin ophthalmic solution 0.3% or 0.5% was administered to one eye of 6 healthy male subjects each in an escalated dosing regimen starting with a single 2 drop dose, then 2 drops 4 times daily for 7 days, and finally 2 drops 8 times daily for 3 days. At all time points, serum gatifloxacin levels were below the lower limit of quantification (5 ng/mL) in all subjects. ### Microbiology - Gatifloxacin is an 8-methoxyfluoroquinolone with a 3-methylpiperazinyl substituent at C7. The antibacterial action of gatifloxacin results from inhibition of DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. The mechanism of action of fluoroquinolones including gatifloxacin is different from that of aminoglycoside, macrolide, and tetracycline antibiotics. Therefore, gatifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to gatifloxacin. There is no cross-resistance between gatifloxacin and the aforementioned classes of antibiotics. Cross-resistance has been observed between systemic gatifloxacin and some other fluoroquinolones. - Resistance to gatifloxacin in vitro develops via multiple-step mutations. Resistance to gatifloxacin in vitro occurs at a general frequency of 1 x 10-7 to 10-10. - Gatifloxacin has been shown to be active against most isolates of the following organisms both microbiologically and clinically, in conjunctival infections as described in the INDICATIONS AND USAGE, Section 1. - Aerobic Gram-Positive Bacteria: - Staphylococcus aureus - Staphylococcus epidermidis - Streptococcus mitis group* - Streptococcus oralis* - Streptococcus pneumoniae - Aerobic Gram-Negative Bacteria: - Haemophilus influenzae - Efficacy for this organism was studied in fewer than 10 infections. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - There was no increase in neoplasms among B6C3F1 mice given gatifloxacin in the diet for 18 months at doses averaging 81 mg/kg/day in males and 90 mg/kg/day in females. These doses are approximately 1600-fold and 1800-fold higher, respectively, than the maximum recommended ophthalmic dose of 0.05 mg/kg/day in a 50 kg human. - There was no increase in neoplasms among Fischer 344 rats given gatifloxacin in the diet for 2 years at doses averaging 47 mg/kg/day in males and 139 mg/kg/day in females (900- and 2800-fold higher, respectively, than the maximum recommended ophthalmic dose). A statistically significant increase in the incidence of large granular lymphocyte (LGL) leukemia was seen in males treated with a high dose of approximately 2000-fold higher than the maximum recommended ophthalmic dose. Fischer 344 rats have a high spontaneous background rate of LGL leukemia and the incidence in high-dose males only slightly exceeded the historical control range established for this strain. - In genetic toxicity tests, gatifloxacin was positive in 1 of 5 strains used in bacterial reverse mutation assays: Salmonella strain TA102. Gatifloxacin was positive in in vitro mammalian cell mutation and chromosome aberration assays. Gatifloxacin was positive in in vitro unscheduled DNA synthesis in rat hepatocytes but not human leukocytes. Gatifloxacin was negative in in vivo micronucleus tests in mice, cytogenetics test in rats, and DNA repair test in rats. The findings may be due to the inhibitory effects of high concentrations on eukaryotic type II DNA topoisomerase. - There were no adverse effects on fertility or reproduction in rats given gatifloxacin orally at doses up to 200 mg/kg/day (approximately 4000-fold higher than the maximum recommended ophthalmic dose for ZYMAXID®). # Clinical Studies - In two randomized, double-masked, multicenter clinical trials, where patients 1-89 years of age were dosed for 5 days, ZYMAXID® solution was clinically superior to its vehicle on day 6 in patients with conjunctivitis and positive conjunctival cultures. Clinical outcomes for the trials demonstrated clinical success (resolution of conjunctival hyperaemia and conjunctival discharge) of 58% (193/333) for the gatifloxacin-treated groups versus 45% (148/325) for the vehicle-treated groups. Microbiological outcomes for the same clinical trials demonstrated a statistically superior eradication rate for causative pathogens of 90% (301/333) for gatifloxacin versus 70% (228/325) for vehicle. Please note that microbiological eradication does not always correlate with clinical outcome in anti-infective trials. # How Supplied - ZYMAXID® (gatifloxacin ophthalmic solution) 0.5% is supplied sterile in a white, low density polyethylene (LDPE) bottle with a controlled dropper tip, and a tan, high impact polystyrene (HIPS) cap in the following size: - 2.5 mL in 5 mL bottle: NDC 0023-3615-25 ## Storage - Store at 15°-25°C (59°-77°F). Protect from freezing. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Avoiding Contamination of the Product - Patients should be instructed to avoid contaminating the applicator tip with material from the eye, fingers, or other source. Avoidance of Contact Lens Wear - Patients should be advised not to wear contact lenses if they have signs and symptoms of bacterial conjunctivitis. # Precautions with Alcohol - Alcohol-Gatifloxacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Tequin, Tequin Teq-Paqs, Zymar, Zymaxid. # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Gatifloxacin
86ca7ba766e4e0a144ffd6c13a9b1d1cdd263d47	wikidoc	Gender-blind	Gender-blind Gender-blind (or unisex) is a term describing activities undertaken and services provided without regard to the gender of those who participate. # Choice of words Unisex is an older term, and a misnomer meaning "one sex". Some feel it carries the connotation of being duo-sex, (which would mean two at the same time) and many being afraid to use the more appropriate term, bisex, because of the sexual connotations. Whereas, gender-blind goes against most tenets of heteronormativity, by not looking at gender at all. # The National Student Genderblind Campaign In 2006 the National Student Genderblind Campaign was created as a collaborative grass-roots organization intended to educate college students, administrators, and others throughout the country. The NSGC advocates for the implementation of gender-inclusive dorm room and bathroom options. The goal of the gender-blind dorm policy campaign is to allow roommates to be assigned without regard to any person’s sex. The backers of the proposal claim it would allow transgender people and people who do not accept gender labels to live in more comfortable settings than may otherwise be possible in single-sex housing. They also claim it is a good policy for heterosexuals who otherwise couldn't live with their partners while at the university. In December 2006, the National Student Genderblind Campaign found itself in national controversy after receiving what it claimed to be biased and negligent coverage by Boston's Fox 25 News. The controversy triggered a formal press statement released nationally and an appearance on Fox News Channel's "Heartland" show with John Kasich on December 16, 2006.	Gender-blind Gender-blind (or unisex) is a term describing activities undertaken and services provided without regard to the gender of those who participate. # Choice of words Template:Weasel Unisex is an older term, and a misnomer meaning "one sex". Some feel it carries the connotation of being duo-sex, (which would mean two at the same time) and many being afraid to use the more appropriate term, bisex, because of the sexual connotations. Whereas, gender-blind goes against most tenets of heteronormativity, by not looking at gender at all. # The National Student Genderblind Campaign In 2006 the National Student Genderblind Campaign was created as a collaborative grass-roots organization intended to educate college students, administrators, and others throughout the country. The NSGC advocates for the implementation of gender-inclusive dorm room and bathroom options. The goal of the gender-blind dorm policy campaign is to allow roommates to be assigned without regard to any person’s sex. The backers of the proposal claim it would allow transgender people and people who do not accept gender labels to live in more comfortable settings than may otherwise be possible in single-sex housing.[citation needed] They also claim it is a good policy for heterosexuals who otherwise couldn't live with their partners while at the university.[citation needed] In December 2006, the National Student Genderblind Campaign found itself in national controversy after receiving what it claimed to be biased and negligent coverage by Boston's Fox 25 News.[1] The controversy triggered a formal press statement released nationally[2] and an appearance on Fox News Channel's "Heartland" show with John Kasich on December 16, 2006.	https://www.wikidoc.org/index.php/Gender-blind
3d86376af0ddae56044ed3d4907044bd20e2bd86	wikidoc	Gene cluster	Gene cluster A gene cluster is a set of two or more genes that serve to encode for the same or similar products. Because populations from a common ancestor tend to possess the same varieties of gene clusters, they are useful for tracing back recent evolutionary history. Because of this, they were used by Luigi Luca Cavalli-Sforza to identify ethnic groups within Homo sapiens and their closeness to each other. An example of a gene cluster is the Human β-globin gene cluster, which contains five functional genes and one non-functional gene for similar proteins. Hemoglobin molecules contain any two identical proteins from this gene cluster, depending on their specific role. As according to the recent finding seem to suggest the evolutionary pathway and the diversion in the genes.	Gene cluster A gene cluster is a set of two or more genes that serve to encode for the same or similar products. Because populations from a common ancestor tend to possess the same varieties of gene clusters, they are useful for tracing back recent evolutionary history. Because of this, they were used by Luigi Luca Cavalli-Sforza to identify ethnic groups within Homo sapiens and their closeness to each other. An example of a gene cluster is the Human β-globin gene cluster, which contains five functional genes and one non-functional gene for similar proteins. Hemoglobin molecules contain any two identical proteins from this gene cluster, depending on their specific role. As according to the recent finding seem to suggest the evolutionary pathway and the diversion in the genes. Template:WS	https://www.wikidoc.org/index.php/Gene_cluster
b8c0d809f96b35bd5884094ecf113559ad449670	wikidoc	Gene project	Gene project Each of the gene infoboxes on WikiDoc display "VALUE_ERROR (nil)" at the top instead of the gene name followed by answers obtained from WikiData for each entry. Compare ZSCAN21 on WikiDoc with ZSCAN21 on Wikipedia. # Source of the Error The {{Infobox_gene}} template calls Module:Infobox gene which in turn calls WikiData using local ref_url = "/". The reason none of the gene inboxes work is that Module:Infobox gene here is the same as Module:Infobox gene on Wikiversity or Wikipedia which both work. In short, WikiDoc is outside the WikiData WMF project computers. # Solutions In order to produce functional gene Infoboxes the Module:Infobox gene needs to be re-programmed to call the original sources of the information to have it appropriately displayed. Some changes along these lines have been introduced into the Infobox gene for Alpha-1-B glycoprotein, which is of interest to me. Constructing the Species Human Mouse table for inclusion has hit a template snag here on WikiDoc. # Not on Wikipedia or WikiData Wikipedia and WikiData do not cover all known human genes that are likely of interest to WikiDoc. Examples include ZSCAN22, ZIM2, ZNF17, ZNF132, ZNF134, ZNF135, ZNF154, ZNF256, ZNF211, TRAPPC2B, ZNF460, ZNF324, ZNF544, ZNF586, ZNF444, ZNF416, ZNF446, ZNF304, USP29, ZNF667, ZSCAN18, ZSCAN5A, ZNF329, ZNF419, ZNF552, ZNF671, ZNF606, ZBTB45, ZNF587, GALP, ZNF551, ZNF835, ZIM3, ZNF837, ZNF543, ZNF787, SMIM17, ZNF418, ZNF417, ZNF548, ZNF582, ZNF583, ZNF550, ZNF584, ZNF549, ZNF547, ZIK1, ZNF776, ZSCAN1, ZSCAN5B, ZNF530, ZNF773, ZNF582-AS1, ZNF470 and MIR6806. # Needed on WikiDoc - Examples added: ACTR1B, SVIL, PHEX, TFIIA, STC1, STC2, SLC34A3, E2F4, HBB, HBA1 same as Hemoglobin, alpha 1, CST1, CST2, ZSCAN22 and Small nucleolar RNA SNORD115. - Needed include ZSCAN4 that are on Wikipedia. # Complement copies # Inverse copies For "AGC, one copy in inverse orientation of the AGC box (AGCCGCC) present as two copies (-1346 and -1314) in the ERE". # Complement-inverse copies # Methylation "Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, methylating the cytosine within a gene can turn the gene off, a mechanism that is part of a larger field of science studying gene regulation that is called epigenetics. Enzymes that add a methyl group are called DNA methyltransferases." In mammals, 70% to 80% of CpG cytosines are methylated. "CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42% GC content, a pair of nucleotides consisting of cytosine followed by guanine would be expected to occur 0.21 - 0.21 = 4.41% of the time. The frequency of CpG dinucleotides in human genomes is 1% — less than one-quarter of the expected frequency." Unmethylated CpG sites can be detected by Toll-Like Receptor 9 "(TLR 9) on plasmacytoid dendritic cells and B cells in humans. This is used to detect intracellular viral, fungal, and bacterial pathogen DNA." Methylation is central to imprinting, along with histone modifications. Most of the methylation occurs a short distance from the CpG islands (at "CpG island shores") rather than in the islands themselves. Methylation of CpG sites within the promoters of genes can lead to their silencing, a feature found in a number of human cancers (for example the silencing of tumor suppressor genes). In contrast, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells. "In eukaryotes, CpG methylation is an epigenetic DNA modification that is important for heterochromatin formation." "CENP-B preferentially binds to the unmethylated CENP-B box DNA." The "CpG methylations of the CENP-B box sequence may function in RNAi-dependent heterochromatin formation by regulating CENP-B-binding to the CENP-B box sequence in the α-satellite repeats." # Deamination The CpG deficiency is due to an increased vulnerability of methylcytosines to spontaneously deaminate to thymine in genomes with CpG cytosine methylation. # Ubiquitination # Phosphorylation # Acknowledgements The content on this page was first contributed by: Henry A. Hoff.	Gene project Each of the gene infoboxes on WikiDoc display "VALUE_ERROR (nil)" at the top instead of the gene name followed by answers obtained from WikiData for each entry. Compare ZSCAN21 on WikiDoc with ZSCAN21 on Wikipedia. # Source of the Error The {{Infobox_gene}} template calls Module:Infobox gene which in turn calls WikiData using local ref_url = "https://www.wikidata.org/wiki/". The reason none of the gene inboxes work is that Module:Infobox gene here is the same as Module:Infobox gene on Wikiversity or Wikipedia which both work. In short, WikiDoc is outside the WikiData WMF project computers. # Solutions In order to produce functional gene Infoboxes the Module:Infobox gene needs to be re-programmed to call the original sources of the information to have it appropriately displayed. Some changes along these lines have been introduced into the Infobox gene for Alpha-1-B glycoprotein, which is of interest to me. Constructing the Species Human Mouse table for inclusion has hit a template snag here on WikiDoc. # Not on Wikipedia or WikiData Wikipedia and WikiData do not cover all known human genes that are likely of interest to WikiDoc. Examples include ZSCAN22, ZIM2, ZNF17, ZNF132, ZNF134, ZNF135, ZNF154, ZNF256, ZNF211, TRAPPC2B, ZNF460, ZNF324, ZNF544, ZNF586, ZNF444, ZNF416, ZNF446, ZNF304, USP29, ZNF667, ZSCAN18, ZSCAN5A, ZNF329, ZNF419, ZNF552, ZNF671, ZNF606, ZBTB45, ZNF587, GALP, ZNF551, ZNF835, ZIM3, ZNF837, ZNF543, ZNF787, SMIM17, ZNF418, ZNF417, ZNF548, ZNF582, ZNF583, ZNF550, ZNF584, ZNF549, ZNF547, ZIK1, ZNF776, ZSCAN1, ZSCAN5B, ZNF530, ZNF773, ZNF582-AS1, ZNF470 and MIR6806. # Needed on WikiDoc - Examples added: ACTR1B, SVIL, PHEX, TFIIA, STC1, STC2, SLC34A3, E2F4, HBB, HBA1 same as Hemoglobin, alpha 1, CST1, CST2, ZSCAN22 and Small nucleolar RNA SNORD115. - Needed include ZSCAN4 that are on Wikipedia. # Complement copies # Inverse copies For "AGC, one copy in inverse orientation of the AGC box (AGCCGCC) [is] present as two copies (-1346 and -1314) in the ERE".[1] # Complement-inverse copies # Methylation "Cytosines in CpG dinucleotides can be methylated to form 5-methylcytosine. In mammals, methylating the cytosine within a gene can turn the gene off, a mechanism that is part of a larger field of science studying gene regulation that is called epigenetics. Enzymes that add a methyl group are called DNA methyltransferases."[2] In mammals, 70% to 80% of CpG cytosines are methylated.[3] "CpG dinucleotides have long been observed to occur with a much lower frequency in the sequence of vertebrate genomes than would be expected due to random chance. For example, in the human genome, which has a 42% GC content, a pair of nucleotides consisting of cytosine followed by guanine would be expected to occur 0.21 * 0.21 = 4.41% of the time. The frequency of CpG dinucleotides in human genomes is 1% — less than one-quarter of the expected frequency."[2] Unmethylated CpG sites can be detected by Toll-Like Receptor 9[4] "(TLR 9) on plasmacytoid dendritic cells and B cells in humans. This is used to detect intracellular viral, fungal, and bacterial pathogen DNA."[2] Methylation is central to imprinting, along with histone modifications.[5] Most of the methylation occurs a short distance from the CpG islands (at "CpG island shores") rather than in the islands themselves.[6] Methylation of CpG sites within the promoters of genes can lead to their silencing, a feature found in a number of human cancers (for example the silencing of tumor suppressor genes). In contrast, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells.[7] "In eukaryotes, CpG methylation is an epigenetic DNA modification that is important for heterochromatin formation."[8] "CENP-B preferentially binds to the unmethylated CENP-B box DNA."[8] The "CpG methylations of the CENP-B box sequence may function in [RNA interference (RNAi)] RNAi-dependent heterochromatin formation by regulating CENP-B-binding to the CENP-B box sequence in the α-satellite repeats."[8] # Deamination The CpG deficiency is due to an increased vulnerability of methylcytosines to spontaneously deaminate to thymine in genomes with CpG cytosine methylation.[9] # Ubiquitination # Phosphorylation # Acknowledgements The content on this page was first contributed by: Henry A. Hoff.	https://www.wikidoc.org/index.php/Gene_project
83185eacb496363ef9dd3c9bb1e035ab77786353	wikidoc	Gene therapy	Gene therapy Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, and hereditary diseases in which a defective mutant allele is replaced with a functional one. Although the technology is still in its infancy, it has been used with some success. Antisense therapy is not strictly a form of gene therapy, but is a genetically-mediated therapy and is often considered together with other methods. # Background On September 14, 1990 at the U.S. National Institutes of Health W. French Anderson, M.D., and his colleagues R. Michael Blaese, M.D., C. Bouzaid, M.D., and Kenneth Culver, M.D., performed the first approved gene therapy procedure on four-year old Ashanthi DeSilva. Born with a rare genetic disease called severe combined immunodeficiency (SCID), she lacked a healthy immune system, and was vulnerable to every passing germ or infection. Children with this illness usually develop overwhelming infections and rarely survive to adulthood; a common childhood illness like chickenpox is life-threatening. Ashanthi led a cloistered existence -- avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics. In Ashanthi's gene therapy procedure, doctors removed white blood cells from the child's body, let the cells grow in the lab, inserted the missing gene into the cells, and then infused the genetically modified blood cells back into the patient's bloodstream. Laboratory tests have shown that the therapy strengthened Ashanthi's immune system by 40%; she no longer has recurrent colds, she has been allowed to attend school, and she was immunized against whooping cough. This procedure was not a cure; the white blood cells treated genetically only work for a few months, after which the process must be repeated (VII, Thompson 1993). As of early 2007, she was still in good health, and she was attending college. However, there is no consensus on what portion of her improvement should be attributed to gene therapy versus other treatments. Some would state that the case is of great importance despite its indefinite results, if only because it demonstrated that gene therapy could be practically attempted without adverse consequences. Although this simplified explanation of a gene therapy procedure sounds like a happy ending, it is little more than an optimistic first chapter in a long story; the road to the first approved gene therapy procedure was rocky and fraught with controversy. The biology of human gene therapy is very complex, and there are many techniques that still need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. The public policy debate surrounding the possible use of genetically engineered material in human subjects has been equally complex. Major participants in the debate have come from the fields of biology, government, law, medicine, philosophy, politics, and religion, each bringing different views to the discussion. Scientists took the logical step of trying to introduce genes straight into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, hemophilia, muscular dystrophy and sickle cell anemia. However, this has been much harder than modifying simple bacteria, primarily because of the problems involved in carrying large sections of DNA and delivering them to the correct site on the comparatively large human genome. # Basic process In most gene therapy studies, a "correct copy" or "wild type" gene is provided or inserted into the genome. Generally, it is not an exact replacement of the "abnormal," disease-causing gene, but rather extra, correct copies of genes are provided to complement the loss of function. A carrier called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, the most common type of vectors are viruses that have been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to harness this ability by manipulating the viral genome to remove disease-causing genes and insert therapeutic ones. Target cells such as the patient's liver or lung cells are infected with the vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state. # Types of gene therapy Gene therapy may be classified into the following types: ### Germ line gene therapy In the case of germ line gene therapy, germ cells, i.e., sperm or eggs, are modified by the introduction of functional genes, which are ordinarily integrated into their genomes. Therefore, the change due to therapy would be heritable and would be passed on to later generations. This new approach, theoretically, should be highly effective in counteracting genetic disorders. However, this option is prohibited for application in human beings, at least for the present, for a variety of technical and ethical reasons. ### Somatic cell gene therapy In somatic cell gene therapy, the gene is introduced only in somatic cells, especially of those tissues in which expression of the concerned gene is critical for health. Expression of the introduced gene relieves/ eliminates symptoms of the disorder, but this effect is not heritable as it does not involve the germ line. At present, somatic cell therapy is the only feasible option, and clinical trials addressing a variety of conditions have already begun. # Broad methods There are a variety of different methods to replace or repair the genes targeted in gene therapy. - A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common. - An abnormal gene could be swapped for a normal gene through homologous recombination. - The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function. - The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered. # Vectors in gene therapy ## Viruses All viruses attack their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hijacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses actually physically insert their genes into the host's genome (a defining feature of retroviruses, the family of viruses that includes HIV, is that the virus will introduce the enzyme reverse transcriptase into the host and thus use its RNA as the "instructions"). This incorporates the genes of that virus among the genes of the host cell for the life span of that cell. Doctors and molecular biologists realized that viruses like this could be used as vehicles to carry 'good' genes into a human cell. First, a scientist would remove the genes in the virus that cause disease. Then they would replace those genes with genes encoding the desired effect (for instance, insulin production in the case of diabetics). This procedure must be done in such a way that the genes which allow the virus to insert its genome into its host's genome are left intact. This can be confusing, and requires significant research and understanding of the virus' genes in order to know the function of each. An example: A virus is found which replicates by inserting its genes into the host cell's genome. This virus has two genes- A and B. Gene A encodes a protein which allows this virus to insert itself into the host's genome. Gene B causes the disease this virus is associated with. Gene C is the "normal" or "desirable" gene we want in the place of gene B. Thus, by re-engineering the virus so that gene B is replaced by gene C, while allowing gene A to properly function, this virus could introduce the required gene - gene C into the host cell's genome without causing any disease. All this is clearly an oversimplification, and numerous problems exist that prevent gene therapy using viral vectors, such as: trouble preventing undesired effects, ensuring the virus will infect the correct target cell in the body, and ensuring that the inserted gene doesn't disrupt any vital genes already in the genome. However, this basic mode of gene introduction currently shows much promise and doctors and scientists are working hard to fix any potential problems that could exist. ### Retroviruses The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase. Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, it can be said that the host cell is now modified to contain a new gene. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately. One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host- it randomly shoves the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites. Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted in the USA when leukemia was reported in three of eleven patients treated in the French Therapy X-linked SCID (XSCID) gene therapy trial. Ten XSCID patients treated in England have not presented leukemia to date and have had similar success in immune reconstitution. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme continue with relative success in the USA, Italy and Japan. ### Adenoviruses Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory (especially the common cold), intestinal, and eye infections in humans. When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene. As a result, treatment with the adenovirus will require readministration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has shown real promise in treating cancer and indeed the first gene therapy product to be licensed to treat cancer is an adenovirus. ### Adeno-associated viruses Adeno-associated viruses, from the parvovirus family, are small viruses with a genome of single stranded DNA. The wild type AAV can insert genetic material at a specific site on chromosome 19 with near 100% certainty. But the recombinant AAV, that does not contain any viral genes and only the therapeutic gene does not integrate into the genome. Instead the recombinant viral genome fuses at its ends via the ITR (inverted terminal repeats) recombination to form circular, episomal forms which are predicted to be the primary cause of the long term gene expression. There are a few disadvantages to using AAV, including the small amount of DNA it can carry (low capacity) and the difficulty in producing it. This type of virus is being used, however, because it is non-pathogenic (most people carry this harmless virus). In contrast to adenoviruses, most people treated with AAV will not build an immune response to remove the virus and the cells that have been successfully treated with it. Several trials with AAV are on-going or in preparation, mainly trying to treat muscle and eye diseases; the two tissues where the virus seems particularly useful. However, clinical trials have also been initiated where AAV vectors are used to deliver genes to the brain. This is possible because AAV viruses can infect non-dividing (quiescent) cells, such as neurons in which their genomes are expressed for a long time. ### Envelope protein pseudotyping of viral vectors The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are refractory to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen (anatomy) induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell. For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, as well as many concerns from the medical community. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies. ## Non-viral methods Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses. ### Naked DNA This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. This success, however, does not compare to that of the other methods, leading to research into more efficient methods for delivery of the naked DNA such as electroporation and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas. ### Oligonucleotides The use of synthetic oligonucleotides in gene therapy is to inactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. ### Lipoplexes and polyplexes To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and its entry into the cell must be facilitated. To this end new molecules, lipoplexes and polyplexes, have been created that have the ability to protect the DNA from undesirable degradation during the transfection process. Plasmid DNA can be covered with lipids in an organized structure like a micelle or a liposome. When the organized structure is complexed with DNA it is called a lipoplex. There are three types of lipids, anionic (negatively charged), neutral, or cationic (positively charged). Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time consuming to produce so attention was turned to the cationic versions. Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of “endosomal escaping”. However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was figured out that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages. The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells, so they may be used for treatment of genetic respiratory diseases such as cystic fibrosis. Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their production is regulated by ionic interactions. One large difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot release their DNA load into the cytoplasm, so to this end, co-transfection with endosome-lytic agents (to lyse the endosome that is made during endocytosis, the process by which the polyplex enters the cell) such as inactivated adenovirus must occur. However, this isn't always the case, polymers such as polyethylenimine have their own method of endosome disruption as does chitosan and trimethylchitosan. ## Hybrid methods Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses. ## Dendrimers A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface. In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complimentarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis. In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect a number of cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches. Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity. # Major developments in gene therapy ## 2002 and earlier New gene therapy approach repairs errors in messenger RNA derived from defective genes. This technique has the potential to treat the blood disorder thalassaemia, cystic fibrosis, and some cancers. See Subtle gene therapy tackles blood disorder at NewScientist.com (October 11, 2002). Researchers at Case Western Reserve University and Copernicus Therapeutics are able to create tiny liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane. See DNA nanoballs boost gene therapy at NewScientist.com (May 12, 2002). Sickle cell disease is successfully treated in mice. See Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease from March 18, 2002, issue of The Scientist. The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) held from 2000 and 2002 was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the United States, the United Kingdom, France, Italy, and Germany. (V. Cavazzana-Calvo, Thrasher and Mavilio 2004; see also 'Miracle' gene therapy trial halted at NewScientist.com, October 3, 2002). In 1993 Andrew Gobea was born with a rare, normally fatal genetic disease - severe combined immunodeficiency (SCID). Genetic screening before birth showed that he had SCID. Blood was removed from Andrew's placenta and umbilical cord immediately after birth, containing stem cells. The allele that codes for ADA was obtained and was inserted into a retrovirus. Retroviruses and stem cells were mixed, after which they entered and inserted the gene into the stem cells' chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood system via a vein. For four years T-cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed. In 2003 a University of California, Los Angeles research team inserted genes into the brain using liposomes coated in a polymer called polyethylene glycol (PEG). The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the "blood-brain barrier." This method has potential for treating Parkinson's disease. See Undercover genes slip into the brain at NewScientist.com (March 20, 2003). RNA interference or gene silencing may be a new way to treat Huntington's. Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced. See Gene therapy may switch off Huntington's at NewScientist.com (March 13, 2003). Scientists at the National Institutes of Health (Bethesda, Maryland) have successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells. This study constitutes the first demonstration that gene therapy can be effective in treating cancer. The study results have been published in Science (October 2006). In May 2006 a team of scientists led by Dr. Luigi Naldini and Dr. Brian Brown from the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in Milan, Italy reported a breakthrough for gene therapy in which they developed a way to prevent the immune system from rejecting a newly delivered gene. Similar to organ transplantation, gene therapy has been plagued by the problem of immune rejection. So far, delivery of the 'normal' gene has been difficult because the immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Dr. Naldini's group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and spectacularly, the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy. In March 2006 an international group of scientists announced the successful use of gene therapy to treat two adult patients for a disease affecting myeloid cells. The study, published in Nature Medicine, is believed to be the first to show that gene therapy can cure diseases of the myeloid system. On 1 May 2007 Moorfields Eye Hospital and University College London's Institute of Ophthalmology announced the world's first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male, Robert Johnson, in early 2007. Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of the Moorfields/UCL trial were published in New England Journal of Medicine in April 2008. They researched the safety of the subretinal delivery of recombinant adeno associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects. # Problems and ethics For the safety of gene therapy, the Weismann barrier is fundamental in the current thinking. Soma-to-germline feedback should therefore be impossible. However, there are indications that the Weissman barrier can be breached. One way it might possibly be breached is if the treatment were somehow misapplied and spread to the testes and therefore would infect the germline against the intentions of the therapy. Some of the problems of gene therapy include: - Short-lived nature of gene therapy - Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy. - Immune response - Anytime a foreign object is introduced into human tissues, the immune system has evolved to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients. - Problems with viral vectors - Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient --toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease. - Multigene disorders - Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy. - Chance of inducing a tumor (insertional mutagenesis) - If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients. - Religious concerns - among people who believe that humans were created in God's image, some may consider the alteration of an individual's genes as tampering or corrupting God's work. Deaths have occurred due to gene therapy, including that of Jesse Gelsinger. from: # In popular culture - Gene therapy is a crucial plot element in the video game Metal Gear Solid, where it has been used to enhance the battle capabilities of enemy soldiers. - Gene therapy plays a major role in the sci-fi series Stargate Atlantis, as a certain type of alien technology can only be used if one has a certain gene which is given to the members of the team through gene therapy. - Gene therapy also plays a major role in the plot of the James Bond movie Die Another Day. - The Yellow Bastard from Frank Miller's Sin City was also apparently the recipient of gene therapy. - In the The Dark Knight Strikes Again, Dick Grayson, the first Robin, becomes a victim of extensive gene therapy for years by Lex Luthor to become The Joker. - Gene therapy plays a recurring role in the present-time sci-fi television program ReGenesis, where it is used to cure various diseases, enhance athletic performance and produce vast profits for bio-tech corporations. (e.g. an undetectable performance-enhancing gene therapy was used by one of the characters on himself, but to avoid copyright infringement, this gene therapy was modified from the tested-to-be-harmless original, which produced a fatal cardiovascular defect) - Gene therapy is the basis for the plot line of the film I Am Legend. - Gene therapy is an important plot key in the game Bioshock where the game contents refer to plasmids and splicers. - The book Next by Michael Crichton unravels a story in which fictitious biotechnology companies which experiment with gene therapy are involved. - In the television show Alias, a breakthrough in molecular gene therapy is discovered, whereby a patient's body is reshaped to identically resemble someone else. Protagonist Sydney Bristow's best friend was secretly killed and her "double" resumed her place.	Gene therapy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, and hereditary diseases in which a defective mutant allele is replaced with a functional one. Although the technology is still in its infancy, it has been used with some success. Antisense therapy is not strictly a form of gene therapy, but is a genetically-mediated therapy and is often considered together with other methods. # Background On September 14, 1990 at the U.S. National Institutes of Health W. French Anderson, M.D., and his colleagues R. Michael Blaese, M.D., C. Bouzaid, M.D., and Kenneth Culver, M.D., performed the first approved gene therapy procedure on four-year old Ashanthi DeSilva. Born with a rare genetic disease called severe combined immunodeficiency (SCID), she lacked a healthy immune system, and was vulnerable to every passing germ or infection. Children with this illness usually develop overwhelming infections and rarely survive to adulthood; a common childhood illness like chickenpox is life-threatening. Ashanthi led a cloistered existence -- avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics. In Ashanthi's gene therapy procedure, doctors removed white blood cells from the child's body, let the cells grow in the lab, inserted the missing gene into the cells, and then infused the genetically modified blood cells back into the patient's bloodstream. Laboratory tests have shown that the therapy strengthened Ashanthi's immune system by 40%; she no longer has recurrent colds, she has been allowed to attend school, and she was immunized against whooping cough. This procedure was not a cure; the white blood cells treated genetically only work for a few months, after which the process must be repeated (VII, Thompson [First] 1993). As of early 2007, she was still in good health, and she was attending college. However, there is no consensus on what portion of her improvement should be attributed to gene therapy versus other treatments. Some would state that the case is of great importance despite its indefinite results, if only because it demonstrated that gene therapy could be practically attempted without adverse consequences.[2] Although this simplified explanation of a gene therapy procedure sounds like a happy ending, it is little more than an optimistic first chapter in a long story; the road to the first approved gene therapy procedure was rocky and fraught with controversy. The biology of human gene therapy is very complex, and there are many techniques that still need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. The public policy debate surrounding the possible use of genetically engineered material in human subjects has been equally complex. Major participants in the debate have come from the fields of biology, government, law, medicine, philosophy, politics, and religion, each bringing different views to the discussion. Scientists took the logical step of trying to introduce genes straight into human cells, focusing on diseases caused by single-gene defects, such as cystic fibrosis, hemophilia, muscular dystrophy and sickle cell anemia. However, this has been much harder than modifying simple bacteria, primarily because of the problems involved in carrying large sections of DNA and delivering them to the correct site on the comparatively large human genome. # Basic process In most gene therapy studies, a "correct copy" or "wild type" gene is provided or inserted into the genome. Generally, it is not an exact replacement of the "abnormal," disease-causing gene, but rather extra, correct copies of genes are provided to complement the loss of function. A carrier called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, the most common type of vectors are viruses that have been genetically altered to carry normal human DNA. Viruses have evolved a way of encapsulating and delivering their genes to human cells in a pathogenic manner. Scientists have tried to harness this ability by manipulating the viral genome to remove disease-causing genes and insert therapeutic ones. Target cells such as the patient's liver or lung cells are infected with the vector. The vector then unloads its genetic material containing the therapeutic human gene into the target cell. The generation of a functional protein product from the therapeutic gene restores the target cell to a normal state. # Types of gene therapy Gene therapy may be classified into the following types: ### Germ line gene therapy In the case of germ line gene therapy, germ cells, i.e., sperm or eggs, are modified by the introduction of functional genes, which are ordinarily integrated into their genomes. Therefore, the change due to therapy would be heritable and would be passed on to later generations. This new approach, theoretically, should be highly effective in counteracting genetic disorders. However, this option is prohibited for application in human beings, at least for the present, for a variety of technical and ethical reasons. ### Somatic cell gene therapy In somatic cell gene therapy, the gene is introduced only in somatic cells, especially of those tissues in which expression of the concerned gene is critical for health. Expression of the introduced gene relieves/ eliminates symptoms of the disorder, but this effect is not heritable as it does not involve the germ line. At present, somatic cell therapy is the only feasible option, and clinical trials addressing a variety of conditions have already begun. # Broad methods There are a variety of different methods to replace or repair the genes targeted in gene therapy.[3] - A normal gene may be inserted into a nonspecific location within the genome to replace a nonfunctional gene. This approach is most common. - An abnormal gene could be swapped for a normal gene through homologous recombination. - The abnormal gene could be repaired through selective reverse mutation, which returns the gene to its normal function. - The regulation (the degree to which a gene is turned on or off) of a particular gene could be altered. # Vectors in gene therapy ## Viruses All viruses attack their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hijacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses actually physically insert their genes into the host's genome (a defining feature of retroviruses, the family of viruses that includes HIV, is that the virus will introduce the enzyme reverse transcriptase into the host and thus use its RNA as the "instructions"). This incorporates the genes of that virus among the genes of the host cell for the life span of that cell. Doctors and molecular biologists realized that viruses like this could be used as vehicles to carry 'good' genes into a human cell. First, a scientist would remove the genes in the virus that cause disease. Then they would replace those genes with genes encoding the desired effect (for instance, insulin production in the case of diabetics). This procedure must be done in such a way that the genes which allow the virus to insert its genome into its host's genome are left intact. This can be confusing, and requires significant research and understanding of the virus' genes in order to know the function of each. An example: A virus is found which replicates by inserting its genes into the host cell's genome. This virus has two genes- A and B. Gene A encodes a protein which allows this virus to insert itself into the host's genome. Gene B causes the disease this virus is associated with. Gene C is the "normal" or "desirable" gene we want in the place of gene B. Thus, by re-engineering the virus so that gene B is replaced by gene C, while allowing gene A to properly function, this virus could introduce the required gene - gene C into the host cell's genome without causing any disease. All this is clearly an oversimplification, and numerous problems exist that prevent gene therapy using viral vectors, such as: trouble preventing undesired effects, ensuring the virus will infect the correct target cell in the body, and ensuring that the inserted gene doesn't disrupt any vital genes already in the genome. However, this basic mode of gene introduction currently shows much promise and doctors and scientists are working hard to fix any potential problems that could exist. ### Retroviruses The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase. Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, it can be said that the host cell is now modified to contain a new gene. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately. One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host- it randomly shoves the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases[1] or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites. Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted in the USA when leukemia was reported in three of eleven patients treated in the French Therapy X-linked SCID (XSCID) gene therapy trial. Ten XSCID patients treated in England have not presented leukemia to date and have had similar success in immune reconstitution. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme continue with relative success in the USA, Italy and Japan. ### Adenoviruses Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory (especially the common cold), intestinal, and eye infections in humans. When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene. As a result, treatment with the adenovirus will require readministration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has shown real promise in treating cancer and indeed the first gene therapy product to be licensed to treat cancer is an adenovirus. ### Adeno-associated viruses Adeno-associated viruses, from the parvovirus family, are small viruses with a genome of single stranded DNA. The wild type AAV can insert genetic material at a specific site on chromosome 19 with near 100% certainty. But the recombinant AAV, that does not contain any viral genes and only the therapeutic gene does not integrate into the genome. Instead the recombinant viral genome fuses at its ends via the ITR (inverted terminal repeats) recombination to form circular, episomal forms which are predicted to be the primary cause of the long term gene expression. There are a few disadvantages to using AAV, including the small amount of DNA it can carry (low capacity) and the difficulty in producing it. This type of virus is being used, however, because it is non-pathogenic (most people carry this harmless virus). In contrast to adenoviruses, most people treated with AAV will not build an immune response to remove the virus and the cells that have been successfully treated with it. Several trials with AAV are on-going or in preparation, mainly trying to treat muscle and eye diseases; the two tissues where the virus seems particularly useful. However, clinical trials have also been initiated where AAV vectors are used to deliver genes to the brain. This is possible because AAV viruses can infect non-dividing (quiescent) cells, such as neurons in which their genomes are expressed for a long time. ### Envelope protein pseudotyping of viral vectors The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are refractory to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen (anatomy) induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell. For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, as well as many concerns from the medical community. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies. ## Non-viral methods Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses. ### Naked DNA This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. This success, however, does not compare to that of the other methods, leading to research into more efficient methods for delivery of the naked DNA such as electroporation and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas. ### Oligonucleotides The use of synthetic oligonucleotides in gene therapy is to inactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. ### Lipoplexes and polyplexes To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and its entry into the cell must be facilitated. To this end new molecules, lipoplexes and polyplexes, have been created that have the ability to protect the DNA from undesirable degradation during the transfection process. Plasmid DNA can be covered with lipids in an organized structure like a micelle or a liposome. When the organized structure is complexed with DNA it is called a lipoplex. There are three types of lipids, anionic (negatively charged), neutral, or cationic (positively charged). Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time consuming to produce so attention was turned to the cationic versions. Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of “endosomal escaping”. However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was figured out that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages. The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells, so they may be used for treatment of genetic respiratory diseases such as cystic fibrosis. Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their production is regulated by ionic interactions. One large difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot release their DNA load into the cytoplasm, so to this end, co-transfection with endosome-lytic agents (to lyse the endosome that is made during endocytosis, the process by which the polyplex enters the cell) such as inactivated adenovirus must occur. However, this isn't always the case, polymers such as polyethylenimine have their own method of endosome disruption as does chitosan and trimethylchitosan. ## Hybrid methods Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses. ## Dendrimers A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface. In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complimentarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis. In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect a number of cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches. Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity. # Major developments in gene therapy ## 2002 and earlier New gene therapy approach repairs errors in messenger RNA derived from defective genes. This technique has the potential to treat the blood disorder thalassaemia, cystic fibrosis, and some cancers. See Subtle gene therapy tackles blood disorder at NewScientist.com (October 11, 2002). Researchers at Case Western Reserve University and Copernicus Therapeutics are able to create tiny liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane. See DNA nanoballs boost gene therapy at NewScientist.com (May 12, 2002). Sickle cell disease is successfully treated in mice. See Murine Gene Therapy Corrects Symptoms of Sickle Cell Disease from March 18, 2002, issue of The Scientist. The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) held from 2000 and 2002 was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the United States, the United Kingdom, France, Italy, and Germany. (V. Cavazzana-Calvo, Thrasher and Mavilio 2004; see also 'Miracle' gene therapy trial halted at NewScientist.com, October 3, 2002). In 1993 Andrew Gobea was born with a rare, normally fatal genetic disease - severe combined immunodeficiency (SCID). Genetic screening before birth showed that he had SCID. Blood was removed from Andrew's placenta and umbilical cord immediately after birth, containing stem cells. The allele that codes for ADA was obtained and was inserted into a retrovirus. Retroviruses and stem cells were mixed, after which they entered and inserted the gene into the stem cells' chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood system via a vein. For four years T-cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed. ## 2003 In 2003 a University of California, Los Angeles research team inserted genes into the brain using liposomes coated in a polymer called polyethylene glycol (PEG). The transfer of genes into the brain is a significant achievement because viral vectors are too big to get across the "blood-brain barrier." This method has potential for treating Parkinson's disease. See Undercover genes slip into the brain at NewScientist.com (March 20, 2003). RNA interference or gene silencing may be a new way to treat Huntington's. Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced. See Gene therapy may switch off Huntington's at NewScientist.com (March 13, 2003). ## 2006 Scientists at the National Institutes of Health (Bethesda, Maryland) have successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells. This study constitutes the first demonstration that gene therapy can be effective in treating cancer. The study results have been published in Science (October 2006). In May 2006 a team of scientists led by Dr. Luigi Naldini and Dr. Brian Brown from the San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET) in Milan, Italy reported a breakthrough for gene therapy in which they developed a way to prevent the immune system from rejecting a newly delivered gene.[1] Similar to organ transplantation, gene therapy has been plagued by the problem of immune rejection. So far, delivery of the 'normal' gene has been difficult because the immune system recognizes the new gene as foreign and rejects the cells carrying it. To overcome this problem, the HSR-TIGET group utilized a newly uncovered network of genes regulated by molecules known as microRNAs. Dr. Naldini's group reasoned that they could use this natural function of microRNA to selectively turn off the identity of their therapeutic gene in cells of the immune system and prevent the gene from being found and destroyed. The researchers injected mice with the gene containing an immune-cell microRNA target sequence, and spectacularly, the mice did not reject the gene, as previously occurred when vectors without the microRNA target sequence were used. This work will have important implications for the treatment of hemophilia and other genetic diseases by gene therapy. In March 2006 an international group of scientists announced the successful use of gene therapy to treat two adult patients for a disease affecting myeloid cells. The study, published in Nature Medicine, is believed to be the first to show that gene therapy can cure diseases of the myeloid system. ## 2007 On 1 May 2007 Moorfields Eye Hospital and University College London's Institute of Ophthalmology announced the world's first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23 year-old British male, Robert Johnson, in early 2007.[2] Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of the Moorfields/UCL trial were published in New England Journal of Medicine in April 2008. They researched the safety of the subretinal delivery of recombinant adeno associated virus (AAV) carrying RPE65 gene, and found it yielded positive results, with patients having modest increase in vision, and, perhaps more importantly, no apparent side-effects.[3] # Problems and ethics For the safety of gene therapy, the Weismann barrier is fundamental in the current thinking. Soma-to-germline feedback should therefore be impossible. However, there are indications [4] that the Weissman barrier can be breached. One way it might possibly be breached is if the treatment were somehow misapplied and spread to the testes and therefore would infect the germline against the intentions of the therapy. Some of the problems of gene therapy include: - Short-lived nature of gene therapy - Before gene therapy can become a permanent cure for any condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be long-lived and stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent gene therapy from achieving any long-term benefits. Patients will have to undergo multiple rounds of gene therapy. - Immune response - Anytime a foreign object is introduced into human tissues, the immune system has evolved to attack the invader. The risk of stimulating the immune system in a way that reduces gene therapy effectiveness is always a possibility. Furthermore, the immune system's enhanced response to invaders it has seen before makes it difficult for gene therapy to be repeated in patients. - Problems with viral vectors - Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient --toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is always the fear that the viral vector, once inside the patient, may recover its ability to cause disease. - Multigene disorders - Conditions or disorders that arise from mutations in a single gene are the best candidates for gene therapy. Unfortunately, some of the most commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are caused by the combined effects of variations in many genes. Multigene or multifactorial disorders such as these would be especially difficult to treat effectively using gene therapy. - Chance of inducing a tumor (insertional mutagenesis) - If the DNA is integrated in the wrong place in the genome, for example in a tumor suppressor gene, it could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.[4] - Religious concerns - among people who believe that humans were created in God's image, some may consider the alteration of an individual's genes as tampering or corrupting God's work. Deaths have occurred due to gene therapy, including that of Jesse Gelsinger. from:http://www.ornl.gov/sci/techresources/Human_Genome/medicine/genetherapy.shtml # In popular culture - Gene therapy is a crucial plot element in the video game Metal Gear Solid, where it has been used to enhance the battle capabilities of enemy soldiers. - Gene therapy plays a major role in the sci-fi series Stargate Atlantis, as a certain type of alien technology can only be used if one has a certain gene which is given to the members of the team through gene therapy. - Gene therapy also plays a major role in the plot of the James Bond movie Die Another Day. - The Yellow Bastard from Frank Miller's Sin City was also apparently the recipient of gene therapy. - In the The Dark Knight Strikes Again, Dick Grayson, the first Robin, becomes a victim of extensive gene therapy for years by Lex Luthor to become The Joker. - Gene therapy plays a recurring role in the present-time sci-fi television program ReGenesis, where it is used to cure various diseases, enhance athletic performance and produce vast profits for bio-tech corporations. (e.g. an undetectable performance-enhancing gene therapy was used by one of the characters on himself, but to avoid copyright infringement, this gene therapy was modified from the tested-to-be-harmless original, which produced a fatal cardiovascular defect) - Gene therapy is the basis for the plot line of the film I Am Legend. - Gene therapy is an important plot key in the game Bioshock where the game contents refer to plasmids and [gene] splicers. - The book Next by Michael Crichton unravels a story in which fictitious biotechnology companies which experiment with gene therapy are involved. - In the television show Alias, a breakthrough in molecular gene therapy is discovered, whereby a patient's body is reshaped to identically resemble someone else. Protagonist Sydney Bristow's best friend was secretly killed and her "double" resumed her place.	https://www.wikidoc.org/index.php/Gene_therapy
2273d8d482ab10e2bb2f564195e1d28bb7d191df	wikidoc	Generic drug	Generic drug # Overview A generic drug (pl. generic drugs, short: generics) is a drug which is produced and distributed without patent protection. A generic must contain the same active ingredients as the original formulation. In most cases, it is considered bioequivalent to the brand name counterpart with respect to pharmacokinetic and pharmacodynamic properties. By extension, therefore, generics are assumed to be identical in dose, strength, route of administration, safety, efficacy, and intended use. In most cases, generic products are not available until the patent protections afforded to the original developer have expired. When generic products become available, the market competition often leads to substantially lower prices for both the original brand name product and the generic forms. The time it takes a generic drug to appear on the market varies. Drug patents give twenty years of protection, but they are applied for before clinical trials begin, so the effective life of a drug patent tends to be between seven and twelve years. # Economics The principal reason for the relatively low price of generic medicines is that these companies incur fewer costs in creating the generic drug, and are therefore able to maintain profitability while offering the drug at a lower cost to consumers. The costs of these generic drugs are so low that many developing countries can easily afford. For example Thailand is going to import millions of generic version pills of Plavix, a blood-thinning treatment to prevent heart attacks, costs just 3 US cents per pill from India, the leading manufacturer of generic drugs. Generic manufacturers do not incur the cost of drug discovery, and instead are able to reverse-engineer known drug compounds to allow them to manufacture bioequivalent versions. Generic manufacturers also do not bear the burden of proving the safety and efficacy of the drugs through clinical trials, since these trials have already been conducted by the brand name company. In most countries, generic manufacturers must only prove that their preparation is bioequivalent to the existing drug in order to gain regulatory approval. It has been estimated that the average cost to brand-name drug companies of discovering and testing a new innovative drug (with a new chemical entity) may be as much as $800 million. However, these estimations are strongly disputed as much too high. Generic drug companies may also receive the benefit of the previous marketing efforts of the brand-name drug company, including media advertising, presentations by drug representatives, and distribution of free samples. Many of the drugs introduced by generic manufacturers have already been on the market for a decade or more, and may already be well-known to patients and providers (although often under their branded name). Prior to the expiration of a drug patent, a brand name company enjoys a period of "market exclusivity" or monopoly, in which the company is able to set the price of the drug at the level which maximizes profitability. This price often greatly exceeds the production costs of the drug, which can enable the drug company to make a significant profit on their investment in research and development. The advantage of generic drugs to consumers comes in the introduction of competition, which prevents any single company from dictating the overall market price of the drug. With multiple firms, the profit-maximizing price generally reflects the ongoing cost of producing the drug, which is usually much lower than the monopoly price. # Patent issues ## When can a generic drug be produced? When a pharmaceutical company first markets a drug, it is usually under a patent that allows only the pharmaceutical company that developed the drug to sell it. Generic drugs can be legally produced for drugs where: 1) the patent has expired, 2) the generic company certifies the brand company's patents are either invalid, unenforceable or will not be infringed, 3) for drugs which have never held patents, or 4) in countries where a patent(s) is/are not in force. The expiration of a patent removes the monopoly of the patent holder on drug sales licensing. Patent lifetime differs from country to country, and typically there is no way to renew a patent after it expires. A new version of the drug with significant changes to the compound could be patented, but this requires new clinical trials and does not prevent the generic versions of the original drug. This allows the company to recoup the cost of developing that particular drug. After the patent on a drug expires, any pharmaceutical company can manufacture and sell that drug. Since the drug has already been tested and approved, the cost of simply manufacturing the drug will be a fraction of the original cost of testing and developing that particular drug. ## Challenging patents Brand-name drug companies have used a number of strategies to extend the period of market exclusivity on their drugs, and prevent generic competition. This may involve aggressive litigation to preserve or extend patent protection on their medicines, a process referred to by critics as "evergreening." Patents are typically issued on novel pharmacological compounds quite early in the drug development process, at which time the 'clock' to patent expiration begins ticking. Later in the process, drug companies may seek new patents on the production of specific forms of these compounds, such as single enantiomers of drugs which can exist in both "left-handed" and "right-handed" forms, different inactive components in a drug salt, or a specific hydrate form of the drug salt. If granted, these patents 'reset the clock' on patent expiration. These sorts of patents may later be targeted for invalidation by generic drug manufacturers. ## Generic drug exclusivity The U.S. Food and Drug Administration offers a 180 day exclusivity period to generic drug manufacturers in specific cases. During this period only one (or sometimes a few) generic manufacturers can produce the generic version of a drug. This exclusivity period is only used when a generic manufacturer argues that a patent is invalid or is not violated in the generic production of a drug, and the period acts as a reward for the generic manufacturer who is willing to risk liability in court and the cost of patent court litigation. There is often contention around these 180 day exclusivity periods because a generic producer does not have to produce the drug during this period and can file an application first to prevent other generic producers from selling the drug. Large pharmaceutical companies often spend thousands of dollars protecting their patents from generic competition. Apart from litigation, companies use other methods such as reformulation or licensing a subsidiary (or another company) to sell generics under the original patent. Generics sold under license from the patent holder are known as authorized generics; they are not affected by the 180 day exclusivity period as they fall under the patent holder's original drug application. A prime example of how this works is simvastatin (Zocor), a popular drug created and manufactured by U.S. based pharmaceutical Merck & Co., which lost its US patent protection on June 23, 2006. India-based Ranbaxy Laboratories (at the 80-mg strength) and Israel-based Teva Pharmaceutical Industries (at all other strengths) received 180 day exclusivity periods for simvastatin; due to Zocor's popularity, both companies began marketing their products immediately after the patent expired. However, Dr. Reddy's Laboratories also markets an authorized generic version of simvastatin under license from Zocor's manufacturer, Merck & Co.; some packages of Dr. Reddy's simvastatin even show Merck as the actual manufacturer and have Merck's logo on the bottom. # Approval and regulation ## Ensuring bioequivalence Most nations require generic drug manufacturers to prove that their formulation exhibits bioequivalence to the innovator product. Over the past several years there have been studies that have shown the effectiveness and safety of some generic drugs. Generic drugs are always less expensive and can save patients and insurance companies thousands of dollars supposedly without compromising the quality of care. The FDA must approve generic drugs just as innovator drugs must be approved. Bioequivalence, however, does not mean that generic drugs are exactly the same as their innovator product counterparts, as chemical differences do exist. Some doctors and patients emphatically believe that certain generic drugs are not as effective as the products they are meant to replace (ie. Prozac, Oxycontin), and consumers would undoubtedly benefit from more clinical studies done on drug by drug basis. Generic drugs start out at first being fairly expensive, however the price of the generic product decreases as the rate of production increases. As an interesting case study in the use of generic equivalents of name-brand agents, warfarin has been only available under the trade name Coumadin in North America until recently. Warfarin (either under the trade name or the generic equivalent) has a narrow therapeutic window and requires frequent blood tests to make sure patients do not have a subtherapeutic or a toxic level. A study performed in the Canadian province of Ontario showed that replacing Coumadin with generic warfarin was considered safe. In spite of the study, many physicians are not comfortable in allowing their patients to take the branded generic equivalent agents. ## U.S. generics approval process Enacted in 1984, the U.S. Drug Price Competition and Patent Term Restoration Act, informally known as the "Hatch-Waxman Act", standardized U.S. procedures for recognition of generic drugs. An applicant files an Abbreviated New Drug Application (or "ANDA") with the Food and Drug Administration (FDA) and seeks to demonstrate therapeutic equivalence to a specified,previously approved "reference listed drug." When an ANDA is approved, the FDA adds the drug to its Approved Drug Products list, also known as the "Orange Book", and annotates the list to show equivalence between the reference listed drug and the approved generic. The FDA also recognizes drugs using the same ingredients with different bioavailability and divides them into therapeutic equivalence groups. For example, as of 2006 diltiazem hydrochloride had four equivalence groups all using the same active ingredient but considered equivalent only within a group.	Generic drug # Overview A generic drug (pl. generic drugs, short: generics) is a drug which is produced and distributed without patent protection. A generic must contain the same active ingredients as the original formulation. In most cases, it is considered bioequivalent to the brand name counterpart with respect to pharmacokinetic and pharmacodynamic properties. By extension, therefore, generics are assumed to be identical in dose, strength, route of administration, safety, efficacy, and intended use. In most cases, generic products are not available until the patent protections afforded to the original developer have expired. When generic products become available, the market competition often leads to substantially lower prices for both the original brand name product and the generic forms. The time it takes a generic drug to appear on the market varies. Drug patents give twenty years of protection, but they are applied for before clinical trials begin, so the effective life of a drug patent tends to be between seven and twelve years. # Economics The principal reason for the relatively low price of generic medicines is that these companies incur fewer costs in creating the generic drug, and are therefore able to maintain profitability while offering the drug at a lower cost to consumers. The costs of these generic drugs are so low that many developing countries can easily afford. For example Thailand is going to import millions of generic version pills of Plavix, a blood-thinning treatment to prevent heart attacks, costs just 3 US cents per pill from India, the leading manufacturer of generic drugs. Generic manufacturers do not incur the cost of drug discovery, and instead are able to reverse-engineer known drug compounds to allow them to manufacture bioequivalent versions. Generic manufacturers also do not bear the burden of proving the safety and efficacy of the drugs through clinical trials, since these trials have already been conducted by the brand name company. In most countries, generic manufacturers must only prove that their preparation is bioequivalent to the existing drug in order to gain regulatory approval. It has been estimated that the average cost to brand-name drug companies of discovering and testing a new innovative drug (with a new chemical entity) may be as much as $800 million.[1] However, these estimations are strongly disputed as much too high. Generic drug companies may also receive the benefit of the previous marketing efforts of the brand-name drug company, including media advertising, presentations by drug representatives, and distribution of free samples. Many of the drugs introduced by generic manufacturers have already been on the market for a decade or more, and may already be well-known to patients and providers (although often under their branded name). Prior to the expiration of a drug patent, a brand name company enjoys a period of "market exclusivity" or monopoly, in which the company is able to set the price of the drug at the level which maximizes profitability. This price often greatly exceeds the production costs of the drug, which can enable the drug company to make a significant profit on their investment in research and development. The advantage of generic drugs to consumers comes in the introduction of competition, which prevents any single company from dictating the overall market price of the drug. With multiple firms, the profit-maximizing price generally reflects the ongoing cost of producing the drug, which is usually much lower than the monopoly price. # Patent issues ## When can a generic drug be produced? When a pharmaceutical company first markets a drug, it is usually under a patent that allows only the pharmaceutical company that developed the drug to sell it. Generic drugs can be legally produced for drugs where: 1) the patent has expired, 2) the generic company certifies the brand company's patents are either invalid, unenforceable or will not be infringed, 3) for drugs which have never held patents, or 4) in countries where a patent(s) is/are not in force. The expiration of a patent removes the monopoly of the patent holder on drug sales licensing. Patent lifetime differs from country to country, and typically there is no way to renew a patent after it expires. A new version of the drug with significant changes to the compound could be patented, but this requires new clinical trials and does not prevent the generic versions of the original drug. This allows the company to recoup the cost of developing that particular drug. After the patent on a drug expires, any pharmaceutical company can manufacture and sell that drug. Since the drug has already been tested and approved, the cost of simply manufacturing the drug will be a fraction of the original cost of testing and developing that particular drug. ## Challenging patents Brand-name drug companies have used a number of strategies to extend the period of market exclusivity on their drugs, and prevent generic competition. This may involve aggressive litigation to preserve or extend patent protection on their medicines, a process referred to by critics as "evergreening." Patents are typically issued on novel pharmacological compounds quite early in the drug development process, at which time the 'clock' to patent expiration begins ticking. Later in the process, drug companies may seek new patents on the production of specific forms of these compounds, such as single enantiomers of drugs which can exist in both "left-handed" and "right-handed" forms,[2] different inactive components in a drug salt,[3] or a specific hydrate form of the drug salt.[4] If granted, these patents 'reset the clock' on patent expiration. These sorts of patents may later be targeted for invalidation by generic drug manufacturers.[5][6][7] ## Generic drug exclusivity The U.S. Food and Drug Administration offers a 180 day exclusivity period to generic drug manufacturers in specific cases. During this period only one (or sometimes a few) generic manufacturers can produce the generic version of a drug. This exclusivity period is only used when a generic manufacturer argues that a patent is invalid or is not violated in the generic production of a drug, and the period acts as a reward for the generic manufacturer who is willing to risk liability in court and the cost of patent court litigation. There is often contention around these 180 day exclusivity periods because a generic producer does not have to produce the drug during this period and can file an application first to prevent other generic producers from selling the drug. Large pharmaceutical companies often spend thousands of dollars protecting their patents from generic competition. Apart from litigation, companies use other methods such as reformulation or licensing a subsidiary (or another company) to sell generics under the original patent. Generics sold under license from the patent holder are known as authorized generics; they are not affected by the 180 day exclusivity period as they fall under the patent holder's original drug application. A prime example of how this works is simvastatin (Zocor), a popular drug created and manufactured by U.S. based pharmaceutical Merck & Co., which lost its US patent protection on June 23, 2006. India-based Ranbaxy Laboratories (at the 80-mg strength) and Israel-based Teva Pharmaceutical Industries (at all other strengths) received 180 day exclusivity periods for simvastatin; due to Zocor's popularity, both companies began marketing their products immediately after the patent expired. However, Dr. Reddy's Laboratories also markets an authorized generic version of simvastatin under license from Zocor's manufacturer, Merck & Co.; some packages of Dr. Reddy's simvastatin even show Merck as the actual manufacturer and have Merck's logo on the bottom. # Approval and regulation ## Ensuring bioequivalence Most nations require generic drug manufacturers to prove that their formulation exhibits bioequivalence to the innovator product. Over the past several years there have been studies that have shown the effectiveness and safety of some generic drugs. Generic drugs are always less expensive and can save patients and insurance companies thousands of dollars supposedly without compromising the quality of care. The FDA must approve generic drugs just as innovator drugs must be approved. Bioequivalence, however, does not mean that generic drugs are exactly the same as their innovator product counterparts, as chemical differences do exist. Some doctors and patients emphatically believe that certain generic drugs are not as effective as the products they are meant to replace (ie. Prozac, Oxycontin), and consumers would undoubtedly benefit from more clinical studies done on drug by drug basis. Generic drugs start out at first being fairly expensive, however the price of the generic product decreases as the rate of production increases. As an interesting case study in the use of generic equivalents of name-brand agents, warfarin has been only available under the trade name Coumadin in North America until recently. Warfarin (either under the trade name or the generic equivalent) has a narrow therapeutic window and requires frequent blood tests to make sure patients do not have a subtherapeutic or a toxic level. A study performed in the Canadian province of Ontario showed that replacing Coumadin with generic warfarin was considered safe.[8] In spite of the study, many physicians are not comfortable in allowing their patients to take the branded generic equivalent agents.[9] ## U.S. generics approval process Enacted in 1984, the U.S. Drug Price Competition and Patent Term Restoration Act, informally known as the "Hatch-Waxman Act", standardized U.S. procedures for recognition of generic drugs. An applicant files an Abbreviated New Drug Application (or "ANDA") with the Food and Drug Administration (FDA) and seeks to demonstrate therapeutic equivalence to a specified,previously approved "reference listed drug." When an ANDA is approved, the FDA adds the drug to its Approved Drug Products list, also known as the "Orange Book", and annotates the list to show equivalence between the reference listed drug and the approved generic. The FDA also recognizes drugs using the same ingredients with different bioavailability and divides them into therapeutic equivalence groups. For example, as of 2006 diltiazem hydrochloride had four equivalence groups all using the same active ingredient but considered equivalent only within a group.[10]	https://www.wikidoc.org/index.php/Generic
e7aabb0c3a1c3af058dc02b34091a1d1a2f96107	wikidoc	Geochemistry	Geochemistry The field of geochemistry involves study of the chemical composition of the Earth and other planets, chemical processes and reactions that govern the composition of rocks and soils, and the cycles of matter and energy that transport the Earth's chemical components in time and space, and their interaction with the hydrosphere and the atmosphere. The most important fields of geochemistry are: - Isotope geochemistry: Determination of the relative and absolute concentrations of the elements and their isotopes in the earth and on earth's surface. - Examination of the distribution and movements of elements in different parts of the earth (crust, mantle, hydrosphere etc.) and in minerals with the goal to determine the underlying system of distribution and movement. - Cosmochemistry: Analysis of the distribution of elements and their isotopes in the cosmos . - Organic geochemistry: A study of the role of processes and compounds that are derived from living or once-living organisms. - Regional, environmental and exploration geochemistry: Applications to environmental, hydrological and mineral exploration studies. The man considered by most to be the father of modern geochemistry was Victor Goldschmidt, and the ideas of the subject were formed by him in a series of publications from 1922 under the title ‘Geochemische Verteilungsgesetze der Elemente’. See also: Petrology, Important publications in geochemistry # Chemical characteristics The more common rock constituents are nearly all oxides; chlorine, sulfur and fluorine are the only important exceptions to this and their total amount in any rock is usually much less than 1%. F. W. Clarke has calculated that a little more than 47% of the earth's crust consists of oxygen. It occurs principally in combination as oxides, of which the chief are silica, alumina, iron oxides, lime, magnesia, potash and soda. The silica functions principally as an acid, forming silicates, and all the commonest minerals of igneous rocks are of this nature. From a computation based on 1672 analyses of all kinds of rocks Clarke arrived at the following as the average percentage composition: SiO2=59.71, Al2O3=15.41, Fe2O3=2.63, FeO=3.52, MgO=4.36, CaO=4.90, Na2O=3.55, K2O=2.80, H2O=1.52, TiO2=0.60, P2O5=0.22, total 99.22%). All the other constituents occur only in very small quantities, usually much less than 1%. These oxides combine in a haphazard way. The potash and soda, for example, combine to produce feldspars. In some cases they may take other forms, such as nepheline, leucite and muscovite, but in the great majority of instances they are found as felspar. The phosphoric acid with lime forms apatite. The titanium dioxide with ferrous oxide gives rise to ilmenite. Part of the lime forms lime felspar. Magnesia and iron oxides with silica crystallize as olivine or enstatite, or with alumina and lime form the complex ferro-magnesian silicates of which the pyroxenes, amphiboles and biotites are the chief. Any excess of silica above what is required to neutralize the bases will separate out as quartz; excess of alumina crystallizes as corundum. These must be regarded only as general tendencies. It is possible by inspection of a rock analysis to say approximately what minerals the rock will contain, but there are numerous exceptions to any rule which can be laid down. ## Mineral constitution Hence we may say that except in acid or siliceous rocks containing 66% of silica and over, quartz will not be abundant. In basic rocks (containing 60% of silica or less) it is rare and accidental. If magnesia and iron be above the average while silica is low olivine may be expected; where silica is present in greater quantity over ferro-magnesian minerals, such as augite, hornblende, enstatite or biotite, occur rather than olivine. Unless potash is high and silica relatively low leucite will not be present, for leucite does not occur with free quartz. Nepheline, likewise, is usually found in rocks with much soda and comparatively little silica. With high alcalis soda-bearing pyroxenes and amphiboles may be present. The lower the percentage of silica and the alkalis the greater is the prevalence of t lime felspar as contracted with soda or potash felspar. Clarke has calculated the relative abundance of the principal rock-forming minerals with the following results: Apatite=0.6, titanium minerals=1.5, quartz=12.0, felspars=59.5, biotite=3.8, hornblende and pyroxene=16.8, total=94.2%. This, however, can only be a rough approximation. The other determining factor, namely the physical conditions attending consolidation, plays on the whole a smaller part, yet is by no means negligible, as a few instances will prove. There are certain minerals which are practically confined to deep-seated intrusive rocks, e.g. microcline, muscovite, diallage. Leucite is very rare in plutonic masses; many minerals have special peculiarities in microscopic character according to whether they crystallized in depth or near the surface, e.g. hypersthene, orthoclase, quartz. There are some curious instances of rocks having the same chemical composition but consisting of entirely different minerals, e.g. the hornblendite of Gran, in Norway, containing only hornblende, has the same composition as some of the camptonites of the same locality which contain felspar and hornblende of a different variety. In this connection we may repeat what has been said above about the corrosion of porphyritic minerals in igneous rocks. In rhyolites and trachytes early crystals of hornblende and biotite may be found in great numbers partially converted into augite and magnetite. The hornblende and biotite were stable under the pressures and other conditions which obtained below the surface, but unstable at higher levels. In the ground-mass of these rocks augite is almost universally present. But the plutonic representatives of the same magma, granite and syenite contain biotite and hornblende far more commonly than augite. ## Acid, intermediate and basic igneous rocks Those rocks which contain most silica and on crystallizing yield free quartz are erected into a group generally designated the "acid" rocks. Those again which contain least silica and most magnesia and iron, so that quartz is absent while olivine is usually abundant, form the "basic" group. The "intermediate" rocks include those which are characterized by the general absence of both quartz and olivine. An important subdivision of these contains a very high percentage of alkalis, especially soda, and consequently has minerals such as nepheline and leucite not common in other rocks. It is often separated from the others as the "alkali" or "soda" rocks, and there is a corresponding series of basic rocks. Lastly a small sub-group rich in olivine and without felspar has been called the "ultrabasic" rocks. They have very low percentages of silica but much iron and magnesia. Except these last practically all rocks contain felspars or felspathoid minerals. In the acid rocks the common felspars are orthoclase, which perthite, microcline, oligoclase, all having much silica and alkalis. In the basic rocks labradorite, anorthite and bytownite prevail, being rich in lime and poor in silica, potash and soda. Augite is the commonest ferro-magnesian of the basic rocks, but biotite and hornblende are on the whole more frequent in the acid. The rocks which contain leucite or nepheline, either partly or wholly replacing felspar are not included in this table. They are essentially of intermediate or of basic character. We might in consequence regard them as varieties of syenite, diorite, gabbro, etc., in which felspathoid minerals occur, and indeed there are many transitions between syenites of ordinary type and nepheline — or leucite — syenite, and between gabbro or dolerite and theralite or essexite. But as many minerals develop in these "alcali" rocks which are uncommon elsewhere, it is convenient in a purely formal classification like that which is outlined here to treat the whole assemblage as a distinct series. This classification is based essentially on the mineralogical constitution of the igneous rocks. Any chemical distinctions between the different groups, though implied, are relegated to a subordinate position. It is admittedly artificial by it has grown up with the grown of the science and is still adopted as the basis on which more minute subdivisions are erected. The subdivisions are by no means of equal value. The syenites, for example, and the peridotites, are far less important than the granites, diorites and gabbros. Moreover, the effusive andesites do not always correspond to the plutonic diorites but partly also to the gabbros. As the different kinds of rock, regarded as aggregates of minerals, pass gradually into one another, transitional types are very common and are often so important as to receive special names. The quartz-syenites and nordmarkites may be interposed between granite and syenite, the tonalites and adamellites between granite and diorite, the monzoaites between syenite and diorite, norites and hyperites between diorite and gabbro, and so on..	Geochemistry The field of geochemistry involves study of the chemical composition of the Earth and other planets, chemical processes and reactions that govern the composition of rocks and soils, and the cycles of matter and energy that transport the Earth's chemical components in time and space, and their interaction with the hydrosphere and the atmosphere. The most important fields of geochemistry are: - Isotope geochemistry: Determination of the relative and absolute concentrations of the elements and their isotopes in the earth and on earth's surface. - Examination of the distribution and movements of elements in different parts of the earth (crust, mantle, hydrosphere etc.) and in minerals with the goal to determine the underlying system of distribution and movement. - Cosmochemistry: Analysis of the distribution of elements and their isotopes in the cosmos . - Organic geochemistry: A study of the role of processes and compounds that are derived from living or once-living organisms. - Regional, environmental and exploration geochemistry: Applications to environmental, hydrological and mineral exploration studies. The man considered by most to be the father of modern geochemistry was Victor Goldschmidt, and the ideas of the subject were formed by him in a series of publications from 1922 under the title ‘Geochemische Verteilungsgesetze der Elemente’. See also: Petrology, Important publications in geochemistry # Chemical characteristics The more common rock constituents are nearly all oxides; chlorine, sulfur and fluorine are the only important exceptions to this and their total amount in any rock is usually much less than 1%. F. W. Clarke has calculated that a little more than 47% of the earth's crust consists of oxygen. It occurs principally in combination as oxides, of which the chief are silica, alumina, iron oxides, lime, magnesia, potash and soda. The silica functions principally as an acid, forming silicates, and all the commonest minerals of igneous rocks are of this nature. From a computation based on 1672 analyses of all kinds of rocks Clarke arrived at the following as the average percentage composition: SiO2=59.71, Al2O3=15.41, Fe2O3=2.63, FeO=3.52, MgO=4.36, CaO=4.90, Na2O=3.55, K2O=2.80, H2O=1.52, TiO2=0.60, P2O5=0.22, total 99.22%). All the other constituents occur only in very small quantities, usually much less than 1%. These oxides combine in a haphazard way. The potash and soda, for example, combine to produce feldspars. In some cases they may take other forms, such as nepheline, leucite and muscovite, but in the great majority of instances they are found as felspar. The phosphoric acid with lime forms apatite. The titanium dioxide with ferrous oxide gives rise to ilmenite. Part of the lime forms lime felspar. Magnesia and iron oxides with silica crystallize as olivine or enstatite, or with alumina and lime form the complex ferro-magnesian silicates of which the pyroxenes, amphiboles and biotites are the chief. Any excess of silica above what is required to neutralize the bases will separate out as quartz; excess of alumina crystallizes as corundum. These must be regarded only as general tendencies. It is possible by inspection of a rock analysis to say approximately what minerals the rock will contain, but there are numerous exceptions to any rule which can be laid down. ## Mineral constitution Hence we may say that except in acid or siliceous rocks containing 66% of silica and over, quartz will not be abundant. In basic rocks (containing 60% of silica or less) it is rare and accidental. If magnesia and iron be above the average while silica is low olivine may be expected; where silica is present in greater quantity over ferro-magnesian minerals, such as augite, hornblende, enstatite or biotite, occur rather than olivine. Unless potash is high and silica relatively low leucite will not be present, for leucite does not occur with free quartz. Nepheline, likewise, is usually found in rocks with much soda and comparatively little silica. With high alcalis soda-bearing pyroxenes and amphiboles may be present. The lower the percentage of silica and the alkalis the greater is the prevalence of t lime felspar as contracted with soda or potash felspar. Clarke has calculated the relative abundance of the principal rock-forming minerals with the following results: Apatite=0.6, titanium minerals=1.5, quartz=12.0, felspars=59.5, biotite=3.8, hornblende and pyroxene=16.8, total=94.2%. This, however, can only be a rough approximation. The other determining factor, namely the physical conditions attending consolidation, plays on the whole a smaller part, yet is by no means negligible, as a few instances will prove. There are certain minerals which are practically confined to deep-seated intrusive rocks, e.g. microcline, muscovite, diallage. Leucite is very rare in plutonic masses; many minerals have special peculiarities in microscopic character according to whether they crystallized in depth or near the surface, e.g. hypersthene, orthoclase, quartz. There are some curious instances of rocks having the same chemical composition but consisting of entirely different minerals, e.g. the hornblendite of Gran, in Norway, containing only hornblende, has the same composition as some of the camptonites of the same locality which contain felspar and hornblende of a different variety. In this connection we may repeat what has been said above about the corrosion of porphyritic minerals in igneous rocks. In rhyolites and trachytes early crystals of hornblende and biotite may be found in great numbers partially converted into augite and magnetite. The hornblende and biotite were stable under the pressures and other conditions which obtained below the surface, but unstable at higher levels. In the ground-mass of these rocks augite is almost universally present. But the plutonic representatives of the same magma, granite and syenite contain biotite and hornblende far more commonly than augite. ## Acid, intermediate and basic igneous rocks Those rocks which contain most silica and on crystallizing yield free quartz are erected into a group generally designated the "acid" rocks. Those again which contain least silica and most magnesia and iron, so that quartz is absent while olivine is usually abundant, form the "basic" group. The "intermediate" rocks include those which are characterized by the general absence of both quartz and olivine. An important subdivision of these contains a very high percentage of alkalis, especially soda, and consequently has minerals such as nepheline and leucite not common in other rocks. It is often separated from the others as the "alkali" or "soda" rocks, and there is a corresponding series of basic rocks. Lastly a small sub-group rich in olivine and without felspar has been called the "ultrabasic" rocks. They have very low percentages of silica but much iron and magnesia. Except these last practically all rocks contain felspars or felspathoid minerals. In the acid rocks the common felspars are orthoclase, which perthite, microcline, oligoclase, all having much silica and alkalis. In the basic rocks labradorite, anorthite and bytownite prevail, being rich in lime and poor in silica, potash and soda. Augite is the commonest ferro-magnesian of the basic rocks, but biotite and hornblende are on the whole more frequent in the acid. The rocks which contain leucite or nepheline, either partly or wholly replacing felspar are not included in this table. They are essentially of intermediate or of basic character. We might in consequence regard them as varieties of syenite, diorite, gabbro, etc., in which felspathoid minerals occur, and indeed there are many transitions between syenites of ordinary type and nepheline — or leucite — syenite, and between gabbro or dolerite and theralite or essexite. But as many minerals develop in these "alcali" rocks which are uncommon elsewhere, it is convenient in a purely formal classification like that which is outlined here to treat the whole assemblage as a distinct series. This classification is based essentially on the mineralogical constitution of the igneous rocks. Any chemical distinctions between the different groups, though implied, are relegated to a subordinate position. It is admittedly artificial by it has grown up with the grown of the science and is still adopted as the basis on which more minute subdivisions are erected. The subdivisions are by no means of equal value. The syenites, for example, and the peridotites, are far less important than the granites, diorites and gabbros. Moreover, the effusive andesites do not always correspond to the plutonic diorites but partly also to the gabbros. As the different kinds of rock, regarded as aggregates of minerals, pass gradually into one another, transitional types are very common and are often so important as to receive special names. The quartz-syenites and nordmarkites may be interposed between granite and syenite, the tonalites and adamellites between granite and diorite, the monzoaites between syenite and diorite, norites and hyperites between diorite and gabbro, and so on.[1].	https://www.wikidoc.org/index.php/Geochemistry
0f3575a203795804c29dcb0be178e52195ff2106	wikidoc	Gideon Rodan	Gideon Rodan Dr. Gideon Alfred Rodan (born June 14, 1934 in Bucharest, Romania; died January 1 2006 in Bryn Mawr, Pennsylvania) was an American biochemist and osteopath. Rodan studied at the Hebrew University in Jerusalem and at the Weizmann Institute of Science in Rehovot, Israel. He researched the deformation of bone cells. His most notable work was about Osteoporosis. Rodan researched the connection between osteoblasts and osteoclasts and helped to analyse and describe the two. In the 1990s, Rodan, now director of the department for bone biology and osteoporosis at the Merck Research Laboratories, helped to created a compound to block osteoblast-mediated bone-resorption. This compound became known as Alendronate or Fosamax. In further works he examined the role of steroid in bone metabolism and the communication between bones and hormones. From 1970 to 1985, Gideon Rodan taught at the University of Connecticut School of Dental Medicine until he swithched over to Merck. In 1987, Rodan became president of the American Society for Bone and Mineral Research. He was the editor of the book Principles of Bone Biology (1996). Gideon Rodan died on January 1, 2006 of cancer. de:Gideon Rodan	Gideon Rodan Dr. Gideon Alfred Rodan (born June 14, 1934 in Bucharest, Romania; died January 1 2006 in Bryn Mawr, Pennsylvania) was an American biochemist and osteopath. Rodan studied at the Hebrew University in Jerusalem and at the Weizmann Institute of Science in Rehovot, Israel. He researched the deformation of bone cells. His most notable work was about Osteoporosis. Rodan researched the connection between osteoblasts and osteoclasts and helped to analyse and describe the two. In the 1990s, Rodan, now director of the department for bone biology and osteoporosis at the Merck Research Laboratories, helped to created a compound to block osteoblast-mediated bone-resorption. This compound became known as Alendronate or Fosamax. In further works he examined the role of steroid in bone metabolism and the communication between bones and hormones. From 1970 to 1985, Gideon Rodan taught at the University of Connecticut School of Dental Medicine until he swithched over to Merck. In 1987, Rodan became president of the American Society for Bone and Mineral Research. He was the editor of the book Principles of Bone Biology (1996). Gideon Rodan died on January 1, 2006 of cancer. de:Gideon Rodan Template:Persondata Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gideon_Rodan
58f6d6f94133453610dc0ffb047e38a0ee10f442	wikidoc	Giemsa stain	Giemsa stain Giemsa stain, named after Gustav Giemsa, an early malariologist, is used for the histopathological diagnosis of malaria and other parasites. It is a mixture of methylene blue and eosin. The stain is usually prepared from commercially available Giemsa powder. It is specific for the phosphate groups of DNA and attaches itself to regions of DNA where there are high amounts of adenine-thymine bonding. Giemsa stain is used in Giemsa banding, commonly called G-banding, to stain chromosomes and often used to create a karyotype. It can identify chromosomal aberrations such as translocations and interchanges. Giemsa stain is also a differential stain. It can be used to study the adherence of pathogenic bacteria to human cells. It differentially stains human and bacterial cells pink and purple respectively. It can be used for histopathological diagnosis of malaria and some other spirochete and protozoan blood parasites. Also used in Wolbach's tissue stain. Giemsa stain is a classical blood film stain for peripheral blood smears and bone marrow specimens. Erythrocytes stain pink, platelets show a light pale pink, lymphocyte cytoplasm stains sky blue, monocyte cytoplasm stains pale blue, and leukocyte nuclear chromatin stains magenta. Giemsa stain is also used to visualize chromosomes. A thin film of the specimen on a microscope slide is fixed in pure methanol for 30 seconds, by immersing it or by putting a few drops of methanol on the slide. The slide is immersed to a freshly prepared 5% Giemsa stain solution for 20-30 minutes (in emergencies 5-10 minutes in 10% solution can be used), then flushed with tap water and left dry.	Giemsa stain Giemsa stain, named after Gustav Giemsa, an early malariologist, is used for the histopathological diagnosis of malaria and other parasites. It is a mixture of methylene blue and eosin. The stain is usually prepared from commercially available Giemsa powder. It is specific for the phosphate groups of DNA and attaches itself to regions of DNA where there are high amounts of adenine-thymine bonding. Giemsa stain is used in Giemsa banding, commonly called G-banding, to stain chromosomes and often used to create a karyotype. It can identify chromosomal aberrations such as translocations and interchanges. Giemsa stain is also a differential stain. It can be used to study the adherence of pathogenic bacteria to human cells. It differentially stains human and bacterial cells pink and purple respectively. It can be used for histopathological diagnosis of malaria and some other spirochete and protozoan blood parasites. Also used in Wolbach's tissue stain. Giemsa stain is a classical blood film stain for peripheral blood smears and bone marrow specimens. Erythrocytes stain pink, platelets show a light pale pink, lymphocyte cytoplasm stains sky blue, monocyte cytoplasm stains pale blue, and leukocyte nuclear chromatin stains magenta. Giemsa stain is also used to visualize chromosomes. A thin film of the specimen on a microscope slide is fixed in pure methanol for 30 seconds, by immersing it or by putting a few drops of methanol on the slide. The slide is immersed to a freshly prepared 5% Giemsa stain solution for 20-30 minutes (in emergencies 5-10 minutes in 10% solution can be used), then flushed with tap water and left dry. [1]	https://www.wikidoc.org/index.php/Giemsa
0b5987985e12707ca89603802346614e95f39158	wikidoc	Gilteritinib	Gilteritinib # 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 Gilteritinib is a signal transduction inhibitor that is FDA approved for the treatment of given to adults who have relapsed into refractory acute myeloid leukemia. They would also have to have the mutation FLT3 which will be confirmed by an FDA-approved test. There is a Black Box Warning for this drug as shown here. Common adverse reactions include adverse reactions that more than 20% of the patients have are “myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting”. These are the most common. If there is suspicion of an adverse reaction, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Plasma Concentration - After 15 days, the plasma concentration becomes steady - Maximum Concentration: 374 ng/mL - AUC: 6943 ng.h/mL The Data is different in people who are fasting - The Maximum Concentration decreased by 26% - AUC decreased by 10% ### Gilteritinib is indicated for - Given to adult patients who have relapsed into refractory acute myeloid leukemia. They would also have to have the mutation FLT3 which will be confirmed by an FDA-approved test. ### Limitations of Use Patients with Acute Myeloid Lymphoma with the mutation of the receptor tyrosine kinase are administered Gilteritinib. Furthermore, it is prescribed to patients whose acute myeloid lymphoma of that mutation has worsened or returned after trials with other chemotherapy medications ### Dosing Considerations - It is recommended to start off a patient with a dose of 120 mg orally everyday. It does not matter if the patient has had food or not. The response to the medication could take up to 6 months, so keep the dosing going if the patient does not develop hypersensitivity, adverse reactions, or disease progression. - DO NOT CRUSH OR BREAK THE XOSPATA TABLETS. Make sure to keep a scheduled time everyday to administer the pill. If it could not be administered at the correct time, the patient may take the medication on the same day, as long as it is 12 hours before the next dose. - Some dosing modifications include: If the adverse reaction of Posterior Reversible Encephalopathy Syndrome occurs, DISCONTINUE Gilteritinib If pancreatitis is present, temporarily stop Gilteritinib until pancreatitis is resolved. To start up the medication, give patients a daily dose of 80 mg. - If the adverse reaction of Posterior Reversible Encephalopathy Syndrome occurs, DISCONTINUE Gilteritinib - If pancreatitis is present, temporarily stop Gilteritinib until pancreatitis is resolved. To start up the medication, give patients a daily dose of 80 mg. ### Preparation of GILTERITINIB - Patients should make sure they are not allergic to any of the ingredients in Gileritinib. Talk to the medical professional about any potential allergies with other medications or Gilteritinib. - Patients should alert their doctor of the other medications, vitamins, nutritional supplements etc that they are planning on taking along with Gilteritinib. - Patients should talk to their doctor about any prolonged QT intervals they might have had. Some of the symtoms of prolonged QT interval include fainting, loss of consciousness, seizures, or sudden death, a slow, fast, or irregular heartbeat, or low levels of potassium or magnesium in the blood. - Patients should alert their doctors if they plan to or are pregnant, or want to father a child. People with the ability to become pregnant should take a pregnancy test at least 7 days before initiating treatment, use birth control during treatment, and up to 6 months after treatment. Anyone that does not have the ability to become pregent, but has a partner who can, should use birth control during their treatment and for 4 months after their final dose. Gilteritinib may harm the fetus, so patients should call their doctor is they or their partner becomes pregnant during treatment. - Patients should not breastfeed during treatment and 2 months after the last dose. ### Administration of GILTERITINIB - Gilteritinib is administered orally and taken once daily for at least 6 months, or the time length prescribed by the medical practitioner. Gilteritinib does not depend on food, and may be taken with or without food. - Patients should carefully read their prescription label and be aware of what it entails. Patients should follow their prescription label and clarify any misconceptions with their doctors. - Patients should take their prescription exactly as prescribed on the prescription label, not any more or any less of it. They should continue to take the medication even if they do not feel sick. - Gilteritinib should be swallowed as a whole tablet. DO NOT CHEW, SPLIT, OR CRUSH THE TABLETS BEFORE INGESTING THEM. - Medical paractitioners will monitor their patients regularly, and change/stop temporarily or permanently the dose they are administering depending on how the patients react to the medication. Patients should talk to their doctors about how they are feeling. - Patients should not stop taking their daily dose of Gilteritinib without their doctor's consent. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding GILTERITINIB Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding GILTERITINIB 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 GILTERITINIB FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding GILTERITINIB Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding GILTERITINIB Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications Gilteritinib is contraindicated in patients that seem to react badly to the medicine or any of its ingredients. Check the package label to get more information on the ingredients. It is important to note that clinical studies have shown effects of anaphylactic reactions. # Warnings ### Delayed QT Interval The delayed cardiac ventricular repolarization may require temporary discontinuation of Gilteritinib, and dosage reduction. Patients should take an electrocardiogram to confirm proper heart rhythm prior to initializing Gilteritinib dosage, on days 8 and 15 of cycle 1, and before initiating the two successive cycles If the electrocardiogram results demonstrate a QTcF >500 msec, then patients should temporarily discontinue Gilteritinib and reduce the dosage. Patients should talk to their doctor about the dosage reduction. There is a QT prolongation risk for patients who show signs of Hypokalemia or hypomagnesemia. It is important to correct these problems before initiating Gilteritinib. These could be fixed with a potassium rich diet, but patients should talk to their doctor to address the severity and the following steps needed to take. ### Posterior Reversible Encephalopathy Syndrome Patients run a minor risk of developing Posterior Reversible Encephalopathy Syndrome. However, if symptoms such as seizures and altered mental statuses occur, patients should immediately report to a medical professional. Doctors will confirm the development through brain imaging, usually magnetic resonance imaging (MRI). Patients who develop Posterior Encephalopathy Syndrome should IMMEDIATELY discontinue Gilteritinib - There is limited information on monitoring disease manifestations after Gilteritinib Discontinuation ### Infusion Reactions - There is limited information on infusion reactions pertaining to the administration of Gilteritinib - See adverse reactions to monitor symptoms # Adverse Reactions ## Clinical Trials Experience - The clinical trial is based on 292 patients who have relapsed or refractory Acute Myeloid Leukemia (AML). They are given a dose of 120 mg of Gilteritinib daily. This trial’s course time was 3 months, the maximum amount of time patients were exposed to Gilteritinib. - About 8% of the patients immediately discontinued Gilteritinib due to a serious adverse reaction. Some of the reactions that led patients to discontinue include pneumonia , sepsis, and dyspnea. ## Postmarketing Experience There is limited information regarding Gilteritinib Postmarketing Experience in the drug label. # Drug Interactions ### P-gp and Strong CYP3A Inducers Combining use of Gilteritinib with P-gp and strong CYP3A inducers may result in decreased Gilteritinib exposure and decrease its efficacy. Patients should avoid using P-gp and strong CYP3A inducers with Gilteritinib. ### Strong CYP3A Inhibitors Using strong CYP3A inhibitors with Gilteritinib increases Gilteritinib exposure that may lead to toxicity. Patients should talk to their doctors to consider alternative therapies to avoid strong CYP3A inhibitors. If both are essential for the patient's well-being and therapy, monitor patients carefully more frequently for adverse reactions. Immediately dicontinue concomitant use and treatment with Gilteritinib if unacceptable toxicity arises. ### Drugs Targeting 5HT2B Receptor or Sigma Nonspecific Receptor Avoid using Gilteritinib with drugs that target 5HT2B receptors or sigma nonspecific receptors concomitantly because Gilteritinib reduce efficacy of those drugs. If using both are essential, patients and doctors should interact and monitor adverse reactions and drug effect carefully and routinely. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnant women run the risk of drug-associated developmental outcomes, if they are ingesting Gilteritinib. There are no studies available for pregnant women that indicate this, but clinical studies in rats have shown harm. Studies administered Gilteritinib to pregnant rats, and it resulted in fetal developmental outcomes including “embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures.” It is important to note that these outcomes occur regardless the health of the mother. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gilteritinib in women who are pregnant. ### Labor and Delivery The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. ### Nursing Mothers There has been no seen data that proves Gilteritinib or its metabolites were present in human milk. However, since there is a risk of adverse reactions for the child ingesting the milk, medical professionals have advised patients to abstain from breastfeeding until 2 months after the last dose of XOSPATA ### Pediatric Use The safety and efficacy of GILTERITINIB for the treatment of PNH in pediatric patients have not been established. ### Geriatic Use Clinical studies of GILTERITINIB of 292 patients show 41% of the patients were of the age 65 and older, and 13% were of the age 75 and older. There were no serious differences between the administration in younger patients compared to ones that aged 65 and up. ### Gender There is no FDA guidance on the use of GILTERITINIB with respect to specific gender populations. ### Race There is no FDA guidance on the use of GILTERITINIB with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of GILTERITINIB in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of GILTERITINIB in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of GILTERITINIB in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of GILTERITINIB in patients who are immunocompromised. # Administration and Monitoring ### Administration - Gilteritinib is administered orally and taken once daily for at least 6 months, or the time length prescribed by the medical practitioner. Gilteritinib does not depend on food, and may be taken with or without food. - Doctors will monitor patients for adverse reactions (see adverse reactions) ### Monitoring There is limited information regarding Gilteritinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Gilteritinib and IV administrations. # Overdosage There is limited information regarding Andexanet alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Gilteritinib is a powerful and selective inhibitor that detects both the mutations internal tandem duplication(ITD) and the tyrosine kinase domain(TKD) which are both of the FLT3 receptor. Gilteritinib inhibits AXL and ALK as well, as AXL and FLT3 are molecules that contribute to the growth of cancer cells. Gilteritinib actively inhibits the phosphorylation of FLT3 and eventually downstream targets such as STAT5, ERK, and AKT. However, studies have shown in patients with acute myeloid lymphoma that about 30% had a "mutationally activated isoform." The muatations ITD results in poor patient outcomes, and TKD a resistance to the FLT3 tyrosine kinase inhibitors. Furthermore, AXL is associated with producing resistance mechanisms to chemotherapy. There was an interest in FLT3 transmembrane tyrosine kinases. ## Structure There is limited information regarding GILTERITINIB Structure in the drug label. ## Pharmacodynamics ## Pharmacokinetics - Inhibited the receptor tyrosine kinase which regulates FLT3 in acute myeloid luekemia Trials Phase 1 and 2: - Complete response: 41% - Overall Response Rate: 52% - Duration of Response(Median): 20 weeks - Overall Survival(Median): 31 weeks Phase 3: - Complete Remission - Complete Remission with limited blood recovery: 21% of patients - Central Volume of Distribution is approximately 1092 L - Peripheral Volume of Distribution is approximately 1100 L - About 64.5% of the administered dose is excreted in the feces - About 16.4% of the administered dose goes through the urine - Patients are advised not to breastfeed while undergoing treatment with Gilteritinib. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Carcinogenesis have not yet been performed alongside Gilteritinib. The effect of Gilteritinib on the impairment of human fertility is unknown. However, in a study with dogs administered 10 mg/kg per day Gilteritinib in the 4-week study, there was a result of degredation of germ cells and spermatid giant cell formation in the testis. There was also a single cell necrosis of "epididymal duct epithelia of the epididymal head." # Clinical Studies The medicinal value of Gilteritinib was analyzed from five clinical trials Results: - Elimination was through feces - Exposure to the drug (effectiveness) was similar with and without fasting - Administering Gilteritinib with itraconazole(strong P-glycoprotein and CYP3A4 inhibitor) or rifampicin(strong P-glycoprotein and CYP3A inducer) lowered the effectiveness of the drug and altered its structure - Administering Gilteritinib with midazolam(CYP3A4 substrate) did not alter the effectiveness - Hepatic impairment(liver impairment) does not affect the unbound exposure of the drug # How Supplied - The tablets appear light yellow, round-shaped, and film-coated. They have the inscription of Astellas logo and ‘235’ on the same side. - The tablets are 40 mg each, and they come in a child resistant container containing 90 tablets. - The authorized dose for patients on Gilteritinib is 120 mg but may go up to 200 mg is the response from the patient is dissatisfactory ## Storage - XOSPATA tablets should be stored at 20ºC -25ºC (about 68°F to 77°F) - It is ok if the tablets are exposed to temperatures ranging from 15ºC to 30ºC ( about 59°F to 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information It is recommended that patients read the FDA-approved patients labelling. There is a risk that patients may develop Posterior Reversible Encephalopathy Syndrome. Clinical studies and patient reactions have shown rare cases of this reaction. Patients should immediately report any symptoms of PRES to their doctors. These symptoms may include, but are not limited to, seizures and an altered mental status. The medical practitioner will bring the patient in for further evaluation. ### Prolonged QT Interval There is a slightly higher risk patients may develop a prolonged cardiac ventricular depolarization. FDA reports that about 8% of patients in the clinical trial have a period of prolongment greater than 60 milliseconds. If patients find symptoms such as feeling faint, losing consciousness, or arrhythmia, it is recommended they go see a healthcare professional immediately. Patients who may find signs/ symptoms or have a history with hypokalemia or hypomagnesemia should be made aware of the importance of monitoring their electrolytes. ## Pancreatitis Pancreatitis development is rare solely based on taking Gilteritinib. Medical practitioners should advise patients of the risk of developing this disease, and research the symptoms associated with it. Patients should immediately call their doctor if any of the signs arise. Some of the signs and symptoms of pancreatitis include “severe and persistent stomach pain, with or without nausea and vomiting” ### Infusion reactions - There is limited information on infusion reactions relating to Gilteritinib. - See adverse reactions to monitor symtoms # Precautions with Alcohol Alcohol-Gilteritinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Xospata # Look-Alike Drug Names There is limited information regarding GILTERITINIB Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Gilteritinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Uma Maveli[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. # Black Box Warning # Overview Gilteritinib is a signal transduction inhibitor that is FDA approved for the treatment of given to adults who have relapsed into refractory acute myeloid leukemia. They would also have to have the mutation FLT3 which will be confirmed by an FDA-approved test. There is a Black Box Warning for this drug as shown here. Common adverse reactions include adverse reactions that more than 20% of the patients have are “myalgia/arthralgia, transaminase increase, fatigue/malaise, fever, noninfectious diarrhea, dyspnea, edema, rash, pneumonia, nausea, stomatitis, cough, headache, hypotension, dizziness and vomiting”. These are the most common. If there is suspicion of an adverse reaction, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Plasma Concentration - After 15 days, the plasma concentration becomes steady - Maximum Concentration: 374 ng/mL - AUC: 6943 ng.h/mL The Data is different in people who are fasting - The Maximum Concentration decreased by 26% - AUC decreased by 10% ### Gilteritinib is indicated for - Given to adult patients who have relapsed into refractory acute myeloid leukemia. They would also have to have the mutation FLT3 which will be confirmed by an FDA-approved test. ### Limitations of Use Patients with Acute Myeloid Lymphoma with the mutation of the receptor tyrosine kinase are administered Gilteritinib. Furthermore, it is prescribed to patients whose acute myeloid lymphoma of that mutation has worsened or returned after trials with other chemotherapy medications ### Dosing Considerations - It is recommended to start off a patient with a dose of 120 mg orally everyday. It does not matter if the patient has had food or not. The response to the medication could take up to 6 months, so keep the dosing going if the patient does not develop hypersensitivity, adverse reactions, or disease progression. - DO NOT CRUSH OR BREAK THE XOSPATA TABLETS. Make sure to keep a scheduled time everyday to administer the pill. If it could not be administered at the correct time, the patient may take the medication on the same day, as long as it is 12 hours before the next dose. - Some dosing modifications include: If the adverse reaction of Posterior Reversible Encephalopathy Syndrome occurs, DISCONTINUE Gilteritinib If pancreatitis is present, temporarily stop Gilteritinib until pancreatitis is resolved. To start up the medication, give patients a daily dose of 80 mg. - If the adverse reaction of Posterior Reversible Encephalopathy Syndrome occurs, DISCONTINUE Gilteritinib - If pancreatitis is present, temporarily stop Gilteritinib until pancreatitis is resolved. To start up the medication, give patients a daily dose of 80 mg. ### Preparation of GILTERITINIB - Patients should make sure they are not allergic to any of the ingredients in Gileritinib. Talk to the medical professional about any potential allergies with other medications or Gilteritinib. - Patients should alert their doctor of the other medications, vitamins, nutritional supplements etc that they are planning on taking along with Gilteritinib. - Patients should talk to their doctor about any prolonged QT intervals they might have had. Some of the symtoms of prolonged QT interval include fainting, loss of consciousness, seizures, or sudden death, a slow, fast, or irregular heartbeat, or low levels of potassium or magnesium in the blood. - Patients should alert their doctors if they plan to or are pregnant, or want to father a child. People with the ability to become pregnant should take a pregnancy test at least 7 days before initiating treatment, use birth control during treatment, and up to 6 months after treatment. Anyone that does not have the ability to become pregent, but has a partner who can, should use birth control during their treatment and for 4 months after their final dose. Gilteritinib may harm the fetus, so patients should call their doctor is they or their partner becomes pregnant during treatment. - Patients should not breastfeed during treatment and 2 months after the last dose. ### Administration of GILTERITINIB - Gilteritinib is administered orally and taken once daily for at least 6 months, or the time length prescribed by the medical practitioner. Gilteritinib does not depend on food, and may be taken with or without food. - Patients should carefully read their prescription label and be aware of what it entails. Patients should follow their prescription label and clarify any misconceptions with their doctors. - Patients should take their prescription exactly as prescribed on the prescription label, not any more or any less of it. They should continue to take the medication even if they do not feel sick. - Gilteritinib should be swallowed as a whole tablet. DO NOT CHEW, SPLIT, OR CRUSH THE TABLETS BEFORE INGESTING THEM. - Medical paractitioners will monitor their patients regularly, and change/stop temporarily or permanently the dose they are administering depending on how the patients react to the medication. Patients should talk to their doctors about how they are feeling. - Patients should not stop taking their daily dose of Gilteritinib without their doctor's consent. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding GILTERITINIB Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding GILTERITINIB 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 GILTERITINIB FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding GILTERITINIB Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding GILTERITINIB Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications Gilteritinib is contraindicated in patients that seem to react badly to the medicine or any of its ingredients. Check the package label to get more information on the ingredients. It is important to note that clinical studies have shown effects of anaphylactic reactions. # Warnings ### Delayed QT Interval The delayed cardiac ventricular repolarization may require temporary discontinuation of Gilteritinib, and dosage reduction. Patients should take an electrocardiogram to confirm proper heart rhythm prior to initializing Gilteritinib dosage, on days 8 and 15 of cycle 1, and before initiating the two successive cycles If the electrocardiogram results demonstrate a QTcF >500 msec, then patients should temporarily discontinue Gilteritinib and reduce the dosage. Patients should talk to their doctor about the dosage reduction. There is a QT prolongation risk for patients who show signs of Hypokalemia or hypomagnesemia. It is important to correct these problems before initiating Gilteritinib. These could be fixed with a potassium rich diet, but patients should talk to their doctor to address the severity and the following steps needed to take. ### Posterior Reversible Encephalopathy Syndrome Patients run a minor risk of developing Posterior Reversible Encephalopathy Syndrome. However, if symptoms such as seizures and altered mental statuses occur, patients should immediately report to a medical professional. Doctors will confirm the development through brain imaging, usually magnetic resonance imaging (MRI). Patients who develop Posterior Encephalopathy Syndrome should IMMEDIATELY discontinue Gilteritinib - There is limited information on monitoring disease manifestations after Gilteritinib Discontinuation ### Infusion Reactions - There is limited information on infusion reactions pertaining to the administration of Gilteritinib - See adverse reactions to monitor symptoms # Adverse Reactions ## Clinical Trials Experience - The clinical trial is based on 292 patients who have relapsed or refractory Acute Myeloid Leukemia (AML). They are given a dose of 120 mg of Gilteritinib daily. This trial’s course time was 3 months, the maximum amount of time patients were exposed to Gilteritinib. - About 8% of the patients immediately discontinued Gilteritinib due to a serious adverse reaction. Some of the reactions that led patients to discontinue include pneumonia , sepsis, and dyspnea. ## Postmarketing Experience There is limited information regarding Gilteritinib Postmarketing Experience in the drug label. # Drug Interactions ### P-gp and Strong CYP3A Inducers Combining use of Gilteritinib with P-gp and strong CYP3A inducers may result in decreased Gilteritinib exposure and decrease its efficacy. Patients should avoid using P-gp and strong CYP3A inducers with Gilteritinib. ### Strong CYP3A Inhibitors Using strong CYP3A inhibitors with Gilteritinib increases Gilteritinib exposure that may lead to toxicity. Patients should talk to their doctors to consider alternative therapies to avoid strong CYP3A inhibitors. If both are essential for the patient's well-being and therapy, monitor patients carefully more frequently for adverse reactions. Immediately dicontinue concomitant use and treatment with Gilteritinib if unacceptable toxicity arises. ### Drugs Targeting 5HT2B Receptor or Sigma Nonspecific Receptor Avoid using Gilteritinib with drugs that target 5HT2B receptors or sigma nonspecific receptors concomitantly because Gilteritinib reduce efficacy of those drugs. If using both are essential, patients and doctors should interact and monitor adverse reactions and drug effect carefully and routinely. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnant women run the risk of drug-associated developmental outcomes, if they are ingesting Gilteritinib. There are no studies available for pregnant women that indicate this, but clinical studies in rats have shown harm. Studies administered Gilteritinib to pregnant rats, and it resulted in fetal developmental outcomes including “embryo-fetal lethality, suppressed fetal growth, and teratogenicity at maternal exposures.” It is important to note that these outcomes occur regardless the health of the mother. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gilteritinib in women who are pregnant. ### Labor and Delivery The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. ### Nursing Mothers There has been no seen data that proves Gilteritinib or its metabolites were present in human milk. However, since there is a risk of adverse reactions for the child ingesting the milk, medical professionals have advised patients to abstain from breastfeeding until 2 months after the last dose of XOSPATA ### Pediatric Use The safety and efficacy of GILTERITINIB for the treatment of PNH in pediatric patients have not been established. ### Geriatic Use Clinical studies of GILTERITINIB of 292 patients show 41% of the patients were of the age 65 and older, and 13% were of the age 75 and older. There were no serious differences between the administration in younger patients compared to ones that aged 65 and up. ### Gender There is no FDA guidance on the use of GILTERITINIB with respect to specific gender populations. ### Race There is no FDA guidance on the use of GILTERITINIB with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of GILTERITINIB in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of GILTERITINIB in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of GILTERITINIB in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of GILTERITINIB in patients who are immunocompromised. # Administration and Monitoring ### Administration - Gilteritinib is administered orally and taken once daily for at least 6 months, or the time length prescribed by the medical practitioner. Gilteritinib does not depend on food, and may be taken with or without food. - Doctors will monitor patients for adverse reactions (see adverse reactions) ### Monitoring There is limited information regarding Gilteritinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Gilteritinib and IV administrations. # Overdosage There is limited information regarding Andexanet alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action Gilteritinib is a powerful and selective inhibitor that detects both the mutations internal tandem duplication(ITD) and the tyrosine kinase domain(TKD) which are both of the FLT3 receptor. Gilteritinib inhibits AXL and ALK as well, as AXL and FLT3 are molecules that contribute to the growth of cancer cells. Gilteritinib actively inhibits the phosphorylation of FLT3 and eventually downstream targets such as STAT5, ERK, and AKT. However, studies have shown in patients with acute myeloid lymphoma that about 30% had a "mutationally activated isoform." The muatations ITD results in poor patient outcomes, and TKD a resistance to the FLT3 tyrosine kinase inhibitors. Furthermore, AXL is associated with producing resistance mechanisms to chemotherapy. There was an interest in FLT3 transmembrane tyrosine kinases. ## Structure There is limited information regarding GILTERITINIB Structure in the drug label. ## Pharmacodynamics - ## Pharmacokinetics - Inhibited the receptor tyrosine kinase which regulates FLT3 in acute myeloid luekemia Trials Phase 1 and 2: - Complete response: 41% - Overall Response Rate: 52% - Duration of Response(Median): 20 weeks - Overall Survival(Median): 31 weeks Phase 3: - Complete Remission - Complete Remission with limited blood recovery: 21% of patients - Central Volume of Distribution is approximately 1092 L - Peripheral Volume of Distribution is approximately 1100 L - About 64.5% of the administered dose is excreted in the feces - About 16.4% of the administered dose goes through the urine - Patients are advised not to breastfeed while undergoing treatment with Gilteritinib. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, Impairment of Fertility Studies with Carcinogenesis have not yet been performed alongside Gilteritinib. The effect of Gilteritinib on the impairment of human fertility is unknown. However, in a study with dogs administered 10 mg/kg per day Gilteritinib in the 4-week study, there was a result of degredation of germ cells and spermatid giant cell formation in the testis. There was also a single cell necrosis of "epididymal duct epithelia of the epididymal head." # Clinical Studies The medicinal value of Gilteritinib was analyzed from five clinical trials Results: - Elimination was through feces - Exposure to the drug (effectiveness) was similar with and without fasting - Administering Gilteritinib with itraconazole(strong P-glycoprotein and CYP3A4 inhibitor) or rifampicin(strong P-glycoprotein and CYP3A inducer) lowered the effectiveness of the drug and altered its structure - Administering Gilteritinib with midazolam(CYP3A4 substrate) did not alter the effectiveness - Hepatic impairment(liver impairment) does not affect the unbound exposure of the drug # How Supplied - The tablets appear light yellow, round-shaped, and film-coated. They have the inscription of Astellas logo and ‘235’ on the same side. - The tablets are 40 mg each, and they come in a child resistant container containing 90 tablets. - The authorized dose for patients on Gilteritinib is 120 mg but may go up to 200 mg is the response from the patient is dissatisfactory ## Storage - XOSPATA tablets should be stored at 20ºC -25ºC (about 68°F to 77°F) - It is ok if the tablets are exposed to temperatures ranging from 15ºC to 30ºC ( about 59°F to 86°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information It is recommended that patients read the FDA-approved patients labelling. There is a risk that patients may develop Posterior Reversible Encephalopathy Syndrome. Clinical studies and patient reactions have shown rare cases of this reaction. Patients should immediately report any symptoms of PRES to their doctors. These symptoms may include, but are not limited to, seizures and an altered mental status. The medical practitioner will bring the patient in for further evaluation. ### Prolonged QT Interval There is a slightly higher risk patients may develop a prolonged cardiac ventricular depolarization. FDA reports that about 8% of patients in the clinical trial have a period of prolongment greater than 60 milliseconds. If patients find symptoms such as feeling faint, losing consciousness, or arrhythmia, it is recommended they go see a healthcare professional immediately. Patients who may find signs/ symptoms or have a history with hypokalemia or hypomagnesemia should be made aware of the importance of monitoring their electrolytes. ## Pancreatitis Pancreatitis development is rare solely based on taking Gilteritinib. Medical practitioners should advise patients of the risk of developing this disease, and research the symptoms associated with it. Patients should immediately call their doctor if any of the signs arise. Some of the signs and symptoms of pancreatitis include “severe and persistent stomach pain, with or without nausea and vomiting” ### Infusion reactions - There is limited information on infusion reactions relating to Gilteritinib. - See adverse reactions to monitor symtoms # Precautions with Alcohol Alcohol-Gilteritinib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Xospata # Look-Alike Drug Names There is limited information regarding GILTERITINIB Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Gilteritinib
2071586ed6a4adbdbc23d4a0eb844b82a63cd87e	wikidoc	Glabrousness	Glabrousness Glabrousness (from Latin glaber = bald, hairless) is the technical term for an anatomically abnormal lack of hair or down. This may be due to a physical condition, such as alopecia universalis, which causes hair to fall out and/or prevents its growth. More commonly, glabrousness is a result of culturally-motivated hair removal by depilation (surface removal by shaving or dissolving) or epilation (removal of the entire hair, such as waxing or plucking). In botany and mycology, glabrous is an adjective used to describe a morphological feature as smooth, glossy, having no hair or bristles or glaucousness (see also indumentum). Tactile sensitivity is greatest on glabrous skin # Aesthetic removal and fashion Although the appearance of secondary hair on parts of the body is a sign of puberty, in Western cultures it is socially accepted, often encouraged, for women to remove body hair (as hairlessness is considered feminine and often youthful). Commonly depilated areas are the underarms, face, arms and legs; pubic hair may be partially or entirely removed, and at times individuals even depilate areas which are typically left alone, such as the forearms. Conversely, people who oppose the social concepts behind these practices will forego them, whether for personal satisfaction or to make a public statement. In recent years, bodily depilation has increased in popularity among Western males. As with any cosmetic practice, the particulars of hair removal have changed over the years. Male hair removal is a less constant practice, usually due to trends that alternately promote either the smooth, hairless aesthetic or the hairy, natural one. Western female depilation has waxed and waned throughout history and has been significantly influenced by the evolution of clothing in the past century. Leg and underarm shaving became popular again in Western Society with the advent of off-the-shoulder dresses, higher hemlines and transparent stockings. The reduction of the minimum acceptable standards for bodily coverage over the years has resulted in the exposure of more flesh, giving rise to even more extensive hair removal. At present, this has resulted in the Brazilian waxing trend, a term used to describe the partial or full removal of pubic hair, as the thongs worn on Brazilian beaches are too small to conceal very much of it. Indeed, a culture is now emerging around "intimate shaving" and other hair-removal options geared specifically around the pubic area. What was once kept a personal secret is now discussed more openly, though still in carefully non-explicit language, in magazines and on television. # Religion, subculture, and other influences In ancient Egypt, depilation was commonly practiced to prevent infestation by lice. Typically, tweezers were used to pluck out individual hairs. In both Ancient Greece and Rome, the removal of body and pubic hair was common with both men and women, especially in artistic depictions of male and female nudity. Most Muslims believe that the Sunnah directs all adults to remove pubic hair, including that in the armpits and pubic area, as a hygienic measure. In Islam, removing unwanted hair from the body is an act of fitrah. Referring to this, the Prophet is reported to have said “The fitrah is five things: circumcision, trimming the mustache, cutting the nails, plucking the armpit hairs and shaving the pubic hairs” (Al-Bukhari and Muslim). Baptized Sikhs, however, are specifically instructed never to cut, shave, or otherwise remove any hair on their bodies; this is a major tenet of the Sikh faith. In Japan, it is commonplace for women to shave their underarm hair, but not to shave or even trim their pubic hair beyond the requirements of swimwear, etc. The culture of public baths (onsen or sentō) could discourage anyone so inclined, since shaved pubic hair has long been recognized as a sign of extreme sexuality. The fact that Japanese pornography laws originally banned the display of pubic hair per se also indicates that pubic hair is appreciated as an erotic feature in Japanese culture. Traditionally, erotic display in Japan has concentrated more on suggestive concealment rather than nudity which may still be considered commonplace. In the clothes free movement, the term "smoothie" is often used to describe an acomoclitic individual. In the past, such open displays were frowned upon and in some cases, members of clothes-free clubs were actually forbidden to remove their pubic hair: violators could face exclusion from the club. Others have grouped together and formed societies of their own. Depilation has become popular over the past 30 years with smoothies becoming a major percentage at many nudist venues. Athletes may depilate as an enhancement to their abilities. For example, male and female competitive swimmers often remove their body hair and pubic hair in order to help streamline their bodies. # Sexuality To some, hairlessness is aesthetically pleasing and arousing. Such people claim that it enhances sexual activity in ways such as providing a change in sensation and facilitating the performance of oral sex. Many people say that the pleasurable feelings during sex are much more intense when the pubic hair has been shaved leading to stronger orgasms. At times, pubic shaving is explored as a related erotic activity. Individuals less familiar with the practice of pubic hair removal may be taken aback. Additionally, preferring hairlessness is not always a fetish, in either the traditional or the colloquial sense of the word. Paraphilias for glabrousness and depilation exist, but only in a minority of individuals; partially or completely depilated genitalia have become so commonplace in mainstream Western pornography that it is no longer considered a "fetish", leading to the growth of hirsutism porn as a separate niche, although such porn rarely features people with actual hirsutism or abnormal hair growth. # Glabrous skin On the human body, glabrous skin is skin that is hairless. It is found on fingers, palmar surfaces of hands, soles of feet, lips, and penises. Tinea corporis is a mycosis that targets glaborous skin. There are four main types of mechanoreceptors in the glabrous skin of humans; Pacinian corpuscles, Meissner's corpuscles, Merkel's discs, and Ruffini corpuscles.	Glabrousness Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Glabrousness (from Latin glaber = bald, hairless) is the technical term for an anatomically abnormal lack of hair or down. This may be due to a physical condition, such as alopecia universalis, which causes hair to fall out and/or prevents its growth. More commonly, glabrousness is a result of culturally-motivated hair removal by depilation (surface removal by shaving or dissolving) or epilation (removal of the entire hair, such as waxing or plucking). In botany and mycology, glabrous is an adjective used to describe a morphological feature as smooth, glossy, having no hair or bristles or glaucousness (see also indumentum). Tactile sensitivity is greatest on glabrous skin # Aesthetic removal and fashion Although the appearance of secondary hair on parts of the body is a sign of puberty, in Western cultures it is socially accepted, often encouraged, for women to remove body hair (as hairlessness is considered feminine and often youthful). Commonly depilated areas are the underarms, face, arms and legs; pubic hair may be partially or entirely removed, and at times individuals even depilate areas which are typically left alone, such as the forearms. Conversely, people who oppose the social concepts behind these practices will forego them, whether for personal satisfaction or to make a public statement. In recent years, bodily depilation has increased in popularity among Western males.[citation needed] As with any cosmetic practice, the particulars of hair removal have changed over the years. Male hair removal is a less constant practice, usually due to trends that alternately promote either the smooth, hairless aesthetic or the hairy, natural one. Western female depilation has waxed and waned throughout history and has been significantly influenced by the evolution of clothing in the past century. Leg and underarm shaving became popular again in Western Society with the advent of off-the-shoulder dresses, higher hemlines and transparent stockings. The reduction of the minimum acceptable standards for bodily coverage over the years has resulted in the exposure of more flesh, giving rise to even more extensive hair removal.[1] At present, this has resulted in the Brazilian waxing trend, a term used to describe the partial or full removal of pubic hair, as the thongs worn on Brazilian beaches are too small to conceal very much of it. Indeed, a culture is now emerging around "intimate shaving" and other hair-removal options geared specifically around the pubic area. What was once kept a personal secret is now discussed more openly, though still in carefully non-explicit language, in magazines and on television. # Religion, subculture, and other influences In ancient Egypt, depilation was commonly practiced to prevent infestation by lice. Typically, tweezers were used to pluck out individual hairs. In both Ancient Greece and Rome, the removal of body and pubic hair was common with both men and women, especially in artistic depictions of male and female nudity.[citation needed] Most Muslims believe that the Sunnah directs all adults to remove pubic hair, including that in the armpits and pubic area, as a hygienic measure. In Islam, removing unwanted hair from the body is an act of fitrah. Referring to this, the Prophet is reported to have said “The fitrah is five things: circumcision, trimming the mustache, cutting the nails, plucking the armpit hairs and shaving the pubic hairs” (Al-Bukhari and Muslim). Baptized Sikhs, however, are specifically instructed never to cut, shave, or otherwise remove any hair on their bodies; this is a major tenet of the Sikh faith. In Japan, it is commonplace for women to shave their underarm hair, but not to shave or even trim their pubic hair beyond the requirements of swimwear, etc[citation needed]. The culture of public baths (onsen or sentō) could discourage anyone so inclined, since shaved pubic hair has long been recognized as a sign of extreme sexuality[citation needed]. The fact that Japanese pornography laws originally banned the display of pubic hair per se also indicates that pubic hair is appreciated as an erotic feature in Japanese culture[citation needed]. Traditionally, erotic display in Japan has concentrated more on suggestive concealment rather than nudity which may still be considered commonplace.[citation needed] In the clothes free movement, the term "smoothie" is often used to describe an acomoclitic individual. In the past, such open displays were frowned upon and in some cases, members of clothes-free clubs were actually forbidden to remove their pubic hair: violators could face exclusion from the club. Others have grouped together and formed societies of their own. Depilation has become popular over the past 30 years with smoothies becoming a major percentage at many nudist venues.[2] Athletes may depilate as an enhancement to their abilities. For example, male and female competitive swimmers often remove their body hair and pubic hair in order to help streamline their bodies. # Sexuality To some, hairlessness is aesthetically pleasing and arousing. Such people claim that it enhances sexual activity in ways such as providing a change in sensation and facilitating the performance of oral sex. Many people say that the pleasurable feelings during sex are much more intense when the pubic hair has been shaved leading to stronger orgasms. At times, pubic shaving is explored as a related erotic activity. Individuals less familiar with the practice of pubic hair removal may be taken aback. Additionally, preferring hairlessness is not always a fetish, in either the traditional or the colloquial sense of the word. Paraphilias for glabrousness and depilation exist, but only in a minority of individuals; partially or completely depilated genitalia have become so commonplace in mainstream Western pornography that it is no longer considered a "fetish", leading to the growth of hirsutism porn as a separate niche, although such porn rarely features people with actual hirsutism or abnormal hair growth. # Glabrous skin On the human body, glabrous skin is skin that is hairless. It is found on fingers, palmar surfaces of hands, soles of feet, lips, and penises. Tinea corporis is a mycosis that targets glaborous skin. [3] There are four main types of mechanoreceptors in the glabrous skin of humans; Pacinian corpuscles, Meissner's corpuscles, Merkel's discs, and Ruffini corpuscles.	https://www.wikidoc.org/index.php/Glabrousness
7ec2a37ad56f202e3204ace3ab22abf0431f5a36	wikidoc	Glacial Milk	Glacial Milk Glacial Milk is Innovative Technologies Corporation of America's brand of liquid nutritional supplements. This brand includes the following bottled products: - Complete Nutrition - NONI Complete - Coral Calcium Plus - JOINT FORMULA Plus - Hair of the Dog - CARB CRUSHER The company participates in Sam's Club roadshows, offering samples of these liquids to store customers and allowing customers to buy these products in the store during the roadshow. These products have not been evaluated by the Food and Drug Administration (FDA).	Glacial Milk Glacial Milk is Innovative Technologies Corporation of America's brand of liquid nutritional supplements. This brand includes the following bottled products: - Complete Nutrition - NONI Complete - Coral Calcium Plus - JOINT FORMULA Plus - Hair of the Dog - CARB CRUSHER The company participates in Sam's Club roadshows, offering samples of these liquids to store customers and allowing customers to buy these products in the store during the roadshow. These products have not been evaluated by the Food and Drug Administration (FDA). # External links - Product web site Template:Drink-stub Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Glacial_Milk
c760b7d828dc4fc6e54440fd27cc01108d078563	wikidoc	Glossophobia	Glossophobia # Background Glossophobia or speech anxiety is the fear of public speaking. The word glossophobia comes from the Greek Template:Unicode glōssa, meaning tongue, and φόβος phobos, fear or dread. Glossophobia may be a symptom of stage fright. # Symptoms Symptoms include: - intense anxiety prior to, or simply at the thought of having to verbally communicate with any group, - avoidance of events which focus the group's attention on individuals in attendance, - physical distress, nausea, or feelings of panic in such circumstances. The more specific symptoms of speech anxiety can be grouped into three categories: physical, verbal, and non-verbal. Physical symptoms result from the Autonomic Nervous System responding to the situation with a “fight or flight” reaction. These symptoms include acute hearing, increased heart rate, increased blood pressure, dilated pupils, increased perspiration, increased oxygen intake, stiffening of neck/upper back muscles, and dry mouth. The verbal symptoms include, but are not limited to a tense voice, a quivering voice, and repetition of “Umms” and “Ahhs” which tend to comfort anxious speakers. One form of speech anxiety is dysfunctional speech anxiety, in which the intensity of the “fight or flight” response prevents an individual from performing effectively. Many people report stress-induced speech disorders which are only present during public speech. If you don't get up in front of an audience you never have to worry about stage fright. Some glossophobics have been able to dance or perform in public as long as they do not have to speak, or even speak (such as in a play) or sing as long as they cannot see the audience or they feel that they are a character or stage persona rather than presenting as themselves. # Causes The root cause of glossophobia, although occasionally unknown, can usually be attributed to: - a single or multiple traumatic incidents, usually experienced personally but sometimes associated with someone who has, or - a slow build-up from avoiding public speaking over time until it builds into a more severe form of glossophobia -r - a series of beliefs formed early in life some of which have to do with speaking (ex.What I have to say is not important) and some of which have to do with competence and failure (ex. If I fail, I'll be rejected; I'm not capable). The causes of this anxiety are self-defeating thoughts and anxiety-provoking situations. Self-defeating thoughts are thoughts in which the speaker pictures oneself failing, thinking that everything must be perfect, and a desire for complete approval. Situations that provoke anxiety are ones that hold great importance to the speaker, situations in which one is the center of attention, and situations in which the speaker is of subordinate status to the audience. # Help and relief Some organizations, such as Toastmasters International and International Training in Communication, and training courses in public speaking may help to reduce the fear to manageable levels. Self-help materials that address public speaking are among the best selling self-help topics. Some affected people have turned to certain types of drugs, typically beta-blockers to temporarily treat their phobia.	Glossophobia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Glossophobia or speech anxiety is the fear of public speaking. The word glossophobia comes from the Greek Template:Unicode glōssa, meaning tongue, and φόβος phobos, fear or dread. Glossophobia may be a symptom of stage fright. # Symptoms Symptoms include: - intense anxiety prior to, or simply at the thought of having to verbally communicate with any group, - avoidance of events which focus the group's attention on individuals in attendance, - physical distress, nausea, or feelings of panic in such circumstances. The more specific symptoms of speech anxiety can be grouped into three categories: physical, verbal, and non-verbal. Physical symptoms result from the Autonomic Nervous System responding to the situation with a “fight or flight” reaction. These symptoms include acute hearing, increased heart rate, increased blood pressure, dilated pupils, increased perspiration, increased oxygen intake, stiffening of neck/upper back muscles, and dry mouth. The verbal symptoms include, but are not limited to a tense voice, a quivering voice, and repetition of “Umms” and “Ahhs” which tend to comfort anxious speakers. One form of speech anxiety is dysfunctional speech anxiety, in which the intensity of the “fight or flight” response prevents an individual from performing effectively. Many people report stress-induced speech disorders which are only present during public speech. If you don't get up in front of an audience you never have to worry about stage fright. Some glossophobics have been able to dance or perform in public as long as they do not have to speak, or even speak (such as in a play) or sing as long as they cannot see the audience or they feel that they are a character or stage persona rather than presenting as themselves. # Causes The root cause of glossophobia, although occasionally unknown, can usually be attributed to[citation needed]: - a single or multiple traumatic incidents, usually experienced personally but sometimes associated with someone who has, or - a slow build-up from avoiding public speaking over time until it builds into a more severe form of glossophobia or - a series of beliefs formed early in life some of which have to do with speaking (ex.What I have to say is not important) and some of which have to do with competence and failure (ex. If I fail, I'll be rejected; I'm not capable). The causes of this anxiety are self-defeating thoughts and anxiety-provoking situations. Self-defeating thoughts are thoughts in which the speaker pictures oneself failing, thinking that everything must be perfect, and a desire for complete approval. Situations that provoke anxiety are ones that hold great importance to the speaker, situations in which one is the center of attention, and situations in which the speaker is of subordinate status to the audience. # Help and relief Some organizations, such as Toastmasters International and International Training in Communication, and training courses in public speaking may help to reduce the fear to manageable levels. Self-help materials that address public speaking are among the best selling self-help topics. Some affected people have turned to certain types of drugs, typically beta-blockers to temporarily treat their phobia.	https://www.wikidoc.org/index.php/Glossophobia
8fe9ae3db72dec3fbfff0d1912acb499fa9b1822	wikidoc	Glottal stop	Glottal stop The glottal stop or voiceless glottal plosive is a type of consonantal sound, used in many spoken languages. The symbol in the International Phonetic Alphabet that represents this sound is Template:IPA. The glottal stop is the sound made when the vocal cords are pressed together to stop the flow of air and then released; for example, the break separating the syllables of the interjection uh-oh. While this segment is not a phoneme in English, it is present in nearly all dialects of English as an allophone of /t/. Some foreign language learning texts (e.g. Arabic) spend considerable space explaining this sound (in non-technical terms) to English speakers, although most English speakers make this consonant easily and daily. In the traditional Romanization of many languages, such as Arabic, the glottal stop is transcribed with an apostrophe, , and this is the source of the IPA letter Template:IPA. In many Polynesian languages which use the Latin alphabet, however, the glottal stop is written with a reversed apostrophe, (called ‘okina in Hawaiian), which, confusingly, is also used to transcribe the ayin Arabic and is the source of the IPA character for the voiced pharyngeal fricative . # Features Features of the glottal stop: - Its manner of articulation is plosive or stop, which means it is produced by obstructing airflow in the vocal tract. - Its place of articulation is glottal which means it is articulated by the vocal folds. - Its phonation type is voiceless, which means it is produced without vibrations of the vocal cords. - It is an oral consonant, which means air is allowed to escape through the mouth. - Because it is pronounced in the throat; without a component in the mouth, the central/lateral dichotomy does not apply. - The airstream mechanism is pulmonic egressive, which means it is articulated by pushing air out of the lungs and through the vocal tract, rather than from the glottis or the mouth. # Occurrence	Glottal stop Template:Infobox IPA The glottal stop or voiceless glottal plosive is a type of consonantal sound, used in many spoken languages. The symbol in the International Phonetic Alphabet that represents this sound is Template:IPA. The glottal stop is the sound made when the vocal cords are pressed together to stop the flow of air and then released; for example, the break separating the syllables of the interjection uh-oh. While this segment is not a phoneme in English, it is present in nearly all dialects of English as an allophone of /t/. Some foreign language learning texts (e.g. Arabic) spend considerable space explaining this sound (in non-technical terms) to English speakers, although most English speakers make this consonant easily and daily. In the traditional Romanization of many languages, such as Arabic, the glottal stop is transcribed with an apostrophe, <’>, and this is the source of the IPA letter Template:IPA. In many Polynesian languages which use the Latin alphabet, however, the glottal stop is written with a reversed apostrophe, <‘> (called ‘okina in Hawaiian), which, confusingly, is also used to transcribe the ayin Arabic and is the source of the IPA character for the voiced pharyngeal fricative <Template:IPA>. # Features Features of the glottal stop: - Its manner of articulation is plosive or stop, which means it is produced by obstructing airflow in the vocal tract. - Its place of articulation is glottal which means it is articulated by the vocal folds. - Its phonation type is voiceless, which means it is produced without vibrations of the vocal cords. - It is an oral consonant, which means air is allowed to escape through the mouth. - Because it is pronounced in the throat; without a component in the mouth, the central/lateral dichotomy does not apply. - The airstream mechanism is pulmonic egressive, which means it is articulated by pushing air out of the lungs and through the vocal tract, rather than from the glottis or the mouth. # Occurrence	https://www.wikidoc.org/index.php/Glottal_stop
ba03d4afb0bb8401daa519fae5bca3bbdd9ce745	wikidoc	Glucarpidase	Glucarpidase # 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 Glucarpidase is an methotrexate rescue agent that is FDA approved for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Common adverse reactions include paraesthesia, flushing, nausea and/or vomiting, hypotension, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. - Glucarpidase is not indicated for use in patients who exhibit the expected clearance of methotrexate (plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) or those with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate. - Administer Glucarpidase as a single intravenous injection of 50 Units per kg. - Administer Glucarpidase intravenously as a bolus injection over 5 minutes. Flush intravenous line before and after administration of Glucarpidase . - Reconstitute the contents of the vial with 1 mL of sterile saline for injection, USP. - Roll and tilt the vial gently to mix. Do not shake. - Inspect the vial and discard Glucarpidase if the solution is not clear, colorless, and free of particulate matter. - Use reconstituted Glucarpidase immediately or store under refrigeration at 36° to 46°F (2° to 8°C) for up to 4 hours if not used immediately. Glucarpidase contains no preservative and is supplied as a single-use vial. *Discard any unused product. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glucarpidase in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Glucarpidase in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glucarpidase in pediatric patients. # Contraindications - None # Warnings - Serious allergic reactions occurred in less than 1% of patients . - Methotrexate concentrations within 48 hours following administration of Glucarpidase can only be reliably measured by a chromatographic method. DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) is an inactive metabolite of methotrexate resulting from treatment with Glucarpidase . DAMPA interferes with the measurement of methotrexate concentration using immunoassays resulting in an erroneous measurement which overestimates the methotrexate concentration. Due to the long half-life of DAMPA (t1/2 of approximately 9 hours), measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following Glucarpidase administration . - Continue to administer leucovorin after Glucarpidase . Do not administer leucovorin within 2 hours before or after a dose of Glucarpidase because leucovorin is a substrate for Glucarpidase . - For the first 48 hours after Glucarpidase , administer the same leucovorin dose as given prior to Glucarpidase . Beyond 48 hours after Glucarpidase , administer leucovorin based on the measured methotrexate concentration. Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. - Continue hydration and alkalinization of the urine as indicated. # Adverse Reactions ## Clinical Trials Experience - Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with Glucarpidase are paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache. - Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of Glucarpidase cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. - The evaluation of adverse reactions in patients treated with Glucarpidase is confounded by the population in which it was studied, patients with toxic plasma methotrexate levels due to impaired renal function. Adverse reactions related to toxic methotrexate levels due to prolonged methotrexate clearance include myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure. - The safety of Glucarpidase is based on data from 290 patients who were treated in 2 single-arm, open-label, multicenter trials enrolling patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was greater than 50 μmol/L at 24 hours, greater that 5 μmol/L at 48 hours, or greater than 2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration and there was a 2-fold or greater increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate level was greater than 10 μmol/L more than 42 hours after the start of the methotrexate or the plasma level was greater than 2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate and the serum creatinine was greater than 1.5 times the upper limit of normal or the creatinine clearance was less than 60 mL/min at least 12 hours following methotrexate administration. - Study 1, conducted by the National Cancer Institute (NCI), enrolled 184 patients; safety information is available for 149 patients. Glucarpidase was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. Patients with pre-Glucarpidase methotrexate concentrations >100 μmol/L were to receive a second dose of Glucarpidase 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Glucarpidase . - In Study 1, Glucarpidase -related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as "glucarpidase toxicity." Additional safety information was collected from clinical records submitted by treating physicians. This information was abstracted and categorized using the National Cancer Institute (NCI) "Common Terminology Criteria for Adverse Events" (CTCAE) version 3 scale. - The Study 1 population enrolled patients with a median age of 18 years (1 month to 85 years); 63% were male, and the underlying malignancies were osteosarcoma/sarcomas in 32%, and leukemia or lymphoma in 63% of patients. One (n=106) or 2 (n= 30) doses of Glucarpidase were administered intravenously; the number of doses was not specified in 13 patients. Doses ranged from 18 to 98 Units/kg, with a median dose of 49 Units/kg. - Study 2 is an ongoing expanded access program. At the time of data cut-off, 243 patients were enrolled and safety data was available for 141 patients. Glucarpidase was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. The criterion for allowing patients to receive a second glucarpidase dose was not specified in the protocol. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Glucarpidase . - Study 2 enrolled patients with a median age of 17 years (6 months to 85 years); 64% were male, and the underlying malignancies were osteogenic sarcoma in 32%, and leukemia or lymphoma in 62% of patients. One (n=122) or 2 (n= 18) doses of Glucarpidase were administered intravenously; the number of doses was not specified for 1 patient. Doses ranged from 6 to 189 Units/kg, with a median dose of 50 Units/kg. - In Study 2 only Glucarpidase -related adverse reactions were collected and severity was graded according to NCI CTCAE version 3. - Among the 290 patients included in the safety evaluation of Glucarpidase , there were 8 deaths within 30 days of Glucarpidase exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to Glucarpidase . Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1). - As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials, 121 patients who received one (n=99), two (n=21), or three (n=1) doses of Glucarpidase were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following Glucarpidase administration, of which 19 received a single dose of Glucarpidase and 6 received two doses of Glucarpidase . Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies. - Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti-glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of Glucarpidase . However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. - 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 Glucarpidase with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Glucarpidase in the drug label. # Drug Interactions - Leucovorin is a substrate for Glucarpidase . Do not administer leucovorin within 2 hours before or after a dose of Glucarpidase . No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patient’s pre-Glucarpidase methotrexate concentration . - Other potential exogenous substrates of Glucarpidase may include reduced folates and folate antimetabolites. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well controlled studies with Glucarpidase in pregnant women and animal reproduction studies have not been conducted with Glucarpidase . Therefore, it is not known whether Glucarpidase can cause fetal harm when administered to a pregnant woman. Glucarpidase should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glucarpidase in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Glucarpidase during labor and delivery. ### Nursing Mothers - It is not known if Glucarpidase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Glucarpidase is administered to a nursing woman. ### Pediatric Use - The effectiveness of Glucarpidase in pediatric patients was established in Study 1. Of the 22 patients in the efficacy dataset in Study 1, 12 were pediatric patients with ages ranging from 5 to 16 years. Three of the six pediatric patients with a pre-Glucarpidase methotrexate concentration of 1-50 μmol/L achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, while none of the six pediatric patients with a pre-Glucarpidase methotrexate concentration >50 μmol/L achieved a RSCIR . - The pooled clinical safety database for Glucarpidase included data for 147 patients from 1 month up to 17 years of age. No overall differences in safety were observed between these patients and adult patients. ### Geriatic Use - Of the total number of 290 patients in clinical studies of Glucarpidase , 15% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Glucarpidase with respect to specific gender populations. ### Race There is no FDA guidance on the use of Glucarpidase with respect to specific racial populations. ### Renal Impairment - No dose adjustment of Glucarpidase is recommended for patients with renal impairment ### Hepatic Impairment - No specific studies of Glucarpidase in patients with hepatic impairment have been conducted. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Glucarpidase in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Glucarpidase in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Glucarpidase in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Glucarpidase in the drug label. # Overdosage - There are no known cases of overdose with Glucarpidase . # Pharmacology ## Mechanism of Action - Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. Glucarpidase provides an alternative non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment. ## Structure - Glucarpidase (glucarpidase) is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. Each potency Unit corresponds to the enzymatic cleavage of 1 μmol/L of methotrexate per minute at 37°C. - Glucarpidase is supplied as a sterile, preservative-free, white lyophilized powder in single-use vials. Each vial contains 1,000 Units of glucarpidase, lactose monohydrate (10 mg), Tris-HCl (0.6 mg) and zinc acetate dihydrate (0.002 mg). ## Pharmacodynamics - Plasma methotrexate concentrations within 48 hours following administration of Glucarpidase can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays. Following administration of Glucarpidase 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients, and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients ## Pharmacokinetics - The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of Glucarpidase 50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA. - Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours. The mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-inf) was 23.3 μgh/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t1/2 of 9 hours. - The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in four subjects with severe renal impairment (creatinine clearance <30 mL/min). Following an intravenous dose of 50 Units/kg of Glucarpidase , the mean pharmacokinetic parameters were similar to those observed in healthy subjects except for a longer t1/2 of 8.2 hours as compared to 5.6 hours in healthy subjects by the enzymatic assay. - In a study of cancer patients receiving a high-dose methotrexate (≥1 g/m2) and leucovorin rescue regimen, intravenous administration of 50 Units/kg Glucarpidase 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52%, and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93% ## Nonclinical Toxicology - Glucarpidase has not been evaluated in animals for carcinogenic or mutagenic potential or for impairment of fertility. # Clinical Studies - The efficacy of Glucarpidase was evaluated in a subset consisting of 22 treatment-evaluable patients enrolled in Study 1. Study 1 was a single-arm, open-label study in patients who had markedly delayed methotrexate clearance (defined as more than 2 standard deviations greater than the mean excretion curve for methotrexate) secondary to renal dysfunction. All patients received Glucarpidase 50 Units/kg as an intravenous injection over 5 minutes; those patients with pre-Glucarpidase methotrexate concentrations >100 μmol/L were to receive a second dose of Glucarpidase 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Glucarpidase . - Efficacy was evaluated in a subset of patients enrolled in Study 1 who met the inclusion criteria for the study, had a pre-Glucarpidase methotrexate concentration >1 μmol/L, and had both pre- and post-treatment plasma samples available for determination of methotrexate concentration by a chromatographic method analysis. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, defined as an attainment of plasma methotrexate concentration ≤1 μmol/L at 15 minutes that was sustained for up to 8 days following the initial injection. - Of the 22 patients in the efficacy dataset, the median age was 15.5 years (5 to 84 years); 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia or lymphoma (45%). - Ten of the 22 patients achieved RSCIR . Of the 12 patients who failed to achieve RSCIR, 5 patients (23%) attained a transient plasma methotrexate concentration of ≤ 1 μmol/L. In these 5 patients, the median increase of plasma methotrexate concentration from their nadir was 1.4 μmol/L (0.3 to 2.5 μmol/L). - Table 2 summarizes the results of RSCIR and exploratory analyses following the first dose administration of Glucarpidase . An exploratory analysis in subgroups determined by pre-Glucarpidase methotrexate concentration suggests that the likelihood of attaining a RSCIR following the first Glucarpidase injection correlates with the pre-Glucarpidase methotrexate concentration (Table 2). In an additional exploratory analysis, all 9 patients with pre-glucarpidase methotrexate concentrations >50 μmol/L achieved greater than a 95% reduction in methotrexate concentrations for up to 8 days following the initial injection of Glucarpidase although none of them achieved a RSCIR - Six of the seven patients with pre-first dose Glucarpidase methotrexate concentrations >100 μmol/L received a second 50 Units/kg dose of Glucarpidase administered 48 hours after the first dose. Among them, none of the four patients with pre-second dose Glucarpidase methotrexate concentrations >1 μmol/L achieved a RSCIR. The remaining two patients achieved a RSCIR but their pre-second dose Glucarpidase methotrexate concentrations were already ≤1 μmol/L. - There are no controlled trials comparing Glucarpidase plus supportive care to supportive care measures alone in patients with toxic plasma methotrexate concentrations due to impaired renal function, therefore there are no data regarding the effect of Glucarpidase on survival or toxic deaths due to methotrexate. Glucarpidase did not prevent fatal methotrexate toxicity in 3% of patients in the safety population. # How Supplied - Glucarpidase is supplied as a sterile, preservative-free white lyophilized powder in an individually packaged glass vial closed with a bromo butyl elastomeric stopper and blue flip-off seal. 1,000 Units of glucarpidase per vial (1 vial per carton) NDC 50633-210-11 ## Storage - Store Glucarpidase at 36°F to 46°F (2°C to 8°C). Do not freeze. Do not use Glucarpidase after the expiration date on the vial. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Glucarpidase Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Glucarpidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - VORAXAZE® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Glucarpidase Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, 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. # Overview Glucarpidase is an methotrexate rescue agent that is FDA approved for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Common adverse reactions include paraesthesia, flushing, nausea and/or vomiting, hypotension, and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. - Glucarpidase is not indicated for use in patients who exhibit the expected clearance of methotrexate (plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) or those with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate. - Administer Glucarpidase as a single intravenous injection of 50 Units per kg. - Administer Glucarpidase intravenously as a bolus injection over 5 minutes. Flush intravenous line before and after administration of Glucarpidase . - Reconstitute the contents of the vial with 1 mL of sterile saline for injection, USP. - Roll and tilt the vial gently to mix. Do not shake. - Inspect the vial and discard Glucarpidase if the solution is not clear, colorless, and free of particulate matter. - Use reconstituted Glucarpidase immediately or store under refrigeration at 36° to 46°F (2° to 8°C) for up to 4 hours if not used immediately. Glucarpidase contains no preservative and is supplied as a single-use vial. *Discard any unused product. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glucarpidase in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Glucarpidase in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Glucarpidase in pediatric patients. # Contraindications - None # Warnings - Serious allergic reactions occurred in less than 1% of patients . - Methotrexate concentrations within 48 hours following administration of Glucarpidase can only be reliably measured by a chromatographic method. DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) is an inactive metabolite of methotrexate resulting from treatment with Glucarpidase . DAMPA interferes with the measurement of methotrexate concentration using immunoassays resulting in an erroneous measurement which overestimates the methotrexate concentration. Due to the long half-life of DAMPA (t1/2 of approximately 9 hours), measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following Glucarpidase administration . - Continue to administer leucovorin after Glucarpidase . Do not administer leucovorin within 2 hours before or after a dose of Glucarpidase because leucovorin is a substrate for Glucarpidase . - For the first 48 hours after Glucarpidase , administer the same leucovorin dose as given prior to Glucarpidase . Beyond 48 hours after Glucarpidase , administer leucovorin based on the measured methotrexate concentration. Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days. - Continue hydration and alkalinization of the urine as indicated. # Adverse Reactions ## Clinical Trials Experience - Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with Glucarpidase are paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache. - Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of Glucarpidase cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. - The evaluation of adverse reactions in patients treated with Glucarpidase is confounded by the population in which it was studied, patients with toxic plasma methotrexate levels due to impaired renal function. Adverse reactions related to toxic methotrexate levels due to prolonged methotrexate clearance include myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure. - The safety of Glucarpidase is based on data from 290 patients who were treated in 2 single-arm, open-label, multicenter trials enrolling patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was greater than 50 μmol/L at 24 hours, greater that 5 μmol/L at 48 hours, or greater than 2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration and there was a 2-fold or greater increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate level was greater than 10 μmol/L more than 42 hours after the start of the methotrexate or the plasma level was greater than 2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate and the serum creatinine was greater than 1.5 times the upper limit of normal or the creatinine clearance was less than 60 mL/min at least 12 hours following methotrexate administration. - Study 1, conducted by the National Cancer Institute (NCI), enrolled 184 patients; safety information is available for 149 patients. Glucarpidase was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. Patients with pre-Glucarpidase methotrexate concentrations >100 μmol/L were to receive a second dose of Glucarpidase 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Glucarpidase . - In Study 1, Glucarpidase -related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as "glucarpidase toxicity." Additional safety information was collected from clinical records submitted by treating physicians. This information was abstracted and categorized using the National Cancer Institute (NCI) "Common Terminology Criteria for Adverse Events" (CTCAE) version 3 scale. - The Study 1 population enrolled patients with a median age of 18 years (1 month to 85 years); 63% were male, and the underlying malignancies were osteosarcoma/sarcomas in 32%, and leukemia or lymphoma in 63% of patients. One (n=106) or 2 (n= 30) doses of Glucarpidase were administered intravenously; the number of doses was not specified in 13 patients. Doses ranged from 18 to 98 Units/kg, with a median dose of 49 Units/kg. - Study 2 is an ongoing expanded access program. At the time of data cut-off, 243 patients were enrolled and safety data was available for 141 patients. Glucarpidase was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. The criterion for allowing patients to receive a second glucarpidase dose was not specified in the protocol. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Glucarpidase . - Study 2 enrolled patients with a median age of 17 years (6 months to 85 years); 64% were male, and the underlying malignancies were osteogenic sarcoma in 32%, and leukemia or lymphoma in 62% of patients. One (n=122) or 2 (n= 18) doses of Glucarpidase were administered intravenously; the number of doses was not specified for 1 patient. Doses ranged from 6 to 189 Units/kg, with a median dose of 50 Units/kg. - In Study 2 only Glucarpidase -related adverse reactions were collected and severity was graded according to NCI CTCAE version 3. - Among the 290 patients included in the safety evaluation of Glucarpidase , there were 8 deaths within 30 days of Glucarpidase exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to Glucarpidase . Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1). - As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials, 121 patients who received one (n=99), two (n=21), or three (n=1) doses of Glucarpidase were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following Glucarpidase administration, of which 19 received a single dose of Glucarpidase and 6 received two doses of Glucarpidase . Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies. - Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti-glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of Glucarpidase . However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity. - 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 Glucarpidase with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Glucarpidase in the drug label. # Drug Interactions - Leucovorin is a substrate for Glucarpidase . Do not administer leucovorin within 2 hours before or after a dose of Glucarpidase . No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patient’s pre-Glucarpidase methotrexate concentration . - Other potential exogenous substrates of Glucarpidase may include reduced folates and folate antimetabolites. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - There are no adequate and well controlled studies with Glucarpidase in pregnant women and animal reproduction studies have not been conducted with Glucarpidase . Therefore, it is not known whether Glucarpidase can cause fetal harm when administered to a pregnant woman. Glucarpidase should be given to a pregnant woman only if clearly needed. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glucarpidase in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Glucarpidase during labor and delivery. ### Nursing Mothers - It is not known if Glucarpidase is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Glucarpidase is administered to a nursing woman. ### Pediatric Use - The effectiveness of Glucarpidase in pediatric patients was established in Study 1. Of the 22 patients in the efficacy dataset in Study 1, 12 were pediatric patients with ages ranging from 5 to 16 years. Three of the six pediatric patients with a pre-Glucarpidase methotrexate concentration of 1-50 μmol/L achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, while none of the six pediatric patients with a pre-Glucarpidase methotrexate concentration >50 μmol/L achieved a RSCIR . - The pooled clinical safety database for Glucarpidase included data for 147 patients from 1 month up to 17 years of age. No overall differences in safety were observed between these patients and adult patients. ### Geriatic Use - Of the total number of 290 patients in clinical studies of Glucarpidase , 15% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. ### Gender There is no FDA guidance on the use of Glucarpidase with respect to specific gender populations. ### Race There is no FDA guidance on the use of Glucarpidase with respect to specific racial populations. ### Renal Impairment - No dose adjustment of Glucarpidase is recommended for patients with renal impairment ### Hepatic Impairment - No specific studies of Glucarpidase in patients with hepatic impairment have been conducted. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Glucarpidase in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Glucarpidase in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Glucarpidase in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Glucarpidase in the drug label. # Overdosage - There are no known cases of overdose with Glucarpidase . # Pharmacology ## Mechanism of Action - Glucarpidase is a recombinant bacterial enzyme that hydrolyzes the carboxyl-terminal glutamate residue from folic acid and classical antifolates such as methotrexate. Glucarpidase converts methotrexate to its inactive metabolites 4-deoxy-4-amino-N10-methylpteroic acid (DAMPA) and glutamate. Glucarpidase provides an alternative non-renal pathway for methotrexate elimination in patients with renal dysfunction during high-dose methotrexate treatment. ## Structure - Glucarpidase (glucarpidase) is a carboxypeptidase produced by recombinant DNA technology in genetically modified Escherichia coli. Glucarpidase is a 390-amino acid homodimer protein with a molecular weight of 83 kDa. Each potency Unit corresponds to the enzymatic cleavage of 1 μmol/L of methotrexate per minute at 37°C. - Glucarpidase is supplied as a sterile, preservative-free, white lyophilized powder in single-use vials. Each vial contains 1,000 Units of glucarpidase, lactose monohydrate (10 mg), Tris-HCl (0.6 mg) and zinc acetate dihydrate (0.002 mg). ## Pharmacodynamics - Plasma methotrexate concentrations within 48 hours following administration of Glucarpidase can only be reliably measured by a chromatographic method because DAMPA interferes with the immunoassays. Following administration of Glucarpidase 50 Units/kg to patients in Study 1, methotrexate concentration measured by a chromatographic method was reduced by ≥ 97% within 15 minutes in all 22 treatment-evaluable patients, and was maintained at a > 95% reduction up to 8 days in 20 of the 22 patients ## Pharmacokinetics - The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in eight healthy subjects following an intravenous injection of Glucarpidase 50 Units/kg over 5 minutes. Serum glucarpidase activity levels were measured by an enzymatic assay and serum total glucarpidase concentrations were measured by ELISA. - Serum glucarpidase activity levels declined with a mean elimination half-life (t1/2) of 5.6 hours. The mean Cmax was 3.3 μg/mL and the mean area under the curve (AUC0-inf) was 23.3 μg•h/mL. The mean systemic clearance (CL) was 7.5 mL/min. The mean volume of distribution (Vd) was 3.6 L, suggesting that glucarpidase distribution is restricted to plasma volume. The pharmacokinetic parameters derived from the serum total glucarpidase concentrations were similar to those generated by serum glucarpidase activity levels except for a longer t1/2 of 9 hours. - The pharmacokinetics of glucarpidase in the absence of methotrexate were studied in four subjects with severe renal impairment (creatinine clearance <30 mL/min). Following an intravenous dose of 50 Units/kg of Glucarpidase , the mean pharmacokinetic parameters were similar to those observed in healthy subjects except for a longer t1/2 of 8.2 hours as compared to 5.6 hours in healthy subjects by the enzymatic assay. - In a study of cancer patients receiving a high-dose methotrexate (≥1 g/m2) and leucovorin rescue regimen, intravenous administration of 50 Units/kg Glucarpidase 2 hours before leucovorin reduced (6S)-leucovorin AUC0-3h by 33% and Cmax by 52%, and also reduced its active metabolite, (6S)-5-methyltetrahydrofolate, AUC0-3h by 92% and Cmax by 93% ## Nonclinical Toxicology - Glucarpidase has not been evaluated in animals for carcinogenic or mutagenic potential or for impairment of fertility. # Clinical Studies - The efficacy of Glucarpidase was evaluated in a subset consisting of 22 treatment-evaluable patients enrolled in Study 1. Study 1 was a single-arm, open-label study in patients who had markedly delayed methotrexate clearance (defined as more than 2 standard deviations greater than the mean excretion curve for methotrexate) secondary to renal dysfunction. All patients received Glucarpidase 50 Units/kg as an intravenous injection over 5 minutes; those patients with pre-Glucarpidase methotrexate concentrations >100 μmol/L were to receive a second dose of Glucarpidase 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after Glucarpidase . - Efficacy was evaluated in a subset of patients enrolled in Study 1 who met the inclusion criteria for the study, had a pre-Glucarpidase methotrexate concentration >1 μmol/L, and had both pre- and post-treatment plasma samples available for determination of methotrexate concentration by a chromatographic method analysis. The main outcome measure was the proportion of patients who achieved a rapid and sustained clinically important reduction (RSCIR) in plasma methotrexate concentration, defined as an attainment of plasma methotrexate concentration ≤1 μmol/L at 15 minutes that was sustained for up to 8 days following the initial injection. - Of the 22 patients in the efficacy dataset, the median age was 15.5 years (5 to 84 years); 59% were male, and the most common underlying cancers were osteogenic sarcoma (50%) and leukemia or lymphoma (45%). - Ten of the 22 patients achieved RSCIR [45% (95% CI 27, 65%)]. Of the 12 patients who failed to achieve RSCIR, 5 patients (23%) attained a transient plasma methotrexate concentration of ≤ 1 μmol/L. In these 5 patients, the median increase of plasma methotrexate concentration from their nadir was 1.4 μmol/L (0.3 to 2.5 μmol/L). - Table 2 summarizes the results of RSCIR and exploratory analyses following the first dose administration of Glucarpidase . An exploratory analysis in subgroups determined by pre-Glucarpidase methotrexate concentration suggests that the likelihood of attaining a RSCIR following the first Glucarpidase injection correlates with the pre-Glucarpidase methotrexate concentration (Table 2). In an additional exploratory analysis, all 9 patients with pre-glucarpidase methotrexate concentrations >50 μmol/L achieved greater than a 95% reduction in methotrexate concentrations for up to 8 days following the initial injection of Glucarpidase although none of them achieved a RSCIR - Six of the seven patients with pre-first dose Glucarpidase methotrexate concentrations >100 μmol/L received a second 50 Units/kg dose of Glucarpidase administered 48 hours after the first dose. Among them, none of the four patients with pre-second dose Glucarpidase methotrexate concentrations >1 μmol/L achieved a RSCIR. The remaining two patients achieved a RSCIR but their pre-second dose Glucarpidase methotrexate concentrations were already ≤1 μmol/L. - There are no controlled trials comparing Glucarpidase plus supportive care to supportive care measures alone in patients with toxic plasma methotrexate concentrations due to impaired renal function, therefore there are no data regarding the effect of Glucarpidase on survival or toxic deaths due to methotrexate. Glucarpidase did not prevent fatal methotrexate toxicity in 3% of patients in the safety population. # How Supplied - Glucarpidase is supplied as a sterile, preservative-free white lyophilized powder in an individually packaged glass vial closed with a bromo butyl elastomeric stopper and blue flip-off seal. 1,000 Units of glucarpidase per vial (1 vial per carton) NDC 50633-210-11 ## Storage - Store Glucarpidase at 36°F to 46°F (2°C to 8°C). Do not freeze. Do not use Glucarpidase after the expiration date on the vial. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Glucarpidase Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Glucarpidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - VORAXAZE® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Glucarpidase
a984a54518a0b991bcd33ce6c049726f1fbf87d9	wikidoc	Glutethimide	Glutethimide # Overview Glutethimide is a hypnotic sedative that was introduced by Ciba in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms. Doriden was the brand-name version of the drug; it was also available under the brand names Elrodorm, Noxyron, Glimid and others. Both the generic and brand-name forms are very rarely prescribed today. Current production levels in the United States (the annual quota for manufacturing imposed by the DEA has been three grams, enough for six Doriden tablets, for a number of years) point to it only being used in small scale research. # Long term use Long term use rebound effects, which resembled those seen in withdrawal, have anecdotally been described in patients who were still taking a stable dose of the drug. The symptoms included delirium, hallucinosis, convulsions and fever. # Recreational use Glutethimide is a CYP2D6 enzyme inducer. When taken with codeine, it enables the body to convert higher amounts of the codeine (higher than the average 5 - 10%) to morphine. The general sedative effect also adds to the effect of the combination. The effect was also used clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, e.g. as a Substitutionmittel that may be a useful alternative to methadone The combination was known as Dors & Fours, a Six Pack, Loads, etc. as two Doriden tablets and four Tylenol (or Emprin, Emprazil or other drugs) With Codeine No. 4, or plain 60 mg codeine tablets were sold as a set. The demand for this combination, in western Pennsylvania and surrounding areas of other states and perhaps elsewhere, has led to small-scale clandestine synthesis of glutethimide since 1984, a process that is, like methaqualone synthesis, somewhat difficult and fraught with potential bad outcomes when less-than-gifted chemists are doing the deed with industrial-grade precursors without adequate quality control. The fact that the simpler clandestine synthesis of other extinct pharmaceutical depressants like ethchlorvynol, methyprylon, or the oldest barbiturates is not reported would seem to point to a high level of motivation surrounding a unique drug, again much like methaqualone. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, whereas purported methaqualone is in a significant minority of cases found to be inert, or contain diphenhydramine or benzodiazepines The enzyme induction is apparently several times stronger than that induced by promethazine (Phenergan, Atosil), a phenothiazine antihistamine used clinically as an opioid potentiator (Phenergan VC With Codeine, Mepergan (pethidine + promethazine), mixing the antihistamine with alphaprodine and other such drugs in an IV) # Legal status Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances. It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II, after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination. It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g. # Chemistry Glutethimide (2-ethyl-2-phenylgutarimide) is synthesized by addition of 2-phenylbutyronitrile to the methylacrylate (Michael reaction), and the subsequent alkaline hydrolysis of the nitrile group in the obtained compound into an amide group, and the subsequent acidic cyclization of the product into the desired glutethimide. The (R) isomer has a faster onset and more potent anticonvulsant activity in animal models than the (S) isomer.	Glutethimide Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Glutethimide is a hypnotic sedative that was introduced by Ciba[1] in 1954 as a safe alternative to barbiturates to treat insomnia. Before long, however, it had become clear that glutethimide was just as likely to cause addiction and caused similarly severe withdrawal symptoms. Doriden was the brand-name version of the drug; it was also available under the brand names Elrodorm, Noxyron, Glimid and others. Both the generic and brand-name forms are very rarely prescribed today. Current production levels in the United States (the annual quota for manufacturing imposed by the DEA has been three grams, enough for six Doriden tablets, for a number of years) point to it only being used in small scale research. # Long term use Long term use rebound effects, which resembled those seen in withdrawal, have anecdotally been described in patients who were still taking a stable dose of the drug. The symptoms included delirium, hallucinosis, convulsions and fever.[2] # Recreational use Glutethimide is a CYP2D6 enzyme inducer. When taken with codeine, it enables the body to convert higher amounts of the codeine (higher than the average 5 - 10%) to morphine. The general sedative effect also adds to the effect of the combination. The effect was also used clinically, including some research in the 1970s in various countries of using it under carefully monitored circumstances as a form of oral opioid agonist substitution therapy, e.g. as a Substitutionmittel that may be a useful alternative to methadone[3][4] The combination was known as Dors & Fours, a Six Pack, Loads, etc. as two Doriden tablets and four Tylenol (or Emprin, Emprazil or other drugs) With Codeine No. 4, or plain 60 mg codeine tablets were sold as a set. The demand for this combination, in western Pennsylvania and surrounding areas of other states and perhaps elsewhere, has led to small-scale clandestine synthesis of glutethimide since 1984,[5] a process that is, like methaqualone synthesis, somewhat difficult and fraught with potential bad outcomes when less-than-gifted chemists are doing the deed with industrial-grade precursors without adequate quality control. The fact that the simpler clandestine synthesis of other extinct pharmaceutical depressants like ethchlorvynol, methyprylon, or the oldest barbiturates is not reported would seem to point to a high level of motivation surrounding a unique drug, again much like methaqualone. Analysis of confiscated glutethimide seems to invariably show the drug or the results of attempted synthesis, whereas purported methaqualone is in a significant minority of cases found to be inert, or contain diphenhydramine or benzodiazepines [6] The enzyme induction is apparently several times stronger than that induced by promethazine (Phenergan, Atosil), a phenothiazine antihistamine used clinically as an opioid potentiator (Phenergan VC With Codeine, Mepergan (pethidine + promethazine), mixing the antihistamine with alphaprodine and other such drugs in an IV) # Legal status Glutethimide is a Schedule II drug under the Convention on Psychotropic Substances.[7] It was originally a Schedule III drug in the United States under the Controlled Substances Act, but in 1991 it was upgraded to Schedule II,[8] after it was discovered that misuse combined with codeine increased the effect of the codeine and deaths had resulted from the combination.[9][10] It has a DEA ACSCN of 2550 and a 2013 production quota of 3 g. # Chemistry Glutethimide (2-ethyl-2-phenylgutarimide) is synthesized by addition of 2-phenylbutyronitrile to the methylacrylate (Michael reaction), and the subsequent alkaline hydrolysis of the nitrile group in the obtained compound into an amide group, and the subsequent acidic cyclization of the product into the desired glutethimide.[11] The (R) isomer has a faster onset and more potent anticonvulsant activity in animal models than the (S) isomer.[12]	https://www.wikidoc.org/index.php/Glutethimide
e839bf80524a6b7f4ca8e86275c6a2f6edb163fb	wikidoc	Glycogenin-1	Glycogenin-1 Glycogenin-1 is an enzyme that is involved in the biosynthesis of glycogen. This enzyme is important for the function of self-glucosylated to form an oligosaccharide primer that serves as substrate for glycogen synthase. This is done through an inter-subunit mechanism. It also plays a role in glycogen metabolism regulation and in the maximal glycogen levels attaintment in skeletal muscle. Recombinant human glycogenin-1 was expressed in E. coli and purified by using conventional chromatography techniques. # Glycogen metabolism Glycogen is a multi branched polysaccharide. It is the way all the animal cells have to store glucose. In the human body, the two main tissues of glycogen accumulation are liver and skeletal muscle. The concentration of this polysaccharide is superior at the liver, but, due to the major mass of skeletal muscle, that humans have, this tissue contains three quarters of the corporal glycogen. ## Location of glycogen On the one hand, the function of the liver glycogen is to maintain glucose homeostasis as a way to compensate the decrease of glucose levels that is given between meals. Thanks to the presence of the glucose-6-phosphatase enzyme (G6PC), the hepatocytes are capable to turn G6PC to glucose and release it to blood so as to prevent the hypoglycemia. On the other hand, in the skeletal muscle, glycogen is used as an energy source to perform muscular contraction during exercise. The different functions of glycogen in muscles or liver make the regulation mechanisms of its metabolism differ in each tissue. These mechanisms are based mainly in the differences on structure and on the regulations of the enzymes that catalyze the way for its synthesis, glycogen synthase (GS), and for its degradation, glycogen phosphorylase (GF). ## Glycogen synthesis Glycogenin is the initiator of the glycogen biosynthesis. This protein is a glycosyl transferase that have the ability of autoglycosilation using UDP-glucose, which helps in the growth of itself until forming an oligosaccharide made by 8 glucoses. Glycogenin is an oligomer, and it's capable of interacting with several proteins. In recent years, a family of proteins has been identified, the GNIPs (glycogenin-interacting protein), that interacts with glycogenin stimulating its autoglycolsilation activity. ## Glycogenin-1 In humans, two isoforms of glycogenin can be expressed: glycogenin-1, with a molecular weight of 37 kDa and codified by GYG1 gen, which is expressed mostly in muscles; and glycogenin-2, with a molecular weight of 66 kDa and codified by GYG2 gen, which is expressed mainly in liver, cardiac muscle and other types of tissue, but not in skeletal muscle. Glycogenin-1 was described analyzing the glycogen of skeletal muscle. It was determinate that this molecule was united by a covalent bond to each mature molecule of muscular glycogen. # Gene ## Structure The glycogenin-1 gene, which spans over 13kb, consists of seven exons and six introns. Its proximal promoter contains a TATA box, a cyclic AMP responsive element, and two putative Sp1 binding sites in a CpG island, a DNA region with a high frequency of CpG sites. There are also nine E-boxes that bind the basic helix-loop-helix of muscle-specific transcription factors. ## Location and transcription The GYG1 gene is located on the long arm of the chromosome 3, between positions 24 and 25, from base pair 148,709,194 to base pair 148,745,455. Transcription of human glycogenin-1 is mainly initiated at 80bp and 86bp upstream the translator’s codon beginning. Transcriptions factors have different binding sites for its development, some examples are: GATA, activator protein 1 and 2 (AP-1 and AP-2), and numerous potential Octamer-1 binding sites. # Deficiency A Glycogenin-1 deficiency leads to Glycogen storage disease type XV. ## Mutation Deficiency of glycogenin-1 is detected in the sequence of the glycogenin-1 gene, GYG1, which revealed a non-sense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglycosylation of glycogenin-1, which is necessary for the priming of glycogen synthesis in muscle. Autoglycosylation of glycogenin-1 occurs at Tyr195 by a gluose-1-O-tyrosine linkage. An induced missense mutation of this residue results in inactivated autoglycosylation. However, missense mutation affecting some other residues of glycogenin-1 has also been shown to eliminate autoglycosilation. ## Consequences The phenotypic features of the skeletal muscle in a patient with this disorder are muscle glycogen depletion, mitochondrial proliferation, and a marked predominance of slow-twich, oxidative muscle fibres. The mutations in the glycogenin-1 gene GYG1 are also a cause of cardiomyopathy and arrhythmia.	Glycogenin-1 Glycogenin-1 is an enzyme that is involved in the biosynthesis of glycogen. This enzyme is important for the function of self-glucosylated to form an oligosaccharide primer that serves as substrate for glycogen synthase. This is done through an inter-subunit mechanism. It also plays a role in glycogen metabolism regulation and in the maximal glycogen levels attaintment in skeletal muscle. Recombinant human glycogenin-1 was expressed in E. coli and purified by using conventional chromatography techniques.[1] # Glycogen metabolism Glycogen is a multi branched polysaccharide. It is the way all the animal cells have to store glucose. In the human body, the two main tissues of glycogen accumulation are liver and skeletal muscle.[2] The concentration of this polysaccharide is superior at the liver, but, due to the major mass of skeletal muscle, that humans have, this tissue contains three quarters of the corporal glycogen. ## Location of glycogen On the one hand, the function of the liver glycogen is to maintain glucose homeostasis as a way to compensate the decrease of glucose levels that is given between meals. Thanks to the presence of the glucose-6-phosphatase enzyme (G6PC), the hepatocytes are capable to turn G6PC to glucose and release it to blood so as to prevent the hypoglycemia. On the other hand, in the skeletal muscle, glycogen is used as an energy source to perform muscular contraction during exercise. The different functions of glycogen in muscles or liver make the regulation mechanisms of its metabolism differ in each tissue.[3] These mechanisms are based mainly in the differences on structure and on the regulations of the enzymes that catalyze the way for its synthesis, glycogen synthase (GS), and for its degradation, glycogen phosphorylase (GF). ## Glycogen synthesis Glycogenin is the initiator of the glycogen biosynthesis.[4][5] This protein is a glycosyl transferase that have the ability of autoglycosilation using UDP-glucose,[6] which helps in the growth of itself until forming an oligosaccharide made by 8 glucoses. Glycogenin is an oligomer, and it's capable of interacting with several proteins. In recent years, a family of proteins has been identified, the GNIPs (glycogenin-interacting protein), that interacts with glycogenin stimulating its autoglycolsilation activity. ## Glycogenin-1 In humans, two isoforms of glycogenin can be expressed: glycogenin-1, with a molecular weight of 37 kDa and codified by GYG1 gen, which is expressed mostly in muscles; and glycogenin-2, with a molecular weight of 66 kDa and codified by GYG2 gen, which is expressed mainly in liver, cardiac muscle and other types of tissue, but not in skeletal muscle.[7] Glycogenin-1 was described analyzing the glycogen of skeletal muscle. It was determinate that this molecule was united by a covalent bond to each mature molecule of muscular glycogen.[8] # Gene ## Structure The glycogenin-1 gene, which spans over 13kb, consists of seven exons and six introns. Its proximal promoter contains a TATA box, a cyclic AMP responsive element, and two putative Sp1 binding sites in a CpG island, a DNA region with a high frequency of CpG sites. There are also nine E-boxes that bind the basic helix-loop-helix of muscle-specific transcription factors.[9] ## Location and transcription The GYG1 gene is located on the long arm of the chromosome 3, between positions 24 and 25, from base pair 148,709,194 to base pair 148,745,455.[10] Transcription of human glycogenin-1 is mainly initiated at 80bp and 86bp upstream the translator’s codon beginning. Transcriptions factors have different binding sites for its development, some examples are: GATA, activator protein 1 and 2 (AP-1 and AP-2), and numerous potential Octamer-1 binding sites.[11] # Deficiency A Glycogenin-1 deficiency leads to Glycogen storage disease type XV. ## Mutation Deficiency of glycogenin-1 is detected in the sequence of the glycogenin-1 gene, GYG1, which revealed a non-sense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglycosylation of glycogenin-1, which is necessary for the priming of glycogen synthesis in muscle. Autoglycosylation of glycogenin-1 occurs at Tyr195 by a gluose-1-O-tyrosine linkage. An induced missense mutation of this residue results in inactivated autoglycosylation. However, missense mutation affecting some other residues of glycogenin-1 has also been shown to eliminate autoglycosilation. ## Consequences The phenotypic features of the skeletal muscle in a patient with this disorder are muscle glycogen depletion, mitochondrial proliferation, and a marked predominance of slow-twich, oxidative muscle fibres. The mutations in the glycogenin-1 gene GYG1 are also a cause of cardiomyopathy and arrhythmia.[7]	https://www.wikidoc.org/index.php/Glycogenin-1
dd43acd00a17e12b24d528fb13c27b3d23cf2561	wikidoc	Stearic acid	Stearic acid # Overview Stearic acid (IUPAC systematic name: octadecanoic acid) is one of the useful types of saturated fatty acids that come from many animal and vegetable fats and oils. It is a waxy solid, and its chemical formula is CH3(CH2)16COOH. Its name comes from the Greek word stéar (genitive: stéatos), which means tallow. The term stearate is applied to the salts and esters of stearic acid. # Production Stearic acid is prepared by treating animal fat with water at a high pressure and temperature, leading to the hydrolysis of triglycerides. It can also be obtained from the hydrogenation of some unsaturated vegetable oils. Common stearic acid is actually a mix of stearic acid and palmitic acid, although purified stearic acid is available separately. # Uses Stearic acid is useful as an ingredient in making candles, soaps, plastics, oil pastels and cosmetics, and for softening rubber. Stearic acid is used to harden soaps, particularly those made with vegetable oil. Stearic acid is also used as a parting compound when making plaster castings from a plaster piece mold or waste mold and when making the mold from a shellacked clay original. In this use, powdered stearic acid is dissolved in water and the solution is brushed onto the surface to be parted after casting. Esters of stearic acid with ethylene glycol, glycol stearate and glycol distearate are used to produce a pearly effect in shampoos, soaps, and other cosmetic products. They are added to the product in molten form and allowed to crystalize under controlled conditions. In fireworks, stearic acid is often used to coat metal powders such as aluminium and iron. This prevents oxidation allowing compositions to be stored for longer. It is used along with simple sugar or corn syrup as a hardener in candies. # Reactions Stearic acid undergoes the typical reactions of saturated carboxylic acids, notably reduction to stearyl alcohol, and esterification with a range of alcohols. # Metabolism An isotope labeling study in humans concluded that the fraction of dietary stearic acid oxidatively desaturated to oleic acid was 2.4 times higher than the fraction of palmitic acid analogously converted to palmitoleic acid. Also, stearic acid was less likely to be incorporated into cholesterol esters. These findings may indicate that stearic acid is less unhealthy than other saturated fatty acids.	Stearic acid Template:FixHTML Template:Chembox new Template:FixHTML Template:FixHTML Template:FixHTML # Overview Stearic acid (IUPAC systematic name: octadecanoic acid) is one of the useful types of saturated fatty acids that come from many animal and vegetable fats and oils. It is a waxy solid, and its chemical formula is CH3(CH2)16COOH. Its name comes from the Greek word stéar (genitive: stéatos), which means tallow. The term stearate is applied to the salts and esters of stearic acid. # Production Stearic acid is prepared by treating animal fat with water at a high pressure and temperature, leading to the hydrolysis of triglycerides. It can also be obtained from the hydrogenation of some unsaturated vegetable oils. Common stearic acid is actually a mix of stearic acid and palmitic acid, although purified stearic acid is available separately. # Uses Stearic acid is useful as an ingredient in making candles, soaps, plastics, oil pastels and cosmetics, and for softening rubber. Stearic acid is used to harden soaps, particularly those made with vegetable oil. Stearic acid is also used as a parting compound when making plaster castings from a plaster piece mold or waste mold and when making the mold from a shellacked clay original. In this use, powdered stearic acid is dissolved in water and the solution is brushed onto the surface to be parted after casting. Esters of stearic acid with ethylene glycol, glycol stearate and glycol distearate are used to produce a pearly effect in shampoos, soaps, and other cosmetic products. They are added to the product in molten form and allowed to crystalize under controlled conditions. In fireworks, stearic acid is often used to coat metal powders such as aluminium and iron. This prevents oxidation allowing compositions to be stored for longer. It is used along with simple sugar or corn syrup as a hardener in candies. # Reactions Stearic acid undergoes the typical reactions of saturated carboxylic acids, notably reduction to stearyl alcohol, and esterification with a range of alcohols. # Metabolism An isotope labeling study in humans[1] concluded that the fraction of dietary stearic acid oxidatively desaturated to oleic acid was 2.4 times higher than the fraction of palmitic acid analogously converted to palmitoleic acid. Also, stearic acid was less likely to be incorporated into cholesterol esters. These findings may indicate that stearic acid is less unhealthy than other saturated fatty acids.	https://www.wikidoc.org/index.php/Glycol_stearate
6906e92b74a21442e76cc107b9f7972e2cbca1f9	wikidoc	Gonadotropin	Gonadotropin Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. Gonadotropin is sometimes abbreviated Gn. The British spelling is gonadotrophin. # Types The two principal gonadotropins are luteinizing hormone (LH) and follicle stimulating hormone (FSH). Both hormones consist of two peptide chains, an alpha chain and a beta chain, linked by disulfide bonds. LH and FSH share nearly identical alpha chains, while the beta chain provides specificity for receptor interactions. A third human gonadotropin is human chorionic gonadotropin (hCG), produced by the placenta during pregnancy. # Mechanism Gonadotropin receptors are embedded in the surface of the target cell membranes and coupled to the G-protein system. Signals triggered by binding to the receptor are relayed within the cells by the cyclic AMP second messenger system. Gonadotropins are released under the control of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus and preoptic area of the hypothalamus. The gonads — testes and ovaries — are the primary target organs for LH and FSH. The gonadotropins affect multiple cell types and elicit multiple responses from the target organs. As a simplified generalization, LH stimulates the Leydig cells of the testes and the theca cells of the ovaries to produce testosterone (and indirectly estradiol), while FSH stimulates the spermatogenic tissue of the testes and the granulosa cells of ovarian follicles. # Diseases Gonadotropin deficiency due to pituitary disease results in hypogonadism, which can lead to infertility. Treatment include administered gonadotropins, which therefore work as fertility medication. Such can either by produced by extraction and purification from urine or it can be produced by recombinant DNA. Failure or loss of the gonads usually results in elevated levels of LH and FSH in the blood, since the pituitary gland tries to compensate for the insufficient gonads.	Gonadotropin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753 Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. Gonadotropin is sometimes abbreviated Gn. The British spelling is gonadotrophin. # Types The two principal gonadotropins are luteinizing hormone (LH) and follicle stimulating hormone (FSH). Both hormones consist of two peptide chains, an alpha chain and a beta chain, linked by disulfide bonds. LH and FSH share nearly identical alpha chains, while the beta chain provides specificity for receptor interactions. A third human gonadotropin is human chorionic gonadotropin (hCG), produced by the placenta during pregnancy. # Mechanism Gonadotropin receptors are embedded in the surface of the target cell membranes and coupled to the G-protein system. Signals triggered by binding to the receptor are relayed within the cells by the cyclic AMP second messenger system. Gonadotropins are released under the control of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus and preoptic area of the hypothalamus. The gonads — testes and ovaries — are the primary target organs for LH and FSH. The gonadotropins affect multiple cell types and elicit multiple responses from the target organs. As a simplified generalization, LH stimulates the Leydig cells of the testes and the theca cells of the ovaries to produce testosterone (and indirectly estradiol), while FSH stimulates the spermatogenic tissue of the testes and the granulosa cells of ovarian follicles. # Diseases Gonadotropin deficiency due to pituitary disease results in hypogonadism, which can lead to infertility. Treatment include administered gonadotropins, which therefore work as fertility medication. Such can either by produced by extraction and purification from urine or it can be produced by recombinant DNA. Failure or loss of the gonads usually results in elevated levels of LH and FSH in the blood, since the pituitary gland tries to compensate for the insufficient gonads. # External links - Gonadotropins at the US National Library of Medicine Medical Subject Headings (MeSH) - Template:EMedicineDictionary Template:Sex hormones de:Gonadotropine it:Gonadotropina lt:Gonadotropinai simple:Gonadotropin Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gonadotrophin
f838167bb67589a82dc4161ba339f962c3779a68	wikidoc	Gouy balance	Gouy balance The Gouy balance is a simple technique for measuring the magnetic susceptibility of metals or metal complexes. This method was invented by the French scientist Louis Georges Gouy (19 February 1854 - 27 January 1926). A long, cylindrical sample that is to be tested is suspended from a balance, partially entering between the poles of a magnet. The balance measures the apparent change in the mass of the sample as it is repelled or attracted by the region of high magnetic field between the poles. Some commercially available balances have a port at its base for this application. # Notes - ↑ Saunderson, A. (1968). "A permanent magnet Gouy balance". Physics Education. 3: 272–273. doi:10.1088/0031-9120/3/5/007..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}	Gouy balance Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The Gouy balance is a simple technique for measuring the magnetic susceptibility of metals or metal complexes. This method was invented by the French scientist Louis Georges Gouy (19 February 1854 - 27 January 1926). A long, cylindrical sample that is to be tested is suspended from a balance, partially entering between the poles of a magnet. The balance measures the apparent change in the mass of the sample as it is repelled or attracted by the region of high magnetic field between the poles.[1] Some commercially available balances have a port at its base for this application. # Notes - ↑ Saunderson, A. (1968). "A permanent magnet Gouy balance". Physics Education. 3: 272–273. doi:10.1088/0031-9120/3/5/007..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} Template:WH Template:WS	https://www.wikidoc.org/index.php/Gouy_balance
51a21213f95803cef5e2b83f608e4cdf0d0574c9	wikidoc	Graeme Clark	Graeme Clark Professor Graeme Clark AC AO (born 16 August 1935) pioneered the multiple-channel cochlear implant which has brought hearing and speech understanding to tens of thousands of people with severe-to-profound hearing loss in more than 80 countries. He is the founder of the Bionic Ear Institute, which has a Cooperative Research Centre agreement with Cochlear Limited. He was also appointed a Companion of the Order of Australia, made a Fellow of the Royal Society, and has won numerous awards including the Australian Father Of The Year award in 2004 and the Centenary Medal in 2003. Clark was born 16 August, 1935 in Camden, New South Wales to Colin M Clark and Dorothy May Thomas. He was educated at Sydney Boys High School, The Scots College and the University of Sydney.	Graeme Clark Professor Graeme Clark AC AO (born 16 August 1935) pioneered the multiple-channel cochlear implant which has brought hearing and speech understanding to tens of thousands of people with severe-to-profound hearing loss in more than 80 countries. He is the founder of the Bionic Ear Institute, which has a Cooperative Research Centre agreement with Cochlear Limited. He was also appointed a Companion of the Order of Australia, made a Fellow of the Royal Society, and has won numerous awards including the Australian Father Of The Year award in 2004 and the Centenary Medal in 2003. Clark was born 16 August, 1935 in Camden, New South Wales to Colin M Clark and Dorothy May Thomas. He was educated at Sydney Boys High School, The Scots College and the University of Sydney.[1]	https://www.wikidoc.org/index.php/Graeme_Clark
dae9771a6b95a85c2f4f9798afa5ccf0945818e4	wikidoc	Gramicidin S	Gramicidin S Gramicidin S or Gramicidin Soviet is an antibiotic effective against some Gram positive and Gram negative bacteria as well as some fungi. It is a derivative of gramicidin, produced by the Gram positive bacterium Bacillus brevis. Gramicidin S is a cyclodecapeptide, constructed as two identical pentapeptides joined head to tail, formally written as cyclo(-Val-Orn-Leu-D-Phe-Pro-)2. That is to say, it forms a ring structure composed of five different amino acids, each one used twice within the structure.Another interesting point is that it utilizes two amino acids uncommon in peptides: ornithine as well as the unnatural stereoisomer of phenylalanine. It is synthesized by gramicidin S synthetase. # History Gramicidin S was discovered by Russian microbiologist Georgyi Frantsevitch Gause and his wife Maria Brazhnikovain 1942. Within the year Gramicidin S was being used in Soviet military hospitals to treat infection and eventually found usage at the front lines of combat by 1946.Gause was awarded the Stalin Prize for Medicine for his discovery in 1946. In 1944, Gramicind S was sent by the Soviet Ministry of Health to Great Britain via the International Red Cross in a collaborative effort to establish the exact structure. English chemist Richard Synge proved that the compound was an original antibiotic and a polypeptide using paper chromatography. He would later go on to receive the Nobel Prize for his work in chromatography. The crystal structure was finally established by Dorothy Hodgkin and Gerchardt Schmidt. The importance of Gramicidin S and antibiotic research in general was so great that Gause was not persecuted during the period of Lysenkoism in the USSR, while many of his colleagues were being executed. Indeed, it was his need for developing new strains to mass produce antibiotics that allowed politically sanctioned collaborations with geneticists like Joseph Rapoport and Alexander Malinovsky, who would both actively participate in the downfall of Lysenkoism. # Structure and Pharmacological effect Structurally, Gramicidin S differs from Gramicidin D, which is a linear peptide and forms a beta helix in cellular membranes. The mode of action is not entirely agreed upon, but it is generally accepted that it is the disruption of the barrier properties of cellular membranes which causes cell death. Recent research revels that Gramicind S interacts more so with with anionic membranes (such as those of bacteria) vs. zwitterionic membranes and more fluid membranes. It has a molecular mass of ca. 1,140 and is a solid, usually encapsulated in two-percent sterile spirit solution. In vitro assays show it has a MIC of 5-15 μg/mL. # Use Gramicidin S has historically been employed as a topical antibiotic for the treatment of infections from superficial wounds. It exhibits strong antibiotic activity against a broad spectrum of Gram negative and Gram-positive bacteria and against several pathogenic fungi. Like Gramicidin D, Gramicidin S causes hemolysis at low concentrations, thus is not an effective drug for the treatment of systematic infections. Additionally, Gramicidin S has been employed as a spermicide and therapeutic for genital ulcers caused by sexually transmitted disease.	Gramicidin S Gramicidin S or Gramicidin Soviet[1] is an antibiotic effective against some Gram positive and Gram negative bacteria as well as some fungi. It is a derivative of gramicidin, produced by the Gram positive bacterium Bacillus brevis. Gramicidin S is a cyclodecapeptide, constructed as two identical pentapeptides joined head to tail, formally written as cyclo(-Val-Orn-Leu-D-Phe-Pro-)2. That is to say, it forms a ring structure composed of five different amino acids, each one used twice within the structure.[2]Another interesting point is that it utilizes two amino acids uncommon in peptides: ornithine as well as the unnatural stereoisomer of phenylalanine. It is synthesized by gramicidin S synthetase.[3] # History Gramicidin S was discovered by Russian microbiologist Georgyi Frantsevitch Gause and his wife Maria Brazhnikovain 1942. Within the year Gramicidin S was being used in Soviet military hospitals to treat infection and eventually found usage at the front lines of combat by 1946.[4]Gause was awarded the Stalin Prize for Medicine for his discovery in 1946. In 1944, Gramicind S was sent by the Soviet Ministry of Health to Great Britain via the International Red Cross in a collaborative effort to establish the exact structure. English chemist Richard Synge proved that the compound was an original antibiotic and a polypeptide using paper chromatography[5]. He would later go on to receive the Nobel Prize for his work in chromatography. The crystal structure was finally established by Dorothy Hodgkin and Gerchardt Schmidt. The importance of Gramicidin S and antibiotic research in general was so great that Gause was not persecuted during the period of Lysenkoism in the USSR, while many of his colleagues were being executed. Indeed, it was his need for developing new strains to mass produce antibiotics that allowed politically sanctioned collaborations with geneticists like Joseph Rapoport and Alexander Malinovsky, who would both actively participate in the downfall of Lysenkoism.[6] # Structure and Pharmacological effect Structurally, Gramicidin S differs from Gramicidin D, which is a linear peptide and forms a beta helix in cellular membranes. The mode of action is not entirely agreed upon, but it is generally accepted that it is the disruption of the barrier properties of cellular membranes which causes cell death. Recent research revels that Gramicind S interacts more so with with anionic membranes (such as those of bacteria) vs. zwitterionic membranes and more fluid membranes.[8] It has a molecular mass of ca. 1,140 and is a solid, usually encapsulated in two-percent sterile spirit solution. In vitro assays show it has a MIC of 5-15 μg/mL.[9] # Use Gramicidin S has historically been employed as a topical antibiotic for the treatment of infections from superficial wounds. It exhibits strong antibiotic activity against a broad spectrum of Gram negative and Gram-positive bacteria and against several pathogenic fungi. Like Gramicidin D, Gramicidin S causes hemolysis at low concentrations, thus is not an effective drug for the treatment of systematic infections. Additionally, Gramicidin S has been employed as a spermicide and therapeutic for genital ulcers caused by sexually transmitted disease[10].	https://www.wikidoc.org/index.php/Gramicidin_S
92ac9a825590f35a6147d0660db52866023021af	wikidoc	Granule cell	Granule cell # Overview In neuroscience, granule cells refer to tiny neurons (a type of cell) that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum, layer 4 of cerebral cortex, the dentate gyrus of the hippocampus, and in the olfactory bulb. While anatomically similar, granule cells in different brain regions are functionally diverse. For instance, olfactory bulb granule cells are GABAergic and axonless, while granule cells in the dentate gyrus have glutamatergic projection axons. Interestingly, these two populations of granule cells are also the only major neuronal populations that undergo adult neurogenesis, while cerebellar and cortical granule cells do not. Cerebellar granule cells account for nearly half of the neurons in the central nervous system. Granule cells receive excitatory input from mossy fibers originating from pontine nuclei. Cerebellar granule cells send parallel fibers up through the Purkinje layer into the molecular layer where they branch out and spread through Purkinje cell dendritic arbors. These parallel fibers form thousands of excitatory synapses with Purkinje cells. Layer 4 granule cells of the cerebral cortex receive driving inputs from thalamus and convey driving inputs largely to supragranular layers 2-3, but also to infragranular layers of the cerebral cortex.	Granule cell Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In neuroscience, granule cells refer to tiny neurons (a type of cell) that are around 10 micrometres in diameter. Granule cells are found within the granular layer of the cerebellum, layer 4 of cerebral cortex, the dentate gyrus of the hippocampus, and in the olfactory bulb. While anatomically similar, granule cells in different brain regions are functionally diverse. For instance, olfactory bulb granule cells are GABAergic and axonless, while granule cells in the dentate gyrus have glutamatergic projection axons. Interestingly, these two populations of granule cells are also the only major neuronal populations that undergo adult neurogenesis, while cerebellar and cortical granule cells do not. Cerebellar granule cells account for nearly half of the neurons in the central nervous system. Granule cells receive excitatory input from mossy fibers originating from pontine nuclei. Cerebellar granule cells send parallel fibers up through the Purkinje layer into the molecular layer where they branch out and spread through Purkinje cell dendritic arbors. These parallel fibers form thousands of excitatory synapses with Purkinje cells. Layer 4 granule cells of the cerebral cortex receive driving inputs from thalamus and convey driving inputs largely to supragranular layers 2-3, but also to infragranular layers of the cerebral cortex. # External links - Template:BrainMaps de:Körnerzelle Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Granular_cell
54137630c5c03448ecebc44ee1c632878953af33	wikidoc	Greek citron	Greek citron The Greek citron is called "Citrus Medica variety etrog" because of its major use for the Jewish ritual during the Feast of Tabernacles. Initially, it was mainly grown on the island of Corfu, but nowadays not one citron tree is found on that island. As of today, it is the leading variety in Israel. The variety is best selling for the religious ritual, because of its natural beauty, and usually persistent style and stigma. It could still be found in some Greek Islands for e.g. Crete and Naxos where they are distilling it into certain special liqueurs, but for the ritual use it is mostly cultivated only in Israel. This Greek Citron got into use for the Ashkenazic community during the wars of Napoleon, when the Yanova Citron import was ceased due to the battles. The use of a newly imported citron was questioned during decades, regarding the poor information about grafting or hybridization. Rabbi Efraim Zalman Margalioth in his response Beis Efraim (volume 1;56) verified in his time that no grafted trees are found on the grounds of Corfu. This certification as well as the lenient position of many other authorities eventually permitted the Esrog. While the Greek market expanded, citrons were also imported from the shores of Greece itself, especially from the regions of Parga, Rapiza and Agia. Several conflicts arose if those plantations are in the same state of kashrus each to another, and to the ones of the Corfu Island. # Introduction to Israel At the same time (about 1850) effort was done by Sir Moshe Montifuri to establish Esrog plantation in Israel, in order to help the Jewish settlers to survive from hunger and pain. As the Beladdi of Palestine was not so greatful in shape, color etc., with almost no persistent style, the Sephardic settlers who were always lenient about the Corfu, planted their seeds into coastal region of Israel, especially in region of Jaffa. During days, the Arabic farmers imported cutting from Greece which were budded onto lemon rootstock. Besides, the Corfu variety which they called Kabbud abu Nunia (-the citron with persistent style) suffered difficulties to acclimatize in the Palestinian land, and grafting started to be practiced in a large scale. The Sephardic rabbis, as well as some Ashkenazic, permitted the citrons of Jaffa upon inspection prior to pick each and every citron. The major Ashkenazic authorities of Jerusalem permitted only the Beladdi which was mainly grown around the towns of Safed, Sh'khem or the Arabic village Um el-Fahm. Also the plantations near Tiberias were accepted. According to the Hebrew writer "Osof Gur", in his work named Toldos Hoesrog Beretz Yisroel, the variety is distinct by crispiness and slight sweetness in the inner rind. The pulp is high Acid.	Greek citron The Greek citron is called "Citrus Medica variety etrog" because of its major use for the Jewish ritual during the Feast of Tabernacles. Initially, it was mainly grown on the island of Corfu, but nowadays not one citron tree is found on that island. As of today, it is the leading variety in Israel. The variety is best selling for the religious ritual, because of its natural beauty, and usually persistent style and stigma. It could still be found in some Greek Islands for e.g. Crete and Naxos where they are distilling it into certain special liqueurs, but for the ritual use it is mostly cultivated only in Israel. This Greek Citron got into use for the Ashkenazic community during the wars of Napoleon, when the Yanova Citron import was ceased due to the battles. The use of a newly imported citron was questioned during decades, regarding the poor information about grafting or hybridization. Rabbi Efraim Zalman Margalioth in his response Beis Efraim (volume 1;56) verified in his time that no grafted trees are found on the grounds of Corfu. This certification as well as the lenient position of many other authorities eventually permitted the Esrog. While the Greek market expanded, citrons were also imported from the shores of Greece itself, especially from the regions of Parga, Rapiza and Agia. Several conflicts arose if those plantations are in the same state of kashrus each to another, and to the ones of the Corfu Island. # Introduction to Israel At the same time (about 1850) effort was done by Sir Moshe Montifuri to establish Esrog plantation in Israel, in order to help the Jewish settlers to survive from hunger and pain. As the Beladdi of Palestine was not so greatful in shape, color etc., with almost no persistent style, the Sephardic settlers who were always lenient about the Corfu, planted their seeds into coastal region of Israel, especially in region of Jaffa. During days, the Arabic farmers imported cutting from Greece which were budded onto lemon rootstock. Besides, the Corfu variety which they called Kabbud abu Nunia (-the citron with persistent style) suffered difficulties to acclimatize in the Palestinian land, and grafting started to be practiced in a large scale. The Sephardic rabbis, as well as some Ashkenazic, permitted the citrons of Jaffa upon inspection prior to pick each and every citron. The major Ashkenazic authorities of Jerusalem permitted only the Beladdi which was mainly grown around the towns of Safed, Sh'khem or the Arabic village Um el-Fahm. Also the plantations near Tiberias were accepted. According to the Hebrew writer "Osof Gur", in his work named Toldos Hoesrog Beretz Yisroel, the variety is distinct by crispiness and slight sweetness in the inner rind. The pulp is high Acid.	https://www.wikidoc.org/index.php/Greek_citron
845e6500b06ccc71b52e5eac0ad94b60e682daf6	wikidoc	Griseofulvin	Griseofulvin # 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 Griseofulvin is a antifungal that is FDA approved for the {{{indicationType}}} of ringworm infections. Common adverse reactions include skin rashes, urticaria, erythema multiform-like drug reactions, and angioneurotic edema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Griseofulvin ultramicrosize is indicated for the treatment of the following ringworm infections; tinea corporis (ringworm of the body), tinea pedis (athlete's foot), tinea cruris (ringworm of the groin and thigh), tinea barbae (barber's itch), tinea capitis (ringworm of the scalp), and tinea unguium (onychomycosis, ringworm of the nails), when caused by one or more of the following genera of fungi: Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Trichophyton interdigitalis,Trichophyton verrucosum, Trichophyton megnini, Trichophyton gallinae, Trichophyton crateriform, Trichophyton sulphureum, Trichophyton schoenleini, Microsporum audouini, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. NOTE: Prior to therapy, the type of fungi responsible for the infection should be identified. The use of the drug is not justified in minor or trivial infections which will respond to topical agents alone. Griseofulvin is not effective in the following: bacterial infections, candidiasis (moniliasis), histoplasmosis, actinomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, North American blastomycosis, cryptococcosis (torulosis), tinea versicolor and nocardiosis. - Daily administration of 375 mg (as a single dose or in divided doses) will give a satisfactory response in most patients with tinea corporis, tinea cruris, and tinea capitis. For those fungal infections more difficult to eradicate, such as tinea pedis and tinea unguium, a divided dose of 750 mg is recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Griseofulvin in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Griseofulvin 500 mg daily for 2 to 4 weeks. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Griseofulvin ultramicrosize is indicated for the treatment of the following ringworm infections; tinea corporis (ringworm of the body), tinea pedis (athlete's foot), tinea cruris (ringworm of the groin and thigh), tinea barbae (barber's itch), tinea capitis (ringworm of the scalp), and tinea unguium (onychomycosis, ringworm of the nails), when caused by one or more of the following genera of fungi: Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Trichophyton interdigitalis,Trichophyton verrucosum, Trichophyton megnini, Trichophyton gallinae, Trichophyton crateriform, Trichophyton sulphureum, Trichophyton schoenleini, Microsporum audouini, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. NOTE: Prior to therapy, the type of fungi responsible for the infection should be identified. The use of the drug is not justified in minor or trivial infections which will respond to topical agents alone. Griseofulvin is not effective in the following: bacterial infections, candidiasis (moniliasis), histoplasmosis, actinomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, North American blastomycosis, cryptococcosis (torulosis), tinea versicolor and nocardiosis. - Approximately 3.3 mg per pound of body weight per day of ultramicrosize griseofulvin is an effective dose for most pediatric patients. On this basis, the following dosage schedule is suggested: Children weighing 35-60 pounds - 125 mg to 187.5 mg daily. Pediatric patients weighing over 60 pounds - 187.5 mg to 375 mg daily. Children and infants 2 years of age and younger - dosage has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Griseofulvin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Griseofulvin in pediatric patients. # Contraindications - Two cases of conjoined twins have been reported since 1977 in patients taking griseofulvin during the first trimester of pregnancy. Griseofulvin should not be prescribed to pregnant patients. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - This drug is contraindicated in patients with porphyria or hepatocellular failure and in individuals with a history of hypersensitivity to griseofulvin. # Warnings - Prophylactic Usage - Safety and efficacy of griseofulvin for prophylaxis of fungal infections have not been established. - Serious Skin Reactions - Severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) and erythema multiforme have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. If severe skin reactions occur, griseofulvin should be discontinued. - Hepatotoxicity - Elevations in AST, ALT, bilirubin, and jaundice have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. Patients should be monitored for hepatic adverse events and discontinuation of griseofulvin considered if warranted. - Animal Toxicology - Chronic feeding of griseofulvin, at levels ranging from 0.5%-2.5% of the diet resulted in the development of liver tumors in several strains of mice, particularly in males. Smaller particle sizes result in an enhanced effect. Lower oral dosage levels have not been tested. Subcutaneous administration of relatively small doses of griseofulvin once a week during the first three weeks of life has also been reported to induce hepatomata in mice. Thyroid tumors, mostly adenomas but some carcinomas, have been reported in male rats receiving griseofulvin at levels of 2.0%, 1.0% and 0.2% of the diet, and in female rats receiving the two higher dose levels. Although studies in other animal species have not yielded evidence of tumorigenicity, these studies were not of adequate design to form a basis for conclusion in this regard. In subacute toxicity studies, orally administered griseofulvin produced hepatocellular necrosis in mice, but this has not been seen in other species. Disturbances in porphyrin metabolism have been reported in griseofulvin-treated laboratory animals. Griseofulvin has been reported to have a colchicine-like effect on mitosis and cocarcinogenicity with methylcholanthrene in cutaneous tumor induction in laboratory animals. ### Precautions - Patients on prolonged therapy with any potent medication should be under close observation. Periodic monitoring of organ system function, including renal, hepatic and hematopoietic, should be done. Since griseofulvin is derived from species of Penicillium, the possibility of cross-sensitivity with penicillin exists; however, known penicillin-sensitive patients have been treated without difficulty. Since a photosensitivity reaction is occasionally associated with griseofulvin therapy, patients should be warned to avoid exposure to intense natural or artificial sunlight. Occasionally slight abnormalities in liver enzymes (irrespective of drug relationship) were reported with an incidence of less than 1%, specifically elevated ALT and/orAST. The majority of subjects with elevated liver enzymes also had concomitant medical conditions and were taking other drugs that may have increased the propensity for elevated values. When follow-up was provided, changes in elevated liver enzymes appeared to be reversible. Lupus erythematosus or lupus-like syndromes have been reported in patients receiving griseofulvin. Griseofulvin decreases the activity of warfarin-type anticoagulants so that patients receiving these drugs concomitantly may require dosage adjustment of the anticoagulant during and after griseofulvin therapy. Barbiturates usually depress griseofulvin activity and concomitant administration may require a dosage adjustment of the antifungal agent. There have been reports in the literature of possible interactions between griseofulvin and oral contraceptives. The effect of alcohol may be potentiated by griseofulvin, producing such effects as tachycardia and flush. # Adverse Reactions ## Clinical Trials Experience - There have been post-marketing reports of severe skin and hepatic adverse events associated with griseofulvin use (see WARNINGS section). - When adverse reactions occur, they are most commonly of the hypersensitivity type such as skin rashes, urticaria, erythema multiform-like drug reactions, and rarely, angioneurotic edema, and may necessitate withdrawal of therapy and appropriate countermeasures. Paresthesia of the hands and feet have been reported after extended therapy. Other side effects reported occasionally are oral thrush, nausea, vomiting, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, mental confusion, and impairment of performance of routine activities. Proteinuria and leukopenia have been reported rarely. Administration of the drug should be discontinued if granulocytopenia occurs. When rare, serious reactions occur with griseofulvin, they are usually associated with high dosages, long periods of therapy, or both. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Griseofulvin in the drug label. # Drug Interactions There is limited information regarding Griseofulvin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Griseofulvin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Griseofulvin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Griseofulvin with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Griseofulvin with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Griseofulvin with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Griseofulvin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Griseofulvin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Griseofulvin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Griseofulvin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Griseofulvin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Griseofulvin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Griseofulvin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Griseofulvin in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Griseofulvin in the drug label. # Pharmacology ## Mechanism of Action - Griseofulvin is fungistatic with in vitro activity against various species of Microsporum, Epidermophyton and Trichophyton. It has no effect on bacteria or other genera of fungi. ## Structure - Gris-PEG® Tablets contain ultramicrosize crystals of griseofulvin, an antibiotic derived from a species of Penicillium. - Each Gris-PEG® tablet contains: - Active Ingredient: griseofulvin ultramicrosize .... 125 mg - Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, methylcellulose, methylparaben, polyethylene glycol 400 and 8000, povidone, and titanium dioxide. - or - Active Ingredient: griseofulvin ultramicrosize .... 250 mg - Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, methylcellulose, methylparaben, polyethylene glycol 400 and 8000, povidone, sodium lauryl sulfate, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Griseofulvin in the drug label. ## Pharmacokinetics - Following oral administration, griseofulvin is deposited in the keratin precursor cells and has a greater affinity for diseased tissue. The drug is tightly bound to the new keratin which becomes highly resistant to fungal invasions. - The efficiency of gastrointestinal absorption of ultramicrocrystalline griseofulvin is approximately one and one-half times that of the conventional microsize griseofulvin. This factor permits the oral intake of two-thirds as much ultramicrocrystalline griseofulvin as the microsize form. However, there is currently no evidence that this lower dose confers any significant clinical differences with regard to safety and/or efficacy. - In a bioequivalence study conducted in healthy volunteers (N=24) in the fasted state, 250 mg ultramicrocrystalline griseofulvin tablets were compared with 250 mg ultramicrocrystalline griseofulvin tablets that were physically altered (crushed) and administered with applesauce. The 250 mg ultramicrocrystalline griseofulvin tablets were found to be bioequivalent to the physically altered (crushed) 250 mg ultramicrocrystalline griseofulvin tablets (See Table 1). ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Griseofulvin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Griseofulvin in the drug label. # How Supplied - Gris-PEG® (griseofulvin ultramicrosize) Tablets, 125 mg, white scored, elliptical-shaped, embossed "Gris-PEG" on one side and "125" on the other. Gris-PEG® (griseofulvin ultramicrosize) Tablets, 250 mg, white scored, capsule-shaped, embossed "Gris-PEG" on one side and "250" on the other. The 125 mg strength is available in bottles of 100 (NDC 0884-0763-04). The 250 mg strength is available in bottles of 100 (NDC 0884-0773-04). Both strengths are film-coated. - Store Gris-PEG ® tablets at controlled room temperature 15° - 30°C (59° - 86°F) in tight, light-resistant containers. ## Storage There is limited information regarding Griseofulvin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Griseofulvin in the drug label. # Precautions with Alcohol - Alcohol-Griseofulvin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Gris-PEG® # Look-Alike Drug Names There is limited information regarding Griseofulvin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Griseofulvin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, 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. # Overview Griseofulvin is a antifungal that is FDA approved for the {{{indicationType}}} of ringworm infections. Common adverse reactions include skin rashes, urticaria, erythema multiform-like drug reactions, and angioneurotic edema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Griseofulvin ultramicrosize is indicated for the treatment of the following ringworm infections; tinea corporis (ringworm of the body), tinea pedis (athlete's foot), tinea cruris (ringworm of the groin and thigh), tinea barbae (barber's itch), tinea capitis (ringworm of the scalp), and tinea unguium (onychomycosis, ringworm of the nails), when caused by one or more of the following genera of fungi: Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Trichophyton interdigitalis,Trichophyton verrucosum, Trichophyton megnini, Trichophyton gallinae, Trichophyton crateriform, Trichophyton sulphureum, Trichophyton schoenleini, Microsporum audouini, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. NOTE: Prior to therapy, the type of fungi responsible for the infection should be identified. The use of the drug is not justified in minor or trivial infections which will respond to topical agents alone. Griseofulvin is not effective in the following: bacterial infections, candidiasis (moniliasis), histoplasmosis, actinomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, North American blastomycosis, cryptococcosis (torulosis), tinea versicolor and nocardiosis. - Daily administration of 375 mg (as a single dose or in divided doses) will give a satisfactory response in most patients with tinea corporis, tinea cruris, and tinea capitis. For those fungal infections more difficult to eradicate, such as tinea pedis and tinea unguium, a divided dose of 750 mg is recommended. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Griseofulvin in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Griseofulvin 500 mg daily for 2 to 4 weeks. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Griseofulvin ultramicrosize is indicated for the treatment of the following ringworm infections; tinea corporis (ringworm of the body), tinea pedis (athlete's foot), tinea cruris (ringworm of the groin and thigh), tinea barbae (barber's itch), tinea capitis (ringworm of the scalp), and tinea unguium (onychomycosis, ringworm of the nails), when caused by one or more of the following genera of fungi: Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, Trichophyton interdigitalis,Trichophyton verrucosum, Trichophyton megnini, Trichophyton gallinae, Trichophyton crateriform, Trichophyton sulphureum, Trichophyton schoenleini, Microsporum audouini, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum. NOTE: Prior to therapy, the type of fungi responsible for the infection should be identified. The use of the drug is not justified in minor or trivial infections which will respond to topical agents alone. Griseofulvin is not effective in the following: bacterial infections, candidiasis (moniliasis), histoplasmosis, actinomycosis, sporotrichosis, chromoblastomycosis, coccidioidomycosis, North American blastomycosis, cryptococcosis (torulosis), tinea versicolor and nocardiosis. - Approximately 3.3 mg per pound of body weight per day of ultramicrosize griseofulvin is an effective dose for most pediatric patients. On this basis, the following dosage schedule is suggested: Children weighing 35-60 pounds - 125 mg to 187.5 mg daily. Pediatric patients weighing over 60 pounds - 187.5 mg to 375 mg daily. Children and infants 2 years of age and younger - dosage has not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Griseofulvin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Griseofulvin in pediatric patients. # Contraindications - Two cases of conjoined twins have been reported since 1977 in patients taking griseofulvin during the first trimester of pregnancy. Griseofulvin should not be prescribed to pregnant patients. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - This drug is contraindicated in patients with porphyria or hepatocellular failure and in individuals with a history of hypersensitivity to griseofulvin. # Warnings - Prophylactic Usage - Safety and efficacy of griseofulvin for prophylaxis of fungal infections have not been established. - Serious Skin Reactions - Severe skin reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) and erythema multiforme have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. If severe skin reactions occur, griseofulvin should be discontinued. - Hepatotoxicity - Elevations in AST, ALT, bilirubin, and jaundice have been reported with griseofulvin use. These reactions may be serious and may result in hospitalization or death. Patients should be monitored for hepatic adverse events and discontinuation of griseofulvin considered if warranted. - Animal Toxicology - Chronic feeding of griseofulvin, at levels ranging from 0.5%-2.5% of the diet resulted in the development of liver tumors in several strains of mice, particularly in males. Smaller particle sizes result in an enhanced effect. Lower oral dosage levels have not been tested. Subcutaneous administration of relatively small doses of griseofulvin once a week during the first three weeks of life has also been reported to induce hepatomata in mice. Thyroid tumors, mostly adenomas but some carcinomas, have been reported in male rats receiving griseofulvin at levels of 2.0%, 1.0% and 0.2% of the diet, and in female rats receiving the two higher dose levels. Although studies in other animal species have not yielded evidence of tumorigenicity, these studies were not of adequate design to form a basis for conclusion in this regard. In subacute toxicity studies, orally administered griseofulvin produced hepatocellular necrosis in mice, but this has not been seen in other species. Disturbances in porphyrin metabolism have been reported in griseofulvin-treated laboratory animals. Griseofulvin has been reported to have a colchicine-like effect on mitosis and cocarcinogenicity with methylcholanthrene in cutaneous tumor induction in laboratory animals. ### Precautions - Patients on prolonged therapy with any potent medication should be under close observation. Periodic monitoring of organ system function, including renal, hepatic and hematopoietic, should be done. Since griseofulvin is derived from species of Penicillium, the possibility of cross-sensitivity with penicillin exists; however, known penicillin-sensitive patients have been treated without difficulty. Since a photosensitivity reaction is occasionally associated with griseofulvin therapy, patients should be warned to avoid exposure to intense natural or artificial sunlight. Occasionally slight abnormalities in liver enzymes (irrespective of drug relationship) were reported with an incidence of less than 1%, specifically elevated ALT and/orAST. The majority of subjects with elevated liver enzymes also had concomitant medical conditions and were taking other drugs that may have increased the propensity for elevated values. When follow-up was provided, changes in elevated liver enzymes appeared to be reversible. Lupus erythematosus or lupus-like syndromes have been reported in patients receiving griseofulvin. Griseofulvin decreases the activity of warfarin-type anticoagulants so that patients receiving these drugs concomitantly may require dosage adjustment of the anticoagulant during and after griseofulvin therapy. Barbiturates usually depress griseofulvin activity and concomitant administration may require a dosage adjustment of the antifungal agent. There have been reports in the literature of possible interactions between griseofulvin and oral contraceptives. The effect of alcohol may be potentiated by griseofulvin, producing such effects as tachycardia and flush. # Adverse Reactions ## Clinical Trials Experience - There have been post-marketing reports of severe skin and hepatic adverse events associated with griseofulvin use (see WARNINGS section). - When adverse reactions occur, they are most commonly of the hypersensitivity type such as skin rashes, urticaria, erythema multiform-like drug reactions, and rarely, angioneurotic edema, and may necessitate withdrawal of therapy and appropriate countermeasures. Paresthesia of the hands and feet have been reported after extended therapy. Other side effects reported occasionally are oral thrush, nausea, vomiting, epigastric distress, diarrhea, headache, fatigue, dizziness, insomnia, mental confusion, and impairment of performance of routine activities. Proteinuria and leukopenia have been reported rarely. Administration of the drug should be discontinued if granulocytopenia occurs. When rare, serious reactions occur with griseofulvin, they are usually associated with high dosages, long periods of therapy, or both. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Griseofulvin in the drug label. # Drug Interactions There is limited information regarding Griseofulvin Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Griseofulvin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Griseofulvin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Griseofulvin with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Griseofulvin with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Griseofulvin with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Griseofulvin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Griseofulvin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Griseofulvin in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Griseofulvin in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Griseofulvin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Griseofulvin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Griseofulvin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Griseofulvin in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Griseofulvin in the drug label. # Pharmacology ## Mechanism of Action - Griseofulvin is fungistatic with in vitro activity against various species of Microsporum, Epidermophyton and Trichophyton. It has no effect on bacteria or other genera of fungi. ## Structure - Gris-PEG® Tablets contain ultramicrosize crystals of griseofulvin, an antibiotic derived from a species of Penicillium. - Each Gris-PEG® tablet contains: - Active Ingredient: griseofulvin ultramicrosize .... 125 mg - Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, methylcellulose, methylparaben, polyethylene glycol 400 and 8000, povidone, and titanium dioxide. - or - Active Ingredient: griseofulvin ultramicrosize .... 250 mg - Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, methylcellulose, methylparaben, polyethylene glycol 400 and 8000, povidone, sodium lauryl sulfate, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Griseofulvin in the drug label. ## Pharmacokinetics - Following oral administration, griseofulvin is deposited in the keratin precursor cells and has a greater affinity for diseased tissue. The drug is tightly bound to the new keratin which becomes highly resistant to fungal invasions. - The efficiency of gastrointestinal absorption of ultramicrocrystalline griseofulvin is approximately one and one-half times that of the conventional microsize griseofulvin. This factor permits the oral intake of two-thirds as much ultramicrocrystalline griseofulvin as the microsize form. However, there is currently no evidence that this lower dose confers any significant clinical differences with regard to safety and/or efficacy. - In a bioequivalence study conducted in healthy volunteers (N=24) in the fasted state, 250 mg ultramicrocrystalline griseofulvin tablets were compared with 250 mg ultramicrocrystalline griseofulvin tablets that were physically altered (crushed) and administered with applesauce. The 250 mg ultramicrocrystalline griseofulvin tablets were found to be bioequivalent to the physically altered (crushed) 250 mg ultramicrocrystalline griseofulvin tablets (See Table 1). ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Griseofulvin in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Griseofulvin in the drug label. # How Supplied - Gris-PEG® (griseofulvin ultramicrosize) Tablets, 125 mg, white scored, elliptical-shaped, embossed "Gris-PEG" on one side and "125" on the other. Gris-PEG® (griseofulvin ultramicrosize) Tablets, 250 mg, white scored, capsule-shaped, embossed "Gris-PEG" on one side and "250" on the other. The 125 mg strength is available in bottles of 100 (NDC 0884-0763-04). The 250 mg strength is available in bottles of 100 (NDC 0884-0773-04). Both strengths are film-coated. - Store Gris-PEG ® tablets at controlled room temperature 15° - 30°C (59° - 86°F) in tight, light-resistant containers. ## Storage There is limited information regarding Griseofulvin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Griseofulvin in the drug label. # Precautions with Alcohol - Alcohol-Griseofulvin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Gris-PEG®[1] # Look-Alike Drug Names There is limited information regarding Griseofulvin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Griseofulvin
be5cc7e582598fba2eb8b4b3f9d561e1da413bcb	wikidoc	Guanethidine	Guanethidine # Overview Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such as norepinephrine. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug's action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine.It may also inhibit the release of granules by decreasing norepinephrine. # Side effects Side effects include orthostatic and exercise hypotension, sexual dysfunction (delayed or retrograde ejaculation), and diarrhea. # Pharmacology Guanethidine is transported by uptake 1 into the presynaptic terminal transported by Norepinephrine transporter (NET). (In this it competes with norepinephrine so can potentiate exogenously applied norepinephrine.) It becomes concentrated in norepinephrine transmitter vesicles, replacing norepinephrine in these vesicles. This leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the release of norepinephrine in response to arrival of an action potential. Spontaneous release is not affected. # Uses Guanethidine was once a mainstay for hypertension resistant to other agents, and was often used safely during pregnancy, but it is no longer used in the US due to lack of availability. It is still licensed in some countries, e.g., UK, for the rapid control of blood pressure in a hypertensive emergency. Intravenous nerve block (Bier block) using guanethidine has been used to treat chronic pain caused by complex regional pain syndrome. # Chemical synthesis Guanethidine is synthesized beginning with the alkylation of azocine with chloroacetonitrile. This reaction which forms 1-azocinylacetonitrile, which can be reduced into 1-(2-aminoethyl)azocine by using lithium aluminium hydride as a reductant. This compound reacts with S-methylthiourea forming guanethidine.	Guanethidine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such as norepinephrine. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug's action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine.It may also inhibit the release of granules by decreasing norepinephrine. # Side effects Side effects include orthostatic and exercise hypotension, sexual dysfunction (delayed or retrograde ejaculation), and diarrhea. # Pharmacology Guanethidine is transported by uptake 1 into the presynaptic terminal transported by Norepinephrine transporter (NET). (In this it competes with norepinephrine so can potentiate exogenously applied norepinephrine.) It becomes concentrated in norepinephrine transmitter vesicles, replacing norepinephrine in these vesicles. This leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the release of norepinephrine in response to arrival of an action potential. Spontaneous release is not affected. # Uses Guanethidine was once a mainstay for hypertension resistant to other agents, and was often used safely during pregnancy, but it is no longer used in the US due to lack of availability. It is still licensed in some countries, e.g., UK, for the rapid control of blood pressure in a hypertensive emergency. Intravenous nerve block (Bier block) using guanethidine has been used to treat chronic pain caused by complex regional pain syndrome.[1] # Chemical synthesis Guanethidine is synthesized beginning with the alkylation of azocine with chloroacetonitrile. This reaction which forms 1-azocinylacetonitrile, which can be reduced into 1-(2-aminoethyl)azocine by using lithium aluminium hydride as a reductant. This compound reacts with S-methylthiourea forming guanethidine.[2][3][4]	https://www.wikidoc.org/index.php/Guanethidine
6cc2e7f8885fbcaba248fd851e0572dabf1634f0	wikidoc	Gubernaculum	Gubernaculum The paired gubernacula are folds of peritoneum that attach to the caudal end of the gonads (testes in males and ovaries in females). # Function during development As the scrotum and labia majora form in males and females, respectively, the gubernaculum aids in the descent of the gonads (both testes and ovaries). The testis descends to a greater degree than the ovary and ultimately pass through the inguinal canal. # Adult structures The gubernaculum is present only during the development of the urinary and reproductive organs, being replaced by distinct vestiges in males and females. ## Males In males: - The upper part of the gubernaculum degenerates. - The lower part persists as the gubernaculum testis ("scrotal ligament"). This ligament secures the testis to the most inferior portion of the scrotum, tethering it in place and limiting the degree to which the testis can move within the scrotum. ## Females In females: - The upper part of the gubernaculum, together with the ovarian artery and vein form the suspensory ligament of the ovary, which suspends the ovary from the pelvic wall. - The lower gubernaculum has two vestigial remnants in females, the ovarian ligament and the round ligament of the uterus (ligamentum teres uteri) which respectively serve to support the ovaries and uterus in the pelvis.	Gubernaculum Template:Infobox Embryology The paired gubernacula are folds of peritoneum that attach to the caudal end of the gonads (testes in males and ovaries in females). # Function during development As the scrotum and labia majora form in males and females, respectively, the gubernaculum aids in the descent of the gonads (both testes and ovaries). The testis descends to a greater degree than the ovary and ultimately pass through the inguinal canal. # Adult structures The gubernaculum is present only during the development of the urinary and reproductive organs, being replaced by distinct vestiges in males and females. ## Males In males: - The upper part of the gubernaculum degenerates. - The lower part persists as the gubernaculum testis ("scrotal ligament"). This ligament secures the testis to the most inferior portion of the scrotum, tethering it in place and limiting the degree to which the testis can move within the scrotum. ## Females In females: - The upper part of the gubernaculum, together with the ovarian artery and vein form the suspensory ligament of the ovary,[1] which suspends the ovary from the pelvic wall. - The lower gubernaculum has two vestigial remnants in females, the ovarian ligament and the round ligament of the uterus (ligamentum teres uteri) which respectively serve to support the ovaries and uterus in the pelvis.	https://www.wikidoc.org/index.php/Gubernaculum
da044730e0849dfee7a28e5c37e31e196c46ae90	wikidoc	Gutta-percha	Gutta-percha # Overview Gutta-percha (Palaquium) is a genus of tropical trees native to Southeast Asia and northern Australasia, from Taiwan south to Malaya and east to the Solomon Islands. It is also an inelastic natural latex produced from the sap of these trees, particularly from the species Palaquium gutta. Chemically, gutta-percha is a polyterpene, a polymer of isoprene (trans-1,4-polyisoprene). The word 'gutta-percha' comes from the plant's name in Malay, getah perca, which translates as "percha rubber". The trees are 5–30 metres tall and up to 1 metre in trunk diameter. The leaves are evergreen, alternate or spirally arranged, simple, entire, 8–25 cm long, and glossy green above, often yellow or glaucous below. The flowers are produced in small clusters along the stems, each flower with a white corolla with 4–7 (mostly 6) acute lobes. The fruit is an ovoid 3–7 cm berry, containing 1–4 seeds; in many species the fruit is edible. # Uses The latex is bioinert, resilient, and is a good electrical insulator due to a high dielectric strength. The wood of many species is also valuable. Western inventors discovered the properties of gutta-percha latex in 1842, although the local population in its Malayan habitat had used it for a variety of applications for centuries. Allowing this fluid to evaporate and coagulate in the sun produced a latex which could be made flexible again with hot water, but which did not become brittle, unlike unvulcanized rubber already in use. By 1845, telegraph wires insulated with gutta-percha were being manufactured in Great Britain. Gutta-percha served as the insulating material for some of the earliest undersea telegraph cables, including the first transatlantic telegraph cable. Gutta-percha was particularly suitable for this purpose, as it was not attacked by marine plants or animals, a problem which had disabled previous undersea cables. In the mid-nineteenth century, gutta-percha was also used to make furniture, notably by the Gutta-Percha Company (established in 1847). Several of these highly ornate, revival-style pieces were shown at the 1851 Great Exhibition. Molded furniture forms, emulating carved wood, were attacked by proponents of the design reform movement who advocated truth to materials. It was also used to make "mourning" jewelry because it was dark in color and could be easily carved into beads or other shapes. The material was quickly adopted for numerous other applications. The "guttie" golf ball (which had a solid gutta-percha core) revolutionized the game. Gutta-percha remained an industrial staple well into the 20th century, when it was gradually replaced with superior (generally synthetic) materials, though a similar and cheaper natural material called balatá is often used in gutta-percha's place. The two materials are almost identical, and balatá is often called gutta-balatá. The same bio-inertness property that made it suitable for marine cables also means it does not readily react within the human body, and consequently it is used for a variety of surgical devices and for dental applications including padding inside fillings or inside the root-canal during root canal therapy. It was also used as pistol grips for the same reason. ## Dentistry Gutta percha is the predominant material used to obturate, or fill the empty space of, a tooth after it has undergone endodontic therapy. Its physical and chemical properties, including but not limited to its inertness and biocompatibility, melting point, ductility and malleability afford it an important role in the field of endodontics for a long time to come. # Trivia - Congressman Preston Brooks' cane that he used to beat Senator Charles Sumner on the floor of the United States Senate was made out of Gutta-percha wood. - Gutta-percha was featured in the pilot movie Cocoon for the long-running television series Hawaii Five-O. The criminal Wo Fat used it to seal the eyes, nose and ears of his victims. - In the movie Gorky Park, a forensic dentist identifies a murder victim as an American because he had a root canal filled with gutta percha, which was not used in Europe for that purpose. - Up until the 1950s, Gutta-percha was applied to ropes used in British executions in order to avoid a metal component catching and marking the skin. It was later replaced with Vulcanised Rubber due to Gutta-percha's tendency to splinter when cold. # References and external links - Germplasm Resources Information Network: Palaquium - Gutta-percha on the Transatlantic cable site - The Gutta Percha Company on the History of the Atlantic Cable site zh-min-nan:Gutta-percha cs:Gutaperča de:Guttapercha eo:Gutaperko id:Getah perca it:Guttaperca hu:Guttaperka (tejnedv) nl:Guttapercha no:Guttaperka sk:Gutaperča fi:Guttaperkka sv:Guttaperka	Gutta-percha Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Gutta-percha (Palaquium) is a genus of tropical trees native to Southeast Asia and northern Australasia, from Taiwan south to Malaya and east to the Solomon Islands. It is also an inelastic natural latex produced from the sap of these trees, particularly from the species Palaquium gutta. Chemically, gutta-percha is a polyterpene, a polymer of isoprene (trans-1,4-polyisoprene). The word 'gutta-percha' comes from the plant's name in Malay, getah perca, which translates as "percha rubber". The trees are 5–30 metres tall and up to 1 metre in trunk diameter. The leaves are evergreen, alternate or spirally arranged, simple, entire, 8–25 cm long, and glossy green above, often yellow or glaucous below. The flowers are produced in small clusters along the stems, each flower with a white corolla with 4–7 (mostly 6) acute lobes. The fruit is an ovoid 3–7 cm berry, containing 1–4 seeds; in many species the fruit is edible. # Uses The latex is bioinert, resilient, and is a good electrical insulator due to a high dielectric strength. The wood of many species is also valuable. Western inventors discovered the properties of gutta-percha latex in 1842, although the local population in its Malayan habitat had used it for a variety of applications for centuries. Allowing this fluid to evaporate and coagulate in the sun produced a latex which could be made flexible again with hot water, but which did not become brittle, unlike unvulcanized rubber already in use. By 1845, telegraph wires insulated with gutta-percha were being manufactured in Great Britain. Gutta-percha served as the insulating material for some of the earliest undersea telegraph cables, including the first transatlantic telegraph cable. Gutta-percha was particularly suitable for this purpose, as it was not attacked by marine plants or animals, a problem which had disabled previous undersea cables. In the mid-nineteenth century, gutta-percha was also used to make furniture, notably by the Gutta-Percha Company (established in 1847). Several of these highly ornate, revival-style pieces were shown at the 1851 Great Exhibition. Molded furniture forms, emulating carved wood, were attacked by proponents of the design reform movement who advocated truth to materials. It was also used to make "mourning" jewelry because it was dark in color and could be easily carved into beads or other shapes. The material was quickly adopted for numerous other applications. The "guttie" golf ball (which had a solid gutta-percha core) revolutionized the game. Gutta-percha remained an industrial staple well into the 20th century, when it was gradually replaced with superior (generally synthetic) materials, though a similar and cheaper natural material called balatá is often used in gutta-percha's place. The two materials are almost identical, and balatá is often called gutta-balatá. The same bio-inertness property that made it suitable for marine cables also means it does not readily react within the human body, and consequently it is used for a variety of surgical devices and for dental applications including padding inside fillings or inside the root-canal during root canal therapy. It was also used as pistol grips for the same reason. ## Dentistry Gutta percha is the predominant material used to obturate, or fill the empty space of, a tooth after it has undergone endodontic therapy. Its physical and chemical properties, including but not limited to its inertness and biocompatibility, melting point, ductility and malleability afford it an important role in the field of endodontics for a long time to come. # Trivia - Congressman Preston Brooks' cane that he used to beat Senator Charles Sumner on the floor of the United States Senate was made out of Gutta-percha wood. - Gutta-percha was featured in the pilot movie Cocoon for the long-running television series Hawaii Five-O. The criminal Wo Fat used it to seal the eyes, nose and ears of his victims. - In the movie Gorky Park, a forensic dentist identifies a murder victim as an American because he had a root canal filled with gutta percha, which was not used in Europe for that purpose. - Up until the 1950s, Gutta-percha was applied to ropes used in British executions in order to avoid a metal component catching and marking the skin. It was later replaced with Vulcanised Rubber due to Gutta-percha's tendency to splinter when cold. # References and external links - Germplasm Resources Information Network: Palaquium - Gutta-percha on the Transatlantic cable site - The Gutta Percha Company on the History of the Atlantic Cable site Template:Endodontology zh-min-nan:Gutta-percha cs:Gutaperča de:Guttapercha eo:Gutaperko id:Getah perca it:Guttaperca hu:Guttaperka (tejnedv) nl:Guttapercha no:Guttaperka sk:Gutaperča fi:Guttaperkka sv:Guttaperka Template:Jb1 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Gutta-percha
4e2f97101729eabea6eb190363efb6f41602ce38	wikidoc	H3F3B (gene)	H3F3B (gene) H3 histone, family 3B (H3.3B) is a protein in humans that is encoded by the H3F3B gene. # Function Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. # Gene This gene contains introns and its mRNA is poyadenylated, unlike most histone genes. The protein encoded is a member of the histone H3 family. Unlike most histone genes, H3F3B is not located in a cluster, but rather is isolated in the telomeric region of chromosome 17. # Clinical significance Somatic mutations in the H3F3B gene are associated with chondroblastoma. A rare de novo germline mutation of the H3F3B gene (A30P) has been linked to a syndrome with a range of developmental and behavioral abnormalities including microcephaly, mild strabismus, seizure disorder, autistic continuum, hypothyroidism, global developmental delay, and low muscle tone.	H3F3B (gene) H3 histone, family 3B (H3.3B) is a protein in humans that is encoded by the H3F3B gene.[1] # Function Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. # Gene This gene contains introns and its mRNA is poyadenylated, unlike most histone genes. The protein encoded is a member of the histone H3 family. Unlike most histone genes, H3F3B is not located in a cluster, but rather is isolated in the telomeric region of chromosome 17.[2] # Clinical significance Somatic mutations in the H3F3B gene are associated with chondroblastoma.[3] A rare de novo germline mutation of the H3F3B gene (A30P) has been linked to a syndrome with a range of developmental and behavioral abnormalities including microcephaly, mild strabismus, seizure disorder, autistic continuum, hypothyroidism, global developmental delay, and low muscle tone.[4]	https://www.wikidoc.org/index.php/H3F3B_(gene)
8153b4622250115f72b82150ee858a93d8bad91e	wikidoc	HM (patient)	HM (patient) # Overview HM (also known as "H.M." and "Henry M.," born 1926 in Connecticut) is an anonymous memory-impaired patient who has been widely studied since the late 1950s and has been very important in the development of theories that explain the link between brain function and memory, and in the development of cognitive neuropsychology, a branch of psychology that studies brain injury to infer normal psychological function. He is still alive today and resides in a care institute located in Hartford, Connecticut, where he remains in ongoing investigation. Audio-recordings from the 1990s of him talking to scientists were released in early 2007. # History HM suffered from intractable epilepsy that has been often—though inconclusively—attributed to a bicycle accident at the age of seven. He suffered from partial seizures for many years, and then several tonic-clonic seizures following his sixteenth birthday. In 1953, HM was referred to William Scoville, a surgeon at Hartford Hospital, for treatment. Scoville localized HM's epilepsy to his medial temporal lobe (MTLs) and suggested surgical resection of the MTLs as a treatment. On September 1, 1953, Scoville removed parts of HM's medial temporal lobe on both sides of his brain. HM lost approximately two-thirds of his hippocampal formation, parahippocampal gyrus (all his entorhinal cortex was destroyed), and amygdala. His hippocampus appears entirely nonfunctional because the remaining 2 cm of hippocampal tissue appears atrophic and because the entire entorhinal (which forms the major sensory input to the hippocampus) was destroyed. Some of his anterolateral temporal cortex was also destroyed. After the surgery he suffered from severe anterograde amnesia: although his short-term memory was intact, he could not commit new events to long-term memory. According to some scientists (e.g., Schmolck, Kensinger, Corkin, & Squire, 2002), HM is impaired in his ability to form new semantic knowledge but researchers argue over the extent of this impairment. He also suffered moderate retrograde amnesia, and could not remember most events in the 3-4 day period before surgery, and some events up to 11 years before, meaning that his amnesia was temporally graded. However, his ability to form long-term procedural memories was still intact; thus he could, as an example, learn new motor skills, despite not being able to remember learning them. The case was first reported in a paper by Scoville and Brenda Milner in 1957. # Insights into memory formation HM has been important not only for the knowledge he has provided about memory impairment and amnesia, but also because his exact brain surgery has allowed a good understanding of how particular areas of the brain may be linked to specific processes hypothesized to occur in memory formation. In this way, he has provided vital information about brain pathology, and has helped form theories of normal memory function. Particularly, that he seems to be able to complete tasks that require recall from short-term memory and procedural memory but not long term episodic memory suggests that recall from these memory systems may be mediated, at least in part, by different areas of the brain. Similarly, that HM cannot create new long-term memories, but can recall long-term memories that existed well before his surgery suggests that encoding and retrieval of long-term memory information may also be mediated by distinct systems. # HM's lifelong contribution to science The study of the patient HM has revolutionized our understanding of the organization of human memory. It has provided broad evidence for the rejection of old theories, as well as the formation of new theories on human memory, in particular about its processes and the underlying neural structures (cf. Kolb & Whishaw, 1996). In the following, some of the major insights are outlined. Since the age of 10, the patient HM suffered from increasing epileptic seizures. Eventually the seizures became so intense and frequent that by the age of 27 his doctors suggested removing parts of the brain that were thought to be responsible for his disorder. In 1953, the surgeon Scoville performed brain surgery on HM's medial temporal lobes. Regarding the exact areas of surgery. Scoville & Milner (1957) noted: “bilateral medial temporal lobe resection was carried out, extending posteriorly for a distance of 8 cm from the midpoints of the tips of the temporal lobes, with the temporal horns constituting the lateral edges of resection” (p. 107). HM recovered from the operation, which eased his epileptic seizures to a manageable degree. However, the surgery had induced serious side-effects, which were first described by Scoville & Milner (1957) as “a complete loss of memory for events , together with a partial retrograde amnesia for the three years leading up to his operation” (p. 108). Furthermore, they found that “early memories are seemingly normal and there is no impairment of personality or general intelligence” (p. 108). HM's general condition has been described as heavy anterograde amnesia, as well as temporally graded retrograde amnesia (Smith & Kosslyn, 2007). HM is highly unable to form new long-term memories of new events or new semantic knowledge –- he basically lives in the past (Corkin, 2002). Since HM did not show any memory impairment before the surgery, the removal of the medial temporal lobes can be held responsible for his memory disorder. Consequently, the medial temporal lobes can be assumed to be a major component involved in the formation of semantic and episodic long-term memories (cf. medial temporal lobes described as a convergence zone for episodic encoding in Smith & Kosslyn, 2007). Further evidence for this assumption has been gained by studies of other patients with lesions of their medial temporal lobe structures (cf. Kolb & Whishaw, 1996; Scoville & Milner, 1957). Despite of his amnesic symptoms, HM performs quite normal in tests of intellectual ability and shows largely intact language abilities indicating that some memory functions (e.g., short-term stores, stores for words, phonemes etc.) were not impaired by the surgery (Smith & Kosslyn, 2007; Corkin, 2002). HM is able to remember information over short intervals of time. This has been tested in a working memory experiment involving the recall of previously presented numbers; in fact, his performance is not worse than that of control subjects (Smith & Kosslyn, 2007). This finding provides evidence that working memory does not rely on medial temporal structures. It further supports the general distinction between short-term and long-term stores of memory (Kolb & Whishaw, 1996). HM's largely intact language abilities provide evidence that language production and comprehension, as well as lexical memory, are independent of the medial temporal structures (Corkin, 2002). In addition to his intact working memory and intellectual abilities, studies of HM's ability to acquire new motor skills demonstrated preserved motor learning (Corkin, 2002). In a study conducted by Milner in the early 1960s, HM acquired the new skill of drawing a figure by looking at its reflection in a mirror (Corkin, 2002). Further evidence for intact motor learning was provided in a study carried out by Corkin (1968). In this study, HM was tested on three different motor learning tasks and HM demonstrated full motor learning abilities in all three tasks. HM's ability to learn certain problem-solving procedures has also been shown with the Tower of Hanoi task (Kolb & Whishaw, 1996). Experiments involving repetition priming underscored HM's ability to acquire implicit (non-conscious) memories, in contrast to his inability to acquire new explicit semantic and episodic memories (Corkin, 2002). These findings provide evidence that memory of skills and repetition priming rely on different neural structures than memories of episodes and facts; whereas procedural memory and repetition priming do not rely on the medial temporal structures removed in HM, semantic and episodic memory do (cf. Corkin, 1984). The dissociation of HM's implicit and explicit learning abilities along their underlying neural structures has served as an important contribution to our understanding of human memory: Long-term memories are not unitary and can be differentiated as being either declarative and non-declarative (Smith & Kosslyn, 2007). According to Corkin (2002), studies of HM's memory abilities have also provided insights regarding the neural structures responsible for spatial memory and processing of spatial information. Despite his general inability to form new episodic or factual long-term memories, as well as his heavy impairment on certain spatial memory tests, HM was able to draw a quite detailed map of the topographical layout of his residence. This finding is remarkable since HM had moved to the house five years after his surgery and hence, given his severe anterograde amnesia and insights from other cases, the common expectation was that the acquisition of topographical memories would have been impaired as well. Corkin (2002) hypothesized that HM “was able to construct a cognitive map of the spatial layout of his house as the result of daily locomotion from room to room” (p. 156). Regarding the underlying neural structures, Corkin (2002) argues that HM's ability to acquire the floor plan is due to partly intact structures of his spatial processing network (e.g. the posterior part of his parahippocampal gyrus). In addition to his topographical memory, HM showed some learning in a picture memorization-recognition task, as well as in a famous faces recognition test, but in the latter only when he was provided with a phonemic cue. HM's positive performance in the picture recognition task might be due to spared parts of his ventral perirhinal cortex. Furthermore, Corkin (2002) argues that despite HM's general ability to form new declarative memories, he seems to be able to acquire small and impoverished pieces of information regarding public life (e.g., cued retrieval of celebrities names). These findings underscore the importance of HM's spared extrahippocampal sites in semantic and recognition memory and enhance our understanding of the interrelations between the different medial temporal lobe structures. HM's heavy impairment in certain spatial tasks provides further evidence for the association of the hippocampus with spatial memory (Kolb & Whishaw, 1996). Another contribution of HM to our understanding of human memory regards the neural structures of the memory consolidation process, which is responsible for forming stable long-term memories (Eysenck & Keane, 2005). HM displayed a temporally graded retrograde amnesia in the way that he “could still recall childhood memories, but he had difficulty remembering events that happened during the years immediately preceding the surgery” (Smith & Kosslyn, 2007, p. 214). His old memories were not impaired, whereas the ones relatively close to the surgery were. This is evidence that the older childhood memories do not rely on the medial temporal lobe, whereas the younger long-term memories seem to do so (Smith & Kosslyn, 2007). The medial temporal structures, which were removed in the surgery, are hypothesized to be involved in the consolidation of memories in the way that “interactions between the medial temporal lobe and various lateral cortical regions are thought to store memories outside the medial temporal lobes by slowly forming direct links between the cortical representations of the experience” (Smith & Kosslyn, 2007, p. 214). # Related Chapters - Amnesia - Cognitive neuropsychology - Phineas Gage - Memory - Clive Wearing - Cenn Fáelad mac Aillila	HM (patient) Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview HM (also known as "H.M." and "Henry M.," born 1926 in Connecticut) is an anonymous memory-impaired patient who has been widely studied since the late 1950s and has been very important in the development of theories that explain the link between brain function and memory, and in the development of cognitive neuropsychology, a branch of psychology that studies brain injury to infer normal psychological function. He is still alive today and resides in a care institute located in Hartford, Connecticut, where he remains in ongoing investigation.[1] Audio-recordings from the 1990s of him talking to scientists were released in early 2007. # History HM suffered from intractable epilepsy that has been often—though inconclusively—attributed to a bicycle accident at the age of seven. He suffered from partial seizures for many years, and then several tonic-clonic seizures following his sixteenth birthday. In 1953, HM was referred to William Scoville, a surgeon at Hartford Hospital, for treatment. Scoville localized HM's epilepsy to his medial temporal lobe (MTLs) and suggested surgical resection of the MTLs as a treatment. On September 1, 1953, Scoville removed parts of HM's medial temporal lobe on both sides of his brain. HM lost approximately two-thirds of his hippocampal formation, parahippocampal gyrus (all his entorhinal cortex was destroyed), and amygdala. His hippocampus appears entirely nonfunctional because the remaining 2 cm of hippocampal tissue appears atrophic and because the entire entorhinal (which forms the major sensory input to the hippocampus) was destroyed. Some of his anterolateral temporal cortex was also destroyed. After the surgery he suffered from severe anterograde amnesia: although his short-term memory was intact, he could not commit new events to long-term memory. According to some scientists (e.g., Schmolck, Kensinger, Corkin, & Squire, 2002), HM is impaired in his ability to form new semantic knowledge but researchers argue over the extent of this impairment. He also suffered moderate retrograde amnesia, and could not remember most events in the 3-4 day period before surgery, and some events up to 11 years before, meaning that his amnesia was temporally graded. However, his ability to form long-term procedural memories was still intact; thus he could, as an example, learn new motor skills, despite not being able to remember learning them. The case was first reported in a paper by Scoville and Brenda Milner in 1957. # Insights into memory formation HM has been important not only for the knowledge he has provided about memory impairment and amnesia, but also because his exact brain surgery has allowed a good understanding of how particular areas of the brain may be linked to specific processes hypothesized to occur in memory formation. In this way, he has provided vital information about brain pathology, and has helped form theories of normal memory function. Particularly, that he seems to be able to complete tasks that require recall from short-term memory and procedural memory but not long term episodic memory suggests that recall from these memory systems may be mediated, at least in part, by different areas of the brain. Similarly, that HM cannot create new long-term memories, but can recall long-term memories that existed well before his surgery suggests that encoding and retrieval of long-term memory information may also be mediated by distinct systems. # HM's lifelong contribution to science The study of the patient HM has revolutionized our understanding of the organization of human memory. It has provided broad evidence for the rejection of old theories, as well as the formation of new theories on human memory, in particular about its processes and the underlying neural structures (cf. Kolb & Whishaw, 1996). In the following, some of the major insights are outlined. Since the age of 10, the patient HM suffered from increasing epileptic seizures. Eventually the seizures became so intense and frequent that by the age of 27 his doctors suggested removing parts of the brain that were thought to be responsible for his disorder. In 1953, the surgeon Scoville performed brain surgery on HM's medial temporal lobes. Regarding the exact areas of surgery. Scoville & Milner (1957) noted: “bilateral medial temporal lobe resection was carried out, extending posteriorly for a distance of 8 cm from the midpoints of the tips of the temporal lobes, with the temporal horns constituting the lateral edges of resection” (p. 107). HM recovered from the operation, which eased his epileptic seizures to a manageable degree. However, the surgery had induced serious side-effects, which were first described by Scoville & Milner (1957) as “a complete loss of memory for events [...], together with a partial retrograde amnesia for the three years leading up to his operation” (p. 108). Furthermore, they found that “early memories are seemingly normal and there is no impairment of personality or general intelligence” (p. 108). HM's general condition has been described as heavy anterograde amnesia, as well as temporally graded retrograde amnesia (Smith & Kosslyn, 2007). HM is highly unable to form new long-term memories of new events or new semantic knowledge –- he basically lives in the past (Corkin, 2002). Since HM did not show any memory impairment before the surgery, the removal of the medial temporal lobes can be held responsible for his memory disorder. Consequently, the medial temporal lobes can be assumed to be a major component involved in the formation of semantic and episodic long-term memories (cf. medial temporal lobes described as a convergence zone for episodic encoding in Smith & Kosslyn, 2007). Further evidence for this assumption has been gained by studies of other patients with lesions of their medial temporal lobe structures (cf. Kolb & Whishaw, 1996; Scoville & Milner, 1957). Despite of his amnesic symptoms, HM performs quite normal in tests of intellectual ability and shows largely intact language abilities indicating that some memory functions (e.g., short-term stores, stores for words, phonemes etc.) were not impaired by the surgery (Smith & Kosslyn, 2007; Corkin, 2002). HM is able to remember information over short intervals of time. This has been tested in a working memory experiment involving the recall of previously presented numbers; in fact, his performance is not worse than that of control subjects (Smith & Kosslyn, 2007). This finding provides evidence that working memory does not rely on medial temporal structures. It further supports the general distinction between short-term and long-term stores of memory (Kolb & Whishaw, 1996). HM's largely intact language abilities provide evidence that language production and comprehension, as well as lexical memory, are independent of the medial temporal structures (Corkin, 2002). In addition to his intact working memory and intellectual abilities, studies of HM's ability to acquire new motor skills demonstrated preserved motor learning (Corkin, 2002). In a study conducted by Milner in the early 1960s, HM acquired the new skill of drawing a figure by looking at its reflection in a mirror (Corkin, 2002). Further evidence for intact motor learning was provided in a study carried out by Corkin (1968). In this study, HM was tested on three different motor learning tasks and HM demonstrated full motor learning abilities in all three tasks. HM's ability to learn certain problem-solving procedures has also been shown with the Tower of Hanoi task (Kolb & Whishaw, 1996). Experiments involving repetition priming underscored HM's ability to acquire implicit (non-conscious) memories, in contrast to his inability to acquire new explicit semantic and episodic memories (Corkin, 2002). These findings provide evidence that memory of skills and repetition priming rely on different neural structures than memories of episodes and facts; whereas procedural memory and repetition priming do not rely on the medial temporal structures removed in HM, semantic and episodic memory do (cf. Corkin, 1984). The dissociation of HM's implicit and explicit learning abilities along their underlying neural structures has served as an important contribution to our understanding of human memory: Long-term memories are not unitary and can be differentiated as being either declarative and non-declarative (Smith & Kosslyn, 2007). According to Corkin (2002), studies of HM's memory abilities have also provided insights regarding the neural structures responsible for spatial memory and processing of spatial information. Despite his general inability to form new episodic or factual long-term memories, as well as his heavy impairment on certain spatial memory tests, HM was able to draw a quite detailed map of the topographical layout of his residence. This finding is remarkable since HM had moved to the house five years after his surgery and hence, given his severe anterograde amnesia and insights from other cases, the common expectation was that the acquisition of topographical memories would have been impaired as well. Corkin (2002) hypothesized that HM “was able to construct a cognitive map of the spatial layout of his house as the result of daily locomotion from room to room” (p. 156). Regarding the underlying neural structures, Corkin (2002) argues that HM's ability to acquire the floor plan is due to partly intact structures of his spatial processing network (e.g. the posterior part of his parahippocampal gyrus). In addition to his topographical memory, HM showed some learning in a picture memorization-recognition task, as well as in a famous faces recognition test, but in the latter only when he was provided with a phonemic cue. HM's positive performance in the picture recognition task might be due to spared parts of his ventral perirhinal cortex. Furthermore, Corkin (2002) argues that despite HM's general ability to form new declarative memories, he seems to be able to acquire small and impoverished pieces of information regarding public life (e.g., cued retrieval of celebrities names). These findings underscore the importance of HM's spared extrahippocampal sites in semantic and recognition memory and enhance our understanding of the interrelations between the different medial temporal lobe structures. HM's heavy impairment in certain spatial tasks provides further evidence for the association of the hippocampus with spatial memory (Kolb & Whishaw, 1996). Another contribution of HM to our understanding of human memory regards the neural structures of the memory consolidation process, which is responsible for forming stable long-term memories (Eysenck & Keane, 2005). HM displayed a temporally graded retrograde amnesia in the way that he “could still recall childhood memories, but he had difficulty remembering events that happened during the years immediately preceding the surgery” (Smith & Kosslyn, 2007, p. 214). His old memories were not impaired, whereas the ones relatively close to the surgery were. This is evidence that the older childhood memories do not rely on the medial temporal lobe, whereas the younger long-term memories seem to do so (Smith & Kosslyn, 2007). The medial temporal structures, which were removed in the surgery, are hypothesized to be involved in the consolidation of memories in the way that “interactions between the medial temporal lobe and various lateral cortical regions are thought to store memories outside the medial temporal lobes by slowly forming direct links between the cortical representations of the experience” (Smith & Kosslyn, 2007, p. 214). # Related Chapters - Amnesia - Cognitive neuropsychology - Phineas Gage - Memory - Clive Wearing - Cenn Fáelad mac Aillila # External Links - The Day His World Stood Still - Article on HM from Brain Connection - H.M.'s Brain and the History of Memory - NPR Piece on HM	https://www.wikidoc.org/index.php/HM_(patient)
b07111c11c7f1b2446a3643b14138682745187d0	wikidoc	Haematoxylin	Haematoxylin Haematoxylin, hematoxylin, Natural Black 1, or C.I. 75290 is extracted from the wood of the logwood tree. When oxidised it forms haematein, a compound with rich blue-purple colour, and is used, together with a suitable mordant (most commonly Fe(III) or Al(III) salts), to stain cell nuclei prior to examination under a microscope. Structures that stain with haematoxylin are called basophilic. Haematoxylin and eosin stain is one of the most commonly used stains in histology. It is a permanent stain as opposed to temporary stains (e.g. iodine solution in KI). Other common stain is phosphotungstic acid haematoxylin, a mix of haematoxylin with phosphotungstic acid. In 1970's, due to clear felling of forests in Brazil and Central America, there was a shortage of logwood and therefore of haematoxylin. Its price went to record heights, which affected the cost of diagnostic histopathology, and prompted a search for alternative nuclear stains. Before the use of any alternatives became firmly established, hematoxylin returned to the market, though at a higher price, and resumed its place in histopathology. There were several dyes recommended as replacements: Celestine blue B (CI 51050), Gallocyanin (CI 51030), Gallein (CI 45445) and Solochrome cyanin (CI 43820). All four used Fe(III) as the mordant. Another alternative is the red dye brazilin, which differs from hematoxylin by only one hydroxyl group. # Hematoxylin Staining Solutions These stains are commonly employed for histologic studies. The mordants used to demonstrate nuclear and cytoplasmic structures are Alum and Iron, forming lakes or colored complexes (dye-mordant-tissue complexes), the color of which will depend on the salt used. Aluminum salt lakes are usually colored blue white while Ferric salt lakes are colored blue-black. ## Aluminum Hematoxylin Solutions The two main Alum Hematoxylin solutions employed are Ehrlich's Hematoxylin and Harris Hematoxylin. Alum Hematoxylin solutions impart on the nucleus a light transparent blue stain which rapidly turns red in the presence of an acid. Alum or Potassium Aluminum Sulfate used as the mordant usually dissociates in an alkaline solution, combining with -OH of water to form insoluble Aluminum Hydroxide. In the presence of excess acid, Aluminum Hydroxide cannot be formed thus failure of Aluminum Hematoxylin dye-lake to form, due to lack of –OH ions. Hence, acid solutions of Alum Hematoxylin become red. During staining Alum Hematoxylin stained sections are usually passed on to an alkaline solution (e.g. 1% Hydroxide) in order to neutralize the acid and free the OH group, to form an insoluble blue Aluminum Hematin-Tissue Lake. Such procedure is known as Blueing. When tap water is not sufficiently alkaline, or is even acid and is unsatisfactory for Blueing Hematoxylin, Tap Water Substitute consisting of 33.5 g NaHCO4 and 20 grams MgSO4 in 1000 cc of water, with Thymol (to inhibit formation of molds), is used to accelerate blueing of thin paraffin sections. Use of very cold water slows down the process while warming accelerates it. In fact, the use of very cold water below 10°C for blueing sections may even produce pink artifact discolorations on the tissue. ### Ehrlich’s Hematoxylin Formula: - 1 g Hematoxylin - 100 ml Absolute Ethanol - 60 g Potassium Alum (Aluminum Potassium Sulfate) - 100 ml Glycerin - 100 ml Distilled water - 10 ml Glacial Acetic Acid (HOAc) First, Dissolve 1 g Hematoxylin in 100 ml of Absolute Ethanol with gentle heat. Second, dissolve the 60 g of Potassium Alum (Aluminum Potassium Sulfate) in 100 ml Distilled water with 100 ml Glycerin with gentle heating and agitation. Third, mix the two solutions and add 10 ml Glacial HOAc. Then Expose to the air and sunlight for several weeks or months in a flask lightly plugged with cotton. Shake the solution daily. Finally, transfer the solution in a well-stoppered bottle and store in a warm place. Hematoxylin may be partially oxidized and the stain may be used by addition of 0.3 g Sodium Iodate. As Hematoxylin solutions becomes oxidized, the color of the solution will change from purplish to deep red, while the pungent odor of HOAc will be replaced by a pleasant vineous aroma. Glycerin acts as a stabilizer and retards evaporation of the solution. However, glycerin appears to slow down ripening and hence may be added 4 to 6 weeks after the initial preparation. Ehrlich's Hematoxylin is generally used for regressive staining, differentiated with 1% HCl in 70% Acid-Alcohol until the nucleus is selectively stained. Mucopolysaccharide substance such as cartilage and cement lines of bones are also stained intensely blue. Staining time is usually 15 to 40 minutes. ### Harris Hematoxylin Formula: - 1 g Hematoxylin - 10 ml Absolute Ethanol - 20 g Ammonium/Potassium Alum - 190 ml Distilled water - 0.5 g Mercuric Oxide (Red) - 10 ml Glacial Acetic Acid (HOAc) First, dissolve 1 g Hematoxylin in 10 ml of Absolute Ethanol with gentle heating. Second, dissolve 20 g of Ammonium or Potassium Alum in 190 ml Distilled water inside a 500 ml flask or beaker. Third, add Mercuric Oxide and plunge immediately into cold water for rapid cooling. Using a wide-mouth container or flask will prevent a violent explosion due to the liberation of Oxygen upon addition of Mercuric Oxide to the solution. The solution should assume a dark purple color upon addition of Mercuric Oxide. The addition of 4% Glacial HOAc will give a more precise nuclear staining. Finally, the solution is then filtered and transferred into a well-stoppered bottle, and may be used off-hand or stored since it remains stable for a long time. Harris Hematoxylin is widely used for routine nuclear staining in Exfoliative Cytology and for staining of sex chromosomes. The usual staining time is 5 to 20 minutes. ### Cole’s Hematoxylin Cole's Hematoxylin is another Alum Hematoxylin solution recommended for routine purposes, especially used in sequence with Celestine Blue. Formula: - 1.5 g Hematoxylin - 50 ml of 1% Iodine in 95% Alcohol - 700 ml of Saturated Aq. Ammonium Alum - 250 ml Distilled water Dissolve 1.5 g Hematoxylin in warm 250 ml Distilled water, and mix with 50 ml Iodine solution. Add 700 ml Saturated Aq. Ammonium Alum then boil. Finally, cool and filter before use. Staining time is 10 minutes. ### Mayer’s Hematoxylin Mayer's Hematoxylin is more vigorous in action than Ehrlich's Solution, giving little or no staining of Mucopolysaccharides. It is used in Celestine Blue Hemalum method of Nuclear Staining. Formula: - 1 g Hematoxylin - 0.2 g Sodium Iodate - 50 g Potassium Alum - 1 g Citric Acid - 50 g Chloral Hydrate - 1000 ml Distilled water Allow Hematoxylin, Alum, Sodium iodate to dissolve in water overnight. Then add Chloral Hydrate and Citric Acid. Boil for 5 minutes and cool. ## Iron Hematoxylin Solutions Two main Iron Hematoxylin solutions are employed for routine work in the laboratory: Weigert's Solution, using Ferric Ammonium Chloride, and Heidenhain's Solution, using Ferric Ammonium Sulfate (Iron Alum) as mordants. Both are active oxidizing agents; hence, do not prolong in storage as a prepared fixative. They can be applied to tissues fixed in virtually all fixatives, producing permanent stains, provided all Iron mordants have been wiped out. Tissues that have been stored in alcohol for years and which would ordinarily fail to stain, will normally take Iron Hematoxylin. Tissue structures are stained blackish or grayish, according to the extent of differentiation, producing minimal eyestrain; hence, making it useful for photomicrography. ### Weigert's Hematoxylin Weigert's Solution is the standard Iron Hematoxylin used in the laboratory, especially for demonstrating muscle fibers and connective tissues. It is particularly recommended when the preceding stains contain acid (e.g. Van Gieson's Stain containing Picric Acid) which decolorizes nuclei stained with Alum Hematoxylin. Formula - Solution A: - Solution B: Hematoxylin is dissolved in Alcohol with gentle heating, while FeCl3, HCl and Water are mixed in a different container. Both solutions are stable and may be stored 6 weeks before use. Ferric Chloride is usually added to the staining solution just before use, by mixing equal parts of the two solutions, producing a deep black mixture. The working solution will remain active for 1 to 2 days. ### Heidenhain’s Hematoxylin Heidanhain's solution is a cytological stain recommended for regressive staining of thin sections. It is utilized for the demonsrtation of both nuclear and cytoplasmic inclusions such as chromatin, chromosomes and mitochondria. Voluntary muscle striations and myelin are also well stained. Formula - Mordant Differentiator: - Hematoxylin Stain: Clear violet crystal of Alum are used and dissolved in distilled water. Then, Hematoxylin is dissolved in Ethanol with water in another container. Allow to ripen for 4 to 5 weeks, and store in tightly stoppered bottles. The Mordant Differentiator is used separately during the process of staining, instead of being added to the solution. ### Phosphotungstic Acid Hematoxylin (PTAH) PTAH usually demonstrates structures in paraffin as well as celloidin and frozen sections. Staining time is usually 12 to 24 hours. Formula - 1 g Hematoxylin - 20 g Phosphotungstic Acid - 1000 ml Distilled water Completely dissolve the solids in separate portions of distilled water. Then, add together and stand under the light to ripen for several weeks. Immediate ripening may be obtained by adding 0.177 g Potassium. The color of the solution ranges from reddish-brown to purple, although this is not a reliable guide for the study of stained tissues. Nuclei, fibrin, muscle striations, myofibrils and fibroglia are colored blue while collagen, bone and cartilage take an orange-red or brownish red to deep brick-red stain. Staining is usually progressive, hence, microscopic examination of the materials every hour is recommended. 95% Alcohol usually removes the red component of the stain, so that dehydration and rinsing of sections should be brief.	Haematoxylin Template:Chembox new Haematoxylin, hematoxylin, Natural Black 1, or C.I. 75290 is extracted from the wood of the logwood tree. When oxidised it forms haematein, a compound with rich blue-purple colour, and is used, together with a suitable mordant (most commonly Fe(III) or Al(III) salts), to stain cell nuclei prior to examination under a microscope. Structures that stain with haematoxylin are called basophilic. Template:SMILESCAS Haematoxylin and eosin stain is one of the most commonly used stains in histology. It is a permanent stain as opposed to temporary stains (e.g. iodine solution in KI). Other common stain is phosphotungstic acid haematoxylin, a mix of haematoxylin with phosphotungstic acid. In 1970's, due to clear felling of forests in Brazil and Central America, there was a shortage of logwood and therefore of haematoxylin. Its price went to record heights, which affected the cost of diagnostic histopathology, and prompted a search for alternative nuclear stains. Before the use of any alternatives became firmly established, hematoxylin returned to the market, though at a higher price, and resumed its place in histopathology. There were several dyes recommended as replacements: Celestine blue B (CI 51050), Gallocyanin (CI 51030), Gallein (CI 45445) and Solochrome cyanin (CI 43820). All four used Fe(III) as the mordant. Another alternative is the red dye brazilin, which differs from hematoxylin by only one hydroxyl group. # Hematoxylin Staining Solutions These stains are commonly employed for histologic studies. The mordants used to demonstrate nuclear and cytoplasmic structures are Alum and Iron, forming lakes or colored complexes (dye-mordant-tissue complexes), the color of which will depend on the salt used. Aluminum salt lakes are usually colored blue white while Ferric salt lakes are colored blue-black. ## Aluminum Hematoxylin Solutions The two main Alum Hematoxylin solutions employed are Ehrlich's Hematoxylin and Harris Hematoxylin. Alum Hematoxylin solutions impart on the nucleus a light transparent blue stain which rapidly turns red in the presence of an acid. Alum or Potassium Aluminum Sulfate used as the mordant usually dissociates in an alkaline solution, combining with -OH of water to form insoluble Aluminum Hydroxide. In the presence of excess acid, Aluminum Hydroxide cannot be formed thus failure of Aluminum Hematoxylin dye-lake to form, due to lack of –OH ions. Hence, acid solutions of Alum Hematoxylin become red. During staining Alum Hematoxylin stained sections are usually passed on to an alkaline solution (e.g. 1% Hydroxide) in order to neutralize the acid and free the OH group, to form an insoluble blue Aluminum Hematin-Tissue Lake. Such procedure is known as Blueing. When tap water is not sufficiently alkaline, or is even acid and is unsatisfactory for Blueing Hematoxylin, Tap Water Substitute consisting of 33.5 g NaHCO4 and 20 grams MgSO4 in 1000 cc of water, with Thymol (to inhibit formation of molds), is used to accelerate blueing of thin paraffin sections. Use of very cold water slows down the process while warming accelerates it. In fact, the use of very cold water below 10°C for blueing sections may even produce pink artifact discolorations on the tissue. ### Ehrlich’s Hematoxylin Formula: - 1 g Hematoxylin - 100 ml Absolute Ethanol - 60 g Potassium Alum (Aluminum Potassium Sulfate) - 100 ml Glycerin - 100 ml Distilled water - 10 ml Glacial Acetic Acid (HOAc) First, Dissolve 1 g Hematoxylin in 100 ml of Absolute Ethanol with gentle heat. Second, dissolve the 60 g of Potassium Alum (Aluminum Potassium Sulfate) in 100 ml Distilled water with 100 ml Glycerin with gentle heating and agitation. Third, mix the two solutions and add 10 ml Glacial HOAc. Then Expose to the air and sunlight for several weeks or months in a flask lightly plugged with cotton. Shake the solution daily. Finally, transfer the solution in a well-stoppered bottle and store in a warm place. Hematoxylin may be partially oxidized and the stain may be used by addition of 0.3 g Sodium Iodate. As Hematoxylin solutions becomes oxidized, the color of the solution will change from purplish to deep red, while the pungent odor of HOAc will be replaced by a pleasant vineous aroma. Glycerin acts as a stabilizer and retards evaporation of the solution. However, glycerin appears to slow down ripening and hence may be added 4 to 6 weeks after the initial preparation. Ehrlich's Hematoxylin is generally used for regressive staining, differentiated with 1% HCl in 70% Acid-Alcohol until the nucleus is selectively stained. Mucopolysaccharide substance such as cartilage and cement lines of bones are also stained intensely blue. Staining time is usually 15 to 40 minutes. ### Harris Hematoxylin Formula: - 1 g Hematoxylin - 10 ml Absolute Ethanol - 20 g Ammonium/Potassium Alum - 190 ml Distilled water - 0.5 g Mercuric Oxide (Red) - 10 ml Glacial Acetic Acid (HOAc) First, dissolve 1 g Hematoxylin in 10 ml of Absolute Ethanol with gentle heating. Second, dissolve 20 g of Ammonium or Potassium Alum in 190 ml Distilled water inside a 500 ml flask or beaker. Third, add Mercuric Oxide and plunge immediately into cold water for rapid cooling. Using a wide-mouth container or flask will prevent a violent explosion due to the liberation of Oxygen upon addition of Mercuric Oxide to the solution. The solution should assume a dark purple color upon addition of Mercuric Oxide. The addition of 4% Glacial HOAc will give a more precise nuclear staining. Finally, the solution is then filtered and transferred into a well-stoppered bottle, and may be used off-hand or stored since it remains stable for a long time. Harris Hematoxylin is widely used for routine nuclear staining in Exfoliative Cytology and for staining of sex chromosomes. The usual staining time is 5 to 20 minutes. ### Cole’s Hematoxylin Cole's Hematoxylin is another Alum Hematoxylin solution recommended for routine purposes, especially used in sequence with Celestine Blue. Formula: - 1.5 g Hematoxylin - 50 ml of 1% Iodine in 95% Alcohol - 700 ml of Saturated Aq. Ammonium Alum - 250 ml Distilled water Dissolve 1.5 g Hematoxylin in warm 250 ml Distilled water, and mix with 50 ml Iodine solution. Add 700 ml Saturated Aq. Ammonium Alum then boil. Finally, cool and filter before use. Staining time is 10 minutes. ### Mayer’s Hematoxylin Mayer's Hematoxylin is more vigorous in action than Ehrlich's Solution, giving little or no staining of Mucopolysaccharides. It is used in Celestine Blue Hemalum method of Nuclear Staining. Formula: - 1 g Hematoxylin - 0.2 g Sodium Iodate - 50 g Potassium Alum - 1 g Citric Acid - 50 g Chloral Hydrate - 1000 ml Distilled water Allow Hematoxylin, Alum, Sodium iodate to dissolve in water overnight. Then add Chloral Hydrate and Citric Acid. Boil for 5 minutes and cool. ## Iron Hematoxylin Solutions Two main Iron Hematoxylin solutions are employed for routine work in the laboratory: Weigert's Solution, using Ferric Ammonium Chloride, and Heidenhain's Solution, using Ferric Ammonium Sulfate (Iron Alum) as mordants. Both are active oxidizing agents; hence, do not prolong in storage as a prepared fixative. They can be applied to tissues fixed in virtually all fixatives, producing permanent stains, provided all Iron mordants have been wiped out. Tissues that have been stored in alcohol for years and which would ordinarily fail to stain, will normally take Iron Hematoxylin. Tissue structures are stained blackish or grayish, according to the extent of differentiation, producing minimal eyestrain; hence, making it useful for photomicrography. ### Weigert's Hematoxylin Weigert's Solution is the standard Iron Hematoxylin used in the laboratory, especially for demonstrating muscle fibers and connective tissues. It is particularly recommended when the preceding stains contain acid (e.g. Van Gieson's Stain containing Picric Acid) which decolorizes nuclei stained with Alum Hematoxylin. Formula - Solution A: - Solution B: Hematoxylin is dissolved in Alcohol with gentle heating, while FeCl3, HCl and Water are mixed in a different container. Both solutions are stable and may be stored 6 weeks before use. Ferric Chloride is usually added to the staining solution just before use, by mixing equal parts of the two solutions, producing a deep black mixture. The working solution will remain active for 1 to 2 days. ### Heidenhain’s Hematoxylin Heidanhain's solution is a cytological stain recommended for regressive staining of thin sections. It is utilized for the demonsrtation of both nuclear and cytoplasmic inclusions such as chromatin, chromosomes and mitochondria. Voluntary muscle striations and myelin are also well stained. Formula - Mordant Differentiator: - Hematoxylin Stain: Clear violet crystal of Alum are used and dissolved in distilled water. Then, Hematoxylin is dissolved in Ethanol with water in another container. Allow to ripen for 4 to 5 weeks, and store in tightly stoppered bottles. The Mordant Differentiator is used separately during the process of staining, instead of being added to the solution. ### Phosphotungstic Acid Hematoxylin (PTAH) PTAH usually demonstrates structures in paraffin as well as celloidin and frozen sections. Staining time is usually 12 to 24 hours. Formula - 1 g Hematoxylin - 20 g Phosphotungstic Acid - 1000 ml Distilled water Completely dissolve the solids in separate portions of distilled water. Then, add together and stand under the light to ripen for several weeks. Immediate ripening may be obtained by adding 0.177 g Potassium. The color of the solution ranges from reddish-brown to purple, although this is not a reliable guide for the study of stained tissues. Nuclei, fibrin, muscle striations, myofibrils and fibroglia are colored blue while collagen, bone and cartilage take an orange-red or brownish red to deep brick-red stain. Staining is usually progressive, hence, microscopic examination of the materials every hour is recommended. 95% Alcohol usually removes the red component of the stain, so that dehydration and rinsing of sections should be brief.	https://www.wikidoc.org/index.php/Haematoxylin
df296a38e9f47305369efb09f7b4000b58762761	wikidoc	Hemodialysis	Hemodialysis # Overview The goal of hemodialysis is removing toxins and aim to maintain euvolemia. Ninety three percent of ESRD patients in the United States and 89% worldwide, are under hemodialysis. Solute diffusion across a membrane is the basic principle for hemodialysis. Metabolic waste products move across a semipermeable membrane depending on their concentration gradient between plasma and dialysate. Concentration gradient, membrane surface area, the membrane thickness, and size of solute molecule are important factors determining rate of diffusion. Small molecules clear more efficiently than larger molecules. Fluid removal is another advantage of hemodialysis that could be achieved by ultrafiltration. In-center hemodialysis and home hemodialysis are available for ESRD patients requiring renal replacement therapy; the choice of modality is based on patient condition, patient preference, and the availability of equipments. # Components ## The Dialyzer Dialyzer is usually made of bundles of hollow fibers permitting a high flow rate of blood and dialysate simultaneously. Parallel plates are another type of dialyzer that are barely used in recent times. Most of the dialyzers are synthetic with a variety of materials including polyamide, polyarylethersulfone, polyvinylpyrrolidone, polyacrylonitrile, and polysulfone. Biocompatible membranes have the advantage of not activating complement system. ## The Dialysate The dialysate is a paramount composition in hemodialysis. Solutes diffuse across the dialyzer between blood and dialysate. The dialysate composition should be individualized to restore plasma normal values. The main solutes in dialysate include sodium, potassium, calcium, magnesium, chloride, bicarbonate , and glucose. These electrolytes are treated with water during the process. About 100 liters of water is needed for each dialysis session. The water used for hemodialysis should be processed in order to have a balanced concentration of solutes. Also, contaminants including bacteria, viruses, and heavy metals, such as aluminium should be removed from water. This removal could be done either by using reverse osmosis or deionization. Filters may be used to improve water quality by removing particles. The dialyzate temperature could also be adjusted to cause vasoconstriction and improve patient's hemodynamics. The choice of the dialysate is important to maintain or correct the electrolytes. - Sodium: Usually, sodium concentration of 140-145 mEq/L is suitable for most of the patients but, it could be adjusted based on patient's sodium level. - Potassium: The potassium concentration in dialysate solution depends on patient potassium level. For example: For patients with hyperkalemia, a potassium concentration of 2-3 mEq/L is appropriate and for patients with hypokalemia, a potassium concentration of 4 mEq/L is appropriate. - Calcium: Dialysate concentration for calcium are available with 2.5 ,3, or 3.5 mEq/L. In most of the cases a 2.5 mEq/L solution which is equivalent to 5 mg/dl ionized calcium is used. ## Blood Delivery System The blood pump delivers blood from the arterial line to the dialyzer and then return it to the venous line. It's speed could be adjusted based on patient condition typically between 200 to 600 mL/min. This pump allows creating a transmembrane pressure in dialyzer by sucking dialysate. The dialysate flow rate is between 500 to 800 mL/min. # Vascular Access - The establishment and maintenance of reliable vascular access is crucial for long-term hemodialysis. - Creating arteriovenous (AV) access by establishing arteriovenous fistula (AVF) is the most reliable vascular access. On the other hand, arteriovenous graft (AVG) may provide access in certain circumstances by placing a prosthetic or biograft. However, majority of patients need temporary access by tunneled catheters for initiating hemodialysis. - Insertion of central catheter may cause complications, such as arterial and ventricular dysrhythmias, arterial puncture, hemothorax, pneumothorax, air embolism, perforation of central vein or cardiac chamber, and pericardial tamponade. - Infection is another concern regarding catheter care. Migration of bacteria from patient's skin is the mechanism of catheter infection. Skin preparation before procedure by using chlorhexidine at the catheter exit site could prevent catheter infection. Staphylococcus epidermidis, is the most common isolate. Prompt catheter removal is recommended if evidences of site infection is present even in the absence of systemic signs. - Catheter thrombosis may cause block blood flow is another aspect of catheter care. Instilling alteplase in the affected catheter lumen for 30 to 120 minutes is the preferred treatment. - Central vein stenosis: Subclavian vein catheters have a higher risk of stenosis. Using a dilator and ultrasound guided inserting may decrease the risk of vessel trauma and consequently minimize the likelihood of stenosis. # Anticoagulation Dialysis patients tend to have greater risk of thrombosis due to increased factor VII activity, increased fibrinolytic activity, and elevated fibrinogen levels. However, uremic state may poses patients to bleeding diathesis. Also, dialysis procedure may increase turbulent blood flows with high shear stress which may activate platelets. All of these concepts emerge the use of anticoagulants during hemodialysis. Heparin (UFH) is the most frequently used form of anticoagulants. The usual heparin dose is 50 to 100 U/kg bolus at the initiation which followed by 100 U/hour. Activated clotting time (ACT) is measured in certain circumstances to assess the level of anticoagulation by maintaining it above 200 to 250 sec. Some patients have a higher risk of bleeding which requires a regional anticoagulation. In this method, extracorporeal dialyzer is heparinized in the arterial line and protamine is administered in the venous line. Another strategy is not using any forms of anticoagulation which hemodialysis is initiated with a high blood flow rate to decrease the risk of thrombosis and using saline flush technique which, the dialyzer is flushed with 50 mL of saline every 15 to 60 minutes. # Monitoring and Adequacy The dialysis adequacy is measured by using two factors, Kt/V and the urea reduction rate: - Kt/V: measures the ratio of cleared plasma (Kt) to the volume of urea distribution (V). The goal is to keep the ratio above 1.2 however, Kt/V higher than 1.4 may show more efficient dialysis. - Urea reduction ratio (URR): It reflects the removal of urea. URR is calculated by using the pre and post dialysis BUN measures. URR = (BUN pre-BUN post) / BUN pre It is recommended to keep URR 65% to 70%. A typical hemodialysis is usually between 3 to 4 hours and three times a week. Blood flow is between 400 to 500 mL/min. However, for central venous catheter it might be lower about 350 to 400 mL/min. Dialysate flow rate is between 500 to 800 mL/min. Large size dialyzer may improve the adequacy.	Hemodialysis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2] # Overview The goal of hemodialysis is removing toxins and aim to maintain euvolemia. Ninety three percent of ESRD patients in the United States and 89% worldwide, are under hemodialysis.[1] Solute diffusion across a membrane is the basic principle for hemodialysis. Metabolic waste products move across a semipermeable membrane depending on their concentration gradient between plasma and dialysate. Concentration gradient, membrane surface area, the membrane thickness, and size of solute molecule are important factors determining rate of diffusion. Small molecules clear more efficiently than larger molecules. Fluid removal is another advantage of hemodialysis that could be achieved by ultrafiltration. In-center hemodialysis and home hemodialysis are available for ESRD patients requiring renal replacement therapy; the choice of modality is based on patient condition, patient preference, and the availability of equipments. # Components ## The Dialyzer Dialyzer is usually made of bundles of hollow fibers permitting a high flow rate of blood and dialysate simultaneously. Parallel plates are another type of dialyzer that are barely used in recent times. Most of the dialyzers are synthetic with a variety of materials including polyamide, polyarylethersulfone, polyvinylpyrrolidone, polyacrylonitrile, and polysulfone. Biocompatible membranes have the advantage of not activating complement system. ## The Dialysate The dialysate is a paramount composition in hemodialysis. Solutes diffuse across the dialyzer between blood and dialysate. The dialysate composition should be individualized to restore plasma normal values. The main solutes in dialysate include sodium, potassium, calcium, magnesium, chloride, bicarbonate , and glucose. These electrolytes are treated with water during the process. About 100 liters of water is needed for each dialysis session. The water used for hemodialysis should be processed in order to have a balanced concentration of solutes. Also, contaminants including bacteria, viruses, and heavy metals, such as aluminium should be removed from water. This removal could be done either by using reverse osmosis or deionization. Filters may be used to improve water quality by removing particles. The dialyzate temperature could also be adjusted to cause vasoconstriction and improve patient's hemodynamics. The choice of the dialysate is important to maintain or correct the electrolytes. - Sodium: Usually, sodium concentration of 140-145 mEq/L is suitable for most of the patients but, it could be adjusted based on patient's sodium level. - Potassium: The potassium concentration in dialysate solution depends on patient potassium level. For example: For patients with hyperkalemia, a potassium concentration of 2-3 mEq/L is appropriate and for patients with hypokalemia, a potassium concentration of 4 mEq/L is appropriate. - Calcium: Dialysate concentration for calcium are available with 2.5 ,3, or 3.5 mEq/L. In most of the cases a 2.5 mEq/L solution which is equivalent to 5 mg/dl ionized calcium is used. ## Blood Delivery System The blood pump delivers blood from the arterial line to the dialyzer and then return it to the venous line. It's speed could be adjusted based on patient condition typically between 200 to 600 mL/min. This pump allows creating a transmembrane pressure in dialyzer by sucking dialysate. The dialysate flow rate is between 500 to 800 mL/min. # Vascular Access - The establishment and maintenance of reliable vascular access is crucial for long-term hemodialysis. - Creating arteriovenous (AV) access by establishing arteriovenous fistula (AVF) is the most reliable vascular access. On the other hand, arteriovenous graft (AVG) may provide access in certain circumstances by placing a prosthetic or biograft. However, majority of patients need temporary access by tunneled catheters for initiating hemodialysis. - Insertion of central catheter may cause complications, such as arterial and ventricular dysrhythmias, arterial puncture, hemothorax, pneumothorax, air embolism, perforation of central vein or cardiac chamber, and pericardial tamponade. - Infection is another concern regarding catheter care. Migration of bacteria from patient's skin is the mechanism of catheter infection. Skin preparation before procedure by using chlorhexidine at the catheter exit site could prevent catheter infection. Staphylococcus epidermidis, is the most common isolate. Prompt catheter removal is recommended if evidences of site infection is present even in the absence of systemic signs. - Catheter thrombosis may cause block blood flow is another aspect of catheter care. Instilling alteplase in the affected catheter lumen for 30 to 120 minutes is the preferred treatment. - Central vein stenosis: Subclavian vein catheters have a higher risk of stenosis. Using a dilator and ultrasound guided inserting may decrease the risk of vessel trauma and consequently minimize the likelihood of stenosis. # Anticoagulation Dialysis patients tend to have greater risk of thrombosis due to increased factor VII activity, increased fibrinolytic activity, and elevated fibrinogen levels. However, uremic state may poses patients to bleeding diathesis. Also, dialysis procedure may increase turbulent blood flows with high shear stress which may activate platelets. All of these concepts emerge the use of anticoagulants during hemodialysis. Heparin (UFH) is the most frequently used form of anticoagulants. The usual heparin dose is 50 to 100 U/kg bolus at the initiation which followed by 100 U/hour. Activated clotting time (ACT) is measured in certain circumstances to assess the level of anticoagulation by maintaining it above 200 to 250 sec. Some patients have a higher risk of bleeding which requires a regional anticoagulation. In this method, extracorporeal dialyzer is heparinized in the arterial line and protamine is administered in the venous line. Another strategy is not using any forms of anticoagulation which hemodialysis is initiated with a high blood flow rate to decrease the risk of thrombosis and using saline flush technique which, the dialyzer is flushed with 50 mL of saline every 15 to 60 minutes. # Monitoring and Adequacy The dialysis adequacy is measured by using two factors, Kt/V and the urea reduction rate: - Kt/V: measures the ratio of cleared plasma (Kt) to the volume of urea distribution (V). The goal is to keep the ratio above 1.2 however, Kt/V higher than 1.4 may show more efficient dialysis. - Urea reduction ratio (URR): It reflects the removal of urea. URR is calculated by using the pre and post dialysis BUN measures. URR = (BUN pre-BUN post) / BUN pre It is recommended to keep URR 65% to 70%. A typical hemodialysis is usually between 3 to 4 hours and three times a week. Blood flow is between 400 to 500 mL/min. However, for central venous catheter it might be lower about 350 to 400 mL/min. Dialysate flow rate is between 500 to 800 mL/min. Large size dialyzer may improve the adequacy.	https://www.wikidoc.org/index.php/Haemodialysis
bcd62efdedc925e47901837f3e4832756e274005	wikidoc	Hemodynamics	Hemodynamics # Overview - The circulatory system transports blood and helps in delivering oxygen, nutrients and chemicals to the cells of the body and in removing cell wastes. - Hemodynamics, meaning literally "blood movement", is the study of blood flow or the circulation and it includes studying the following concepts: Cardiac output Blood flow Blood pressure - Cardiac output - Blood flow - Blood pressure - The factors influencing hemodynamics are extensive and include circulating fluid volume, respiration, vascular diameter and resistance, and blood viscosity. Each of these may in turn be influenced by physiological factors, such as diet, exercise, disease, drugs or alcohol, obesity and excess weight. # The Circulatory System - The circulatory system is a connected series of tubes, which includes the heart, the arteries, the micro-circulation, and the veins. The “beating” of the heart generates pulsatile blood flow which is conducted into the arteries, across the micro-circulation and eventually, back via the venous system to the heart. - The heart, vessels and lungs are all actively involved in maintaining healthy cells and organs, and all influence hemodynamics. ## The Components of the Circulatory System - The Heart The heart is the driver of the circulatory system generating cardiac output (CO) by rhythmically contracting and relaxing. This creates changes in regional pressures, and, combined with a complex valvular system in the heart and the veins, ensures that the blood moves around the circulatory system in one direction. - The heart is the driver of the circulatory system generating cardiac output (CO) by rhythmically contracting and relaxing. This creates changes in regional pressures, and, combined with a complex valvular system in the heart and the veins, ensures that the blood moves around the circulatory system in one direction. - The Arterial System The aorta, the main artery, leaves the left heart and proceeds to divide into smaller and smaller arteries until they become arterioles, and eventually capillaries, where oxygen transfer occurs. - The aorta, the main artery, leaves the left heart and proceeds to divide into smaller and smaller arteries until they become arterioles, and eventually capillaries, where oxygen transfer occurs. - The microcirculation The micro-circulation, formed by the arterioles, capillaries and venules, constitutes most of the area of the vascular system and is the site of the transfer of, O2, glucose and substrates into the cells. - The micro-circulation, formed by the arterioles, capillaries and venules, constitutes most of the area of the vascular system and is the site of the transfer of, O2, glucose and substrates into the cells. - The Venous System The venous system returns the deoxygenated blood to the right heart where it is pumped into the lungs to become oxygenated and CO2 and other gaseous wastes exchanged and expelled during breathing. Blood then returns to the left side of the heart where it begins the process again. - The venous system returns the deoxygenated blood to the right heart where it is pumped into the lungs to become oxygenated and CO2 and other gaseous wastes exchanged and expelled during breathing. Blood then returns to the left side of the heart where it begins the process again. # Cardiac Output - Cardiac output (CO) is defined as the amount of blood pumped by the left ventricle in unit time. CO = Stroke Volume x Heart Rate The normal cardiac output is 5-6L/min and it can increase up to 5 times during exercise. CO is an indicator of the left ventricular function. - CO = Stroke Volume x Heart Rate - The normal cardiac output is 5-6L/min and it can increase up to 5 times during exercise. - CO is an indicator of the left ventricular function. - Cardiac index (CI) is the output of the heart per minute per body surface area. CI = CO / Body Surface Area The normal cardiac index is 3.2 L/min/m2. - CI = CO / Body Surface Area - The normal cardiac index is 3.2 L/min/m2. - Stroke volume (SV) is the amount of blood pumped by the left ventricle in a single cardiac cycle. At the start of systole, the left ventricle is filled with blood to the capacity known as end diastolic volume EDV. During systole, the left ventricle contracts and ejects blood until it reaches its minimum capacity known as end systolic volume ESV. Stroke Volume (SV) = EDV – ESV - At the start of systole, the left ventricle is filled with blood to the capacity known as end diastolic volume EDV. - During systole, the left ventricle contracts and ejects blood until it reaches its minimum capacity known as end systolic volume ESV. - Stroke Volume (SV) = EDV – ESV ## Factors affecting the cardiac output - CO = Stroke volume x Heart rate - The cardiac output changes when there is any change in the stroke volume, the heart rate or both. ### Factors affecting the heart rate: - The electrical activity of the heart is generated spontaneously in the sinoatrial node. However, the autonomic nervous system affects the speed at which the electrical activity of the heart is generated and hence affects the heart rate. The sympathetic nervous system increases the heart rate (positive chronotropy). The parasympathetic nervous system decreases the heart rate (negative chronotropy). - The sympathetic nervous system increases the heart rate (positive chronotropy). - The parasympathetic nervous system decreases the heart rate (negative chronotropy). ### Factors affecting the stroke volume - 1- Preload: The preload is the volume that fills in the heart during diastole, and it is referred to as the end diastolic volume (EDV). According to Frank Starling's law, the larger the blood volume filling the heart is, the larger the degree of cardiac stretching is and consequently more blood is pumped. - The preload is the volume that fills in the heart during diastole, and it is referred to as the end diastolic volume (EDV). - According to Frank Starling's law, the larger the blood volume filling the heart is, the larger the degree of cardiac stretching is and consequently more blood is pumped. - 2- Afterload: The afterload is the pressure corresponding to the mean arterial pressure that the heart needs to overcome when pumping blood. When the afterload increases, it makes it harder for the heart to pump the blood, and thus the volume remaining in the ventricles after ventricular contraction (end systolic volume) will increase and the stroke volume will be low. - The afterload is the pressure corresponding to the mean arterial pressure that the heart needs to overcome when pumping blood. - When the afterload increases, it makes it harder for the heart to pump the blood, and thus the volume remaining in the ventricles after ventricular contraction (end systolic volume) will increase and the stroke volume will be low. - 3- The contractility of the heart: The contractility of the heart is defined as the intrinsic force with which the heart contracts. Factors that increase the contractility of the heart (positive ionotropy) are: catecholamines, xanthines (caffeine), medications (Digitalis). Factors that decrease the contractlity of the heart (negative ionotropy) are: hypercapnea, hypoxia, acidosis, medications (quinidine, procainamide, barbiturates), heart failure. - The contractility of the heart is defined as the intrinsic force with which the heart contracts. - Factors that increase the contractility of the heart (positive ionotropy) are: catecholamines, xanthines (caffeine), medications (Digitalis). - Factors that decrease the contractlity of the heart (negative ionotropy) are: hypercapnea, hypoxia, acidosis, medications (quinidine, procainamide, barbiturates), heart failure. ## Clinical Correlation - Diseases of the cardiovascular system are often associated with changes in CO. Cardiomyopathy and heart failure cause a reduction in cardiac output. Hypertension, infection and sepsis are known to increase cardiac output. - Cardiomyopathy and heart failure cause a reduction in cardiac output. - Hypertension, infection and sepsis are known to increase cardiac output. # Blood Flow - Blood flows from one site to another proportionally to the difference of pressures between these sites and inversely proportionally to the resistance of conduits (which are the vessels) in which blood is circulating. - This is the same concept of Ohm's law and it can be illustrated in the following formula: Flow = Difference in Pressure/Resistance Difference in pressure= Pressure at the first site - Pressure at the second site Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4 - Flow = Difference in Pressure/Resistance - Difference in pressure= Pressure at the first site - Pressure at the second site - Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4 - Circulation is influenced by the resistance of the vascular bed against which the heart is pumping. Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart. Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart. - Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart. - Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart. - The vessels actively change diameter under the influence of physiology or therapy: Vasoconstrictors decrease vessel diameter and increase resistance and hence decrease the blood flow. Vasodilators increase vessel diameter and decrease resistance and hence increase the blood flow. - Vasoconstrictors decrease vessel diameter and increase resistance and hence decrease the blood flow. - Vasodilators increase vessel diameter and decrease resistance and hence increase the blood flow. # Blood Pressure - Blood pressure (BP) is the pressure exerted by the circulating blood on the walls of the blood vessels. - The blood pressure can be clinically measured using a plethysmograph or cuff connected to a pressure sensor (mercury or aneroid manometer). - Blood pressure varies during each cardiac cycle: Systolic blood pressure: It is the maximal blood pressure during each cycle. It is normally around 120 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is contracting and pushing blood into the aorta. Diastolic blood pressure: It is the minimal blood pressure during each cycle. It is normally around 70 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is relaxing. - Systolic blood pressure: It is the maximal blood pressure during each cycle. It is normally around 120 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is contracting and pushing blood into the aorta. - It is the maximal blood pressure during each cycle. - It is normally around 120 mmHg. - It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is contracting and pushing blood into the aorta. - Diastolic blood pressure: It is the minimal blood pressure during each cycle. It is normally around 70 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is relaxing. - It is the minimal blood pressure during each cycle. - It is normally around 70 mmHg. - It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is relaxing. - The average pressure throughout the cardiac cycle is referred to as mean arterial pressure (MAP). MAP = diastolic BP + (systolic BP - diastolic BP)/3= (systolic BP + 2x diastolic pressure)/3 - MAP = diastolic BP + (systolic BP - diastolic BP)/3= (systolic BP + 2x diastolic pressure)/3 ## Factors Influencing Blood Pressure - Blood Pressure = Cardiac Output x Peripheral vascular resistance - Any factor that affects the cardiac output, peripheral resistance or both will alter the blood pressure. ## Regulation of Blood Pressure - The regulation of the blood pressure is complex as it involves the interaction between the cardiovascular, renal and neurological systems among others. ### 1- Short term regulation of the blood pressure: - Arterial baroreceptor reflex is the most important factor in the short term regulation of the blood pressure. - Other cardiovascular reflexes: Reflexes of heart and lungs Chemoreceptors Reflexes of the exercising skeletal muscles - Reflexes of heart and lungs - Chemoreceptors - Reflexes of the exercising skeletal muscles ### 2- Long term regulation of the blood pressure: - Fluid balance by the renin-angiotensin system(RAAS) is the main contributor of the long term regulation of the blood pressure.	Hemodynamics Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor(s)-in-Chief: Rim Halaby # Overview - The circulatory system transports blood and helps in delivering oxygen, nutrients and chemicals to the cells of the body and in removing cell wastes. - Hemodynamics, meaning literally "blood movement", is the study of blood flow or the circulation and it includes studying the following concepts: Cardiac output Blood flow Blood pressure - Cardiac output - Blood flow - Blood pressure - The factors influencing hemodynamics are extensive and include circulating fluid volume, respiration, vascular diameter and resistance, and blood viscosity. Each of these may in turn be influenced by physiological factors, such as diet, exercise, disease, drugs or alcohol, obesity and excess weight. # The Circulatory System - The circulatory system is a connected series of tubes, which includes the heart, the arteries, the micro-circulation, and the veins. The “beating” of the heart generates pulsatile blood flow which is conducted into the arteries, across the micro-circulation and eventually, back via the venous system to the heart. - The heart, vessels and lungs are all actively involved in maintaining healthy cells and organs, and all influence hemodynamics. ## The Components of the Circulatory System - The Heart The heart is the driver of the circulatory system generating cardiac output (CO) by rhythmically contracting and relaxing. This creates changes in regional pressures, and, combined with a complex valvular system in the heart and the veins, ensures that the blood moves around the circulatory system in one direction. - The heart is the driver of the circulatory system generating cardiac output (CO) by rhythmically contracting and relaxing. This creates changes in regional pressures, and, combined with a complex valvular system in the heart and the veins, ensures that the blood moves around the circulatory system in one direction. - The Arterial System The aorta, the main artery, leaves the left heart and proceeds to divide into smaller and smaller arteries until they become arterioles, and eventually capillaries, where oxygen transfer occurs. - The aorta, the main artery, leaves the left heart and proceeds to divide into smaller and smaller arteries until they become arterioles, and eventually capillaries, where oxygen transfer occurs. - The microcirculation The micro-circulation, formed by the arterioles, capillaries and venules, constitutes most of the area of the vascular system and is the site of the transfer of, O2, glucose and substrates into the cells. - The micro-circulation, formed by the arterioles, capillaries and venules, constitutes most of the area of the vascular system and is the site of the transfer of, O2, glucose and substrates into the cells. - The Venous System The venous system returns the deoxygenated blood to the right heart where it is pumped into the lungs to become oxygenated and CO2 and other gaseous wastes exchanged and expelled during breathing. Blood then returns to the left side of the heart where it begins the process again. - The venous system returns the deoxygenated blood to the right heart where it is pumped into the lungs to become oxygenated and CO2 and other gaseous wastes exchanged and expelled during breathing. Blood then returns to the left side of the heart where it begins the process again. # Cardiac Output - Cardiac output (CO) is defined as the amount of blood pumped by the left ventricle in unit time. CO = Stroke Volume x Heart Rate The normal cardiac output is 5-6L/min and it can increase up to 5 times during exercise. CO is an indicator of the left ventricular function. - CO = Stroke Volume x Heart Rate - The normal cardiac output is 5-6L/min and it can increase up to 5 times during exercise. - CO is an indicator of the left ventricular function. - Cardiac index (CI) is the output of the heart per minute per body surface area. CI = CO / Body Surface Area The normal cardiac index is 3.2 L/min/m2.[1] - CI = CO / Body Surface Area - The normal cardiac index is 3.2 L/min/m2.[1] - Stroke volume (SV) is the amount of blood pumped by the left ventricle in a single cardiac cycle. At the start of systole, the left ventricle is filled with blood to the capacity known as end diastolic volume EDV. During systole, the left ventricle contracts and ejects blood until it reaches its minimum capacity known as end systolic volume ESV. Stroke Volume (SV) = EDV – ESV - At the start of systole, the left ventricle is filled with blood to the capacity known as end diastolic volume EDV. - During systole, the left ventricle contracts and ejects blood until it reaches its minimum capacity known as end systolic volume ESV. - Stroke Volume (SV) = EDV – ESV ## Factors affecting the cardiac output - CO = Stroke volume x Heart rate - The cardiac output changes when there is any change in the stroke volume, the heart rate or both. ### Factors affecting the heart rate: - The electrical activity of the heart is generated spontaneously in the sinoatrial node. However, the autonomic nervous system affects the speed at which the electrical activity of the heart is generated and hence affects the heart rate. The sympathetic nervous system increases the heart rate (positive chronotropy). The parasympathetic nervous system decreases the heart rate (negative chronotropy).[2] - The sympathetic nervous system increases the heart rate (positive chronotropy). - The parasympathetic nervous system decreases the heart rate (negative chronotropy).[2] ### Factors affecting the stroke volume - 1- Preload: The preload is the volume that fills in the heart during diastole, and it is referred to as the end diastolic volume (EDV). According to Frank Starling's law, the larger the blood volume filling the heart is, the larger the degree of cardiac stretching is and consequently more blood is pumped. - The preload is the volume that fills in the heart during diastole, and it is referred to as the end diastolic volume (EDV). - According to Frank Starling's law, the larger the blood volume filling the heart is, the larger the degree of cardiac stretching is and consequently more blood is pumped. - 2- Afterload: The afterload is the pressure corresponding to the mean arterial pressure that the heart needs to overcome when pumping blood. When the afterload increases, it makes it harder for the heart to pump the blood, and thus the volume remaining in the ventricles after ventricular contraction (end systolic volume) will increase and the stroke volume will be low. - The afterload is the pressure corresponding to the mean arterial pressure that the heart needs to overcome when pumping blood. - When the afterload increases, it makes it harder for the heart to pump the blood, and thus the volume remaining in the ventricles after ventricular contraction (end systolic volume) will increase and the stroke volume will be low. - 3- The contractility of the heart: The contractility of the heart is defined as the intrinsic force with which the heart contracts. Factors that increase the contractility of the heart (positive ionotropy) are: catecholamines, xanthines (caffeine), medications (Digitalis). Factors that decrease the contractlity of the heart (negative ionotropy) are: hypercapnea, hypoxia, acidosis, medications (quinidine, procainamide, barbiturates), heart failure.[3] - The contractility of the heart is defined as the intrinsic force with which the heart contracts. - Factors that increase the contractility of the heart (positive ionotropy) are: catecholamines, xanthines (caffeine), medications (Digitalis). - Factors that decrease the contractlity of the heart (negative ionotropy) are: hypercapnea, hypoxia, acidosis, medications (quinidine, procainamide, barbiturates), heart failure.[3] ## Clinical Correlation - Diseases of the cardiovascular system are often associated with changes in CO. Cardiomyopathy and heart failure cause a reduction in cardiac output. Hypertension, infection and sepsis are known to increase cardiac output. - Cardiomyopathy and heart failure cause a reduction in cardiac output. - Hypertension, infection and sepsis are known to increase cardiac output. # Blood Flow - Blood flows from one site to another proportionally to the difference of pressures between these sites and inversely proportionally to the resistance of conduits (which are the vessels) in which blood is circulating. - This is the same concept of Ohm's law and it can be illustrated in the following formula: Flow = Difference in Pressure/Resistance Difference in pressure= Pressure at the first site - Pressure at the second site Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4 - Flow = Difference in Pressure/Resistance - Difference in pressure= Pressure at the first site - Pressure at the second site - Resistance= 8 x viscosity of blood x length of vessels/ Pi x radius of vessels^4 - Circulation is influenced by the resistance of the vascular bed against which the heart is pumping. Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart. Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart. - Pulmonary Vascular Resistance (PVR) is created by the pulmonary bed on the right side of the heart. - Systemic Vascular Resistance (SVR) is created by the systemic vascular bed on the left side of the heart. - The vessels actively change diameter under the influence of physiology or therapy: Vasoconstrictors decrease vessel diameter and increase resistance and hence decrease the blood flow. Vasodilators increase vessel diameter and decrease resistance and hence increase the blood flow. - Vasoconstrictors decrease vessel diameter and increase resistance and hence decrease the blood flow. - Vasodilators increase vessel diameter and decrease resistance and hence increase the blood flow. # Blood Pressure - Blood pressure (BP) is the pressure exerted by the circulating blood on the walls of the blood vessels. - The blood pressure can be clinically measured using a plethysmograph or cuff connected to a pressure sensor (mercury or aneroid manometer). - Blood pressure varies during each cardiac cycle: Systolic blood pressure: It is the maximal blood pressure during each cycle. It is normally around 120 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is contracting and pushing blood into the aorta. Diastolic blood pressure: It is the minimal blood pressure during each cycle. It is normally around 70 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is relaxing. - Systolic blood pressure: It is the maximal blood pressure during each cycle. It is normally around 120 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is contracting and pushing blood into the aorta. - It is the maximal blood pressure during each cycle. - It is normally around 120 mmHg. - It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is contracting and pushing blood into the aorta. - Diastolic blood pressure: It is the minimal blood pressure during each cycle. It is normally around 70 mmHg. It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is relaxing. - It is the minimal blood pressure during each cycle. - It is normally around 70 mmHg. - It corresponds to the pressure exerted by the circulating blood on the walls of the vessels as the left ventricle is relaxing. - The average pressure throughout the cardiac cycle is referred to as mean arterial pressure (MAP). MAP = diastolic BP + (systolic BP - diastolic BP)/3= (systolic BP + 2x diastolic pressure)/3 [4] - MAP = diastolic BP + (systolic BP - diastolic BP)/3= (systolic BP + 2x diastolic pressure)/3 [4] ## Factors Influencing Blood Pressure - Blood Pressure = Cardiac Output x Peripheral vascular resistance - Any factor that affects the cardiac output, peripheral resistance or both will alter the blood pressure. ## Regulation of Blood Pressure - The regulation of the blood pressure is complex as it involves the interaction between the cardiovascular, renal and neurological systems among others. ### 1- Short term regulation of the blood pressure: - Arterial baroreceptor reflex is the most important factor in the short term regulation of the blood pressure. - Other cardiovascular reflexes: Reflexes of heart and lungs Chemoreceptors Reflexes of the exercising skeletal muscles[5] - Reflexes of heart and lungs - Chemoreceptors - Reflexes of the exercising skeletal muscles[5] ### 2- Long term regulation of the blood pressure: - Fluid balance by the renin-angiotensin system(RAAS) is the main contributor of the long term regulation of the blood pressure.[6]	https://www.wikidoc.org/index.php/Haemodynamics
b60f87387532c346a83187b02e26e7958dabcb68	wikidoc	Hemoglobin C	Hemoglobin C # Overview Hemoglobin C (abbreviated as Hb C or HbC) is an abnormal hemoglobin in which substitution of a glutamic acid residue with a lysine residue at the 6th position of the β-globin chain has occurred (E6K substitution). In those who are heterozygous for the mutation, about 28–44% of total hemoglobin (Hb) is HbC, and no anemia develops. In homozygotes, nearly all Hb is in the HbC form, resulting in moderate normocytic hemolytic anemia. Individuals heterozygous for both HbC and Hb S (Hb SC disease) or for HbC and thalassemia are known, and have atypical hemolytic anemias; sickling is enhanced in Hb SC disease. Hemoglobin C is found predominantly in West Africa and has been shown to protect against severe malaria. The "C" designation for HbC is from the name of the city where it was discovered—Christchurch, New Zealand. # Clinical significance This mutated form reduces the normal plasticity of host erythrocytes causing a hemoglobinopathy. In those who are heterozygous for the mutation, about 28–44% of total hemoglobin (Hb) is HbC, and no anemia develops. In homozygotes, nearly all Hb is in the HbC form, resulting in mild hemolytic anemia. # Presentation Target cells, microspherocytes and HbC crystals are found in a blood smear from a homozygous patient. # Combinations with other conditions Individuals with sickle cell–hemoglobin C (HbSC), have the gene for HbS inherited from one parent and the gene for HbC is inherited from the other parent: they are "heterozygous". Since HbC does not polymerize as readily as HbS, there is less sickling (fewer sickle cells). The peripheral smear demonstrates mostly target cells and only a few sickle cells. There are fewer acute vaso-occlusive events. However, persons with hemoglobin SC disease (HbSC) have more significant retinopathy, ischemic necrosis of bone, and priapism than those with pure SS disease. # Epidemiology Hemoglobin C gene is found in 2-3% of US Blacks while 8% of US Blacks have hemoglobin S (Sickle) gene. Thus Hemoglobin SC disease is significantly more common than Hemoglobin CC disease. Hemoglobin C is found predominantly in Yorubas (A profile of sickle cell disease in Nigeria By O.O Akinyanju, Department of Medicine University of Lagos). It is also found in areas of West Africa, such as Ghana, where Yorubas once lived (MAN Volume 56 March 1956 pages 34-36)	Hemoglobin C Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hemoglobin C (abbreviated as Hb C or HbC) is an abnormal hemoglobin in which substitution of a glutamic acid residue with a lysine residue at the 6th position of the β-globin chain has occurred (E6K substitution).[1] In those who are heterozygous for the mutation, about 28–44% of total hemoglobin (Hb) is HbC, and no anemia develops. In homozygotes, nearly all Hb is in the HbC form, resulting in moderate normocytic hemolytic anemia. Individuals heterozygous for both HbC and Hb S (Hb SC disease) or for HbC and thalassemia are known, and have atypical hemolytic anemias; sickling is enhanced in Hb SC disease. Hemoglobin C is found predominantly in West Africa and has been shown to protect against severe malaria. The "C" designation for HbC is from the name of the city where it was discovered—Christchurch, New Zealand. # Clinical significance This mutated form reduces the normal plasticity of host erythrocytes causing a hemoglobinopathy. In those who are heterozygous for the mutation, about 28–44% of total hemoglobin (Hb) is HbC, and no anemia develops. In homozygotes, nearly all Hb is in the HbC form, resulting in mild hemolytic anemia.[2] # Presentation Target cells, microspherocytes and HbC crystals are found in a blood smear from a homozygous patient. # Combinations with other conditions Individuals with sickle cell–hemoglobin C (HbSC), have the gene for HbS inherited from one parent and the gene for HbC is inherited from the other parent: they are "heterozygous". Since HbC does not polymerize as readily as HbS, there is less sickling (fewer sickle cells). The peripheral smear demonstrates mostly target cells and only a few sickle cells. There are fewer acute vaso-occlusive events. However, persons with hemoglobin SC disease (HbSC) have more significant retinopathy, ischemic necrosis of bone, and priapism than those with pure SS disease. [2] # Epidemiology Hemoglobin C gene is found in 2-3% of US Blacks while 8% of US Blacks have hemoglobin S (Sickle) gene. Thus Hemoglobin SC disease is significantly more common than Hemoglobin CC disease. Hemoglobin C is found predominantly in Yorubas (A profile of sickle cell disease in Nigeria By O.O Akinyanju, Department of Medicine University of Lagos). It is also found in areas of West Africa, such as Ghana, where Yorubas once lived (MAN Volume 56 March 1956 pages 34-36)[3]	https://www.wikidoc.org/index.php/Haemoglobin_C_disease
22c87c94c8aea8bee3d4091681701a94cc8b54fb	wikidoc	Hemoglobin E	Hemoglobin E # Overview Hemoglobin E or haemoglobin E (HbE) is an abnormal hemoglobin with a single point mutation in the β chain. At position 26 there is a change in the amino acid, from glutamic acid to lysine. HbE is one of the most common variant of normal hemoglobin. Hemoglobin E can be detected on electrophoresis. This hemoglobin variant is very common in Southeast Asia and it has a low frequency in black and white people. The βE mutation affects β-gene expression creating an alternate splicing site in the mRNA at codons 25-27 of the β-globin gene. Through this mechanism, there is a mild deficiency in normal β mRNA and production of small amounts of anomalous β mRNA. The reduced synthesis of β chain may cause β thalassemia. Also, this hemoglobin variant has a weak union between α and β globin, causing instability when there is a high amount of oxidant. # Hemoglobin E disease (EE) Hemoglobin E disease results when the offspring inherits the gene for HbE from both parents. At birth, babies homozygous for the hemoglobin E allele do not present symptoms due to HbF (fetal hemoglobin) they still have. In the first months of life, fetal hemoglobin disappears and the amount of hemoglobin E increases, so the subjects start to have a mild β thalassemia. People with hemoglobin E do not show any symptoms (there is usually no anemia or hemolysis). Subjects homozygous for the hemoglobin E allele have a mild hemolytic anemia and mild splenomegaly. # Hemoglobin E trait: heterozygotes for HbE (AE) Heterozygous AE occurs when the gene for haemoglobin E is inherited from one parent and the gene for haemoglobin A from the other. This is called hemoglobin E trait, and it is not a disease. People who have hemoglobin E trait (heterozygous) are asymptomatic and their state does not usually result in health problems. They may have a low mean corpuscular volume (MCV) and very abnormal red blood cells (target cells). Its clinical relevance is exclusively due to the potential for transmitting E or β thalassemia. # Heterozygotes for HbE (SE) Compound heterozygotes with hemoglobin sickle E disease result when the gene of hemoglobin E is inherited from one parent and the gene for hemoglobin S from the other. As the amount of fetal hemoglobin decreases and hemoglobin S increases, a mild hemolytic anemia appears in the early stage of development. # Hemoglobin E/β-thalassaemia People who have hemoglobin E/β thalassemia have inherited one gene for hemoglobin E from one parent and one gene for β thalassemia from the other parent. Hemoglobin E/β thalassemia is a severe disease and it still has not got a universal cure. It affects more than a million people in the world. The consequences of hemoglobin E/β thalassemia when it is not treated can be heart failure, the enlargement of the liver, problems in the bones, etc. There is a variety of genotypes depending on the interaction of HbE and α thalassemia. The presence of the α thalassemia reduces the among of HbE usually found in HbE heterozygotes. In other cases, in combination with certain thalassemia mutations, it provides an increased resistance to malaria (P. falciparum). # Epidemiology Hemoglobin E is most prevalent in Southeast Asia (Thailand, Myanmar, Cambodia, Laos, Vietnam), where its prevalence can reach 30 or 40%, and North-East India, where in certain areas carrier rates reach 60% of the population. In Thailand the mutation can reach 50 or 70%, and it is higher in the North-East of the country. It is also found in China, the Philippines, Turkey, Nepal, Sri Lanka, Pakistan, etc. The mutation is estimated to have arisen within the last 5,000 years. In Europe there have been found cases of families with hemoglobin E, but in these cases, the mutation differs from the one found in South-East Asia. This means that there may be different origins of the βE mutation.	Hemoglobin E Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hemoglobin E or haemoglobin E (HbE) is an abnormal hemoglobin with a single point mutation in the β chain. At position 26 there is a change in the amino acid, from glutamic acid to lysine. HbE is one of the most common variant of normal hemoglobin. Hemoglobin E can be detected on electrophoresis. This hemoglobin variant is very common in Southeast Asia and it has a low frequency in black and white people. The βE mutation affects β-gene expression creating an alternate splicing site in the mRNA at codons 25-27 of the β-globin gene. Through this mechanism, there is a mild deficiency in normal β mRNA and production of small amounts of anomalous β mRNA. The reduced synthesis of β chain may cause β thalassemia. Also, this hemoglobin variant has a weak union between α and β globin, causing instability when there is a high amount of oxidant.[1] # Hemoglobin E disease (EE) Hemoglobin E disease results when the offspring inherits the gene for HbE from both parents. At birth, babies homozygous for the hemoglobin E allele do not present symptoms due to HbF (fetal hemoglobin) they still have. In the first months of life, fetal hemoglobin disappears and the amount of hemoglobin E increases, so the subjects start to have a mild β thalassemia. People with hemoglobin E do not show any symptoms (there is usually no anemia or hemolysis). Subjects homozygous for the hemoglobin E allele have a mild hemolytic anemia and mild splenomegaly. # Hemoglobin E trait: heterozygotes for HbE (AE) Heterozygous AE occurs when the gene for haemoglobin E is inherited from one parent and the gene for haemoglobin A from the other. This is called hemoglobin E trait, and it is not a disease. People who have hemoglobin E trait (heterozygous) are asymptomatic and their state does not usually result in health problems. They may have a low mean corpuscular volume (MCV) and very abnormal red blood cells (target cells). Its clinical relevance is exclusively due to the potential for transmitting E or β thalassemia.[citation needed] # Heterozygotes for HbE (SE) Compound heterozygotes with hemoglobin sickle E disease result when the gene of hemoglobin E is inherited from one parent and the gene for hemoglobin S from the other. As the amount of fetal hemoglobin decreases and hemoglobin S increases, a mild hemolytic anemia appears in the early stage of development. # Hemoglobin E/β-thalassaemia People who have hemoglobin E/β thalassemia have inherited one gene for hemoglobin E from one parent and one gene for β thalassemia from the other parent. Hemoglobin E/β thalassemia is a severe disease and it still has not got a universal cure. It affects more than a million people in the world[2]. The consequences of hemoglobin E/β thalassemia when it is not treated can be heart failure, the enlargement of the liver, problems in the bones, etc. There is a variety of genotypes depending on the interaction of HbE and α thalassemia. The presence of the α thalassemia reduces the among of HbE usually found in HbE heterozygotes. In other cases, in combination with certain thalassemia mutations, it provides an increased resistance to malaria (P. falciparum).[3] # Epidemiology Hemoglobin E is most prevalent in Southeast Asia (Thailand, Myanmar, Cambodia, Laos, Vietnam[4]), where its prevalence can reach 30 or 40%, and North-East India, where in certain areas carrier rates reach 60% of the population. In Thailand the mutation can reach 50 or 70%, and it is higher in the North-East of the country. It is also found in China, the Philippines, Turkey, Nepal, Sri Lanka, Pakistan, etc. The mutation is estimated to have arisen within the last 5,000 years[5]. In Europe there have been found cases of families with hemoglobin E, but in these cases, the mutation differs from the one found in South-East Asia. This means that there may be different origins of the βE mutation.[6][7] # External links - http://www.doh.wa.gov/ehsphl/phl/newborn/pubs/HBEFactSheet.pdf - http://asheducationbook.hematologylibrary.org/content/2007/1/79.full - http://www.orpha.net/data/patho/GB/uk-HbE.pdf - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1684388/pdf/ajhg00163-0214.pdf	https://www.wikidoc.org/index.php/Haemoglobin_E_disease
8fae08286ac4324171b9bd0b85595bc0779d518d	wikidoc	Plasmodiidae	Plasmodiidae Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. The Plasmodiidae are a family of apicomplexan parasites, including the type genus Plasmodium, which is responsible for malaria. They are given their own order - the Haemosporida. # Diagnostic criteria The diagnostic criteria of this family are: - macrogametes and microgamonts develop independently - syzygy absent - microgametocyte produces 8 flagellated microgametes - zygote is motile (known as an ookinete) - conoid present in ookinete stage only - sporozoites naked in oocyst (that is without a sporocyst) - heteroxenous: merogony and gamogony occur in vertebrate host and fertilization and sporogony in definitive host (a blood sucking insect) - hemozoin pigment produced in some genera # Related genera Currently there are a number of genera recognised in this family. Like many of the protist groupings these may be significantly revised in light of findings from the DNA sequences. While more complete listings of the vertebrate host species can be found on the genus pages, typical hosts are given here. Biguetiella - bats Billbraya Bioccala - bats Dionisia - bats Haemoproteus - birds Hepatocystis - bats, monkeys, hippopotamus, squirrels Leukocytozoon - birds Mesnilium - fish Nycteria - bats Plasmodium - mammals, birds and reptiles Polchromophilus - bats Rayella - flying squirrels Saurocytozoon - reptiles # Related species Families: Lankesterellidae - Lainsonia - Lankesterella - Schellackia Genera: The hameogregarines: Cyrilia Desseria Hepatozoon Hemogregarina Hemolivia Karyolysus Others: Chelonplasma Pirhemocyton Sauroplasma Serpentoplasma	Plasmodiidae Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. The Plasmodiidae are a family of apicomplexan parasites, including the type genus Plasmodium, which is responsible for malaria. They are given their own order - the Haemosporida. # Diagnostic criteria The diagnostic criteria of this family are: - macrogametes and microgamonts develop independently - syzygy absent - microgametocyte produces 8 flagellated microgametes - zygote is motile (known as an ookinete) - conoid present in ookinete stage only - sporozoites naked in oocyst (that is without a sporocyst) - heteroxenous: merogony and gamogony occur in vertebrate host and fertilization and sporogony in definitive host (a blood sucking insect) - hemozoin pigment produced in some genera # Related genera Currently there are a number of genera recognised in this family. Like many of the protist groupings these may be significantly revised in light of findings from the DNA sequences. While more complete listings of the vertebrate host species can be found on the genus pages, typical hosts are given here. Biguetiella - bats Billbraya Bioccala - bats Dionisia - bats Haemoproteus - birds Hepatocystis - bats, monkeys, hippopotamus, squirrels Leukocytozoon - birds Mesnilium - fish Nycteria - bats Plasmodium - mammals, birds and reptiles Polchromophilus - bats Rayella - flying squirrels Saurocytozoon - reptiles # Related species Families: Lankesterellidae - Lainsonia - Lankesterella - Schellackia Genera: The hameogregarines: Cyrilia Desseria Hepatozoon Hemogregarina Hemolivia Karyolysus Others: Chelonplasma Pirhemocyton Sauroplasma Serpentoplasma	https://www.wikidoc.org/index.php/Haemosporasina
70bd66e7d345e7614ade1adfdef1ddb80e9520d6	wikidoc	Halofantrine	Halofantrine # Overview Halofantrine is a drug used to treat malaria. Halofantrine's structure contains a substituted phenanthrene, and is related to the antimalarial drugs quinine and lumefantrine. Marketed as Halfan, halofantrine is never used to prevent malaria and its mode of action is unknown, although a crystallographic study showed that it binds to hematin in vitro, suggesting a possible mechanism of action. Halofantrine has also been shown to bind to plasmpesin, a haemoglobin degrading enzyme unique to the malarial parasites. Halofantrine was developed at SRI International for the Walter Reed Army Institute of Research from 1965 to 1975 by a team led by medicinal chemist William Colwell. # Adverse reactions Halofantrine can cause abdominal pain, diarrhea, vomiting, rash, headache, itching and elevated liver enzymes. It can be associated with cardiotoxicity. The most dangerous side effect is cardiac arrhythmias: halofantrine causes significant QT prolongation, and this effect is seen even at standard doses. The drug should therefore not be given to patients with cardiac conduction defects and should not be combined with mefloquine. A survey from 2009 suggests that the drug is safe when correctly administered it # Other adverse reactions Consumption of grapefruit combined with certain medications can cause serious side effects, even death. Halofantrine combined with this fruit or grapefruit juice is dangerous. The mechanism of action is inhibition of CYP3A4, which is necessary to metabolize the drug and eliminate it from the body. Without CYP3A4, levels of the drug will become toxic in the body. # Pharmacology The mechanism of action of halofantrine is unknown. The absorption of halofantrine is erratic, but is increased when taken with fatty food. Because of fears of toxicity due to increased halofantrine blood levels, halofantrine should be taken on an empty stomach. Plasma levels peak at 16 hours and the half-life of the drug is about 4 days. # Uses Halofantrine is only used to treat malaria. It is not used to prevent malaria (prophylaxis) because of the risk of toxicity and unreliable absorption. # Dosing Adult dose: Three doses of 500 mg six hours apart. Halofantrine should be taken on an empty stomach. # Manufacturing information and availability Halfan (GlaxoSmithKline) is available as 250 mg tablets. A full treatment cost (6 tablets) costs US$1.40 in the developing world. Halofantrine is not available in the UK or U.S. # Synthesis	Halofantrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Halofantrine is a drug used to treat malaria. Halofantrine's structure contains a substituted phenanthrene, and is related to the antimalarial drugs quinine and lumefantrine. Marketed as Halfan, halofantrine is never used to prevent malaria and its mode of action is unknown, although a crystallographic study showed that it binds to hematin in vitro, suggesting a possible mechanism of action.[1] Halofantrine has also been shown to bind to plasmpesin, a haemoglobin degrading enzyme unique to the malarial parasites.[2] Halofantrine was developed at SRI International for the Walter Reed Army Institute of Research from 1965 to 1975 by a team led by medicinal chemist William Colwell.[3] # Adverse reactions Halofantrine can cause abdominal pain, diarrhea, vomiting, rash, headache, itching and elevated liver enzymes. It can be associated with cardiotoxicity.[4] The most dangerous side effect is cardiac arrhythmias: halofantrine causes significant QT prolongation,[5] and this effect is seen even at standard doses. The drug should therefore not be given to patients with cardiac conduction defects and should not be combined with mefloquine. A survey from 2009 suggests that the drug is safe when correctly administered [6]it # Other adverse reactions Consumption of grapefruit combined with certain medications can cause serious side effects, even death. Halofantrine combined with this fruit or grapefruit juice is dangerous. The mechanism of action is inhibition of CYP3A4, which is necessary to metabolize the drug and eliminate it from the body. Without CYP3A4, levels of the drug will become toxic in the body. # Pharmacology The mechanism of action of halofantrine is unknown. The absorption of halofantrine is erratic, but is increased when taken with fatty food. Because of fears of toxicity due to increased halofantrine blood levels, halofantrine should be taken on an empty stomach. Plasma levels peak at 16 hours and the half-life of the drug is about 4 days. # Uses Halofantrine is only used to treat malaria. It is not used to prevent malaria (prophylaxis) because of the risk of toxicity and unreliable absorption. # Dosing Adult dose: Three doses of 500 mg six hours apart. Halofantrine should be taken on an empty stomach. # Manufacturing information and availability Halfan (GlaxoSmithKline) is available as 250 mg tablets. A full treatment cost (6 tablets) costs US$1.40 in the developing world. Halofantrine is not available in the UK or U.S. # Synthesis	https://www.wikidoc.org/index.php/Halfan
92c27373303c23d57f41d95383db14077a3c4a94	wikidoc	Halonium ion	Halonium ion A halonium ion in organic chemistry is any onium compound (ion) containing a bridged halogen atom carrying a positive charge. This cation has the general structure R-X+-R where X is any halogen and R any organic residue and this structure can be cyclic or an open chain molecular structure. Halonium ions were first postulated in 1937 by Roberts and Kimball to account for observed diastereoselectivity in halogen addition reactions to alkenes. They correctly argued that if the initial reaction intermediate in bromination is the open-chain X--C-C+, rotation around the C-C single bond would be possible leading to a mixture of equal amounts of dihalogen cis isomer and trans isomer which is not the case. They also asserted that a positively charged halogen atom is isoelectronic with oxygen and that carbon and bromine have comparable ionization potentials. In 1970 George A. Olah succeeded in preparing and isolating halonium salts by adding a methyl halide such as methyl bromide or methyl chloride in sulfur dioxide at -78°C to a complex of antimony pentafluoride and tetrafluoromethane in sulfur dioxide. After evaporation of sulfur dioxide this procedure left crystals of CH3-X+-CH3SbF6-, stable at room temperature but not to moisture. A halonium ion also seems to refer generically to the simpler onium compounds (ions) based on halogens: fluoronium, H2F+; chloronium, H2Cl+; bromonium, H2Br+; iodonium, H2I+.	Halonium ion A halonium ion in organic chemistry is any onium compound (ion) containing a bridged halogen atom carrying a positive charge. This cation has the general structure R-X+-R where X is any halogen and R any organic residue and this structure can be cyclic or an open chain molecular structure. Halonium ions were first postulated in 1937 by Roberts and Kimball [1] to account for observed diastereoselectivity in halogen addition reactions to alkenes. They correctly argued that if the initial reaction intermediate in bromination is the open-chain X--C-C+, rotation around the C-C single bond would be possible leading to a mixture of equal amounts of dihalogen cis isomer and trans isomer which is not the case. They also asserted that a positively charged halogen atom is isoelectronic with oxygen and that carbon and bromine have comparable ionization potentials. In 1970 George A. Olah succeeded in preparing and isolating halonium salts [2] by adding a methyl halide such as methyl bromide or methyl chloride in sulfur dioxide at -78°C to a complex of antimony pentafluoride and tetrafluoromethane in sulfur dioxide. After evaporation of sulfur dioxide this procedure left crystals of CH3-X+-CH3SbF6-, stable at room temperature but not to moisture. A halonium ion also seems to refer generically to the simpler onium compounds (ions) based on halogens: fluoronium, H2F+; chloronium, H2Cl+; bromonium, H2Br+; iodonium, H2I+.	https://www.wikidoc.org/index.php/Halonium_ion
19d16cf30df596f707d956bb6c4a877f75a761d6	wikidoc	Hand surgeon	Hand surgeon # Overview Hand surgeons are a surgeons specializing in the care and treatment of problems relating to the hand, wrist, and forearm including trauma and hand infection. Many hand surgeons also treat the elbow, arm and shoulder. Hand surgeons do not just engage in surgery - they are the primary medical doctors to deal with these issues, and often use non-surgical approaches. In the US, hand surgery is a subspecialty of surgery. A hand surgeon must first qualify as a general surgeon, plastic surgeon, or orthopedic surgeon, and then must do a one year long fellowship in hand practice. Board certified general, plastic, or orthopedics surgeons who have completed approved fellowship training in hand surgery and have met a number of other practice requirements are qualified to take the "Certificate of Added Qualifications in Surgery of the Hand" examination, commonly referred to as the "CAQSH." The historical context for the three qualifying fields is that both plastic surgery and orthopedic surgery are more recent branches off the general surgery main trunk. Modern hand surgery began in World War II as a military planning decision. US Army Surgeon General, Major General Norman T. Kirk, knew that hand injuries in World War I had poor outcomes in part because there was no formal system to deal with them. Kirk also knew that his civilian general surgical colleague Dr. Sterling Bunnell had a special interest and experience in hand reconstruction. Kirk tapped Bunnell to train military surgeons in the management of hand injuries to treat the war casualties, and at that time hand surgery became a formal specialty. Orthopedic surgeons continued to develop special techniques to manage small bones, as found in the wrist and hand. Pioneering plastic surgeons developed microsurgical techniques for repairing the small nerves and arteries of the hand. Surgeons from all three specialties have contributed to the development of techniques for repairing tendons and managing a broad range of acute and chronic hand injuries. Hand surgery incorporates techniques from orthopaedics, plastic surgery, general surgery, neurosurgery, vascular and microvascular surgery and psychiatry and is a complex, fascinating specialty. Two medical societies exist in the United States to provide continuing medical education to hand surgeons: the American Society for Surgery of the Hand and the American Association for Hand Surgery. # Notes - ↑ "Why Visit a Hand Surgeon", American Society for Surgery of the Hand. Retrieved on 2008-11-20. - ↑ "About Physician Specialties", American Board of Medical Specialties. Retrieved on 2008-11-20. - ↑ Stern, Peter J, "Subspecialty certification in hand surgery." Clinical orthopaedics and related research 2006; 449: 165-8. PMID 16735880 - ↑ "Certificate of Added Qualifications in Surgery of the Hand" The American Board of Orthopaedic Surgery. Retrieved on 2008-11-20. - ↑ American Society for Surgery of the Hand. (1995). The First Fifty Years. "The Second World War to 1971: The Founding," pp. 1-17. New York: Churchill Livingstone Inc. ISBN 0-443-07761-4 hu:Kézsebész	Hand surgeon Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2] # Overview Hand surgeons are a surgeons specializing in the care and treatment of problems relating to the hand, wrist, and forearm including trauma and hand infection.[1] Many hand surgeons also treat the elbow, arm and shoulder. Hand surgeons do not just engage in surgery - they are the primary medical doctors to deal with these issues, and often use non-surgical approaches. In the US, hand surgery is a subspecialty of surgery.[2] A hand surgeon must first qualify as a general surgeon, plastic surgeon, or orthopedic surgeon, and then must do a one year long fellowship in hand practice.[3] Board certified general, plastic, or orthopedics surgeons who have completed approved fellowship training in hand surgery and have met a number of other practice requirements are qualified to take the "Certificate of Added Qualifications in Surgery of the Hand" examination, commonly referred to as the "CAQSH."[4] The historical context for the three qualifying fields is that both plastic surgery and orthopedic surgery are more recent branches off the general surgery main trunk. Modern hand surgery began in World War II as a military planning decision. US Army Surgeon General, Major General Norman T. Kirk, knew that hand injuries in World War I had poor outcomes in part because there was no formal system to deal with them.[5] Kirk also knew that his civilian general surgical colleague Dr. Sterling Bunnell had a special interest and experience in hand reconstruction. Kirk tapped Bunnell to train military surgeons in the management of hand injuries to treat the war casualties, and at that time hand surgery became a formal specialty. Orthopedic surgeons continued to develop special techniques to manage small bones, as found in the wrist and hand. Pioneering plastic surgeons developed microsurgical techniques for repairing the small nerves and arteries of the hand. Surgeons from all three specialties have contributed to the development of techniques for repairing tendons and managing a broad range of acute and chronic hand injuries. Hand surgery incorporates techniques from orthopaedics, plastic surgery, general surgery, neurosurgery, vascular and microvascular surgery and psychiatry and is a complex, fascinating specialty. Two medical societies exist in the United States to provide continuing medical education to hand surgeons: the American Society for Surgery of the Hand and the American Association for Hand Surgery. # Notes - ↑ "Why Visit a Hand Surgeon", American Society for Surgery of the Hand. Retrieved on 2008-11-20. - ↑ "About Physician Specialties", American Board of Medical Specialties. Retrieved on 2008-11-20. - ↑ Stern, Peter J, "Subspecialty certification in hand surgery." Clinical orthopaedics and related research 2006; 449: 165-8. PMID 16735880 - ↑ "Certificate of Added Qualifications in Surgery of the Hand" The American Board of Orthopaedic Surgery. Retrieved on 2008-11-20. - ↑ American Society for Surgery of the Hand. (1995). The First Fifty Years. "The Second World War to 1971: The Founding," pp. 1-17. New York: Churchill Livingstone Inc. ISBN 0-443-07761-4 hu:Kézsebész	https://www.wikidoc.org/index.php/Hand_surgeon
f4f3d77a5f0affa56b7a36c04bffd3c518d6d465	wikidoc	Hand washing	Hand washing # Overview Hand washing is the act of cleansing the hands with water or another liquid, with or without the use of soap or other detergents, for the purpose of removing soil and/or microorganisms. # Purpose The main purpose of washing hands is to cleanse the hands of pathogens (including bacteria or viruses) and chemicals which can cause personal harm or disease. This is especially important for people who handle food or work in the medical field. The Centers for Disease Control and Prevention (CDC) has stated that "It is well-documented that the most important measure for preventing the spread of pathogens is effective handwashing." While hot water may more effectively clean your hands, this is primarily due to its increased capability as a solvent, and not due to hot water actually killing germs. Hot water is more effective at removing dirt, oils and/or chemicals, but contrary to popular belief, it does not kill microorganisms. A temperature that is comfortable for hand washing (about 45 °C) is not nearly hot enough to kill any microorganism. It would take more than double that temperature to effectively kill germs (typically 100 °C). # Personal hand washing To maintain good hygiene, hands should always be washed after using the toilet, changing a diaper, tending to someone who is sick, or handling raw meat, fish, or poultry. Hands should also be washed before eating, handling or cooking food. Conventionally, the use of soap and warm running water and the washing of all surfaces thoroughly, including under fingernails is seen as necessary. One should rub wet, soapy hands together outside the stream of running water for at least 20 seconds, before rinsing thoroughly and then drying with a clean or disposable towel. After drying, a dry paper towel should be used to turn off the water (and open the exit door if one is in a restroom or other separate room). Moisturizing lotion is often recommended to keep the hands from drying out, should one's hands require washing more than a few times per day. Antibacterial soaps have been heavily promoted to a health-conscious public. To date, there is no evidence that using recommended antiseptics or disinfectants selects for antibiotic-resistant organisms in nature. However, antibacterial soaps contain common antibiotics such as Triclosan, which has an extensive list of resistant strains of organisms. So, even if antibacterial soaps do not select for antibiotic resistant strains, they might not be as effective as they are marketed to be. These soaps are quite different from the non-water-based hand hygiene agents referred to below, which also do not promote antibiotic resistance. # Medical hand washing The purpose of hand washing in the health care setting is to remove or destroy (disinfect) pathogenic microorganisms ("germs") to avoid transmitting them to a patient. The application of water alone is ineffective for cleaning skin because water is unable to remove fats, oils, and proteins, which are components of organic soil. Therefore, removal of microorganisms from skin requires the addition of soaps or detergents to water. Plain soap does not kill pathogens. However, the addition of antiseptic chemicals to soap ("medicated" or "antimicrobial" soaps) does confer killing action to a hand washing agent. Such killing action may be desired prior to performing surgery or in settings in which antibiotic-resistant organisms are highly prevalent. The proper washing of hands in a medical setting generally consists of the use of generous amounts of soap and water to lather and rub each part of ones hands systematically for 15 to 20 seconds. Hands should be rubbed together with digits interlocking. If there is debris under fingernails, a bristle brush is often used to remove it. Finally, it is necessary to rinse well and wipe dry with a paper towel. After drying, a dry paper towel should be used to turn off the water (and open any exit door if necessary). To 'scrub' one's hands for a surgical operation, a tap that can be turned on and off without touching with the hands, some chlorhexidine or iodine wash, sterile towels for drying the hands after washing, and a sterile brush for scrubbing and another sterile instrument for cleaning under the fingernails are required. All jewelery should be removed. This procedure requires washing the hands and forearms up to the elbows, and one must in this situation ensure that all parts of the hands and forearms are well scrubbed several times. When rinsing, it is ensured at all times that one does not allow water to drip back from the elbow to your hands. When done hands are dried with a sterile cloth and a surgical gown is donned. In the late 1990s and early part of the 21st century, non-water-based hand hygiene agents (also known as alcohol-based hand rubs, antiseptic hand rubs, or hand sanitizers) began to gain popularity. Most are based on isopropyl alcohol or ethanol formulated together with a humectant such as glycerin into a gel, liquid, or foam for ease of use and to decrease the drying effect of the alcohol. The increasing use of these agents is based on their ease of use, rapid killing activity against microorganisms, and lower tendency to induce irritant contact dermatitis as compared to soap and water hand washing. Despite their effectiveness, the non-water agents do not clean hands of organic material, they simply disinfect them. However, disinfection does prevent transmission of infectious microorganisms. Visible soiling of any sort on the hands must be washed with soap and water because alcohol-based hand rubs are ineffective in the presence of organic material. In addition, alcohols are ineffective against non-lipid-enveloped viruses (e.g., Noroviruses) and the spores of bacteria (e.g., Clostridium difficile) and protozoa (e.g., Giardia lamblia). When such microorganisms are likely to be encountered, soap and water hand washing is preferable. The New England Journal of Medicine reports that hand washing remains at unacceptable levels in most medical environments, with large numbers of doctors and nurses routinely forgetting to wash their hands before touching patients. One study has shown that proper hand washing and other simple procedures can decrease the rate of catheter-related bloodstream infections by 66 percent. # Truths, myths, and misinformation Plain soaps have minimal if any antimicrobial activity. In several clinical studies, hand washing with plain soap failed to remove bad microorganisms (pathogens) from the hands of hospital personnel. Hand washing with plain soap can result in an increase in bacterial counts on the skin. Occasionally, contaminated plain soaps have colonized hands with Gram-negative bacteria. The skin on your body is covered with microorganisms. Our environment is contaminated with good and bad microorganisms. You cannot kill all of the microorganisms on your hands. Your large intestine contains large numbers of microorganisms. All of these sources of germs stimulate your immune response. CDC guidelines for health care workers call for alcohol rubs to be used 60 or more times a day between patients and after touching contaminated surfaces. Killing germs on your hands will not decrease your immunity but it will help prevent disease. Hand sanitizers containing a minimum of 60 to 95% alcohol are very efficient germ killers. Alcohol rub sanitizers kill bacteria, multi-drug resistant bacteria (MRSA and VRE), tuberculosis, and viruses (including HIV, herpes, RSV, rhinovirus, vaccinia, influenza, and hepatitis) and fungus. Alcohol rub sanitizers containing 70% alcohol kill 3.5 log10 (99.9%) of the bacteria on hands 30 seconds after application and 4 to 5 log10 (99.99 to 99.999%) of the bacteria on hands 1 minute after application. Alcohol rub sanitizers can prevent the transfer of health-care associated pathogens (Gram-negative bacteria) better than soap and water. Alcohol rub sanitizers are not appropriate for use when your hands are visibly dirty, soiled or contaminated with blood. Use soap and water for dirty or soiled hands. Good germs are microorganisms normally found on human skin and bad germs are pathogenic (disease producing) microorganisms. The numbers of good germs and bad germs on the hands are variable from one person to the next but remain relatively constant for each individual. Good germs cannot protect you against bad germs. Anyone can become contaminated with bad germs (pathogens). Bad germs (pathogens) do not always cause disease and good germs can, under the right conditions, cause disease. Frequent use of alcohol-based formulations for hand sanitizers can cause dry skin unless emollients and/or skin moisturizers are added to the formula. The drying effect of alcohol can be reduced or eliminated by adding glycerin and/or other emollients to the formula. In several prospective clinical trials, alcohol based hand sanitizers containing emollients caused substantially less skin irritation and dryness than soaps or antimicrobial detergents. Allergic contact dermatitis, contact urticaria syndrome or hypersensitivity to alcohol or additives present in alcohol hand rubs rarely occurs. Dead microorganisms don’t mutate. Alcohol rubs (biocides) kill microorganisms. Current scientific evidence has not shown a link exists between the use of topical antimicrobial formulations and antiseptic or antibiotic resistance. Antiseptics (biocides) have multiple (thousands) of nonspecific killing sites on and in the microbial cell which cannot easily mutate. Antibiotics and antibacterial soaps (triclosan) have one very specific killing site on and in the microbial cell which can easily mutate. Antibiotic resistance has no effect on the effectiveness of antiseptics. Alcohol rubs and combination hand sanitizers are effective at killing germs on your hands, but not effective at removing dirt. Conversely, soap and water are very effective at cleaning dirty or soiled hands, but are not good at killing germs (as discussed above). Many clinical studies have shown that alcohol rubs containing two germ killers (ie. Alcohol and Chlorhexidine gluconate or Benzalkonium chloride) are significantly better germ killers than alcohol rubs containing alcohol alone. # Hand washing as compensation Excessive hand washing is commonly seen as a symptom of obsessive-compulsive disorder (OCD). It has also been found that people, after having recalled or contemplated unethical acts, tend to wash hands more often than others, and tend to value hand washing equipment more. Furthermore, those who are allowed to wash their hands after such a contemplation are less likely to engage in other "cleansing" compensatory actions, such as volunteering. # Symbolic hand washing Ritual handwashing is a feature of many religions, including Bahá'í Faith, Hinduism and tevilah and netilat yadayim in Judaism. Similar to these are the practises of Lavabo in Christianity, Wudu in Islam and Misogi in Shintoism. # Idioms When someone "washes their hands of" something, this means that they are declaring their unwillingness to take responsibility for it or share complicity in it. Matthew 27:24 gives an account of Pontius Pilate washing his hands of the decision to crucify Jesus: "When Pilate saw that he could prevail nothing, but that rather a tumult was made, he took water, and washed his hands before the multitude, saying, I am innocent of the blood of this just person: see ye to it."	Hand washing # Overview Hand washing is the act of cleansing the hands with water or another liquid, with or without the use of soap or other detergents, for the purpose of removing soil and/or microorganisms. # Purpose The main purpose of washing hands is to cleanse the hands of pathogens (including bacteria or viruses) and chemicals which can cause personal harm or disease. This is especially important for people who handle food or work in the medical field. The Centers for Disease Control and Prevention (CDC) has stated that "It is well-documented that the most important measure for preventing the spread of pathogens is effective handwashing." While hot water may more effectively clean your hands, this is primarily due to its increased capability as a solvent, and not due to hot water actually killing germs. Hot water is more effective at removing dirt, oils and/or chemicals, but contrary to popular belief, it does not kill microorganisms. A temperature that is comfortable for hand washing (about 45 °C) is not nearly hot enough to kill any microorganism. It would take more than double that temperature to effectively kill germs (typically 100 °C). # Personal hand washing To maintain good hygiene, hands should always be washed after using the toilet, changing a diaper, tending to someone who is sick, or handling raw meat, fish, or poultry. Hands should also be washed before eating, handling or cooking food. Conventionally, the use of soap and warm running water and the washing of all surfaces thoroughly, including under fingernails is seen as necessary. One should rub wet, soapy hands together outside the stream of running water for at least 20 seconds, before rinsing thoroughly and then drying with a clean or disposable towel.[1] After drying, a dry paper towel should be used to turn off the water (and open the exit door if one is in a restroom or other separate room). Moisturizing lotion is often recommended to keep the hands from drying out, should one's hands require washing more than a few times per day. [2] Antibacterial soaps have been heavily promoted to a health-conscious public. To date, there is no evidence that using recommended antiseptics or disinfectants selects for antibiotic-resistant organisms in nature.[3] However, antibacterial soaps contain common antibiotics such as Triclosan, which has an extensive list of resistant strains of organisms. So, even if antibacterial soaps do not select for antibiotic resistant strains, they might not be as effective as they are marketed to be. These soaps are quite different from the non-water-based hand hygiene agents referred to below, which also do not promote antibiotic resistance[4]. # Medical hand washing The purpose of hand washing in the health care setting is to remove or destroy (disinfect) pathogenic microorganisms ("germs") to avoid transmitting them to a patient. The application of water alone is ineffective for cleaning skin because water is unable to remove fats, oils, and proteins, which are components of organic soil. Therefore, removal of microorganisms from skin requires the addition of soaps or detergents to water. Plain soap does not kill pathogens. However, the addition of antiseptic chemicals to soap ("medicated" or "antimicrobial" soaps) does confer killing action to a hand washing agent. Such killing action may be desired prior to performing surgery or in settings in which antibiotic-resistant organisms are highly prevalent.[5] The proper washing of hands in a medical setting generally consists of the use of generous amounts of soap and water to lather and rub each part of ones hands systematically for 15 to 20 seconds. Hands should be rubbed together with digits interlocking. If there is debris under fingernails, a bristle brush is often used to remove it. Finally, it is necessary to rinse well and wipe dry with a paper towel. After drying, a dry paper towel should be used to turn off the water (and open any exit door if necessary). To 'scrub' one's hands for a surgical operation, a tap that can be turned on and off without touching with the hands, some chlorhexidine or iodine wash, sterile towels for drying the hands after washing, and a sterile brush for scrubbing and another sterile instrument for cleaning under the fingernails are required. All jewelery should be removed. This procedure requires washing the hands and forearms up to the elbows, and one must in this situation ensure that all parts of the hands and forearms are well scrubbed several times. When rinsing, it is ensured at all times that one does not allow water to drip back from the elbow to your hands. When done hands are dried with a sterile cloth and a surgical gown is donned. In the late 1990s and early part of the 21st century, non-water-based hand hygiene agents (also known as alcohol-based hand rubs, antiseptic hand rubs, or hand sanitizers) began to gain popularity. Most are based on isopropyl alcohol or ethanol formulated together with a humectant such as glycerin into a gel, liquid, or foam for ease of use and to decrease the drying effect of the alcohol. The increasing use of these agents is based on their ease of use, rapid killing activity against microorganisms, and lower tendency to induce irritant contact dermatitis as compared to soap and water hand washing. Despite their effectiveness, the non-water agents do not clean hands of organic material, they simply disinfect them. However, disinfection does prevent transmission of infectious microorganisms. Visible soiling of any sort on the hands must be washed with soap and water because alcohol-based hand rubs are ineffective in the presence of organic material. In addition, alcohols are ineffective against non-lipid-enveloped viruses (e.g., Noroviruses) and the spores of bacteria (e.g., Clostridium difficile) and protozoa (e.g., Giardia lamblia). When such microorganisms are likely to be encountered, soap and water hand washing is preferable. The New England Journal of Medicine reports that hand washing remains at unacceptable levels in most medical environments, with large numbers of doctors and nurses routinely forgetting to wash their hands before touching patients.[6] One study has shown that proper hand washing and other simple procedures can decrease the rate of catheter-related bloodstream infections by 66 percent.[7][1] # Truths, myths, and misinformation Plain soaps have minimal if any antimicrobial activity. In several clinical studies, hand washing with plain soap failed to remove bad microorganisms (pathogens) from the hands of hospital personnel. Hand washing with plain soap can result in an increase in bacterial counts on the skin. Occasionally, contaminated plain soaps have colonized hands with Gram-negative bacteria.[8] The skin on your body is covered with microorganisms. Our environment is contaminated with good and bad microorganisms. You cannot kill all of the microorganisms on your hands. Your large intestine contains large numbers of microorganisms. All of these sources of germs stimulate your immune response. CDC guidelines for health care workers call for alcohol rubs to be used 60 or more times a day between patients and after touching contaminated surfaces. Killing germs on your hands will not decrease your immunity but it will help prevent disease.[8] Hand sanitizers containing a minimum of 60 to 95% alcohol are very efficient germ killers. Alcohol rub sanitizers kill bacteria, multi-drug resistant bacteria (MRSA and VRE), tuberculosis, and viruses (including HIV, herpes, RSV, rhinovirus, vaccinia, influenza, and hepatitis) and fungus. Alcohol rub sanitizers containing 70% alcohol kill 3.5 log10 (99.9%) of the bacteria on hands 30 seconds after application and 4 to 5 log10 (99.99 to 99.999%) of the bacteria on hands 1 minute after application. Alcohol rub sanitizers can prevent the transfer of health-care associated pathogens (Gram-negative bacteria) better than soap and water. Alcohol rub sanitizers are not appropriate for use when your hands are visibly dirty, soiled or contaminated with blood. Use soap and water for dirty or soiled hands.[8] Good germs are microorganisms normally found on human skin and bad germs are pathogenic (disease producing) microorganisms. The numbers of good germs and bad germs on the hands are variable from one person to the next but remain relatively constant for each individual. Good germs cannot protect you against bad germs. Anyone can become contaminated with bad germs (pathogens). Bad germs (pathogens) do not always cause disease and good germs can, under the right conditions, cause disease. [9] Frequent use of alcohol-based formulations for hand sanitizers can cause dry skin unless emollients and/or skin moisturizers are added to the formula. The drying effect of alcohol can be reduced or eliminated by adding glycerin and/or other emollients to the formula. In several prospective clinical trials, alcohol based hand sanitizers containing emollients caused substantially less skin irritation and dryness than soaps or antimicrobial detergents. Allergic contact dermatitis, contact urticaria syndrome or hypersensitivity to alcohol or additives present in alcohol hand rubs rarely occurs.[8][10] Dead microorganisms don’t mutate. Alcohol rubs (biocides) kill microorganisms. Current scientific evidence has not shown a link exists between the use of topical antimicrobial formulations and antiseptic or antibiotic resistance. Antiseptics (biocides) have multiple (thousands) of nonspecific killing sites on and in the microbial cell which cannot easily mutate. Antibiotics and antibacterial soaps (triclosan) have one very specific killing site on and in the microbial cell which can easily mutate. Antibiotic resistance has no effect on the effectiveness of antiseptics.[11] Alcohol rubs and combination hand sanitizers are effective at killing germs on your hands, but not effective at removing dirt. Conversely, soap and water are very effective at cleaning dirty or soiled hands, but are not good at killing germs (as discussed above).[12] Many clinical studies have shown that alcohol rubs containing two germ killers (ie. Alcohol and Chlorhexidine gluconate or Benzalkonium chloride) are significantly better germ killers than alcohol rubs containing alcohol alone.[10] # Hand washing as compensation Excessive hand washing is commonly seen as a symptom of obsessive-compulsive disorder (OCD). It has also been found that people, after having recalled or contemplated unethical acts, tend to wash hands more often than others, and tend to value hand washing equipment more. Furthermore, those who are allowed to wash their hands after such a contemplation are less likely to engage in other "cleansing" compensatory actions, such as volunteering.[13] # Symbolic hand washing Template:Prose Ritual handwashing is a feature of many religions, including Bahá'í Faith, Hinduism and tevilah and netilat yadayim in Judaism. Similar to these are the practises of Lavabo in Christianity, Wudu in Islam and Misogi in Shintoism. # Idioms When someone "washes their hands of" something, this means that they are declaring their unwillingness to take responsibility for it or share complicity in it. Matthew 27:24 gives an account of Pontius Pilate washing his hands of the decision to crucify Jesus: "When Pilate saw that he could prevail nothing, but that rather a tumult was made, he took water, and washed his hands before the multitude, saying, I am innocent of the blood of this just person: see ye to it."	https://www.wikidoc.org/index.php/Hand_washing
be3c91d8f4a56b0d9b013b7c1b68de0a9a6d541f	wikidoc	Hard science	Hard science Hard science is a term used to describe certain fields of the natural sciences or physical sciences that are perceived to be more accurate than other sciences like the social sciences. The hard sciences usually rely on experimental, empirical, quantifiable data or the scientific method and focus on accuracy and objectivity. The hard versus soft distinction is controversial in some circles. Although associated with notions of scientific realism, this distinction is drawn more from commonsense than a deep immersion in the philosophy of science. Much work by modern historians of science, starting with the work done by Thomas Kuhn, has focused on the ways in which the "hard sciences" have functioned in ways which were less "hard" than previously assumed, emphasizing that decisions over the veracity of a given theory owed much more to "subjective" influences than the "hard" label would emphasize (and begin to question whether there are any real distinctions between "hard" and "soft" science). Some, such as those who subscribe to the "strong program" of the sociology of scientific knowledge, would go even further, and remove the barrier between "hard science" and "nonscience" completely. Despite these objections, hard versus soft distinction is popular and widely used. One perceived difference supporting the distinction is the degree to which conclusions in different fields are controversial within those fields. Some believe that conclusions from physics or chemistry tend to be less controversial among physicists and chemists, versus how much of political science is controversial among political scientists. However, in most physical sciences there has been extensive debate about issues like whether atoms exist and whether randomness is inherent in subatomic particles. Russ Roberts from George Mason University claims that although many people romanticize about the objectivity of the so-called hard scientists, many physical scientists constantly engage in controversies and arguments. There is much difficulty distinguishing between soft and hard sciences because many social sciences, like economics and psychology, use the scientific process to formulate hypotheses and test them using empirical data. Furthermore, many social scientists engage in experimental work within the field of experimental economics. In most cases the methodology used by practitioners of the so-called soft scientist are the same as those used by practitioners of the hard sciences and the only difference is the object studied. Physical scientists tend to look at atoms, energy, waves, etc while social scientists tend to look at societies, individuals, firms, etc. The argument that societies, nations, and so on tend to display behavior that is more unpredictable than the behavior of atoms, waves, and so on, is also shaky because of advances in Quantum Physics that illustrate just how unpredictable subatomic particles are. Furthermore, the behavior of small units aggregated can yield behavior that is more predictable than the behavior of the small units themselves. This is due to aggregation canceling out randomness. In all experimental or empirical sciences there is a need to set up experiments. One necessary feature of experiments is the need to control all factors. It may be hard to control all factors in an experiment because the experimenter may not account for all factors. This problem exists in the social sciences and the physical sciences. To establish causation the experimenter needs to have a control group where only one variable, the variable of interest, is changed, and all other variables held constant. The difficulty is in how to control for all other variables when there could potentially be infinite variables. The graphism thesis maintains that hard sciences such as natural sciences make heavier use of graphs than soft sciences such as sociology. However, Bill Mann claims that an example of a discipline that uses graphs heavily but is not at all scientific is technical analysis.	Hard science Hard science is a term used to describe certain fields of the natural sciences or physical sciences that are perceived to be more accurate than other sciences like the social sciences.[citation needed] The hard sciences usually rely on experimental, empirical, quantifiable data or the scientific method and focus on accuracy and objectivity. The hard versus soft distinction is controversial in some circles. Although associated with notions of scientific realism, this distinction is drawn more from commonsense than a deep immersion in the philosophy of science. Much work by modern historians of science, starting with the work done by Thomas Kuhn, has focused on the ways in which the "hard sciences" have functioned in ways which were less "hard" than previously assumed, emphasizing that decisions over the veracity of a given theory owed much more to "subjective" influences than the "hard" label would emphasize (and begin to question whether there are any real distinctions between "hard" and "soft" science). Some, such as those who subscribe to the "strong program" of the sociology of scientific knowledge, would go even further, and remove the barrier between "hard science" and "nonscience" completely. Despite these objections, hard versus soft distinction is popular and widely used. One perceived difference supporting the distinction is the degree to which conclusions in different fields are controversial within those fields. Some believe that conclusions from physics or chemistry tend to be less controversial among physicists and chemists, versus how much of political science is controversial among political scientists. However, in most physical sciences there has been extensive debate about issues like whether atoms exist and whether randomness is inherent in subatomic particles. Russ Roberts from George Mason University claims that although many people romanticize about the objectivity of the so-called hard scientists, many physical scientists constantly engage in controversies and arguments[1]. There is much difficulty distinguishing between soft and hard sciences because many social sciences, like economics and psychology, use the scientific process to formulate hypotheses and test them using empirical data. Furthermore, many social scientists engage in experimental work within the field of experimental economics. In most cases the methodology used by practitioners of the so-called soft scientist are the same as those used by practitioners of the hard sciences and the only difference is the object studied. Physical scientists tend to look at atoms, energy, waves, etc while social scientists tend to look at societies, individuals, firms, etc. The argument that societies, nations, and so on tend to display behavior that is more unpredictable than the behavior of atoms, waves, and so on, is also shaky because of advances in Quantum Physics that illustrate just how unpredictable subatomic particles are. Furthermore, the behavior of small units aggregated can yield behavior that is more predictable than the behavior of the small units themselves. This is due to aggregation canceling out randomness. In all experimental or empirical sciences there is a need to set up experiments. One necessary feature of experiments is the need to control all factors. It may be hard to control all factors in an experiment because the experimenter may not account for all factors. This problem exists in the social sciences and the physical sciences. To establish causation the experimenter needs to have a control group where only one variable, the variable of interest, is changed, and all other variables held constant. The difficulty is in how to control for all other variables when there could potentially be infinite variables. The graphism thesis maintains that hard sciences such as natural sciences make heavier use of graphs than soft sciences such as sociology. However, Bill Mann claims that an example of a discipline that uses graphs heavily but is not at all scientific is technical analysis.[2]	https://www.wikidoc.org/index.php/Hard_science
0d8b945d4ab5d5290bddcfb288ac7421b2d60e35	wikidoc	Harvest mite	Harvest mite Harvest mites (genus Trombicula; also known as red bugs, trombiculid mites, scrub-itch mites, berry bugs or, in their larval stage, as chiggers) are mites in the family Trombiculidae that live in forests and grasslands. In their larval stage they attach to various animals including humans and feed on skin, often causing itching. These relatives of ticks are nearly microscopic measuring 0.4 mm (1/100 of an inch) and have a chrome-orange hue. A common species of harvest mite in Northern America is Trombicula alfreddugesi; in the UK the most prevalent harvest mite is Trombicula autumnalis. Harvest mite larvae are small, tiny, irritating, red immatures between the egg and nymph stages, which have not yet become adult mites. They are usually microscopic. The larvae often live in berry patches, tall grass and weeds, woodland edges, pine straw, leaves, and treebark, or in typical habitats of their hosts (especially rodents). The larval mites feed on the skin cells, but not blood, of animals, including humans. The six-legged parasitic larva feeds on a large variety of creatures including humans, rabbits, toads, box turtles, quail, and even some insects. After crawling onto their host, they inject digestive enzymes into the skin that break down skin cells. They do not actually "bite," but instead form a hole in the skin and chew up tiny parts of the inner skin, thus causing severe irritation and swelling. The severe itching is accompanied by red pimple-like bumps (papules) or hives and skin rash or lesions on a sun-exposed area. For humans, itching usually occurs after the larvae detach from the skin. Chiggers are known for never spreading from host to host. After feeding on their hosts, the larvae drop to the ground and become nymphs, then mature into adults which have 8 legs and are harmless to humans. In the post larval stage, they are not parasitic and feed on plant materials. The females lay 3-8 eggs in a litter, usually on a leaf or under the roots of a plant, and die by autumn. # Where harvest mite are found Many areas of the world are plagued by chiggers, or some form thereof. In Europe and North America, they tend to be more prevalent in the hot and humid parts. In the more temperate regions, they are found only in the summer (in French, harvest mites are called aoûtat, or "August" flies). In the United States, they are found mostly in the southeast, the south, and the midwest. They are not present, or barely found, in far northern areas, in high mountains and in deserts. # Chiggers as disease vectors Although the harvest mite chigger usually does not carry diseases in North American temperate climates, the mites are considered a dangerous pest in East Asia and the South Pacific because they often carry Rickettsia tsutsugamushi (Orientia tsutsugamushi), the tiny parasite that causes scrub typhus, which is known alternatively as the Japanese river disease, scrub disease, or tsutsugamushi. The mites usually are infected by the disease by their infected rodent hosts. The disease is transmitted to the next generation of offspring by breeding mites. Symptoms of scrub typhus in humans include fever, headache, muscle pain, cough, and gastrointestinal symptoms. The North American genus and species can cause severe illness in children. This only occurs when the infestation is particularly heavy. Symptoms include a hallucinatory sense of floating outside one's body, fatigue, fever and general malaise. # Myth versus fact Contrary to popular belief, the larvae do not burrow deep into the skin and live there. Rather, the larvae pierce the skin and inject powerful enzymes that digest cellular contents, which become liquified and are consumed by the larvae. Another myth is that application of rubbing alcohol kills the chiggers or helps with symptoms. This method serves only to cause great burning pain and discomfort to the victim. # Treatment The most effective way of removing chiggers is by taking a hot shower and washing the affected areas with mildly hot water and soap. This must be done as soon as possible after exposure or possible exposure. Carefully wash the ankles, feet, behind the knees, and under the arms and chest. An Epsom salt bath may help alleviate pruritus. If one is near the seashore, wading for a few minutes in salt water will both get rid of the mites on one's skin and clothing and also alleviate the itching from their bites. Another good way of removing chiggers is to cover the chiggers with scotch tape and pull them off that way. However once symptoms appear, it may be too late to prevent further bites. Taking a hot bath when already covered with chigger bites may in fact be very uncomfortable and increase itching symptoms. Do not rub and scratch the skin aggressively, but instead gently but firmly rub the irritated skin with warm soapy water. Clothing, especially pants and socks, should be immediately discarded after returning from areas where exposure may have occurred. Try not to scratch the affected regions. Scratching could scrape off chigger larvae, but it may also cause increased irritation by breaking the skin and leaving it vulnerable to a more serious infection. A covering to reduce air exposure over the itchy area, such as calamine lotion, petroleum jelly, or baby oil, may help relieve the pain (but does not cure the bites). The application of a small drop of finger nail polish (usually clear nail polish) is one of the most popular remedies and is claimed to reduce itching and dry the itchy sores in the fewest number of days. This has a better chance of being effective if done early. Later, people sometimes may end up mistaking the red dot in the middle of the bite as the chigger itself (the chigger is long gone). There is a misconception that the mite has burrowed into the skin, and that coating their bites with vaseline, nail polish, or some other air-inhibiting seal will "suffocate" the chigger. Medication such as antihistamines or corticosteroid creams may be prescribed by doctors, and might help in some instances. # Prevention Chiggers seem to affect warm covered areas of the body more than drier areas. Thus, areas covered by socks and shoes, behind the knees and around the groin are often trouble spots. Special attention should be given to small children, as areas higher in the body (chest, back, waist-band, and under-arms) may be affected more easily than in adults, since children are shorter and may more likely than adults come in contact with low-lying vegetation and dry grass where chiggers thrive. To avoid being afflicted by chiggers, always wear tight weave, protective clothing and long pants. Spray insect repellent on your skin for further protection. Application of repellent to the shoes and lower trousers is helpful. Staying on trails, roads, or paths can help prevent contact. Dusting sulfur is used commercially for mite control and can be used to control chiggers in yards. The dusting of shoes, socks and trouser legs with sulfur can be highly effective in repelling chiggers. People who pick wild blueberries in the summer have traditionally been very vulnerable to chigger bites and have suggested applying deodorant soap to the skin and letting it dry without rinsing may help prevent bites. Another helpful avoidance is to recognize the chigger habitat to avoid exposure in the first place. Chiggers in North America thrive late in summer, in dry tall grasses and other thick, unshaded vegetation. Insect repellents containing one of the following active ingredients are recommended: DEET, Catnip oil extract - Nepetalactone, Citronella or eucalyptus oil extract. However, a study reported in the March 1993 issue of the Southeast Asian Journal of Tropical Medicine & Public Health (volume 24, issue 1: pp165-169) tested two commercial repellants: DEET and citrus oil: "All chiggers exposed on the filter papers treated with DEET died and did not move off the treated papers. None of the chiggers that were placed on papers treated with citrus oil were killed." It was concluded that DEET was more effective than citrus oil. Chiggers can also be treated using common household vinegar (5% acetic acid). This was reported in the March 12, 2001 issue of the Archives of Internal Medicine.	Harvest mite Harvest mites (genus Trombicula; also known as red bugs, trombiculid mites, scrub-itch mites, berry bugs or, in their larval stage, as chiggers) are mites in the family Trombiculidae that live in forests and grasslands. In their larval stage they attach to various animals including humans and feed on skin, often causing itching. These relatives of ticks are nearly microscopic measuring 0.4 mm (1/100 of an inch) and have a chrome-orange hue. A common species of harvest mite in Northern America is Trombicula alfreddugesi; in the UK the most prevalent harvest mite is Trombicula autumnalis. Harvest mite larvae are small, tiny, irritating, red immatures between the egg and nymph stages, which have not yet become adult mites. They are usually microscopic. The larvae often live in berry patches, tall grass and weeds, woodland edges, pine straw, leaves, and treebark, or in typical habitats of their hosts (especially rodents). The larval mites feed on the skin cells, but not blood, of animals, including humans. The six-legged parasitic larva feeds on a large variety of creatures including humans, rabbits, toads, box turtles, quail, and even some insects. After crawling onto their host, they inject digestive enzymes into the skin that break down skin cells. They do not actually "bite," but instead form a hole in the skin and chew up tiny parts of the inner skin, thus causing severe irritation and swelling. The severe itching is accompanied by red pimple-like bumps (papules) or hives and skin rash or lesions on a sun-exposed area. For humans, itching usually occurs after the larvae detach from the skin. Chiggers are known for never spreading from host to host. After feeding on their hosts, the larvae drop to the ground and become nymphs, then mature into adults which have 8 legs and are harmless to humans. In the post larval stage, they are not parasitic and feed on plant materials. The females lay 3-8 eggs in a litter, usually on a leaf or under the roots of a plant, and die by autumn. # Where harvest mite are found Many areas of the world are plagued by chiggers, or some form thereof. In Europe and North America, they tend to be more prevalent in the hot and humid parts. In the more temperate regions, they are found only in the summer (in French, harvest mites are called aoûtat, or "August" flies). In the United States, they are found mostly in the southeast, the south, and the midwest. They are not present, or barely found, in far northern areas, in high mountains and in deserts. # Chiggers as disease vectors Although the harvest mite chigger usually does not carry diseases in North American temperate climates, the mites are considered a dangerous pest in East Asia and the South Pacific because they often carry Rickettsia tsutsugamushi (Orientia tsutsugamushi), the tiny parasite that causes scrub typhus, which is known alternatively as the Japanese river disease, scrub disease, or tsutsugamushi. The mites usually are infected by the disease by their infected rodent hosts. The disease is transmitted to the next generation of offspring by breeding mites. Symptoms of scrub typhus in humans include fever, headache, muscle pain, cough, and gastrointestinal symptoms. The North American genus and species can cause severe illness in children. This only occurs when the infestation is particularly heavy. Symptoms include a hallucinatory sense of floating outside one's body, fatigue, fever and general malaise. # Myth versus fact Contrary to popular belief, the larvae do not burrow deep into the skin and live there. Rather, the larvae pierce the skin and inject powerful enzymes that digest cellular contents, which become liquified and are consumed by the larvae.[1] Another myth is that application of rubbing alcohol kills the chiggers or helps with symptoms. This method serves only to cause great burning pain and discomfort to the victim. # Treatment The most effective way of removing chiggers is by taking a hot shower and washing the affected areas with mildly hot water and soap. This must be done as soon as possible after exposure or possible exposure. Carefully wash the ankles, feet, behind the knees, and under the arms and chest. An Epsom salt bath may help alleviate pruritus. If one is near the seashore, wading for a few minutes in salt water will both get rid of the mites on one's skin and clothing and also alleviate the itching from their bites. Another good way of removing chiggers is to cover the chiggers with scotch tape and pull them off that way. However once symptoms appear, it may be too late to prevent further bites. Taking a hot bath when already covered with chigger bites may in fact be very uncomfortable and increase itching symptoms. Do not rub and scratch the skin aggressively, but instead gently but firmly rub the irritated skin with warm soapy water. Clothing, especially pants and socks, should be immediately discarded after returning from areas where exposure may have occurred. Try not to scratch the affected regions. Scratching could scrape off chigger larvae, but it may also cause increased irritation by breaking the skin and leaving it vulnerable to a more serious infection. A covering to reduce air exposure over the itchy area, such as calamine lotion, petroleum jelly, or baby oil, may help relieve the pain (but does not cure the bites). The application of a small drop of finger nail polish (usually clear nail polish) is one of the most popular remedies and is claimed to reduce itching and dry the itchy sores in the fewest number of days. This has a better chance of being effective if done early. Later, people sometimes may end up mistaking the red dot in the middle of the bite as the chigger itself (the chigger is long gone). There is a misconception that the mite has burrowed into the skin, and that coating their bites with vaseline, nail polish, or some other air-inhibiting seal will "suffocate" the chigger. Medication such as antihistamines or corticosteroid creams may be prescribed by doctors, and might help in some instances. # Prevention Chiggers seem to affect warm covered areas of the body more than drier areas. Thus, areas covered by socks and shoes, behind the knees and around the groin are often trouble spots. Special attention should be given to small children, as areas higher in the body (chest, back, waist-band, and under-arms) may be affected more easily than in adults, since children are shorter and may more likely than adults come in contact with low-lying vegetation and dry grass where chiggers thrive. To avoid being afflicted by chiggers, always wear tight weave, protective clothing and long pants. Spray insect repellent on your skin for further protection. Application of repellent to the shoes and lower trousers is helpful. Staying on trails, roads, or paths can help prevent contact. Dusting sulfur is used commercially for mite control and can be used to control chiggers in yards. The dusting of shoes, socks and trouser legs with sulfur can be highly effective in repelling chiggers. People who pick wild blueberries in the summer have traditionally been very vulnerable to chigger bites and have suggested applying deodorant soap to the skin and letting it dry without rinsing may help prevent bites. Another helpful avoidance is to recognize the chigger habitat to avoid exposure in the first place. Chiggers in North America thrive late in summer, in dry tall grasses and other thick, unshaded vegetation. Insect repellents containing one of the following active ingredients are recommended: DEET, Catnip oil extract - Nepetalactone, Citronella or eucalyptus oil extract. However, a study reported in the March 1993 issue of the Southeast Asian Journal of Tropical Medicine & Public Health (volume 24, issue 1: pp165-169) tested two commercial repellants: DEET and citrus oil: "All chiggers exposed on the filter papers treated with DEET died and did not move off the treated papers. None of the chiggers that were placed on papers treated with citrus oil were killed." It was concluded that DEET was more effective than citrus oil. Chiggers can also be treated using common household vinegar (5% acetic acid). This was reported in the March 12, 2001 issue of the Archives of Internal Medicine.	https://www.wikidoc.org/index.php/Harvest_mite
e3559877331bd3b1dddf4a6d7a9899fb58822532	wikidoc	Hazard ratio	Hazard ratio # Overview The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For a less technical definition than is provided here, consider hazard ratio to be an estimate of relative risk and see the explanation on that page. The instantaneous hazard rate is the limit of the number of events per unit time divided by the number at risk as the time interval decreases. where N(t) is the number at risk at the beginning of an interval. The hazard ratio is the effect on this hazard rate of a difference, such as group membership (for example, treatment or control, male or female), as estimated by regression models which treat the log of the hazard rate as a function of a baseline hazard h_0(t) and a linear combination of explanatory variables: Such models are generally classed proportional hazards regression models (they differ in their treatment of h_0(t), the underlying pattern the hazard rate over time), and include the Cox semi-parametric proportional hazards model, and the exponential, Gompertz and Weibull parametric models. For two individuals who differ only in the relevant membership (e.g. treatment vs control) their predicted log-hazard will differ additively by the relevant parameter estimate, which is to say that their predicted hazard rate will differ by e^\beta, i.e. multiplicatively by the anti-log of the estimate. Thus the estimate can be considered a hazard ratio, that is, the ratio between the predicted hazard for a member of one group and that for a member of the other group, holding everything else constant. For a continuous explanatory variable, the same interpretation applies to a unit difference. Other hazard rate models have different formulations and the interpretation of the parameter estimates differs accordingly.	Hazard ratio Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event. For a less technical definition than is provided here, consider hazard ratio to be an estimate of relative risk and see the explanation on that page. The instantaneous hazard rate is the limit of the number of events per unit time divided by the number at risk as the time interval decreases. where N(t) is the number at risk at the beginning of an interval. The hazard ratio is the effect on this hazard rate of a difference, such as group membership (for example, treatment or control, male or female), as estimated by regression models which treat the log of the hazard rate as a function of a baseline hazard <math>h_0(t)</math> and a linear combination of explanatory variables: Such models are generally classed proportional hazards regression models (they differ in their treatment of <math>h_0(t)</math>, the underlying pattern the hazard rate over time), and include the Cox semi-parametric proportional hazards model, and the exponential, Gompertz and Weibull parametric models. For two individuals who differ only in the relevant membership (e.g. treatment vs control) their predicted log-hazard will differ additively by the relevant parameter estimate, which is to say that their predicted hazard rate will differ by <math>e^\beta</math>, i.e. multiplicatively by the anti-log of the estimate. Thus the estimate can be considered a hazard ratio, that is, the ratio between the predicted hazard for a member of one group and that for a member of the other group, holding everything else constant. For a continuous explanatory variable, the same interpretation applies to a unit difference. Other hazard rate models have different formulations and the interpretation of the parameter estimates differs accordingly.	https://www.wikidoc.org/index.php/Hazard_ratio
a0e713925c3ee96ea28dc2f691ec5302860cf02b	wikidoc	Heat syncope	Heat syncope Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing. # Overview Heat syncope another stage in the same process as heat stroke, occurs under similar conditions as heat stroke and is not distinguished from the latter by some authorities. The basic symptom of heat syncope is a body temperature above 40°C (104°F) with fainting, or without mental confusion, which does occur in heat stroke. Heat syncope is caused by mild overheating with inadequate water or salt. In young persons, it is far more common than true sunstroke. Heat syncope occurs when blood pressure is lowered as the body dilates (widens) capillaries (small blood vessels) in the skin to radiate heat. Also, water is evaporated from the blood, reducing the blood's volume and therefore lowering blood pressure further. The result is less blood to the brain, causing light-headedness and fainting. The basic treatment for heat syncope is like fainting: the patient is positioned in a seating or supine position with legs raised. Water and oral rehydration salt are administered slowly, and the patient is moved to a cooler area.	Heat syncope Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Please help WikiDoc by adding more content here. It's easy! Click here to learn about editing. # Overview Heat syncope another stage in the same process as heat stroke, occurs under similar conditions as heat stroke and is not distinguished from the latter by some authorities. The basic symptom of heat syncope is a body temperature above 40°C (104°F) with fainting, or without mental confusion, which does occur in heat stroke. Heat syncope is caused by mild overheating with inadequate water or salt. In young persons, it is far more common than true sunstroke. Heat syncope occurs when blood pressure is lowered as the body dilates (widens) capillaries (small blood vessels) in the skin to radiate heat. Also, water is evaporated from the blood, reducing the blood's volume and therefore lowering blood pressure further. The result is less blood to the brain, causing light-headedness and fainting. The basic treatment for heat syncope is like fainting: the patient is positioned in a seating or supine position with legs raised. Water and oral rehydration salt are administered slowly, and the patient is moved to a cooler area.	https://www.wikidoc.org/index.php/Heat_syncope
37de6cfdc8ea3c340606395207c3eed29c08313a	wikidoc	Hedera helix	Hedera helix Hedera helix (species name from Ancient Greek "twist, turn"), also called Ivy, Common Ivy, or English Ivy is a species of ivy native to most of Europe and southwest Asia. It is an evergreen climbing plant, growing to 20-30 m high where suitable surfaces (trees, cliffs, walls) are available, and also growing as ground cover where there are no vertical surfaces. It holds on to tree bark and rock by means of short adhesive rootlets. The helix part of the name refers to where there are spirals in the leaves. The leaves are alternate, 4-8 cm long, with a 3-10 cm long petiole; they are of two types, with palmately five-lobed juvenile leaves on creeping and climbing stems, and unlobed cordate adult leaves on fertile flowering stems exposed to full sun, usually high in the crowns of trees or the top of rock faces. The flowers are produced from late summer until late autumn, individually small, in 3-5 cm diameter umbels, greenish-yellow, and very rich in nectar, an important late food source for bees and other insects; the fruit are small black berries ripening in late winter, and are an important food for many birds, though poisonous to humans. The seeds are dispersed by birds eating the fruit. Plants in southeast Europe and southwest Asia (Greece, Turkey) are treated as a distinct subspecies Hedera helix subsp. poetarum, differing in orange ripe fruit. The closely related species Hedera canariensis and Hedera hibernica are often treated as varieties or subspecies of H. helix (Flora Europaea), though they differ in chromosome number so do not hybridise readily (McAllister 1982). H. helix can be best distinguished by its usually smaller and slightly more deeply lobed leaves and somewhat less vigorous growth, though identification is often not easy. ## Cultivation and uses It is widely cultivated as an ornamental plant, with numerous cultivars selected for such traits as yellow, variegated or deeply lobed leaves, purple stems, and slow, dwarfed growth. In North America (where it is often known as English Ivy), it has become naturalised and is sometimes considered an invasive species, especially in the Pacific Northwest where the climate is similar to that in its native area. # Ethnomedical Uses - Leaves and berries are taken orally as an expectorant to treat cough and bronchitis. In 1597, the British herbalist John Gerard recommended water infused with ivy leaves as a wash for sore or watering eyes. # References and external links - ↑ Gerard, John; Woodward, Marcus (ed.) (1985), Gerard's Herbal: The History of Plants, New York: Crescent Books, ISBN 0-517-464705CS1 maint: Extra text: 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} - Huxley, A., ed. (1992). New RHS Dictionary of Gardening. Macmillan. - McAllister, H. (1982). New work on ivies. Int. Dendrol. Soc. Yearbook 1981: 106-109. - Flora Europaea: Hedera helix - Ecoflora: Hedera helix - USDA Plants Profile: Hedera helix - Plant Encyclopedia: Hedera helix (Photos) bg:Бръшлян ca:Heura cs:Břečťan popínavý da:Almindelig Vedbend de:Efeu gl:Hedra hsb:Wšědny blušć is:Bergflétta it:Hedera helix he:קיסוס החורש hu:Borostyán mk:Бршлен nl:Klimop nap:Ellera no:Eføy nrm:Glléru sl:Navadni bršljan sr:Бршљан sv:Murgröna	Hedera helix Hedera helix (species name from Ancient Greek "twist, turn"), also called Ivy, Common Ivy, or English Ivy is a species of ivy native to most of Europe and southwest Asia. It is an evergreen climbing plant, growing to 20-30 m high where suitable surfaces (trees, cliffs, walls) are available, and also growing as ground cover where there are no vertical surfaces. It holds on to tree bark and rock by means of short adhesive rootlets. The helix part of the name refers to where there are spirals in the leaves. The leaves are alternate, 4-8 cm long, with a 3-10 cm long petiole; they are of two types, with palmately five-lobed juvenile leaves on creeping and climbing stems, and unlobed cordate adult leaves on fertile flowering stems exposed to full sun, usually high in the crowns of trees or the top of rock faces. The flowers are produced from late summer until late autumn, individually small, in 3-5 cm diameter umbels, greenish-yellow, and very rich in nectar, an important late food source for bees and other insects; the fruit are small black berries ripening in late winter, and are an important food for many birds, though poisonous to humans. The seeds are dispersed by birds eating the fruit. Plants in southeast Europe and southwest Asia (Greece, Turkey) are treated as a distinct subspecies Hedera helix subsp. poetarum, differing in orange ripe fruit. The closely related species Hedera canariensis and Hedera hibernica are often treated as varieties or subspecies of H. helix (Flora Europaea), though they differ in chromosome number so do not hybridise readily (McAllister 1982). H. helix can be best distinguished by its usually smaller and slightly more deeply lobed leaves and somewhat less vigorous growth, though identification is often not easy. ## Cultivation and uses It is widely cultivated as an ornamental plant, with numerous cultivars selected for such traits as yellow, variegated or deeply lobed leaves, purple stems, and slow, dwarfed growth. In North America (where it is often known as English Ivy), it has become naturalised and is sometimes considered an invasive species, especially in the Pacific Northwest where the climate is similar to that in its native area. # Ethnomedical Uses - Leaves and berries are taken orally as an expectorant to treat cough and bronchitis[citation needed]. In 1597, the British herbalist John Gerard recommended water infused with ivy leaves as a wash for sore or watering eyes.[1] # References and external links - ↑ Gerard, John; Woodward, Marcus (ed.) (1985), Gerard's Herbal: The History of Plants, New York: Crescent Books, ISBN 0-517-464705CS1 maint: Extra text: 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} - Huxley, A., ed. (1992). New RHS Dictionary of Gardening. Macmillan. - McAllister, H. (1982). New work on ivies. Int. Dendrol. Soc. Yearbook 1981: 106-109. - Flora Europaea: Hedera helix - Ecoflora: Hedera helix - USDA Plants Profile: Hedera helix - Plant Encyclopedia: Hedera helix (Photos) bg:Бръшлян ca:Heura cs:Břečťan popínavý da:Almindelig Vedbend de:Efeu gl:Hedra hsb:Wšědny blušć is:Bergflétta it:Hedera helix he:קיסוס החורש hu:Borostyán mk:Бршлен nl:Klimop nap:Ellera no:Eføy nrm:Glléru sl:Navadni bršljan sr:Бршљан sv:Murgröna Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hedera_helix
c36de4fdca828aa8bcf8debfda194f34086ae36e	wikidoc	Hegar's sign	Hegar's sign # Overview Hegar's sign is an indication of pregnancy in a woman, specifically the compressibility and softening of the cervical isthmus (the portion of the cervix between the uterus and the vaginal portion of the cervix) and the uterine cervix appearing bluish and engorged. The sign is usually present during second and third months of pregnancy from the fourth to sixth week. It is not a positive indicator of pregnancy, and its absence does not exclude pregnancy. The indicator was originally described by Ernst Ludwig Alfred Hegar, a German gynecologist, in 1895. Hegar credits one of his students for discovering the sign.	Hegar's sign Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hegar's sign is an indication of pregnancy in a woman, specifically the compressibility and softening of the cervical isthmus (the portion of the cervix between the uterus and the vaginal portion of the cervix) and the uterine cervix appearing bluish and engorged. The sign is usually present during second and third months of pregnancy from the fourth to sixth week. It is not a positive indicator of pregnancy, and its absence does not exclude pregnancy. The indicator was originally described by Ernst Ludwig Alfred Hegar, a German gynecologist, in 1895. Hegar credits one of his students for discovering the sign.	https://www.wikidoc.org/index.php/Hegar%27s_sign
267e0b4c67a4cb39d3d0060dcb320baa5a8794d5	wikidoc	Helen Keller	Helen Keller Helen Adams Keller (June 27, 1880 – June 1, 1968) was an American author, activist and lecturer. She was the first deafblind person to graduate from college. The story of how Keller's teacher, Anne Sullivan, broke through the isolation imposed by a near complete lack of language, allowing the girl to blossom as she learned to communicate, has become known worldwide through the dramatic depictions of the play The Miracle Worker. What is less well known is how Keller's life developed after she completed her education. A prolific author, she was well traveled, and was outspoken in her opposition to war. She campaigned for women's suffrage, workers' rights and socialism, as well as many other progressive causes. # Early childhood and illness Helen Keller was born at an estate called Ivy Green in Tuscumbia, Alabama, on June 27, 1880, to Captain Arthur H. Keller, a former officer of the Confederate Army, and Kate Adams Keller, a cousin of Robert E. Lee and daughter of Charles W. Adams, a former Confederate general. The Keller family originates from Germany, and at least one source claims her father was of Swiss descent. She was not born blind and deaf; it was not until nineteen months of age that she came down with an illness described by doctors as "an acute congestion of the stomach and the brain", which could have possibly been scarlet fever or meningitis. The illness did not last for a particularly long time, but it left her deaf and blind. At that time her only communication partner was Martha Washington, the six-year-old daughter of the family cook, who was able to create a sign language with her; by age seven, she had over 60 home signs to communicate with her family. In his doctoral dissertation, "Deaf-blind Children (psychological development in a process of education)" (1971, Moscow Defectology Institute), Soviet blind-deaf psychologist Meshcheryakov asserted that Washington's friendship and teaching was crucial for Keller's later developments. In 1886, her mother, inspired by an account in Charles Dickens' American Notes of the successful education of another deafblind child, Laura Bridgman, dispatched young Helen, accompanied by her father, to seek out Dr. J. Julian Chisolm, an eye, ear, nose and throat specialist in Baltimore, for advice. He, subsequently, put them in touch with Alexander Graham Bell, who was working with deaf children at the time. Bell advised the couple to contact the Perkins Institute for the Blind, the school where Bridgman had been educated, which was then located in South Boston. The school delegated teacher and former student Anne Sullivan, herself visually impaired and then only 20 years old, to become Keller's instructor.It was the beginning of a 49-year-long relationship, eventually evolving into governess and then eventual companion. Sullivan got permission from Keller's father to isolate the girl from the rest of the family in a little house in their garden. Her first task was to instill discipline in the spoiled girl. Keller's big breakthrough in communication came one day when she realized that the motions her teacher was making on her palm, while running cool water over her hand, symbolized the idea of "water"; she then nearly exhausted Sullivan demanding the names of all the other familiar objects in her world (including her prized doll). In 1890, ten-year-old Helen Keller was introduced to the story of Ragnhild Kåta, a deafblind Norwegian girl who had learned to speak. Kåta's success inspired Keller to want to learn to speak as well. Sullivan taught her charge to speak using the Tadoma method of touching the lips and throat of others as they speak, combined with fingerspelling letters on the palm of the child's hand. Later Keller learned Braille, and used it to read not only English but also French, German, Greek, and Latin. # Formal education In 1888, Keller attended the Royal Institute For the Blind. In 1894, Helen Keller and Anne Sullivan moved to New York City to attend the Wright-Humason School for the Deaf and Horace Mann School for the Deaf. In 1896, they returned to Massachusetts and Helen entered The Cambridge School for Young Ladies before gaining admittance, in 1900, to Radcliffe College. Her admirer Mark Twain had introduced her to Standard Oil magnate Henry Huttleton Rogers, who, with his wife, paid for her education. In 1904, at the age of 24, Keller graduated from Radcliffe magna cum laude, becoming the first deafblind person to earn a Bachelor of Arts degree. # Companions Anne Sullivan stayed as a companion to Helen Keller long after she taught her. Anne married John Macy in 1905, and her health started failing around 1914. Polly Thompson was hired to keep house. She was a young woman from Scotland who didn't have experience with deaf or blind people. She progressed to working as a secretary as well, and eventually became a constant companion to Helen. After Anne died in 1936, Helen and Polly moved to Connecticut. They travelled worldwide raising funding for the blind. Polly had a stroke in 1957 from which she never fully recovered, and died in 1960. Winnie Corbally was Helen's companion for the rest of her life. # Political activities Keller went on to become a world-famous speaker and author. She is remembered as an advocate for people with disabilities amid numerous other causes. She was a suffragist, a pacifist, a Wilson opposer, a radical socialist, and a birth control supporter. In 1915, Helen Keller and George Kessler founded the Helen Keller International (HKI) organization. This organization is devoted to research in vision, health and nutrition. In 1920, she helped to found the American Civil Liberties Union (ACLU). Keller and Sullivan traveled to over 39 countries, making several trips to Japan and becoming a favorite of the Japanese people. Keller met every US President from Grover Cleveland to Lyndon B. Johnson and was friends with many famous figures, including Alexander Graham Bell, Charlie Chaplin and Mark Twain. Keller was a member of the Socialist Party and actively campaigned and wrote in support of the working classes from 1909 to 1921. She supported Socialist Party candidate Eugene V. Debs in each of his campaigns for the presidency. Newspaper columnists who had praised her courage and intelligence before she expressed her socialist views now called attention to her disabilities. The editor of the Brooklyn Eagle wrote that her "mistakes sprung out of the manifest limitations of her development." Keller responded to that editor, referring to having met him before he knew of her political views: Keller joined the Industrial Workers of the World (known as the IWW or the Wobblies) in 1912, saying that parliamentary socialism was "sinking in the political bog." She wrote for the IWW between 1916 and 1918. In Why I Became an IWW, Keller explained that her motivation for activism came in part from her concern about blindness and other disabilities: The last sentence refers to prostitution and syphilis, the latter a leading cause of blindness. Keller and her friend Mark Twain were both considered radicals in the socio-political context present in the United States at the beginning of the 20th century, and as a consequence, their political views have been forgotten or glossed over in popular perception. # Writings One of Keller's earliest pieces of writing, at the age of eleven, was "The Frost King" (1891). There were allegations that this story had been plagiarized from The Frost Fairies by Margaret Canby. An investigation into the matter revealed that Keller may have suffered from cryptomnesia, having once had Canby's story read to her, only to forget about it, although the memory had remained hidden in her subconscious. At the age of 23, Keller published her autobiography, The Story of My Life (1903), with help from Sullivan and Sullivan's husband, John Macy. It includes letters that Keller wrote and the story of her life up to age 21, and was written during her time in college. Helen wrote "The World I Live In" in 1908 giving readers an insight into how she felt about the world. "Out of the Dark", a series of essays on Socialism, was published in 1913. Her spiritual autobiography, My Religion, was published in 1927 and re-issued as Light in my Darkness. It advocates the teachings of Emanuel Swedenborg, the controversial mystic who claimed to have witnessed the Last Judgment and second coming of Jesus Christ, and the movement named after him, Swedenborgianism. In total Keller wrote 12 books and numerous articles. # Akita dog When Keller visited Akita Prefecture in Japan in July 1937, she inquired about Hachikō, the famed Akita dog that had died in 1935. She told a Japanese person that she would like to have an Akita dog; one was given to her within a month, with the name of Kamikaze-go. When he died of canine distemper, his older brother, Kenzan-go, was presented to her as an official gift from the Japanese government in July 1939. Keller mushkaa is credited with having introduced the Akita to the United States through these two dogs. By 1938 a breed standard had been established and dog shows had been held, but such activities stopped after World War II began. Keller wrote in the Akita Journal: # Later life Keller suffered a series of strokes in 1961 and spent the last years of her life at her home. On September 14 1964, President Lyndon B. Johnson awarded Helen Keller the Presidential Medal of Freedom, one of the United States' highest two civilian honors. In 1965 she was elected to the Women's Hall of Fame at the New York World's Fair. Keller devoted much of her later life to raise funds for the American Foundation for the Blind. She died in her sleep on June 1 1968, passing away 26 days before her 88th birthday, at her home in Arcan Ridge near Westport, Connecticut. A service was held in her honor at the National Cathedral in Washington, DC and her ashes were placed there next to her constant companions, Anne Sullivan and Polly Thompson. # Posthumous honors In 1999, Keller was listed in Gallup's Most Widely Admired People of the 20th Century. In 2003, Alabama honored its native daughter on its state quarter. The Helen Keller Hospital in Sheffield, Alabama is dedicated to her. # Portrayals of Helen Keller Keller's life has been interpreted many times. She appeared in a silent film, Deliverance (1919), which told her story in a melodramatic, allegorical style. The Miracle Worker is a cycle of dramatic works ultimately derived from her autobiography, The Story of My Life. The various dramas each describe the relationship between Keller and Sullivan, depicting how the teacher led her from a state of almost feral wildness into education, activism, and intellectual celebrity. The common title of the cycle echoes Mark Twain's description of Sullivan as a "miracle worker". Its first realization was the 1957 Playhouse 90 teleplay of that title by William Gibson. He adapted it for a Broadway production in 1959 and an Oscar-winning feature film in 1962. It was remade for television in 1979 and 2000. She was also the subject of the documentaries Helen Keller in Her Story, narrated by Katharine Cornell, and The Story of Helen Keller, part of the Famous Americans series produced by Hearst Entertainment. In 1984, Helen Keller's life story was made into a TV movie called The Miracle Continues. This semi-sequel to The Miracle Worker recounts her college years and her early adult life. None of the early movies hint at the social activism that would become the hallmark of Keller's later life, although The Walt Disney Company version produced in 2000 states in the credits that she became an activist for social equality. The Hindi Bollywood movie Black (2005) was largely based on Keller's story, from her childhood to her graduation. A documentary called Shining Soul: Helen Keller's Spiritual Life and Legacy was produced by the Swedenborg Foundation in the same year. The film focuses on the role played by Emanuel Swedenborg's spiritual theology in her life and how it inspired Keller's triumph over her triple disabilities of blindness, deafness and a severe speech impediment. On March 6, 2008, the New England Historic Genealogical Society announced that a staff member had discovered a rare 1888 photograph showing Helen and Anne, which, although previously published, had escaped widespread attention. Depicting Helen holding one of her many dolls, it is believed to be the earliest surviving photograph of Anne. In 2008 Arcana Comics began publishing Helen Killer, a comic book by Andrew Kreisberg with art by Matthew Rice. In it, a college aged Keller is given a device which allows her to see and hear and which increases her physical abilities, at which point she is hired to protect the President of the United States.	Helen Keller Template:Infobox Person Helen Adams Keller (June 27, 1880 – June 1, 1968) was an American author, activist and lecturer. She was the first deafblind person to graduate from college. The story of how Keller's teacher, Anne Sullivan, broke through the isolation imposed by a near complete lack of language, allowing the girl to blossom as she learned to communicate, has become known worldwide through the dramatic depictions of the play The Miracle Worker. What is less well known is how Keller's life developed after she completed her education. A prolific author, she was well traveled, and was outspoken in her opposition to war. She campaigned for women's suffrage, workers' rights and socialism, as well as many other progressive causes. # Early childhood and illness Helen Keller was born at an estate called Ivy Green[1] in Tuscumbia, Alabama, on June 27, 1880, to Captain Arthur H. Keller, a former officer of the Confederate Army, and Kate Adams Keller, a cousin of Robert E. Lee and daughter of Charles W. Adams, a former Confederate general.[2] The Keller family originates from Germany, and at least one source claims her father was of Swiss descent.[3] She was not born blind and deaf; it was not until nineteen months of age that she came down with an illness described by doctors as "an acute congestion of the stomach and the brain", which could have possibly been scarlet fever or meningitis. The illness did not last for a particularly long time, but it left her deaf and blind. At that time her only communication partner was Martha Washington, the six-year-old daughter of the family cook, who was able to create a sign language with her; by age seven, she had over 60 home signs to communicate with her family. In his doctoral dissertation, "Deaf-blind Children (psychological development in a process of education)" (1971, Moscow Defectology Institute), Soviet blind-deaf psychologist Meshcheryakov asserted that Washington's friendship and teaching was crucial for Keller's later developments.[4] In 1886, her mother, inspired by an account in Charles Dickens' American Notes of the successful education of another deafblind child, Laura Bridgman, dispatched young Helen, accompanied by her father, to seek out Dr. J. Julian Chisolm, an eye, ear, nose and throat specialist in Baltimore, for advice.[5] He, subsequently, put them in touch with Alexander Graham Bell, who was working with deaf children at the time. Bell advised the couple to contact the Perkins Institute for the Blind, the school where Bridgman had been educated, which was then located in South Boston. The school delegated teacher and former student Anne Sullivan, herself visually impaired and then only 20 years old, to become Keller's instructor.It was the beginning of a 49-year-long relationship, eventually evolving into governess and then eventual companion. Sullivan got permission from Keller's father to isolate the girl from the rest of the family in a little house in their garden. Her first task was to instill discipline in the spoiled girl. Keller's big breakthrough in communication came one day when she realized that the motions her teacher was making on her palm, while running cool water over her hand, symbolized the idea of "water"; she then nearly exhausted Sullivan demanding the names of all the other familiar objects in her world (including her prized doll). In 1890, ten-year-old Helen Keller was introduced to the story of Ragnhild Kåta, a deafblind Norwegian girl who had learned to speak. Kåta's success inspired Keller to want to learn to speak as well. Sullivan taught her charge to speak using the Tadoma method of touching the lips and throat of others as they speak, combined with fingerspelling letters on the palm of the child's hand. Later Keller learned Braille, and used it to read not only English but also French, German, Greek, and Latin. # Formal education In 1888, Keller attended the Royal Institute For the Blind. In 1894, Helen Keller and Anne Sullivan moved to New York City to attend the Wright-Humason School for the Deaf and Horace Mann School for the Deaf. In 1896, they returned to Massachusetts and Helen entered The Cambridge School for Young Ladies before gaining admittance, in 1900, to Radcliffe College. Her admirer Mark Twain had introduced her to Standard Oil magnate Henry Huttleton Rogers, who, with his wife, paid for her education. In 1904, at the age of 24, Keller graduated from Radcliffe magna cum laude, becoming the first deafblind person to earn a Bachelor of Arts degree.[6] # Companions Anne Sullivan stayed as a companion to Helen Keller long after she taught her. Anne married John Macy in 1905, and her health started failing around 1914. Polly Thompson was hired to keep house. She was a young woman from Scotland who didn't have experience with deaf or blind people. She progressed to working as a secretary as well, and eventually became a constant companion to Helen.[7] After Anne died in 1936, Helen and Polly moved to Connecticut. They travelled worldwide raising funding for the blind. Polly had a stroke in 1957 from which she never fully recovered, and died in 1960.[6] Winnie Corbally was Helen's companion for the rest of her life.[6] # Political activities Keller went on to become a world-famous speaker and author. She is remembered as an advocate for people with disabilities amid numerous other causes. She was a suffragist, a pacifist, a Wilson opposer, a radical socialist, and a birth control supporter. In 1915, Helen Keller and George Kessler founded the Helen Keller International (HKI) organization. This organization is devoted to research in vision, health and nutrition. In 1920, she helped to found the American Civil Liberties Union (ACLU). Keller and Sullivan traveled to over 39 countries, making several trips to Japan and becoming a favorite of the Japanese people. Keller met every US President from Grover Cleveland to Lyndon B. Johnson and was friends with many famous figures, including Alexander Graham Bell, Charlie Chaplin and Mark Twain. Keller was a member of the Socialist Party and actively campaigned and wrote in support of the working classes from 1909 to 1921. She supported Socialist Party candidate Eugene V. Debs in each of his campaigns for the presidency. Newspaper columnists who had praised her courage and intelligence before she expressed her socialist views now called attention to her disabilities. The editor of the Brooklyn Eagle wrote that her "mistakes sprung out of the manifest limitations of her development." Keller responded to that editor, referring to having met him before he knew of her political views: Keller joined the Industrial Workers of the World (known as the IWW or the Wobblies) in 1912,[9] saying that parliamentary socialism was "sinking in the political bog." She wrote for the IWW between 1916 and 1918. In Why I Became an IWW,[10] Keller explained that her motivation for activism came in part from her concern about blindness and other disabilities: The last sentence refers to prostitution and syphilis, the latter a leading cause of blindness. Keller and her friend Mark Twain were both considered radicals in the socio-political context present in the United States at the beginning of the 20th century, and as a consequence, their political views have been forgotten or glossed over in popular perception.[9] # Writings One of Keller's earliest pieces of writing, at the age of eleven, was "The Frost King" (1891). There were allegations that this story had been plagiarized from The Frost Fairies by Margaret Canby. An investigation into the matter revealed that Keller may have suffered from cryptomnesia, having once had Canby's story read to her, only to forget about it, although the memory had remained hidden in her subconscious.[6] At the age of 23, Keller published her autobiography, The Story of My Life (1903), with help from Sullivan and Sullivan's husband, John Macy. It includes letters that Keller wrote and the story of her life up to age 21, and was written during her time in college.[6] Helen wrote "The World I Live In" in 1908 giving readers an insight into how she felt about the world.[11] "Out of the Dark", a series of essays on Socialism, was published in 1913. Her spiritual autobiography, My Religion, was published in 1927 and re-issued as Light in my Darkness. It advocates the teachings of Emanuel Swedenborg, the controversial mystic who claimed to have witnessed the Last Judgment and second coming of Jesus Christ, and the movement named after him, Swedenborgianism. In total Keller wrote 12 books and numerous articles. # Akita dog When Keller visited Akita Prefecture in Japan in July 1937, she inquired about Hachikō, the famed Akita dog that had died in 1935. She told a Japanese person that she would like to have an Akita dog; one was given to her within a month, with the name of Kamikaze-go. When he died of canine distemper, his older brother, Kenzan-go, was presented to her as an official gift from the Japanese government in July 1939. Keller mushkaa is credited with having introduced the Akita to the United States through these two dogs. By 1938 a breed standard had been established and dog shows had been held, but such activities stopped after World War II began. Keller wrote in the Akita Journal: # Later life Keller suffered a series of strokes in 1961 and spent the last years of her life at her home.[6] On September 14 1964, President Lyndon B. Johnson awarded Helen Keller the Presidential Medal of Freedom, one of the United States' highest two civilian honors.[14] In 1965 she was elected to the Women's Hall of Fame at the New York World's Fair.[6] Keller devoted much of her later life to raise funds for the American Foundation for the Blind. She died in her sleep on June 1 1968, passing away 26 days before her 88th birthday, at her home in Arcan Ridge near Westport, Connecticut. A service was held in her honor at the National Cathedral in Washington, DC and her ashes were placed there next to her constant companions, Anne Sullivan and Polly Thompson.[6] # Posthumous honors In 1999, Keller was listed in Gallup's Most Widely Admired People of the 20th Century. In 2003, Alabama honored its native daughter on its state quarter.[15] The Helen Keller Hospital in Sheffield, Alabama is dedicated to her.[16] # Portrayals of Helen Keller Keller's life has been interpreted many times. She appeared in a silent film, Deliverance (1919), which told her story in a melodramatic, allegorical style.[17] The Miracle Worker is a cycle of dramatic works ultimately derived from her autobiography, The Story of My Life. The various dramas each describe the relationship between Keller and Sullivan, depicting how the teacher led her from a state of almost feral wildness into education, activism, and intellectual celebrity. The common title of the cycle echoes Mark Twain's description of Sullivan as a "miracle worker". Its first realization was the 1957 Playhouse 90 teleplay of that title by William Gibson. He adapted it for a Broadway production in 1959 and an Oscar-winning feature film in 1962. It was remade for television in 1979 and 2000. She was also the subject of the documentaries Helen Keller in Her Story, narrated by Katharine Cornell, and The Story of Helen Keller, part of the Famous Americans series produced by Hearst Entertainment. In 1984, Helen Keller's life story was made into a TV movie called The Miracle Continues.[18] This semi-sequel to The Miracle Worker recounts her college years and her early adult life. None of the early movies hint at the social activism that would become the hallmark of Keller's later life, although The Walt Disney Company version produced in 2000 states in the credits that she became an activist for social equality. The Hindi Bollywood movie Black (2005) was largely based on Keller's story, from her childhood to her graduation. A documentary called Shining Soul: Helen Keller's Spiritual Life and Legacy was produced by the Swedenborg Foundation in the same year. The film focuses on the role played by Emanuel Swedenborg's spiritual theology in her life and how it inspired Keller's triumph over her triple disabilities of blindness, deafness and a severe speech impediment. On March 6, 2008, the New England Historic Genealogical Society announced that a staff member had discovered a rare 1888 photograph showing Helen and Anne, which, although previously published, had escaped widespread attention.[19] Depicting Helen holding one of her many dolls, it is believed to be the earliest surviving photograph of Anne.[20][21] In 2008 Arcana Comics began publishing Helen Killer, a comic book by Andrew Kreisberg with art by Matthew Rice. In it, a college aged Keller is given a device which allows her to see and hear and which increases her physical abilities, at which point she is hired to protect the President of the United States.[22][23]	https://www.wikidoc.org/index.php/Helen_Keller
0a71842677ce6ed40636db63069038ae7ad42e3d	wikidoc	Helicobacter	Helicobacter # Overview Helicobacter is a genus of Gram-negative bacteria possessing a characteristic helix shape. They were initially considered to be members of the Campylobacter genus, but since 1989 they have been grouped in their own genus. Some species have been found living in the lining of the upper gastrointestinal tract, as well as the liver of mammals and some birds.. The most widely known species of the genus is H. pylori which infects up to 50% of the human population. Some strains of this bacterium are pathogenic to humans as it is strongly associated with peptic ulcers, chronic gastritis, duodenitis, and stomach cancer. It also serves as the type species of the genus. Helicobacter spp. are able to thrive in the very acidic mammalian stomach by producing large quantities of the enzyme urease, which locally raises the pH from ~2 to a more biocompatible range of 6 to 7. Bacteria belonging to this genus are usually susceptible to antibiotics such as penicillin, are microaerophilic (require small amounts of oxygen), and are fast-moving with their flagella. ## Helicobacter Facts. Curved cells discovered in 1979 in stomach biopsied specimens. Causes 90% of stomach & duodenal ulcers. People with type O blood have a 1.5-2X higher rate of ulcers. Produces large amounts of urease. Infection common especially in lower socioeconomic class/developing nations. Humans primary reservoir. Person-to-person spread via fecal-oral route. Ubiquitous, no seasonal incidence. ## Diseases In 1994, the World Health Organization’s International Agency for Research on Cancer (IARC) classified H. pylori as a Group 1 carcinogen. This decision was based on the results of numerous studies that confirmed the association between H. pylori infection and gastric adenocarcinoma. H. pylori infection also significantly increases the risk of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) (Suerbaum, 2002). While H. pylori remains the most medically important bacterial inhabitant of the human stomach, other species of the genus Helicobacter have been identified in other mammals and some birds, and some of these can infect humans. Helicobacter species have also been found to infect the livers of certain mammals and to cause liver disease. ## Diagnosis H. pylori infection can be confirmed by invasive or noninvasive methods. Invasive tests require upper esophagogastroduodenal (EGD) endoscopy, which is considered the reference method of diagnosis. During endoscopy, biopsy specimens of the stomach and duodenum are obtained, and the diagnosis of H. pylori can be made by urease testing, histology and/or culture. If possible, noninvasive testing is done before tissue testing. H. pylori stool antigen (HpSA) testing is based on monoclonal antibody immunochromatography of stool samples. This testing method identifies active infection and can be used to detect eradication after treatment. A sensitivity and specificity range of 92–98% is reported in the literature for stool antigen testing. Serological assays (blood serum) measure specific H. pylori immunoglobulin G (IgG) antibodies that can determine if an individual has been infected. The sensitivity and specificity of these assays range from 80–95%, depending on the assay used. Serological testing has been the mainstay of H. pylori diagnosis, particularly in primary care, due to the accessibility, rapid results and low cost of this testing method. Urease test, Urease Breath Test (UBT) (positive in as little as 2 hours) # Treatment Therapy with tetracycline, metronidazole, bismuth (Peptobismol)	Helicobacter # Overview Helicobacter is a genus of Gram-negative bacteria possessing a characteristic helix shape. They were initially considered to be members of the Campylobacter genus, but since 1989 they have been grouped in their own genus.[1][2][3] Some species have been found living in the lining of the upper gastrointestinal tract, as well as the liver of mammals and some birds.[4]. The most widely known species of the genus is H. pylori which infects up to 50% of the human population.[3] Some strains of this bacterium are pathogenic to humans as it is strongly associated with peptic ulcers, chronic gastritis, duodenitis, and stomach cancer. It also serves as the type species of the genus. Helicobacter spp. are able to thrive in the very acidic mammalian stomach by producing large quantities of the enzyme urease, which locally raises the pH from ~2 to a more biocompatible range of 6 to 7.[5] Bacteria belonging to this genus are usually susceptible to antibiotics such as penicillin, are microaerophilic (require small amounts of oxygen), and are fast-moving with their flagella.[6][7] ## Helicobacter Facts.[8] Curved cells discovered in 1979 in stomach biopsied specimens. Causes 90% of stomach & duodenal ulcers. People with type O blood have a 1.5-2X higher rate of ulcers. Produces large amounts of urease. Infection common especially in lower socioeconomic class/developing nations. Humans primary reservoir. Person-to-person spread via fecal-oral route. Ubiquitous, no seasonal incidence. ## Diseases In 1994, the World Health Organization’s International Agency for Research on Cancer (IARC) classified H. pylori as a Group 1 carcinogen. This decision was based on the results of numerous studies that confirmed the association between H. pylori infection and gastric adenocarcinoma. H. pylori infection also significantly increases the risk of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) (Suerbaum, 2002). While H. pylori remains the most medically important bacterial inhabitant of the human stomach, other species of the genus Helicobacter have been identified in other mammals and some birds, and some of these can infect humans.[9] Helicobacter species have also been found to infect the livers of certain mammals and to cause liver disease.[10] ## Diagnosis H. pylori infection can be confirmed by invasive or noninvasive methods. Invasive tests require upper esophagogastroduodenal (EGD) endoscopy, which is considered the reference method of diagnosis. During endoscopy, biopsy specimens of the stomach and duodenum are obtained, and the diagnosis of H. pylori can be made by urease testing, histology and/or culture. If possible, noninvasive testing is done before tissue testing. H. pylori stool antigen (HpSA) testing is based on monoclonal antibody immunochromatography of stool samples. This testing method identifies active infection and can be used to detect eradication after treatment. A sensitivity and specificity range of 92–98% is reported in the literature for stool antigen testing. Serological assays (blood serum) measure specific H. pylori immunoglobulin G (IgG) antibodies that can determine if an individual has been infected. The sensitivity and specificity of these assays range from 80–95%, depending on the assay used. Serological testing has been the mainstay of H. pylori diagnosis, particularly in primary care, due to the accessibility, rapid results and low cost of this testing method. Urease test, Urease Breath Test (UBT) (positive in as little as 2 hours) [11] # Treatment Therapy with tetracycline, metronidazole, bismuth (Peptobismol)	https://www.wikidoc.org/index.php/Helicobacter
4caae7d8c0aa143f6a844072ebd0a276d7c37a8d	wikidoc	Hematidrosis	Hematidrosis Hematidrosis (also called hematohidrosis) He-ma-ti-drosis is a very rare condition in which a human being sweats blood. It may occur when a person is suffering extreme levels of stress, for example, facing his or her own death. Several historical references have been described; notably by Leonardo da Vinci: describing a soldier who sweated blood before battle, as well as descriptions in the Bible, that Jesus experienced hematidrosis when he was praying in the garden of Gethsemane. There are a few names and conditions which may pertain to this, such as hematochromatosis, or staining of tissues with blood pigment. Hemochromatosis a disorder due to deposition of hemosiderin in the parenchymal cells, causing tissue damage and dysfunction of the liver, pancreas, heart, and pituitary. Other clinical signs include bronze pigmentation of skin, arthropathy, diabetes, cirrhosis, hepatosplenomegaly, hypogonadism, and loss of body hair. Full development of the disease among women is restricted by menstruation and pregnancy. There are varying degrees of hemochromatosis, including: # Acquired hemochromatosis Results from blood transfusions or excessive dietary iron, or secondary to other disease, e.g., thalassemia or sideroblastic anemia; called also secondary hemochromatosis. # Genetic, hereditary, and idiopathic hemochromatosis An autosomal recessive disorder of iron metabolism associated with a gene tightly linked to the A locus of the human leukocyte antigens (HLA). complex on chromosome 6; iron accumulation is lifelong, with symptoms appearing usually in the fifth or sixth decades of life. # Neonatal and perinatal hemochromatosis A rare fulminant disease of the liver, of unknown cause, characterized by massive deposition of iron in the liver, pancreas, heart, and endocrine glands; symptoms are those of neonatal hepatitis and appear in utero or within the first week of life, with death usually occurring by 4 months of age. # Cutaneous hemorrhage According to Dr. Frederick Zugibe (Chief Medical Examiner of Rockland County, New York) it is well-known, and there have been many cases of it. The clinical term is hematohidrosis. "Around the sweat glands, there are multiple blood vessels in a net-like form. Under the pressure of great stress the vessels constrict. Then as the anxiety passes the blood vessels dilate to the point of rupture. The blood goes into the sweat glands. As the sweat glands are producing a lot of sweat, it pushes the blood to the surface - coming out as droplets of blood mixed with sweat." In a lecture, Dr. Zugibe stated: "The severe mental anxiety...activated the sympathetic nervous system to invoke the stress-fight or flight reaction to such a degree causing hemorrhage of the vessels supplying the sweat glands into the ducts of the sweat glands and extruding out onto the skin. While hematidrosis has been reported to occur from other rare medical entities, the presence of profound fear accounted for a significant number of reported cases including six cases in men condemned to execution, a case occurring during the London blitz, a case involving a fear of being raped, a fear of a storm while sailing, etc. The effects on the body is that of weakness and mild to moderate dehydration from the severe anxiety and both the blood and sweat loss."	Hematidrosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Hematidrosis (also called hematohidrosis) He-ma-ti-drosis is a very rare condition in which a human being sweats blood. It may occur when a person is suffering extreme levels of stress, for example, facing his or her own death.[1] Several historical references have been described; notably by Leonardo da Vinci: describing a soldier who sweated blood before battle, as well as descriptions in the Bible, that Jesus experienced hematidrosis when he was praying in the garden of Gethsemane. There are a few names and conditions which may pertain to this, such as hematochromatosis, or staining of tissues with blood pigment. Hemochromatosis a disorder due to deposition of hemosiderin in the parenchymal cells, causing tissue damage and dysfunction of the liver, pancreas, heart, and pituitary. Other clinical signs include bronze pigmentation of skin, arthropathy, diabetes, cirrhosis, hepatosplenomegaly, hypogonadism, and loss of body hair. Full development of the disease among women is restricted by menstruation and pregnancy. There are varying degrees of hemochromatosis, including: # Acquired hemochromatosis Results from blood transfusions or excessive dietary iron, or secondary to other disease, e.g., thalassemia or sideroblastic anemia; called also secondary hemochromatosis. # Genetic, hereditary, and idiopathic hemochromatosis An autosomal recessive disorder of iron metabolism associated with a gene tightly linked to the A locus of the human leukocyte antigens (HLA). complex on chromosome 6; iron accumulation is lifelong, with symptoms appearing usually in the fifth or sixth decades of life. # Neonatal and perinatal hemochromatosis A rare fulminant disease of the liver, of unknown cause, characterized by massive deposition of iron in the liver, pancreas, heart, and endocrine glands; symptoms are those of neonatal hepatitis and appear in utero or within the first week of life, with death usually occurring by 4 months of age. # Cutaneous hemorrhage According to Dr. Frederick Zugibe (Chief Medical Examiner of Rockland County, New York) it is well-known, and there have been many cases of it. The clinical term is hematohidrosis. "Around the sweat glands, there are multiple blood vessels in a net-like form. Under the pressure of great stress the vessels constrict. Then as the anxiety passes the blood vessels dilate to the point of rupture. The blood goes into the sweat glands. As the sweat glands are producing a lot of sweat, it pushes the blood to the surface - coming out as droplets of blood mixed with sweat."[citation needed] In a lecture, Dr. Zugibe stated: "The severe mental anxiety...activated the sympathetic nervous system to invoke the stress-fight or flight reaction to such a degree causing hemorrhage of the vessels supplying the sweat glands into the ducts of the sweat glands and extruding out onto the skin. While hematidrosis has been reported to occur from other rare medical entities, the presence of profound fear accounted for a significant number of reported cases including six cases in men condemned to execution, a case occurring during the London blitz, a case involving a fear of being raped, a fear of a storm while sailing, etc. The effects on the body is that of weakness and mild to moderate dehydration from the severe anxiety and both the blood and sweat loss."	https://www.wikidoc.org/index.php/Hematidrosis
0f82f5f32afcb727d51d1f08f908af2e083bca9f	wikidoc	Hepatic vein	Hepatic vein # Overview In human anatomy, the hepatic veins are the blood vessels that drain de-oxygenated blood from the liver and blood cleaned by the liver (from the stomach, pancreas, small intestine and colon) into the inferior vena cava. They arise from the substance of the liver, more specifically the central vein of the liver lobule. None of the hepatic veins have valves. # Groups They can be differentiated into two groups, the upper group and lower group. - The upper group typically arises from the posterior aspect of the liver, are three in number, and drain the quadrate lobe and left lobe. - The lower group arise from the right lobe and caudate lobe, are variable in number, and are typically smaller than those in the upper group. # Pathology Occlusion of the hepatic veins is known as Budd-Chiari syndrome.	Hepatic vein Template:Infobox Vein Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview In human anatomy, the hepatic veins are the blood vessels that drain de-oxygenated blood from the liver and blood cleaned by the liver (from the stomach, pancreas, small intestine and colon) into the inferior vena cava. They arise from the substance of the liver, more specifically the central vein of the liver lobule. None of the hepatic veins have valves. # Groups They can be differentiated into two groups, the upper group and lower group. - The upper group typically arises from the posterior aspect of the liver, are three in number, and drain the quadrate lobe and left lobe. - The lower group arise from the right lobe and caudate lobe, are variable in number, and are typically smaller than those in the upper group. # Pathology Occlusion of the hepatic veins is known as Budd-Chiari syndrome. # External links - Hepatic Histology: The Lobule - Describes the liver lobule and central vein. - Hepatic veins - definition - medterms.com - Template:EMedicineDictionary ## Images of the hepatic veins - Hepatic veins - Ultrasound - University of the Health Sciences in Bethesda, Maryland - 3-D reconstruction of the liver anatomy (for transplantation) - MeVis Distant Services - Hepatic veins - CT angiogram - Contrast Techniques for Hepatic Multidetector CT Angiography - Havard Medical School. - Template:ViennaCrossSection # Additional images - Human embryo with heart and anterior body-wall removed to show the sinus venosus and its tributaries. - The portal vein and its tributaries. - Longitudinal section of a hepatic vein. Template:Veins Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hepatic_vein
2eea3ad55e9ff03077371dc4bbf64f0b9c12591b	wikidoc	Hickman line	Hickman line A Hickman line is an intravenous catheter most often used for the administration of chemotherapy or other medications, as well as for the withdrawal of blood for analysis. Some types of Hickman lines are used mainly for the purpose of apheresis or dialysis. Hickman lines may remain in place for extended periods and are used when long-term intravenous access is needed. The insertion of a Hickman line is usually done under sedation or a general anesthetic by a radiologist or surgeon. It involves two incisions, one at the jugular vein or another nearby vein or groove, and one on the chest wall. At the former incision site (known as the "entrance" site), a tunnel is created from there through to the latter incision site (known as the "exit" site), and the catheter is pushed through this tunnel until it "exits" the latter incision site. The exit site is where the lumens are seen as coming out of the chest wall. The catheter at the entrance site area is then inserted back through the exit site and advanced into the superior vena cava, preferably near the junction of it and the right atrium of the heart. The entrance site is sutured. The catheter at the exit site is secured by means of a "cuff" just under the skin at the exit site, and the lumens are held down otherwise by a sterile gauze or dressing centered on the exit site, which also serves the purpose of preventing potential contamination at the exit site. Throughout the procedure, ultrasound and X-rays are used to ascertain the positioning of the catheter. Long-term venous catheters became available in 1968, and the design was improved by Broviac et al in 1973. Hickman et al, after whom the system is named, further modified the principles with subcutaneous tunneling and a Dacron cuff that formed an infection barrier. Dr Robert O. Hickman was a pediatric nephrologist at the Seattle Children's Hospital and Regional Medical Center. Potential complications of placement of such a line include hemorrhage and pneumothorax during insertion and thrombosis or infection at later stages. Patients with a Hickman line therefore require regular flushes of the catheter with heparin, in order to prevent the line becoming blocked by blood clots. Preventing contamination at the exit site and ensuring that the lumens are flushed frequently is especially important for oncology patients, as they may have become immunocompromised as a result of cytotoxic chemotherapy. Pyrexia (fever) is one of the symptoms of contamination. This symptom, and others, including the observance of swelling or bleeding at the exit site, indicate that the patient should seek medical attention as soon as possible.	Hickman line Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A Hickman line is an intravenous catheter most often used for the administration of chemotherapy or other medications, as well as for the withdrawal of blood for analysis. Some types of Hickman lines are used mainly for the purpose of apheresis or dialysis. Hickman lines may remain in place for extended periods and are used when long-term intravenous access is needed. The insertion of a Hickman line is usually done under sedation or a general anesthetic by a radiologist or surgeon. It involves two incisions, one at the jugular vein or another nearby vein or groove, and one on the chest wall. At the former incision site (known as the "entrance" site), a tunnel is created from there through to the latter incision site (known as the "exit" site), and the catheter is pushed through this tunnel until it "exits" the latter incision site. The exit site is where the lumens are seen as coming out of the chest wall. The catheter at the entrance site area is then inserted back through the exit site and advanced into the superior vena cava, preferably near the junction of it and the right atrium of the heart. The entrance site is sutured. The catheter at the exit site is secured by means of a "cuff" just under the skin at the exit site, and the lumens are held down otherwise by a sterile gauze or dressing centered on the exit site, which also serves the purpose of preventing potential contamination at the exit site. Throughout the procedure, ultrasound and X-rays are used to ascertain the positioning of the catheter. Long-term venous catheters became available in 1968, and the design was improved by Broviac et al in 1973. Hickman et al, after whom the system is named, further modified the principles with subcutaneous tunneling and a Dacron cuff that formed an infection barrier. Dr Robert O. Hickman was a pediatric nephrologist at the Seattle Children's Hospital and Regional Medical Center. Potential complications of placement of such a line include hemorrhage and pneumothorax during insertion and thrombosis or infection at later stages. Patients with a Hickman line therefore require regular flushes of the catheter with heparin, in order to prevent the line becoming blocked by blood clots. Preventing contamination at the exit site and ensuring that the lumens are flushed frequently is especially important for oncology patients, as they may have become immunocompromised as a result of cytotoxic chemotherapy. Pyrexia (fever) is one of the symptoms of contamination. This symptom, and others, including the observance of swelling or bleeding at the exit site, indicate that the patient should seek medical attention as soon as possible.	https://www.wikidoc.org/index.php/Hickman_line
b7cb821ba48ac83c3496d09e7856fc4f92b4f02c	wikidoc	Hiclone Work	Hiclone Work # Hiclone Work # Hiclone Work Hiclone is a simple non moving stainless steel. Part_Numbers_Starting_With_D. How Does It Work? Most 4WD engines are less than 100% efficient. The Original Fuelsaver and Induction enhancement since the rail and boost control systems that work! and no check engine light issues. how do audio systems work very few actually work as they say. Now i have heared mixed stories on these. If you look at the top of some snorkels, they. Hiclone Europe Limited are the European importers of a range of auto accessory products,. They are work advantage apartment hiclone and are still adertised. I have been told of a product called Hiclone. ### Hiclone Work - Technical "1)How many times has the question been asked? 2)How many times has it been answered? 3)has anybody ever said "yes it works it is a great little gadget. Mechanical Repairs. Book-In Here ? Contact Us. 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[MIXTEXT]<a id="icePage_SearchResults_ResultsRepeaterByRelevance_ResultRepeater_ctl15_WebResult_ListingDescriptionLink" class="listingDescriptionLink" onMouseOver=HTTP/1.0 510 Unknown Date: Mon, 18 Jul 2011 18:59:57 GMT Server: Microsoft-IIS/6.0 X-Powered-By: ASP.NET X-Aspnet-Version: 2.0.50727 Pragma: no-cache Set-Cookie: .ASPXANONYMOUS=ARjp6idl-5onDmxneKKBQ-bDqSHahcqTSOvnZTuyxY_QVs_8omYgqjwnDThSWhXPUR7N43LuMUGZ6Bd3LVw2_pyvM8mpn0R7vhIVvKOhe4jhIEMU56Ub5rrs_KXEv6aAIK0UzKxAtnhrLW0FngluHFw9i2X-E4vPTZcbBQlp0qU-T_H60; expires=Wed, 12-Jun-2013 05:39:56 GMT; path=/ Set-Cookie: ASP.NET_SessionId=noibrg24dmxq4aiwvsfq1nuy; path=/ Set-Cookie: DomainSession=TransactionId=c177447dac1549a6ab245e4f1845cc01&SessionId=d0ecdfe276464efab1b15e4f1845cc01&ActionId=62a6556256594e9098215e4f1845cc01&CookieDomain=.excite.com&PrevActionId=5a09a4b6a54748c194165e4f1845cc01; domain=.excite.com; expires=Mon, 18-Jul-2011 19:19:57 GMT; path=/ Set-Cookie: DomainUserProfile=AnonymousId=08ebab2930d447439ebe5e4f1845cc01&LastSeenDateTime=7/18/2011 6:59:56 PM&IssueDateTime=7/18/2011 6:59:56 PM&CookieDomain=.excite.com; domain=.excite.com; expires=Wed, 24-Jun-2111 18:59:57 GMT; path=/ Set-Cookie: wsTemp=bigIP+3842544906.20480.0000+cacheId+ms23:1311015597188; path=/ Set-Cookie: wsRecent=hiclone+work,Web,Relevance,; path=/ Cache-Control: private Content-Type: text/html; charset=utf-8 Content-Length: 30356 Vary: Accept-Encoding, User-Agent X-Cache: MISS from www.tsudlaw.com X-Cache-Lookup: MISS from www.tsudlaw.com:3128 Via: 1.0 www.tsudlaw.com:3128 (squid/2.6.STABLE21) Proxy-Connection: close <!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Transitional//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-transitional.dtd"> <html id="icePage_DocumentRoot" xmlns="http://www.w3.org/1999/xhtml"> <meta name="Description" content="" /> <link id="OpenDescriptionLink" rel="search" type="application/opensearchdescription+xml" title="Excite Search" href="http://msxml.excite.com/excite/ws/provider/_iceUrlFlag=11?_IceUrl=true" /> <script type="text/javascript" language="javascript" src="http://ttl60m.wsds.infospace.com.edgesuite.net/excite/ws/jquery-min.js/_iceUrlFlag=11?_IceUrl=true"></script> <input type="hidden" name="__VIEWSTATE" id="__VIEWSTATE" value="/wEPDwULLTEwNzYxNjAxNjBkGAEFHl9fQ29udHJvbHNSZXF1aXJlUG9zdEJhY2tLZXlfXxYDBTBpY2VQYWdlJGFkdmFuY2VkU2VhcmNoJEFkdmFuY2VkU2VhcmNoV2ViJGluY2x1ZGUFMGljZVBhZ2UkYWR2YW5jZWRTZWFyY2gkQWR2YW5jZWRTZWFyY2hXZWIkZXhjbHVkZQUwaWNlUGFnZSRhZHZhbmNlZFNlYXJjaCRBZHZhbmNlZFNlYXJjaFdlYiRleGNsdWRlOzBdhQ5abh41PHke/iWNUoUIw9k=" /> - Further Your Career at Walden An Accredited Online University. - Don't waste your money, use it to put fuel in your tank. I had installed 2 x Hiclones to my Nissan Patrol, and immediately noticed I will be going back agin shortly to have more work done. - Performance, European, Japanese ,water pumps, Hiclone, emmission testing,CV boots,air. Hiclone Fuel Saver Do you want to get better fuel economy from you vehicle without The Hiclones work well on petrol, diesel or LPG vehicles and we give you a 60 day. - I labs for blood work the idea. Professional training courses to meet health and safety requirements in the work Hiclone Europe The Home page of Hiclone swirling air device that imporves torque and. - An engine that is working correctly to start with will always get a positive result. Feb 13, 2006 vehicles do not have any work done on the car in the interval is a Hiclone promises fuel savings of up to 20%, power increase of up. Miele Professional Limited Abingdon Oxfordshire UK Web: www.miele-professional.co.uk Miele Professional are the global leader in manufacturing high quality commercial. Dec 23, 2008 When installed on the vehicle, Hiclone improves fuel economy and engine We are committed to work with an ethos of environmental. 4acdfe3556 They worked on my 4.5ltr patol on LPG (more torque down low and better work work job board did work out exercises work on the 3ltr Di (already has an inbuilt swirl port), don't know if it will. it will make your mileage worse and add restriction to the air intake tract. Two HiClones - Nissan Navara D22 3.0l Turbo Diesel AU KI 63 (AirFilter for 1987 diesel Nissan navara good master level social work and a great work horse starts first. Model driven: 2011 Jeep Grand quiz work safety Laredo, 3.6-litre V6 petrol with five-speed automatic transmission: ,000 (MLP) The latest Jeep Grand Cherokee is a complete. Wikipedia	https://www.wikidoc.org/index.php/Hiclone_Work
1a1cf00b10a4bd5d86f0e8856271e3ce703e08d9	wikidoc	Hidrocystoma	Hidrocystoma # Overview Hidrocystoma (also known as cystadenoma, a Moll's gland cyst, and a sudoriferous cyst) is an adenoma of the sweat glands.:787 Hidrocystomas are cysts of sweat ducts, usually on the eyelids.:664 They are not tumours (a similar sounding lesion called hidroadenoma is a benign tumour). There are three types of "sweat" glands: True sweat glands or eccrine glands, sebaceous glands which have an oily secretion around hair follicles and apocrine glands which have more oily product than eccrine glands and are found on the face, armpit and groin. Hidrocystomas usually arise from apocrine glands. They are also called Cysts of Moll or sudoriferous cysts. There may be a type of hidroadenoma that arises from eccrine glands but these are uncommon. Other related conditions on the eyelids include chalazion ( a granulomatous reaction to sebaceous glands on the eyelid), lacrimal duct cysts (cysts related to tear ducts) and nasolacrimal duct cysts (the nasolacrimal duct drains tears into the nose via a punctum on the lower eyelid). # Diagnosis ## Physical examination ### Skin - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas. - Eccrine hidrocystoma. Adapted from Dermatology Atlas.	Hidrocystoma Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Overview Hidrocystoma (also known as cystadenoma,[1] a Moll's gland cyst,[1] and a sudoriferous cyst[1]) is an adenoma of the sweat glands.[2]:787 Hidrocystomas are cysts of sweat ducts, usually on the eyelids.[3]:664 They are not tumours (a similar sounding lesion called hidroadenoma is a benign tumour). There are three types of "sweat" glands: True sweat glands or eccrine glands, sebaceous glands which have an oily secretion around hair follicles and apocrine glands which have more oily product than eccrine glands and are found on the face, armpit and groin. Hidrocystomas usually arise from apocrine glands. They are also called Cysts of Moll or sudoriferous cysts. There may be a type of hidroadenoma that arises from eccrine glands but these are uncommon. Other related conditions on the eyelids include chalazion ( a granulomatous reaction to sebaceous glands on the eyelid), lacrimal duct cysts (cysts related to tear ducts) and nasolacrimal duct cysts (the nasolacrimal duct drains tears into the nose via a punctum on the lower eyelid). # Diagnosis ## Physical examination ### Skin - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4] - Eccrine hidrocystoma. Adapted from Dermatology Atlas.[4]	https://www.wikidoc.org/index.php/Hidrocystoma
2503fdb57f0f6ed8a874a59c818d0b00feaf1a68	wikidoc	Hilda Molina	Hilda Molina Dr Hilda Molina is the former chief neurosurgeon of Cuba. Molina was also a deputy in the Cuban National Assembly but has been a critic of the Cuban government since the early 1990s. Her criticisms focus primarily on Cuba's state-governed healthcare system. In 1987, Molina founded the neurosurgery center in Havana. By 1991, her center had become one of the most important scientific centers in Cuba. The same year, Molina claims she was informed by the then Minister of Health, Julio Teja, that her center was henceforth to treat foreigners paying in U.S. dollars. Previously, the center had treated only Cuban patients. Dr. Molina subsequently resigned her position at the center and her seat at the National Assembly. Molina claims that she and her son were subjected to mob retaliation in what are termed "acts of repudiation". She has continuously been denied a visa to travel for personal as well as professional reasons. # Requests for travel Dr. Molina has made many requests to visit family members residing in Argentina. In 2004, after Molina was again denied a visa by the Cuban government, an Argentinian free-market oriented thinktank forwarded a letter from Dr. Molina to the United Nations Human Rights Commission and other international human rights groups. In the letter Molina stated: "The Cuban government impeded me from temporarily visiting Argentina for a reunion, after 11 years of forcible separation, with my son, who is a naturalized Argentinian, and with his wife who is an Argentine citizen". She also listed numerous examples where she believed her rights had been violated by the Cuban authorities going on to state that "the arbitrary state organs that delay or deny, provoking the tearing apart of thousands of innocent families, that submerges them in paralyzing fear, so they are incapacitated to reclaim the respect for their rights most elemental." In July 2006, a week before Fidel Castro's illness led to the Cuban transfer of presidential duties to brother Raúl Castro, the Cuban President was questioned by international leaders and journalists on the issue whilst attending a conference in Argentina. Argentine President Néstor Kirchner took the opportunity to press the Cuban leader to allow surgeon Hilda Molina, a one-time Castro ally, to leave Cuba to be with her children and grandchildren already in Argentina. At an improvised press conference, Miami's Channel 41 reporter Juan Manuel Cao asked Castro about Molina, a reportedly infuriated Castro asked the reporter, "Who is paying you?" and later accused him of being "a mercenary" for President Bush . Juan Manuel Cao was later confirmed to have been one of at least ten South Florida journalists to have received regular payments from the U.S. government.	Hilda Molina Dr Hilda Molina is the former chief neurosurgeon of Cuba. Molina was also a deputy in the Cuban National Assembly but has been a critic of the Cuban government since the early 1990s. Her criticisms focus primarily on Cuba's state-governed healthcare system. In 1987, Molina founded the neurosurgery center in Havana. By 1991, her center had become one of the most important scientific centers in Cuba. The same year, Molina claims she was informed by the then Minister of Health, Julio Teja, that her center was henceforth to treat foreigners paying in U.S. dollars. Previously, the center had treated only Cuban patients. Dr. Molina subsequently resigned her position at the center and her seat at the National Assembly. Molina claims that she and her son were subjected to mob retaliation in what are termed "acts of repudiation". She has continuously been denied a visa to travel for personal as well as professional reasons. # Requests for travel Dr. Molina has made many requests to visit family members residing in Argentina. In 2004, after Molina was again denied a visa by the Cuban government, an Argentinian free-market oriented thinktank forwarded a letter from Dr. Molina to the United Nations Human Rights Commission and other international human rights groups. In the letter Molina stated: "The Cuban government impeded me from temporarily visiting Argentina for a reunion, after 11 years of forcible separation, with my son, who is a naturalized Argentinian, and with his wife who is an Argentine citizen". She also listed numerous examples where she believed her rights had been violated by the Cuban authorities going on to state that "the arbitrary state organs that delay or deny, provoking the tearing apart of thousands of innocent families, that submerges them in paralyzing fear, so they are incapacitated to reclaim the respect for their rights most elemental."[1] In July 2006, a week before Fidel Castro's illness led to the Cuban transfer of presidential duties to brother Raúl Castro, the Cuban President was questioned by international leaders and journalists on the issue whilst attending a conference in Argentina. Argentine President Néstor Kirchner took the opportunity to press the Cuban leader to allow surgeon Hilda Molina, a one-time Castro ally, to leave Cuba to be with her children and grandchildren already in Argentina.[2] At an improvised press conference, Miami's Channel 41 reporter Juan Manuel Cao asked Castro about Molina, a reportedly infuriated Castro asked the reporter, "Who is paying you?" and later accused him of being "a mercenary" for President Bush [3]. Juan Manuel Cao was later confirmed to have been one of at least ten South Florida journalists to have received regular payments from the U.S. government.[1]	https://www.wikidoc.org/index.php/Hilda_Molina
25f156d099d1fc80cd7fd19a13b82479023d6208	wikidoc	Hilton's law	Hilton's law Hilton's law is the observation that in the study of anatomy, one often finds that a nerve that innervates a joint also tends to innervate the muscles that move the joint and the skin that covers the attachments of those muscles. For example, the musculocutaneous nerve supplies the elbow joint of humans with pain and proprioception fibres. It also supplies biceps brachii, brachialis, and the forearm skin close to the insertion of each of those muscles. Hilton's law arises as a result of the embryological development of humans (or indeed other animals). # Extensions of the law Hilton's law is described above. Similar observations can be made, to extend the theory; often a nerve will supply both the muscles and skin relating to a particular joint. The observation often holds true in reverse - that is to say, a nerve that supplies skin or a muscle will often supply the applicable joint.	Hilton's law Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Hilton's law is the observation that in the study of anatomy, one often finds that a nerve that innervates a joint also tends to innervate the muscles that move the joint and the skin that covers the attachments of those muscles. For example, the musculocutaneous nerve supplies the elbow joint of humans with pain and proprioception fibres. It also supplies biceps brachii, brachialis, and the forearm skin close to the insertion of each of those muscles. Hilton's law arises as a result of the embryological development of humans (or indeed other animals). ## Extensions of the law Hilton's law is described above. Similar observations can be made, to extend the theory; often a nerve will supply both the muscles and skin relating to a particular joint. The observation often holds true in reverse - that is to say, a nerve that supplies skin or a muscle will often supply the applicable joint. Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hilton%27s_law
6b638c5a8e4a0cee3acb3f68b0d9550a068e6a56	wikidoc	Hip fracture	Hip fracture # Overview The "hip" joint is known as a ball-and-socket joint. It allows the femur bone to bend and rotate at the pelvis. Comparing to the injuries to the knee, ankle, and shoulder which are well documented, injuries to the hip, pelvis, and thigh get little attentions due to their lower prevalence. A hip fracture is a known as a fracture of the upper quarter of the femur bone while any other types of injuries to the socket, or acetabulum, itself is not considered a "hip fracture." Management of fractures to the socket is a completely different consideration. The hip fracture count as a serious problems associated with serious and life-threatening complications. Hip fractures most commonly occur due to the: - Fall to the side of the hip - A direct blow to the side of the hip - Other medical conditions such as osteoporosis, cancer, or stress injuries affecting the strength. During fracture the most common site of fracture are: - The head of the femur - The neck of the femur - Between or below the greater trochanter and the lesser trochanters # Historical Perspective There are no reliable information regarding the historical perspective of the hip bone fracture. # Causes The main etiology of the hip fracture is thought to be a loading may be placed on a leg during falling or from a direct blow to the side of the hip. The main cause of hip fracture is trauma. Such as the most fractures the hip fracture is caused by a falling or automobile accident. Meanwhile, the normal healthy bones are extremely tough and resilient and can withstand most powerful impacts. As a person age, two factors cause higher risk of fractures: - Weaker bones - Greater risk of falling Stress fractures as a common causes of fractures can be found due to the repeated stresses and strains. Importantly children having more physically active lifestyles than adults, are also prone to fractures. People with any underlying diseases such as osteoporosis, infection, or a tumor affecting their bones having a higher risk of fractures. As mentioned in previous chapters, this type of fracture is known as a pathological fracture. Stress fractures, which result from repeated stresses and strains, commonly found among professional sports people, are also common causes of fractures. ## Life-threatening Causes - There are no life-threatening causes of hip fracture , however complications resulting from hip fracture is common. ## Common Causes Common causes of hip fracture may include: - Trauma ## Less Common Causes Less common causes of hip fracture include conditions that predisposes to fracture: - Osteoporosis - Osteopenia - Malignancies ## Causes by Organ System ## Causes in Alphabetical Order List the causes of the disease in alphabetical order: - Trauma - Osteopenia - Osteoporosis # Pathophysiology ## Mechanism The hip fracture is caused by a fall or from a direct blow to the side of the hip. The form and severity of this fracture depends on the position of the hip joint at the moment of hitting the ground. The width of this mentioned angle affects the localization of the fracture. Pronation, supination and abduction positions leads the direction of the force and the compression of carpus and different appearances of injury. Its known that the hip fracture in normal healthy adults can be caused due to the high-energy trauma (e.g., motor vehicle accidents), sport related injuries, falling from height. But it should be noted that the most important Risk factors for insufficiency fractures is chronic metabolic disease such as steoporosis, osteopenia, eating-disordered behavior, higher age, prolonged corticosteroid usage, female gender, lower BMI, history of a recent falling, and prior fracture. Its been said that If the elbow is flexed during the falling, the chance of a type II or III lesion is high. ## Pathophysiology The pattern of bone fracture and severity of injury depends on variety of factors such as: - Patients age - Patients Weight - Patients past medical history specifically any bone diseases affecting the quality of bone (such as osteoporosis, malignancies) - Energy of trauma - Bone quality - Position of the specific organ during the trauma - The below-mentioned processes cause decreased bone mass density: - Autophagy is the mechanism through which osteocytes evade oxidative stress. - The capability of autophagy in cells decreases as they age, a major factor of aging. - As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density # Differentiating Hip fracture from other Diseases In the orthopedic medicine its important to know that the Hip fracture should be evaluated using radiography for both confirming diagnosis and also for evaluating the surrounding tissues. Other injuries such as possible femoral fracture-dislocation or collateral ligament injury, might be seen in Hip fracture. If the mechanism of injury suggests particularly low energy then the Osteoporosis should be considered. The pathological Fractures occurring in a bone with a tumor or Paget's disease) are rare but possible. Also it should be noted that the both bone fractures can be complicated by acute compartment syndrome. Signs suggesting compartment syndrome are pain on extension of digits, and marked edema. As another important fact in orthopedic fracture is if both-bone fractures were found in pediatric which is common after accidental trauma, but it may also be the due to the of child abuse; and in these cases a careful attention and evaluation should be considered if a child abuse is suspected. - Hip Pointer - Hip Tendonitis and Bursitis - Acetabular fracture - Snapping Hip Syndrome - Slipped Capital Femoral Epiphysis - Femoral Neck Stress Fracture - Femoral head fracture - Femoral Head Avascular Necrosis - Femoral Neck Fracture - Femoral Injuries and Fractures - Femoral Neck Fracture - Femoral shaft Fracture - Iliopsoas Tendinitis - Slipped Capital Femoral Epiphysis - Pubic rami fracture - Osteitis Pubis - Septic hip # Epidemiology and Demographics The Hip fracture is an important problem of all ages specially for the older people. It is most commonly occurs in women. The available epidemiological information differed between countries, but totally it's been globally estimated that hip fractures affect around 5%% of men and 20% of women worldwide. Also, the total number of hip fractures is predicted to increase from 1.26 million in 1990 to around 5 million by the year 2050. In the United States the hip fractures occurred in 280,000 Americans per year at a rate of over 5000 per week and it was estimated that its incidence will rise to over 500,000 annually over the next 40 years. And, this type of fracture cost the US approximately $7.2 billion annually and it is estimated that this cost will rise up to 16 billion USD annually by the year 2041. It should be noted that in the United States, the hip fracture and related mortality among persons older than 65 years of age is declining, while related comorbidities have increased. # Risk Factors The Pathophysiology of hip fractures is multifactorial, but the related risk factors for this condition can be divided into two main subgroups: risk factors decreasing bone mineral density (BMD) risk factors increasing the rate of falls Meanwhile, there are different risk factors that presidpose patient for the Hip fracture that include:: - High-risk contact sports - Higher age (elderly adults are higher prone to such fractures) - Low body frame size - Low BMI - Reduced exposure to sunlight - Direct trauma - Road / traffic accidents - Falling - Gunshot wounds - Domestic violence - Falling - Glucocorticoid use - Anabolic steroid use - Paget disease of the bone - Female sex - Alcohol and tobacco - Medical problems - Physical inactivity - Homocysteine - Osteoporosis - osteomalacia - osteopetrosis - osteogenesis imperfecta - Metastatic disorders affecting the bone system - Infection in the bone which is a rare cause of hip bone fracture. # Classification Hip fractures classified into: Intracapsular fractures (known as femoral neck fractures): 45% of all acute hip fractures in the elderly Usually due to a low-impact fall from a standing position or from twisting on a planted foot Femoral neck fractures are susceptible to malunion and avascular necrosis of the femoral head further Classification based on radiographic findings - Type 1: undisplaced and incomplete fracture - Type 2: undisplaced complete fracture - Type 3: complete fracture but incompletely displaced - Type 4: complete fracture and completely displaced Extracapsular fractures A: Intertrochanteric fracture: - Between the greater and the lesser trochanter - Common in the osteoporotic elderly population - Due to a fall from a standing height with direct contact of the lateral thigh or torsion of the lower extremity. - avascular necrosis or nonunion is rare. B: Subtronchanteric fracture: - Below the lesser trochanter, approximately 2.5 inches below - 5% due to tumor, bone cysts, or Paget’s disease. - 50% due to osteoporosis - almost all of cases have osteopenia The most common types of the hip fractures : - Femoral neck fracture: common among older adults and related to osteoporosis. Complication: cuts off the blood supply to the head of the femur which forms the hip joint. - Intertrochanteric hip fracture: An intertrochanteric hip fracture occurs three to four inches from the hip joint. Complication: Normally does not interrupt the blood supply to the hip joint. # Screening Osteoporosis is an important risk factor for human affecting human bone especially in men with the age of older than 50 years old and postmenopausal and women. Based on the US Preventive Services Task Force (USPSTF) there are three groups of patients need to be screened for the osteoporosis: - · Men with no history of osteoporosis - · Women with the age of 65≤ year old, with no previous history of pathological fracture due to the osteoporosis - · Women with the age of <65 years, with 10-year fracture risk of not less than a 65-year-old white woman (who has not any other risk factor) Accordingly women older than age of 50 are the main target for the osteoporosis screening. There is no specific recommendation to screen men for the osteoporosis. The USPSTF recommendations from 2002 included: Meanwhile, there are two major modalities for the osteoporosis screening: - · Dual energy x-ray absorptiometry (DXA) of the hip and lumbar spine bones - · Quantitative ultrasonography of the calcaneus *It should be noted of the two above mentioned modalities for screening the ultrasonograhy is preferred to the DXA due to its lower cost, lower ionizing radiation, more availability. After the primary evaluation of the osteoporosis, the further evaluation are required in some cases such as: · Women with normal bone density or mild osteopenia: T-score of greater than −1.50 – should have screening for 15 years. · Women with moderate osteopenia: T-score of −1.50 to −1.99 – should have screening for 5 years. · Women with advanced osteopenia: T-score of −2.00 to −2.49 - should have screening for 1 year. # Natural History, Complications and Prognosis ## Natural History - In cases with untreated hip fractures the malunion and deformity of HIP joint can be occurred. ## Complication The type and frequency of complications of the hip fractures varies. The main complication of the hip fractures is the high risk of re-fracture due to their instability. In general the following are the most common complications of the hip fractures : - Infection of the bone - Infection of soft tissue - Compartment syndrome - Non-union of the fracture - Mal-union - Arm shortening - Nerve Damage - Vascular injury - Vascular bleeding - Re-fracture - Decreased Motion - Painful movement ## Prognosis Generally, the hip fractures carry an approximately 30% risk of mortality at 1 year also around 25% to 75% of adults may not reach their pre-fracture functional level. Most of the hip fractures heal well with no functional or gross problems in the appearance of the injured bone. But, proper immobilized and proper orthopedic follow-up are required due to the higher risk of re-fracture, complete fracture and displacement of the fracture. The followoing mentioned factores affect the patients mortality rate: comorbid disease, low pre-injury cognitive function, abnormal preoperative ECG, age >85 years, and decreased pre-fracture mobility. # History and Symptoms The diagnosis of a hip fracture is based on: patient history, physical examination, and radiography. The related signs and symptoms include: - Deformity - Skin lacerations - Weak pulse - Open fractures - Bruising - Swelling - Stiffness - Inability to move - Pain in touch - Loss of function of the leg - Difficulties in detection of pulses - An antalgic gait pattern In the physical exam the orthopedic surgeon should check the vascular status and amount of swelling in the leg. In MULTI-trauma patients or a tense compartment with neurological signs or stretch pain should be considered as the compartment syndrome, and the compartment pressures should be measured and monitored. # Physical Examination The related signs and symptoms include: - Inability to move - Pain in hip or groin - Inability to put weight on the involved leg - Stiffness in and around injured hip area - bruising in and around injured hip area - swelling in and around injured hip area - Shorter leg on the side of injured hip - Edema around injured hip area Most of the time the edema will be a non-pitting edema Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of leg - Most of the time the edema will be a non-pitting edema - Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of leg - Bruising As a manifestation of internal injury to the local vessels by trauma or fractures bone - As a manifestation of internal injury to the local vessels by trauma or fractures bone - Decrease in range of motion Movement of the fractures limb will be painful if possible at all - Movement of the fractures limb will be painful if possible at all - Tenderness - Deformity Fractured bone deformity may be touchable in the internal side of the leg if the fracture is displaced - Fractured bone deformity may be touchable in the internal side of the leg if the fracture is displaced Physical examination of patients with hip fractures is usually remarkable for swelling, tenderness, bruises, ecchymosis, deformity and restricted range of motion of the leg. ## Appearance of the Patient - Patients with hip fractures usually appears normal unless the patients had a high energy trauma causing the open wound fracture. ## Vital Signs - Weak pulse may be seen when associated with polytrauma. - Low blood pressure with normal pulse pressure may be present due to compound fracture with blood loss. ## Skin - Skin examination of patients with hip fractures includes: Bruises Ecchymosis - Bruises - Ecchymosis ## HEENT - HEENT examination of patients withhip fractures is usually normal. ## Neck - Neck examination of patients with hip fractures is normal. ## Lungs - Pulmonary examination of patients with hip fractures is usually normal. ## Heart - Cardiovascular examination of patients with hip fractures is usually normal. ## Abdomen - Abdominal examination of patients with hip fractures is usually normal. ## Back - Back examination of patients with hip fractures is usually normal. ## Genitourinary - Genitourinary examination of patients with hip fractures is usually normal. ## Neuromuscular - Neuromuscular examination of patients with hip fractures is usually normal. - However, some patients may develop neuropraxia of the branch of the Ulnar nerve resulting in decreased sensation of fingers. # Laboratory Findings There is a limited laboratory tests useful in the diagnosis of bone fractures such as hip fractures Meanwhile, aged men and women may have some abnormalities in their laboratory findings suggestive of osteoporosis. - Laboratory tests for the diagnosis of osteoporosis are: - Complete blood count (CBC) - Serum total calcium level - Serum Ionized calcium level - Serum phosphate level - Serum alkaline phosphatase level - Serum 25-(OH)-vitamin D level # X Ray The orthopedic surgeon should consider to have at least two radiographic projections (ie, anteroposterior and lateral) of the hip. These show the fracture, the extent of displacement, and the extent of comminution. The orthopedic surgeon should pay serious attention toward finding any foreign bodies in open fractures and gunshot injuries. Also imperative is to include the hip joint in the radiographs of hip fractures to ensure that the distal radioulnar joint injuries are not missed A tuberosity view is helpfull ascertain the rotational displacement of the fracture. Also, it would be helpful for the orthopedic surgeon in planning how much supination or pronation is needed to achieve accurate anatomic reduction. The ulna is laid flat on the cassette with its subcutaneous border in contact with the cassette; the x-ray tube is tilted toward the olecranon by 20°. This radiograph is then compared with a standard set of diagrams that show the prominence of the radial tuberosity in various degrees of pronation and supination in order to determine the scope of the rotational deformity - Fracture at the base of the right femoral neck. - Fracture at the base of the right femoral neck. - Fracture at the base of the right femoral neck. # CT - CT-scan in the case of Hip fracture is the best modality if you can not have an exclusive diagnosis by X-ray itself can not be made. - Its been reported that the articular fractures of the distal radius were statistically more likely to occur at the intervals between the ligament attachments than at the ligament attachments. - The most common fracture sites were the center of the sigmoid notch, between the short and long radiolunate ligaments, and the central and ulnar aspects of the scaphoid fossa dorsally. These results suggest that CT may be used to identify the subsequent propagation of the fracture and the likely site of the impaction of the carpus on the distal radius articular surface. - Fracture-dislocation of hip. CT scan shows posterior dislocation of femoral head associated with fracture of both anterior and posterior columns of acetabulum. - Coronal non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - Axial non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - Sagittal non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - 3D. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - Coronal non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. # MRI Magnetic resonance imaging (MRI) is an expensive technique that should not be used routinely. MRI is a powerful diagnostic tool to assess the abnormalities of the bone, ligaments and soft tissues associated with the Hip fractures, but it is known as a limited utility in radioulnar injuries and is not indicated in uncomplicated hip fractures. Meanwhile, the MRI can be useful in in following mentioned evaluations: Evaluation of occult fractures Evaluation of the post-traumatic or avascular necrosis of bones Evaluation of tendons Evaluation of nerve Evaluation of carpal tunnel syndrome - Coronal T1 Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. - Coronal T2 fat sat Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. - Coronal Axial T2 fat sat Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. - Coronal Sagittal T2 fat sat Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. # Other Imaging Findings There are no other imaging findings associated with Hip fracture. # Other Diagnostic Studies There are no other imaging findings associated with Hip fracture. # Treatment The first step in managing a patient with a fracture is to stabilize the patient if he/she is unstable due to blood loss, etc by giving them intravenous fluids and giving them some painkillers if the pain is severe. If only one bone is broken, using cast or brace might be a possible treatment option. The hip fracture management is usually a combination of surgery and rehabilitation. It also depends on the location of the fracture and whether that fracture is displaced. Specific types of hip fractures can be considered stable enough to be managed with nonsurgical treatment. ## Non-surgical therapy - The first step in managing a patient with a fracture is to stabilize the patient if he/she is unstable due to blood loss, etc by giving them intravenous fluids and giving them some painkillers if the pain is severe. - In children, the usual plan is to attempt closed reduction followed by cast immobilization. In adults, treatment with immobilization in a molded long arm cast can be used in those rare occasions of a non-displaced fracture of the leg bone. If the fracture shifts in position, it may require surgery to put the bones back together. - Rigid immobilization is suggested in preference to removable splints in nonoperative treatment for the management of Hip bone fractures. - For all patients with Hip fractures, a post-reduction true lateral radiograph is suggested . - Patients probably do not need to begin early leg motion routinely after stable fracture fixation. - Adjuvant treatment of Hip fractures with vitamin C is suggested for the prevention of disproportionate pain. - If operative treatment is refused or the risks of surgery are considered to be too high the main emphasis of treatment is on pain relief. Skeletal traction may be considered for long term treatment. - Shortened left leg due to displacement of the femoral head superiorly and severe degenerative changes of the hip joint. The femoral head and neck have lost their normal anatomical configuration and morphology due to callus formation. Left greater trochanter is several centimeters higher when compared to the contralateral side. ## Complications of Non-surgical therapy Failure of non-surgical therapy is common: - Re-displacement to its original position even in a cast - Stiffness - Post traumatic osteoarthritis leading to hip pain and loss of function - Other risks specific to cast treatment include: Compression of the swollen leg causing compartment syndrome Reflex sympathetic dystrophy is a serious complication Stiffness is universal following a prolonged period of immobilization and swelling DVT/pulmonary embolism Pressure sores and - Compression of the swollen leg causing compartment syndrome - Reflex sympathetic dystrophy is a serious complication - Stiffness is universal following a prolonged period of immobilization and swelling - DVT/pulmonary embolism - Pressure sores and # Surgery - Treatment of Hip fractures is important. Important complications such as avascular necrosis and non-union are very common without surgical intervention. The treatment options include non-operative management, internal fixation or prosthetic replacement. - There are a variety of methods and implants useful to stabilize the Hip bone fracture, ranging from closed reduction and percutaneous pin fixation to the use of intra-medullary devices. - However, the most common fixation methods to treat complex Hip fracture include external fixation, and open reduction and internal fixation. - A minimally displaced periprosthetic fracture is visible around the lateral aspect of the stem of the prosthesis, corresponding to a Vancouver B1 fracture (see key image). Porotic bone structure. Incidentally an inhomogenous calcified mass is visible in the pelvis. - Vancouver type B2 periprosthetic femur fracture of the right hip. - The right hip hemiarthroplasty is normally aligned and uncomplicated. There is a segment (approx 10cm) of disconnected surgical drain tubing in the lateral soft tissues of the left hip. Mild left hip osteoarthritis. ## External Fixation With or Without Percutaneous Pin Fixation - Spanning external fixation employs ligamentotaxis to restore and maintain length, alignment, and rotation of bone. - Reduction is typically obtained through closed or minimally open methods and preserves the fracture biology. - The addition of percutaneous pins enhances the ability to reduce and stabilize fracture fragments. ### Complications of External Fixation - Pin tract infection - Injury to the superficial branch of the nerve - Complex regional pain syndrome ## Open reduction and internal fixation with plates and screws - This is the most common type of surgical repair for Hip Fracture - During this type of procedure, the bone fragments are first repositioned (reduced) into their normal alignment. - The bones held together with special screws and metal plates attached to the outer surface of the bone. ### Complications of open reduction and internal fixation with plates and screws - Infection - Damage to nerves and blood vessels - Synostosis - Nonunion ## Pain Management Pain after an injury or surgery is a natural part of the healing process. Medications are often prescribed for short-term pain relief after surgery or an injurysuch as: - opioids - non-steroidal anti-inflammatory drugs (NSAIDs) - local anesthetics ## Be aware that although opioids help relieve pain after surgery or an injury, they are a narcotic and can be addictive. It is important to use opioids only as directed by doctor. ## Interventions The following options can be helpful for patients to rehabilitate after their fracture : - Joints mobilization - compression bandage - Soft tissue massage - Exercises and Activity modification ## Postoperative Rehabilitation - Complex Hip fracture warrant individualized immobilization and rehabilitation strategies. - Because some Hip bone fractures are the result of high-energy injuries, a prolonged period of leg immobilization and soft-tissue rest may be beneficial and has not been shown to affect clinical outcomes. - The hip is typically immobilized for 2 weeks post-operatively in a sugar tong splint with neutral leg rotation. - Full weight bearing exercises at approximately 3 months post-operatively - The presence of varying degrees of Hip area stiffness is inevitable and may result from poor pain control, lack of effort in controlled mobilization, edema, concomitant ipsilateral upper extremity fractures, or peripheral nerve injuries. - Internal rotation from hip flexion - Avoiding the impact activities for six weeks postoperative - unloaded or partially loaded mobilize postoperatively crucial to the joint with active and passive range of motion (ROM) based on the surgical procedure - Avoiding straight leg raise for 4 weeks postoperatively - Cardiovascular training is important - Hip flexion greater than 70–90° - External rotation of the leg - Adduction of the leg past midline - Should not bend forward from the waist more than 90 - Early stretching and mobilization of the intrinsic and extrinsic tendons of the hand is important to prevent finger stiffness. - Edema control can be initiated with compression gloves, digital massage, and active and passive ROM of the leg. - A home exercise program or outpatient occupational therapy is started immediately post-operatively to maintain full range of motion of the leg and limit the development of intrinsic muscle tightness # Primary Prevention There are various preventive options to reduce the incidence of the Hip bone fracture-dislocation - Using suitable hip joint guards during practicing sports (skating, biking) and/or driving motorbikes - Avoid falls in elderly individuals - Prevention and/or treatment of osteoporosis - Healthy diet # Secondary Prevention It should be noted that the Post-menopausal women specially older than the age of 65 are at the higher risk of osteoporosis consequently these type of patients at greater risk for the pathological fractures . So the Calcium and vitamin D supplementation play important role in increasing the bone mineral density (BMD) consequently decrease the risk of fracture in these type of patients. Also, avoiding excessive alcohol and quitting smoking play important role in this regard. ## Detecting osteoporosis - DEXA(dual-energy x-ray absorptiometry) scan - Serum calcium and vitamin D levels - Ultrasonography of the calcaneus ## Pharmacological therapy - The primary goal for the treatment of osteoporosis is to reduce longtime fracture risk in patients. Increasing bone mineral density (BMD) in response to the treatment is far less important than improvement of clinical aspects of osteoporosis, i.e., osteoporotic fracture. Therefore, most of the drugs efficacy is measured by the extent they improve the fracture risk instead of increasing BMD. - During the treatment, if a single fracture happens, it does not necessarily indicate treatment failure or the need to be started on an alternative treatment or patient referral to a specialist. - Calcium and vitamin D supplementation have been found to be effective in reducing the long term fracture risk, significantly. In order to suggest the people to use vitamin D and calcium supplements, the physician needs to make sure that patient is not able to obtain the nutrients through the daily intake. The available supplemental ions of calcium include calcium carbonate, calcium citrate, and vitamin D3 in various dosage forms. ## Life style modifications - Exercise: Exercise promotes the mineralization of bone and bone accumulation particularly during growth. High impact exercise, in particular, has been shown to prevent the development of osteoporosis. However, it can have a negative effect on bone mineralization in cases of poor nutrition, such as anorexia nervosa and celiac disease. - Nutrition: A diet high in calcium and vitamin D prevents bone loss. Patients at risk for osteoporosis, such as persons with chronic steroid use are generally treated with vitamin D and calcium supplementation. In renal disease, more active forms of vitamin D, such as 1,25-dihydroxycholecalciferol or calcitriol are used; as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol), which is the storage form of vitamin D. - By quitting smoking, osteoporosis as well as other diseases can be prevented. - Avoiding excessive alcohol intake or drinking only in moderation (1–2 alcoholic beverages/day). - Taking least possible dosages of certain medications that are associated with osteoporosis (anticonvulsants or corticosteroids).	Hip fracture Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2]. # Overview [1][2][3] The "hip" joint is known as a ball-and-socket joint. It allows the femur bone to bend and rotate at the pelvis. Comparing to the injuries to the knee, ankle, and shoulder which are well documented, injuries to the hip, pelvis, and thigh get little attentions due to their lower prevalence. A hip fracture is a known as a fracture of the upper quarter of the femur bone while any other types of injuries to the socket, or acetabulum, itself is not considered a "hip fracture." Management of fractures to the socket is a completely different consideration. The hip fracture count as a serious problems associated with serious and life-threatening complications. Hip fractures most commonly occur due to the: - Fall to the side of the hip - A direct blow to the side of the hip - Other medical conditions such as osteoporosis, cancer, or stress injuries affecting the strength. During fracture the most common site of fracture are: - The head of the femur - The neck of the femur - Between or below the greater trochanter and the lesser trochanters # Historical Perspective There are no reliable information regarding the historical perspective of the hip bone fracture. # Causes [4][5][6][7][8][9][1] The main etiology of the hip fracture is thought to be a loading may be placed on a leg during falling or from a direct blow to the side of the hip. The main cause of hip fracture is trauma. Such as the most fractures the hip fracture is caused by a falling or automobile accident. Meanwhile, the normal healthy bones are extremely tough and resilient and can withstand most powerful impacts. As a person age, two factors cause higher risk of fractures: - Weaker bones - Greater risk of falling Stress fractures as a common causes of fractures can be found due to the repeated stresses and strains. Importantly children having more physically active lifestyles than adults, are also prone to fractures. People with any underlying diseases such as osteoporosis, infection, or a tumor affecting their bones having a higher risk of fractures. As mentioned in previous chapters, this type of fracture is known as a pathological fracture. Stress fractures, which result from repeated stresses and strains, commonly found among professional sports people, are also common causes of fractures. ## Life-threatening Causes - There are no life-threatening causes of hip fracture , however complications resulting from hip fracture is common. ## Common Causes Common causes of hip fracture may include: - Trauma ## Less Common Causes Less common causes of hip fracture include conditions that predisposes to fracture: - Osteoporosis - Osteopenia - Malignancies ## Causes by Organ System ## Causes in Alphabetical Order List the causes of the disease in alphabetical order: - Trauma - Osteopenia - Osteoporosis # Pathophysiology[7][5][10][11][12][13] ## Mechanism [14] The hip fracture is caused by a fall or from a direct blow to the side of the hip. The form and severity of this fracture depends on the position of the hip joint at the moment of hitting the ground. The width of this mentioned angle affects the localization of the fracture. Pronation, supination and abduction positions leads the direction of the force and the compression of carpus and different appearances of injury. Its known that the hip fracture in normal healthy adults can be caused due to the high-energy trauma (e.g., motor vehicle accidents), sport related injuries, falling from height. But it should be noted that the most important Risk factors for insufficiency fractures is chronic metabolic disease such as steoporosis, osteopenia, eating-disordered behavior, higher age, prolonged corticosteroid usage, female gender, lower BMI, history of a recent falling, and prior fracture. Its been said that If the elbow is flexed during the falling, the chance of a type II or III lesion is high. ## Pathophysiology [15][14] The pattern of bone fracture and severity of injury depends on variety of factors such as: - Patients age - Patients Weight - Patients past medical history specifically any bone diseases affecting the quality of bone (such as osteoporosis, malignancies) - Energy of trauma - Bone quality - Position of the specific organ during the trauma - The below-mentioned processes cause decreased bone mass density: - Autophagy is the mechanism through which osteocytes evade oxidative stress. - The capability of autophagy in cells decreases as they age, a major factor of aging. - As osteocytes grow, viability of cells decrease thereby decreasing the bone mass density # Differentiating Hip fracture from other Diseases[16][14][13][12] In the orthopedic medicine its important to know that the Hip fracture should be evaluated using radiography for both confirming diagnosis and also for evaluating the surrounding tissues. Other injuries such as possible femoral fracture-dislocation or collateral ligament injury, might be seen in Hip fracture. If the mechanism of injury suggests particularly low energy then the Osteoporosis should be considered. The pathological Fractures occurring in a bone with a tumor or Paget's disease) are rare but possible[3]. Also it should be noted that the both bone fractures can be complicated by acute compartment syndrome. Signs suggesting compartment syndrome are pain on extension of digits, and marked edema[3]. As another important fact in orthopedic fracture is if both-bone fractures were found in pediatric which is common after accidental trauma, but it may also be the due to the of child abuse; and in these cases a careful attention and evaluation should be considered if a child abuse is suspected. - Hip Pointer - Hip Tendonitis and Bursitis - Acetabular fracture - Snapping Hip Syndrome - Slipped Capital Femoral Epiphysis - Femoral Neck Stress Fracture - Femoral head fracture - Femoral Head Avascular Necrosis - Femoral Neck Fracture - Femoral Injuries and Fractures - Femoral Neck Fracture - Femoral shaft Fracture - Iliopsoas Tendinitis - Slipped Capital Femoral Epiphysis - Pubic rami fracture - Osteitis Pubis - Septic hip # Epidemiology and Demographics[17][18][19][20] The Hip fracture is an important problem of all ages specially for the older people. It is most commonly occurs in women. The available epidemiological information differed between countries, but totally it's been globally estimated that hip fractures affect around 5%% of men and 20% of women worldwide. Also, the total number of hip fractures is predicted to increase from 1.26 million in 1990 to around 5 million by the year 2050. In the United States the hip fractures occurred in 280,000 Americans per year at a rate of over 5000 per week and it was estimated that its incidence will rise to over 500,000 annually over the next 40 years. And, this type of fracture cost the US approximately $7.2 billion annually and it is estimated that this cost will rise up to 16 billion USD annually by the year 2041. It should be noted that in the United States, the hip fracture and related mortality among persons older than 65 years of age is declining, while related comorbidities have increased. # Risk Factors [21][22][23][24][25][26][11] The Pathophysiology of hip fractures is multifactorial, but the related risk factors for this condition can be divided into two main subgroups: risk factors decreasing bone mineral density (BMD) risk factors increasing the rate of falls Meanwhile, there are different risk factors that presidpose patient for the Hip fracture that include:: - High-risk contact sports - Higher age (elderly adults are higher prone to such fractures) - Low body frame size - Low BMI - Reduced exposure to sunlight - Direct trauma - Road / traffic accidents - Falling - Gunshot wounds - Domestic violence - Falling - Glucocorticoid use - Anabolic steroid use - Paget disease of the bone - Female sex - Alcohol and tobacco - Medical problems - Physical inactivity - Homocysteine - Osteoporosis - osteomalacia - osteopetrosis - osteogenesis imperfecta - Metastatic disorders affecting the bone system - Infection in the bone which is a rare cause of hip bone fracture. # Classification [27][28][29][30][31][26] Hip fractures classified into: Intracapsular fractures (known as femoral neck fractures): 45% of all acute hip fractures in the elderly Usually due to a low-impact fall from a standing position or from twisting on a planted foot Femoral neck fractures are susceptible to malunion and avascular necrosis of the femoral head further Classification based on radiographic findings - Type 1: undisplaced and incomplete fracture - Type 2: undisplaced complete fracture - Type 3: complete fracture but incompletely displaced - Type 4: complete fracture and completely displaced Extracapsular fractures A: Intertrochanteric fracture: - Between the greater and the lesser trochanter - Common in the osteoporotic elderly population - Due to a fall from a standing height with direct contact of the lateral thigh or torsion of the lower extremity. - avascular necrosis or nonunion is rare. B: Subtronchanteric fracture: - Below the lesser trochanter, approximately 2.5 inches below - 5% due to tumor, bone cysts, or Paget’s disease. - 50% due to osteoporosis - almost all of cases have osteopenia The most common types of the hip fractures : - Femoral neck fracture: common among older adults and related to osteoporosis. Complication: cuts off the blood supply to the head of the femur which forms the hip joint. - Intertrochanteric hip fracture: An intertrochanteric hip fracture occurs three to four inches from the hip joint. Complication: Normally does not interrupt the blood supply to the hip joint. # Screening [32][14][33] Osteoporosis is an important risk factor for human affecting human bone especially in men with the age of older than 50 years old and postmenopausal and women. Based on the US Preventive Services Task Force (USPSTF) there are three groups of patients need to be screened for the osteoporosis: - · Men with no history of osteoporosis - · Women with the age of 65≤ year old, with no previous history of pathological fracture due to the osteoporosis - · Women with the age of <65 years, with 10-year fracture risk of not less than a 65-year-old white woman (who has not any other risk factor) Accordingly women older than age of 50 are the main target for the osteoporosis screening. There is no specific recommendation to screen men for the osteoporosis. The USPSTF recommendations from 2002 included: Meanwhile, there are two major modalities for the osteoporosis screening: - · Dual energy x-ray absorptiometry (DXA) of the hip and lumbar spine bones - · Quantitative ultrasonography of the calcaneus *It should be noted of the two above mentioned modalities for screening the ultrasonograhy is preferred to the DXA due to its lower cost, lower ionizing radiation, more availability. After the primary evaluation of the osteoporosis, the further evaluation are required in some cases such as: · Women with normal bone density or mild osteopenia: T-score of greater than −1.50 – should have screening for 15 years. · Women with moderate osteopenia: T-score of −1.50 to −1.99 – should have screening for 5 years. · Women with advanced osteopenia: T-score of −2.00 to −2.49 - should have screening for 1 year. # Natural History, Complications and Prognosis[31][29][34][32] ## Natural History - In cases with untreated hip fractures the malunion and deformity of HIP joint can be occurred. ## Complication The type and frequency of complications of the hip fractures varies. The main complication of the hip fractures is the high risk of re-fracture due to their instability. In general the following are the most common complications of the hip fractures : - Infection of the bone - Infection of soft tissue - Compartment syndrome - Non-union of the fracture - Mal-union - Arm shortening - Nerve Damage - Vascular injury - Vascular bleeding - Re-fracture - Decreased Motion - Painful movement ## Prognosis Generally, the hip fractures carry an approximately 30% risk of mortality at 1 year also around 25% to 75% of adults may not reach their pre-fracture functional level. Most of the hip fractures heal well with no functional or gross problems in the appearance of the injured bone. But, proper immobilized and proper orthopedic follow-up are required due to the higher risk of re-fracture, complete fracture and displacement of the fracture. The followoing mentioned factores affect the patients mortality rate: comorbid disease, low pre-injury cognitive function, abnormal preoperative ECG, age >85 years, and decreased pre-fracture mobility. # History and Symptoms The diagnosis of a hip fracture is based on: patient history, physical examination, and radiography. The related signs and symptoms include: - Deformity - Skin lacerations - Weak pulse - Open fractures - Bruising - Swelling - Stiffness - Inability to move - Pain in touch - Loss of function of the leg - Difficulties in detection of pulses - An antalgic gait pattern In the physical exam the orthopedic surgeon should check the vascular status and amount of swelling in the leg. In MULTI-trauma patients or a tense compartment with neurological signs or stretch pain should be considered as the compartment syndrome, and the compartment pressures should be measured and monitored. # Physical Examination[35] The related signs and symptoms include: - Inability to move - Pain in hip or groin - Inability to put weight on the involved leg - Stiffness in and around injured hip area - bruising in and around injured hip area - swelling in and around injured hip area - Shorter leg on the side of injured hip - Edema around injured hip area Most of the time the edema will be a non-pitting edema Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of leg - Most of the time the edema will be a non-pitting edema - Depends on the edema extent, it may even lead to compartment syndrome in the anterior and internal compartment of leg - Bruising As a manifestation of internal injury to the local vessels by trauma or fractures bone - As a manifestation of internal injury to the local vessels by trauma or fractures bone - Decrease in range of motion Movement of the fractures limb will be painful if possible at all - Movement of the fractures limb will be painful if possible at all - Tenderness - Deformity Fractured bone deformity may be touchable in the internal side of the leg if the fracture is displaced - Fractured bone deformity may be touchable in the internal side of the leg if the fracture is displaced Physical examination of patients with hip fractures is usually remarkable for swelling, tenderness, bruises, ecchymosis, deformity and restricted range of motion of the leg. ## Appearance of the Patient - Patients with hip fractures usually appears normal unless the patients had a high energy trauma causing the open wound fracture. ## Vital Signs - Weak pulse may be seen when associated with polytrauma. - Low blood pressure with normal pulse pressure may be present due to compound fracture with blood loss. ## Skin - Skin examination of patients with hip fractures includes: Bruises Ecchymosis - Bruises - Ecchymosis ## HEENT - HEENT examination of patients withhip fractures is usually normal. ## Neck - Neck examination of patients with hip fractures is normal. ## Lungs - Pulmonary examination of patients with hip fractures is usually normal. ## Heart - Cardiovascular examination of patients with hip fractures is usually normal. ## Abdomen - Abdominal examination of patients with hip fractures is usually normal. ## Back - Back examination of patients with hip fractures is usually normal. ## Genitourinary - Genitourinary examination of patients with hip fractures is usually normal. ## Neuromuscular - Neuromuscular examination of patients with hip fractures is usually normal. - However, some patients may develop neuropraxia of the branch of the Ulnar nerve resulting in decreased sensation of fingers. # Laboratory Findings[36] There is a limited laboratory tests useful in the diagnosis of bone fractures such as hip fractures Meanwhile, aged men and women may have some abnormalities in their laboratory findings suggestive of osteoporosis. - Laboratory tests for the diagnosis of osteoporosis are: - Complete blood count (CBC) - Serum total calcium level - Serum Ionized calcium level - Serum phosphate level - Serum alkaline phosphatase level - Serum 25-(OH)-vitamin D level # X Ray[37][38][39][35] The orthopedic surgeon should consider to have at least two radiographic projections (ie, anteroposterior [AP] and lateral) of the hip. These show the fracture, the extent of displacement, and the extent of comminution. The orthopedic surgeon should pay serious attention toward finding any foreign bodies in open fractures and gunshot injuries. Also imperative is to include the hip joint in the radiographs of hip fractures to ensure that the distal radioulnar joint injuries are not missed A tuberosity view is helpfull ascertain the rotational displacement of the fracture. Also, it would be helpful for the orthopedic surgeon in planning how much supination or pronation is needed to achieve accurate anatomic reduction. The ulna is laid flat on the cassette with its subcutaneous border in contact with the cassette; the x-ray tube is tilted toward the olecranon by 20°. This radiograph is then compared with a standard set of diagrams that show the prominence of the radial tuberosity in various degrees of pronation and supination in order to determine the scope of the rotational deformity - Fracture at the base of the right femoral neck. - Fracture at the base of the right femoral neck. - Fracture at the base of the right femoral neck. # CT[38][40][35] - CT-scan in the case of Hip fracture is the best modality if you can not have an exclusive diagnosis by X-ray itself can not be made. - Its been reported that the articular fractures of the distal radius were statistically more likely to occur at the intervals between the ligament attachments than at the ligament attachments. - The most common fracture sites were the center of the sigmoid notch, between the short and long radiolunate ligaments, and the central and ulnar aspects of the scaphoid fossa dorsally. These results suggest that CT may be used to identify the subsequent propagation of the fracture and the likely site of the impaction of the carpus on the distal radius articular surface. - Fracture-dislocation of hip. CT scan shows posterior dislocation of femoral head associated with fracture of both anterior and posterior columns of acetabulum. - Coronal non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - Axial non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - Sagittal non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - 3D. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. - Coronal non-contrast. Comminuted intertrochanteric fracture involving the left proximal femur with internal rotation the femur following a road traffic accident. # MRI[40][41][35] Magnetic resonance imaging (MRI) is an expensive technique that should not be used routinely. MRI is a powerful diagnostic tool to assess the abnormalities of the bone, ligaments and soft tissues associated with the Hip fractures, but it is known as a limited utility in radioulnar injuries and is not indicated in uncomplicated hip fractures. Meanwhile, the MRI can be useful in in following mentioned evaluations: Evaluation of occult fractures Evaluation of the post-traumatic or avascular necrosis of bones Evaluation of tendons Evaluation of nerve Evaluation of carpal tunnel syndrome - Coronal T1 Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. - Coronal T2 fat sat Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. - Coronal Axial T2 fat sat Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. - Coronal Sagittal T2 fat sat Extensive marrow edema within the femoral head and neck. There is a subchondral fracture within the femoral head. # Other Imaging Finding[35]s There are no other imaging findings associated with Hip fracture. # Other Diagnostic Studies[35] There are no other imaging findings associated with Hip fracture. # Treatment [42][43][1][3] The first step in managing a patient with a fracture is to stabilize the patient if he/she is unstable due to blood loss, etc by giving them intravenous fluids and giving them some painkillers if the pain is severe. If only one bone is broken, using cast or brace might be a possible treatment option. The hip fracture management is usually a combination of surgery and rehabilitation. It also depends on the location of the fracture and whether that fracture is displaced. Specific types of hip fractures can be considered stable enough to be managed with nonsurgical treatment. ## Non-surgical therapy [42][44][43][1][3] - The first step in managing a patient with a fracture is to stabilize the patient if he/she is unstable due to blood loss, etc by giving them intravenous fluids and giving them some painkillers if the pain is severe. - In children, the usual plan is to attempt closed reduction followed by cast immobilization. In adults, treatment with immobilization in a molded long arm cast can be used in those rare occasions of a non-displaced fracture of the leg bone. If the fracture shifts in position, it may require surgery to put the bones back together. - Rigid immobilization is suggested in preference to removable splints in nonoperative treatment for the management of Hip bone fractures. - For all patients with Hip fractures, a post-reduction true lateral radiograph is suggested . - Patients probably do not need to begin early leg motion routinely after stable fracture fixation. - Adjuvant treatment of Hip fractures with vitamin C is suggested for the prevention of disproportionate pain. - If operative treatment is refused or the risks of surgery are considered to be too high the main emphasis of treatment is on pain relief. Skeletal traction may be considered for long term treatment. - Shortened left leg due to displacement of the femoral head superiorly and severe degenerative changes of the hip joint. The femoral head and neck have lost their normal anatomical configuration and morphology due to callus formation. Left greater trochanter is several centimeters higher when compared to the contralateral side. ## Complications of Non-surgical therapy Failure of non-surgical therapy is common: - Re-displacement to its original position even in a cast - Stiffness - Post traumatic osteoarthritis leading to hip pain and loss of function - Other risks specific to cast treatment include: Compression of the swollen leg causing compartment syndrome Reflex sympathetic dystrophy is a serious complication Stiffness is universal following a prolonged period of immobilization and swelling DVT/pulmonary embolism Pressure sores and - Compression of the swollen leg causing compartment syndrome - Reflex sympathetic dystrophy is a serious complication - Stiffness is universal following a prolonged period of immobilization and swelling - DVT/pulmonary embolism - Pressure sores and # Surgery [45][25][15][42][43][3][1] - Treatment of Hip fractures is important. Important complications such as avascular necrosis and non-union are very common without surgical intervention. The treatment options include non-operative management, internal fixation or prosthetic replacement. - There are a variety of methods and implants useful to stabilize the Hip bone fracture, ranging from closed reduction and percutaneous pin fixation to the use of intra-medullary devices. - However, the most common fixation methods to treat complex Hip fracture include external fixation, and open reduction and internal fixation. - A minimally displaced periprosthetic fracture is visible around the lateral aspect of the stem of the prosthesis, corresponding to a Vancouver B1 fracture (see key image). Porotic bone structure. Incidentally an inhomogenous calcified mass is visible in the pelvis. - Vancouver type B2 periprosthetic femur fracture of the right hip. - The right hip hemiarthroplasty is normally aligned and uncomplicated. There is a segment (approx 10cm) of disconnected surgical drain tubing in the lateral soft tissues of the left hip. Mild left hip osteoarthritis. ## External Fixation With or Without Percutaneous Pin Fixation - Spanning external fixation employs ligamentotaxis to restore and maintain length, alignment, and rotation of bone. - Reduction is typically obtained through closed or minimally open methods and preserves the fracture biology. - The addition of percutaneous pins enhances the ability to reduce and stabilize fracture fragments. ### Complications of External Fixation - Pin tract infection - Injury to the superficial branch of the nerve - Complex regional pain syndrome ## Open reduction and internal fixation with plates and screws - This is the most common type of surgical repair for Hip Fracture - During this type of procedure, the bone fragments are first repositioned (reduced) into their normal alignment. - The bones held together with special screws and metal plates attached to the outer surface of the bone. - ### Complications of open reduction and internal fixation with plates and screws - Infection - Damage to nerves and blood vessels - Synostosis - Nonunion ## Pain Management[46] Pain after an injury or surgery is a natural part of the healing process. Medications are often prescribed for short-term pain relief after surgery or an injurysuch as: - opioids - non-steroidal anti-inflammatory drugs (NSAIDs) - local anesthetics ## Be aware that although opioids help relieve pain after surgery or an injury, they are a narcotic and can be addictive. It is important to use opioids only as directed by doctor. ## Interventions [8][47] The following options can be helpful for patients to rehabilitate after their fracture : - Joints mobilization - compression bandage - Soft tissue massage - Exercises and Activity modification ## Postoperative Rehabilitation [48][49][50][8] [47][46] - Complex Hip fracture warrant individualized immobilization and rehabilitation strategies. - Because some Hip bone fractures are the result of high-energy injuries, a prolonged period of leg immobilization and soft-tissue rest may be beneficial and has not been shown to affect clinical outcomes. - The hip is typically immobilized for 2 weeks post-operatively in a sugar tong splint with neutral leg rotation. - Full weight bearing exercises at approximately 3 months post-operatively - The presence of varying degrees of Hip area stiffness is inevitable and may result from poor pain control, lack of effort in controlled mobilization, edema, concomitant ipsilateral upper extremity fractures, or peripheral nerve injuries. - Internal rotation from hip flexion - Avoiding the impact activities for six weeks postoperative - unloaded or partially loaded mobilize postoperatively crucial to the joint with active and passive range of motion (ROM) based on the surgical procedure - Avoiding straight leg raise for 4 weeks postoperatively - Cardiovascular training is important - Hip flexion greater than 70–90° - External rotation of the leg - Adduction of the leg past midline - Should not bend forward from the waist more than 90 - Early stretching and mobilization of the intrinsic and extrinsic tendons of the hand is important to prevent finger stiffness. - Edema control can be initiated with compression gloves, digital massage, and active and passive ROM of the leg. - A home exercise program or outpatient occupational therapy is started immediately post-operatively to maintain full range of motion of the leg and limit the development of intrinsic muscle tightness # Primary Prevention[32][23][51] There are various preventive options to reduce the incidence of the Hip bone fracture-dislocation - Using suitable hip joint guards during practicing sports (skating, biking) and/or driving motorbikes - Avoid falls in elderly individuals - Prevention and/or treatment of osteoporosis - Healthy diet # Secondary Prevention[23][51][52][50][46][8] It should be noted that the Post-menopausal women specially older than the age of 65 are at the higher risk of osteoporosis consequently these type of patients at greater risk for the pathological fractures . So the Calcium and vitamin D supplementation play important role in increasing the bone mineral density (BMD) consequently decrease the risk of fracture in these type of patients. Also, avoiding excessive alcohol and quitting smoking play important role in this regard. ## Detecting osteoporosis[22] - DEXA(dual-energy x-ray absorptiometry) scan - Serum calcium and vitamin D levels - Ultrasonography of the calcaneus ## Pharmacological therapy[4][53] - The primary goal for the treatment of osteoporosis is to reduce longtime fracture risk in patients. Increasing bone mineral density (BMD) in response to the treatment is far less important than improvement of clinical aspects of osteoporosis, i.e., osteoporotic fracture. Therefore, most of the drugs efficacy is measured by the extent they improve the fracture risk instead of increasing BMD. - During the treatment, if a single fracture happens, it does not necessarily indicate treatment failure or the need to be started on an alternative treatment or patient referral to a specialist. - Calcium and vitamin D supplementation have been found to be effective in reducing the long term fracture risk, significantly. In order to suggest the people to use vitamin D and calcium supplements, the physician needs to make sure that patient is not able to obtain the nutrients through the daily intake. The available supplemental ions of calcium include calcium carbonate, calcium citrate, and vitamin D3 in various dosage forms. ## Life style modifications [4][53][51] - Exercise: Exercise promotes the mineralization of bone and bone accumulation particularly during growth. High impact exercise, in particular, has been shown to prevent the development of osteoporosis. However, it can have a negative effect on bone mineralization in cases of poor nutrition, such as anorexia nervosa and celiac disease. - Nutrition: A diet high in calcium and vitamin D prevents bone loss. Patients at risk for osteoporosis, such as persons with chronic steroid use are generally treated with vitamin D and calcium supplementation. In renal disease, more active forms of vitamin D, such as 1,25-dihydroxycholecalciferol or calcitriol are used; as the kidney cannot adequately generate calcitriol from calcidiol (25-hydroxycholecalciferol), which is the storage form of vitamin D. - By quitting smoking, osteoporosis as well as other diseases can be prevented. - Avoiding excessive alcohol intake or drinking only in moderation (1–2 alcoholic beverages/day). - Taking least possible dosages of certain medications that are associated with osteoporosis (anticonvulsants or corticosteroids).	https://www.wikidoc.org/index.php/Hip_Fractures
a1c73cb75d8379fca741ea306067d2b6ca9d516d	wikidoc	Hippotherapy	Hippotherapy According to the American Hippotherapy Association, Inc., "Hippotherapy is a physical, occupational and speech therapy treatment strategy that utilizes equine movement." In the hippotherapy environment, a therapist uses the horse's movement to provide carefully graded sensory input. A foundation is established to improve neurological function and sensory processing, which can be generalized to a wide range of daily activities. Unlike in therapeutic horseback riding where specific riding skills are taught, in hippotherapy the movement of the horse is a means to a treatment goal. # What is the difference between Hippotherapy and Therapeutic Riding? In hippotherapy, a PT, OT or Speech Therapist is working directly with a patient on the horse to help the patient improve their functional skills. In Therapeutic Riding, a certified therapeutic riding instructor is teaching a person with special needs how to ride. # How does the horse help in Hippotherapy? Physical Function Adults and children with disabilities can improve their posture, muscle tone, coordination, balance, and motor development. The horse's movement provides physical and sensory input, which is variable, but also rhythmic and repetitive. The variability of the horse's gait enables the therapist to grade the degree of input to the patient, then utilize this movement in combination with other treatment strategies to achieve desired results. In addition, the three-dimensional movement of the horse's pelvis leads to a movement response in the patient's pelvis which is similar to the movement patterns of walking. A foundation is established to improve neurological function and sensory processing, which can be generalized to a wide range of daily activities. Hippotherapy can only be provided by a licensed physical therapist, speech therapist or occupational therapist. Hippotherapy comes from the Greek roots hippo-, meaning horse, and therapy. # What does hippotherapy help with? - Gross motor skills - Speech and language abilities - Fine motor skills - Behavioral and cognitive abilities # Hippotherapy as a speech and language therapy Although many people associate hippotherapy with physical therapy, hippotherapy as a speech and language therapy strategy is growing more common. Hippotherapy uses a horse to accomplish traditional speech, language, cognitive, and swallowing goals. Carefully modulated, well cadenced equine movement offers an effective means of addressing speech and language deficits through facilitation of the physiological systems that support speech and language function. Utilizing hippotherapy, appropriate sensory integration strategies have been integrated into the treatment to facilitate successful communication. Sensory integration via hippotherapy simultaneously addresses the vestibular, proprioceptive, tactile, visual, olfactory, and auditory systems. # Medical conditions for which hippotherapy is indicated Some medical conditions for which hippotherapy may be commonly indicated are listed below. However, hippotherapy is not for every patient; specially trained health professionals must evaluate each potential patient on an individual basis. - Autism Spectrum Disorders - Cerebral palsy - Cerebral vascular accident (stroke) - Developmental delay - Down syndrome - Functional spinal curvature (scoliosis) - Learning or language disabilities - Multiple Sclerosis - Sensory integrative dysfunction - Traumatic brain injury # HPCS certification Hippotherapy Clinical Specialty (HPCS) Certification is a designation indicating board certification of therapists who have advanced knowledge and experience in hippotherapy. Physical therapists, occupational therapists, and speech and language pathologists who have been practicing their profession for at least three years (6,000 hours) and have 100 hours of hippotherapy practice within the three years prior are permitted to take the Hippotherapy Clinical Specialty Certification Examination. Those who pass become board certified in hippotherapy and are entitled to use the HPCS designation after their name. HPCS certification lasts for five years.	Hippotherapy According to the American Hippotherapy Association, Inc., "Hippotherapy is a physical, occupational and speech therapy treatment strategy that utilizes equine movement." In the hippotherapy environment, a therapist uses the horse's movement to provide carefully graded sensory input. A foundation is established to improve neurological function and sensory processing, which can be generalized to a wide range of daily activities. Unlike in therapeutic horseback riding where specific riding skills are taught, in hippotherapy the movement of the horse is a means to a treatment goal. # What is the difference between Hippotherapy and Therapeutic Riding? In hippotherapy, a PT, OT or Speech Therapist is working directly with a patient on the horse to help the patient improve their functional skills. In Therapeutic Riding, a certified therapeutic riding instructor is teaching a person with special needs how to ride. # How does the horse help in Hippotherapy? Physical Function Adults and children with disabilities can improve their posture, muscle tone, coordination, balance, and motor development. The horse's movement provides physical and sensory input, which is variable, but also rhythmic and repetitive. The variability of the horse's gait enables the therapist to grade the degree of input to the patient, then utilize this movement in combination with other treatment strategies to achieve desired results. In addition, the three-dimensional movement of the horse's pelvis leads to a movement response in the patient's pelvis which is similar to the movement patterns of walking. A foundation is established to improve neurological function and sensory processing, which can be generalized to a wide range of daily activities. Hippotherapy can only be provided by a licensed physical therapist, speech therapist or occupational therapist. Hippotherapy comes from the Greek roots hippo-, meaning horse, and therapy. # What does hippotherapy help with? - Gross motor skills - Speech and language abilities - Fine motor skills - Behavioral and cognitive abilities # Hippotherapy as a speech and language therapy Although many people associate hippotherapy with physical therapy, hippotherapy as a speech and language therapy strategy is growing more common. Hippotherapy uses a horse to accomplish traditional speech, language, cognitive, and swallowing goals. Carefully modulated, well cadenced equine movement offers an effective means of addressing speech and language deficits through facilitation of the physiological systems that support speech and language function. Utilizing hippotherapy, appropriate sensory integration strategies have been integrated into the treatment to facilitate successful communication. Sensory integration via hippotherapy simultaneously addresses the vestibular, proprioceptive, tactile, visual, olfactory, and auditory systems. # Medical conditions for which hippotherapy is indicated Template:Refimprovesect Some medical conditions for which hippotherapy may be commonly indicated are listed below. However, hippotherapy is not for every patient; specially trained health professionals must evaluate each potential patient on an individual basis. - Autism Spectrum Disorders[citation needed] - Cerebral palsy[1] - Cerebral vascular accident (stroke)[citation needed] - Developmental delay[citation needed] - Down syndrome[citation needed] - Functional spinal curvature (scoliosis)[citation needed] - Learning or language disabilities[citation needed] - Multiple Sclerosis[citation needed] - Sensory integrative dysfunction[citation needed] - Traumatic brain injury[citation needed] # HPCS certification Hippotherapy Clinical Specialty (HPCS) Certification is a designation indicating board certification of therapists who have advanced knowledge and experience in hippotherapy. Physical therapists, occupational therapists, and speech and language pathologists who have been practicing their profession for at least three years (6,000 hours) and have 100 hours of hippotherapy practice within the three years prior are permitted to take the Hippotherapy Clinical Specialty Certification Examination. Those who pass become board certified in hippotherapy and are entitled to use the HPCS designation after their name. HPCS certification lasts for five years.	https://www.wikidoc.org/index.php/Hippotherapy
c7045dd101015df8697b2f7485d507a97c256fb4	wikidoc	Histogenesis	Histogenesis Histogenesis is the formation of different tissues from undifferentiated cells. These cells are constituents of three primary germ layers, the endoderm, mesoderm, and ectoderm. The science of the microscopic structures of the tissues formed within histogenesis is termed histology. # Germ layers A germ layer is a collection of cells, formed during animal and mammalian embryogenesis. Germ layers are typically pronounced within vertebrate organisms; however,animals or mammals more complex than sponges (eumetazoans and agnotozoans) produce two or three primary tissue layers. Animals with radial symmetry, such as cnidarians, produce two layers, called the ectoderm and endoderm. Therefore, they are diploblastic. Animals with bilateral symmetry produce a third layer in-between called mesoderm, making them triploblastic. Germ layers will eventually give rise to all of an animal’s or mammal's tissues and organs through a process called organogenesis. ## Endoderm The endoderm is one of the germ layers formed during animal embryogenesis. Cells migrating inward along the archenteron form the inner layer of the gastrula, which develops into the endoderm. Initially, the endoderm consists of flattened cells, which subsequently become columnar. ## Mesoderm The mesoderm germ layer forms in the embryos of animals and mammals more complex than cnidarians, making them triploblastic. During gastrulation, some of the cells migrating inward to form the endoderm form an additional layer between the endoderm and the ectoderm. This key innovation evolved hundreds of millions of years ago and led to the evolution of nearly all large, complex animals. The formation of a mesoderm led to the formation of a coelom. Organs formed inside a coelom can freely move, grow, and develop independently of the body wall while fluid cushions and protects them from shocks. ## Ectoderm The ectoderm is the start of a tissue that covers the body surfaces. It emerges first and forms from the outermost of the germ layers. # Production The proceeding graph represents the products produced by the three germ layers.	Histogenesis Histogenesis is the formation of different tissues from undifferentiated cells.[1] These cells are constituents of three primary germ layers, the endoderm, mesoderm, and ectoderm. The science of the microscopic structures of the tissues formed within histogenesis is termed histology. # Germ layers A germ layer is a collection of cells, formed during animal and mammalian embryogenesis. Germ layers are typically pronounced within vertebrate organisms; however,animals or mammals more complex than sponges (eumetazoans and agnotozoans) produce two or three primary tissue layers. Animals with radial symmetry, such as cnidarians, produce two layers, called the ectoderm and endoderm. Therefore, they are diploblastic. Animals with bilateral symmetry produce a third layer in-between called mesoderm, making them triploblastic. Germ layers will eventually give rise to all of an animal’s or mammal's tissues and organs through a process called organogenesis. ## Endoderm The endoderm is one of the germ layers formed during animal embryogenesis. Cells migrating inward along the archenteron form the inner layer of the gastrula, which develops into the endoderm. Initially, the endoderm consists of flattened cells, which subsequently become columnar. ## Mesoderm The mesoderm germ layer forms in the embryos of animals and mammals more complex than cnidarians, making them triploblastic. During gastrulation, some of the cells migrating inward to form the endoderm form an additional layer between the endoderm and the ectoderm. This key innovation evolved hundreds of millions of years ago and led to the evolution of nearly all large, complex animals. The formation of a mesoderm led to the formation of a coelom. Organs formed inside a coelom can freely move, grow, and develop independently of the body wall while fluid cushions and protects them from shocks. ## Ectoderm The ectoderm is the start of a tissue that covers the body surfaces. It emerges first and forms from the outermost of the germ layers. # Production The proceeding graph represents the products produced by the three germ layers.	https://www.wikidoc.org/index.php/Histogenesis
1882477293c827530dcb34d94f8deb191711c379	wikidoc	Homeobox A10	Homeobox A10 Homeobox protein Hox-A10 is a protein that in humans is encoded by the HOXA10 gene. # Function In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor that may regulate gene expression, morphogenesis, and differentiation. More specifically, it may function in fertility, embryo viability, and regulation of hematopoietic lineage commitment. Alternatively spliced transcript variants encoding different isoforms have been described. Downregualtion of HOXA10 is observed in the human and baboon decidua after implantation and this downregulation promotes trophoblast invasion by activating STAT3 # Interactions Homeobox A10 has been shown to interact with PTPN6.	Homeobox A10 Homeobox protein Hox-A10 is a protein that in humans is encoded by the HOXA10 gene.[1][2][3] # Function In vertebrates, the genes encoding the class of transcription factors called homeobox genes are found in clusters named A, B, C, and D on four separate chromosomes. Expression of these proteins is spatially and temporally regulated during embryonic development. This gene is part of the A cluster on chromosome 7 and encodes a DNA-binding transcription factor that may regulate gene expression, morphogenesis, and differentiation. More specifically, it may function in fertility, embryo viability, and regulation of hematopoietic lineage commitment. Alternatively spliced transcript variants encoding different isoforms have been described.[3] Downregualtion of HOXA10 is observed in the human and baboon decidua after implantation and this downregulation promotes trophoblast invasion by activating STAT3[4] # Interactions Homeobox A10 has been shown to interact with PTPN6.[5]	https://www.wikidoc.org/index.php/Homeobox_A10
1e6ccfe270f988d5eeac0f2db94587816741c59b	wikidoc	Homo (genus)	Homo (genus) # Overview Homo is the genus that includes modern humans and their close relatives. The genus is estimated to be about 2.5 million years old, evolving from Australopithecine ancestors with the appearance of Homo habilis. Appearance of Homo coincides with the first evidence of stone tools (the Oldowan industry), and thus by definition with the beginning of the Lower Paleolithic. All species except Homo sapiens (modern humans) are extinct. Homo neanderthalensis, traditionally considered the last surviving relative, died out 24,000 years ago while a recent discovery suggests that another species, Homo floresiensis, may have lived as recently as 12,000 years ago. A minority of zoologists consider that the two species of chimpanzees (usually treated in the genus Pan), and maybe the gorillas (usually treated in the genus Gorilla) should also be included in the genus based on genetic similarities. Most scientists argue that chimpanzees and gorillas have too many anatomical differences between themselves and humans to be part of Homo. Given the large number of morphological similarities exhibited, Homo is closely related to several extinct hominin genera, most notably Kenyanthropus, Paranthropus and Australopithecus. As of 2007, there is no universally accepted recognition of which taxa Homo radiated from. The word homo is Latin for "man", in the original sense of "human being", or "person". The word "human" itself is from Latin humanus, an adjective cognate to homo, both derived from Proto-Indo-European language Template:PIE "earth". Cf. Hebrew adam, meaning "human", cognate to adamah, meaning "ground". (And cf. Latin humus, meaning "soil".) # Species - †Homo habilis (Handy Man) - †Homo rudolfensis (Rudolf Man) - †Homo ergaster (Working Man) - †Homo erectus (Upright Man) - †Homo floresiensis (Flores Man; discovered 2003. Species status remains under debate.) - †Homo antecessor (Predecessor Man) - †Homo heidelbergensis (Heidelberg Man) - †Homo neanderthalensis (Neanderthal Man) - †Homo rhodesiensis (Rhodesia Man) - †Homo cepranensis (Ceprano Man) - †Homo georgicus (Georgia Man) - Homo sapiens †Homo sapiens idaltu (elderly wise man — discovered 1997) Homo sapiens sapiens (Wise Man; modern humans) - †Homo sapiens idaltu (elderly wise man — discovered 1997) - Homo sapiens sapiens (Wise Man; modern humans) H. heidelbergensis and H. neanderthalensis are closely related to each other and have been considered to be subspecies of H. sapiens, but analysis of mitochondrial DNA from Homo neanderthalensis fossils shows that H. neanderthalensis is more closely related to chimpanzees than H. sapiens is, thereby suggesting that H. sapiens is the more derived of the two. H. rhodesiensis and H. cepranensis are also more closely related to each other than to the other species.	Homo (genus) Template:Otheruses3 # Overview Homo is the genus that includes modern humans and their close relatives. The genus is estimated to be about 2.5 million years old, evolving from Australopithecine ancestors with the appearance of Homo habilis. Appearance of Homo coincides with the first evidence of stone tools (the Oldowan industry), and thus by definition with the beginning of the Lower Paleolithic. All species except Homo sapiens (modern humans) are extinct. Homo neanderthalensis, traditionally considered the last surviving relative, died out 24,000 years ago while a recent discovery suggests that another species, Homo floresiensis, may have lived as recently as 12,000 years ago. A minority of zoologists consider that the two species of chimpanzees (usually treated in the genus Pan), and maybe the gorillas (usually treated in the genus Gorilla) should also be included in the genus based on genetic similarities. Most scientists argue that chimpanzees and gorillas have too many anatomical differences between themselves and humans to be part of Homo. Given the large number of morphological similarities exhibited, Homo is closely related to several extinct hominin genera, most notably Kenyanthropus, Paranthropus and Australopithecus. As of 2007, there is no universally accepted recognition of which taxa Homo radiated from. The word homo is Latin for "man", in the original sense of "human being", or "person". The word "human" itself is from Latin humanus, an adjective cognate to homo, both derived from Proto-Indo-European language Template:PIE "earth"[1]. Cf. Hebrew adam, meaning "human", cognate to adamah, meaning "ground". (And cf. Latin humus, meaning "soil".) # Species - †Homo habilis (Handy Man) - †Homo rudolfensis (Rudolf Man) - †Homo ergaster (Working Man) - †Homo erectus (Upright Man) - †Homo floresiensis (Flores Man; discovered 2003. Species status remains under debate.) - †Homo antecessor (Predecessor Man) - †Homo heidelbergensis (Heidelberg Man) - †Homo neanderthalensis (Neanderthal Man) - †Homo rhodesiensis (Rhodesia Man) - †Homo cepranensis (Ceprano Man) - †Homo georgicus (Georgia Man) - Homo sapiens †Homo sapiens idaltu (elderly wise man — discovered 1997) Homo sapiens sapiens (Wise Man; modern humans) - †Homo sapiens idaltu (elderly wise man — discovered 1997) - Homo sapiens sapiens (Wise Man; modern humans) H. heidelbergensis and H. neanderthalensis are closely related to each other and have been considered to be subspecies of H. sapiens, but analysis of mitochondrial DNA from Homo neanderthalensis fossils shows that H. neanderthalensis is more closely related to chimpanzees than H. sapiens is, thereby suggesting that H. sapiens is the more derived of the two.[1] H. rhodesiensis and H. cepranensis are also more closely related to each other than to the other species. Template:Homo	https://www.wikidoc.org/index.php/Homo_(genus)
b45a01b347fdba2790b03804b1f898f508287d4b	wikidoc	Homo erectus	Homo erectus Homo erectus (Latin: "upright man") is an extinct species of the genus Homo. Dutch anatomist Eugene Dubois (1890s) first described it as Pithecanthropus erectus, based on a calotte (skullcap) and a modern-looking femur found from the bank of the Solo River at Trinil, in central Java. However, thanks to Canadian anatomist Davidson Black's (1921) initial description of a lower molar, which was dubbed Sinanthropus pekinensis, most of the early and spectacular discoveries of this taxon took place at Zhoukoudian in China. German anatomist Franz Weidenreich provided much of the detailed description of this material in several monographs published in the journal Palaeontologica Sinica (Series D). However, nearly all of the original specimens were lost during World War II. High quality Weidenreichian casts do exist and are considered to be reliable evidence; these are curated at the American Museum of Natural History (NYC) and at the Institute of Vertebrate Paleontology and Paleoanthropology (Beijing). Throughout much of the 20th century, anthropologists debated the role of H. erectus in human evolution. Early in the century, due to discoveries on Java and at Zhoukoudian, it was believed that modern humans first evolved in Asia. This contradicted Charles Darwin's idea of African human origin. However, during the 1950s and 1970s, numerous fossil finds from East Africa (Kenya) yielded evidence that the oldest hominins originated there. It is now believed that H. erectus is a descendant of earlier hominins such as Australopithecus and early Homo species (e.g., H. habilis); although, new findings in 2007 suggest that H. habilis and H. erectus coexisted and may be separate lineages from a common ancestor. H. erectus originally migrated from Africa during the Early Pleistocene, possibly as a result of the operation of the Saharan pump, around 2.0 million years ago, and dispersed throughout most of the Old World, reaching as far as Southeast Asia. Fossilized remains 1.8 and 1.0 million years old have been found in Africa (e.g., Lake Turkana and Olduvai Gorge), Europe (Georgia, Spain), Indonesia (e.g., Sangiran and Trinil), Vietnam, and China (e.g., Shaanxi). H. erectus is an important hominin because it is believed to have been the first to leave Africa. However, some scholars believe that H. erectus is not the direct ancestor of modern H. sapiens. A homo erectus skull, Tchadanthropus uxoris, discovered in 1961, is the partial skull of the first early hominid till then discovered in Central Africa, found in Chad during an expedition led by the anthropologist Yves Coppens. While some then thought it was a variety of the Homo habilis, the Tchadanthropus uxoris is no longer considered to be a separate species, and scholars consider it to be Homo erectus, and it is even argued that the skull is just a modern human, Homo sapiens sapiens, weathered by the elements to look like an australopithecine skull. # Description Homo erectus has fairly derived morphological features and a larger cranial capacity than that of Homo habilis, although new finds from Dmanisi in the Republic of Georgia show distinctively small crania. The forehead (frontal bone) is less sloping and the teeth are smaller (quantification of these differences is difficult, however; see below). Homo erectus would bear a striking resemblance to modern humans, but had a brain about 75 percent (950 to 1100 cc) of the size of that of a modern human. These early hominines were tall, on average standing about 1.79 m (5 feet, 10 inches). The sexual dimorphism between males and females was slightly greater than seen in modern Homo sapiens with males being about 20-30% larger than females. The discovery of the skeleton KNM-WT 15000 (Turkana boy) made near Lake Turkana, Kenya by Richard Leakey and Kamoya Kimeu in 1984 was a breakthrough in interpreting the physiological status of H. erectus. # Usage of tools and general abilities Homo erectus used more diverse and sophisticated tools than its predecessors. This has been theorized to have been a result of Homo erectus first using tools of the Oldowan style and later progressing to the Acheulean style. The surviving tools from both periods are all made of stone. Oldowan tools are the oldest known formed tools and date as far back as about 2.6 million years ago. The Acheulean era began about 1.2 million years ago and ended about 500,000 years ago. The primary innovation associated with Acheulean handaxes is that the stone was chipped on both sides to form two cutting edges. # Social aspects Homo erectus (along with Homo ergaster) was probably the first early human species to fit squarely into the category of a hunter gatherer society. Anthropologists such as Richard Leakey believe that H. erectus was socially closer to modern humans than the more primitive species before it. The increased cranial capacity generally coincides with the more sophisticated tool technology occasionally found with the species' remains. The discovery of Turkana boy in 1984 has shown evidence that despite H. erectus's human-like anatomy, they were not capable of producing sounds of a complexity comparable to modern speech. H. erectus migrated all throughout the Great Rift Valley, even up to the Red Sea. Early humans, in the person of Homo erectus, were learning to master their environment for the first time. Attributed to H. erectus, around 1.8 million years ago in the Olduvai Gorge, is the oldest known evidence of mammoth consumption (BioScience, April 2006, Vol. 56 No. 4, p. 295). Bruce Bower has suggested that H. erectus may have built rafts and traveled over oceans, although this possibility is considered controversial. A site called Terra Amata, which lies on an ancient beach location on the French Riviera, seems to have been occupied by Homo erectus and contains the earliest (least disputed) evidence of controlled fire dated at around 300,000 years BP. There are also older Homo erectus sites in France, China, Vietnam, and other areas that seem to indicate controlled use of fire, some dating back 500,000 to 1.5 million years ago. A presentation at the Paleoanthropology Society annual meeting in Montreal, Canada in March of 2004 stated that there is evidence for controlled fires in excavations in northern Israel from about 690,000 to 790,000 years ago. Despite these examples, some scholars continue to assert that the controlled use of fire was atypical of Homo erectus, and that the use of controlled fire is more typical of advanced species of the Homo genus (such as Homo antecessor, H. heidelbergensis and H. neanderthalensis). # Classification There has almost always been a great deal of discussion concerning the taxonomy of Homo erectus (see the 1984 and 1994 volumes of Courier Forschungsinstitut Senckenberg), and it relates to the question whether or not H. erectus is a geographically widespread species (found in Africa, Europe, and Asia), or is it a classic Asian lineage that evolved from less cranially derived African H. ergaster. While some have argued (and insisted) that Ernst Mayr's biological species definition cannot be used here to test the above hypotheses, we can, however, examine the amount of morphological (cranial) variation within known H. erectus / H. ergaster specimens, and compare it to what we see in different extant primate groups with similar geographical distribution or close evolutionary relationship. Thus, if the amount of variation between H. erectus and H. ergaster is greater than what we see within a species of, say, macaques, then H. erectus and H. ergaster should be considered as two different species. Of course, the extant model (of comparison) is very important and choosing the right one(s) can be difficult. # Descendants and subspecies Homo erectus remains one of the most successful and long-lived species of the Homo genus. It is generally considered to have given rise to a number of descendant species and subspecies. The oldest known specimen of the ancient human was found in Africa. - Homo erectus Homo erectus yuanmouensis Homo erectus lantianensis Homo erectus pekinensis Homo erectus palaeojavanicus Homo erectus soloensis - Homo erectus yuanmouensis - Homo erectus lantianensis - Homo erectus pekinensis - Homo erectus palaeojavanicus - Homo erectus soloensis Other species - Homo floresiensis - Homo antecessor - Homo heidelbergensis - Homo neanderthalensis - Homo sapiens Homo sapiens sapiens - Homo sapiens sapiens - Homo rhodesiensis - Homo cepranensis The discovery of Homo floresiensis, and particularly its recent survival, has raised the possibility that numerous descendant species of Homo erectus may have existed in the islands of south-east Asia which await fossil discovery. Some scientists are skeptical about the claim that Homo floresiensis is a descendant of Homo erectus. One theory holds that the fossils are from a modern human with microcephaly, while another one claims that they are from a group of pygmys. # Individual fossils Some of the major Homo erectus fossils: - Indonesia (island of Java): Trinil 2 (holotype), Sangiran collection, Sambungmachan collection, Ngandong collection - China: Lantian (Gongwangling and Chenjiawo), Yunxian, Zhoukoudian, Nanjing, Hexian - India: Narmada (taxonomic status debated!) - Kenya: WT 15000 (Nariokotome), ER 3883, ER 3733 - Tanzania: OH 9 - Vietnam: Northern, Tham Khuyen, Hoa Binh - Republic of Georgia: Dmanisi collection Some scholars consider specimens outside of Asia to be Homo ergaster. In other words, Homo erectus is an Asian lineage derived from Homo ergaster, which originated in Africa ca. 2.0 million years ago (Ma).	Homo erectus Homo erectus (Latin: "upright man") is an extinct species of the genus Homo. Dutch anatomist Eugene Dubois (1890s) first described it as Pithecanthropus erectus, based on a calotte (skullcap) and a modern-looking femur found from the bank of the Solo River at Trinil, in central Java. However, thanks to Canadian anatomist Davidson Black's (1921) initial description of a lower molar, which was dubbed Sinanthropus pekinensis, most of the early and spectacular discoveries of this taxon took place at Zhoukoudian in China. German anatomist Franz Weidenreich provided much of the detailed description of this material in several monographs published in the journal Palaeontologica Sinica (Series D). However, nearly all of the original specimens were lost during World War II. High quality Weidenreichian casts do exist and are considered to be reliable evidence; these are curated at the American Museum of Natural History (NYC) and at the Institute of Vertebrate Paleontology and Paleoanthropology (Beijing). Throughout much of the 20th century, anthropologists debated the role of H. erectus in human evolution. Early in the century, due to discoveries on Java and at Zhoukoudian, it was believed that modern humans first evolved in Asia. This contradicted Charles Darwin's idea of African human origin. However, during the 1950s and 1970s, numerous fossil finds from East Africa (Kenya) yielded evidence that the oldest hominins originated there. It is now believed that H. erectus is a descendant of earlier hominins such as Australopithecus and early Homo species (e.g., H. habilis); although, new findings in 2007 suggest that H. habilis and H. erectus coexisted and may be separate lineages from a common ancestor.[1] H. erectus originally migrated from Africa during the Early Pleistocene, possibly as a result of the operation of the Saharan pump, around 2.0 million years ago, and dispersed throughout most of the Old World, reaching as far as Southeast Asia. Fossilized remains 1.8 and 1.0 million years old have been found in Africa (e.g., Lake Turkana and Olduvai Gorge), Europe (Georgia, Spain), Indonesia (e.g., Sangiran and Trinil), Vietnam, and China (e.g., Shaanxi). H. erectus is an important hominin because it is believed to have been the first to leave Africa. However, some scholars believe that H. erectus is not the direct ancestor of modern H. sapiens. A homo erectus skull, Tchadanthropus uxoris, discovered in 1961, is the partial skull of the first early hominid till then discovered in Central Africa, found in Chad during an expedition led by the anthropologist Yves Coppens.[2] While some then thought it was a variety of the Homo habilis,[3] the Tchadanthropus uxoris is no longer considered to be a separate species, and scholars consider it to be Homo erectus,[2][4] and it is even argued that the skull is just a modern human, Homo sapiens sapiens, weathered by the elements to look like an australopithecine skull.[5] # Description Homo erectus has fairly derived morphological features and a larger cranial capacity than that of Homo habilis, although new finds from Dmanisi in the Republic of Georgia show distinctively small crania. The forehead (frontal bone) is less sloping and the teeth are smaller (quantification of these differences is difficult, however; see below). Homo erectus would bear a striking resemblance to modern humans, but had a brain about 75 percent (950 to 1100 cc) of the size of that of a modern human. These early hominines were tall, on average standing about 1.79 m (5 feet, 10 inches). The sexual dimorphism between males and females was slightly greater than seen in modern Homo sapiens with males being about 20-30% larger than females. The discovery of the skeleton KNM-WT 15000 (Turkana boy) made near Lake Turkana, Kenya by Richard Leakey and Kamoya Kimeu in 1984 was a breakthrough in interpreting the physiological status of H. erectus. # Usage of tools and general abilities Homo erectus used more diverse and sophisticated tools than its predecessors. This has been theorized to have been a result of Homo erectus first using tools of the Oldowan style and later progressing to the Acheulean style. The surviving tools from both periods are all made of stone. Oldowan tools are the oldest known formed tools and date as far back as about 2.6 million years ago. The Acheulean era began about 1.2 million years ago and ended about 500,000 years ago. The primary innovation associated with Acheulean handaxes is that the stone was chipped on both sides to form two cutting edges. # Social aspects Homo erectus (along with Homo ergaster) was probably the first early human species to fit squarely into the category of a hunter gatherer society. Anthropologists such as Richard Leakey believe that H. erectus was socially closer to modern humans than the more primitive species before it. The increased cranial capacity generally coincides with the more sophisticated tool technology occasionally found with the species' remains. The discovery of Turkana boy in 1984 has shown evidence that despite H. erectus's human-like anatomy, they were not capable of producing sounds of a complexity comparable to modern speech. H. erectus migrated all throughout the Great Rift Valley, even up to the Red Sea.[6] Early humans, in the person of Homo erectus, were learning to master their environment for the first time. Attributed to H. erectus, around 1.8 million years ago in the Olduvai Gorge, is the oldest known evidence of mammoth consumption (BioScience, April 2006, Vol. 56 No. 4, p. 295). Bruce Bower has suggested that H. erectus may have built rafts and traveled over oceans, although this possibility is considered controversial.[7] A site called Terra Amata, which lies on an ancient beach location on the French Riviera, seems to have been occupied by Homo erectus and contains the earliest (least disputed) evidence of controlled fire dated at around 300,000 years BP. There are also older Homo erectus sites in France, China, Vietnam, and other areas that seem to indicate controlled use of fire, some dating back 500,000 to 1.5 million years ago. A presentation at the Paleoanthropology Society annual meeting in Montreal, Canada in March of 2004 stated that there is evidence for controlled fires in excavations in northern Israel from about 690,000 to 790,000 years ago. Despite these examples, some scholars continue to assert that the controlled use of fire was atypical of Homo erectus, and that the use of controlled fire is more typical of advanced species of the Homo genus (such as Homo antecessor, H. heidelbergensis and H. neanderthalensis). # Classification There has almost always been a great deal of discussion concerning the taxonomy of Homo erectus (see the 1984 and 1994 volumes of Courier Forschungsinstitut Senckenberg), and it relates to the question whether or not H. erectus is a geographically widespread species (found in Africa, Europe, and Asia), or is it a classic Asian lineage that evolved from less cranially derived African H. ergaster. While some have argued (and insisted) that Ernst Mayr's biological species definition cannot be used here to test the above hypotheses, we can, however, examine the amount of morphological (cranial) variation within known H. erectus / H. ergaster specimens, and compare it to what we see in different extant primate groups with similar geographical distribution or close evolutionary relationship. Thus, if the amount of variation between H. erectus and H. ergaster is greater than what we see within a species of, say, macaques, then H. erectus and H. ergaster should be considered as two different species. Of course, the extant model (of comparison) is very important and choosing the right one(s) can be difficult. # Descendants and subspecies Homo erectus remains one of the most successful and long-lived species of the Homo genus. It is generally considered to have given rise to a number of descendant species and subspecies. The oldest known specimen of the ancient human was found in Africa. - Homo erectus Homo erectus yuanmouensis Homo erectus lantianensis Homo erectus pekinensis Homo erectus palaeojavanicus Homo erectus soloensis - Homo erectus yuanmouensis - Homo erectus lantianensis - Homo erectus pekinensis - Homo erectus palaeojavanicus - Homo erectus soloensis Other species - Homo floresiensis - Homo antecessor - Homo heidelbergensis - Homo neanderthalensis - Homo sapiens Homo sapiens sapiens - Homo sapiens sapiens - Homo rhodesiensis - Homo cepranensis The discovery of Homo floresiensis, and particularly its recent survival, has raised the possibility that numerous descendant species of Homo erectus may have existed in the islands of south-east Asia which await fossil discovery. Some scientists are skeptical about the claim that Homo floresiensis is a descendant of Homo erectus. One theory holds that the fossils are from a modern human with microcephaly, while another one claims that they are from a group of pygmys. # Individual fossils Some of the major Homo erectus fossils: - Indonesia (island of Java): Trinil 2 (holotype), Sangiran collection, Sambungmachan collection, Ngandong collection - China: Lantian (Gongwangling and Chenjiawo), Yunxian, Zhoukoudian, Nanjing, Hexian - India: Narmada (taxonomic status debated!) - Kenya: WT 15000 (Nariokotome), ER 3883, ER 3733 - Tanzania: OH 9 - Vietnam: Northern, Tham Khuyen, Hoa Binh - Republic of Georgia: Dmanisi collection Some scholars consider specimens outside of Asia to be Homo ergaster. In other words, Homo erectus is an Asian lineage derived from Homo ergaster, which originated in Africa ca. 2.0 million years ago (Ma).	https://www.wikidoc.org/index.php/Homo_erectus
8a1f07f91af0639cb90e99e032d95baa016ef27a	wikidoc	Homo habilis	Homo habilis Homo habilis (IPA Template:IPA) ("handy man", "skillful person") is a species of the genus Homo, which lived from approximately 2.6 million to at least 1.4 million years ago at the beginning of the Pleistocene. The definition of this species is credited to both Mary and Louis Leakey, who found fossils in Tanzania, East Africa, between 1962 and 1964. Homo habilis is arguably the first species of the Homo genus to appear. In its appearance and morphology, H. habilis was the least similar to modern humans of all species to be placed in the genus Homo (except possibly Homo rudolfensis). Homo habilis was short and had disproportionately long arms compared to modern humans; however, it had a reduction in the protrusion in the face. It is thought to have descended from a species of australopithecine hominid. Its immediate ancestor may have been the more massive and ape-like Homo rudolfensis. Homo habilis had a cranial capacity slightly less than half of the size of modern humans. Despite the ape-like morphology of the bodies, H. habilis remains are often accompanied by primitive stone tools (e.g. Olduvai Gorge, Tanzania and Lake Turkana, Kenya). Homo habilis has often been thought to be the ancestor of the lankier and more sophisticated Homo ergaster, which in turn gave rise to the more human-appearing species, Homo erectus. Debates continue over whether H. habilis is a direct human ancestor, and whether all of the known fossils are properly attributed to the species. However, in 2007, new findings suggest that the two species coexisted and may be separate lineages from a common ancestor instead of H. erectus being descended from H. habilis. # Findings One set of fossil remains (OH 62), discovered by Donald Johanson and Tim White in Olduvai Gorge in 1986, included the important upper and lower limbs. An older (1963) finding from the Olduvai site found by N. Mbuika had included a lower jaw fragment, teeth and upper mandible possibly from a female dating 1.7 million years old. The remains from 3 skeletons demonstrated australopithecine-like body with a more human-like face and smaller teeth. Compared to australopithecines, H. habilis's brain capacity of 590 and 650 cc was on average 50% larger than australopithecines, but considerably smaller than the 1350 to 1450 cc range of modern Homo sapiens. These hominins were smaller than modern humans, on average standing no more than 1.3 m (4'3") tall. The small size and rather primitive attributes have led some experts (Richard Leakey among them) to propose excluding H. habilis from the genus Homo, and renaming as "Australopithecus habilis". ## KNM ER 1813 KNM ER 1813 is a relatively complete cranium which dates 1.9 million years old, discovered at Koobi Fora, Kenya by Kamoya Kimeu in 1973. The brain capacity is 510cc, not as impressive as other early specimen and forms of Homo habilis discovered. ## OH 7 OH 7 dates 1.75 million years old and was discovered by Jonathan Leakey on November 4, 1960 at Olduvai Gorge, Tanzania. It is a lower jaw complete with teeth and due to the size of the small teeth; researchers estimate this individual had a brain volume of 363cc. ## OH 24 OH 24 (AKA Twiggy) is a roughly deformed cranium dating 1.8 million years old discovered in October 1968 at Olduvai Gorge, Tanzania by Peter Nzube. The brain volume is just under 600cc; also a reduction in a protruding face is present compared to members of more primitive Australopithecines. Twiggy was found in a distorted matrix with a coating of limestone rock. ## KNM ER 1805 KNM ER 1805 is a specimen of an adult H. habilis made of 3 pieces of cranium dating 1.74 million years old from Koobi Fora, Kenya. Previous assumptions were that this specimen belongs to H. erectus based on the degree of prognathism and overall cranial shape. # Interpretations Homo habilis is thought to have mastered the Olduwan era (Early Paleolithic) tool case which utilized stone flakes. These stone flakes were more advanced than any tools previously used, and gave H. habilis the edge it needed to prosper in hostile environments previously too formidable for primates. Whether H. habilis was the first hominin to master stone tool technology remains controversial, as Australopithecus garhi, dated to 2.6 million years ago, has been found along with stone tool implements at least 100,000 - 200,000 years older than H. habilis. Most experts assume the intelligence and social organization of H. habilis were more sophisticated than typical australopithecines or chimpanzees. Yet despite tool usage, H. habilis was not the master hunter that its sister species (or descendants) proved to be, as there is ample fossil evidence that H. habilis was a staple in the diet of large predatory animals such as Dinofelis, a large scimitar-toothed predatory cat the size of a jaguar. H. habilis used tools primarily for scavenging, such as cleaving meat off of carrion, rather than defense or hunting. Homo habilis is thought to be the ancestor of the lankier and more sophisticated Homo ergaster, which in turn gave rise to the more human-appearing species Homo erectus. Debates continue over whether H. habilis is a direct human ancestor, and whether all of the known fossils are properly attributed to the species. Homo habilis co-existed with other Homo-like bipedal primates, such as Paranthropus boisei, some of which prospered for many millennia. However, H. habilis, possibly because of its early tool innovation and a less specialized diet, became the precursor of an entire line of new species, whereas Paranthropus boisei and its robust relatives disappeared from the fossil record. The classification of H. habilis into the Homo genus is controversial. Like Homo rudolfensis, H. habilis lacked many of the things that were unique to later hominins such as slim hips for walking long distances, a sophisticated sweating system, narrow birth canal, and legs longer than arms. Such traits as noticeable whites in the eyes, smaller hairs resulting in exposed skin, and a naked appearance remain theoretical. Despite larger brains than earlier species, and bipedal locomotion, many scientists think H. habilis and its close relative H. rudolfensis to be more ape-like, and not properly belonging in the Homo genus. # Stratification and expansion The evolution of Homo habilis is associated with the species' movement from the central Saharan region of Africa into the more demanding, yet resourceful habitats of Europe and to a lesser extent Asia. The major developments which contributed to this phenomena were the greater knowledge and skill with which Homo habilis crafted the rock blade, increasing knowledge about climate and how to adapt accordingly and the evolution of the voice-box which allowed greater co-ordination in hunting than was hitherto possible. Homo habilis, due perhaps to many years of adaptation, were able to create flint blades with 4 inches of cutting blade, this finer blade was strong enough to advance Homo habilis from scavenger to hunter. After many thousands of years of adaptation, humans were eventually able to accumulate enough information about the climate to adapt accordingly, building fires and wearing thick hides to stave off the cold. The evolution, or more so the moving of the voice box from the top of the throat to the bottom allowed a greater variety of speech required to co-ordinate and communicate during hunts. All of these evolutionary measures allowed Homo habilis to exploit the harsher climates of Asia and the borders of Europe. The western and central region of Europe was not settled by humanoids until the time of Homo erectus.	Homo habilis Homo habilis (IPA Template:IPA) ("handy man", "skillful person") is a species of the genus Homo, which lived from approximately 2.6 million to at least 1.4 million years ago at the beginning of the Pleistocene.[1] The definition of this species is credited to both Mary and Louis Leakey, who found fossils in Tanzania, East Africa, between 1962 and 1964.[2] Homo habilis is arguably the first species of the Homo genus to appear. In its appearance and morphology, H. habilis was the least similar to modern humans of all species to be placed in the genus Homo (except possibly Homo rudolfensis). Homo habilis was short and had disproportionately long arms compared to modern humans; however, it had a reduction in the protrusion in the face. It is thought to have descended from a species of australopithecine hominid. Its immediate ancestor may have been the more massive and ape-like Homo rudolfensis. Homo habilis had a cranial capacity slightly less than half of the size of modern humans. Despite the ape-like morphology of the bodies, H. habilis remains are often accompanied by primitive stone tools (e.g. Olduvai Gorge, Tanzania and Lake Turkana, Kenya). Homo habilis has often been thought to be the ancestor of the lankier and more sophisticated Homo ergaster, which in turn gave rise to the more human-appearing species, Homo erectus. Debates continue over whether H. habilis is a direct human ancestor, and whether all of the known fossils are properly attributed to the species. However, in 2007, new findings suggest that the two species coexisted and may be separate lineages from a common ancestor instead of H. erectus being descended from H. habilis.[3] # Findings One set of fossil remains (OH 62), discovered by Donald Johanson and Tim White in Olduvai Gorge in 1986, included the important upper and lower limbs. An older (1963) finding from the Olduvai site found by N. Mbuika had included a lower jaw fragment, teeth and upper mandible possibly from a female dating 1.7 million years old. The remains from 3 skeletons[4] demonstrated australopithecine-like body with a more human-like face and smaller teeth. Compared to australopithecines, H. habilis's brain capacity of 590 and 650 cc was on average 50% larger than australopithecines, but considerably smaller than the 1350 to 1450 cc range of modern Homo sapiens. These hominins were smaller than modern humans, on average standing no more than 1.3 m (4'3") tall. The small size and rather primitive attributes have led some experts (Richard Leakey among them) to propose excluding H. habilis from the genus Homo, and renaming as "Australopithecus habilis". ## KNM ER 1813 KNM ER 1813 is a relatively complete cranium which dates 1.9 million years old, discovered at Koobi Fora, Kenya by Kamoya Kimeu in 1973. The brain capacity is 510cc, not as impressive as other early specimen and forms of Homo habilis discovered. ## OH 7 OH 7 dates 1.75 million years old and was discovered by Jonathan Leakey on November 4, 1960 at Olduvai Gorge, Tanzania. It is a lower jaw complete with teeth and due to the size of the small teeth; researchers estimate this individual had a brain volume of 363cc. ## OH 24 OH 24 (AKA Twiggy) is a roughly deformed cranium dating 1.8 million years old discovered in October 1968 at Olduvai Gorge, Tanzania by Peter Nzube. The brain volume is just under 600cc; also a reduction in a protruding face is present compared to members of more primitive Australopithecines. Twiggy was found in a distorted matrix with a coating of limestone rock. ## KNM ER 1805 KNM ER 1805 is a specimen of an adult H. habilis made of 3 pieces of cranium dating 1.74 million years old from Koobi Fora, Kenya. Previous assumptions were that this specimen belongs to H. erectus based on the degree of prognathism and overall cranial shape. # Interpretations Homo habilis is thought to have mastered the Olduwan era (Early Paleolithic) tool case which utilized stone flakes. These stone flakes were more advanced than any tools previously used, and gave H. habilis the edge it needed to prosper in hostile environments previously too formidable for primates. Whether H. habilis was the first hominin to master stone tool technology remains controversial, as Australopithecus garhi, dated to 2.6 million years ago, has been found along with stone tool implements at least 100,000 - 200,000 years older than H. habilis. Most experts assume the intelligence and social organization of H. habilis were more sophisticated than typical australopithecines or chimpanzees. Yet despite tool usage, H. habilis was not the master hunter that its sister species (or descendants) proved to be, as there is ample fossil evidence[citation needed] that H. habilis was a staple in the diet of large predatory animals such as Dinofelis, a large scimitar-toothed predatory cat the size of a jaguar. H. habilis used tools primarily for scavenging, such as cleaving meat off of carrion, rather than defense or hunting. Homo habilis is thought to be the ancestor of the lankier and more sophisticated Homo ergaster, which in turn gave rise to the more human-appearing species Homo erectus. Debates continue over whether H. habilis is a direct human ancestor, and whether all of the known fossils are properly attributed to the species. Homo habilis co-existed with other Homo-like bipedal primates, such as Paranthropus boisei, some of which prospered for many millennia. However, H. habilis, possibly because of its early tool innovation and a less specialized diet, became the precursor of an entire line of new species, whereas Paranthropus boisei and its robust relatives disappeared from the fossil record. The classification of H. habilis into the Homo genus is controversial. Like Homo rudolfensis, H. habilis lacked many of the things that were unique to later hominins such as slim hips for walking long distances, a sophisticated sweating system, narrow birth canal, and legs longer than arms. Such traits as noticeable whites in the eyes, smaller hairs resulting in exposed skin, and a naked appearance remain theoretical. Despite larger brains than earlier species, and bipedal locomotion, many scientists think H. habilis and its close relative H. rudolfensis to be more ape-like, and not properly belonging in the Homo genus. # Stratification and expansion The evolution of Homo habilis is associated with the species' movement from the central Saharan region of Africa into the more demanding, yet resourceful habitats of Europe and to a lesser extent Asia. The major developments which contributed to this phenomena were the greater knowledge and skill with which Homo habilis crafted the rock blade, increasing knowledge about climate and how to adapt accordingly and the evolution of the voice-box which allowed greater co-ordination in hunting than was hitherto possible. Homo habilis, due perhaps to many years of adaptation, were able to create flint blades with 4 inches of cutting blade, this finer blade was strong enough to advance Homo habilis from scavenger to hunter. After many thousands of years of adaptation, humans were eventually able to accumulate enough information about the climate to adapt accordingly, building fires and wearing thick hides to stave off the cold. The evolution, or more so the moving of the voice box from the top of the throat to the bottom allowed a greater variety of speech required to co-ordinate and communicate during hunts. All of these evolutionary measures allowed Homo habilis to exploit the harsher climates of Asia and the borders of Europe. The western and central region of Europe was not settled by humanoids until the time of Homo erectus.[citation needed]	https://www.wikidoc.org/index.php/Homo_habilis
0691cb536777403ccea797d70e6cd46eb0681f5f	wikidoc	How to login	How to login # Overview It is not necessary to log in before viewing or editing pages. It does provide additional features, and is generally recommended. # Logging in Creating a user account means that you supply a username (your real name or a nickname) and a password. The system will reject a username that is already in use. A user account is created only once. You are then "logged in". Next time you log in you supply your username again and demonstrate with the password that you are the same person. Edits you make are recorded under your username. If you are not logged in your edits are recorded under your IP address. Some MediaWiki projects form a family in the sense that one logs in into the family as a whole, and that common preference settings apply. Notably this is the case for the more than 1000 Wikia projects. On Wikimedia projects logging in and setting preferences are currently done separately on each wiki. However, see m:Single login. You can see your IP address, if you are not logged in, by going to the page history. # Why log in? You don't have to log in to read any MediaWiki wiki. You don't even have to log in to edit a MediaWiki wiki - anyone can edit almost anypage, even without logging in. However, it's still a good idea to log in, for these reasons: - Other users will be able to recognise you by your username when you make changes to pages. As a "name" an IP address is somewhat clumsy. Also, if you use computers at different locations (home, office, internet cafe, etc.) you have a different IP-address in each case; even in the same location, depending on the Internet connection, the IP-address may be different each time. Therefore a username is better to maintain an identity. - You will have your own user page where you can write a bit about yourself, and a user talk page which you can use to communicate with other users. - You will be able to mark an edit as minor, which avoids inconvenience for other users. - You will be able to keep track of changes to pages you are interested in using a watch list. - If you choose to give an email address, other users will be able to contact you by email. This feature is anonymous - the user who emails you will not know your email address. You don't have to give your email address if you don't want to. Check the privacy policy of the individual site you're visiting, if any (for example, Wikipedia's draft privacy policy) - Check the privacy policy of the individual site you're visiting, if any (for example, Wikipedia's draft privacy policy) - You will be able to rename pages. - You will be able to set your own preferences, to change things such as: The number of pages displayed in Recent changes The fonts, colours and layout of the site, by using different skins. - The number of pages displayed in Recent changes - The fonts, colours and layout of the site, by using different skins. # How to log in First, make sure that your browser accepts cookies. Some browsers can accept or reject cookies from individual sites; users of these should configure the browser to accept cookies from each wiki you plan to edit, such as wikipedia.org. Click on the Log in link at the top right of the page. You will then be prompted to enter your username and password. If you have not logged in before, you will need to use the link provided to create an account. You may give your email address if you like. Other users will be able to send email to the address, but they won't be able to find out what the address is. If you click the box Remember me, you will not have to give your password again when you access MediaWiki wiki from the same computer. This feature will only work if your password was not generated by the Mediawiki software. So change your password please. Logging in and setting preferences are done separately on each wiki (for plans of changing this see m:Single login). You may like to maintain a cross-wiki identity by using the same username on each wiki that you use, if that name is still free. ## Log in problems If you find yourself unable to log in, you may have one of several problems. ### Capitalization Both usernames and passwords are case-sensitive on Wikipedia. Did you remember to type in the right capitalization? For example, if you registered under MyUserName, you will not be able to log in as Myusername (notice the subtle difference in spelling). The same goes for your password. The only exception is the first character of the username, which is capital by default. ### Did you register to this version of Wikipedia? If you have registered under one of Wikipedia's other languages (such as es.wikipedia.org) or projects (like en.wikibooks.org), you will have to recreate a username for this version of Wikipedia. ### Enable cookies If you appear to have logged in, but as soon as you try to look at a page after 'Log in successful', you appear logged out again, it is very likely to be a cookieproblem. See this brief tutorial on how to enable cookies for your browser. Make sure your computer's date and time are set correctly; if they are not, cookies may expire before they are supposed to. Note that some firewall and ad-blocking software may interfere with the cookie that wikidoc uses to keep a person logged in. ### Immediately logging out Some ISPs use transparent proxies which cause problems logging in. If you find that you are automatically logged out just after you have logged in, and removing all your Wikipedia cookies does not fix the issue, try using the secure server (much slower) to bypass the proxy. This happens most often with some satellite ISPs (particularly HughesNet/DirecWay/DirecPC). ### Occasional issues A user may occasionally find him/herself "automatically " logged out in between beginning an edit and saving it, or when switching between multiple wikidoc pages open in multiple windows. This can be a result of your browser's cookie, cache, or firewall settings, but due to the nature of the MediaWiki software, some user ID information is stored in the servers; sometimes, especially during heavy server load, the system can "glitch" and your ID information will be misplaced, resulting in a logout. ### Best solution Regardless of the reason for the logout, the simplest solution to the problem is to check the Remember me box. If you do this on a computer that can be accessed by more than one person (i.e. at the library, at work, at school), please find and erase your user ID cookies after your editing session or click the "log out" button. ## What if I forget the password? If you previously entered an e-mail address when signing up for the account or in your Preferences, you can enter your username on the login screen and click 'E-mail new password', which will send a temporary password to your e-mail address that will allow you to retrieve your account. If you did not enter an e-mail address, or the address was out of date, you will have to create a new account. ## Creating an account To create an account, select Log in (top right of page) then create an account. You will need to provide a username and password as well as answer a visual 'captcha' (Completely Automated Public Turing test to tell Computers and Humans Apart). This is a very simple visual test to make sure you are a human! Users with text, speech, or legacy browsers will be unable to create an account if they can not view this image. If you are unable to view captchas, you can request for an account to be created for you at Wikipedia:Request an account. Since September 26, 2006, the symbol "@" has not been permitted in usernames. # How to set preferences Click on the Preferences link at the top right of the page for various options, including: - Changing your password. - Changing the skin, which changes the way that the web pages look. See Help:Preferences. # Your User page and User talk page As a logged in user, you will be able to create your own user page and user talk page. When you are logged in, you will see your username displayed at the top right of the page. Click on this to get to your user page, which you can edit in the same way as any MediaWiki wiki page. Most users write a little bit about themselves and their interests on their user page. You also have a User talk page. You can access this by clicking on the Talk link next to your username at the top right of the page. Other people may write messages in your user talk page by editing it, and you can respond. See Talk page for more. # How to log out You can log out any time by clicking on the Log out link at the top right of the page. # Other advice ## Username impersonation Note that in some sans-serif fonts I (capital-i) and l (lowercase-L) look exactly the same, e.g. in Arial: I and l. If your username contains one of the two, it may be wise to register another account, but swap the letters (so if your username contains lowercase l change that to capital i). This is to prevent impersonation. You may then redirect the userpage of the "dummy" account to your real account. However, since the implementation of bugzilla:2290, accounts similar to existing ones can only be created by administrators. If you can't create an account because it's too similar to yours, nobody else (apart from administrators) can; since such an account cannot be used for impersonation, there is no need to create it as a doppleganger.	How to login Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview It is not necessary to log in before viewing or editing pages. It does provide additional features, and is generally recommended. # Logging in Creating a user account means that you supply a username (your real name or a nickname) and a password. The system will reject a username that is already in use. A user account is created only once. You are then "logged in". Next time you log in you supply your username again and demonstrate with the password that you are the same person. Edits you make are recorded under your username. If you are not logged in your edits are recorded under your IP address. Some MediaWiki projects form a family in the sense that one logs in into the family as a whole, and that common preference settings apply. Notably this is the case for the more than 1000 Wikia projects. On Wikimedia projects logging in and setting preferences are currently done separately on each wiki. However, see m:Single login. You can see your IP address, if you are not logged in, by going to the page history. # Why log in? You don't have to log in to read any MediaWiki wiki. You don't even have to log in to edit a MediaWiki wiki - anyone can edit almost anypage, even without logging in. However, it's still a good idea to log in, for these reasons: - Other users will be able to recognise you by your username when you make changes to pages. As a "name" an IP address is somewhat clumsy. Also, if you use computers at different locations (home, office, internet cafe, etc.) you have a different IP-address in each case; even in the same location, depending on the Internet connection, the IP-address may be different each time. Therefore a username is better to maintain an identity. - You will have your own user page where you can write a bit about yourself, and a user talk page which you can use to communicate with other users. - You will be able to mark an edit as minor, which avoids inconvenience for other users. - You will be able to keep track of changes to pages you are interested in using a watch list. - If you choose to give an email address, other users will be able to contact you by email. This feature is anonymous - the user who emails you will not know your email address. You don't have to give your email address if you don't want to. Check the privacy policy of the individual site you're visiting, if any (for example, Wikipedia's draft privacy policy) - Check the privacy policy of the individual site you're visiting, if any (for example, Wikipedia's draft privacy policy) - You will be able to rename pages. - You will be able to set your own preferences, to change things such as: The number of pages displayed in Recent changes The fonts, colours and layout of the site, by using different skins. - The number of pages displayed in Recent changes - The fonts, colours and layout of the site, by using different skins. # How to log in First, make sure that your browser accepts cookies. Some browsers can accept or reject cookies from individual sites; users of these should configure the browser to accept cookies from each wiki you plan to edit, such as wikipedia.org. Click on the Log in link at the top right of the page. You will then be prompted to enter your username and password. If you have not logged in before, you will need to use the link provided to create an account. You may give your email address if you like. Other users will be able to send email to the address, but they won't be able to find out what the address is. If you click the box Remember me, you will not have to give your password again when you access MediaWiki wiki from the same computer. This feature will only work if your password was not generated by the Mediawiki software. So change your password please. Logging in and setting preferences are done separately on each wiki (for plans of changing this see m:Single login). You may like to maintain a cross-wiki identity by using the same username on each wiki that you use, if that name is still free. ## Log in problems If you find yourself unable to log in, you may have one of several problems. ### Capitalization Both usernames and passwords are case-sensitive on Wikipedia. Did you remember to type in the right capitalization? For example, if you registered under MyUserName, you will not be able to log in as Myusername (notice the subtle difference in spelling). The same goes for your password. The only exception is the first character of the username, which is capital by default. ### Did you register to this version of Wikipedia? If you have registered under one of Wikipedia's other languages (such as es.wikipedia.org) or projects (like en.wikibooks.org), you will have to recreate a username for this version of Wikipedia. ### Enable cookies If you appear to have logged in, but as soon as you try to look at a page after 'Log in successful', you appear logged out again, it is very likely to be a cookieproblem. See this brief tutorial on how to enable cookies for your browser. Make sure your computer's date and time are set correctly; if they are not, cookies may expire before they are supposed to. Note that some firewall and ad-blocking software may interfere with the cookie that wikidoc uses to keep a person logged in. ### Immediately logging out Some ISPs use transparent proxies which cause problems logging in. If you find that you are automatically logged out just after you have logged in, and removing all your Wikipedia cookies does not fix the issue, try using the secure server (much slower) to bypass the proxy. This happens most often with some satellite ISPs (particularly HughesNet/DirecWay/DirecPC). ### Occasional issues A user may occasionally find him/herself "automatically " logged out in between beginning an edit and saving it, or when switching between multiple wikidoc pages open in multiple windows. This can be a result of your browser's cookie, cache, or firewall settings, but due to the nature of the MediaWiki software, some user ID information is stored in the servers; sometimes, especially during heavy server load, the system can "glitch" and your ID information will be misplaced, resulting in a logout. ### Best solution Regardless of the reason for the logout, the simplest solution to the problem is to check the Remember me box. If you do this on a computer that can be accessed by more than one person (i.e. at the library, at work, at school), please find and erase your user ID cookies after your editing session or click the "log out" button. ## What if I forget the password? If you previously entered an e-mail address when signing up for the account or in your Preferences, you can enter your username on the login screen and click 'E-mail new password', which will send a temporary password to your e-mail address that will allow you to retrieve your account. If you did not enter an e-mail address, or the address was out of date, you will have to create a new account. ## Creating an account To create an account, select Log in (top right of page) then create an account. You will need to provide a username and password as well as answer a visual 'captcha' (Completely Automated Public Turing test to tell Computers and Humans Apart). This is a very simple visual test to make sure you are a human! Users with text, speech, or legacy browsers will be unable to create an account if they can not view this image. If you are unable to view captchas, you can request for an account to be created for you at Wikipedia:Request an account. Since September 26, 2006, the symbol "@" has not been permitted in usernames. # How to set preferences Click on the Preferences link at the top right of the page for various options, including: - Changing your password. - Changing the skin, which changes the way that the web pages look. See Help:Preferences. # Your User page and User talk page As a logged in user, you will be able to create your own user page and user talk page. When you are logged in, you will see your username displayed at the top right of the page. Click on this to get to your user page, which you can edit in the same way as any MediaWiki wiki page. Most users write a little bit about themselves and their interests on their user page. You also have a User talk page. You can access this by clicking on the Talk link next to your username at the top right of the page. Other people may write messages in your user talk page by editing it, and you can respond. See Talk page for more. # How to log out You can log out any time by clicking on the Log out link at the top right of the page. # Other advice ## Username impersonation Note that in some sans-serif fonts I (capital-i) and l (lowercase-L) look exactly the same, e.g. in Arial: I and l. If your username contains one of the two, it may be wise to register another account, but swap the letters (so if your username contains lowercase l change that to capital i). This is to prevent impersonation. You may then redirect the userpage of the "dummy" account to your real account. However, since the implementation of bugzilla:2290, accounts similar to existing ones can only be created by administrators. If you can't create an account because it's too similar to yours, nobody else (apart from administrators) can; since such an account cannot be used for impersonation, there is no need to create it as a doppleganger. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/How_to_login
df74beda39da5c744b777582f19c2f1667b93ba0	wikidoc	Hydrogen ion	Hydrogen ion Hydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes. Depending on the charge of the ion, two different classes can be distinguished: # Cation (positively charged) When hydrogen loses its electron, the following cations can be formed: - Hydron: general name referring to the positive ion of any hydrogen isotope (H+) - Proton: 1H+ - Deuteron: 2H+, D+ - Triton: 3H+, T+ In addition, the ions produced by the reaction of these cations with water as well as their hydrates are called hydrogen ions: - Hydronium ion: H3O+ - Zundel cation: H5O2+ - Eigen cation: H9O4+ The latter two play an important role in proton hopping according to the Grotthuss mechanism. In connection with acids, hydrogen ions typically refer to hydrons. # Anion (negatively charged) Hydrogen anions are formed when additional electrons are acquired: - Hydride: general name referring to the negative ion of any hydrogen isotope - Deuteride: 2H-, D- - Tritide: 3H-, T- In organic chemistry, a hydrogen atom in a molecule is often referred to simply as a proton. The hydrogen anion has played an important role in quantum physics.	Hydrogen ion Hydrogen ion is recommended by IUPAC as a general term for all ions of hydrogen and its isotopes.[1] Depending on the charge of the ion, two different classes can be distinguished: # Cation (positively charged) When hydrogen loses its electron, the following cations can be formed: - Hydron: general name referring to the positive ion of any hydrogen isotope (H+) - Proton: 1H+ - Deuteron: 2H+, D+ - Triton: 3H+, T+ In addition, the ions produced by the reaction of these cations with water as well as their hydrates are called hydrogen ions: - Hydronium ion: H3O+ - Zundel cation: H5O2+ - Eigen cation: H9O4+ The latter two play an important role in proton hopping according to the Grotthuss mechanism. In connection with acids, hydrogen ions typically refer to hydrons. # Anion (negatively charged) Hydrogen anions are formed when additional electrons are acquired: - Hydride: general name referring to the negative ion of any hydrogen isotope - Deuteride: 2H-, D- - Tritide: 3H-, T- In organic chemistry, a hydrogen atom in a molecule is often referred to simply as a proton. The hydrogen anion has played an important role in quantum physics.	https://www.wikidoc.org/index.php/Hydrogen_ion
6e77f6e9f393f4a2d54bd41385a8e8e6fb952a41	wikidoc	Hydroperoxyl	Hydroperoxyl # Overview HO2, usually termed either hydroperoxyl radical or perhydroxyl radical, is the protonated form of superoxide; the protonation/deprotonation equilibrium exhibits a pK(a) of around 4.80. Consequently, about 0.3% of any superoxide present in the cytosol of a typical cell is in the protonated form. This ratio is rather accurately reflected by the published literature on the two species, as identified by a PubMed search; at the time of writing only 28 articles mention "HO2," "hydroperoxyl" or "perhydroxyl" in their titles, as against 9228 mentioning superoxide. Here it is argued that this correlation is not justifiable: that HO2's biological and biomedical importance far exceeds the attention it has received. Several key observations of recent years are reviewed that can be explained much more economically when the participation of HO2- is postulated. It is suggested that a more widespread appreciation of the possible role of HO2- in biological systems would be of considerable benefit to biomedical research. Because dielectric constant has a strong effect on pKa, and the dielectric constant of air is quite low, superoxide produced (photochemically) in the athmosphere is almost exclusively present as HO2. As HO2 is quite reactive, it acts as a "cleanser" of the atmosphere by degrading certain organic polutants. As such, the chemistry of HO2 is of considerable geochemical importance. # Source - The standard enthalpy of formation and standard entropy values at 298 K were provided by Martin J. Rabinowitz of NASA Lewis Research Center (marty@lerc.nasa.gov) - HO2 molecule in action	Hydroperoxyl # Overview HO2, usually termed either hydroperoxyl radical or perhydroxyl radical, is the protonated form of superoxide; the protonation/deprotonation equilibrium exhibits a pK(a) of around 4.80. Consequently, about 0.3% of any superoxide present in the cytosol of a typical cell is in the protonated form. This ratio is rather accurately reflected by the published literature on the two species, as identified by a PubMed search; at the time of writing only 28 articles mention "HO2," "hydroperoxyl" or "perhydroxyl" in their titles, as against 9228 mentioning superoxide. Here it is argued that this correlation is not justifiable: that HO2's biological and biomedical importance far exceeds the attention it has received. Several key observations of recent years are reviewed that can be explained much more economically when the participation of HO2* is postulated. It is suggested that a more widespread appreciation of the possible role of HO2* in biological systems would be of considerable benefit to biomedical research. Because dielectric constant has a strong effect on pKa, and the dielectric constant of air is quite low, superoxide produced (photochemically) in the athmosphere is almost exclusively present as HO2. As HO2 is quite reactive, it acts as a "cleanser" of the atmosphere by degrading certain organic polutants. As such, the chemistry of HO2 is of considerable geochemical importance. # Source - The standard enthalpy of formation and standard entropy values at 298 K were provided by Martin J. Rabinowitz of NASA Lewis Research Center (marty@lerc.nasa.gov) - HO2 molecule in action Template:WH Template:WS	https://www.wikidoc.org/index.php/Hydrogen_superoxide
1557347019bbc1a1ad9b43dfd68531cfaf35c377	wikidoc	Hydroquinone	Hydroquinone # 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 Hydroquinone is a dermatological agent that is FDA approved for the treatment of discoloration of skin, hyperpigmentation of skin. Common adverse reactions include burning sensation, contact dermatitis, localized erythema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Skin Lightening - To gradually lighten hyperpigmentation of the skin such as age spots, liver spots, freckles or hyperpigmentation that can occur as a result of pregnancy or the use of oral contraceptives. # Dosing - Use fingertips to apply a thin layer to affected areas. Use both morning and night or as directed by a physician. Gradual lightening of the discolored area can be expected in most cases. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use # Indications and Dosage - Discoloration of skin: emulsion, apply topically twice daily to affected area(s) or as directed by physician for no longer than 2 months. - Hyperpigmentation of skin: cream and gel, with or without sunscreens, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; rub in well. - Hyperpigmentation of skin: cream with sunblock, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; do not rub in. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroquinone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Hydroquinone FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use # Indications and Dosage - Safety and efficacy not established in children less than 12 years of age; not recommended for use except under physician supervision. - Discoloration of skin: 12 years and older; emulsion, apply topically twice daily to affected area(s) or as directed by physician for no longer than 2 months. - Hyperpigmentation of skin: 12 years and older; cream and gel, with or without sunscreens, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; rub in well. - Hyperpigmentation of skin: 12 years and older; cream with sunblock, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; do not rub in. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroquinone in pediatric patients. # Contraindications - Hypersensitivity to hydroquinone or any component of hydroquinone products. - Pregnancy, safety not established. - Children 12 years of age and under; safety not established. # Warnings There is limited information regarding Warnings of Hydroquinone in patients. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Hydroquinone Clinical Trials Experience in the drug label. ## Postmarketing Experience Dermatologic: Burning sensation, contact dermatitis, localized erythema # Drug Interactions There is limited information regarding Drug Interactions of Hydroquinone in patients. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Hydroquinone in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroquinone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Hydroquinone during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Hydroquinone in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Hydroquinone in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Hydroquinone in geriatric settings. ### Gender There is no FDA guidance on the use of Hydroquinone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Hydroquinone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Hydroquinone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Hydroquinone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Hydroquinone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Hydroquinone in patients who are immunocompromised. ### Others # Administration and Monitoring ### Administration Topical - Avoid exposure of treated areas to sunlight. - Avoid contact with eyes. ### Monitoring - Repigmentation # IV Compatibility There is limited information regarding IV Compatibility of Hydroquinone in patients. # Overdosage There is limited information regarding Overdose of Hydroquinone in patients. # Pharmacology ## Mechanism of Action - Hydroquinone acts by inhibiting the breakdown of tyrosine to 3-(3,4-dihydroxyphenyl) alanine (dopa) and thus suppresseing metabolic processes of melanocytes, to produce depigmentation of the skin which is reversible ## Structure There is limited information regarding Hydroquinone Structure in the drug label. ## Pharmacodynamics There is limited information regarding Hydroquinone Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Hydroquinone Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Hydroquinone Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Hydroquinone Clinical Studies in the drug label. # How Supplied There is limited information regarding Hydroquinone How Supplied in the drug label. ## Storage - Store at room temperature (15-30°C / 59-86°F). - Close cap securely after each use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Hydroquinone Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Hydroquinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names ACTIVE 4 # Look-Alike Drug Names There is limited information regarding Hydroquinone Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Hydroquinone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [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. # Overview Hydroquinone is a dermatological agent that is FDA approved for the treatment of discoloration of skin, hyperpigmentation of skin. Common adverse reactions include burning sensation, contact dermatitis, localized erythema. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Skin Lightening - To gradually lighten hyperpigmentation of the skin such as age spots, liver spots, freckles or hyperpigmentation that can occur as a result of pregnancy or the use of oral contraceptives. # Dosing - Use fingertips to apply a thin layer to affected areas. Use both morning and night or as directed by a physician. Gradual lightening of the discolored area can be expected in most cases. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use # Indications and Dosage - Discoloration of skin: emulsion, apply topically twice daily to affected area(s) or as directed by physician for no longer than 2 months. - Hyperpigmentation of skin: cream and gel, with or without sunscreens, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; rub in well. - Hyperpigmentation of skin: cream with sunblock, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; do not rub in. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroquinone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Hydroquinone FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use # Indications and Dosage - Safety and efficacy not established in children less than 12 years of age; not recommended for use except under physician supervision. - Discoloration of skin: 12 years and older; emulsion, apply topically twice daily to affected area(s) or as directed by physician for no longer than 2 months. - Hyperpigmentation of skin: 12 years and older; cream and gel, with or without sunscreens, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; rub in well. - Hyperpigmentation of skin: 12 years and older; cream with sunblock, apply topically twice daily to the affected area(s) or as directed by physician for no longer than 2 months; do not rub in. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hydroquinone in pediatric patients. # Contraindications - Hypersensitivity to hydroquinone or any component of hydroquinone products. - Pregnancy, safety not established. - Children 12 years of age and under; safety not established. # Warnings There is limited information regarding Warnings of Hydroquinone in patients. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Hydroquinone Clinical Trials Experience in the drug label. ## Postmarketing Experience Dermatologic: Burning sensation, contact dermatitis, localized erythema # Drug Interactions There is limited information regarding Drug Interactions of Hydroquinone in patients. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Hydroquinone in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydroquinone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Hydroquinone during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Hydroquinone in women who are nursing. ### Pediatric Use There is no FDA guidance on the use of Hydroquinone in pediatric settings. ### Geriatic Use There is no FDA guidance on the use of Hydroquinone in geriatric settings. ### Gender There is no FDA guidance on the use of Hydroquinone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Hydroquinone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Hydroquinone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Hydroquinone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Hydroquinone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Hydroquinone in patients who are immunocompromised. ### Others # Administration and Monitoring ### Administration Topical - Avoid exposure of treated areas to sunlight. - Avoid contact with eyes. ### Monitoring - Repigmentation # IV Compatibility There is limited information regarding IV Compatibility of Hydroquinone in patients. # Overdosage There is limited information regarding Overdose of Hydroquinone in patients. # Pharmacology ## Mechanism of Action - Hydroquinone acts by inhibiting the breakdown of tyrosine to 3-(3,4-dihydroxyphenyl) alanine (dopa) and thus suppresseing metabolic processes of melanocytes, to produce depigmentation of the skin which is reversible ## Structure There is limited information regarding Hydroquinone Structure in the drug label. ## Pharmacodynamics There is limited information regarding Hydroquinone Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Hydroquinone Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Hydroquinone Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Hydroquinone Clinical Studies in the drug label. # How Supplied There is limited information regarding Hydroquinone How Supplied in the drug label. ## Storage - Store at room temperature (15-30°C / 59-86°F). - Close cap securely after each use. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Hydroquinone Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Hydroquinone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names ACTIVE 4 # Look-Alike Drug Names There is limited information regarding Hydroquinone Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Hydroquinone
f8609c7225244d4b7dedcc72eed03a524ce117d0	wikidoc	Hydrotalcite	Hydrotalcite # Overview Hydrotalcite is a layered double hydroxide of general formula Mg6Al2CO3(OH)16·4(H2O), whose name is derived from its resemblance with talc and its high water content. The layers of the structure may stack in different ways, to produce a 3-layer rhombohedral structure (3R Polytype), or a 2-layer hexagonal structure (2H polytype) which was formerly known under the name manasseite. The two polytypes are often intergrown. The carbonate anions that lie between the structural layers are weakly bound, so hydrotalcite has anion exchange capabilities. It was first described in 1842 for an occurrence in a serpentine - magnesite deposit in Snarum, Modum, Buskerud, Norway. It occurs as an alteration mineral in serpentinite in association with serpentine, dolomite and hematite. Hydrotalcite has been studied as potential getter for iodide in order to scavenge the long-lived 129I (T1/2 = 15.7 million years) and also other fission products such as 79Se (T1/2 = 295 000 years) and 99Tc, (T1/2 = 211 000 years) present in spent nuclear fuel to be disposed under oxidising conditions in volcanic tuff at the Yucca Mountain nuclear waste repository. Unfortunately carbonate easily replaces iodide in its interlayer. Another difficulty arising in the quest of an iodide getter for radioactive waste is the long-term stability of the sequestrant that must survive over geological time scales. Layered double hydroxides are well known for their anion exchange properties. Hydrotalcite is also used as an antacid.	Hydrotalcite Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hydrotalcite is a layered double hydroxide of general formula Mg6Al2CO3(OH)16·4(H2O), whose name is derived from its resemblance with talc and its high water content. The layers of the structure may stack in different ways, to produce a 3-layer rhombohedral structure (3R Polytype), or a 2-layer hexagonal structure (2H polytype) which was formerly known under the name manasseite. The two polytypes are often intergrown.[1][2][3] The carbonate anions that lie between the structural layers are weakly bound, so hydrotalcite has anion exchange capabilities. It was first described in 1842 for an occurrence in a serpentine - magnesite deposit in Snarum, Modum, Buskerud, Norway.[1] It occurs as an alteration mineral in serpentinite in association with serpentine, dolomite and hematite.[2] Hydrotalcite has been studied as potential getter for iodide in order to scavenge the long-lived 129I (T1/2 = 15.7 million years) and also other fission products such as 79Se (T1/2 = 295 000 years) and 99Tc, (T1/2 = 211 000 years) present in spent nuclear fuel to be disposed under oxidising conditions in volcanic tuff at the Yucca Mountain nuclear waste repository. Unfortunately carbonate easily replaces iodide in its interlayer. Another difficulty arising in the quest of an iodide getter for radioactive waste is the long-term stability of the sequestrant that must survive over geological time scales. Layered double hydroxides are well known for their anion exchange properties. Hydrotalcite is also used as an antacid.	https://www.wikidoc.org/index.php/Hydrotalcite
0062fa24dc2d59bc14c639c111f55c4bcfaa27e4	wikidoc	Hygromycin B	Hygromycin B Hygromycin B, is an antibiotic produced by the bacterium Streptomyces hygroscopicus. It is an aminoglycoside that kills bacteria, fungi and higher eukaryotic cells by inhibiting protein synthesis. # History Hygromycin B was originally developed in the 1950's for use with animals and is still added into swine and chicken feed as an anthelmintic or anti-worming agent (product name: Hygromix). Hygromycin B is produced by Streptomyces hygroscopicus, a bacteria isolated in 1953 from a soil sample. Resistance genes were discovered in the early 1980's. # Use in research In the laboratory it is used for the selection and maintenance of prokaryotic and eukaryotic cells that contain the hygromycin resistance gene. The resistance gene is a kinase that inactivates hygromycin B through phosphorylation. Since the discovery of hygromycin-resistance genes, hygromycin B has become a standard selection antibiotic in gene transfer experiments in many prokaryotic and eukaryotic cells.	Hygromycin B Hygromycin B, is an antibiotic produced by the bacterium Streptomyces hygroscopicus. It is an aminoglycoside that kills bacteria, fungi and higher eukaryotic cells by inhibiting protein synthesis[1]. # History Hygromycin B was originally developed in the 1950's for use with animals and is still added into swine and chicken feed as an anthelmintic or anti-worming agent (product name: Hygromix). Hygromycin B is produced by Streptomyces hygroscopicus, a bacteria isolated in 1953 from a soil sample. Resistance genes were discovered in the early 1980's.[2][3] # Use in research In the laboratory it is used for the selection and maintenance of prokaryotic and eukaryotic cells that contain the hygromycin resistance gene. The resistance gene is a kinase that inactivates hygromycin B through phosphorylation.[4] Since the discovery of hygromycin-resistance genes, hygromycin B has become a standard selection antibiotic in gene transfer experiments in many prokaryotic and eukaryotic cells. # External links Information from hygromycin.net (InvivoGen) - mechanism of action: [1] - resistance genes: [2] - chemistry, stability: [3]	https://www.wikidoc.org/index.php/Hygromycin_B
13bcc4e4fcba4f797008a4fa31dd25a3cd1cf265	wikidoc	Hyperalgesia	Hyperalgesia Hyperalgesia is an extreme sensitivity to pain, which in one form is caused by damage to nociceptors in the body's soft tissues. Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form. The focal form is typically associated with injury, and is divided into two subtypes: - Primary hyperalgesia describes pain sensitivity that occurs directly in the damaged tissues. - Secondary hyperalgesia describes pain sensitivity that occurs in surrounding undamaged tissues. Hyperalgesia is induced by Platelet Aggregating Factor (PAF) which comes about in an inflammatory or an allergic response. This seems to occur via immune cells interacting with the peripheral nervous system and releasing pain-producing chemicals (cytokines and chemokines) (see Marchand, Perretti, & McMahon, 2005). One unusual cause of focal hyperalgesia is platypus venom. Ikeda, Stark, Fischer, Wagner, Drdla, Jäger, et al. (2006) showed that stimulation of pain fibres in a pattern consistent with that from inflammation switched on a form of amplification in the spinal cord, long term potentiation. This occurred where the pain fibres contacted a pain pathway, the periaqueductal grey. Ikeda et al. argued that amplification in the spinal cord is another way of producing hyperalgesia.	Hyperalgesia Template:Distinguish2 Hyperalgesia is an extreme sensitivity to pain, which in one form is caused by damage to nociceptors in the body's soft tissues. Hyperalgesia can be experienced in focal, discrete areas, or as a more diffuse, body-wide form. Conditioning studies have established that it is possible to experience a learned hyperalgesia of the latter, diffuse form. The focal form is typically associated with injury, and is divided into two subtypes: - Primary hyperalgesia describes pain sensitivity that occurs directly in the damaged tissues. - Secondary hyperalgesia describes pain sensitivity that occurs in surrounding undamaged tissues. Hyperalgesia is induced by Platelet Aggregating Factor (PAF) which comes about in an inflammatory or an allergic response. This seems to occur via immune cells interacting with the peripheral nervous system and releasing pain-producing chemicals (cytokines and chemokines) (see Marchand, Perretti, & McMahon, 2005). One unusual cause of focal hyperalgesia is platypus venom. Ikeda, Stark, Fischer, Wagner, Drdla, Jäger, et al. (2006) showed that stimulation of pain fibres in a pattern consistent with that from inflammation switched on a form of amplification in the spinal cord, long term potentiation. This occurred where the pain fibres contacted a pain pathway, the periaqueductal grey. Ikeda et al. argued that amplification in the spinal cord is another way of producing hyperalgesia.	https://www.wikidoc.org/index.php/Hyperalgesia
fbb1f952f661481409aa59d6ec18aa09862e35d5	wikidoc	Hyperkinesia	Hyperkinesia Hyperkinesia, in medicine, refers to an abnormal increase in muscular activity. The opposite of Hyperkinesia is known as "Hypokinesia". Hyperkinesia is separated into 2 types: Rhythmic and Nonrhythmic. Rhythmic disorders consist of mainly tremours. Nonrhythmic disorders are mostly involuntary muscle contractions. One example of a nonrhythmic hyperkinesia disorder is tics. # Etiology The word Hyperkinesia comes from the Greek hyper, meaning increased, and kinein, meaning to move. # Causes Drug Side Effect: - Amobarbital sodium - Pergolide - Secobarbital sodium # Sources	Hyperkinesia Hyperkinesia, in medicine, refers to an abnormal increase in muscular activity. The opposite of Hyperkinesia is known as "Hypokinesia". Hyperkinesia is separated into 2 types: Rhythmic and Nonrhythmic. Rhythmic disorders consist of mainly tremours. Nonrhythmic disorders are mostly involuntary muscle contractions. One example of a nonrhythmic hyperkinesia disorder is tics. # Etiology The word Hyperkinesia comes from the Greek hyper, meaning increased, and kinein, meaning to move. # Causes Drug Side Effect: - Amobarbital sodium - Pergolide - Secobarbital sodium Template:Neuroscience-stub # Sources - [1] Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hyperkinesia
7e9c149819d486d1959d318b8d41c23ec5000662	wikidoc	Hyperpyrexia	Hyperpyrexia Hyperpyrexia is an excessive and unusual elevation of set body temperature greater than or equal to 41.1° Celsius (106°F), or extremely high fever. It differs from hyperthermia in that the body's temperature regulation mechanism sets the body temperature too high, whereas in hyperthermia the body temperature is too high above the set point. # Differential Diagnosis of Causes of Hyperpyrexia Some of the more common causes of hyperpyrexia include: - excessive exposure to heat or the sun (also called heat hyperpyrexia, a part of heatstroke) - amphetamine or other stimulant abuse, which can aggravate the effects of heat hyperpyrexia - withdrawal from barbiturates, alcohol, or other anxiolytics, although it is less common with benzodiazepines - septicemia (a generalized bacterial infection of the blood) - some viral infections, such as mononucleosis - a thyrotoxic crisis (in hyperthyroidism) - Malignant hyperpyrexia is a particular condition caused by the breakdown of muscle following its over-excitation, in response to certain stimuli, such as extreme exercise (especially in a high ambient temperature), intense and prolonged convulsions, anesthesia, fever or some drugs, such as cocaine, alcohol and aspirin. - Neuroleptic malignant syndrome (NMS) can also cause hyperprexia after the administration of antipsychotic drugs.	Hyperpyrexia Template:Search infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Hyperpyrexia is an excessive and unusual elevation of set body temperature greater than or equal to 41.1° Celsius (106°F), or extremely high fever. It differs from hyperthermia in that the body's temperature regulation mechanism sets the body temperature too high, whereas in hyperthermia the body temperature is too high above the set point. # Differential Diagnosis of Causes of Hyperpyrexia Some of the more common causes of hyperpyrexia include: [1] [2] - excessive exposure to heat or the sun (also called heat hyperpyrexia, a part of heatstroke) - amphetamine or other stimulant abuse, which can aggravate the effects of heat hyperpyrexia - withdrawal from barbiturates, alcohol, or other anxiolytics, although it is less common with benzodiazepines - septicemia (a generalized bacterial infection of the blood) - some viral infections, such as mononucleosis - a thyrotoxic crisis (in hyperthyroidism) - Malignant hyperpyrexia is a particular condition caused by the breakdown of muscle following its over-excitation, in response to certain stimuli, such as extreme exercise (especially in a high ambient temperature), intense and prolonged convulsions, anesthesia, fever or some drugs, such as cocaine, alcohol and aspirin. - Neuroleptic malignant syndrome (NMS) can also cause hyperprexia after the administration of antipsychotic drugs. # External links - Template:GPNotebook Template:Skin and subcutaneous tissue symptoms and signs Template:Nervous and musculoskeletal system symptoms and signs Template:Urinary system symptoms and signs Template:Cognition, perception, emotional state and behaviour symptoms and signs Template:Speech and voice symptoms and signs Template:General symptoms and signs Template:WikiDoc Sources - ↑ Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:77 ISBN 1591032016 - ↑ Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:68 ISBN 140510368X	https://www.wikidoc.org/index.php/Hyperpyrexia
98f33131175138d801caa1a2b3b47b628740f7be	wikidoc	Hypnosurgery	Hypnosurgery Hypnosurgery is the term given to an operation where the patient is sedated using hypnotherapy rather than traditional anaesthetics. It is still in its experimental stages, and not widely used. Only a few successful cases have been reported. Chemical anesthesia is still the standard of care, mainly because of its high reliability and the fact that it's more complete, i.e. while hypnosurgery patients will almost always feel some pain, patients under general anesthesia are completely unaware of the operation. During hypnosurgery, a hypnotist helps the patient control their subconcious reflexes so that they do not feel pain in the traditional sense. Patients are aware of sensation as the operation progresses and often describe a tingling or tickling sensation when pain would normally be expected. The main benefit of hypnosurgery is that there are fewer side effects, and generally a patient can leave hospital sooner than if normal anaesthetics are used. A reduction in blood loss and post-operative nausea have also been recorded. It should be noted, however, that further studies are being performed and that hypnosurgery is not suitable for all patients. In April 2006, the British television channel More4 broadcast a live hernia hypnosurgery operation.	Hypnosurgery Hypnosurgery is the term given to an operation where the patient is sedated using hypnotherapy rather than traditional anaesthetics. It is still in its experimental stages, and not widely used. Only a few successful cases have been reported. Chemical anesthesia is still the standard of care, mainly because of its high reliability and the fact that it's more complete, i.e. while hypnosurgery patients will almost always feel some pain, patients under general anesthesia are completely unaware of the operation. During hypnosurgery, a hypnotist helps the patient control their subconcious reflexes so that they do not feel pain in the traditional sense.[citation needed] Patients are aware of sensation as the operation progresses and often describe a tingling or tickling sensation when pain would normally be expected.[citation needed] The main benefit of hypnosurgery is that there are fewer side effects, and generally a patient can leave hospital sooner than if normal anaesthetics are used.[citation needed] A reduction in blood loss and post-operative nausea have also been recorded.[citation needed] It should be noted, however, that further studies are being performed and that hypnosurgery is not suitable for all patients.[citation needed] In April 2006, the British television channel More4 broadcast a live hernia hypnosurgery operation. # External links Template:Wiktionarypar - More4: Hypnosurgery live - the entire episode is available for download online (must register to watch). - Cesarean section video Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Hypnosurgery
80a0fe030f05e3b5796414e98f83b88235d5c798	wikidoc	Hypochondria	Hypochondria # Overview Hypochondria (or hypochondriasis, sometimes referred to as health anxiety/health phobia) refers to an excessive preoccupation or worry about having a serious illness. Often, hypochondria persists even after a physician has evaluated a person and reassured him/her that his/her concerns about symptoms do not have an underlying medical basis or, if there is a medical illness, the concerns are far in excess of what is appropriate for the level of disease. Many people suffering from this disorder focus on a particular symptom as the catalyst of their worrying, such as gastro-intestinal problems, palpitations, or muscle fatigue. The DSM-IV-TR defines this disorder, “Hypochondriasis,” as a somatoform disorder and it is thought to plague about 1-5% of the general population. Hypochondria is often characterized by fears that minor bodily symptoms may indicate a serious illness, constant self-examination and self-diagnosis, and a preoccupation with one's body. Many individuals with hypochondriasis express doubt and disbelief in the doctors' diagnosis, and report that doctors’ reassurance about an absence of a serious medical condition is unconvincing, or un-lasting. Many hypochondriacs require constant reassurance, either from doctors, family, or friends, and the disorder can become a disabling torment for the individual with hypochondriasis, as well as his or her family and friends. Some hypochondriacal individuals are completely avoidant of any reminder of illness, whereas others are frequent visitors of doctors’ offices. Other hypochondriacs will never speak about their terror, convinced that their fear of having a serious illness will not be taken seriously by those in whom they confide. Hypochondria is often associated with obsessive-compulsive disorder (OCD), depression, and anxiety, and can also be brought on by stress. It is distinct from factitious disorders and malingering, in which an individual intentionally fakes, exaggerates, or induces mental or physical illnesses. # Etymology and colloquial use The term hypochondria comes from the Greek hypo- (below) and chondros (cartilage - of the breast bone), and is thought to have been originally coined by Hippocrates. It was thought by many Greek physicians of antiquity that many ailments were caused by the movement of the spleen, an organ located near the hypochondrium (the upper region of the abdomen just below the ribs on either side of the epigastrium). Later use in the 19th Century employed the term to mean, “illness without a specific cause,” and it is thought that around that time period the term evolved to be the male counterpart to female hysteria. In modern usage, the term hypochondriac is often used as a pejorative label for individuals who hold the belief that they have a serious illness despite repeated reassurance from physicians that they are perfectly healthy. # Manifestation and comorbidity Hypochondriasis manifests in various ways. Some people have numerous intrusive thoughts and physical sensations that push them to check with family, friends and physicians. Other people are so afraid of any reminder of illness that they will avoid medical professionals for a seemingly minor problem, sometimes to the point of becoming neglectful of their health when a serious condition may exist and go undiagnosed. Yet, some others live in despair and depression, certain that they have a life-threatening disease and no physician can help them, considering the disease as a punishment for past misdeeds. Hypochondriasis is often accompanied by other psychological disorders. Clinical depression, obsessive-compulsive disorder (also known as OCD), phobias and somatization disorder are the most common accompanying conditions in people with hypochondriasis, as well as a generalized anxiety disorder diagnosis at some point in their life. Many people with hypochondriasis experience a cycle of intrusive thoughts followed by compulsive checking, which is very similar to the symptoms of obsessive-compulsive disorder. However, while people with hypochondriasis are afraid of having an illness, patients with OCD worry about getting an illness or of transmitting an illness to others. Although some people might have both, these are distinct conditions. Patients with hypochondriasis often are not aware that depression and anxiety produce their own physical symptoms that might be mistaken for signs of a serious medical disease. For example, people with depression often experience changes in appetite and weight fluctuation, fatigue, decreased interest in sex and motivation in life overall. Intense anxiety is associated with rapid heart beat, palpitations, sweating, muscle tension, stomach discomfort, and numbness or tingling in certain parts of the body (hands, forehead, etc.). # Factors contributing to Hypochondria Cyberchondria is a colloquial term for hypochondria in individuals who have researched medical conditions on the internet. The media and the internet often contribute to hypochondria, as articles, TV shows and advertisements regarding serious illnesses such as cancer and multiple sclerosis (some of the common diseases hypochondriacs think they have) often portray these diseases as being random, obscure and somewhat inevitable. Inaccurate portrayal of risk and the identification of non-specific symptoms as signs of serious illness contribute to exacerbating the hypochondriac’s fear that they actually have that illness. Major disease outbreaks or predicted pandemics can also contribute to hypochondria. Statistics regarding certain illnesses, such as cancer, will give hypochondriacs the illusion that they are more likely to develop the disease. A simple suggestion of mental illness can often trigger one with hypochondria to obsess over the possibility. It is common for serious illnesses or deaths of family members or friends to trigger hypochondria in certain individuals. Similarly, when approaching the age of a parent's premature death from disease, many otherwise healthy, happy individuals fall prey to hypochondria. These individuals believe they are suffering from the same disease that caused their parent's death, sometimes causing panic attacks with corresponding symptoms. A majority of people who experience physical pains or anxieties over non-existent ailments are not actually "faking it", but rather, experience the natural results of other emotional issues, such as very high amounts of stress. Our emotions have cognitive, physiological and feeling components. For example, when one is sad, an individual may simultaneously experience muscle weakness and loss of energy. Whether it is an emotional memory, a vivid fantasy, or a present situation, the brain treats it the same. It is a real experience processed through neural paths. Family studies of hypochondriasis do not show a genetic transmission of the disorder. Among relatives of people suffering from hypochondriasis only somatization disorder and generalized anxiety disorder were more common than in average families. Other studies have shown that the first degree relatives of patients with OCD have a higher than expected frequency of a somatoform disorder (either hypochondriasis or body dysmorphic disorder). Many people with hypochondriasis point out a pattern of paying close attention to bodily sensations, preventative investigations, and checking with physicians, that they have learned from family members, but there is no definitive scientific support for this notion. Many people are aware that anxiety and depression are mediated by problems with brain chemicals such as serotonin and norepinephrine. The physical symptoms that people with anxiety or depression feel are indeed real bodily symptoms, and are in fact triggered by neurochemical changes. For example, too much norepinephrine will result in severe panic attacks with symptoms of increased heart rate and sweating, shortness of breath, and fear. Too little serotonin can result in severe depression, accompanied by an inability to sleep, severe fatigue, and needs fixing. # Treatment To treat hypochondriasis, one must acknowledge the interplay of body and mind. If a person is sick with a medical disease such as diabetes or arthritis, there will often be psychological consequences, such as depression. Some even report being suicidal. In the same way, someone with psychological issues such as depression or anxiety will sometimes experience physical manifestations of these affective fluctuations, often in the form of medically unexplained symptoms. Common symptoms include headaches, abdominal, back, joint, rectal, or urinary pain, nausea,itching, diarrhea, dizziness, or balance problems. Many people with hypochondriasis accompanied by medically unexplained symptoms feel they are not understood by their physicians, and are frustrated by their doctors’ repeated failure to provide symptom relief. Common to the different approaches to the treatment of hypochondriasis is the effort to help each patient find a better way to overcome the way his/her medically unexplained symptoms and illness concerns rule her/his life. Current research makes clear that this excessive worry can be helped by either appropriate medicine or targeted psychotherapy. For a long time, hypochondriasis was considered untreatable. However, recent scientific studies show that cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine and paroxetine) are effective treatment options for hypochondriasis as demonstrated in clinical trials . CBT, a psycho-educational "talk" therapy, helps the worrier to address and cope with bothersome physical symptoms and illness worries and is found helpful in reducing the intensity and frequency of troubling bodily symptoms. SSRIs can reduce obsessional worry through readjusting neurotransmitter levels, have been shown to be effective as treatments for anxiety and depression, as well as for hypochondriasis. NIH-funded studies are now underway to compare different treatment approaches for hypochondriasis: a study in the NYC area and a study in the Boston area. In these studies, patients will be given one of four treatments: supportive therapy with fluoxetine, supportive therapy with placebo, cognitive behavior therapy, or cognitive behavior therapy with fluoxetine. For more information you can also visit external links. In Norway a clinic specializing in the treatment of hypochondria has been opened. # Tips for hypochondriacs If one is worried about having a serious medical illness despite receiving reassurance to the contrary by a physician during a comprehensive evaluation, it might be beneficial to put these techniques into practice: - Keeping a journal describing symptoms or events that led to your episodes of illness should allow one to see the illness clearer. - Trying to restrict or put a time limit on one's internet medical research, reading of medical books, or self-checking behaviors, as they tend to increase illness worries. - Maintaining a healthy lifestyle, including a good night sleep, well-balanced diet and a positive outlook. A good tip is to follow the PEAS tool sometimes used to combat depression: Pleasure, Exercise, Achievement and Socializing - try to add an aspect of each to daily activities. - Practicing relaxation techniques, such as breathing, meditation or other methods may help to decrease anxiety and the effects of stress. - Trying interrupt one's worries with activities that will fully engage one's attention and shift it away from illness; for example, hobbies, word or number games, exercise or walking, talking with a humorous friend, or recalling happy memories. - Thinking about alternative explanations for one's physical sensations that might include stress or normal bodily changes. - Breaking one's habits of worrying one step at a time. # Self-Help Books The following self-help books might be helpful as well. - Minding the Body, Mending the Mind. Joan Borysenko. Bantam, 1988. - The Wellness Book. Herbert Benson and Eileen Stuart. Simon & Schuster/Fireside, 1992 - The Woman’s Comfort Book. Jennifer Louden. Harper SanFrancisco, 1992. - The Stress Solution-An Action Plan to Manage the Stress in Your Life. Lyle Miller and Alma Dell Smith. Pocket Book, 1993. - Wellness at Work-Building Resilience to Job Stress. Valerie O’Hara. New Harbinger Publications, 1995. - Stop Suffering Now. Arthur J. Barsky and Emily C. Deans. HarperCollins, 2005. - Phantom Illness: Recognizing, Understanding, and Overcoming Hypochondria. Carla Cantor and Brian Fallon. Mariner Books, 1997. - Hypochondria: Woeful Imaginings. Susan Baur. University of California Press, 1989. - Managing Pain Before It Manages You. Margaret Caudill. Guilford Press, 1995. - Healing Mind, Healthy Woman. Alice Domar and Henry Dreher. Henry Holt & Co,1996. - Living a Healthy Life with a Chronic Condition. Kate Lorig, Holstead Holman. Bull Publishing Co, 1994. - The Healthy Mind Healthy Body Handbook. David Sobel and Robert Ornstein. HarperCollins,1996. - It’s Not All in Your Head. Gordon JG Asmundson and Steven Taylor. Guilford Press, 2005 - Stop worrying About your Health! George Zgourides. Oakland, CA: New Harbinger Publications, 2002 - Back Sense. Ronald D. Siegel, Michael H. Urdang, Douglas R. Johnson. Broadway Books, 2001. - The Feeling Good Handbook. David Burns. Penguin, 1989. - Mind Over Mood. Dennis Greenberger and Christine Padesky. Guilford Press, 1995. # Pop Culture In the 2001 film Le Fabuleux Destin d'Amélie Poulain (The Fabulous Life of Amélie Poulain), Isabelle Nanty's character Georgette is a hypochondriac. In the 2005 DreamWorks Animation film Madagascar, a giraffe (Melman) is portrayed as a hypochondriac. On the show South Park, Stan Marsh's father, Randy Marsh, is described by his son as a hypochondriac in the episode "Bloody Mary". In the film My Girl the leading character Vada is a hypochondriac most likely due to her being raised in a funeral home. In the film, Bandits, one of the bank robbers (portrayed by Billy Bob Thornton), Terry, is a hypochondriac. The other bank robber, Joe, used this to an advantage once, and claimed that his brother received a brain tumor from smelling burning feathers as a joke to get Terry to worry. In the TV series, Scrubs, recurring character Harvey Korman, portrayed by actor Richard Kind, is a hypochondriac that appears in several episodes. His most notable appearance being in the episode, "My New Old Friend." In the 1986 hit film Ferris Bueller's Day Off, Ferris' friend Cameron Frye (portrayed by Alan Ruck) was displaying some symptoms of hypochondria throughout the movie, notably when he is lying in bed thinking he is sick, until Ferris convinces him that it's all in his head. In the TV series, Boy Meets World Cory is diagnosed with hypochondria and sees it as a real illness. In the book It, Eddie Kaspbrak's mother is a hypochondriac who convinces her son that he is frail and has asthma, even though he does not. She even argues with doctors regarding her son's health.	Hypochondria For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hypochondria (or hypochondriasis, sometimes referred to as health anxiety/health phobia) refers to an excessive preoccupation or worry about having a serious illness. Often, hypochondria persists even after a physician has evaluated a person and reassured him/her that his/her concerns about symptoms do not have an underlying medical basis or, if there is a medical illness, the concerns are far in excess of what is appropriate for the level of disease. Many people suffering from this disorder focus on a particular symptom as the catalyst of their worrying, such as gastro-intestinal problems, palpitations, or muscle fatigue. The DSM-IV-TR defines this disorder, “Hypochondriasis,” as a somatoform disorder and it is thought to plague about 1-5% of the general population.[1] Hypochondria is often characterized by fears that minor bodily symptoms may indicate a serious illness, constant self-examination and self-diagnosis, and a preoccupation with one's body. Many individuals with hypochondriasis express doubt and disbelief in the doctors' diagnosis, and report that doctors’ reassurance about an absence of a serious medical condition is unconvincing, or un-lasting. Many hypochondriacs require constant reassurance, either from doctors, family, or friends, and the disorder can become a disabling torment for the individual with hypochondriasis, as well as his or her family and friends. Some hypochondriacal individuals are completely avoidant of any reminder of illness, whereas others are frequent visitors of doctors’ offices. Other hypochondriacs will never speak about their terror, convinced that their fear of having a serious illness will not be taken seriously by those in whom they confide. Hypochondria is often associated with obsessive-compulsive disorder (OCD), depression, and anxiety, and can also be brought on by stress. It is distinct from factitious disorders and malingering, in which an individual intentionally fakes, exaggerates, or induces mental or physical illnesses. # Etymology and colloquial use The term hypochondria comes from the Greek hypo- (below) and chondros (cartilage - of the breast bone), and is thought to have been originally coined by Hippocrates. It was thought by many Greek physicians of antiquity that many ailments were caused by the movement of the spleen, an organ located near the hypochondrium (the upper region of the abdomen just below the ribs on either side of the epigastrium). Later use in the 19th Century employed the term to mean, “illness without a specific cause,” and it is thought that around that time period the term evolved to be the male counterpart to female hysteria. In modern usage, the term hypochondriac is often used as a pejorative label for individuals who hold the belief that they have a serious illness despite repeated reassurance from physicians that they are perfectly healthy. # Manifestation and comorbidity Hypochondriasis manifests in various ways. Some people have numerous intrusive thoughts and physical sensations that push them to check with family, friends and physicians. Other people are so afraid of any reminder of illness that they will avoid medical professionals for a seemingly minor problem, sometimes to the point of becoming neglectful of their health when a serious condition may exist and go undiagnosed. Yet, some others live in despair and depression, certain that they have a life-threatening disease and no physician can help them, considering the disease as a punishment for past misdeeds. [2] Hypochondriasis is often accompanied by other psychological disorders. Clinical depression, obsessive-compulsive disorder (also known as OCD), phobias and somatization disorder are the most common accompanying conditions in people with hypochondriasis, as well as a generalized anxiety disorder diagnosis at some point in their life. [3] Many people with hypochondriasis experience a cycle of intrusive thoughts followed by compulsive checking, which is very similar to the symptoms of obsessive-compulsive disorder. However, while people with hypochondriasis are afraid of having an illness, patients with OCD worry about getting an illness or of transmitting an illness to others. [2] Although some people might have both, these are distinct conditions. Patients with hypochondriasis often are not aware that depression and anxiety produce their own physical symptoms that might be mistaken for signs of a serious medical disease. For example, people with depression often experience changes in appetite and weight fluctuation, fatigue, decreased interest in sex and motivation in life overall. Intense anxiety is associated with rapid heart beat, palpitations, sweating, muscle tension, stomach discomfort, and numbness or tingling in certain parts of the body (hands, forehead, etc.). # Factors contributing to Hypochondria Cyberchondria is a colloquial term for hypochondria in individuals who have researched medical conditions on the internet. The media and the internet often contribute to hypochondria, as articles, TV shows and advertisements regarding serious illnesses such as cancer and multiple sclerosis (some of the common diseases hypochondriacs think they have) often portray these diseases as being random, obscure and somewhat inevitable. Inaccurate portrayal of risk and the identification of non-specific symptoms as signs of serious illness contribute to exacerbating the hypochondriac’s fear that they actually have that illness. Major disease outbreaks or predicted pandemics can also contribute to hypochondria. Statistics regarding certain illnesses, such as cancer, will give hypochondriacs the illusion that they are more likely to develop the disease. A simple suggestion of mental illness can often trigger one with hypochondria to obsess over the possibility. It is common for serious illnesses or deaths of family members or friends to trigger hypochondria in certain individuals. Similarly, when approaching the age of a parent's premature death from disease, many otherwise healthy, happy individuals fall prey to hypochondria. These individuals believe they are suffering from the same disease that caused their parent's death, sometimes causing panic attacks with corresponding symptoms. A majority of people who experience physical pains or anxieties over non-existent ailments are not actually "faking it", but rather, experience the natural results of other emotional issues, such as very high amounts of stress. Template:Rquote Our emotions have cognitive, physiological and feeling components. For example, when one is sad, an individual may simultaneously experience muscle weakness and loss of energy. Whether it is an emotional memory, a vivid fantasy, or a present situation, the brain treats it the same. It is a real experience processed through neural paths. Family studies of hypochondriasis do not show a genetic transmission of the disorder. Among relatives of people suffering from hypochondriasis only somatization disorder and generalized anxiety disorder were more common than in average families. [2] Other studies have shown that the first degree relatives of patients with OCD have a higher than expected frequency of a somatoform disorder (either hypochondriasis or body dysmorphic disorder). [4] Many people with hypochondriasis point out a pattern of paying close attention to bodily sensations, preventative investigations, and checking with physicians, that they have learned from family members, but there is no definitive scientific support for this notion. Many people are aware that anxiety and depression are mediated by problems with brain chemicals such as serotonin and norepinephrine. The physical symptoms that people with anxiety or depression feel are indeed real bodily symptoms, and are in fact triggered by neurochemical changes. For example, too much norepinephrine will result in severe panic attacks with symptoms of increased heart rate and sweating, shortness of breath, and fear. Too little serotonin can result in severe depression, accompanied by an inability to sleep, severe fatigue, and needs fixing. # Treatment To treat hypochondriasis, one must acknowledge the interplay of body and mind. If a person is sick with a medical disease such as diabetes or arthritis, there will often be psychological consequences, such as depression. Some even report being suicidal. In the same way, someone with psychological issues such as depression or anxiety will sometimes experience physical manifestations of these affective fluctuations, often in the form of medically unexplained symptoms. Common symptoms include headaches, abdominal, back, joint, rectal, or urinary pain, nausea,itching, diarrhea, dizziness, or balance problems. Many people with hypochondriasis accompanied by medically unexplained symptoms feel they are not understood by their physicians, and are frustrated by their doctors’ repeated failure to provide symptom relief. Common to the different approaches to the treatment of hypochondriasis is the effort to help each patient find a better way to overcome the way his/her medically unexplained symptoms and illness concerns rule her/his life. Current research makes clear that this excessive worry can be helped by either appropriate medicine or targeted psychotherapy. For a long time, hypochondriasis was considered untreatable. However, recent scientific studies show that cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs, e.g., fluoxetine and paroxetine) are effective treatment options for hypochondriasis as demonstrated in clinical trials [5] [6] [7] [8] [9]. CBT, a psycho-educational "talk" therapy, helps the worrier to address and cope with bothersome physical symptoms and illness worries and is found helpful in reducing the intensity and frequency of troubling bodily symptoms. SSRIs can reduce obsessional worry through readjusting neurotransmitter levels, have been shown to be effective as treatments for anxiety and depression, as well as for hypochondriasis. NIH-funded studies are now underway to compare different treatment approaches for hypochondriasis: a study in the NYC area and a study in the Boston area. In these studies, patients will be given one of four treatments: supportive therapy with fluoxetine, supportive therapy with placebo, cognitive behavior therapy, or cognitive behavior therapy with fluoxetine. For more information you can also visit external links. In Norway a clinic specializing in the treatment of hypochondria has been opened. # Tips for hypochondriacs If one is worried about having a serious medical illness despite receiving reassurance to the contrary by a physician during a comprehensive evaluation, it might be beneficial to put these techniques into practice: - Keeping a journal describing symptoms or events that led to your episodes of illness should allow one to see the illness clearer. - Trying to restrict or put a time limit on one's internet medical research, reading of medical books, or self-checking behaviors, as they tend to increase illness worries. - Maintaining a healthy lifestyle, including a good night sleep, well-balanced diet and a positive outlook. A good tip is to follow the PEAS tool sometimes used to combat depression: Pleasure, Exercise, Achievement and Socializing - try to add an aspect of each to daily activities. - Practicing relaxation techniques, such as breathing, meditation or other methods may help to decrease anxiety and the effects of stress. - Trying interrupt one's worries with activities that will fully engage one's attention and shift it away from illness; for example, hobbies, word or number games, exercise or walking, talking with a humorous friend, or recalling happy memories. - Thinking about alternative explanations for one's physical sensations that might include stress or normal bodily changes. - Breaking one's habits of worrying one step at a time. # Self-Help Books The following self-help books might be helpful as well. - Minding the Body, Mending the Mind. Joan Borysenko. Bantam, 1988. - The Wellness Book. Herbert Benson and Eileen Stuart. Simon & Schuster/Fireside, 1992 - The Woman’s Comfort Book. Jennifer Louden. Harper SanFrancisco, 1992. - The Stress Solution-An Action Plan to Manage the Stress in Your Life. Lyle Miller and Alma Dell Smith. Pocket Book, 1993. - Wellness at Work-Building Resilience to Job Stress. Valerie O’Hara. New Harbinger Publications, 1995. - Stop Suffering Now. Arthur J. Barsky and Emily C. Deans. HarperCollins, 2005. - Phantom Illness: Recognizing, Understanding, and Overcoming Hypochondria. Carla Cantor and Brian Fallon. Mariner Books, 1997. - Hypochondria: Woeful Imaginings. Susan Baur. University of California Press, 1989. - Managing Pain Before It Manages You. Margaret Caudill. Guilford Press, 1995. - Healing Mind, Healthy Woman. Alice Domar and Henry Dreher. Henry Holt & Co,1996. - Living a Healthy Life with a Chronic Condition. Kate Lorig, Holstead Holman. Bull Publishing Co, 1994. - The Healthy Mind Healthy Body Handbook. David Sobel and Robert Ornstein. HarperCollins,1996. - It’s Not All in Your Head. Gordon JG Asmundson and Steven Taylor. Guilford Press, 2005 - Stop worrying About your Health! George Zgourides. Oakland, CA: New Harbinger Publications, 2002 - Back Sense. Ronald D. Siegel, Michael H. Urdang, Douglas R. Johnson. Broadway Books, 2001. - The Feeling Good Handbook. David Burns. Penguin, 1989. - Mind Over Mood. Dennis Greenberger and Christine Padesky. Guilford Press, 1995. # Pop Culture In the 2001 film Le Fabuleux Destin d'Amélie Poulain (The Fabulous Life of Amélie Poulain), Isabelle Nanty's character Georgette is a hypochondriac. In the 2005 DreamWorks Animation film Madagascar, a giraffe (Melman) is portrayed as a hypochondriac. On the show South Park, Stan Marsh's father, Randy Marsh, is described by his son as a hypochondriac in the episode "Bloody Mary". In the film My Girl the leading character Vada is a hypochondriac most likely due to her being raised in a funeral home. In the film, Bandits, one of the bank robbers (portrayed by Billy Bob Thornton), Terry, is a hypochondriac. The other bank robber, Joe, used this to an advantage once, and claimed that his brother received a brain tumor from smelling burning feathers as a joke to get Terry to worry. In the TV series, Scrubs, recurring character Harvey Korman, portrayed by actor Richard Kind, is a hypochondriac that appears in several episodes. His most notable appearance being in the episode, "My New Old Friend." In the 1986 hit film Ferris Bueller's Day Off, Ferris' friend Cameron Frye (portrayed by Alan Ruck) was displaying some symptoms of hypochondria throughout the movie, notably when he is lying in bed thinking he is sick, until Ferris convinces him that it's all in his head. In the TV series, Boy Meets World Cory is diagnosed with hypochondria and sees it as a real illness. In the book It, Eddie Kaspbrak's mother is a hypochondriac who convinces her son that he is frail and has asthma, even though he does not. She even argues with doctors regarding her son's health.	https://www.wikidoc.org/index.php/Hypochondria
b3277eededffe88a43e1265f3f3cc0b03f6a1dbd	wikidoc	Hypouricemia	Hypouricemia # Overview Hypouricemia is a condition where the level of uric acid is below a certain threshold (between 2 mg/dL and 4 mg/dL, according to different sources.) The upper end of the normal range is 530 micromol/L (6 mg/dL) for women and 619 micromol/L (7 mg/dL) for men. # Causes Hypouricemia is associated with several conditions, including: - Hyperthyroidism - Nephritis - Fanconi syndrome - Wilson's disease - Myeloma - Multiple Sclerosis Half of the cases can be associated with drugs (allopurinol) and toxic agents. Uric acid clearance should also be performed, increase in clearance points to proximal tubular defects in the kidney, normal or reduced clearance points to a defect in xanthine oxidase. It can also be associated with total parenteral nutrition. AJCN Vegetarian diet has been found to result in mean serum uric acid values as low as 239 micromol/L (2.7 mg/dL) . While a vegetarian diet is typically seen as beneficial with respect to conditions such as gout , care should be taken to avoid hypouricemia and associated health conditions. A specific condition, Dalmatian hypouricemia, is known to have a genetic component. (Online Mendelian Inheritance in Man (OMIM) 220150) In one study, hypouricemia was found in 4.8% of hospitalized women and 6.5% of hospitalized men. (The definition was less than 0.14 mmol l-1 for women and less than 0.20 mmol l-1 in men.) PMID 8140400	Hypouricemia Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Hypouricemia is a condition where the level of uric acid is below a certain threshold (between 2 mg/dL and 4 mg/dL, according to different sources.) The upper end of the normal range is 530 micromol/L (6 mg/dL) for women and 619 micromol/L (7 mg/dL) for men. [2] # Causes Hypouricemia is associated with several conditions, including: - Hyperthyroidism - Nephritis - Fanconi syndrome - Wilson's disease - Myeloma - Multiple Sclerosis [3] Half of the cases can be associated with drugs (allopurinol) and toxic agents. Uric acid clearance should also be performed, increase in clearance points to proximal tubular defects in the kidney, normal or reduced clearance points to a defect in xanthine oxidase. It can also be associated with total parenteral nutrition. AJCN Vegetarian diet has been found to result in mean serum uric acid values as low as 239 micromol/L (2.7 mg/dL) [4]. While a vegetarian diet is typically seen as beneficial with respect to conditions such as gout [5], care should be taken to avoid hypouricemia and associated health conditions. A specific condition, Dalmatian hypouricemia, is known to have a genetic component. (Online Mendelian Inheritance in Man (OMIM) 220150) In one study, hypouricemia was found in 4.8% of hospitalized women and 6.5% of hospitalized men. (The definition was less than 0.14 mmol l-1 for women and less than 0.20 mmol l-1 in men.) PMID 8140400	https://www.wikidoc.org/index.php/Hypouricemia
8d51d95c07fda92666247e44ed29039768b647b7	wikidoc	Hypromellose	Hypromellose # 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 Hypromellose is a ophthalmic solution that is FDA approved for the treatment of dryness of the eye and prevent further irritation. Common adverse reactions include eye pain, changes in vision. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Relieves dryness of the eye. - Temporarily relieves discomfort due to minor irritations of the eye or from exposure to wind and sun. - As a protectant against further irritation. ### Dosage - Put 1 or 2 drops in the affected eye(s) as needed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Hypromellose in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hypromellose in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Hypromellose in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Hypromellose in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hypromellose in pediatric patients. # Contraindications There is limited information regarding Hypromellose Contraindications in the drug label. # Warnings - For external use only. - Do not use if sealed bottle tip is broken or punctured. - If solution changes color or becomes cloudy, do not use. ### When using this product - To avoid contamination, do not touch tip of container to any surface. - Replace cap after using. ### Stop use and ask a physician - If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours, discontinue use and consult a doctor. # Adverse Reactions ## Clinical Trials Experience - eye pain - changes in vision ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Hypromellose in the drug label. # Drug Interactions There is limited information regarding Hypromellose Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Hypromellose in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hypromellose in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Hypromellose during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Hypromellose with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Hypromellose with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Hypromellose with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Hypromellose with respect to specific gender populations. ### Race There is no FDA guidance on the use of Hypromellose with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Hypromellose in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Hypromellose in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Hypromellose in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Hypromellose in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ophthalmic solution ### Monitoring There is limited information regarding Monitoring of Hypromellose in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Hypromellose in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Hypromellose in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Hypromellose Mechanism of Action in the drug label. ## Structure There is limited information regarding Hypromellose Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Hypromellose in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Hypromellose in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Hypromellose in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Hypromellose in the drug label. # How Supplied There is limited information regarding Hypromellose How Supplied in the drug label. ## Storage - Store at room temperature 15°-30°C (59°-86°F). - Do not freeze. - Keep box for complete information. # Images ## Drug Images ## Package and Label Display Panel ### Principal display panel ### Ingredients and Appearance # Patient Counseling Information - When using this product do not touch tip of container to any surface. Replace cap after using. - Stop use and ask a doctor if you experience any of the following: - eye pain - changes in vision - continued redness or irritation of the eye - condition worsens or persists for more than 72 hours - If swallowed, get medical help or contact a Poison Control Center right away. # Precautions with Alcohol - Alcohol-Hypromellose interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GenTeal® # Look-Alike Drug Names There is limited information regarding Hypromellose Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Hypromellose 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 Hypromellose is a ophthalmic solution that is FDA approved for the treatment of dryness of the eye and prevent further irritation. Common adverse reactions include eye pain, changes in vision. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Relieves dryness of the eye. - Temporarily relieves discomfort due to minor irritations of the eye or from exposure to wind and sun. - As a protectant against further irritation. ### Dosage - Put 1 or 2 drops in the affected eye(s) as needed. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Hypromellose in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hypromellose in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Hypromellose in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Hypromellose in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Hypromellose in pediatric patients. # Contraindications There is limited information regarding Hypromellose Contraindications in the drug label. # Warnings - For external use only. - Do not use if sealed bottle tip is broken or punctured. - If solution changes color or becomes cloudy, do not use. ### When using this product - To avoid contamination, do not touch tip of container to any surface. - Replace cap after using. ### Stop use and ask a physician - If you experience eye pain, changes in vision, continued redness or irritation of the eye, or if the condition worsens or persists for more than 72 hours, discontinue use and consult a doctor. # Adverse Reactions ## Clinical Trials Experience - eye pain - changes in vision ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Hypromellose in the drug label. # Drug Interactions There is limited information regarding Hypromellose Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Hypromellose in women who are pregnant. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hypromellose in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Hypromellose during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Hypromellose with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Hypromellose with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Hypromellose with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Hypromellose with respect to specific gender populations. ### Race There is no FDA guidance on the use of Hypromellose with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Hypromellose in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Hypromellose in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Hypromellose in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Hypromellose in patients who are immunocompromised. # Administration and Monitoring ### Administration - Ophthalmic solution ### Monitoring There is limited information regarding Monitoring of Hypromellose in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Hypromellose in the drug label. # Overdosage There is limited information regarding Chronic Overdose of Hypromellose in the drug label. # Pharmacology ## Mechanism of Action There is limited information regarding Hypromellose Mechanism of Action in the drug label. ## Structure There is limited information regarding Hypromellose Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Hypromellose in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Hypromellose in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Hypromellose in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Hypromellose in the drug label. # How Supplied There is limited information regarding Hypromellose How Supplied in the drug label. ## Storage - Store at room temperature 15°-30°C (59°-86°F). - Do not freeze. - Keep box for complete information. # Images ## Drug Images ## Package and Label Display Panel ### Principal display panel ### Ingredients and Appearance # Patient Counseling Information - When using this product do not touch tip of container to any surface. Replace cap after using. - Stop use and ask a doctor if you experience any of the following: - eye pain - changes in vision - continued redness or irritation of the eye - condition worsens or persists for more than 72 hours - If swallowed, get medical help or contact a Poison Control Center right away. # Precautions with Alcohol - Alcohol-Hypromellose interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - GenTeal®[1] # Look-Alike Drug Names There is limited information regarding Hypromellose Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Hypromellose
e8cd4c0d79b89baaac73168d6ee9c938e2627b1c	wikidoc	Hysterectomy	Hysterectomy # Overview A hysterectomy (from Greek Template:Polytonic hystera "womb") is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total (removing the body, fundus, and cervix of the uterus; often called "complete") or partial (removal of the uterine body but leaving the cervical stump, also called "supracervical"). In 2005, there were 617,000 hysterectomies performed in the USA. During a hysterectomy, in the last decade, an average of 73% of surgeons removed ovaries and fallopian tubes during the same operation, a procedure known technically as bilateral salpingo-oophorectomy and less formally as ovariohysterectomy. Removal of the uterus renders the patient unable to bear children (as does removal of ovaries and fallopian tubes), and changes their hormonal levels considerably, so the surgery is normally recommended for only a few specific circumstances: - Certain types of reproductive system cancers (uterine, cervical, ovarian); - As a prophylactic treatment for those with either a strong family history of reproductive system cancers (especially breast cancer in conjunction with BRCA1 or BRCA2 mutation) or as part of their recovery from such cancers; - Severe and intractible endometriosis (overgrowth of the uterine lining) and/or adenomyosis (a more severe form of endometriosis, where the uterine lining has grown into and sometimes through the uterine wall) after pharmaceutical and other non-surgical options have been exhausted; - Postpartum to remove either a severe case of placenta praevia (a placenta that has either formed over or inside the birth canal) or placenta accreta (a placenta that has grown into and through the wall of the uterus to attach itself to other organs), as well as a last resort in case of excessive postpartum bleeding; - For transmen, as part of their gender transition. Although hysterectomy is frequently performed for fibroids (benign tumor-like growths inside the uterus itself made up of muscle and connective tissue), conservative options in treatment are available by doctors who are trained and skilled at alternatives. It is well documented in medical literature that myomectomy, surgical removal of fibroids that leaves the uterus intact, has been performed for over a century. The uterus is a hormone-responsive reproductive sex organ, and the ovaries produce the majority of estrogen and progesterone that is available in genetic females of reproductive age. According to the National Center for Health Statistics, of the 617,000 hysterectomies performed in 2004, 73% also involved the surgical removal of the ovaries. In the United States, 1/3 of genetic females can be expected to have a hysterectomy by age 60. There are currently an estimate of 22 million people in the United States who have undergone this procedure. An average of 622,000 hysterectomies a year have been performed for the past decade. Both the uterus and the ovaries have important life-long functions in the maintenance of a woman's health, and there is never an age or a time when the uterus and ovaries are not essential to health and well-being. Additionally, the removal of otherwise healthy ovaries is a form of castration because it involves removal of the female gonads, which many opponents and even some supporters of hysterectomy do not support. # Indications Hysterectomy is usually performed for problems with the uterus itself or problems with the entire female reproductive complex. Some of the conditions treated by hysterectomy include uterine fibroids (myomas), endometriosis (overgrowth of the uterine lining), adenomyosis (a more severe form of endometriosis, where the uterine lining has grown into and sometimes through the uterine wall), several forms of vaginal prolapse, heavy or abnormal menstrual bleeding, and at least three forms of cancer (uterine, advanced cervical, ovarian). Hysterectomy is also a surgical last resort in uncontrollable postpartum obstetrical haemorrhage. Uterine fibroids, although a benign disease, may cause heavy menstrual flow and discomfort to some of those with the condition. Many alternative treatments are available: pharmaceutical options (the use of NSAIDs or opiates for the pain and hormones to suppress the menstrual cycle); myomectomy (removal of uterine fibroids while leaving the uterus intact); uterine artery embolization, high intensity focused ultrasound or watchful waiting. In mild cases, no treatment is necessary. If the fibroids are inside the lining of the uterus (submucosal), and are smaller than 4cm, hysteroscopic removal is an option. A submucosal fibroid larger than 4cm, and fibroids located in other parts of the uterus, can be removed with a laparotomic myomectomy, where a horizontal incision is made above the pubic bone for better access to the uterus. # Technique Most hysterectomies in the United States and in most parts of the world are done via laparotomy, sometimes called the "open technique" or "open hysterectomy". A transverse incision (Pfannenstiel's incision) is made through the abdominal wall, usually above the pubic bone, as close to the upper hair line of the individual's lower pelvis as possible, similar to the incision made for a caesarean section. This technique allows doctors the greatest access to the reproductive structures and is normally done for removal of the entire reproductive complex. The recovery time for an open hysterectomy is 4-6 weeks and sometimes longer due to the need to cut through the abdominal wall. The open technique carries increased risk of hemorrhage due to the large blood supply in the pelvic region, as well as an increased risk of infection from the need to move intestines and bladder in order to reach the reproductive organs and to search for collateral damage from endometriosis or cancer. However, an open hysterectomy provides the most effective way to ensure complete removal of the reproductive system as well as providing a wide opening for visual inspection of the abdominal cavity. An increasing number of uterine removals not involving removal of the ovaries are done through the cervix ("supracervical"), reducing the size of the incision and the recovery time as well. In this technique, the uterus is accessed either via the vaginal canal or through an incision inside the navel (or sometimes both, depending on the uterine problem being addressed by the surgery). The uterus itself is detached at the top of the cervical neck and pulled back through the vaginal canal (or out through the navel incision if fibroids or other indications prevent it from being able to pass through the cervix) , after which the cervical neck is stitched shut. This provides the patient with a comparatively normal-length vagina which helps provide some support to the bladder, as well as a significantly decreased recovery time. The main drawback with supracervical hysterectomy is the increased risk of cervical prolapse due to the removal of the much stronger uterus (which would normally support the organs around it to prevent prolapse). This surgery also does not eliminate the possibility of cervical cancer, since the cervix itself is left in place; those who have undergone this procedure must still have regular PAP smears to check for cervical cancer. The newest technique is robotic-assisted laparoscopic hysterectomy. Instead of a large incision, a few tiny incisions are made through which thin instruments are passed. This new technique significantly reduces scarring, pain, healing time, blood loss, and duration of hospital stay when compared to open technique. # Benefits Women with a risk of breast cancer, especially those with BRCA1 or BRCA2 gene mutations, have been shown to have a significantly reduced risk of developing breast cancer after prophylactic oophorectomy. In addition, removal of the uterus in conjunction with prophylactic oophorectomy allows estrogen-only HRT to be prescribed to aid the individual through their transition into surgical menopause, instead of estrogen-progestin HRT, which has a slightly increased risk of breast cancer as compared with post-menopausal non-hysterectomized women taking HRT. The Maine Women's Health Study of 1994 followed for 12 months time approximately 800 women with similar gynecological problems (pelvic pain, urinary incontinence due to uterine prolapse, severe endometriosis, excessive menstrual bleeding, large fibroids, painful intercourse), around half of whom had a hysterectomy and half of whom did not. The study found that a substantial number of those who had a hysterectomy had marked improvement in their symptoms following hysterectomy, as well as significant improvement in their overall physical and mental health one year out from their surgery. The study concluded that for those who have intractible gynecological problems that had not responded to non-surgical intervention, hysterectomy may be beneficial to their overall health and wellness. One of the conditions most cited by women who have complex pelvic and reproductive issues is pain. This is particularly true for women who have other conditions that amplify pain, such as fibromyalgia and chronic fatigue syndrome. Removal of a condition that is causing pain has a dramatic effect on reducing the overall pain levels of a person with such disorders; for many women with such pain conditions, a hysterectomy is preferable to the continual pain which adds to the burden of their already painful lives, even though the loss of hormones post-surgery may initially contribute to an increase in the symptoms of their disorder. # Risks and side effects The risks for any surgery are: - Allergic reactions to medicines - Breathing problems - Blood clots, which may cause death if they travel to the lungs - Bleeding - Infection - Injury to nearby body areas Risks that are possible from a hysterectomy are: - Injury to the bladder or ureters - Pain during sexual intercourse - Early menopause, if the ovaries are removed or if a woman is close to menopause - Decreased interest in sex The average onset age of menopause in those who underwent hysterectomy is 3.7 years earlier than average. This has been suggested to be due to the disruption of blood supply to the ovaries after a hysterectomy. When the ovaries are also removed, blood estrogen levels fall, removing the protective effects of estrogen on the cardiovascular and skeletal systems. Although sometimes referred to as surgical menopause, that is incorrect and misleading because it implies that its effects are the same as with natural menopause. In fact, those who are naturally menopausal have the benefit of the functions of their uterus and ovaries (which continue to produce small amounts of hormones even after natural menopause), while those who undergo hysterectomy and/or removal of the ovaries have a permanent loss of their functions. When only the uterus is removed there is a three times greater risk of cardiovascular disease. If the ovaries are removed the risk is seven times greater. Several studies have found that osteoporosis (decrease in bone density) and increased risk of bone fractures are associated with hysterectomies. This has been attributed to the modulatory effect of estrogen on calcium metabolism and the drop in serum estrogen levels after menopause can cause excessive loss of calcium leading to bone wasting. Some women find their natural lubrication during sexual arousal is also reduced or eliminated. Those who experience uterine orgasm will not experience it if the uterus is removed. The vagina is shortened and made into a closed pocket and there is a loss of support to the bladder and bowel. Those who have undergone a hysterectomy with both ovaries removed typically have reduced testosterone levels as compared to those left intact. Reduced levels of testosterone in women is predictive of height loss, which may occur as a result of reduced bone density, while conversely, increased testosterone levels in women are associated with a greater sense of sexual desire. Hysterectomy has also been found to be associated with increased bladder function problems, such as incontinence. Removal of the uterus without removing the ovaries can produce a situation that on rare occasions can result in ectopic pregnancy due to an undetected fertilization that had yet to descend into the uterus before surgery. Two cases have been identified and profiled in an issue of the Blackwell Journal of Obstetrics and Gynecology; over 20 other cases have been discussed in additional medical literature. # Alternatives Many alternatives to hysterectomy exist. Those with dysfunctional uterine bleeding may be treated with endometrial ablation, which is an outpatient procedure in which the lining of the uterus is destroyed with heat. Endometrial ablation will greatly reduce or entirely eliminate monthly bleeding in ninety percent of patients with DUB. In addition, uterine fibroids may be removed without removing the uterus. This procedure is called a "myomectomy." A myomectomy may be performed through an open incision or, in appropriate cases, laparoscopically. Various other techniques (such as Fibroid Artery Embolization, Myolysis, HALT, and Focused Ultrasound Surgery) kill the fibroid, and then leave it in place to be (usually only partially) reabsorbed by the body. Prolapse may also be corrected surgically without removal of the uterus. Menorrhagia (heavy or abnormal menstrual bleeding) may also be treated with the less invasive endometrial ablation. # Gender transitioning Hysterectomies with bilateral salpingo-oophorectomy are often performed either prior to or as a part of gender reassignment surgery for transmen. Some in the FTM community prefer to have this operation along with hormone replacement therapy in the early stages of their gender transition to avoid complications from heavy testosterone use while still having female-hormone-producing organs in place (e.g. uterine cancer and hormonally-induced coronary artery disease) or to remove as many sources of female sex hormones as possible in order to better "pass" during the real life experience portion of their transition. Just as many, however, prefer to wait until they have full "bottom surgery" (removal of female sexual organs and construction of male-appearing external anatomy) to avoid undergoing multiple separate operations. Many FTM never complete "bottom surgery" for a number of reasons, and instead choose to have their breasts and reproductive organs removed to eliminate all outward appearances of their femininity.	Hysterectomy For patient information, click here Template:Interventions infobox Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A hysterectomy (from Greek Template:Polytonic hystera "womb") is the surgical removal of the uterus, usually performed by a gynecologist. Hysterectomy may be total (removing the body, fundus, and cervix of the uterus; often called "complete") or partial (removal of the uterine body but leaving the cervical stump, also called "supracervical"). In 2005, there were 617,000 hysterectomies performed in the USA. During a hysterectomy, in the last decade, an average of 73% of surgeons removed ovaries and fallopian tubes during the same operation, a procedure known technically as bilateral salpingo-oophorectomy and less formally as ovariohysterectomy. Removal of the uterus renders the patient unable to bear children (as does removal of ovaries and fallopian tubes), and changes their hormonal levels considerably, so the surgery is normally recommended for only a few specific circumstances: - Certain types of reproductive system cancers (uterine, cervical, ovarian); - As a prophylactic treatment for those with either a strong family history of reproductive system cancers (especially breast cancer in conjunction with BRCA1 or BRCA2 mutation) or as part of their recovery from such cancers; - Severe and intractible endometriosis (overgrowth of the uterine lining) and/or adenomyosis (a more severe form of endometriosis, where the uterine lining has grown into and sometimes through the uterine wall) after pharmaceutical and other non-surgical options have been exhausted; - Postpartum to remove either a severe case of placenta praevia (a placenta that has either formed over or inside the birth canal) or placenta accreta (a placenta that has grown into and through the wall of the uterus to attach itself to other organs), as well as a last resort in case of excessive postpartum bleeding; - For transmen, as part of their gender transition. Although hysterectomy is frequently performed for fibroids (benign tumor-like growths inside the uterus itself made up of muscle and connective tissue), conservative options in treatment are available by doctors who are trained and skilled at alternatives. It is well documented in medical literature that myomectomy, surgical removal of fibroids that leaves the uterus intact, has been performed for over a century. The uterus is a hormone-responsive reproductive sex organ, and the ovaries produce the majority of estrogen and progesterone that is available in genetic females of reproductive age. According to the National Center for Health Statistics, of the 617,000 hysterectomies performed in 2004, 73% also involved the surgical removal of the ovaries. In the United States, 1/3 of genetic females can be expected to have a hysterectomy by age 60.[1] There are currently an estimate of 22 million people in the United States who have undergone this procedure. An average of 622,000 hysterectomies a year have been performed for the past decade.[1] Both the uterus and the ovaries have important life-long functions in the maintenance of a woman's health, and there is never an age or a time when the uterus and ovaries are not essential to health and well-being.[2] Additionally, the removal of otherwise healthy ovaries is a form of castration because it involves removal of the female gonads[3], which many opponents and even some supporters of hysterectomy[4] do not support. # Indications Hysterectomy is usually performed for problems with the uterus itself or problems with the entire female reproductive complex. Some of the conditions treated by hysterectomy include uterine fibroids (myomas), endometriosis (overgrowth of the uterine lining), adenomyosis (a more severe form of endometriosis, where the uterine lining has grown into and sometimes through the uterine wall), several forms of vaginal prolapse, heavy or abnormal menstrual bleeding, and at least three forms of cancer (uterine, advanced cervical, ovarian). Hysterectomy is also a surgical last resort in uncontrollable postpartum obstetrical haemorrhage.[5] Uterine fibroids, although a benign disease, may cause heavy menstrual flow and discomfort to some of those with the condition. Many alternative treatments are available: pharmaceutical options (the use of NSAIDs or opiates for the pain and hormones to suppress the menstrual cycle); myomectomy (removal of uterine fibroids while leaving the uterus intact); uterine artery embolization, high intensity focused ultrasound or watchful waiting. In mild cases, no treatment is necessary. If the fibroids are inside the lining of the uterus (submucosal), and are smaller than 4cm, hysteroscopic removal is an option. A submucosal fibroid larger than 4cm, and fibroids located in other parts of the uterus, can be removed with a laparotomic myomectomy, where a horizontal incision is made above the pubic bone for better access to the uterus. # Technique Most hysterectomies in the United States and in most parts of the world are done via laparotomy, sometimes called the "open technique" or "open hysterectomy". A transverse incision (Pfannenstiel's incision) is made through the abdominal wall, usually above the pubic bone, as close to the upper hair line of the individual's lower pelvis as possible, similar to the incision made for a caesarean section. This technique allows doctors the greatest access to the reproductive structures and is normally done for removal of the entire reproductive complex. The recovery time for an open hysterectomy is 4-6 weeks and sometimes longer due to the need to cut through the abdominal wall. The open technique carries increased risk of hemorrhage due to the large blood supply in the pelvic region, as well as an increased risk of infection from the need to move intestines and bladder in order to reach the reproductive organs and to search for collateral damage from endometriosis or cancer. However, an open hysterectomy provides the most effective way to ensure complete removal of the reproductive system as well as providing a wide opening for visual inspection of the abdominal cavity. An increasing number of uterine removals not involving removal of the ovaries are done through the cervix ("supracervical"), reducing the size of the incision and the recovery time as well. In this technique, the uterus is accessed either via the vaginal canal or through an incision inside the navel (or sometimes both, depending on the uterine problem being addressed by the surgery). The uterus itself is detached at the top of the cervical neck and pulled back through the vaginal canal (or out through the navel incision if fibroids or other indications prevent it from being able to pass through the cervix) , after which the cervical neck is stitched shut. This provides the patient with a comparatively normal-length vagina which helps provide some support to the bladder, as well as a significantly decreased recovery time.[6] The main drawback with supracervical hysterectomy is the increased risk of cervical prolapse due to the removal of the much stronger uterus (which would normally support the organs around it to prevent prolapse). This surgery also does not eliminate the possibility of cervical cancer, since the cervix itself is left in place; those who have undergone this procedure must still have regular PAP smears to check for cervical cancer. The newest technique is robotic-assisted laparoscopic hysterectomy. Instead of a large incision, a few tiny incisions are made through which thin instruments are passed. This new technique significantly reduces scarring, pain, healing time, blood loss, and duration of hospital stay when compared to open technique. # Benefits Women with a risk of breast cancer, especially those with BRCA1 or BRCA2 gene mutations, have been shown to have a significantly reduced risk of developing breast cancer after prophylactic oophorectomy.[7] In addition, removal of the uterus in conjunction with prophylactic oophorectomy allows estrogen-only HRT to be prescribed to aid the individual through their transition into surgical menopause, instead of estrogen-progestin HRT, which has a slightly increased risk of breast cancer as compared with post-menopausal non-hysterectomized women taking HRT.[8] The Maine Women's Health Study of 1994 followed for 12 months time approximately 800 women with similar gynecological problems (pelvic pain, urinary incontinence due to uterine prolapse, severe endometriosis, excessive menstrual bleeding, large fibroids, painful intercourse), around half of whom had a hysterectomy and half of whom did not. The study found that a substantial number of those who had a hysterectomy had marked improvement in their symptoms following hysterectomy, as well as significant improvement in their overall physical and mental health one year out from their surgery. The study concluded that for those who have intractible gynecological problems that had not responded to non-surgical intervention, hysterectomy may be beneficial to their overall health and wellness.[4] One of the conditions most cited by women who have complex pelvic and reproductive issues is pain[9]. This is particularly true for women who have other conditions that amplify pain, such as fibromyalgia and chronic fatigue syndrome. Removal of a condition that is causing pain has a dramatic effect on reducing the overall pain levels of a person with such disorders; for many women with such pain conditions, a hysterectomy is preferable to the continual pain which adds to the burden of their already painful lives, even though the loss of hormones post-surgery may initially contribute to an increase in the symptoms of their disorder[10]. # Risks and side effects The risks for any surgery are: - Allergic reactions to medicines - Breathing problems - Blood clots, which may cause death if they travel to the lungs - Bleeding - Infection - Injury to nearby body areas Risks that are possible from a hysterectomy are: - Injury to the bladder or ureters - Pain during sexual intercourse - Early menopause, if the ovaries are removed or if a woman is close to menopause - Decreased interest in sex The average onset age of menopause in those who underwent hysterectomy is 3.7 years earlier than average.[11] This has been suggested to be due to the disruption of blood supply to the ovaries after a hysterectomy. When the ovaries are also removed, blood estrogen levels fall, removing the protective effects of estrogen on the cardiovascular and skeletal systems. Although sometimes referred to as surgical menopause, that is incorrect and misleading because it implies that its effects are the same as with natural menopause. In fact, those who are naturally menopausal have the benefit of the functions of their uterus and ovaries (which continue to produce small amounts of hormones even after natural menopause), while those who undergo hysterectomy and/or removal of the ovaries have a permanent loss of their functions. When only the uterus is removed there is a three times greater risk of cardiovascular disease. If the ovaries are removed the risk is seven times greater. Several studies have found that osteoporosis (decrease in bone density) and increased risk of bone fractures are associated with hysterectomies.[12][13][14][15][16][17] This has been attributed to the modulatory effect of estrogen on calcium metabolism and the drop in serum estrogen levels after menopause can cause excessive loss of calcium leading to bone wasting. Some women find their natural lubrication during sexual arousal is also reduced or eliminated. Those who experience uterine orgasm will not experience it if the uterus is removed. The vagina is shortened and made into a closed pocket and there is a loss of support to the bladder and bowel. Those who have undergone a hysterectomy with both ovaries removed typically have reduced testosterone levels as compared to those left intact.[18] Reduced levels of testosterone in women is predictive of height loss, which may occur as a result of reduced bone density,[19] while conversely, increased testosterone levels in women are associated with a greater sense of sexual desire.[20] Hysterectomy has also been found to be associated with increased bladder function problems, such as incontinence.[21] Removal of the uterus without removing the ovaries can produce a situation that on rare occasions can result in ectopic pregnancy due to an undetected fertilization that had yet to descend into the uterus before surgery. Two cases have been identified and profiled in an issue of the Blackwell Journal of Obstetrics and Gynecology; over 20 other cases have been discussed in additional medical literature[22]. # Alternatives Many alternatives to hysterectomy exist. Those with dysfunctional uterine bleeding may be treated with endometrial ablation, which is an outpatient procedure in which the lining of the uterus is destroyed with heat. Endometrial ablation will greatly reduce or entirely eliminate monthly bleeding in ninety percent of patients with DUB. In addition, uterine fibroids may be removed without removing the uterus. This procedure is called a "myomectomy." A myomectomy may be performed through an open incision or, in appropriate cases, laparoscopically.[23] Various other techniques (such as Fibroid Artery Embolization, Myolysis, HALT, and Focused Ultrasound Surgery) kill the fibroid, and then leave it in place to be (usually only partially) reabsorbed by the body. Prolapse may also be corrected surgically without removal of the uterus.[24] Menorrhagia (heavy or abnormal menstrual bleeding) may also be treated with the less invasive endometrial ablation.[25] # Gender transitioning Hysterectomies with bilateral salpingo-oophorectomy are often performed either prior to or as a part of gender reassignment surgery for transmen. Some in the FTM community prefer to have this operation along with hormone replacement therapy in the early stages of their gender transition to avoid complications from heavy testosterone use while still having female-hormone-producing organs in place (e.g. uterine cancer and hormonally-induced coronary artery disease) or to remove as many sources of female sex hormones as possible in order to better "pass" during the real life experience portion of their transition.[26] Just as many, however, prefer to wait until they have full "bottom surgery" (removal of female sexual organs and construction of male-appearing external anatomy)[27] to avoid undergoing multiple separate operations.[28] Many FTM never complete "bottom surgery" for a number of reasons, and instead choose to have their breasts and reproductive organs removed to eliminate all outward appearances of their femininity.[29]	https://www.wikidoc.org/index.php/Hysterectomy

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