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/index.php/Virology_(journal)

# Virology (journal) Virology is a peer-reviewed academic journal that covers basic research into viruses affecting animals, plants, bacteria and fungi, including their molecular biology, structure, assembly, pathogenesis, immunity and interactions with the host cell. Molecular aspects of control and prevention are also covered, as well as viral vectors and gene therapy.

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/index.php/Virotherapy

# Virotherapy Virotherapy is an experimental form of cancer treatment using biotechnology to convert viruses into cancer-fighting agents by reprogramming viruses to only attack cancerous cells while healthy cells remained undamaged. The human immunodeficiency virus (HIV), which causes AIDS, is a candidate for this and is currently under investigation. Usually the viruses used are Varicella Zoster Viruses (The Herpes simplex) and Adenoviruses(First isolated in adenoid tissue). It uses viruses as treatment against various diseases, most commonly as a vector used to specifically target cells and DNA in particular. It is not a new idea - as early as the 1950's doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement: this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells. In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumors. In 1956 some of the earliest human clinical trials with oncolytic viruses for the treatment of advanced-stage cervical cancer were started. However, for several years research in this field was delayed due to the inadequate technology available. Research has now started to move forward more quickly in finding ways to use viruses therapeutically. In 2006 researchers from the Hebrew University succeeded in isolating a variant of the Newcastle disease Virus (NDV-HUJ), which usually affects birds, in order to specifically target cancer cells . The researchers tested the new virotherapy on Glioblastoma multiforme patients and achieved promising results for the first time.

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/index.php/Virtual_colonoscopy

# Virtual colonoscopy Virtual colonoscopy (VC) is a Medical imaging procedure which uses x-rays and computers to produce two- and three-dimensional images of the colon (large intestine) from the lowest part, the rectum, all the way to the lower end of the small intestine and display them on a screen. The procedure is used to diagnose colon and bowel disease, including polyps, diverticulosis and cancer. VC can be performed with computed tomography (CT), sometimes called a CAT scan, or with magnetic resonance imaging (MRI). {{#ev:youtube|zM-YUXovFlM}} While preparations for VC vary, the patient will usually be asked to take laxatives or other oral agents at home the day before the procedure to clear stool from the colon. A suppository is also used to cleanse the rectum of any remaining fecal matter. VC takes place in the radiology department of a hospital or medical center. The examination takes about 10 minutes and does not require sedatives. During the procedure, After the examination, the images produced by the scanner must be processed into a 3D image, +/- a fly through (a cine program which allows the user move through the bowel as if performing a normal colonoscopy). A radiologist evaluates the results to identify any abnormalities. The patient may resume normal activity after the procedure, but if abnormalities are found and the patient needs conventional colonoscopy, it may be performed the same day. VC is more comfortable than conventional colonoscopy for some people because it does not use a colonoscope. As a result, no sedation is needed, and the patient can return to his/her usual activities or go home after the procedure without the aid of another person. VC provides clearer, more detailed images than a conventional x-ray using a barium enema, sometimes called a lower gastrointestinal (GI) series. It also takes less time than either a conventional colonoscopy or a lower GI series. According to a recent article on Eurekalert.org, the main disadvantage to VC is cost. Another disadvantage is that a radiologist cannot take tissue samples (biopsy) or remove polyps during VC, so a conventional colonoscopy must be performed if abnormalities are found. Also, VC does not show as much detail as a conventional colonoscopy, so polyps smaller than 2 millimeters in diameter may not show up on the images. Furthermore Virtual Colonoscopy performed with CT exposes the patient to ionizing radiation, however some research has demonstrated that ultra-low dose VC can be just as effective in demonstrating colon and bowel disease due to the great difference in x-ray absorption between air and the tissue comprising the inner wall of the colon. Optical colonoscopy is taken as the "gold standard" for colorectal cancer screening by some groups but not by others. Some radiologists recommend VC as a preferred approach to colorectal screening. However, optical colonoscopy is considered the gold standard by some professionals because it permits complete visualization of the entire colon, hence providing the opportunity to identify precancerous polyps and cancer, and then to do diagnostic biopsies or therapeutic removal of these lesions, as soon as possible.

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/index.php/Virulence

# Virulence Virulence refers to the degree of pathogenicity of a microbe, or in other words the relative ability of a microbe to cause disease. The word virulent, which is the adjective for virulence, derives from the Latin word virulentus, which means "full of poison." From an ecological point of view, virulence can be defined as the host's parasite induced loss of fitness. The ability of bacteria to cause disease is described in terms of the number of infecting bacteria, the route of entry into the body, the effects of host defense mechanisms, and intrinsic characteristics of the bacteria called virulence factors. Host-mediated pathogenesis is often important because the host can respond aggressively to infection with the result that host defense mechanisms do damage to host tissues while the infection is being countered. The virulence factors of bacteria are typically proteins or other molecules that are synthesized by protein enzymes. These proteins are coded for by genes in chromosomal DNA, bacteriophage DNA or plasmids. Viral virulence factors determine whether infection occurs and how severe the resulting viral disease symptoms are. Viruses often require receptor proteins on host cells to which they specifically bind. Typically, these host cell proteins are endocytosed and the bound virus then enters the host cell. Virulent viruses such as the AIDS virus (HIV) have mechanisms for evading host defenses. HIV causes a loss of T-cells and immunosuppression. Death results from opportunistic infections secondary to disruption of the immune system caused by the AIDS virus. Some viral virulence factors confer ability to replicate during the defensive inflammation responses of the host such as during virus-induced fever. Many viruses can exist inside a host for long periods during which little damage is done. Extremely virulent strains can eventually evolve by mutation and natural selection within the virus population inside a host.

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/index.php/Virus_classification

# Virus classification Virus classification involves naming and placing viruses into a taxonomic system. Like the relatively consistent classification systems seen for cellular organisms, virus classification is the subject of ongoing debate and proposals. This is largely due to the pseudo-living nature of viruses, which are not yet definitively living or non-living. As such, they do not fit neatly into the established biological classification system in place for cellular organisms, such as plants and animals, for several reasons. Virus classification is based mainly on phenotypic characteristics, including morphology, nucleic acid type, mode of replication, host organisms, and the type of disease they cause. A combination of two main schemes is currently in widespread use for the classification of viruses. David Baltimore, a Nobel Prize-winning biologist, devised the Baltimore classification system, which places viruses into one of seven groups. These groups are designated by Roman numerals and separate viruses based on their mode of replication, and genome type. Accompanying this broad method of classification are specific naming conventions and further classification guidelines set out by the International Committee on Taxonomy of Viruses. Baltimore classification (first defined in 1971) is a classification system which places viruses into one of seven groups depending on a combination of their nucleic acid (DNA or RNA), strandedness (single-stranded or double-stranded), and method of replication. Other classifications are determined by the disease caused by the virus or its morphology, neither of which are satisfactory due to different viruses either causing the same disease or looking very similar. In addition, viral structures are often difficult to determine under the microscope. Classifying viruses according to their genome means that those in a given category will all behave in a similar fashion, offering some indication of how to proceed with further research. Viruses can be placed in one of the seven following groups: The International Committee on Taxonomy of Viruses began to devise and implement rules for the naming and classification of viruses early in the 1990s, an effort that continues to the present day. The system shares many features with the classification system of cellular organisms, such as taxon structure. Viral classification starts at the level of order and follows as thus, with the taxon suffixes given in italics: So far, only three orders have been established by the ICTV: Caudovirales, Mononegavirales, and Nidovirales. These orders span viruses with varying host ranges. Caudovirales are tailed dsDNA (group I) bacteriophages, Mononegavirales includes non-segmented (-)ss-RNA (Group V) plant and animal viruses, and Nidovirales is composed of (+)-ssRNA (Group IV) viruses with vertebrate hosts. Other variations occur between the orders, for example, Nidovirales are isolated for their differentiation in expressing structural and non-structural proteins separately. However, this system of nomenclature differs from other taxonomic codes on several points. A minor point is that names of orders and families are italicized, as in the ICBN. Most notably, species names generally take the form of [Disease] virus. The recognition of orders is very recent and has been deliberately slow; to date, only three have been named, and most families remain unplaced. Approximately 80 families and 4000 species of virus are known. Holmes (1948) used Carolus Linnaeus system of binomial nomenclature classification system to viruses into 3 groups under one order, Virales. They are placed as follows: The LHT System of Virus Classification is based on chemical and physical characters like nucleic acid (DNA or RNA), Symmetry (Helical or Icosahedral or Complex), presence of envelope, diameter of capsid, number of capsomers. This classification was approved by the Provisional Committee on Nomenclature of Virus (PNVC) of the International Association of Microbiological Societies (1962). It is as follows: Casjens and Kings(1975) classified virus into 4 groups based on type of nucleic acid ,presence of envelope,symmetry and site of assembly. It is as follows: Satellites depend on co-infection of a host cell with a helper virus for productive multiplication. Their nucleic acids have substantially distinct nucleotide sequences from either their helper virus or host. When a satellite subviral agent encodes the coat protein in which it is encapsulated, it's then called a satellite virus. Prions, named for their description as "proteinaceous and infectious particles," lack any detectable (as of 2002) nucleic acids or virus-like particles. They resist inactivation procedures which normally affect nucleic acids.

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/index.php/Visceral_fat

# Visceral fat Visceral fat, also known as inner organ fat, is located inside the peritoneal cavity, packed in between internal organs, as opposed to subcutaneous fat which is found underneath the skin and intramuscular fat which is found interspersed in skeletal muscle. An excess of visceral fat leads to the "pot belly" or "beer belly" effect, in which the abdomen protrudes excessively. This body type is also known as "apple" shaped, as opposed to "pear" shape, in which fat is deposited on the hips and buttocks. Visceral fat is composed of several adipose depots including mesenteric, epididymal white adipose tissue (EWAT) and perirenal depots. Visceral fat accumulation is associated with increased risk of heart disease and type 2 diabetes. Visceral fat can be estimated per area, manually or using a BIA or bioelectrical impedance analysis diagnostic machine or using a CT or computed tomography scan at the umbilical level. The voltage occurring at the flank to the flow between the umbilicus and the back becomes larger as the visceral fat can be different even with subjects with the same Wc because the resistance of intra abdominal fat is greater than the resistance of fat free mass. Visceral fat has been associated with more risk factor syndromes than the BMI or body mass index which is the result of the equation of diving the weight over the height squared.

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/index.php/Visceral_leishmaniasis_causes

# Visceral leishmaniasis causes Several species of Leishmania are known to give rise to the visceral form of the disease. The "Old World" (Africa, Asia, Europe) species are L. donovani and L. infantum and the "New World" (South America) species is L. chagasi.

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/index.php/Visceral_leishmaniasis_epidemiology_and_demographics

# Visceral leishmaniasis epidemiology and demographics The disease is endemic in West Bengal,India where it was first discovered, but is seen at its most deadly in north and east Africa. It can also be found throughout the Arab world and southern Europe, and a slightly different strain of the pathogen, L. chagasi, is responsible for leishmaniasis in the new world. But, while the disease's geographical range is broad, it is not continuous. The disease clusters around areas of drought, famine, and high population density. In Africa, this has meant a knot of infection centers mostly in Sudan, Kenya, and Somalia. Living conditions here have changed very little in the past century, and the people are not normally very mobile. Parts of the Sudan, in particular the Upper Nile region, are almost totally cut off from the rest of the country, and the people are as tied to the place of their birth as any peasant of Europe's dark ages.

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/index.php/Visceral_leishmaniasis_historical_perspective

# Visceral leishmaniasis historical perspective Kala-azar first came to the attention of Western doctors in 1824 in Jessore, India, where it was initially thought to be a form of malaria. India gave kala-azar its common name, which is the Hindi for "black fever", so called for the darkening of the skin on the extremities and abdomen that is a symptom of the Indian form of the disease. The agent of the disease was also first isolated in India — by Scottish doctor William Leishman and Irish physician Charles Donovan, working independently of each other. As they published their discovery almost simultaneously, the species was named for both of them — Leishmania donovani. Today, the name kala-azar is used interchangeably with the scientific name visceral leishmaniasis for the most acute form of the disease caused by L. donovani. Contemporary life has made itself felt even here, however — not as "progress" but in the form of the many small wars of Africa's post-colonial era. In the Sudan, where civil war has been continuous since 1983, the violence has been concentrated in the more populated south, and kala-azar was concentrated there too. But the wars have driven a steady stream of refugees out of the region, and these traveled either across the southern border or into the remoter western part of the country called the Upper Nile, where both war and the disease that went with it had not yet penetrated. These refugees, moving at foot-speed, carried the disease with them, and when it arrived it hit the Upper Nile with a force comparable to smallpox hitting the American Indians. The isolated people of the Upper Nile had no access to medicine or education about the new disease among them. Worse, their immune systems were defenseless against this new pathogen, foreign to them though it came only from another part of their own country. One village at the center of the epidemic, Duar, was left with four survivors out of a population of a thousand, and from the late eighties to the mid-nineties a total of 100,000 succumbed to the sickness in that region alone. In the words of Jill Seaman, the doctor who led relief efforts in the Upper Nile for the French organization Medicins Sans Frontieres, "Where else in the world could 50% of a population die without anyone knowing?" The world's failure to notice the epidemic was not due solely to its primitive setting, but also to the realities of politics. When, in 1991, a group of Sudanese researchers with the World Health Organization warned of a coming kala-azar epidemic and proposed the construction of a treatment center, the Sudanese government stepped in and denied the existence of any epidemic. At war with its own people, the government in Khartoum did not wish to have foreigners aiding the population, and preferred to use limitations on foreign aid as a means of political control. The WHO, a non-governmental organization, could do nothing in the face of opposition from its host government, and so nothing was done. For much of the nineties, Medecins Sans Frontieres battled the disease essentially alone, working not only without borders but without hospitals or visas.

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/index.php/Visceral_leishmaniasis_history_and_symptoms

# Visceral leishmaniasis history and symptoms When a human patient does develop visceral leishmaniasis, the most typical symptoms are fever and the enlargement of the spleen, or splenomegaly, with enlargement of the liver - hepatomegaly, sometimes being seen as well. The blackening of the skin that gave the disease its common name in India does not appear in most strains of the disease, and the other symptoms are very easy to mistake for those of malaria.

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/index.php/Visceral_leishmaniasis_laboratory_findings

# Visceral leishmaniasis laboratory findings The gold standard for diagnosis is visualisation of the amastigotes in splenic aspirate or bone marrow aspirate. This is a technically challenging procedure that is frequently unavailable in areas of the world where visceral leishmaniasis is endemic. Serological testing is much more frequently used in areas where leishmaniasis is endemic. The K39 dipstick test is easy to perform, and village health workers can be easily trained to use it. The kit may be stored at ambient temperature and no additional equipment needs to be carried to remote areas. The DAT anti-leishmania antigen test is standard within MSF is much more cumbersome to use and appears not to have any advantages over the K39 test. There are a number of problems with serological testing: in highly endemic areas, not everyone who becomes infected will actually develop clinical disease or require treatment. Indeed, up to 32% of the healthy population may test positive, but not require treatment. Conversely, because serological tests look for an immune response and not for the organism itself, the test does not become negative after the patient is cured, it cannot be used as a check for cure, or to check for re-infection or relapse. Likewise, patients with abnormal immune systems (e.g., HIV infection) will have false-negative tests.

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/index.php/Visceral_leishmaniasis_medical_therapy

# Visceral leishmaniasis medical therapy As with many diseases in developing nations, (including trypanosomiasis and malaria) effective and affordable chemotherapy is sorely lacking and parasites or insect vectors are becoming increasingly resistant to existing anti-parasite drugs. Presumably due to the lack of financial return, new drugs are slow to emerge and much of the basic research into potential drug targets takes place in universities, funded by charitable organisations. This may or may not change as a result of infection of members of the armed forces from the "developed" nations that currently occupy nations such as Afghanistan and Iraq, where Leishmania is commonplace. The traditional treatment is with pentavalent antimonials such as sodium stibogluconate and meglumine antimoniate. Resistance is now common in India, and the treatment of choice for visceral leishmaniasis acquired in India is now Amphotericin B in its various preparations (Ambisome®, Abelcet®, Amphocil® ) A low dose (0.5–1mg/kg) is given on the first day, increasing to 1–2mg/kg on the second day, followed by 1.5–3mg/kg on the third and subsequent days. Miltefosine Impavido® is the first oral treatment for this disease. The cure rate of miltefosine in phase III clinical trials is 95%; Studies in Ethiopia show that is also effective in Africa. In HIV immunosuppressed people which are coinfected with leishmaniasis it has shown that even in resistant cases 2/3 of the people responded to this new treatment. Miltefosine has received approval by the Indian regulatory authorities in 2002 and in Germany in 2004.It is now registered in many countries. The drug is generally better tolerated than other drugs. Main side effects are gastrointetinal disturbance in the first or second day of treatment (a course of treatment is 28 days) which does not affect the efficiency. Because it is available as an oral formulation, the expense and inconvenience of hospitalisation is avoided, which makes it a drug of choice. The nonprofit Institute for OneWorld Health has developed the drug paromomycin, which they claim is effective and cheap. A treatment with paromomycin will cost about $10. The drug had originally been identified in th 1960's, but had been abandoned because it would not be profitable, as the disease mostly affects poor people. The Indian government approved paromomycin for sale in August 2006.

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/index.php/Visceral_leishmaniasis_natural_history,_complications_and_prognosis

# Visceral leishmaniasis natural history, complications and prognosis Mis-diagnosis is dangerous, as without proper treatment the mortality rate for kala-azar is close to 100%. L. donovani itself is not usually the direct cause of death in kala-azar sufferers, however. Pneumonia, tuberculosis and dysentery are omnipresent in the depressed regions where leishmaniasis thrives, and, as with AIDS, it is these opportunistic infections that are more likely to kill, flaring up in a host whose immune system has been weakened by the L. donovani infection. Progress of the disease is extremely variable, taking anywhere from one to twenty weeks, but a typical duration for the Sudanese strain of the disease is narrower, between twelve and sixteen weeks. Even with recovery, kala-azar does not always leave its hosts unmarked. Some time after successful treatment—generally a few months with African kala-azar, or as much as several years with the Indian strain—a secondary form of the disease may set in, called post kala-azar dermal leishmaniasis, or PKDL. This condition manifests first as small, measle-like skin lesions on the face, which gradually increase in size and spread over the body. Eventually the lesions may coalesce to form disfiguring, swollen structures resembling leprosy, and occasionally causing blindness if they spread to the eyes. (This disease is not the same as cutaneous leishmaniasis, a milder disease caused by another protozoan of the Leishmania genus which also causes skin lesions).

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/index.php/Visceral_leishmaniasis_other_diagnostic_studies

# Visceral leishmaniasis other diagnostic studies Other tests being developed include a latex agglutination test (KAtex), which is currently being tested in Asia and Africa. Another potential test detects erythrosalicylic acid.

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/index.php/Visceral_leishmaniasis_overview

# Visceral leishmaniasis overview Visceral leishmaniasis (VL) is the most severe form of leishmaniasis, a disease caused by parasites of the Leishmania genus. It is the second-largest parasitic killer in the world (after malaria), responsible for an estimated 60 000 who die from the disease each year out of half-million infections worldwide. The parasite migrates to the visceral organs such as liver, spleen and bone marrow and if left untreated will almost always result in the death of the mammalian host. Signs and symptoms include fever, weight loss, anemia and substantial swelling of the liver and spleen. Of particular concern, according to the World Health Organization (WHO), is the emerging problem of HIV/VL co-infection . Other tests being developed include a latex agglutination test (KAtex), which is currently being tested in Asia and Africa. Another potential test detects erythrosalicylic acid.

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/index.php/Visceral_leishmaniasis_pathophysiology

# Visceral leishmaniasis pathophysiology Kala-azar is spread through an insect vector, the sandfly of the Phlebotomus genus in the Old World and the Lutzomyia genus in the New World. Leishmania are tiny creatures, 3-6 micrometers long by 1.5-3 micrometers in diameter, and found in tropical or temperate regions throughout the world. Sand fly larvae grow in warm, moist organic matter, so old trees, house walls or garbage are their most common breeding centers — making them hard to eradicate. The adult female sand fly is a bloodsucker, usually feeding at night on sleeping prey. When the fly bites an animal infected with L. donovani, the pathogen is ingested along with the prey's blood. At this point the protozoan is in the smaller of its two forms, called an amastigote — round, non-motile, and only three to seven micrometers in diameter. Taken into the stomach of the sandfly, the amastigotes quickly transform into a second L. donovani form, called the promastigote. This form is spindle-shaped, triple the size of the amastigote, and has a single flagellum that allows for motility. The promastigotes live extracellularly in the sandfly's alimentary canal, reproducing asexually, then migrate to the proximal end of the gut where they become poised for a regurgitational transmission. This is their means of transmission back into a mammalian host, as the fly injects its saliva into prey when it bites. The promastigotes are introduced locally at the bite site along with the fly's saliva. Once inside the new host, promastigotes invade macrophages. Once inside, they transform back into the smaller amastigote form. As an amastigote, L. donovani can only reproduce intracellularly — and the amastigotes replicate in the most hostile part of the macrophage cell, inside the phagolysosome, whose normal defensive response they are able to prevent. After they have reproduced to a certain extent, the L. donovani lyse their host cell by sheer pressure of mass, but there is some recent speculation that they are able to leave the cell by triggering the exocytosis response of the macrophage. The daughter cell protozoans then migrate through the bloodstream to find new macrophage hosts. In time, L. donovani becomes a systemic infection, spreading to all the host's organs, particularly the spleen and liver. In human hosts, response to infection by L. donovani varies a great deal, not only by the strength but also by the type of the patient's immune reaction. Patients whose immune systems produce large numbers of TH1-type T-Cells, which strengthen cell defenses but do not encourage antibody formation, often recover easily from infection on their own, and after recovery are immune to reinfection. Patients whose systems produce more TH2-type cells, which prompt antibody formation but do nothing for cellular health, are likely to quickly succumb to leishmaniasis. Sadly, some of the stronger strains of L. donovani appear to be able to force a switch in the host from a TH1 to a TH2-type immune response as the infection progresses.

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/index.php/Viscum_album

# Viscum album Viscum album is a species of mistletoe, the species originally so-named, and also known as European Mistletoe or Common Mistletoe to distinguish it from other related species. It is native to Europe, and western and southern Asia. It is a hemi-parasitic shrub, which grows on the stems of other trees. It has stems 30-100 cm long with dichotomous branching. The leaves are in opposite pairs, strap-shaped, entire, leathery textured, 2-8 cm long and 0.8-2.5 cm broad, yellowish-green in colour. Usually dioecious, the flowers are inconspicuous, yellowish-green, 2-3 mm diameter. The fruit is a white or yellow berry containing several seeds embedded in the very sticky, glutinous fruit pulp. Up to four subspecies are commonly accepted (Flora Europaea, Flora of China, Bean 1980, Blamey & Grey-Wilson 1989), and two others sometimes so. They differ in fruit colour, leaf shape and size, and most obviously in the host trees utilised. It has always attracted interest and has been surrounded by a number of myths and legends. In some countries it plays a part in Christmas festivities. It also features in the popular Asterix comic books, where mistletoe collected from oaks was considered to have special qualities.

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/index.php/Visilizumab

# Visilizumab Template:Drugbox-mab Visilizumab (marketed under the trade name Nuvion by PDL BioPharma Inc.) is a humanized monoclonal antibody. It is being investigated for use as an immunosuppressive drug in patients with ulcerative colitis and Crohn disease. Visilizumab binds to the CD3 receptor on certain activated T cells without effecting resting T cells.

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/index.php/Visine

# Visine Visine is a brand of eye drops produced by Johnson & Johnson. Johnson & Johnson acquired Visine, along with Pfizer's entire consumer healthcare portfolio, in December 2006. The active ingredients in the original Visine formulation are potassium chloride and tetrahydrozoline hydrochloride which is a vasoconstrictor, and therefore constricts the eye's superficial blood vessels to "get the red out", as claimed in Johnson & Johnson's advertising . As with other eye drops, Visine is administered topically with 1 to 2 drops applied to the affected eye(s) up to 4 times daily .

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/index.php/Vision

# Visual system The visual system is the part of the nervous system which allows organisms to see. It interprets the information from visible light to build a representation of the world surrounding the body. The visual system has the complex task of (re)constructing a three dimensional world from a two dimensional projection of that world. The psychological manifestation of visual information is known as visual perception. This article mostly describes the visual system of mammals, although other "higher" animals have similar visual systems. In this case, the visual system consists of: Different species are able to see different parts of the light spectrum; for example, bees can see into the ultraviolet, while pit vipers can accurately target prey with their infrared imaging sensors. The eye is a complex biological device. The functioning of a camera is often compared with the workings of the eye, mostly since both focus light from external objects in the visual field onto a light-sensitive medium. In the case of the camera, this medium is film or an electronic sensor; in the case of the eye, it is an array of visual receptors. With this simple geometrical similarity, based on the laws of optics, the eye functions as a transducer, as does a CCD camera. Light entering the eye is refracted as it passes through the cornea. It then passes through the pupil (controlled by the iris) and is further refracted by the lens. The cornea and lens act together as a compound lens to project an inverted image onto the retina. The retina consists of a large number of photoreceptor cells which contain a particular protein molecule called an opsin. In humans, there are two types of opsins, rod opsins and cone opsins. Either opsin absorbs a photon (a particle of light) and transmits a signal to the cell through a signal transduction pathway, resulting in hyperpolarization of the photoreceptor. (For more information, see photoreceptor). Rods and cones differ in function. Rods are found primarily in the periphery of the retina and are used to see at low levels of light. Cones are found primarily in the center (or fovea) of the retina. There are three types of cones that differ in the wavelengths of light they absorb; they are usually called short or blue, middle or green, and long or red. Cones are used primarily to distinguish color and other features of the visual world at normal levels of light. In the retina, the photoreceptors synapse directly onto bipolar cells, which in turn synapse onto ganglion cells of the outermost layer, who will then conduct action potentials to the brain. A significant amount of visual processing arises from the patterns of communication between neurons in the retina. About 130 million photoreceptors absorb light, yet roughly 1.2 million axons of ganglion cells transmit information from the retina to the brain. The processing in the retina includes the formation of center-surround receptive fields of bipolar and ganglion cells in the retina, as well as convergence and divergence from photoreceptor to bipolar cell. In addition, other neurons in the retina, particularly horizontal and amacrine cells, transmit information laterally (from a neuron in one layer to an adjacent neuron in the same layer), resulting in more complex receptive fields that can be either indifferent to color and sensitive to motion or sensitive to color and indifferent to motion. The final result of all this processing is five different populations of ganglion cells that send information to the brain: M cells, with large center-surround receptive fields that are sensitive to depth, indifferent to color, and rapidly adapt to a stimulus; P cells, with smaller center-surround receptive fields that are sensitive to color and shape; K cells, with very large center-only receptive fields that are sensitive to color and indifferent to shape or depth; another population that is intrinsically photosensitive; and a final population that is used for eye movements. A 2006 University of Pennsylvania study calculated the approximate bandwidth of human retinas to be about 8960 kilobits per second, whereas guinea pig retinas transfer at about 875 kilobits. In the visual system, retinal, technically called retinene1 or "retinaldehyde", is a light-sensitive retinene molecule found in the photoreceptor cells of the retina. Retinal is the fundamental structure involved in the transduction of light into visual signals, i.e. nerve impulses in the ocular system of the central nervous system. In the presence of light, the retinal molecule changes configuration and as a result a nerve impulse is generated. The information about the image via the eye is transmitted to the brain along the optic nerve. Different populations of ganglion cells in the retina send information to the brain through the optic nerve. About 90% of the axons in the optic nerve go to the lateral geniculate nucleus in the thalamus. These axons originate from the M, P, and K ganglion cells in the retina. This parallel processing is important for reconstructing the visual world; each type of information will go through a different route to perception. Another population sends information to both the superior colliculus in the midbrain, which assists in controlling eye movements (saccades). A final population of photosensitive ganglion cells (containing melanopsin) sends information to the pretectum (pupillary reflex), and to several structures involved in the control of circadian rhythms and sleep such as the suprachiasmatic nucleus (SCN, the biological clock), the ventrolateral preoptic nucleus (VLPO, a region involved in sleep regulation). The optic nerves from both eyes meet and cross at the optic chiasm, at the base of the hypothalamus of the brain. At this point the information coming from both eyes is combined and then splits according to the visual field. The corresponding halves of the field of view (right and left) are sent to the left and right halves of the brain, respectively, to be processed. That is, the right side of primary visual cortex deals with the left half of the field of view from both eyes, and similarly for the left brain. A small region in the center of the field of view is processed redundantly by both halves of the brain. Information from the right visual field (now on the left side of the brain) travels in the left optic tract. Information from the left visual field travels in the right optic tract. Each optic tract terminates in the lateral geniculate nucleus (LGN) in the thalamus. The lateral geniculate nucleus (LGN) is a sensory relay nucleus in the thalamus of the brain. The LGN consists of six layers in humans and other primates starting from catarhinians, including cercopithecidae and apes. Layers 1, 4, and 6 correspond to information from one eye; layers 2, 3, and 5 correspond to information from the other eye. Layer one (1) contains M cells, which correspond to the M (magnocellular) cells of the optic nerve of the opposite eye, and are concerned with depth or motion. Layers four and six (4 & 6) of the LGN also connect to the opposite eye, but to the P cells (color and edges) of the optic nerve. By contrast, layers two, three and five (2, 3, & 5) of the LGN connect to the M cells and P (parvocellular) cells of the optic nerve for the same side of the brain as its respective LGN. The six layers of the LGN are the area of a credit card, but about three times the thickness of a credit card, rolled up into two ellipsoids about the size and shape of two small birds eggs. In between the six layers are smaller cells that receive information from the K cells (color) in the retina. The neurons of the LGN then relay the visual image to the primary visual cortex (V1) which is located at the back of the brain (caudal end) in the occipital lobe in and close to the calcarine sulcus. The optic radiations carries information from the thalamic lateral geniculate nucleus to layer 4 of the visual cortex. The P layer neurons of the LGN relay to V1 layer 4C β. The M layer neurons relay to V1 layer 4C α. The K layer neurons in the LGN relay to large neurons called blobs in layers 2 and 3 of V1. There is a direct correspondence from an angular position in the field of view of the eye, all the way through the optic tract to a nerve position in V1. At this juncture in V1, the image path ceases to be straightforward; there is more cross-connection within the visual cortex. The visual cortex is the most massive system in the human brain and is responsible for higher-level processing of the visual image. It lies at the rear of the brain (highlighted in the image), above the cerebellum. The interconnections between layers of the cortex, the thalamus, the cerebellum, the hippocampus and the remainder of the areas of the brain are under active investigation. Currently, much of what is known stems from patients with damage to known areas of the brain, with a corresponding study of the cognitive functions which have been spared. See visual modularity for a discussion of the modular thesis of visual perception.

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/index.php/Vision_loss

# Vision loss Vision loss is the absence of vision where it existed before, which can happen either acutely (i.e. abruptly) or chronically (i.e. over a long period of time). It may be caused by media opacities, retinal disease, optic nerve disease, visual pathway disorders, or functional disorders, or it may be due to an abnormality in the central nervous system. In order to gain insight into the pathophysiology of vision loss which will in turn guide treatment decisions, the signs and symptoms should be characterized: Opacities of the clear refractive media of the eye such as the cornea, anterior chamber, lens, and vitreous humor may cause acute visual loss as manifested by blurry vision or reduced visual acuity. While pupillary reflexes may be affected, these conditions generally do not cause a relative afferent pupillary defect. Retinal diseases may cause sudden visual loss. Because the retina is being affected, there is usually a concomitant relative afferent pupillary defect. Conditions that affect or destroy the retina include retinal detachment; macular disease (e.g., macular degeneration); and retinal vascular occlusions, the most important of which is central retinal artery occlusion. Diseases which affect the optic nerve may cause acute visual loss. Signs include an abnormal pupillary reflex, with an afferent pupillary defect when the optic nerve disease is unilateral. The eye is very sensitive to restriction of its supply of oxygen. A dimming of vision (a brownout or greyout) accompanied by loss of peripheral perception may result from low blood pressure, shock, g-LOC (an aviation related problem) or simply standing up suddenly, especially if sick or otherwise infirm. Vision usually returns readily once the conditions restricting blood flow are lifted. Visual pathway disorders are any problems that may impede the visual pathway. Rarely, acute visual loss is caused by homonymous hemianopia and, more rarely, cortical blindness. The term functional disorder is now used where hysterical and malingering were historically used. This shift recognizes the inherent inability of the physician to identify the subjective experience of a patient (and thus whether that patient can truly see or not).

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# Vision loss (patient information) Partial blindness means you have very limited vision. Complete blindness means you cannot see anything and do not see light. (Most people who use the term "blindness" mean complete blindness.) People with vision worse than 20/200 are considered legally blind in most states in the United States. Sudden vision loss is always an emergency, even if you have not completely lost all vision. You should never ignore loss of vision, thinking it will get better. Contact an ophthalmologist or go to the emergency room immediately. Most serious forms of vision loss are painless, and the absence of pain in no way diminishes the urgent need to get medical care. Many forms of vision loss only give you a short amount of time to be successfully treated. The kind of home assistance you need will depend on your type of vision loss. It is important for a blind person to be able to dress, eat, function independently, and stay safe.

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# Vislab The Artificial Vision and Intelligent Systems Laboratory of the University of Parma (also known as Parma VisLab or VisLab) is the artificial vision research laboratory of University of Parma, Dipartimento di Ingegneria dell'Informazione. It started its activities in 1990, with the involvement of the researchers within the Eureka PROMETHEUS Project. Since then the research group is focussed on vehicular applications. VisLab is regarded as one of the leading centers for artificial vision applied to vehicles. VisLab, directed by Alberto Broggi, undertakes research in basic and applied computer vision; the most important field of research is the perception of the surrounding environment in vehicular applications using cameras and fusion with other sensors . Its researchers contribute to fields such as artificial vision, image processing, machine learning, neural networks, robotics, and sensor fusion in the vehicular robotics history. Among them, the ARGO Project and the TerraMax Project. In the eraly years, the research group formed by Alberto Broggi, Massimo Bertozzi and Alessandra Fascioli designed, realized, and successfully tested ARGO. ARGO was a passenger car able to perceive the environment through the use of microcameras, analyze the surroundings, plan a trajectory, and drive itself on normal roads. It was tested in 1998 with a 2000+ km tour in Italy, dubbed MilleMiglia in Automatico. In this test the vehicle drove for more than 94% in automatic mode. It was the first test in the world to use off-the-shelf and low cost technology (a Pentiun 200MHz PC and two low-cost video-phone cameras) in normal conditions of traffic, environment, and weather. Together with Carnegie Mellon's No Hands Across America and Universitat der Bundeswer's test from Munich to Odense, the MilleMiglia in Automatico is regarded as one of the milestones in vehicular robotics. In 2005 a vehicle called TerraMax was able to successfully conclude the DARPA Grand Challenge; VisLab's vision system was its primary means of perception. Despite the large vehicle size, the vehicle was able to negotiate different terrains and detect obstacles thanks to an innovative solution based on a trinocular system that was developed by VisLab. VisLab is located in the University of Parma main campus, south of Parma, Italy. A new location in Wisconsin, friendly dubbed Vislab America, is the homebase for projects with VisLab's american partners.

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/index.php/Visnadine

# Visnadine Visnadine (or visnadin) is a natural vasodilator. It was first isolated from bishop's weed (Ammi visnaga), a plant indigenous to the Mediterranean region which has been used for centuries in Egypt as a spasmolytic.

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/index.php/Visual_acuity

# Visual acuity Visual acuity (VA) is acuteness or clearness of vision, especially form vision, which is dependent on the sharpness of the retinal focus within the eye and the sensitivity of the interpretative faculty of the brain. VA is a quantitative measure of the ability to identify black symbols on a white background at a standardized distance as the size of the symbols is varied. It is the most common clinical measurement of visual function. In the term "20/20 vision" the numerator refers to the distance in feet from which a person can reliably distinguish a pair of objects. The denominator is the distance from which a person with standard VA would be able to distinguish them--the distance at which their separation angle is 1 arc minute. The metric equivalent is 6/6 vision. Twenty feet is essentially infinity from an optical perspective (the difference in optical power required to focus at 20 feet versus infinity is only 0.164 diopters). For that reason, 20/20 vision can be considered nominal performance for human distance vision; 20/40 vision can be considered half that acuity for distance vision and 20/10 vision would be twice normal acuity. The 20/x number does not directly relate to the eyeglass prescription required to correct vision; rather an eye exam seeks to find the prescription that will provide 20/20 vision. To resolve detail, the eye's optical system has to project a focused image on the fovea, a region inside the macula having the highest density of cone photoreceptors (the only kind of photoreceptors existing on the fovea), thus having the highest resolution and best color vision. Acuity and color vision, despite being done by the same cells, are different physiologic functions that don't interrelate except by position. Acuity and color vision can be affected independently. Light travels from the fixation object to the fovea through an imaginary path called the visual axis. The eye's tissues and structures that are in the visual axis (and also the tissues adjacent to it) affect the quality of the image. These structures are: tear film, cornea, anterior chamber, pupil, lens, vitreous, and finally the retina. The posterior part of the retina, called the retinal pigment epithelium (RPE) is responsible for, among many other things, absorbing light that crosses the retina so it cannot bounce to other parts of the retina. (However in many vertebrates, such as cats, where high visual acuity is not a priority, there is a reflecting tapetum layer that gives the photoreceptors a "second chance" to absorb the light, thus improving the ability to see in the dark. This is what causes an animal's eyes to seemingly glow in the dark when a light is shone on them.) The RPE also has a vital function of recycling the chemicals used by the rods and cones in photon detection. If the RPE is damaged and does not clean up this "shed" blindness can result. As in a photographic lens, visual acuity is affected by the size of the pupil. Optical aberrations of the eye that decrease visual acuity are at a maximum when the pupil is largest (about 8 mm), which occurs in low-light conditions. When the pupil is small (1–2 mm), image sharpness may be limited by diffraction of light by the pupil (see Diffraction limit). Between these extremes is the pupil diameter that is generally best for visual acuity in normal, healthy eyes; this tends to be around 3 or 4 mm. If the optics of the eye were otherwise perfect, theoretically acuity would be limited by pupil diffraction which would be a diffraction-limited acuity of 0.4 minutes of arc (minarc) or 20/8 acuity. The smallest cone cells in the fovea have sizes corresponding to 0.4 minarc of the visual field, which also places a lower limit on acuity. The optimal acuity of 0.4 minarc or 20/8 can be demonstrated using a laser interferometer that bypasses any defects in the eye's optics and projects a pattern of dark and light bands directly on the retina. Laser interferometers are now used routinely in patients with optical problems, such as cataracts, to assess the health of the retina before subjecting them to surgery. The visual cortex is the part of the cerebral cortex in the posterior (occipital) part of the brain responsible for processing visual stimuli. The central 10° of field (approximately the extension of the macula) is represented by at least 60% of the visual cortex. Many of these neurons are believed to be involved directly in visual acuity processing. Proper development of normal visual acuity depends on an animal having normal visual input when it is very young. Any visual deprivation, that is, anything intefering with such input over a prolonged period, such as a cataract, severe eye turn or strabismus, or covering or patching the eye during medical treatment, will usually result in a severe and permanent decrease in visual acuity in the affected eye if not treated early in life. The decreased acuity is reflected in various abnormalities in cell properties in the visual cortex. These changes include a marked decrease in the number of cells connected to the affected eye as well as few cells connected to both eyes, resulting in a loss of binocular vision and depth perception, or stereopsis. The period of time over which an animal is highly sensitive to such visual deprivation is referred to as the critical period. The eye is connected to the visual cortex by the optic nerve coming out of the back of the eye. The two optic nerves come together behind the eyes at the optic chiasm, where about half of the fibers from each eye cross over to the opposite side and join fibers from other eye representing the corresponding visual field, the combined nerve fibers from both eyes forming the optic tract. This ultimately forms the physiological basis of binocular vision. The tracts project to a relay station in the midbrain called the lateral geniculate nucleus and then to the visual cortex along a collection of nerve fibers called the optic radiations. Any pathological process in the visual system, even in older humans beyond the critical period, will often cause decreases in visual acuity. Thus measuring visual acuity is a simple test in accessing the health of the eyes, the visual brain, or pathway to the brain. Any relatively sudden decrease in visual acuity is always a cause for concern. Common causes of decreases in visual acuity are cataracts and scarred corneas, which affect the optical path, diseases that affect the retina, such as macular degeneration and diabetes, diseases affecting the optic pathway to the brain such as tumors and multiple sclerosis, and diseases affecting the visual cortex such as tumors and strokes. Visual acuity is often measured according to the size of letters viewed on a Snellen chart or the size of other symbols, such as Landolt Cs or Tumbling E. Using the foot as a unit of measurement, (fractional) visual acuity is expressed relative to 20/20. Otherwise, using the metre, visual acuity is expressed relative to 6/6. For all intents and purposes, 6/6 vision is equivalent to 20/20. In the decimal system, the acuity is defined as the reciprocal value of the size of the gap (measured in arc minutes) of the smallest Landolt C that can be reliably identified. A value of 1.0 is equal to 20/20. LogMAR is another commonly used scale which is expressed as the logarithm of the minimum angle of resolution. LogMAR scale converts the geometric sequence of a traditional chart to a linear scale. It measures visual acuity loss; positive values indicate vision loss, while negative values denote normal or better visual acuity. This scale is rarely used clinically; it is more frequently used in statistical calculations because it provides a more scientific equivalent for the traditional clinical statement of "lines lost" or "lines gained", which is valid only when all steps between lines are equal, which is not usually the case. A visual acuity of 20/20 is frequently described as meaning that a person can see detail from 20 feet away the same as a person with normal eyesight would see from 20 feet. If a person has a visual acuity of 20/40, he is said to see detail from 20 feet away the same as a person with normal eyesight would see it from 40 feet away. It is possible to have vision superior to 20/20: the maximum acuity of the human eye without visual aids (such as binoculars) is generally thought to be around 20/10 (6/3) however, recent test subjects have exceeded 20/8 vision. Recent developments in optometry have resulted in corrective lenses conferring upon the wearer a vision of up to 20/10. Some birds, such as hawks, are believed to have an acuity of around 20/2; in this respect, their vision is much better than human eyesight. When visual acuity is below the largest optotype on the chart, either the chart is moved closer to the patient or the patient is moved closer to the chart until the patient can read it. Once the patient is able to read the chart, the letter size and test distance are noted. If the patient is unable to read the chart at any distance, he or she is tested as follows: Many humans have one eye that has superior visual acuity over the other. If a person cannot achieve a visual acuity of 20/200 (6/60) or above in the better eye, even with the best possible glasses, then that person is considered legally blind in the United States. A person with a visual field narrower than 20 degrees also meets the definition of legally blind. A person's visual acuity is registered documenting the following: whether the test was for distant or near vision, the eye(s) evaluated and whether corrective lenses (i.e. spectacles or contact lenses) were used: Visual acuity is typically measured monocularly rather than binocularly with the aid of an optotype chart for distant vision, an optotype chart for near vision, and an occluder to cover the eye not being tested. The examiner may also occlude an eye by sliding a tissue behind the patient's eyeglasses, or instructing the patient to use his or her hand. This latter method is typically avoided in professional settings as it may inadvertently allow the patient to peek through his or her fingers, or press the eye and alter the measurement when that eye is evaluated. Visual acuity measurement involves more than being able to see the optotypes. The patient should be cooperative, understand the optotypes, be able to communicate with the physician, and many more factors. If any of these factors is missing, then the measurement will not represent the patient's real visual acuity. Visual acuity is a subjective test meaning that if the patient is unwilling or unable to cooperate, the test cannot be done. A patient being sleepy, intoxicated, or having any disease that can alter the patient's consciousness or his mental status can make the measured visual acuity worse than it actually is. Illiterate patients who cannot read letters and/or numbers will be registered as having very low visual acuity if this is not known. Some of the patients will not tell the physician that they don't know the optotypes unless asked directly about it. Brain damage can result in a patient not being able to recognize printed letters, or being unable to spell them. Variables such as pupil size, background adaptation luminance, duration of presentation, type of optotype used, interaction effects from adjacent visual contours (or "crowding") can all affect visual acuity measurement. The measurement of visual acuity in infants, pre-verbal children and special populations (for instance, handicapped individuals) is not always possible with a letter chart. For these populations, specialised testing is necessary. As a basic examination step, one must check whether visual stimuli can be fixed, centered and followed. More formal testing using preferential looking techniques use Teller acuity cards (presented by a technician from behind a window in the wall) to check if the child is more visually attentive to a random presentation of vertical or horizontal bars on one side compared with blank page on the other side - the bars become progressively finer or closer together, and the endpoint is noted when the child in its adult carer's lap equally prefers the two sides. Another popular technique is electro-physiologic testing using visual evoked potentials (VEP), which can be used to estimate visual acuity in doubtful cases and expected severe vision loss cases like Leber's congenital amaurosis. VEP testing of acuity is somewhat similar to preferential looking in using a series of black and white stripes or checkerboard patterns (which produce larger responses than stripes). However, behaviorial responses are not required. Instead brain waves created by the presentation of the patterns are recorded. The patterns become finer and finer until the evoked brain wave just disappears, which is considered to be the endpoint measure of visual acuity. In adults and older, verbal children capable of paying attention and following instructions, the endpoint provided by the VEP corresponds very well to the perceptual endpoint determined by asking the subject when they can no longer see the pattern. There is an assumption that this correspondence also applies to much younger children and infants, though this doesn't necessarily have to be the case. Studies do show the evoked brain waves, as well as derived acuities, are very adult-like by one year of age. For reasons not totally understood, until a child is several years old, visual acuities from behavioral preferential looking techniques typically lag behind those determined using the VEP, a direct physiological measure of early visual processing in the brain. Possibly it takes longer for more complex behavioral and attentional responses, involving brain areas not directly involved in processing vision, to mature. Thus the visual brain may detect the presence of a finer pattern (reflected in the evoked brain wave), but the "behavioral brain" of a small child may not find it salient enough to pay special attention to. A simple but less-used technique is checking oculomotor responses with an optokinetic nystagmus drum, where the subject is placed inside the drum and surrounded by rotating black and white stripes. This creates an involuntary flicking or nystagumus of the eyes as they attempt to track the moving stripes. There is a good correspondence between the optikinetic and usual eye-chart acuities in adults. A potentially serious problem with this technique is that the process is reflexive and mediated in the low-level brain stem, not in the visual cortex. Thus someone can have a normal optokinetic response and yet be cortically blind with no conscious visual sensation. Visual acuity depends upon how accurately light is focused on the retina (mostly the macular region), the integrity of the eye's neural elements, and the interpretative faculty of the brain. "Normal" visual acuity is frequently considered to be what was defined by Snellen as the ability to recognize an optotype when it subtended 5 minutes of arc, that is Snellen's chart 20/20 feet, 6/6 meter, 1.00 decimal or 0.0 logMAR. In humans, the maximum acuity of a healthy, emmetropic eye (and even ametropic eyes with correctors) is approximately 20/16 to 20/12, so it is inaccurate to refer to 20/20 visual acuity as "perfect" vision. 20/20 is the visual acuity needed to discriminate two points separated by 1 arc minute -- about 1/16 of an inch at 20 feet. This is because a 20/20 letter, E for example, has three limbs and two spaces in between them, giving 5 different detailed areas. The ability to resolve this therefore requires 1/5 of the letter's total arc, which in this case would be 1 minute. The significance of the 20/20 standard can best be thought of as the lower limit of normal or as a screening cutoff. When used as a screening test subjects that reach this level need no further investigation, even though the average visual acuity of healthy eyes is 20/16 to 20/12. Some people may suffer from other visual problems, such as color blindness, reduced contrast, or inability to track fast-moving objects and still have normal visual acuity. Thus, normal visual acuity does not mean normal vision. The reason visual acuity is very widely used is that it is a test that corresponds very well with the normal daily activities a person can handle, and evaluate their impairment to do them. Normally visual acuity refers to the ability to resolve two separated points or lines, but there are other measures of the ability of the visual system to discern spatial differences. Vernier acuity measures the ability to align two line segments. Humans can do this with remarkable accuracy. Under optimal conditions of good illumination, high contrast, and long line segments, the limit to vernier acuity is about 8 arc seconds or 0.13 arc minutes, compared to about 0.6 arc minutes (20/12) for normal visual acuity or the 0.4 arc minute diameter of a foveal cone. Because the limit of vernier acuity is well below that imposed on regular visual acuity by the "retinal grain" or size of the foveal cones, it is thought to be a process of the visual cortex rather than the retina. Supporting this idea, vernier acuity seems to correspond very closely (and may have the same underlying mechanism) enabling one to discern very slight differences in the orientations of two lines, where orientation is known to be processed in the visual cortex. The smallest detectable visual angle produced by a single fine dark line against a uniformally illuminated background is also much less than foveal cone size or regular visual acuity. In this case, under optimal conditions, the limit is about 0.5 arc seconds, or only about 2% of the diameter of a foveal cone. This produces a contrast of about 1% with the illumination of surrounding cones. The mechanism of detection is the ability to detect such small differences in contrast or illumination, and does not depend on the angular width of the bar, which cannot be discerned. Thus as the line gets finer, it appears to get fainter but not thinner. Stereoscopic acuity is the ability to detect tiny differences in depth with the two eyes. For more complex targets, stereoacuity is similar to normal monocular visual acuity, or around 0.6-1.0 arc minutes, but for much simpler targets, such as vertical rods, may be as low as only 2 arc seconds. Although stereoacuity normally corresponds very well with monocular acuity, it may be very poor or even absent even with normal monocular acuities. Such individuals typically have abnormal visual development when they are very young, such as an alternating strabismus or eye turn, where both eyes rarely or never point in the same direction and therefore do not function together.

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# Visual cortex The term visual cortex refers to the primary visual cortex (also known as striate cortex or V1) and extrastriate visual cortical areas such as V2, V3, V4, and V5. The primary visual cortex is anatomically equivalent to Brodmann area 17, or BA17. The primary visual cortex, V1, is the koniocortex (sensory type) located in and around the calcarine fissure in the occipital lobe. It receives information directly from the lateral geniculate nucleus. The dichotomy of the dorsal/ventral pathways (also called the "where/what" or "action/perception" streams) was first defined by Ungerleider and Mishkin and is still contentious among vision scientists and psychologists. It is probably an over-simplification of the true state of affairs in the visual cortex. It is based on the findings that visual illusions such as the Ebbinghaus illusion may distort judgements of a perceptual nature, but when the subject responds with an action, such as grasping, no distortion occurs. However, recent work suggests that both the action and perception systems are equally fooled by such illusions. Neurons in the visual cortex fire action potentials when visual stimuli appear within their receptive field. By definition, the receptive field is the region within the entire visual field which elicits an action potential. But for any given neuron, it may respond to a subset of stimuli within its receptive field. This property is called tuning. In the earlier visual areas, neurons have simpler tuning. For example, a neuron in V1 may fire to any vertical stimulus in its receptive field. In the higher visual areas, neurons have complex tuning. For example, in the inferior temporal cortex (IT), a neuron may only fire when a certain face appears in its receptive field. Research on the primary visual cortex can involve recording action potentials from electrodes within the brain of cats, ferrets, rats, mice, or monkeys, or through recording intrinsic optical signals from animals or fMRI signals from human and monkey V1. One recent discovery concerning the human V1 is that signals measured by fMRI show very large attentional modulation. This result strongly contrasts with macaque physiology research showing very small changes (or no changes) in firing associated with attentional modulation. Research with the macaque monkey is usually performed by measuring spiking activity from single neurons. The neural basis of the fMRI signal on the other hand is mostly related to post synaptic potentiation (PSP). This difference therefore does not necessarily indicate a difference between macaque and human physiology. Other current work on V1 seeks to fully characterize its tuning properties, and to use it as a model area for the canonical cortical circuit. Lesions to primary visual cortex usually lead to a scotoma, or hole in the visual field. Interestingly, patients with scotomas are often able to make use of visual information presented to their scotomas, despite being unable to consciously perceive it. This phenomenon, called blindsight, is widely studied by scientists interested in the neural correlate of consciousness. The primary visual cortex is the best studied visual area in the brain. In all mammals studied, it is located in the posterior pole of the occipital cortex (the occipital cortex is responsible for processing visual stimuli). It is the simplest, earliest cortical visual area. It is highly specialized for processing information about static and moving objects and is excellent in pattern recognition. The functionally defined primary visual cortex is approximately equivalent to the anatomically defined striate cortex. The name "striate cortex" is derived from the stria of Gennari, a distinctive stripe visible to the naked eye that represents myelinated axons from the lateral geniculate body terminating in layer 4 of the gray matter. The primary visual cortex is divided into six functionally distinct layers, labelled 1 through 6. Layer 4, which receives most visual input from the lateral geniculate nucleus (LGN), is further divided into 4 layers, labelled 4A, 4B, 4Cα, and 4Cβ. Sublamina 4Cα receives most magnocellular input from the LGN, while layer 4Cβ receives input from parvocellular pathways. The average number of neurons in the adult human primary visual cortex, in each hemisphere, has been estimated at around 140 million (Leuba & Kraftsik, Anatomy and Embryology, 1994). V1 has a very well-defined map of the spatial information in vision. For example, in humans the upper bank of the calcarine sulcus responds strongly to the lower half of visual field (below the center), and the lower bank of the calcarine to the upper half of visual field. Conceptually, this retinotopy mapping is a transformation of the visual image from retina to V1. The correspondence between a given location in V1 and in the subjective visual field is very precise: even the blind spots are mapped into V1. Evolutionarily, this correspondence is very basic and found in most animals that possess a V1. In human and animals with a fovea in the retina, a large portion of V1 is mapped to the small, central portion of visual field, a phenomenon known as cortical magnification. Perhaps for the purpose of accurate spatial encoding, neurons in V1 have the smallest receptive field size of any visual cortex microscopic regions. The tuning properties of V1 neurons (what the neurons respond to) differ greatly over time. Early in time (40 ms and further) individual V1 neurons have strong tuning to a small set of stimuli. That is, the neuronal responses can discriminate small changes in visual orientations, spatial frequencies and colors. Furthermore, individual V1 neurons in human and animals with binocular vision have ocular dominance, namely tuning to one of the two eyes. In V1, and primary sensory cortex in general, neurons with similar tuning properties tend to cluster together as cortical columns. David Hubel and Torsten Wiesel proposed the classic ice-cube organization model of cortical columns for two tuning properties: ocular dominance and orientation. However, this model cannot accommodate the color, spatial frequency and many other features to which neurons are tuned. The exact organization of all these cortical columns within V1 remains a hot topic of current research. Current consensus seems to be that early responses of V1 neurons consists of tiled sets of selective spatiotemporal filters. In the spatial domain, the functioning of V1 can be thought of as similar to many spatially local, complex Fourier transforms. Theoretically, these filters together can carry out neuronal processing of spatial frequency, orientation, motion, direction, speed (thus temporal frequency), and many other spatiotemporal features. Experiments of V1 neurons substantiate these theories, but also raise new questions. Later in time (after 100 ms) neurons in V1 are also sensitive to the more global organisation of the scene (Lamme & Roelfsema, 2000). These response properties probably stem from recurrent processing (the influence of higher-tier cortical areas on lower-tier cortical areas) and lateral connections from pyramidal neurons (Hupe et al 1998). The visual information relayed to V1 is not coded in terms of spatial (or optical) imagery, but rather as the local contrast. As an example, for an image comprising half side black and half side white, the divide line between black and white has strongest local contrast and is encoded, while few neurons code the brightness information (black or white per se). As information is further relayed to subsequent visual areas, it is coded as increasingly non-local frequency/phase signals. Importantly, at these early stages of cortical visual processing, spatial location of visual information is well preserved amid the local contrast encoding. Visual area V2, also called prestriate cortex, is the second major area in the visual cortex, and the first region within the visual association area. It receives strong feedforward connections from V1 and sends strong connections to V3, V4, and V5. It also sends strong feedback connections to V1. Anatomically, V2 is split into four quadrants, a dorsal and ventral representation in the left and the right hemispheres. Together these four regions provide a complete map of the visual world. Functionally, V2 has many properties in common with V1. Cells are tuned to simple properties such as orientation, spatial frequency, and color. The responses of many V2 neurons are also modulated by more complex properties, such as the orientation of illusory contours and whether the stimulus is part of the figure or the ground (Qiu and von der Heydt, 2005). Recent research has shown that V2 cells show a small amount of attentional modulation (more than V1, less than V4), are tuned for moderately complex patterns, and may be driven by multiple orientations at different subregions within a single receptive field. The term third visual complex refers to the region of cortex located immediately in front of V2, which includes the region named visual area V3 in humans. The "complex" nomenclature is justified by the fact that some controversy still exists regarding the exact extent of area V3, with some researchers proposing that the cortex located in front of V2 may include two or three functional subdivisions. For example, David Van Essen and others (1986) have proposed that the existence of a "dorsal V3" in the upper part of the cerebral hemisphere, which is distinct from the "ventral V3" (or ventral posterior area, VP) located in the lower part of the brain. Dorsal and ventral V3 have distinct connections with other parts of the brain, appear different in sections stained with a variety of methods, and contain neurons that respond to different combinations of visual stimulus (for example, colour-selective neurons are more common in the ventral V3). Additional subdivisions, including V3A and V3B have also been reported in humans. These subdivisions are located near dorsal V3, but do not adjoin V2. Dorsal V3 is normally considered to be part of the dorsal stream, receiving inputs from V2 and from the primary visual area and projecting to the posterior parietal cortex. It may be anatomically located in Brodmann area 19. Recent work with fMRI has suggested that area V3/V3A may play a role in the processing of global motion Other studies prefer to consider dorsal V3 as part of a larger area, named the dorsomedial area (DM), which contains a representation of the entire visual field. Neurons in area DM respond to coherent motion of large patterns covering extensive portions of the visual field (Lui and collaborators, 2006). Ventral V3 (VP), has much weaker connections from the primary visual area, and stronger connections with the inferior temporal cortex. While earlier studies proposed that VP only contained a representation of the upper part of the visual field (above the point of fixation), more recent work indicates that this area is more extensive than previously appreciated, and like other visual areas it may contain a complete visual representation. The revised, more extensive VP is referred to as the ventrolateral posterior area (VLP) by Rosa and Tweedale. Visual area V4 is one of the visual areas in the extrastriate visual cortex of the macaque monkey. It is located anterior to V2 and posterior to visual area PIT. It comprises at least four regions (left and right V4d, left and right V4v), and some groups report that it contains rostral and caudal subdivisions as well. It is unknown what the human homologue of V4 is, and this issue is currently the subject of much scrutiny. V4 is the third cortical area in the ventral stream, receiving strong feedforward input from V2 and sending strong connections to the posterior inferotemporal cortex (PIT). It also receives direct inputs from V1, especially for central space. In addition, it has weaker connections to V5 and visual area DP (the dorsal prelunate gyrus). V4 is the first area in the ventral stream to show strong attentional modulation. Most studies indicate that selective attention can change firing rates in V4 by about 20%. A seminal paper by Moran and Desimone characterizing these effects was the first paper to find attention effects anywhere in the visual cortex . Like V1, V4 is tuned for orientation, spatial frequency, and color. Unlike V1, V4 is tuned for object features of intermediate complexity, like simple geometric shapes, although no one has developed a full parametric description of the tuning space for V4. Visual area V4 is not tuned for complex objects such as faces, as areas in the inferotemporal cortex are. The firing properties of V4 were first described by Semir Zeki in the late 1970s, who also named the area. Before that, V4 was known by its anatomical description, the prelunate gyrus. Originally, Zeki argued that the purpose of V4 was to process color information. Work in the early 1980s proved that V4 was as directly involved in form recognition as earlier cortical areas. This research supported the Two Streams hypothesis, first presented by Ungerleider and Mishkin in 1982. Recent work has shown that V4 exhibits long-term plasticity, encodes stimulus salience, is gated by signals coming from the frontal eye fields, shows changes in the spatial profile of its receptive fields with attention. Visual area V5, also known as visual area MT (middle temporal), is a region of extrastriate visual cortex that is thought to play a major role in the perception of motion, the integration of local motion signals into global percepts and the guidance of some eye movements. MT is connected to a wide array of cortical and subcortical brain areas. Its inputs include the visual cortical areas V1, V2, and dorsal V3 (dorsomedial area), the koniocellular regions of the LGN, and the inferior pulvinar. The pattern of projections to MT changes somewhat between the representations of the foveal and peripheral visual fields, with the latter receiving inputs from areas located in the midline cortex and retrosplenial region A standard view is that V1 provides the "most important" input to MT. Nonetheless, several studies have demonstrated that neurons in MT are capable of responding to visual information, often in a direction-selective manner, even after V1 has been destroyed or inactivated. Moreover, research by Semir Zeki and collaborators has suggested that certain types of visual information may reach MT before it even reaches V1. MT sends its major outputs to areas located in the cortex immediately surrounding it, including areas FST, MST and V4t (middle temporal crescent). Other projections of MT target the eye movement-related areas of the frontal and parietal lobes (frontal eye field and lateral intraparietal area). The first studies of the electrophysiological properties of neurons in MT showed that a large portion of the cells were tuned to the speed and direction of moving visual stimuli These results suggested that MT played a significant role in the processing of visual motion. Lesion studies have also supported the role of MT in motion perception and eye movements and neuropsychological studies of a patient who could not see motion, seeing the world in a series of static "frames" instead, suggested that MT in the primate is homologous to V5 in the human. However, since neurons in V1 are also tuned to the direction and speed of motion, these early results left open the question of precisely what MT could do that V1 could not. Much work has been carried out on this region as it appears to integrate local visual motion signals into the global motion of complex objects. For examples, lesion to the V5 lead to deficits in perceiving motion and processing of complex stimuli. It contains many neurons selective for the motion of complex visual features (line ends, corners). Microstimulation of a neuron located in the V5 affects the perception of motion. For example if one finds a neuron with preference for upward motion, and then we use an electrode to stimulate it, the monkey becomes more likely to report 'upward' motion. There is still much controversy over the exact form of the computations carried out in area MT and some research suggests that feature motion is in fact already available at lower levels of the visual system such as V1. MT was shown to be organized in direction columns. DeAngelis argued that MT neurons were also organized based on their tuning for binocular disparity.

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# Visual impairment Visual impairment or vision impairment is vision loss that constitutes a significant limitation of visual capability resulting from disease, trauma, or a congenital or degenerative condition that cannot be corrected by conventional means, including refractive correction, medication, or surgery. This functional loss of vision is typically defined to manifest with 1) best corrected visual acuity of less than 20/60, or significant central field defect, 2) significant peripheral field defect including homonymous or heteronymous bilateral visual field defect or generalized contraction or constriction of field, or 3) reduced peak contrast sensitivity either of the above conditions. According to the U.S. , "the terms partially sighted, low vision, legally blind, and totally blind are used in the educational context to describe students with visual impairments. They are defined as follows: Visual impairment is the consequence of a functional loss of vision, rather than the eye disorder itself. Eye disorders which can lead to visual impairments can include retinal degeneration, albinism, cataracts, glaucoma, muscular problems that result in visual disturbances, corneal disorders, diabetic retinopathy, congenital disorders, and infection." Visual impairment can also be caused by brain and nerve disorders, in which case it is usually termed cortical visual impairment (CVI). The American Medical Association's Guides to the Evaluation of Permanent Impairment attempts to provide "a standardized, objective approach to evaluating medical impairments." The Visual System chapter "provides criteria for evaluating permanent impairment of the visual system as it affects an individual's ability to perform activities of daily living." The Guide has estimated that the loss of one eye equals 25% impairment of the visual system and 24% impairment of the whole person; total loss of vision in both eyes is considered to be 100% visual impairment and 85% impairment of the whole person.

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# Visual processing Visual processing is the sequence of steps that information takes as it flows from visual sensors to cognitive processing. The sensors may be zoological eyes or they may be cameras or sensor arrays that sense various portions of the electromagnetic spectrum.

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# Visual routine A visual routine is a means of extracting information from a visual scene. In his studies on human visual cognition, Shimon Ullman proposed that the human visual system's task of perceiving shape properties and spatial relations is split into two successive stages: an early "bottom-up" state during which base representations are generated from the visual input, and a later "top-down" stage during which high-level primitives dubbed "visual routines" extract the desired information from the base representations. In humans, the base representations generated during the bottom-up stage correspond to retinotopic maps (more than 15 of which exist in the cortex) for properties like color, edge orientation, speed of motion, and direction of motion. These base representations rely on fixed operations performed uniformly over the entire field of visual input, and do not make use of object-specific knowledge, task-specific knowledge, or other higher-level information. The visual routines proposed by Ullman are high-level primitives which parse the structure of a scene, extracting spatial information from the base representations. These visual routines are composed of a sequence of elementary visual operators specific to the task at hand. Visual routines differ from the fixed operations of the base representations in that they are not applied uniformly over the entire visual field --- rather, they are only applied to objects or areas specified by the routines. Ullman lists the following as examples of visual operators: shifting the processing focus, indexing a salient item for further processing, spreading activation over an area delimited by boundaries, tracing boundaries, and marking a location or object for future reference. When combined into visual routines, these elementary operators can be used to perform relatively sophisticated spatial tasks such as counting the number of objects satisfying a certain property, or recognizing a complex shape. A number of researchers have implemented visual routines for processing camera images, to perform tasks like determining the object a human in the camera image is pointing at. Researchers have also applied the visual routines approach to artificial map representations, for playing real-time 2D video games. In those cases, however, the map of the video game was provided directly, alleviating the need to deal with real-world perceptual tasks like object recognition and occlusion compensation.

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/index.php/Vital_heat

# Vital heat Vital heat, also called innate or natural heat, or calidum innatum, is a term that has generally referred to the heat produced within the body, usually the heat produced by the heart and the circulatory system. According to Ancient Greek physicians, vital heat was produced by the heart, maintained by the pneuma (spirit or soul), and circulated throughout the body by blood vessels, which were thought to be intact tubes using blood to transmit heat. Aristotle supported this argument by showing that when the heart is made cold compared to other organs, the individual dies. He believed that the heat produced in the heart caused blood to react in a similar way to boiling, expanding out through the blood vessels with every beat. This extreme heat, according to him, can lead to a self-consuming flame if it is not cooled by air from the lungs. Galen wrote in On the Usefulness of the Parts of the Body (170): "The heart is, as it were, the hearthstone and source of the innate heat by which the animal is governed." In the 11th century, Avicenna agreed with this notion, stating that the heart produced breath, the "vital power or innate heat" within the body, in his Canon of Medicine.

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# Vital signs Vital signs are measures of various physiological statistics often taken by health professionals in order to assess the most basic body functions. Vital signs are an essential part of a case presentation. The phrase "fifth vital sign" usually refers to pain, as perceived by the patient on a Pain scale of 0-10. For example, the Veterans Administration made this their policy in 1999. However, some doctors have noted that pain is actually a subjective symptom, not an objective sign, and therefore object to this classification. There is no standard "sixth vital sign", and the use is much more informal and discipline-dependent than with the above, but some proposals (excluding the fifth sign candidates above) include:

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# Vitamer The vitamers of a particular vitamin are all of the chemical compounds which exhibit vitamin activity. Very commonly "vitamins" are not single compounds, but rather each vitamin, which is defined by its biological activity, not its structure, is actually represented by a number of substances, all of which show vitamin activity. Typically, the vitamin activity of multiple vitamers is due to the body's limited ability to convert one vitamer to another, or many vitamers to the same enzymatic cofactor(s). This is the case even though (as part of the definition of vitamin) the body cannot completely synthesize an optimal amount of vitamin activity from simple foodstuffs, without a minimal vitamer molecule as a basis. Typically not all vitamers possess exactly the same vitamin potency, per mass. This is due to differences in absorption and interconversion of the various different vitamers of a vitamin. Often for the same reason, the toxicity of vitamers varies by molecule, as is the case with vitamin E. A set of chemicals may be (but is not always) grouped under an alphabetized vitamin "generic descriptor" title, such as "vitamin A," which (for example) includes retinal, retinol, and many carotenoids. Examples of vitamers include cyanocobalamin, hydroxocobalamin, methylcobalamin, and 5-deoxyadenosylcobalamin (adenosylcobalamin—AdoB-12), which are all vitamers of B-12, and thus all possess "B-12 activity". Another example is that both niacinamide and nicotinic acid (niacin) have vitamin B-3 activity. Some vitamins have not been given specific alphabetic generic descriptors by naming commissions, and continue to be known by names like biotin and folate (which are B vitamins but have no B number). However, even these vitamins consist of various different active vitamers in both foods and in cellular function.

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# Vitamin A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. A compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and the particular organism. For example, ascorbic acid functions as vitamin C for some animals but not others, and vitamins D and K are required in the human diet only in certain circumstances. Vitamins are defined by their biological activity, not their structure. Thus, each "vitamin" actually refers to a number of vitamer compounds, which form a set of distinct chemical compounds that show the biological activity of a particular vitamin. Such a set of chemicals are grouped under an alphabetized vitamin "generic descriptor" title, such as "vitamin A," which (for example) includes retinal, retinol, and many carotenoids. Vitamers are often inter-convertible in the body. The term vitamin does not include other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids, nor does it encompass the large number of other nutrients that promote health but that are not essential for life. Vitamins have diverse biochemical functions, including function as hormones (e.g. vitamin D), antioxidants (e.g. vitamin E), and mediators of cell signaling and regulators of cell and tissue growth and differentiation (e.g. vitamin A) . The largest number of vitamins (e.g. B complex vitamins) function as precursors for enzyme cofactor bio-molecules (coenzymes), that help act as catalysts and substrates in metabolism. When acting as part of a catalyst, vitamins are bound to enzymes and are called prosthetic groups. For example, biotin is part of enzymes involved in making fatty acids. Vitamins also act as coenzymes to carry chemical groups between enzymes. For example, folic acid carries various forms of carbon group – methyl, formyl and methylene - in the cell. Although these roles in assisting enzyme reactions are vitamins' best-known function, the other vitamin functions are equally important. Until the 1800s, vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) can alter the types and amounts of vitamins ingested. Vitamins have been produced as commodity chemicals and made widely available as inexpensive pills for several decades, allowing supplementation of the dietary intake. The value of eating certain foods to maintain health was recognized long before vitamins were identified. The ancient Egyptians knew that feeding a patient liver would help cure night blindness, an illness now known to be caused by a vitamin A deficiency. The advancement of ocean voyage during the Renaissance resulted in prolonged periods without access to fresh fruits and vegetables, and made illnesses from vitamin deficiency common among ship's crew. In 1749, the Scottish surgeon James Lind discovered that citrus foods helped prevent scurvy, a particularly deadly disease in which collagen is not properly formed, causing poor wound healing, bleeding of the gums, severe pain, and death. In 1753, Lind published his Treatise on the Scurvy, which recommended using lemons and limes to avoid scurvy, which was adopted by the British Royal Navy. This led to the nickname Limey for sailors of that organization. Lind's discovery, however, was not widely accepted by individuals in the Royal Navy's Arctic expeditions in the 19th century, where it was widely believed that scurvy could be prevented by practicing good hygiene, regular exercise, and by maintaining the morale of the crew while on board, rather than by a diet of fresh food. As a result, Arctic expeditions continued to be plagued by scurvy and other deficiency diseases. In the early 20th century, when Robert Falcon Scott made his two expeditions to the Antarctic, the prevailing medical theory was that scurvy was caused by "tainted" canned food. In 1881, Russian surgeon Nikolai Lunin studied the effects of scurvy while at the University of Tartu in present-day Estonia. He fed mice an artificial mixture of all the separate constituents of milk known at that time, namely the proteins, fats, carbohydrates, and salts. The mice that received only the individual constituents died, while the mice fed by milk itself developed normally. He made a conclusion that "a natural food such as milk must therefore contain, besides these known principal ingredients, small quantities of unknown substances essential to life". However, his conclusions were rejected by other researchers when they were unable to reproduce his results. One difference was that he had used table sugar (sucrose), while other researchers had used milk sugar (lactose) that still contained small amounts of vitamin B. In the Orient where polished white rice was the common staple food of the middle class, beriberi resulting from lack of vitamin B was endemic. In 1884, Takaki Kanehiro, a British trained medical doctor of the Japanese Navy observed that beriberi was endemic among low ranking crew who often ate nothing but rice but not among crews of Western navies and officers who were entitled to a Western-style diet. Kanehiro initially believed that lack of protein was the chief cause of beriberi. With the support of Japanese navy, he experimented using crews of two battleships, one crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice, and beans. The group that ate only white rice documented 161 crew with beriberi and 25 deaths, while the latter group had only 14 cases of beriberi and no deaths. This convinced Kanehiro and the Japanese Navy that diet was the cause of beriberi. This was confirmed in 1897, when Christiaan Eijkman discovered that feeding unpolished rice instead of the polished variety to chickens helped to prevent beriberi in the chickens. The following year, Frederick Hopkins postulated that some foods contained "accessory factors"—in addition to proteins, carbohydrates, fats, et cetera—that were necessary for the functions of the human body. Hopkins was awarded the 1929 Nobel Prize for Physiology or Medicine with Christiaan Eijkman for their discovery of several vitamins. In 1910, Japanese scientist Umetaro Suzuki succeeded in extracting a water-soluble complex of micronutrients from rice bran and named it aberic acid. He published this discovery in a Japanese scientific journal. When the article was translated into German, the translation failed to state that it was a newly discovered nutrient, a claim made in the original Japanese article, and hence his discovery failed to gain publicity. Polish biochemist Kazimierz Funk isolated the same complex of micronutrients and proposed the complex be named "Vitamine" (a portmanteau of "vital amine") in 1912. The name soon became synonymous with Hopkins' "accessory factors", and by the time it was shown that not all vitamins were amines, the word was already ubiquitous. In 1920, Jack Cecil Drummond proposed that the final "e" be dropped to deemphasize the "amine" reference after the discovery that vitamin C had no amine component. Throughout the early 1900s, the use of deprivation studies allowed scientists to isolate and identify a number of vitamins. Initially, lipid from fish oil was used to cure rickets in rats, and the fat-soluble nutrient was called "antirachitic A". The irony here is that the first "vitamin" bioactivity ever isolated, which cured rickets, was initially called "vitamin A", the bioactivity of which is now called vitamin D. What we now call "vitamin A" was identified in fish oil because it was inactivated by ultraviolet light. In 1931, Albert Szent-Györgyi and a fellow researcher Joseph Svirbely determined that "hexuronic acid" was actually vitamin C and noted its anti-scorbutic activity. In 1937, Szent-Györgyi was awarded the Nobel Prize for his discovery. In 1943 Edward Adelbert Doisy and Henrik Dam were awarded the Nobel Prize for their discovery of vitamin K and its chemical structure. Vitamins are classified as either water-soluble, meaning that they dissolve easily in water or fat-soluble vitamins, which are absorbed through the intestinal tract with the help of lipids (fats). In general, water-soluble vitamins are readily excreted from the body. Each vitamin is typically used in multiple reactions and, therefore, most have multiple functions. Vitamins are essential for the normal growth and development of a multicellular organism. Using the genetic blueprint inherited from its parents, a fetus begins to develop, at the moment of conception, from the nutrients it absorbs. It requires certain vitamins and minerals to be present at certain times. These nutrients facilitate the chemical reactions that produce among other things, skin, bone, and muscle. If there is serious deficiency in one or more of these nutrients, a child may develop a deficiency disease. Even minor deficiencies may cause permanent damage. For the most part, vitamins are obtained with food, but a few are obtained by other means. For example, microorganisms in the intestine—commonly known as "gut flora"—produce vitamin K and biotin, while one form of vitamin D is synthesized in the skin with the help of natural ultraviolet in sunlight. Humans can produce some vitamins from precursors they consume. Examples include vitamin A, produced from beta carotene, and niacin, from the amino acid tryptophan. Once growth and development are completed, vitamins remain essential nutrients for the healthy maintenance of the cells, tissues, and organs that make up a multicellular organism; they also enable a multicellular life form to efficiently use chemical energy provided by food it eats, and to help process the proteins, carbohydrates, and fats required for respiration. Deficiencies of vitamins are classified as either primary or secondary. A primary deficiency occurs when an organism does not get enough of the vitamin in its food. A secondary deficiency may be due to an underlying disorder that prevents or limits the absorption or use of the vitamin, due to a "lifestyle factor", such as smoking, excessive alcohol consumption, or the use of medications that interfere with the absorption or use of the vitamin. People who eat a varied diet are unlikely to develop a severe primary vitamin deficiency. In contrast, restrictive diets have the potential to cause prolonged vitamin deficits, which may result in often painful and potentially deadly diseases. Because human bodies do not store most vitamins, humans must consume them regularly to avoid deficiency. Human bodily stores for different vitamins vary widely; vitamins A, D, and B12 are stored in significant amounts in the human body, mainly in the liver, and an adult human's diet may be deficient in vitamins A and B12 for many months before developing a deficiency condition. Vitamin B3 is not stored in the human body in significant amounts, so stores may only last a couple of weeks. Well-known human vitamin deficiencies involve thiamine (beriberi), niacin (pellagra), vitamin C (scurvy) and vitamin D (rickets). In much of the developed world, such deficiencies are rare; this is due to (1) an adequate supply of food; and (2) the addition of vitamins and minerals to common foods, often called fortification. In large doses, some vitamins have documented side effects that tend to be more severe with a larger dosage. The likelihood of consuming too much of any vitamin from food is remote, but overdosing from vitamin supplementation does occur. At high enough dosages some vitamins cause side effects such as nausea, diarrhea, and vomiting. When side effects emerge, recovery is often accomplished by reducing the dosage. The concentrations of vitamins an individual can tolerate vary widely, and appear to be related to age and state of health. In the United States, overdose exposure to all formulations of vitamins was reported by 62,562 individuals in 2004 (nearly 80% of these exposures were in children under the age of 6), leading to 53 "major" life-threatening outcomes and 3 deaths —a small number in comparison to the 19,250 people who died of unintentional poisoning of all kinds in the U.S. in the same year (2004). Dietary supplements, often containing vitamins, are used to ensure that adequate amounts of nutrients are obtained on a daily basis, if optimal amounts of the nutrients cannot be obtained through a varied diet. Scientific evidence supporting the benefits of some dietary supplements is well established for certain health conditions, but others need further study. In the United States, advertising for dietary supplements is required to include a disclaimer that the product is not intended to treat, diagnose, mitigate, prevent, or cure disease, and that any health claims have not been evaluated by the Food and Drug Administration. In some cases, dietary supplements may have unwanted effects, especially if taken before surgery, with other dietary supplements or medicines, or if the person taking them has certain health conditions. Vitamin supplements may also contain levels of vitamins many times higher, and in different forms, than one may ingest through food. Intake of excessive quantities can cause vitamin poisoning, most commonly for Vitamin A and Vitamin D. For this reason, most common vitamins have recommended upper daily intake amounts. Most countries place dietary supplements in a special category under the general umbrella of foods, not drugs. This necessitates that the manufacturer, and not the government, be responsible for ensuring that its dietary supplement products are safe before they are marketed. Unlike drug products, that must explicitly be proven safe and effective for their intended use before marketing, there are often no provisions to "approve" dietary supplements for safety or effectiveness before they reach the consumer. Also unlike drug products, manufacturers and distributors of dietary supplements are not generally required to report any claims of injuries or illnesses that may be related to the use of their products. The reason the set of vitamins seems to skip directly from E to K is that the vitamins corresponding to "letters" F-J were either reclassified over time, discarded as false leads, or renamed because of their relationship to "vitamin B", which became a "complex" of vitamins. The German-speaking scientists who isolated and described vitamin K (in addition to naming it as such) did so because the vitamin is intimately involved in the Koagulation of blood following wounding. At the time, most (but not all) of the letters from F through J were already designated, so the use of the letter K was considered quite reasonable. The following table lists chemicals that had previously been classified as vitamins, as well as the earlier names of vitamins that later became part of the B-complex:

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# Vitamin A Vitamin A is an essential human nutrient. It exists not as a single compound, but in several forms. In foods of animal origin, the major form of vitamin A is an alcohol (retinol), but can also exist as an aldehyde (retinal), or as an acid (retinoic acid). Precursors to the vitamin (a provitamin) are present in foods of plant origin as some of the members of the carotenoid family of compounds. The discovery of Vitamin A stemmed from research dating back to 1906, indicating that factors other than carbohydrates, proteins, and fats were necessary to keep cattle healthy. By 1917 one of these substances was independently discovered by Elmer McCollum at the University of Wisconsin-Madison, and Lafayette Mendel and Thomas Osborne at Yale University. Since "water-soluble factor B" (Vitamin B) had recently been discovered, the researchers chose the name "fat-soluble factor A". Vitamin A is found naturally in many foods. Each of the following contains at least 0.15 mg (which is equal to 150 micrograms (mcg). See Recommended Daily Intake below.) of Vitamin A or beta carotene per 1.75-7 oz. (50-200 g): butter, lemon, sweet potatoes, carrots, collard greens, milk, beetroot, pumpkin, spinach, beef, apple, winter squash, apricots, cantaloupe melon, mango, liver, (beef, pork, chicken, turkey, fish) eggs, broccoli, and leafy vegetables. Vitamin A intake is often expressed in international units (IU) or as retinol equivalents (RE), with 1 IU = 0.3 micrograms retinol. Because the production of retinol from provitamins by the human body is regulated by the amount of retinol available to the body, the conversions apply strictly only for Vitamin A deficient humans. The absorption of provitamins also depends greatly on the amount of lipids ingested with the provitamin; lipids increase the uptake of the provitamin. Night blindness, corneal drying (xerosis), triangular gray spots on eye (Bitot's spots), corneal degeneration and blindness (xerophthalmia) , impaired immunity, hypokeratosis (white lumps at hair follicles), keratosis pilaris, softening of the cornea (keratomalacia). As vitamin A is fat-soluble, disposing of any excesses taken in through diet is a lot harder than with water-soluble vitamins B and C. As such, vitamin A toxicity can result. This can lead to nausea, jaundice, irritability, anorexia (not to be confused with anorexia nervosa, the eating disorder), vomiting, blurry vision, headaches, muscle and abdominal pain and weakness, drowsiness and altered mentality. In chronic cases, hair loss, drying of the mucous membranes, fever, insomnia, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity.

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/index.php/Vitamin_A_receptor

# Vitamin A receptor Vitamin A receptor (also known as "Stimulated by retinoic acid 6," or STRA6 protein) was originally discovered as a transmembrane cell-surface receptor for retinol-binding protein. STRA6 is unique as it functions both as a membrane transporter and a cell surface receptor, particularly as a cytokine receptor. In fact, STRA6 may be the first of a whole new class of proteins that might be known as "cytokine signaling transporters." STRA6 is primarily known as the receptor for retinol binding protein and for its relevance in the transport of retinol to specific sites such as the eye (Vitamin A). It does this through the removal of retinol (ROH) from the holo-Retinol Binding Protein (RBP) and transports it into the cell to be metabolized into retinoids and/or kept as a retinylester. As a receptor, after holo-RBP is bound, STRA6 activates the JAK/STAT pathway, resulting in the activation of transcription factor, STAT5. These two functions—retinol transporter and cytokine receptor—while using different pathways, are processes that depend on each other. In the first step, holo-retinol binding protein (holo-RBP; simply means RBP bound to retinol, i.e. the RBP-ROH complex) binds to the extracellular portion of STRA6. This facilitates the release of retinol through the transporter. ROH is then transferred to cellular retinol binding protein 1 (CRBP1), an intracellular acceptor of retinol that attaches to the CRBP Binding Loop (or CBL) on STRA6. This transport of ROH, in turn, activates JAK2, thereby phosphorylating STRA6 at the Y643 (tyrosine) residue. This phosphorylation enables the extension of the CBL further into the cell. Holo-CRBP-I, leaves the CBL and is replaced by apo-CRBP-I (unbound). Holo-CRBP-I will continue to the Endoplasmic Reticulum (ER) where lecithin retinol acyltransferase (LRAT) is bound. ROH is released to LRAT which will convert retinol into retinylesters. Following the release of holo-CRBP-I from intercellular STRA6, STAT5 is recruited to STRA6 phosphorylated Y643 region where it is then phosphorylated by JAK2. This phosphorylation activates STAT5 which then makes its way to the nucleus to induce expression of target genes including suppressor of cytokine signaling 3 (SOCS3), a strong inhibitor of insulin signaling. Research has demonstrated that overexpression of CRBP-I increases the ability of RBP-ROH complex to phosphorylate STRA6 and, later, JAK2 and STAT5. Suppressing CRBP-I, on the other hand, led to decreased ability of RBP-ROH complex to phosphorylate STRA6 and signaling components. Similarly, reducing the expression of LRAT also decreased the ability of RBP-ROH complex to phosphorylate JAK2 and STAT5. Therefore, both CRBP-I and LRAT are necessary for the STRA6 signaling cascade upon the binding and transport of retinol. JAK2 is also conversely responsible for the activation of STRA6, after which apo-CRBP-I is recruited to the intercellular CBL of STRA6 and vitamin A might be transferred by the receptor to CRBP-I. Thus, both STRA6 signaling and STRA6 transport of vitamin A are dependent upon each other. Uptake of retinol is required for STRA6 signaling and JAK2 activation of STRA6 is necessary for retinol uptake. STRA6 can be found at high levels in various tissues including: the choroid plexus, the brain microvascular, tesis, the spleen, kidney, eye, the placenta, and the female reproductive tract. However, it is surprisingly not found in liver tissue where Vitamin A (retinol) is primarily stored. Because of its importance in Vitamin A transport, STRA6 mutations are more commonly associated with problems with eye such as a reduction in retinal thickness and shortening of the inner and outer segments of rod photoreceptors. Therefore, as might be expected, STRA6 mutations result in a number of different abnormalities of the eye such as Microphthalmia, Anophthalmia, and Coloboma. However, STRA6 is clearly vital for more than just eye development as it is expressed in many different tissues detailed above. Other disorders that result from STRA6 mutations include pulmonary dysgenesis, cardiac malformations, and mental retardation. In fact, research has shown that homozygous mutations in human STRA6 gene can lead to Matthew-Wood syndrome, which is a combination of all the mentioned disorders. In this respect, STRA6 mutations can be particularly fatal during the embryonic stage. STRA6 has also been associated with facilitating insulin resistance. This is because STRA6 signaling results in activation of transcription factor STAT5 target genes. One of these target genes is a suppressor of cytokine signaling 3 (SOCS3) which is a strong inhibitor of insulin signaling. As a result, STRA6 signaling suppresses the response to insulin by inhibiting the phosphorylation of the insulin receptor, IR, by an influx of insulin. In other words, increased levels of the RBP in obese animals (which will increase STRA6 activity) can facilitate insulin resistance. Due to this close relationship between STRA6 and insulin resistance, it has been demonstrated that single nucleotide polymorphisms in STRA6 are associated with Type 2 Diabetes.

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/index.php/Vitamin_B12

# Vitamin B12 Vitamin B-12 is a vitamin which is important for the normal functioning of the brain and nervous system, and for the formation of blood. It is normally involved in the metabolism of every cell of the body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production. Vitamin B-12 is the name for a class of chemically-related compounds, all of which have vitamin activity. It is structurally the most complicated vitamin. Biosynthesis of the basic structure of the vitamin can only be accomplished by bacteria, but conversion between different forms of the vitamin can be accomplished in the human body. A common form of the vitamin, cyanocobalamin, does not occur in nature, but is used as a supplement and food additive, due to its stability. It is converted to other forms of the vitamin which are actually used in chemical reactions in the body. Historically, vitamin B-12 was discovered from its relationship to the disease pernicious anemia, which was eventually discovered to result from an effective lack of this vitamin due to problems with the mechanisms in the body which normally absorb it. Many other more subtle kinds of biochemical B-12 deficiencies, and biochemical effects from them, have since been elucidated. The name vitamin B-12, known also as vitamin BTemplate:Ssub (or commonly BTemplate:Ssub or B-12 for short) generally refers to all forms of the vitamin. Some medical practitioners have suggested that its use be split into two different categories, however. Finally, so-called Pseudo-B-12 refers to B-12-like substances which are found in certain organisms, including spirulina (a cyanobacterium) and some algae. These substances are active in tests of B-12 activity by highly sensitive antibody-binding serum assay tests, which measure levels of B-12 and B-12 like compounds in blood. However, these substances do not have B-12 biological activity for humans, a fact which may pose a theoretical danger to vegans and others on limited diets who do not ingest B-12 producing bacteria, but who nevertheless may show normal "B-12" levels in the standard immunoassay which has become the normal medical method for testing for B-12 deficiency. Vitamin B-12 is a collection of cobalt and corrin ring molecules which are defined by their particular vitamin function in the body. All of the substrate cobalt-corrin molecules from which B-12 is made must be synthesized by bacteria. However, after this synthesis is complete, the body has a limited power to convert any form of B-12 to another, by means of enzymatically removing certain prosthetic chemical groups from the cobalt atom. Cyanocobalamin is one such compound that is a vitamin in this B complex, because it can be metabolized in the body to an active co-enzyme form. However, the cyanocobalamin form of B-12 does not occur in nature normally, but is a byproduct of the fact that other forms of B-12 are avid binders of cyanide (-CN) which they pick up in the process of activated charcoal purification of the vitamin after it is made by bacteria in the commercial process. Since the cyanocobalamin form of B-12 is deeply red colored, easy to crystallize, and is not sensitive to air-oxidation, it is typically used as a form of B-12 for food additives and in many common multivitamins. However, this form is not perfectly synonymous with B-12, inasmuch as a number of substances (vitamers) have B-12 vitamin activity and can properly be labeled vitamin B-12, and cyanocobalamin is but one of them. (Thus, all cyanocobalamin is vitamin B-12, but not all vitamin B-12 is cyanocobalamin). B-12 is the most chemically complex of all the vitamins. The structure of B-12 is based on a corrin ring, which is similar to the porphyrin ring found in heme, chlorophyll, and cytochrome. The central metal ion is Co (cobalt). Four of the six coordination sites are provided by the corrin ring, and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the center of reactivity, is variable, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH3) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B-12 forms mentioned above. The covalent C-Co bond is one of first examples of carbon-metal bonds in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds. Vitamin B-12 cannot be made by plants or animals as only bacteria have the enzymes required for its synthesis. The total synthesis of B-12 was reported by Robert Burns Woodward and Albert Eschenmoser, and remains one of the classic feats of organic synthesis. Species from the following genera are known to synthesize B-12: Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Micromonospora, Mycobacterium, Nocardia, Propionibacterium, Protaminobacter, Proteus, Pseudomonas, Rhizobium, Salmonella, Serratia, Streptomyces, Streptococcus and Xanthomonas. Industrial production of B-12 is through fermentation of selected microorganisms. The species most often used, Pseudomonas denitrificans and Propionibacterium shermanii, are frequently genetically engineered and grown under special conditions to enhance yield. Vitamin B-12 is normally involved in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production. However, many (though not all) of the effects of functions of B-12 can be replaced by sufficient quantities of folic acid (another B vitamin), since B-12 is used to regenerate folate in the body. Most "B-12 deficient symptoms" are actually folate deficient symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine. When sufficient folic acid is available, all known B-12 related deficiency syndromes normalize, save those narrowly connected with the B-12 dependent enzymes Methylmalonyl Coenzyme A mutase (MUT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine. If folate is present in quantity, then of the two absolutely B-12 dependent reactions, the MUT reaction shows the most direct and characteristic secondary effects, focusing on the nervous system. Since the late 1990s folic acid has begun to be added to fortify flour in many countries, so that folate deficiency is now more rare. At the same time, since DNA synthetic-sensitive tests for anemia and erythrocyte size are routinely done in even simple medical test clinics (so that these folate mediated-biochemical effects are more often directly detected), the MTR dependent effects of B-12 deficiency are becoming apparent not as anemia (as they were classically), but now mainly as an elevation of homocysteine in the blood and urine (homocysteinuria). This condition may result in long term damage to arteries and in clotting (stroke and heart attack), but is difficult to separate from other processes associated with atherosclerosis and aging. The B-12 dependent MTR reactions may have neurological effects through an indirect mechanism. Adequate methionine (which must otherwise be obtained in the diet) is needed to make S-adenosyl-methionine, which is in turn necessary for methylation of myelin sheath phospholipids. In addition, SAMe is involved in the manufacture of certain neurotransmitters, catecholamines and in brain metabolism. These neurotransmitters are important for maintaining mood, possibly explaining why depression is associated with B-12 deficiency. Methylation of the myelin sheath phospholipids may also depend on adequate folate, which in turn is dependent on MTR recycling, unless ingested in relatively high amounts. The specific myelin damage resulting from from B-12 deficiency has also been connected to B-12 reactions related to MUT, which is needed to convert methylmalonyl coenzyme A into succinyl coenzyme A. Failure of this second reaction to occur results in elevated levels of methylmalonic acid (MMA), a myelin destabilizer. Excessive MAA will prevent normal fatty acid synthesis, or it will be incorporated into fatty acid itself rather than normal malonic acid. If this abnormal fatty acid subsequently is incorporated into myelin, the resulting myelin will be too fragile, and demyelination will occur. Although the precise methanism(s) are not known with certainty, the result is subacute combined degeneration of central nervous system and spinal cord. Whatever the cause, it is known that B-12 deficiency causes neuropathies, even if folic acid is present in good supply, and therefore anemia is not present. The human physiology of vitamin B-12 is complex, and therefore is prone to mishaps leading to vitamin B-12 deficiency. The vitamin as it occurs in foods enters the digestive tract bound to proteins, known as salivary R-binders. Stomach proteolysis of these proteins requires an acid pH, and also requires proper pancreatic release of proteolytic enzymes. (Even small amounts of B-12 taken in supplements bypasses these steps and thus any need for gastric acid, which may be blocked by antacid drugs). The free B-12 then attaches to gastric intrinsic factor, which is generated by the gastric parietal cells. If this step fails due to gastric parietal cell atrophy (the problem in pernicious anemia), sufficient B-12 is not absorbed later on, unless administered orally in relatively massive doses (500 to 1000 mcg/day). The conjugated vitamin B-12-intrinsic factor complex (IF/B-12) is then normally absorbed by the terminal ileum of the small bowel. Absorption of food vitamin B-12 therefore requires an intact and functioning stomach, exocrine pancreas, intrinsic factor, and small bowel. Problems with any one of these organs makes a vitamin B-12 deficiency possible. Once the IF/B-12 complex is recognized by specialized ileal receptors, it is transported into the portal circulation. The vitamin is then transferred to transcobalamin II (TC-II/B-12), which serves as the plasma transporter of the vitamin. Genetic deficiencies of this protein are known, also leading to functional B-12 deficiency. For the vitamin to serve inside cells, the TC-II/B-12 complex must bind to a cell receptor, and be endocytosed. The transcobalamin-II is degraded within a lysozyme, and the B-12 is finally released into the cytoplasm, where it may be transformed into the proper coenzyme, by certain cellular enzymes (see above). Hereditary defects in production of the transcobalamins and their receptors may produce functional deficiencies in B-12 and infantile megaloblastic anemia, and abnormal B-12 related biochemistry, even in some cases with normal blood B-12 levels. The total amount of vitamin B-12 stored in body is about 2,000-5,000 mcg in adults. Around 80% of this is stored in the liver . 0.1 % of this is lost per day by secretions into the gut as not all these secretions are reabsorbed. How fast B-12 levels change depends on the balance between how much B-12 is obtained from the diet, how much is secreted and how much is absorbed. B-12 deficiency may arise in a year if initial stores are low and genetic factors unfavourable or may not appear for decades. In infants, B-12 deficiency can appear much more quickly . B-12 deficiency is the cause of pernicious anemia, a usually-fatal disease of unknown etiology when it was first described in medicine. The cure was discovered by accident. George Whipple had been inducing anemia in dogs by bleeding them, and then conducting experiments in which he fed them various foods to observe which diets allowed them fastest recovery from the anemia produced. In the process, he discovered that ingesting large amounts of liver seemed to most-rapidly cure the anemia of blood loss, and hypothesized that therefore liver ingestion be tried for pernicious anemia, an anemic disease of the time with no known cause or cure. He tried this and reported some signs of success in 1920. After a series of careful clinical studies George Minot and William Murphy set out to partly isolate the substance in liver which cured anemia in dogs, and found that it was iron. They found further that the partly isolated water-soluble liver-substance which cured pernicious anemia in humans, was something else entirely different -- and which had no effect at all on canines under the conditions used. The specific factor treatment for pernicious anemia, found in liver juice, had been found by this coincidence. These experiments were reported by Minot and Murphy in 1926, marking the date of the first real progress with this disease, though for several years, patients were still required to eat large amounts of raw liver or to drink considerable amounts of liver juice. In 1928, the chemist Edwin Cohn prepared a liver extract that was 50 to 100 times more potent than the natural liver products. The extract was the first workable treatment for the disease. For their initial work in pointing the way to a working treatment, Whipple, Minot, and Murphy shared the 1934 Nobel Prize in Physiology or Medicine. The active ingredient in liver was not isolated until 1948 by the chemists Karl A. Folkers of the United States and Alexander R. Todd of Great Britain. The substance was a cobalamin called vitamin B-12. It could also be injected directly into muscle, making it possible to treat pernicious anemia more easily. Eventually, methods of producing the vitamin in large quantities from bacteria cultures were developed in the 1950s, and these led to the modern form of treatment for the disease. Vitamin B-12 deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system. At levels only slightly lower than normal, a range of symptoms such as fatigue, depression, and poor memory may be experienced. However, these symptoms by themselves are too nonspecific to diagnose deficiency of the vitamin. Pathomorphology includes: A spongiform state of neural tissue along with edema of fibers and deficiency of tissue. The myelin decays, along with axial fiber. In later phases, fibric sclerosis of nervous tissues occurs. Those changes apply to dorsal parts of the spinal cord, and to pyramidal tracts in lateral cords. In the brain itself, changes are less severe: they occur as small sources of nervous fibers decay and accumulation of astrocytes, usually subcortically located, an also round hemorrhages with a torus of glial cells. Pathological changes can be noticed as well in the posterior roots of the cord and, to lesser extent, in peripheral nerves. During the course of disease, mental disorders can occur: irritablity, focus/concentration problems, depressive state with suicidal tendencies, paraphrenia complex. These symptoms may not reverse after correction of hematological abnormalities, and the chance of complete reversal decreases with the length of time the neurological symptoms have been present. Vitamin B-12 is naturally found in foods of animal origin including meat (especially liver and shellfish) and milk products. Animals, in turn, must obtain it directly or indirectly from bacteria, and these bacteria may inhabit a section of the gut which is posterior to the section where B-12 is absorbed. Thus, herbivorous animals must either obtain B-12 from bacteria in their rumens, or (if fermenting plant material in the hindgut) by reingestion of cecotrope feces. Eggs are often mentioned as a good B-12 source, but they also contain a factor that blocks absorption. Certain insects such as termites contain B-12 produced by their gut bacteria, in a manner analogous to ruminant animals. An NIH Fact Sheet lists a variety of food sources of vitamin B-12. Plants only supply B-12 to humans when the soil containing B-12-producing microorganisms has not been washed from them. Vegan humans who eat only washed vegetables must take special care to supplement their diets accordingly. According to the U.K. Vegan Society, the only reliable vegan sources of B-12 are foods fortified with B-12 (including some plant milks, some soy products and some breakfast cereals), and B-12 supplements. Fortified breakfast cereals are a particularly valuable source of vitamin B-12 for vegetarians and vegans. While lacto-ovo vegetarians usually get enough B-12 through consuming dairy products, vitamin B-12 may be found to be lacking in those practicing vegan diets who do not use multivitamin supplements or eat B-12 fortified foods, such as fortified breakfast cereals, fortified soy-based products, and fortified energy bars. Claimed sources of B-12 that have been shown through direct studies of vegans to be inadequate or unreliable include, laver (a seaweed), barley grass, and human gut bacteria. People on a vegan raw food diet are also susceptible to B-12 deficiency if no supplementation is used . The Vegan Society, the Vegetarian Resource Group, and the Physicians Committee for Responsible Medicine, among others, recommend that vegans either consistently eat foods fortified with B-12 or take a daily or weekly B-12 supplement. Cyanocobalamin is converted to its active forms, first hydroxocobalamin and then methylcobalamin and adenosylcobalamin in the liver. The sublingual route, in which B-12 is presumably or supposedly absorbed more directly under the tongue, has not proven to be necessary or helpful. A 2003 study found no significant difference in absorption for serum levels from oral vs. sublingual delivery of 500 micrograms of cobalamin. However, if patient has inborn errors in the methyltransfer pathway (cobalamin C disease, combined methylmalonic aciduria and homocystinuria), treating with intravenous or intramuscular hydroxocobalamin is needed. Vitamin B-12 can be supplemented in healthy subjects also by liquid, strip, nasal spray, or injection. B-12 is available singly or in combination with other supplements. Injection is sometimes used in cases where digestive absorption is impaired, but there is some evidence that this course of action may not be necessary with modern high potency oral supplements (such as 500 to 1000 mcg or more). These supplements carry such large doses of the vitamin that the many different components of the B-12 absorption system are not required, and enough of the vitamin (only a few mcg a day) is obtained simply by mass-action transport across the gut. Even pernicious anemia can be treated entirely by the oral route. For the much lower amounts of B-12 found in food sources, however, oral absorption is complex and requires stomach acid, and also specific intestinal transport proteins (intrinsic factor) produced in the stomach. Lack of function in these systems is the causes of much of the increased risk in many elderly persons who develop B-12 deficiency later in life. However, it can be treated with a simple high dose oral B-12 supplement. Cyanocobalamin is also sometimes added to beverages including Diet Coke Plus and many energy drinks, in some cases with over 80 times the recommended intake. However, 500 mcg would be needed to reverse biochemical signs of vitamin B-12 deficiency in older adults. Vitamin B-12 supplements in theory should be avoided in people sensitive or allergic to cobalamin, cobalt, or any other product ingredients. However, direct allergy to a vitamin or nutrient is extremely rare, and if reported, other causes should be sought. The Dietary Reference Intake for an adult ranges from 2 to 3 µg (micrograms). The recommended optimal daily intake (ODI) is 10 to 15 µg. Vitamin B-12 is believed to be safe when used orally in amounts that do not exceed the recommended dietary allowance (RDA). The RDA for vitamin B-12 in pregnant women is 2.6 µg per day and 2.8 µg during lactation periods. There is insufficient reliable information available about the safety of consuming greater amounts of Vitamin B-12 during pregnancy. Hydroxycobalamin, or hydoxocobalamin, also known as Vitamin B-12a, is used in Europe both for vitamin B-12 deficiency and as a treatment for cyanide poisoning, sometimes with a large amount (5-10 g) given intravenously, and sometimes in combination with sodium thiosulfate. The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting harmless B-12 complex is excreted in urine. In the United States, the FDA has approved in 2006 the use of hydroxocobalamin for acute treatment of cyanide poisoning.

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# Vitamin B6 Vitamin B6 is a water-soluble vitamin. Pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction governing the release of glucose from glycogen. Vitamin B6 is a water-soluble compound that was discovered in the 1930s during nutrition studies on rats. The vitamin was named pyridoxine to indicate its structural homology to pyridine. Later it was shown that vitamin B6 could exist in two other, slightly different, chemical forms, termed pyridoxal and pyridoxamine. All three forms of vitamin B6 are precursors of an activated compound known as pyridoxal 5'-phosphate (PLP), which plays a vital role as the cofactor of a large number of essential enzymes in the human body. Enzymes dependent on PLP focus a wide variety of chemical reactions mainly involving amino acids. The reactions carried out by the PLP-dependent enzymes that act on amino acids include transfer of the amino group, decarboxylation, racemization, and beta- or gamma-elimination or replacement. Such versatility arises from the ability of PLP to covalently bind the substrate, and then to act as an electrophilic catalyst, thereby stabilizing different types of carbanionic reaction intermediates. Pyridoxal phosphate, the metabolically active form of vitamin B6, is involved in many aspects of macronutrient metabolism, neurotransmitter synthesis, histamine synthesis, hemoglobin synthesis and function and gene expression. Pyridoxal phosphate generally serves as a coenzyme for many reactions and can help facilitate decarboxylation, transamination, racemization, elimination, replacement and beta-group interconversion reactions . Pyridoxal phosphate (PLP) is a cofactor in transaminases that can catabolize amino acids. PLP is also an essential component of two enzymes that converts methionine to cysteine via two reactions. Low vitamin B6 status will result in decreased activity of these enzymes. PLP is also an essential cofactor for enzymes involved in the metabolism of selenomethionine to selenohomocysteine and then from selenohomocysteine to hydrogen selenide. Vitamin B6 is also required for the conversion of tryptophan to niacin and low vitamin B6 status will impair this conversion . PLP is also used to create physiologically active amines by decarboxylation of amino acids. Some notable examples of this include: histadine to histamine, tryptophan to serotonin, glutamate to GABA (gamma-aminobutyric acid), and dihydroxyphenylalanine to dopamine. Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for the providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase< , the enzyme that is necessary for glycogenolysis to occur. Vitamin B6 is an essential component of enzymes that facilitate the biosynthesis of sphingolipids . Particularly, the synthesis of ceramide requires PLP. In this reaction serine is decarboxylated and combined with palmitoyl-CoA to form sphinganine which is combined with a fatty acyl CoA to form ceramide. The primary role of vitamin B6 is to act as a coenzyme to many other enzymes in the body that are involved predominately in metabolism. This role is performed by the active form, pyridoxal phosphate. This active form is converted from the two other natural forms founds in food: pyridoxal, pyridoxine and pyridoxamine. 1. Transamination: transaminase enzymes needed to breakdown amino acids are dependent on the presence of pyridoxal phosphate. The proper activity of these enzymes are crucial for the process of moving amine groups from one amino acid to another. 2. Transsulfuration: Pyridoxal phosphate is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes work to transform methionine into cysteine. 3. Selenoamino acid metabolism: Selenomethionine is the primary dietary form of selenium. Pyridoxal phosphate is needed as a cofactor for the enzymes that allow selenium to be used from the dietary form. Pyridoxal phosphate also plays a cofactor role in releasing selenium from selenohomocysteine to produce hydrogen selenide. This hydrogen selenide can then be used to incorporate selenium into selenoproteins< . Vitamin B6 also plays a role in gluconeogenesis. Pyridoxal phosphate can catalyze transamination reactions that are essential for providing amino acids as a substrate for gluconeogenesis. Also, vitamin B6 is a required coenzyme of glycogen phosphorylase , the enzyme that is necessary for glycogenolysis to occur. Pyridoxal phosphate has been implicated in increasing or decreasing the expression of certain genes. Increased intracellular levels of the vitamin will lead to a decrease in the transcription of glucocorticoid hormones. Also, vitamin B6 deficiency will lead to the increased expression of albumin mRNA. Also, pyridoxal phosphate will influence gene expression of glycoprotein IIb by interacting with various transcription factors. The result is inhibition of platelet aggregation. The Institute of Medicine notes that "No adverse effects associated with Vitamin B6 from food have been reported. This does not mean that there is no potential for adverse effects resulting from high intakes. Because data on the adverse effects of Vitamin B6 are limited, caution may be warranted. Sensory neuropathy has occurred from high intakes of supplemental forms." Click on the pdf at the end of this sentence to see the Institute of Medicine's Dietary Reference Intake tables for vitamins. Vitamin B6 is widely distributed in foods in both its free and bound forms. Good sources include meats, whole grain products, vegetables, and nuts. Cooking, storage and processing losses of vitamin B6 vary and in some foods may be more than 50%, depending on the form of vitamer present in the food. Plant foods lose the least during processing as they contain mostly pyridoxine which is far more stable than the pyridoxal or pyridoxamine found in animal foods. For example, milk can lose 30-70% of its vitamin B6 content when dried. Vitamin B6 is absorbed in the jejunum and ileum via passive diffusion. With the capacity for absorption being so great, animals are able to absorb quantities much greater than what is needed for physiological demands. The absorption of pyridoxal phosphate and pyridoxamine phosphate involves their phosphorylation catalyzed by a membrane-bound alkaline phosphatase. Those products and non-phosphorylated vitamers in the digestive tract are absorbed by diffusion, which is driven by trapping of the vitamin as 5'-phosphates through the action of phosphorylation (by a pyridoxal kinase) in the jejunal mucosa. The trapped pyridoxine and pyridoxamine are oxidized to pyridoxal phosphate in the tissue. The products of vitamin B6 metabolism are excreted in the urine; the major product of which is 4-pyridoxic acid. It has been estimated that 40-60% of ingested vitamin B6is oxidized to 4-pyridoxic acid. Several studies have shown that 4-pyridoxic acid is undetectable in the urine of vitamin B6 deficient subjects, making it a useful clinical marker to assess the vitamin B6 status of an individual. Other products of vitamin B6metabolism that are excreted in the urine when high doses of the vitamin have been given include pyridoxal, pyridoxamine, and pyridoxine and their phosphates. The classic clinical syndrome for B6 deficiency is a seborrheic dermatitis-like eruption, atrophic glossitis with ulceration, angular cheilitis, conjunctivitis, intertrigo, and neurologic symptoms of somnolence, confusion, and neuropathy. While severe vitamin B6 deficiency results in dermatologic and neurologic changes, less severe cases present with metabolic lesions associated with insufficient acitivities of the coenzyme pyridoxal phosphate. The most prominent of the lesions is due to impaired tryptophan-niacin conversion. This can be detected based on urinary excretion of xanthurenic acid after an oral tryptophan load. Vitamin B6 deficiency can also result from impaired transsulfuration of methionine to cysteine. The pyridoxal phosphate-dependent transaminases and glycogen phosphorylase provide the vitamin with its role in gluconeogenesis, so deprivation of vitamin B6 results in impaired glucose tolerance. A deficiency of vitamin B6 alone is relatively uncommon and often occurs in association with other vitamins of the B complex. The elderly and alcoholics have an increased risk of vitamin B6 deficiency, as well as other micronutrient deficiencies. An overdose of pyridoxine can cause a temporary deadening of certain nerves such as the proprioceptory nerves; causing a feeling of disembodiment common with the loss of proprioception. This condition is reversible when supplementation is stopped. Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, this article only discusses the safety of the supplemental form of vitamin B6 (pyridoxine). Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, very high doses of pyridoxine over long periods of time may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities, and in severe cases difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. None of the studies, in which an objective neurological examination was performed, found evidence of sensory nerve damage at intakes of pyridoxine below 200 mg/day. In order to prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults. Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day. Studies have shown, however, that in the case of individuals diagnosed with autism, high doses of vitamin B6 given with magnesium have been found to be beneficial. At least one preliminary study has found that this vitamin may increase dream vividness or the ability to recall dreams. It is thought that this effect may be due to the role this vitamin plays in the conversion of tryptophan to serotonin. The intake of vitamin B6, from either diet or supplements, could cut the risk of Parkinson's disease by half according to a prospective study from the Netherlands. "Stratified analyses showed that this association was restricted to smokers," wrote the authors. Nutritional supplementation with high dose vitamin B6 and magnesium is claimed to alleviate the symptoms of autism and is one of the most popular complementary and alternative medicine choices for autism. Three small randomized controlled trials have studied this therapy; the smallest one (with 8 individuals) found improved verbal IQ in the treatment group and the other two (with 10 and 15 individuals, respectively) found no significant difference. The short-term side effects seem to be mild, but there may be significant long-term side effects of peripheral neuropathy. Some studies suggest that the B6-magnesium combination can also help attention deficit disorder , citing improvements in hyperactivity, hyperemotivity/aggressiveness and improved school attention. It is also suggested that ingestion of vitamin B6 can alleviate some of the many symptoms of an alcoholic hangover and morning sickness from pregnancy. This might be due to B6's mild diuretic effect.

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# Vitamin C Vitamin C or L-ascorbate is an essential nutrient for higher primates, and a small number of other species. The presence of ascorbate is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms, humans being one notable exception. It is widely known as the vitamin whose deficiency causes scurvy in humans. It is also widely used as a food additive. The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an antioxidant, as it protects the body against oxidative stress, and is a cofactor in several vital enzymatic reactions. Vitamin C is purely the L-enantiomer of ascorbate; the opposite D-enantiomer has no physiological significance. Both forms are mirror images of the same molecular structure. When L-ascorbate, which is a strong reducing agent, carries out its reducing function, it is converted to its oxidized form, L-dehydroascorbate. L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione. L-ascorbate is a weak sugar acid structurally related to glucose which naturally occurs either attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate. In humans, vitamin C is a highly effective antioxidant, acting to lessen oxidative stress, a substrate for ascorbate peroxidase, as well as an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for eight different enzymes: Biological tissues that accumulate over 100 times the level in blood plasma of vitamin C are the adrenal glands, pituitary, thymus, corpus luteum, and retina. Those with 10 to 50 times the concentration present in blood plasma include the brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa, leukocytes, pancreas, kidney and salivary glands. The vast majority of animals and plants are able to synthesize their own vitamin C, through a sequence of four enzyme-driven steps, which convert glucose to vitamin C. The glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process. In reptiles and birds the biosynthesis is carried out in the kidneys. Among the animals that have lost the ability to synthesise vitamin C are simians, guinea pigs, the red-vented bulbul,and fruit-eating bats. Most notably, humans have no capability to manufacture vitamin C. The cause of this phenomenon is that the last enzyme in the synthesis process, L-gulonolactone oxidase, cannot be made by the listed animals because the gene for this enzyme, Pseudogene ΨGULO, is defective. The mutation has not been lethal because vitamin C is abundant in their food sources, with many of these species' natural diets consisting largely of fruit. Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans. This discrepancy constitutes the basis of the controversy on current recommended dietary allowances (see Vitamin C as a macronutrient - Evolutionary rationales). It has been noted that the loss of the ability to synthesize ascorbate strikingly parallels the evolutionary loss of the ability to break down uric acid. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that in higher primates, uric acid has taken over some of the functions of ascorbate. Ascorbic acid can be oxidised (broken down) in the human body by the enzyme ascorbic acid oxidase. An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and the biosynthesis will increase "many fold under stress". Trauma or injury has also been demonstrated to also use up large quantities of vitamin C in humans. Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars. Scurvy is an avitaminosis resulting from lack of vitamin C, as without this vitamin, the synthesised collagen is too unstable to meet its function. Scurvy leads to the formation of liver spots on the skin, spongy gums, and bleeding from all mucous membranes. The spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth and, eventually, death. The human body can store only a certain amount of vitamin C., and so the body soon depletes itself if fresh supplies are not consumed. Smoking cigarettes has a negative correlation to the amount of vitamin c in the blood stream. The relative amounts of vitamin c drop with the increased amount of cigarettes smoked. The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native peoples living in marginal areas incorporated this into their medicinal lore. For example, spruce needles were used in temperate zones in infusions, or the leaves from species of drought-resistant trees in desert areas. In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams. Throughout history, the benefit of plant food to survive long sea voyages has been occasionally recommended by authorities. John Woodall, the first appointed surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his book "The Surgeon's Mate", in 1617. The Dutch writer, Johann Bachstrom, in 1734, gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease." While the earliest documented case of scurvy was described by Hippocrates around the year 400 BC, the first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the British Royal Navy, James Lind. Scurvy was common among those with poor access to fresh fruit and vegetables, such as remote, isolated sailors and soldiers. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations. In the history of science this is considered to be the first occurrence of a controlled experiment comparing results on two populations of a factor applied to one group only with all other factors the same. The results conclusively showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy. Lind's work was slow to be noticed, partly because he gave conflicting evidence within the book, and partly because the British admiralty saw care for the well-being of crews as a sign of weakness. In addition, fresh fruit was very expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles ). Ship captains assumed wrongly that Lind's suggestions didn't work because those juices failed to cure scurvy. It was 1795 before the British navy adopted lemons or lime as standard issue at sea. Limes were more popular as they could be found in British West Indian Colonies, unlike lemons which weren't found in British Dominions, and were therefore more expensive. This practice led to the American use of the nickname "limey" to refer to the British. Captain James Cook had previously demonstrated and proven the principle of the advantages of fresh and preserved foods, such as sauerkraut, by taking his crews to the Hawaiian Islands and beyond without losing any of his men to scurvy. For this otherwise unheard of feat, the British Admiralty awarded him a medal. The name "antiscorbutic" was used in the eighteenth and nineteenth centuries as general term for those foods known to prevent scurvy, even though there was no understanding of the reason for this. These foods included but were not limited to: lemons, limes, and oranges; sauerkraut, cabbage, malt, and portable soup. In 1907, Axel Holst and Theodor Frølich, two Norwegian physicians studying beriberi contracted aboard ship's crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons they used. They fed guinea pigs their test diet, which had earlier produced beriberi in their pigeons, and were surprised when scurvy resulted instead. Until that time scurvy had not been observed in any organism apart from humans, and had been considered an exclusively human disease. In 1912, the Polish-American biochemist Casimir Funk, while researching deficiency diseases, developed the concept of vitamins to refer to the nutrients which are essential to health. Then, from 1928 to 1933, the Hungarian research team of Joseph L Svirbely and Albert Szent-Györgyi and, independently, the American Charles Glen King, first isolated vitamin C and showed it to be ascorbic acid. For this, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine. In 1928 the Arctic anthropologist Vilhjalmur Stefansson attempted to prove his theory of how the Eskimos are able to avoid scurvy with almost no plant food in their diet, despite the disease striking European Arctic explorers living on similar high-meat diets. Stefansson theorised that the natives get their vitamin C from fresh meat that is minimally cooked. Starting in February 1928, for one year he and a colleague lived on an exclusively minimally-cooked meat diet while under medical supervision; they remained healthy. Between 1933 and 1934, the British chemists Sir Walter Norman Haworth and Sir Edmund Hirst and, independently, the Polish chemist Tadeus Reichstein, succeeded in synthesizing the vitamin, the first to be artificially produced. This made possible the cheap mass-production of vitamin C. Only Haworth was awarded the 1937 Nobel Prize in Chemistry for this work, but the process for vitamin C retained Reichstein's name. In 1957 the American J.J. Burns showed that the reason some mammals were susceptible to scurvy was the inability of their liver to produce the active enzyme L-gulonolactone oxidase, which is the last of the chain of four enzymes which synthesize vitamin C. American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the theory that humans possess a mutated form of the L-gulonolactone oxidase coding gene. The North American Dietary Reference Intake recommends 90 milligrams per day and no more than 2 grams per day (2000 milligrams per day). Other related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this reference intake. There is continuing debate within the scientific community over the best dose schedule (the amount and frequency of intake) of vitamin C for maintaining optimal health in humans. It is generally agreed that a balanced diet without supplementation contains enough vitamin C to prevent scurvy in an average healthy adult, while those who are pregnant, smoke tobacco, or are under stress require slightly more. High doses (thousands of milligrams) may result in diarrhea. Proponents of alternative medicine (specifically orthomolecular medicine) claim the onset of diarrhea to be an indication of where the body's true vitamin C requirement lies. Both Cathcart and Cameron have hypothesized that very sick patients with cancer or influenza do not display any evidence of diarrhea at all until ascorbate intake reaches levels as high as 200 grams (nearly half a pound). Some independent researchers have calculated the amount needed for an adult human to achieve similar blood serum levels as vitamin C synthesising mammals as follows: There is a strong advocacy movement for large doses of vitamin C, promoting a great deal of added benefits. Drawing on a wide, but still inconclusive, body of evidence as to the benefits beyond those dosages recommended in the Dietary Reference Intakes, many pro-vitamin C organizations promote usage levels well beyond the current Dietary Reference Intake. The movement is led by scientists and doctors such as Robert Cathcart, Ewan Cameron, Steve Hickey, Irwin Stone and the twice Nobel Prize laureate Linus Pauling and the more controversial Matthias Rath. There is some scientific literature critical of governmental agency dose recommendations. The biological halflife for vitamin C is fairly short, about 30 minutes in blood plasma, a fact which high dose advocates say that mainstream researchers have failed to take into account. Researchers at the National Institutes of Health decided upon the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. Humans carry a mutated and ineffective form of the gene required by all mammals for manufacturing the fourth of the four enzymes that manufacture vitamin C. The inability to produce vitamin C, hypoascorbemia, is, according to the Online Mendeleian Inheritance in Man database, a "public" inborn error of metabolism. The gene, Pseudogene ΨGULO, lost its function millions of years ago, when the anthropoids branched out. In humans, the three functional enzymes continue to produce the precursors to vitamin C, but the process is incomplete; these enzymes ultimately undergo proteolytic degradation. Stone and Pauling calculated, based on the diet of our primate cousins (similar to what our common descendants are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human requiring 2,500 kcal a day. The established RDA has been criticized by Pauling to be one that will prevent acute scurvy, and is not necessarily the dosage for optimal health. Since its discovery vitamin C has been considered by some enthusiastic proponents a "universal panacea", although this led to suspicions by others of it being over-hyped. Other proponents of high dose vitamin C consider that if it is given "in the right form, with the proper technique, in frequent enough doses, in high enough doses, along with certain additional agents and for a long enough period of time," it can prevent and, in many cases, cure, a wide range of common and/or lethal diseases, notably the common cold and heart disease, although the NIH considers there to be "fair scientific evidence against this use." Some proponents issued controversial statements involving it being a cure for AIDS, bird flu, and SARS. Probably the most controversial issue, the putative role of ascorbate in the management of AIDS, is still unresolved, more than 16 years after the landmark study published in the Proceedings of National Academy of Sciences (USA) showing that non toxic doses of ascorbate suppress HIV replication in vitro. Other studies expanded on those results, but still, no large scale trials have yet been conducted. In an animal model of lead intoxication, vitamin C demonstrated "protective effects" on lead-induced nerve and muscle abnormalities In smokers, blood lead levels declined by an average of 81% when supplemented with 1000 mg of vitamin C, while 200 mg were ineffective, suggesting that vitamin C supplements may be an "economical and convenient" approach to reduce lead levels in the blood. The Journal of the American Medical Association published a study which concluded, based on an analysis of blood lead levels in the subjects of the Third National Health and Nutrition Examination Survey, that the independent, inverse relationship between lead levels and vitamin C in the blood, if causal, would "have public health implications for control of lead toxicity". Vitamin C has limited popularity as a treatment for autism spectrum symptoms. A 1993 study of 18 children with ASD found some symptoms reduced after treatment with vitamin C, but these results have not been replicated. Small clinical trials have found that vitamin C might improve the sperm count, sperm motility, and sperm morphology in infertile men , or improve immune function related to the prevention and treatment of age-associated diseases. However, to date, no large clinical trials have verified these findings. A preliminary study published in the Annals of Surgery found that the early administration of antioxidant supplementation using α-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients. More research on this topic is pending. Dehydroascorbic acid, the main form of oxidized Vitamin C in the body, was shown to reduce neurological deficits and mortality following stroke, due to its ability to cross the blood-brain barrier, while "the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier". In this study published by the Proceedings of the National Academy of Sciences in 2001, the authors concluded that such "a pharmacological strategy to increase cerebral levels of ascorbate in stroke has tremendous potential to represent the timely translation of basic research into a relevant therapy for thromboembolic stroke in humans". No such "relevant therapies" are available yet and no clinical trials have been planned. In January 2007 the US Food and Drug Administration approved a Phase I toxicity trial to determine the safe dosage of intravenous vitamin C as a possible cancer treatment for "patients who have exhausted all other conventional treatment options." Additional studies over several years would be needed to demonstrate whether it is effective. In February 2007, an uncontrolled study of 39 terminal cancer patients showed that, on subjective questionnaires, patients reported an improvement in health, cancer symptoms, and daily function after administration of high-dose intravenous vitamin C. The authors concluded that "Although there is still controversy regarding anticancer effects of vitamin C, the use of vitamin C is considered a safe and effective therapy to improve the quality of life of terminal cancer patients". Simple tests use DCPIP to measure the levels of vitamin C in the urine and in serum or blood plasma. However these reflect recent dietary intake rather than the level of vitamin C in body stores. Reverse phase high performance liquid chromatography is used for determining the storage levels of vitamin C within lymphocytes and tissue. It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, those within tissues themselves are more stable and give a better view of the availability of ascorbate within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories. While being harmless in most typical quantities, as with all substances to which the human body is exposed, vitamin C can still cause harm under certain conditions. When taken in large doses, vitamin C causes diarrhea. In one trial, doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes. As vitamin C enhances iron absorption , iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD), can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C. For decades, large doses of vitamin C have been speculated to trigger oxalate formation and increase absorption of dietary oxalate, possibly causing kidney stones. However, this speculation may not be justified since there is no clear relationship between excess ascorbic acid intake and kidney stone formation. During the first month of pregnancy, high doses of vitamin C may suppress the production of progesterone from the corpus luteum. Progesterone, necessary for the maintenance of a pregnancy, is produced by the corpus luteum for the first few weeks, until the placenta is developed enough to produce its own source. By blocking this function of the corpus luteum, high doses of vitamin C (1000+ mg) is theorized to induce an early miscarriage. In a group of spontaneously aborting women at the end of the first trimester, the mean values of vitamin C were significantly higher in the aborting group. However, the authors point out that this relationship may not necessarily be a causal one. As discussed previously, vitamin C exhibits remarkably low toxicity. The LD50 (the dose that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per kilogram when taken orally. The LD50 in humans remains unknown, owing to medical ethics that preclude experiments which would put patients at risk of harm. However, as with all substances tested in this way, the LD50 is taken as a guide to its toxicity in humans and no data to contradict this has been found. The richest natural sources are fruits and vegetables, and of those, the camu camu fruit and the Kakadu plum contain the highest concentration of the vitamin. It is also present in some cuts of meat, especially liver. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, crystals in capsules or naked crystals. Vitamin C is absorbed by the intestines using a sodium-ion dependent channel. It is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms. The presence of large quantities of sugar either in the intestines or in the blood can slow absorption. While plants are generally a good source of vitamin C, the amount in foods of plant origin depends on: the precise variety of the plant, the soil condition, the climate in which it grew, the length of time since it was picked, the storage conditions, and the method of preparation. The following table is approximate and shows the relative abundance in different raw plant sources. As some plants were analyzed fresh while others were dried (thus, artifactually increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of fruit or vegetable and is a rounded average from multiple authoritative sources: The overwhelming majority of species of animals and plants synthesise their own vitamin C, making some, but not all, animal products, sources of dietary vitamin C. Vitamin C is most present in the liver and least present in the muscle. Since muscle provides the majority of meat consumed in the western human diet, animal products are not a reliable source of the vitamin. Vitamin C is present in mother's milk and, in lower amounts, in raw cow's milk, with pasteurized milk containing only trace amounts. All excess Vitamin C is disposed of through the urinary system. The following table shows the relative abundance of vitamin C in various foods of animal origin, given in milligram of vitamin C per 100 grams of food: Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Normally, boiling water at 100°C is not hot enough to cause any significant destruction of the nutrient, which only decomposes at 190°C, despite popular opinion. However, pressure cooking, roasting, frying and grilling food is more likely to reach the decomposition temperature of vitamin C. Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition. Another cause of vitamin C being lost from food is leaching, where the water-soluble vitamin dissolves into the cooking water, which is later poured away and not consumed. However, vitamin C doesn't leach in all vegetables at the same rate; research shows broccoli seems to retain more than any other. Research has also shown that fresh-cut fruit don't lose significant nutrients when stored in the refrigerator for a few days. Vitamin C is the most widely taken dietary supplement. It is available in many forms including caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple antioxidant formulations, and crystalline powder. Timed release versions are available, as are formulations containing bioflavonoids such as quercetin, hesperidin and rutin. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (as ascorbic acid) crystals are typically available in bottles containing 300 g to 1 kg of powder (a teaspoon of vitamin C crystals equals 5,000 mg). Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. Both processes yield approximately 60% vitamin C from the glucose feed. Research is underway at the Scottish Crop Research Institute in the interest of creating a strain of yeast that can synthesise vitamin C in a single fermentation step from galactose, a technology expected to reduce manufacturing costs considerably. World production of synthesised vitamin C is currently estimated at approximately 110,000 tonnes annually. Main producers today are BASF/Takeda, DSM, Merck and the China Pharmaceutical Group Ltd. of the People's Republic of China. China is slowly becoming the major world supplier as its prices undercut those of the US and European manufacturers.

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# Vitamin D Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation. Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. Vitamin D deficiency may also be linked to many forms of cancer. Chemically, the various forms of vitamin D are secosteroids; i.e. broken-open steroids. The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D2 is derived from fungal and plant sources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–290 nm. These wavelengths are present in sunlight at sea level when the sun is more than 45° above the horizon, or when the UV index is greater than 3. At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin only after ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated. In most mammals, including humans, D3 is more effective than D2 at increasing the levels of vitamin D hormone in circulation; D3 is at least 3-fold, and likely closer to 10-fold, more potent than D2. However, in some species, such as rats, vitamin D2 is more effective than D3. Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene. Some forms of activated vitamin D like calcitriol, that are commonly used in the chronic kidney disease population, can cause increase absorption of calcium and phosphorus in the gut leading to high serum levels. Some companies modified the structures of the side-chain decreasing the gut effect and maintaining the effect in the parathyroid gland. These group of compounds includes paricalcitol and the one named after Hector DeLuca, hectorol. Vitamin D is a prohormone, that is, it has no hormone activity itself, but is converted to a hormone 1,25-D which does, through a tightly regulated synthesis mechanism. The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum. The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is reduced. Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. 7-Dehydrocholesterol absorbs UV light most effectively at wavelengths between 270–290 nm and thus the production of vitamin D3 will only occur at those wavelengths. The two most important factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum. A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 mg/cm² of skin) are available in the stratum spinosum and stratum basale of human skin to meet the body's vitamin D requirements, and melanin content does not alter the amount of vitamin D that can be produced. Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. Once vitamin D is produced in the skin or consumed in food, it is converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). Following this conversion, the hormonally active form of vitamin D is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs. The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR allows the VDR to act as a transcription factor that modulates the gene expression of transport proteins (such as TRPV6 and calbindin), which are involved in calcium absorption in the intestine. The Vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDR are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content. The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells. Very few foods are naturally rich in vitamin D, and most vitamin D intake is in the form of fortified products including milk, soy milk and cereal grains. A blood calcidiol (25-hydroxy-vitamin D) level is the accepted way to determine vitamin D nutritional status. The optimal level of serum 25-hydroxyvitamin D remains a point for debate among medical scientists. The U.S. Dietary Reference Intake for Adequate Intake (AI) of vitamin D for infants, children and men and women aged 19–50 is 5 micrograms/day (200 IU/day). Adequate intake increases to 10 micrograms/day (400 IU/day) for men and women aged 51–70 and to 15 micrograms/day (600 IU/day) past the age of 70. Season, geographic latitude, time of day, cloud cover, smog, and sunscreen affect UV ray exposure and vitamin D synthesis in the skin, and it is important for individuals with limited sun exposure to include good sources of vitamin D in their diet. In some countries, foods such as milk, yogurt, margarine, oil spreads, breakfast cereal, pastries, and bread are fortified with vitamin D2 and/or vitamin D3, to minimize the risk of vitamin D deficiency. In the United States and Canada, for example, fortified milk typically provides 100 IU per glass, or one quarter of the estimated adequate intake for adults over the age of 50. There is no consensus on the serum 25-hydroxyvitamin D levels, "25(OH)D", considered "normal". 12 ng per milliliter (50 nmol per liter) ihas been proposed. However, "a common misconception is that the RDA functions as a "cut point" and that nearly the entire population must have a serum 25(OH)D level above 20 ng per milliliter to achieve good bone health. The reality is that the majority (about 97.5%) of the population has a requirement of 20 ng per milliliter or less. Moreover, by definition of an average requirement, approximately half the population has a requirement of 16 ng per milliliter (the EAR) or less. " (italics added) Previous opinions suggested a value equal or less than 20 ng per milliliter (50 nmol per liter) is in the deficient range. , , , The definition can be based on the point at which the parathyroid hormone (PTH) levels off as the cutoff point, which may be at 12 ng per milliliter (30 nmol per liter) or is close to 30 ng per milliliter (75 nmol per liter). Vitamin D deficiency can result from: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. The role of diet in the development of rickets was determined by Edward Mellanby between 1918–1920. In 1921 Elmer McCollum identified an anti-rachitic substance found in certain fats could prevent rickets. Because the newly discovered substance was the fourth vitamin identified, it was called vitamin D. The 1928 Nobel Prize in Chemistry was awarded to Adolf Windaus, who discovered the steroid, 7-dehydrocholesterol, the precursor of vitamin D. Prior to the fortification of milk products with vitamin D, rickets was a major public health problem. In the United States, milk has been fortified with 10 micrograms (400 IU) of vitamin D per quart since the 1930s, leading to a dramatic decline in the number of rickets cases. Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, depression, schizophrenia, seasonal affective disorder and several autoimmune diseases (see role in immunomodulation). There are 2 major forms of vitamin D available, Vitamin D2 and D3. We prefer Vitamin D3 supplements as it is naturally available form and very effective. 25OHD is measured in blood if you suspect vitamin D deficiency and based on the value supplements are given. Normal value of 25OHD is 30-80 ng/ml. If 25OHD is less than 20 ng/ml-50,000 IU Vitamin D3 per week for 6-8 weeks, followed by 800 to 100 IU/ day daily thereafter. If 25OHD is 20 to 30 ng/ml-800-1000 IU vitamin D3 per day for 3 months, after 25OHD reached normal values continue with 800 IU it D per day. In adults with normal 25OHD more than 30 ng/ml- 800 IU of Vitamin D3 daily is recommended. For children and infants with 25OHD less than 20 ng/ml-vitamin D3 1000-500 IU per day for 3 months. During pregnancy vitamin D3 400IU/day is recommended. Vitamin D requirements increase with age, while the ability of skin to convert 7-dehydrocholesterol to pre-vitamin D3 decreases. In addition the ability of the kidneys to convert calcidiol to its active form also decreases with age, prompting the need for increased vitamin D supplementation in elderly individuals. One consensus concluded that for optimal prevention of osteoporotic fracture the blood calcidiol concentration should be higher than 30 ng/mL, which is equal to 75 nmol/L. The American Pediatric Associations advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards. Health Canada recommends 400IU/day (10μg/d). While infant formula is generally fortified with vitamin D, breast milk does not contain significant levels of vitamin D, and parents are usually advised to avoid exposing babies to prolonged sunlight. Therefore, infants who are exclusively breastfed are likely to require vitamin D supplementation beyond early infancy, especially at northern latitudes. Liquid "drops" of vitamin D, as a single nutrient or combined with other vitamins, are available in water based or oil-based preparations ("Baby Drops" in North America, or "Vigantol oil" in Europe). However, babies may be safely exposed to sunlight for short periods; as little as 10 minutes a day without a hat can suffice, depending on location and season. The vitamin D found in supplements and infant formula is less easily absorbed than that produced by the body naturally and carries a risk of overdose that is not present with natural exposure to sunlight. Obese individuals may have lower levels of the circulating form of vitamin D, probably because of reduced bioavailability, and are at higher risk of deficiency. To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their parathyroid glands removed (most commonly renal dialysis patients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism. Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily). The use of sunscreen with a sun protection factor (SPF) of 8 inhibits more than 95% of vitamin D production in the skin. Recent studies showed that, following the successful "Slip-Slop-Slap" health campaign encouraging Australians to cover up when exposed to sunlight to prevent skin cancer, an increased number of Australians and New Zealanders became vitamin D deficient. Ironically, there are indications that vitamin D deficiency may lead to skin cancer. To avoid vitamin D deficiency dermatologists recommend supplementation along with sunscreen use. The reduced pigmentation of light-skinned individuals tends to allow more sunlight to be absorbed even at higher latitudes, thereby reducing the risk of vitamin D deficiency. However, at higher latitudes (above 30°) during the winter months, the decreased angle of the sun's rays, reduced daylight hours, protective clothing during cold weather, and fewer hours of outside activity, diminish absorption of sunlight and the production of vitamin D. Because melanin acts like a sun-block, prolonging the time required to generate vitamin D, dark-skinned individuals, in particular, may require extra vitamin D to avoid deficiency at higher latitudes. At latitudes below 30° where sunlight and day-length are more consistent, vitamin D supplementation may not be required. Individuals clad in full body coverings during all their outdoor activity, most notably women wearing burquas in daylight, are at risk of vitamin D deficiency. This poses a lifestyle-related health risk mostly for female residents of conservative Muslim nations in the Middle East, but also for strict adherents in other parts of the world. Vitamin D stored in the human body as calcidiol (25-hydroxy-vitamin D) has a large volume of distribution and a long half-life (about 20 to 29 days). However, the synthesis of bioactive vitamin D hormone is tightly regulated and vitamin D toxicity usually occurs only if excessive doses (prescription or megavitamin) are taken. Although normal food and pill vitamin D concentration levels are too low to be toxic in adults, because of the high vitamin A content in codliver oil it is possible to reach poisonous levels of vitamin A, if taken in multiples of the normal dose in an attempt to increase the intake of vitamin D. Most cases of vitamin D overdose have occurred due to manufacturing and industrial accidents. Exposure to sunlight for extended periods of time does not cause Vitamin D toxicity. This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded. Maximum endogenous production with full body exposure to sunlight is 250 µg (10,000 IU) per day. The exact long-term safe dose of vitamin D is not entirely known, but dosages up to 60 micrograms (2,400 IU) /day in healthy adults are believed to be safe. , and all known cases of vitamin D toxicity with hypercalcemia involve intake of or over 1,000 micrograms (40,000 IU)/day . The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for children and adults is 50 micrograms/day (2,000 IU/day). In adults, sustained intake of 2500 μg/day (100,000 IU) can produce toxicity within a few months. For infants (birth to 12 months) the tolerable UL is set at 25 micrograms/day (1000 IU/day), and vitamin D concentrations of 1000 micrograms/day (40,000 IU) in infants has been shown to produce toxicity within 1 to 4 months. In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004, leading to 1 death. Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 25 to 40 ng/mL (60 to 100 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose. The symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Gastrointestinal symptoms of vitamin D toxicity can develop including anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop. In one study, hypercalciuria and bone loss occurred in four patients with documented vitamin D toxicity. Another study showed elevated risk of ischaemic heart disease when 25D was above 89 ng/mL. Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible. The United States Preventive Services Task Force in 2013 concluded "the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamins for the prevention of cardiovascular disease or cancer". A systematic review of randomized controlled trials, including the D2d trial , suggests benefit . In the D2d trial, the results were negative; however, the patients mean baseline vitamin D level (28 nl/ml) was above the Academy of Medicine's definition of at risk of inadequacy (levels 12-20 ng/ml) . Vitamin D did not prevent falls in a randomized controlled trial . In this trial of 4 doses of vitamin D (200 [control], 1000, 2000, or 4000 IU of vitamin D3 per day), patients were 70 years and older with vitamin D [25-(OH)D] levels of 25 to 72.5 nmol/L with a mean total 25-(OH)D level of 55.3 nmol/L. The final final vitamin D level achieved was 67.1, 80.3, 87.3, and 119.2 nmol/L for doses of 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. Earlier, in 2012, the USPSTF had recommendated vitamin D supplementation for fall prevention in adults over 65 years old . Subsequently, in 2018, the USPSTF did not make this recommendation . The hormonally active form of vitamin D mediates immunological effects by binding to nuclear vitamin D receptors (VDR) which are present in most immune cell types including both innate and adaptive immune cells. The VDR is expressed constitutively in monocytes and in activated macrophages, dendritic cells, NK cells, T and B cells. In line with this observation, activation of the VDR has potent anti-proliferative, pro-differentiative, and immunomodulatory functions including both immune-enhancing and immunosuppressive effects. Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns. VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression. VDR ligands have also been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages. Active vitamin D hormone also increases the production of cathelicidin, an antimicrobial peptide that is produced in macrophages triggered by bacteria, viruses, and fungi. Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets. These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of; inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis) and in preventing organ transplant rejection. However the effects of supplementation with vitamin D, as yet, remain unclear, and supplementation may be inadvisable for individuals with sarcoidosis and other diseases involving vitamin D hypersensitivity. A 2006 study published in the Journal of the American Medical Association, reported evidence of a link between Vitamin D deficiency and the onset of Multiple Sclerosis; the authors posit that this is due to the immune-response suppression properties of Vitamin D. The vitamin D hormone, calcitriol, has been found to induce death of cancer cells in vitro and in vivo. Although the anti-cancer activity of vitamin D is not fully understood, it is thought that these effects are mediated through vitamin D receptors expressed in cancer cells, and may be related to its immunomodulatory abilities. The anti-cancer activity of vitamin D observed in the laboratory has prompted some to propose that vitamin D supplementation might be beneficial in the treatment or prevention of some types of cancer. In 2005, scientists released a metastudy which demonstrated a beneficial correlation between vitamin D intake and prevention of cancer. Drawing from a meta-analysis of 63 published reports, the authors showed that intake of an additional 1,000 international units (IU) (or 25 micrograms) of vitamin D daily reduced an individual's colon cancer risk by 50%, and breast and ovarian cancer risks by 30%. Research has also shown a beneficial effect of high levels of calcitriol on patients with advanced prostate cancer. . A recent study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers. In June 2007, The Canadian Cancer Society began recommending that all adult Canadians consider taking 1000 IU of vitamin D during the fall and winter months (when typically the country's northern latitude prevents sufficient sun-stimulated production of vitamin D). This kind of recommendation is a first for cancer agencies. Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight. A randomized controlled trial found no benefit . Previously, in 2017, a randomized controlled trial reported no reduction in cancer among postmenopausal women with a mean baseline serum 25-hydroxyvitamin D level of 32.8 ng/mL from supplementation with vitamin D3. . Earlier, a trial found benefit amond 1,200 women receiving vitamin D supplementation (1,100 international units (IU) / day). This resulted in a 60% reduction in cancer incidence over four-years, rising to a 77% reduction if cancers diagnosed in the first year (and therefore more likely to have originated prior to the intervention) were excluded. One of the very first indications of the association between cardiovascular diseases and vitamin D was in the most severe form of the vitamin deficiency, Rickets, in which patients had cardiomyopathy. Evidence of an intracellular vitamin D receptor in rat cardiomyocytes was described in the early 1980's and in human heart tissue in the mid 1990s. Xiang W. et al. provided further evidence of the relationship between vitamin D and cardiovascular diseases in his VDR knockout mouse model, in which the mice had severe cardiac hypertrophy. VDR knockout mice also under-express tissue inhibitors of metalloproteinases (TIMP-1 & TIMP-3) in comparison to the wild-type, which may contribute to increased oxidation of the extracellular matrix proteins and perivascular tissues. Interestingly, spontaneous hypertensive rats (SHR) were found to be more vitamin D deficient as measures of blood pressure increased. Contrary to data in the vitamin D receptor knockout mice model, the wild-type had higher blood pressures compared to the knockout. In vitro data showed that 1,25-hydroxyvitamin D has a regulatory effect on myoblast proliferation as well as some rapid genomic effect, suggesting some action independent of transcription. To further explore possible non-genomic effects, Tishkoff et al. explored the location of the VDR intracellularly and found signaling in the T-tubules, close to the sarcoendoplasmic reticulum Ca++- ATPase (SERCA). They also reported accelerated rates of myocyte contraction and relaxation in VDR knockout mice cells as compared to the wild-type. Dahl salt-sensitive rats (DSS) are an interesting animal model to study direct cardiac vitamin D effects on the heart since the DSS rats become vitamin D deficient, hypertensive and develop increased heart mass if fed with high-salt diet. Bodyak et al. showed decreased heart size and improved contraction by m-mode echocardiography in rats treated with paricalcitol versus rats treated with placebo. Atrial natriuretic factor (ANP) was lower in the treated group, findings which are similar to those previously described in cardiomyocyte cell cultures. There were differences shown in the gene expression profiles between DSS treated with paricalcitol versus vehicle. Multiple epidemiologic studies have shown improved in cardiovascular morbidity and mortality in several populations. One of the earliest associations was shown by Teng et al. in the New England Journal of Medicine in 2003, where they showed a benefit in survival independent of calcium, phosphorus and PTH for patients treated with activated vitamin D. There was controversy regarding the activated vitamin D effects in mortality, because of higher risk of hypercalcemia, hyperposphatemia and their effect in the cardiovascular system. Patients treated with Paricalcitol, an activated vitamin D analogue with less effect on calcium and phosphorus, had improved survival compared to those treated with calcitriol. In further studies in the chronic kidney disease population, the vitamin D level was shown to be predictive of 90-day all-cause and cardiovascular mortality and the administration of activated form of vitamin D was shown to improve survival. Recently, in the New England Journal of Medicine Dr. Lee et al. described how the sicker patients in multiple intesive care units have lower levels of vitamin D. There is discrepancy in the prevalence and in the response to treatment of cardiovascular diseases among different races and ethnicities. In the third National Health and Nutrition Examination Survey (NHANES) black people, who have higher cardiovascular risk compared to whites, had lower levels of 25-hydroxyvitamin D. Moreover, multiple risk factors such as obesity, hypertension and diabetes mellitus were associated with lower 25-hydroxyvitamin D levels. In other studies 25-hydroxyvitamin D levels were inversely correlated with the prevalence of metabolic syndrome, type 2 diabetes mellitus and hypertension. In a cohort study with more than five thousand participants that were followed for twenty years the cumulative incidence of heart failure in black woman was 1.1% and in black men 0.9% compared to 0.8% and 0% in white women and men respectively. Interestingly, paradoxically to other scenarios, the african-american population has a survival advantage compared to whites in hemodialysis. Wolf et al. showed that they are more likely to be treated with activated vitamin D. Therefore, if you compare african-american versus whites in the non-treated population their survival advantage is lost. Zittermann et al. demonstrated that geographic factors such as latitude, altitude, season and place of residency were associated with different cardiovascular risk, mostly for ischemic heart disease. Interestingly, those factors were also associated with 25-hydroxyvitamin D levels. Cardiovascular disease rates were at their zenith in the winter, when the vitamin D levels were at their nadir. Based on studies done by Holick, PhD, MD, we know that the prevalence of vitamin D deficiency is close to somewhere between 40-100% in healthy individuals at the end of the winter in the New England area. Similar seasonal variations have also been shown for heart failure hospitalization rates and in cerebrovascular disease. The Ludwigshafen Risk and Cardiovascular Health Study (LURIC), a prospective cohort design to genetic polymorphisms and biomarkers associated with cardiovascular risks, showed a correlation between 25-hydroxyvitamin D and C-reactive protein (CRP) and interleukin 6 levels (IL-6), serum phospholipid and gluthatione levels and vascular cell adhesion molecule 1 (VCAM1) and intracellular adhesion molecule 1 (ICAM1). Dobnig et al. showed that 25-hydroxyvitamin D levels had a significant hazard ratio of 2.08 for cardiovascular mortality comparing the lowest versus the highest quartiles with a follow up close to eight years, and 1.61 for 1,25-hydroxyvitamin D. Results suggest independent predictive value of 25-hydroxyvitamin D and 1,25-hydroxyvitamin D. The results were independent of coronary artery disease, physical activity level, Charlson Comorbidity Index, variables of mineral metabolism and New York Heart Association functional class. The hazard ratios increased progressively per lower vitamin D level, suggesting a dose-dependent effect and strengthening the association. However, the study assumed that the patients with non-cardiac death had the same probability of dying of cardiac etiologies than the rest of the population, which may not necessarily be true and may bias the estimates. Research indicates that vitamin D plays a role in preventing or reversing coronary disease. As with cancer incidence, the same qualitative inverse correlations exist between coronary disease incidence and serum vitamin D levels, seasonal solar exposure, in temperate latitudes but not tropical latitudes. A nested case-control study with 18,225 men in the Health Professionals Follow-up Study showed that vitamin D deficient people had a relative risk of 2.09 of developing myocardial infarction. Similar findings were also shown in the researchers from the Framingham Offspring study prospectively collected 25-OH D levels in 1739 white individuals without cardiovascular disease or renal disease. For the primary analysis, vitamin D levels were a categorical variable, with cut-offs chosen a priori based on previously published studies. Participants were classified as deficient (<15 ng/ml) or sufficient (>15 ng/ml). Mean level was 19.7 ng/ml among all participants. Low 25-OH D levels were associated with obesity, cigarette smoking, higher systolic blood pressure, diabetes, higher ratio of total to HDL cholesterol, and lower intake of vitamin D or vitamins. Interesting, there was no correlation with physical activity. Over a mean of 7.6 years follow up there were 120 cardiovascular events. A multivariate model was used to correlate 25-OH D status with cardiovascular risk, adjusting for age, sex, blood pressure, medications, diabetes, cigarette smoking, cholesterol, body mass index, and renal function. After adjustment, a 25-OH D level less than 15 ng/ml was independently associated with risk of a cardiovascular event (HR 1.62, CI 1.11 to 2.35, P=0.01). In a three-category model, where participants were classified as sufficient, deficient (10 to 15 ng/ml) or severely deficient (<10 ng/ml), severe deficiency was associated with even greater risk (HR 1.80, CI 1.05 to 3.08, P=0.01). The mechanism by which vitamin D deficiency might increase risk of vascular disease is not entirely known. The authors cite data demonstrating that 1,25-OH D is important for suppression of the renin-angiotensin axis, and possible effects of hyperparathyroidism on myocyte function and vascular inflammation. The possibility always exists that an unmeasured confounder might explain the correlation seen in this study. Nonetheless, it is telling that the majority of participants in this study would qualify as vitamin-D deficient if a cut-off of 20 ng/ml were used, and the body of evidence linking vitamin-D deficiency with chronic illness is impressive. Observational data has shown similar associations of vitamin D not only with coronary artery disease, but with equivalents such as peripheral vascular disease. Differences by race in PVD have also been reported. A retrospective pilot study of hemodialysis patients demonstrated improved diastolic function evaluated with lower E/A ratios on echocardiogram in patients treated with paricalcitol as compared to untreated patients. A cohort of 51 patients was enrolled and followed for 12 months. Treatment was left at discretion of nephrologists. Baseline and 12-month echocardiograms were compared. Randomized controlled trials have not found benefit from Vitamin D supplementation . Cardiovascular disease many be increased when calcium supplementation is added to Vitamin D The treatment group M-mode echocardiography showed pronounced reductions in inverventricular wall thickness, left ventricular posterior wall thickness and left ventricle mass index. There were no differences in blood pressure control, and blood pressure medications were not changed. Data regarding distribution of angiotensin converting enzyme inhibitors and angiotensin receptor blockers between groups is not shown. Plasma renin, angiotensin II and atrial natriuretic peptide decreased over time in the calcitriol group. The study is limited due to its sample size, because it does not specify why some patients received treatment and why some did not, and it does not show the hormonal change in the control group. There are two large randomized double-blind placebo-controlled trials in chronic kidney disease assessing the effect of paricalcitol treatment on diastolic dysfunction, left ventricular mass as well as biomarkers and genetic expression (http://clinicaltrials.gov/ct2/show/NCT00497146 and http://clinicaltrials.gov/ct2/show/NCT00616902 ). These trials promise rigorous data to further characterize the effect, and possible mechanisms of the effect, of activated vitamin D in the heart. The United States Preventive Services Task Force in 2021 gave an "I" recommendation, " the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults", for screening for vitamin D deficiency . The USPSTF recommendation was based on a systematic review

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# Vitamin D deficiency historical perspective ## Historical Perspective Vitamin D deficiency was a common disease that affects both children and adults living in industrialized cities. Rickets was scientifically described by British physicians in the 17th century. In the 20th century, German scientists discovered vitamin D and its influence on bone health. The importance of sunlight and diet to prevent rickets were emphasized in the 20th century. The fortification of milk with vitamin D beginning in the 1930s has made rickets a rare disease in the United States.

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# Vitamin K Vitamin K denotes a group of lipophilic, and hydrophobic, vitamins that are needed for the posttranslational modification of certain proteins, mostly required for blood coagulation. Chemically they are 2-methyl-1,4-naphthoquinone derivatives. Vitamin K ("Koagulation" in German) is a group name for a number of related compounds, which have in common a methylated naphthoquinone ring structure, and which vary in the aliphatic side chain attached at the 3-position (see figure 1). Phylloquinone (also known as vitamin K1) invariably contains in its side chain four isoprenoid residues, one of which is unsaturated. Menaquinones have side chains composed of a variable number of unsaturated isoprenoid residues; generally they are designated as MK-n, where n specifies the number of isoprenoids. It is generally accepted that the naphthoquinone is the functional group, so that the mechanism of action is similar for all K-vitamins. Substantial differences may be expected, however, with respect to intestinal absorption, transport, tissue distribution, and bio-availability. These differences are caused by the different lipophilicity of the various side chains, and by the different food matrices in which they occur. Vitamin K is involved in the carboxylation of certain glutamate residues in proteins to form gamma-carboxyglutamate residues (abbreviated Gla-residues). Gla-residues are usually involved in binding calcium. The Gla-residues are essential for the biological activity of all known Gla-proteins. At this time 14 human Gla-proteins have been discovered, and they play key roles in the regulation of three physiological processes: blood coagulation , bone metabolism and vascular biology . The U.S. Dietary Reference Intake (DRI) for an Adequate Intake (AI) for a 25-year old male for Vitamin K is 120 micrograms/day. No Tolerable Upper Intake Level (UL) has been set. The human body stores Vitamin K, so it is not necessary to take Vitamin K daily. Vitamin K is found in leafy green vegetables such as spinach and lettuce; Brassica vegetables such as kale, cabbage, cauliflower, broccoli, and Brussels sprouts; wheat bran; organ meats; cereals; some fruits, such as avocado, kiwifruit and bananas; meats; cow milk and other dairy products; eggs; and other soy products. Two tablespoons of parsley contains 153% of the recommended daily amount of vitamin K. Phylloquinone (vitamin K1) is the major dietary form of vitamin K. Vitamin K1 is found in chicken egg yolk, butter, cow liver, most cheeses, and products. It is also found in some types of mayonnaise. Vitamin K-deficiency may occur by disturbed intestinal uptake (such as would occur in a bile duct obstruction), by therapeutic or accidental intake of vitamin K-antagonists or, very rarely, by nutritional vitamin K-deficiency. As a result of the acquired vitamin K-deficiency, Gla-residues are not or incompletely formed and hence the Gla-proteins are inactive. Lack of control of the three processes mentioned above may lead to the following: risk of massive, uncontrolled internal bleeding, cartilage calcification and severe malformation of developing bone, or deposition of insoluble calcium salts in the arterial vessel walls. In some countries, injections of Vitamin K are routinely given to newborn babies. Vitamin K is used as prophylactic measure to prevent late-onset haemorrhagic disease (HDN). However, HDN is a relatively rare problem, and many parents now choose for their babies not to have such an injection. In patients with warfarin overanticoagulation, vitamin K administration can decrease the risks of bleeding. Oral and intravenous routes of vitamin K administration are found to be more effective than subcutaneous routes. Also, oral routes are preferred over intravenous routes, due to ease of administration and absence of anaphylaxsis seen with oral routes . In the late 1920s, Danish scientist Henrik Dam investigated the role of cholesterol by feeding chickens a cholesterol-depleted diet. After several weeks, the animals developed hemorrhages and started bleeding. These defects could not be restored by adding purified cholesterol to the diet. It appeared that - together with the cholesterol - a second compound had been extracted from the food, and this compound was called the coagulation vitamin. The new vitamin received the letter K because the initial discoveries were reported in a German journal, in which it was designated as Koagulationsvitamin. Edward Adelbert Doisy (of Saint Louis University) did much of the research that led to the discovery of the structure and chemical nature of Vitamin K. Dam and Doisy shared the 1943 Nobel Prize for medicine for their work on Vitamin K. Several laboratories synthesized the compound in 1939. For several decades the vitamin K-deficient chick model was the only method of quantitating of vitamin K in various foods: the chicks were made vitamin K-deficient and subsequently fed with known amounts of vitamin K-containing food. The extent to which blood coagulation was restored by the diet was taken as a measure for its vitamin K content. The first published report of successful treatment with vitamin K of life-threatening hemorrhage in a jaundiced patient with prothrombin deficiency was made in 1938 at the University of Iowa Department of Pathology by Drs. Harry Pratt Smith, Emory Warner, Kenneth Brinkhous, and Walter Seegers. The precise function of vitamin K was not discovered until 1974, when three laboratories (Stenflo et al. , Nelsestuen et al. , and Magnusson et al. ) isolated the vitamin K-dependent coagulation factor prothrombin (Factor II) from cows that received a high dose of a vitamin K antagonist, warfarin. It was shown that while warfarin-treated cows had a form of prothrombin that contained 10 glutamate amino acid residues near the amino terminus of this protein, the normal (untreated) cows contained 10 unusual residues which were chemically identified as gamma-carboxyglutamate, or Gla. The extra carboxyl group in Gla made clear that vitamin K plays a role in a carboxylation reaction during which Glu is converted into Gla. The biochemistry of how Vitamin K is used to convert Glu to Gla has been elucidated over the past thirty years in academic laboratories throughout the world. Within the cell, Vitamin K undergoes electron reduction to a reduced form of Vitamin K (called Vitamin K hydroquinone) by the enzyme Vitamin K epoxide reductase (or VKOR). Another enzyme then oxidizes Vitamin K hydroquinone to allow carboxylation of Glu to Gla; this enzyme is called the gamma-glutamyl carboxylase or the Vitamin K-dependent carboxylase. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize Vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. Vitamin K epoxide is then re-converted to Vitamin K by the Vitamin K epoxide reductase. These two enzymes comprise the so-called Vitamin K cycle. One of the reasons why Vitamin K is rarely deficient in a human diet is because Vitamin K is continually recycled in our cells. Warfarin and other coumadin drugs block the action of the Vitamin K epoxide reductase. This results in decreased concentrations of Vitamin K and Vitamin K hydroquinone in the tissues, such that the carboxylation reaction catalyzed by the glutamyl carboxylase is inefficient. This results in the production of clotting factors with a greatly diminished or a complete absence of Gla. Without Gla on the amino termini of these factors, they no longer stablely bind to the blood vessel endothelium and cannot activate clotting to allow formation of a clot during tissue injury. As administration of Warfarin to a patient suppresses the clotting response, it must be carefully monitored to avoid over-dosing. See Warfarin. At present, the following human Gla-containing proteins have been characterized to the level of primary structure: the blood coagulation factors II (prothrombin), VII, IX, and X, the anticoagulant proteins C and S, and the Factor X-targeting protein Z. The bone Gla-protein osteocalcin, the calcification inhibiting matrix gla protein (MGP), the cell growth regulating growth arrest specific gene 6 protein (Gas6), and the four transmembrane Gla proteins (TMGPs) the function of which is at present unknown. Gas6 can function as a growth factor that activates the Axl receptor tyrosine kinase and stimulates cell proliferation or prevents apoptosis in some cells. In all cases in which their function was known, the presence of the Gla-residues in these proteins turned out to be essential for functional activity. Gla-proteins are known to occur in a wide variety of vertebrates: mammals, birds, reptiles, and fish. The venom of a number of Australian snakes acts by activating the human blood clotting system. Remarkably, in some cases activation is accomplished by snake Gla-containing enzymes that bind to the endothelium of human blood vessels and catalyze the conversion of procoagulant clotting factors into activated ones, leading to unwanted and potentially deadly clotting. Another interesting class of invertebrate Gla-containing proteins is synthesized by the fish-hunting snail Conus geographus. These snails produce a venom containing hundreds of neuro-active peptides, or conotoxins, which is sufficiently toxic to kill an adult human. Several of the conotoxins contain 2-5 Gla residues. Many bacteria, such as Escherichia coli found in the large intestine, can synthesize Vitamin K2 (menaquinone), but not Vitamin K1 (phylloquinone). In these bacteria, menaquinone will transfer two electrons between two different small molecules, in a process called anaerobic respiration. For example, a small molecule with an excess of electrons (also called an electron donor) such as lactate, formate, or NADH, with the help of an enzyme, will pass two electrons to a menaquinone. The menaquinone, with the help of another enzyme, will in turn transfer these 2 electrons to a suitable oxidant, such fumarate or nitrate (also called an electron acceptor). Adding two electrons to fumarate or nitrate will convert the molecule to succinate or nitrite + water, repectively. Some of these reactions generate a cellular energy source, ATP, in a manner similar to eukaryotic cell aerobic respiration, except that the final electron acceptor is not molecular oxygen, but say fumarate or nitrate (In aerobic respiration, the final oxidant is molecular oxygen (O2) , which accepts four electrons from an electron donor such as NADH to be converted to water.) Escherichia coli can carry out aerobic respiration and menaquninone-mediated anaerobic respiration.

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# Vitamin O Vitamin O is a dietary supplement, which has been marketed and sold by Rose Creek Health Products Inc. since 1998. It is not recognized by nutritional science as a vitamin. It has been claimed that taking the supplement has a beneficial effect on a wide variety of ailments, including angina, anaemia, and various forms of cancer, as well as increasing vigour and improving state of mind. The given reason for this is that vitamin O is "a special supplemented oxygen taken in liquid form and produced through electrical-activation with a saline solution from the ocean," and that the substance increases the amount of oxygen present in the blood. This would in turn promote cellular oxygen uptake. As a result of the Dietary Supplement Health and Education Act, the product could be sold without approval by the Food and Drug Administration, provided claims were never made by the producers of the supplement about its medical efficacy. Rose Creek complied, instead collecting statements from users who attributed wide-ranging benefits to taking it. However, later ads also ran statements from "experts", who provided anecdotal evidence from small-scale clinical trials showing positive results in several patients. Because of this, the Federal Trade Commission filed an injunction in March 1999 against Rose Creek Health Products Inc., stating that the ads being run in both print and online sources, including USA Today, were "blatantly false". Studies run on vitamin O showed it to be composed largely of salt water as well as a small quantity of germanium, which would provide no benefits not attributable to the placebo effect. On April 28 2000, Donald L. Smyth, CEO of Rose Creek Health Products Inc., agreed to pay a cash settlement of $375,000 for consumer redress, and to abstain from making claims as to the scientific accuracy of beneficial effects attributed to the supplement, or promoting its efficacy in treating life-threatening illnesses.

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/index.php/Vitamin_poisoning

# Vitamin poisoning Vitamin poisoning, or hypervitaminosis, refers to a condition of high storage levels of vitamins, which can lead to toxic symptoms. The medical names of the different conditions are derived from the vitamin involved: an excess of vitamin A, for example, is called "hypervitaminosis A". High dosage vitamin A; high dosage, slow release vitamin B3; and very high dosage vitamin B6 alone (i.e. without vitamin B complex) are sometimes associated with vitamin side effects that usually rapidly cease with supplement reduction or cessation. Conversely, certain vitamins do not produce toxicity in excess levels. Vitamin C has been used in dosages over 100,000 mg for serious illness — over 1000 times the daily recommended intake — without ill effects. However, Vitamin C does have a pronounced laxative effect, typically when intake of vitamin C is in the range of 5-20 grams per day for a person in normal "good health". High doses of mineral supplements can also lead to side effects and toxicity. Mineral-supplement poisoning does occur occasionally due to excessive and unusual intake of iron-containing supplements, including some multivitamins, but is not common. Death by vitamin poisoning appears to be quite rare in the US, typically none in a given year. However before 1998, several deaths per year were typically associated with pharmaceutical iron-containing supplements, especially brightly-colored, sugar-coated, high-potency iron supplements, and most deaths were children. Unit packaging restrictions on supplements with more than 30 mg iron have since reduced deaths to 0 or 1 per year. These statistics compare with 59 deaths due to aspirin poisoning in 2003, 147 deaths associated with acetaminophen-containing products in 2003, and an average of 54 deaths per year due to lightning for 1990-2003.

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/index.php/Vitelliform_macular_dystrophy

# Vitelliform macular dystrophy Vitelliform macular dystrophy or vitelliform dystrophy is a genetic eye disorder that can cause progressive vision loss. This disorder affects the retina, specifically cells in a small area near the center of the retina called the macula. The macula is responsible for sharp central vision, which is needed for detailed tasks such as reading, driving, and recognizing faces. Vitelliform macular dystrophy causes a fatty yellow pigment (lipofuscin) to build up in cells underlying the macula. Over time, the abnormal accumulation of this substance can damage cells that are critical for clear central vision. As a result, people with this disorder often lose their central vision and may experience blurry or distorted vision. Vitelliform macular dystrophy does not affect side (peripheral) vision or the ability to see at night. Researchers have described two forms of vitelliform macular dystrophy with similar features. The early-onset form (known as Best disease) usually appears in childhood; however, the onset of symptoms and the severity of vision loss vary widely. The adult-onset form begins later, usually in middle age, and tends to cause relatively mild vision loss. The two forms of vitelliform macular dystrophy each have characteristic changes in the macula that can be detected during an eye examination. Mutations in the RDS and VMD2 genes cause vitelliform macular dystrophy. Mutations in the VMD2 gene are responsible for Best disease. Changes in either the VMD2 or RDS gene can cause the adult-onset form of vitelliform macular dystrophy; however, less than a quarter of cases result from mutations in these two genes. In most cases, the cause of the adult-onset form is unknown. The VMD2 gene provides instructions for making a protein called bestrophin. Although its exact function is uncertain, this protein likely acts as a channel that controls the movement of negatively charged chlorine atoms (chloride ions) into or out of cells in the retina. Mutations in the VMD2 gene probably lead to the production of an abnormally shaped channel that cannot regulate the flow of chloride. Researchers have not determined how these malfunctioning channels are related to the buildup of lipofuscin in the macula and progressive vision loss. The RDS gene provides instructions for making a protein called peripherin. This protein is essential for the normal function of light-sensing (photoreceptor) cells in the retina. Mutations in the RDS gene disrupt the structures in these cells that contain light-sensing pigments, leading to vision loss. It is unclear why RDS mutations affect only central vision in people with adult-onset vitelliform macular dystrophy. Best disease is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person has one parent with the condition. The inheritance pattern of adult-onset vitelliform macular dystrophy is uncertain. Some studies have suggested that it may be inherited in an autosomal dominant pattern. Many affected people, however, have no history of the disorder in their family and only a small number of affected families have been reported.

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/index.php/Vitelline_arteries

# Vitelline arteries The vitelline arteries is the arterial counterpart to the vitelline veins. Like the veins, it plays an important role in the vitelline circulation of blood to and from the yolk sac. It is a branch of the dorsal aorta.

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/index.php/Vitelline_veins

# Vitelline veins They unite on the ventral aspect of the canal, and beyond this are connected to one another by two anastomotic branches, one on the dorsal, and the other on the ventral aspect of the duodenal portion of the intestine, which is thus encircled by two venous rings; into the middle or dorsal anastomosis the superior mesenteric vein opens. The portions of the veins above the upper ring become interrupted by the developing liver and broken up by it into a plexus of small capillary-like vessels termed sinusoids. The vessels draining the plexus into the sinus venosus are termed the venae revehentes, and form the future hepatic veins. Ultimately the left vena revehens no longer communicates directly with the sinus venosus, but opens into the right vena revehens.

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/index.php/Vitellogenin

# Vitellogenin Vitellogenin (Vg) (from latin vitellus = yolk and gener = to produce) is a synonymous term for the gene and the expressed protein. The molecule is classified as a glyco-lipo-protein, having properties of a sugar, fat and protein. Vitellogenin is an egg yolk precursor protein expressed in female fish, dormant in male fish and female insects. In the presence of estrogenic endocrine disruptive chemicals (EDCs), males can express the Vg gene in a dose dependent manner. The use of Vg gene expression in male fish can be used as a molecular marker of exposure to estrogenic EDCs. Honey bees deposit vitellogenin in fat bodies in their abdomen and heads. The fat bodies apparently acts as a food storage reservoir. The glycolipoprotein vitellogenin has additional functionality as it acts as an antioxidant to prolong Queen bee and forager lifespan as well as a hormone that affects future foraging behavior. The health of a honey bee colony is dependent upon the vitellogenin reserves of the nurse bees - the foragers have low levels of vitellogenin. As expendable laborers the foragers are fed just enough protein to keep them working their risky task of collecting nectar and pollen. Vitellogenin is important during the nest stage and thus for worker division of labor. A nurse bees vitellogenin titer that developed in the first four days after emergence, affects its subsequent age to begin foraging and whether it preferentially forages for nectar or pollen. If young workers are short on food their first days of life, they tend to begin foraging early and preferentially for nectar. If they are moderately fed, they forage at normal age preferentially for nectar. If they are abundantly fed, immediately after emergence, their vitellogenin titer is high and they begin foraging later in life, preferentially collecting pollen, which is the only available protein source for honey bees. Vitellogenin is part of a regulatory feedback loop that enables vitellogenin and juvenile hormone to mutually suppress each other. Vitellogenin and juvenile hormone work antagonistically in the honey bee to regulate their development and behavior. Suppression of one leads to high titers of the other. It is likely that the balance between vitellogenin and juvenile hormone levels is also involved in swarming behavior. Juvenile hormone levels drop pre-swarming and it is expected that vitellogenin levels would therefore rise. Swarming bees would want to pack along as much vitellogenin as possible to extend their lifespan and to be able to quickly build a new nest.

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/index.php/Vitiligo

# Vitiligo Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. , Alonso Alvarado, M.D. ,João André Alves Silva, M.D. , Guillermo Rodriguez Nava, M.D. , Jesus Rosario Hernandez, M.D.

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/index.php/Vitiligo_causes

# Vitiligo causes Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison's disease, hyperthyroidism, alopecia areata and pernicious anemia supports the hypothesis that vitiligo is due to an autoimmune process, but it should also be recognized that the majority of patients with vitiligo do not have any associated autoimmune disorder.

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/index.php/Vitiligo_classification

# Vitiligo classification ## Classification Vitiligo can be classified in two clinical subtypes; segmented vitiligo, which affects only 1 segment of the body (face, arm or leg) and non-segmented vitiligo, involving more than 1 segment, such as both knees or both hands.

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/index.php/Vitiligo_differential_diagnosis

# Vitiligo differential diagnosis There are numerous conditions that cause hypopigmentation from which vitiligo must be differentiated, and the most common are pityriasis alba, postinflammatory hypopigmentation, tinea versicolor, halo nevus, tuberous sclerosis and albinism.

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/index.php/Vitiligo_epidemiology_and_demographics

# Vitiligo epidemiology and demographics ## Epidemiology Autoimmune diseases and a family history of vitiligo are considered risk factors for developing this condition. A patient that has a relative with vitiligo has an 18 fold increased risk of developing the disease and having an earlier onset of the disease.

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/index.php/Vitiligo_historical_perspective

# Vitiligo historical perspective Human pigmentation diseases, such as vitiligo, have been described for over 3,000 years by different cultures around the world. Some famous texts, as the Eber Papyrus, Atharva Veda or even the Bible, provide a description of "white spotted-diseases" that could include cases of vitiligo. Celsus was the first to use the word "vitiligo" in the first century A.C. and Moriz Kaposi was one of the first to describe the histopathologic features of vitiligo.

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/index.php/Vitiligo_history_and_symptoms

# Vitiligo history and symptoms In the patient presenting for the first time with patches of skin depigmentation, a thorough history and physical examination should be performed, including examination under the Wood's lamp in order to rule out other potentially life-threatening disorders. The initial onset of the condition may be abrupt, however, afterwards it usually progresses slowly, with expansion of skin depigmentation with no concomitant symptoms. It is important to inquire about history of occupational exposures, since those may aggravate underlying vitiligo lesions or may lead to depigmentation areas, with no connection to the disease. There may be two major subdivisions of vitiligo which may influence the presence of different characteristics and the natural history of the disease. They may be present individually or concomitantly, in which case the segmental lesions will respond poorly to the treatment. Considering that halo nevi are more common in vitiligo patients than in the population in general, it is important to discuss personal or family history of such. This is an important step since existence of multiple halo nevi, is a common indicator of autoimmunity against the nevi, which increases the risk of vitiligo in the presence of history of disease in the family. It is also important to note the skin type of the patient. Since vitiligo is often associated with other autoimmune diseases, it is important to evaluate the presence of such during the consult: Unlike other diseases, vitiligo does not cause any physical symptoms. However, the depigmentation of the skin might have a psychological impact on the individual, leading to social isolation and eventually depression.

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/index.php/Vitiligo_laboratory_findings

# Vitiligo laboratory findings There are no laboratory abnormalities in vitiligo disease. Consideration should be given to ordering laboratory studies to exclude the presence of other associated conditions such as pernicious anemia, Addison's disease and thyroid disease. Despite the absence of laboratory changes in vitiligo disease, it may be associated with other autoimmune diseases. Adequate laboratory tests to evaluate presence of diseases such as hyper/hypothyroidism, diabetes mellitus and pernicious anemia, include:

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/index.php/Vitiligo_medical_therapy

# Vitiligo medical therapy ## Medical Therapy Potent topical corticosteroids (mometasone) and topical calcineurin inhibitors are first-line therapy to achieve repigmentation of vitiligo lesions. Phototherapy has been proven effective for the treatment of generalized vitiligo. Combined treatment with both topical calcineurin inhibitors plus phototherapy have proven more effective in achieving repigmentation in a shorter period of time than single treatments.

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/index.php/Vitiligo_natural_history,_complications_and_prognosis

# Vitiligo natural history, complications and prognosis The natural history of vitiligo is variable. Depigmentation may be stable or progressive and can cause even a total body depigmentation or remit spontaneously, although spontaneous remission is uncommon.

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/index.php/Vitiligo_other_diagnostic_studies

# Vitiligo other diagnostic studies Although not performed routinely, since the diagnosis of vitiligo is often reached by a thorough history assessment and physical examination, a biopsy of the lesion may show microscopical changes undergoing on the hypopigmented region. Frequently not required, since the diagnosis is often suggested by the history and characteristics of the lesions. However, an electron microscopy study of the skin lesions will show the previously mentioned microscopical changes, thereby confirming:

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/index.php/Vitiligo_overview

# Vitiligo overview Vitiligo (IPA Template:IPA) or leukoderma is a chronic skin condition that causes loss of pigment, resulting in irregular pale patches of skin. The cause of vitiligo is complex, may be multifactorial, and is not fully understood. There is some evidence suggesting it is caused by a combination of auto-immune, genetic, and environmental factors. Vitiligo is the most common depigmenting disease with a worldwide incidence of 1%. Vitiligo can be classified in two clinical subtypes. One is segmented vitiligo, which affects only 1 segment of the body (face, arm or leg); and non-segmented vitiligo, involving more than 1 segment, such as both knees or both hands. Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison's disease, hyperthyroidism, alopecia areata and pernicious anemia supports this hypothesis, but it should also be recognized that the majority of patients with vitiligo do not have any autoimmune disorder. Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. Vitiligo is the most common human pigmentation disorder, with a prevalence of 1,000/100,000 (1%) of the population. Males and females are equally affected. Half of patients are diagnosed before the age of 20. The natural history of vitiligo is variable. Depigmentation may be stable or progressive and can cause even a total body depigmentation or remit spontaneously, although spontaneous remission is uncommon. Vitiligo is a chronic skin condition that causes loss of pigment, resulting in irregular pale patches of skin that may be distributed according to different patterns.

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/index.php/Vitiligo_pathophysiology

# Vitiligo pathophysiology Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison's disease, hyperthyroidism, alopecia areata and pernicious anemia supports this hypothesis, but it should also be recognized that the majority of patients with vitiligo do not have any autoimmune disorder. Among 656 people with and without vitiligo in 114 families, several mutations (single-nucleotide polymorphisms) were identified in the NALP1 gene. The NALP1 gene, which is on chromosome 17 located at 17p13, is on a cascade that regulates inflammation and cell death, including myeloid and lymphoid cells. NALP1 is expressed at high levels in T cells and Langerhan's cells, white cells that are involved in skin autoimmunity. Among the inflammatory products of NALP1 are caspase 1 and caspase 5, which activate the inflammatory cytokine interleukin-1β. Interleukin-1β is expressed at high levels in patients with vitiligo. Of the 656 people, 219 had vitiligo only, 70 had vitiligo with autoimmune thyroid disease, and 60 had vitiligo and other autoimmune diseases. Addison's disease (typically an autoimmune destruction of the adrenal glands) may be associated with vitiligo as well. In one of the mutations, the amino acid leucine in the NALP1 protein was replaced by histidine (Leu155->His). The original protein and sequence is highly conserved in evolution, and found in humans, chimpanzee, rhesus monkey, and the bush baby, which means that it's an important protein and an alteration is likely to be harmful. The normal sequence of the DNA code for NALP1 of TCACTCCTCTACCAA is replaced in some of these vitiligo families by the sequence TCACACCTCTACCAA, which respectively code for the amino acid sequence of the normal NALP1 protein SLLYQ being replaced by SHLYQ. Histological examination typically shows an absence of melanocytes in the affected areas of the skin. However, it is possible to sometimes identify degenerating melanocytes at the borders of the affected areas. In these patients, normal melanocytes may be found in normal skin areas yet, even in these regions, changes such as abnormal keratinocytes may be found, showing evidence of vacuolated cytoplasm in the basal layers of cells as well as granular extracellular materials. In certain situations it is possible to identify lymphocytic infiltrates on the margin of the lesions, which is consistent with the underlying immunological mechanism, responsible for the destruction of the melanocytes.

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/index.php/Vitiligo_physical_examination

# Vitiligo physical examination After adequate evaluation of the skin of vitiligo patients, the hypopigmented lesions should also be evaluated in a dark room, under the Wood's light. This is a source of UVA light that allows the evaluation of the skin areas with depigmentation, enhancing the details and tones of these areas. Areas such as axillae and genitalia should be evaluated carefully, since these are frequently involved regions that may be missed without this test. According to the type of vitiligo presented by the patient, there may be different findings on the physical examination, which may be considered characteristic of that specific type of the disease. These may include:

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/index.php/Vitiligo_risk_factors

# Vitiligo risk factors A family history of vitiligo is associated with an 18 fold increase in the risk and the early onset of the disease. The presence of autoimmune diseases in a patient is also considered a risk factor for developing vitiligo. There is an increased risk for developing vitiligo in patients with close relatives in whom the disease is present. The frequency of vitiligo in patients with a positive family history is up to 18 times more than someone with a negative family history. These patients also have an earlier onset of the disease.

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/index.php/Vitreous_humour

# Vitreous humour The vitreous humour (British spelling) or vitreous humor (U.S. spelling) is the clear gel that fills the space between the lens and the retina of the eyeball of humans and other vertebrates. It is often referred to as the vitreous body or simply "the vitreous". The vitreous is 99% water, but has a viscosity two to four times that of pure water, giving it a gelatinous consistency. Other components include salts, sugars, phagocytes, and a network of collagen fibres. Thus, unlike water, it has a refractive index of 1.336 . The phagocytic cells in the vitreous serve to remove unwanted debris in the visual field. The primary purpose of the vitreous humour is to provide structural support to the eyeball while offering a clear unobstructed path for light to reach the retina. The vitreous is also believed to function as a barrier to the forward diffusion of oxygen from the retinal blood supply to the anterior segment of the eye, where it can cause oxidation damage to the lens. Since the vitreous does not regenerate after being removed from the eye (a procedure known as vitrectomy, which is usually performed to allow surgical access to the posterior segment of the eye), early cataract is a frequent complication of retinal surgery. The collagen fibres of the vitreous are held apart by electrical charges. With aging, these charges tend to reduce, and the fibres may clump together. Similarly, the gel may liquefy, a condition known as syneresis, leading to cells and other organic clusters to float freely within the vitreous humour. These commonly lead to floaters which are perceived in the visual field as spots or fibrous strands. Floaters are generally harmless, but the sudden onset of recurring floaters may signify a posterior vitreous detachment (PVD) or other diseases of the eye. The metabolic exchange and equilibration between systemic circulation and vitreous humour is so slow that vitreous humour is sometimes the fluid of choice for postmortem analysis of glucose levels or substances which would be more rapidly diffused, degraded, excreted, or metabolised from the general circulation.

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/index.php/Vitronectin

# Vitronectin Vitronectin (VTN or VN) is a glycoprotein of the hemopexin family which is abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the VTN gene. Vitronectin binds to integrin alpha-V beta-3 and thus promotes cell adhesion and spreading. It also inhibits the membrane-damaging effect of the terminal cytolytic complement pathway and binds to several serpins (serine protease inhibitors). It is a secreted protein and exists in either a single chain form or a clipped, two chain form held together by a disulfide bond. Vitronectin has been speculated to be involved in hemostasis and tumor malignancy. Vitronectin is a 75 kDa glycoprotein, consisting of 459 amino acid residues. About one-third of the protein's molecular mass is composed of carbohydrates. On occasion, the protein is cleaved after arginine 379, to produce two-chain vitronectin, where the two parts are linked by a disulfide bond. No high-resolution structure has been determined experimentally yet, except for the N-terminal domain. Several structures has been reported for the Somatomedin B domain. The protein was initially crystallized in complex with one of its physiological binding partners: the Plasminogen activator inhibitor-1 (PAI-1) and the structure solved for this complex. Subsequently two groups reported NMR structures of the domain. The somatomedin B domain is a close-knit disulfide knot, with 4 disulfide bonds within 35 residues. Different disulfide configurations had been reported for this domain but this ambiguity has been resolved by the crystal structure. The somatomedin B domain of vitronectin binds to plasminogen activator inhibitor-1 (PAI-1), and stabilizes it. Thus vitronectin serves to regulate proteolysis initiated by plasminogen activation. In addition, vitronectin is a component of platelets and is, thus, involved in hemostasis. Vitronectin contains an RGD (45-47) sequence, which is a binding site for membrane-bound integrins, e.g., the vitronectin receptor, which serve to anchor cells to the extracellular matrix. The Somatomedin B domain interacts with the urokinase receptor, and this interaction has been implicated in cell migration and signal transduction. High plasma levels of both PAI-1 and the urokinase receptor have been shown to correlate with a negative prognosis for cancer patients. Cell adhesion and migration are directly involved in cancer metastasis, which provides a probable mechanistic explanation for this observation.

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/index.php/Vivecon

# Vivecon Vivecon targets the gag polyprotein precursor, the main structural protein responsible for assembly and budding of virion particles. By binding to the gag polyprotein, vivecon prevents its cleavage by the protease enzyme into functional subunits. Unlike the protease inhibitors, vivecon binds the gag protein, not the protease enzyme. The resulting virus particles are structurally defective and are incapable of spreading infection through the body.

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/index.php/Vocal_fold_nodule

# Vocal fold nodule A vocal fold nodule (or "Nodules of vocal cords") is a nodule or mass of tissue that grows on the vocal folds (vocal cords). Typically this mass will appear on the anterior one-third of the vocal fold, where contact is most forceful. A vocal fold nodule reduces or obstructs the ability of the vocal folds to create the rapid changes in air pressure which generate human speech. Symptoms include hoarseness of speech, painful speech production, frequent vocal breaks and reduced vocal range. Females are most likely to develop nodules. The nodules appear as symmetric swellings on both sides of the vocal folds. The cause of these formations are usually strenuous or abusive voice practices such as yelling and coughing. Persons who are often susceptible are those who use their voice constantly in a loud environment. Examples include cheerleaders, politicians, teachers, musicians and in some instances Marine Corps drill instructors. The physical impact of having vocal fold nodules does not usually harm one's health, though it can impair one's speaking and singing ability. Perhaps more importantly are the psychological factors when the doctor informs the patient that he/she has nodules. Especially in those who use their voice in their profession (e.g. singers, actors, broadcasters) a nodule can significantly alter the quality of their speech and singing. Treatment usually involves vocal training, speech therapy, and, occasionally, vocal rest. In rare cases, surgery may be required. Removal of vocal fold nodules is a relatively safe and minor surgery. While the patient is subdued under general anesthesia, long thin scissors and knives are used to remove the nodules.

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/index.php/Vocal_folds

# Vocal folds The vocal folds, also known popularly as vocal cords, are composed of twin infoldings of mucous membrane stretched horizontally across the larynx. They vibrate, modulating the flow of air being expelled from the lungs during phonation. Open during inhalation, closed when holding one's breath, and vibrating for speech or singing (opening and closing 440 times per second when singing A above middle C); the folds are controlled via the vagus nerve. They are white because of scant blood circulation. The larynx is a major (but not the only) source of sound in speech, generating sound through the rhythmic opening and closing of the vocal folds. To oscillate, the vocal folds are brought near enough together such that air pressure builds up beneath the larynx. The folds are pushed apart by this increased subglottal pressure, with the inferior part of each fold leading the superior part. The natural resilience of the folds brings them back together. Under the correct conditions, this oscillation pattern will sustain itself. In essence, sound is generated in the larynx by chopping up a steady flow of air into little puffs. The pitch of a person's voice is a [percept] that is determined by a number of different factors, but largely by the fundamental frequency of the sound generated by the larynx. A person's natural fundamental frequency is influenced by many factors, including the length, size, and tension of the vocal folds. In an adult male, this frequency averages about 125 Hz, adult females around 210 Hz, in children the frequency is over 300 Hz. Men and women have different vocal fold sizes. Adult male voices are usually lower pitched and have larger folds. The male vocal folds (which would be measured vertically in the opposite diagram), are between 17 mm and 25 mm in length. Matching the female body, which on the whole has less muscle than the male, females have smaller folds. The female vocal folds are between 12.5 mm and 17.5 mm in length. The folds are located just above the trachea or the windpipe which travels from the lungs. Food and drink does not pass through the folds but is instead taken through the esophagus, an unlinked tube. Both tubes are separated by the tongue and an automatic gag reflex. When food goes down through the folds and trachea it causes choking. Folds in both sexes are ligaments within the larynx. They are attached at the back (side nearest the spinal cord) to the arytenoid cartilages, and at the front (side under the chin) to the thyroid cartilage. Their outer edges (as shown in the illustration) are attached to muscle in the larynx while their inner edges, or margins are free (the hole). They are constructed from epithelium, but they have a few muscle fibres on them, namely the vocalis muscle which tightens the front part of the ligament near to the thyroid cartilage. They are flat triangular bands and are pearly white in colour - whiter in females than they are in males. Above both sides of the vocal cord (the hole and the ligament itself) is the vestibular fold or false vocal fold, which has a small sac between its two folds (not illustrated). The difference in vocal fold size between men and women means that they have differently pitched voices. Additionally, genetics also causes variances amongst the same sex, with men's and women's voices being categorised into types. The term vocal cords is occasionally misspelled 'vocal chords', possibly due to the musical connotations or to confusion with the geometrical definition of the word "chord". The vocal folds discussed above are sometimes called 'true vocal folds' to distinguish them from the false vocal folds. These are a pair of thick folds of mucous membrane that sit just above, and protect, the more delicate true folds. They have minimal role in normal phonation, but are often used in musical screaming and the death grunt singing style.

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/index.php/Voglibose

# Voglibose Voglibose (INN and USAN) is an alpha-glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with diabetes mellitus. It is made in India by Ranbaxy Labs and sold under the trade name Volix. PPHG is termed as Post Prandial Hyperglycemia which is primarily due to first phase insulin secretion. Alpha glucosidase inhibitor is one agent which delays the glucose absorption at the intestine level and thereby prevents sudden surge of glucose post meal. There are three molecules which belong to this class namely, Acarbose, Miglitol and Voglibose. Voglibose is the latest molecule in this class. Voglibose scores over both Acarbose and MIglitol in terms of potency and side effect profile. There are several trials supporting the use of Voglibose in the management of PPHG. Also, it has been established that it is PPHG not FPG which is marker of cardiovascular disorders associated with diabetes. So, controlling PPHG is imperative and Voglibose is indicated for the management of PPHG.

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/index.php/Volatile_anaesthetic

# Volatile anaesthetic The volatile anaesthetics are a class of general anaesthetic drugs. They share the property of being liquid at room temperature, but evaporating easily for administration by inhalation (some experts make a distinction between volatile and gas anesthetics on this basis, but both are treated in this article, since they probably do not differ in mechanism of action). All of these agents share the property of being quite hydrophobic (i.e., as liquids, they are not freely miscible with in water, and as gases they dissolve in oils better than in water). The ideal volatile anaesthetic agent offers smooth and reliable induction and maintenance of general anaesthesia with minimal effects on other organ systems. In addition it is odourless or pleasant to inhale; safe for all ages and in pregnancy; not metabolised; rapid in onset and offset; potent; and safe for exposure to operating room staff. It is also cheap to manufacture; easy to transport and store, with a long shelf life; easy to administer and monitor with existing equipment; stable to light, plastics, metals, rubber and soda lime; non-flammable and environmentally safe. None of the agents currently in use is ideal, although many have some of the desirable characteristics. For example, sevoflurane is pleasant to inhale and is rapid in onset and offset. It is also safe for all ages. However, it is expensive (approximately 3 to 5 times more expensive than isoflurane), and approximately half as potent as isoflurane. Other gases or vapours which produce general anaesthesia by inhalation include nitrous oxide, cyclopropane and xenon. These are stored in cylinders and administered using flowmeters, rather than vaporisers. Cyclopropane is explosive and is no longer used for safety reasons, although otherwise it was found to be an excellent anesthetic. Xenon is odourless and extremely rapid in onset, but is extremely expensive and requires specialised equipment to administer and monitor. Nitrous oxide, even at 80% concentration, does not quite produce surgical level anesthesia in most persons, so it must be used as an adjunct anesthetic, along with other agents. Under hyperbaric conditions, other gasses such as krypton, argon, and nitrogen become anesthetics, although 1 to 1.5 MAC concentrations would not be achieved for nitrogen until pressures of about 20 to 30 atm (bar) . Argon is slightly more than twice as anesthetic as nitrogen per unit of partial pressure (see argox). The full mechanism of action of volatile anesthetic agents is unknown and has been the subject of intense debate. "Anesthetics have been used for 160 years, and how they work is one of the great mysteries of neuroscience," says anesthesiologist James Sonner of the University of California, San Francisco". Anesthesia research "has been for a long time a science of untestable hypotheses," notes Neil L. Harrison of Cornell University. "Most of the injectable anesthetics appear to act on a single molecular target," says Sonner. "It looks like inhaled anesthetics act on multiple molecular targets. That makes it a more difficult problem to pick apart." The possibility of anesthesia by the inert gas argon in particular (even at 10 to 15 bar) suggests that the mechanism of action of volatile anesthetics is an effect best described by physical chemistry, and not a chemical bonding action. However, the agent may bind to a receptor with a weak interaction . A physical interaction such as swelling of nerve cell membranes from gas solution in the lipid bilayer may be operative. Notably, the gases hydrogen, helium, and neon have not been found to have anesthetic properties at any pressure. Helium at high pressures produces nervous irritation ("anti-anesthesia"), suggesting that the anesthetic mechanism(s) may be operated in reverse by this gas (i.e., nerve membrane compression).

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/index.php/Volatile_organic_compound

# Volatile organic compound Volatile organic compounds (VOCs) are organic chemical compounds that have high enough vapour pressures under normal conditions to significantly vaporize and enter the atmosphere. (The term VOC is also occasionally used as an abbreviation, especially in biological contexts, for "volatile organic carbon".) A wide range of carbon-based molecules, such as aldehydes, ketones, and hydrocarbons are VOC's. The term often is used in a legal or regulatory context and in such cases the precise definition is a matter of law. These definitions can be contradictory and may contain "loopholes"; e.g. exceptions, exemptions, and exclusions. Others believe the concept that a volatile organic compound is any organic that participates in a photoreaction, as found in the EPA's definition, is very broad and vague. Organics that are not volatile, as described above, can fall into that definition. The term may refer both to well characterized organic compounds and to mixtures of variable composition. Most often the definition used is one from the United States Environmental Protection Agency (see below). The most common VOC is methane, a greenhouse gas sometimes excluded from analysis of other VOCs using the term non-methane VOCs, or NMVOCs. Major worldwide sources of atmospheric methane include wetlands, ruminants such as cows, energy use, rice agriculture, landfills, and burning biomass such as wood. Common artificial sources of VOCs include paint thinners, dry cleaning solvents, and some constituents of petroleum fuels (eg. gasoline and natural gas). Trees are also an important biological source of VOC; it is known that they emit large amounts of VOCs, especially isoprene and terpenes. Another significant source of VOC emission is crude oil tanking. Both during offloading and loading of crude oil tankers VOC are released to the atmosphere. Lately there has been an environmental focus on this issue resulting in both VOC handling on newer tankers and also crude oil loading terminals. Considered a factor in indoor air quality issues such as sick building syndrome, VOCs "are generated by photocopiers, carpets, and furnishings as they are used or when components oxidize.... One irritant, formeldahyde, present in hundreds of office components, including wood and laminated furniture, shelving, and wall covers. It also evaporates from paints, varnishes, and chemicals used for sealing and finishing walls." Tobacco smoke can contribute high levels of VOCs. VOCs including halogenide and sulfide are emitted through human respiration, and formeldahyde is emitted at a lower rate from the surface of the human body. VOCs are sometimes accidentally released into the environment, where they can damage soil and groundwater. Vapours of VOCs escaping into the air contribute to air pollution. VOCs are an important outdoor air pollutant. In this field they are often divided into the separate categories of methane (CH4) and non-methane (NMVOCs). Methane is an extremely efficient greenhouse gas which contributes to enhanced global warming. Other hydrocarbon VOCs are also significant greenhouse gases via their role in creating ozone and in prolonging the life of methane in the atmosphere, although the effect varies depending on local air quality. Within the NMVOCs, the aromatic compounds benzene, toluene and xylene are suspected carcinogens and may lead to leukemia through prolonged exposure. 1,3-butadiene is another dangerous compound which is often associated with industrial uses. Some VOCs also react with nitrogen oxides in the air in the presence of sunlight to form ozone. Although ozone is beneficial in the upper atmosphere because it absorbs UV thus protecting humans, plants, and animals from exposure to dangerous solar radiation, it poses a health threat in the lower atmosphere by causing respiratory problems. In addition high concentrations of low level ozone can damage crops and buildings. Many VOCs found around the house, such as paint strippers and wood preservatives, contribute to sick building syndrome because of their high vapour pressure. VOC's are often used in paint, carpet backing, plastics, and cosmetics. The United States Environmental Protection Agency (EPA) has found concentrations of VOCs in indoor air to be 2 to 5 times greater than in outdoor air. During certain activities indoor levels of VOCs may reach 1,000 times that of the outside air. Not all organic compounds are volatile; many plastics (polymers) and other large molecules may not have significant vapor pressure at normal temperatures. There are a number of different ways to collectively refer to those chemical compounds that participate in photochemical reactions. That is, those that react with other pollutants, in the presence of sunlight, to form tropospheric ozone. While all these terms are used, it is not always clear which pollutants are included in each term. The term "VOC" has the advantage of having precise definitions codified by regulators such as the European Parliament and the US EPA. Worldwide, legal definitions of the term "VOC" are in many respects, more a matter of policy than a matter of science. For example, because the US EPA Code of Federal Regulations (CFR) has characterized a compound as having "negligible photochemical reactivity" it does not necessarily imply that it is, at any particular time, less reactive than those compounds which are not on the list. Since first establishing the list of exempt compounds in 1977, the EPA has added several to the list, and frequently has several petitions undergoing review. The traditional US standard to determine if a compound is a non-VOC is to compare its reactivity to that of ethane, which was the least reactive compound on the original list. Unfortunately, this is a very difficult comparison to make as it is frequently impossible to duplicate the real-world conditions in a laboratory. To complicate the issue, typical real-world conditions are different from day to day and from place to place. However, there is ongoing study on the use of a compound's reactivity as a better tool for pollution control regulation than the "is or isn't" approach currently in use. The U.S. Environmental Protection Agency definition of VOCs is published in the Code of Federal Regulations. It defines VOCs as "any compound of carbon, excluding carbon monoxide, carbon dioxide, carbonic acid, metallic carbides or carbonates, and ammonium carbonate, which participates in atmospheric photochemical reactions," but also includes a list of dozens of exceptions for compounds "determined to have negligible photochemical reactivity." Under European law, the definition of "VOC" is based on evaporation into the atmosphere, rather than reactivity. For example European Union Directive 2004/42/CE which covers VOC emissions from paints and varnishes defines a VOC as any organic compound having an initial boiling point less than or equal to 250°C measured at a standard atmospheric pressure of 101.3 kPa. Directive 94/63/EC which regulates VOC emissions from storage and distribution of petrol simply defines vapours as any gaseous compound which evaporates from petrol. The British coatings industry has adopted a VOC labelling scheme for all decorative coatings to inform customers about the levels of organic solvents and other volatile materials present. Coatings manufacturers use standard terminology, text and categories for all products. Information is provided according to five 'bands,' and manufacturers may label products with either a British Coatings Federation text box on the back panel, or a graphical globe symbol, the latter subject to licensing from with B&Q plc. Both styles of labels contain the same text, and warn that VOCs contribute to atmospheric pollution. Minimal - VOC content 0% to 0.29% Low - VOC content 0.3% to 7.99% Medium - VOC content 8% to 24.99% High - VOC content 25% to 50% Very High - VOC content more than 50% An example of text box labelling for the Minimal band is shown below, while examples of the graphical globe symbols may be seen on websites of some British coatings companies.

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/index.php/Volhard-Erdmann_cyclization

# Volhard-Erdmann cyclization The Volhard-Erdmann cyclization is an organic synthesis of alkyl and aryl thiophenes by cyclization of disodium succinate or other 1,4-difunctional compounds (γ-oxo acids, 1,4-diketones, chloroacetyl-substituted esters) with phosphorus heptasulfide.The reaction is named after Jacob Volhard and Hugo Erdmann.

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/index.php/Volney_Mathison

# Volney Mathison Dr. Volney G. Mathison was an American experimenter/hobbyist in early biofeedback, galvanic skin response technology, and psychogalvanometer (lie-detector machine) research in the 1940s and 1950s. He was also allegedly a chiropractor and an author of paranormal and science fiction books. Mathison discovered through experiments with early lie-detectors during the 1940s that when the subject was reminded of certain past events, the lie detector needle would fluctuate. He further determined that the degree of fluctuation was in direct proportion to the strength of the subject's reaction. It was Mathison's idea, by way of his study of Carl Jung's theories, to create a special lie-detector for examining unconscious and subconscious reactions rather than conscious ones. This notion, however pseudoscientific, was directly appropriated by fellow science fiction author L. Ron Hubbard, who enlisted Mathison to build similar devices for use in his still-developing concepts of Dianetics and Scientology. The devices were called Mathison E-meters, short for "electro-psychometer" or sometimes "electroencephaloneuromentimograph". Mathison and Hubbard's business relationship ended in the mid-1950s, when Hubbard, who already had coerced Mathison into giving him exclusive rights to the device, now urged Mathison to transfer complete ownership of the patent. He refused. Hubbard discontinued use of the E-meter and issued a statement that read in part: Four years later, in 1958, the E-Meter returned, but it was now called the Hubbard E-Meter, with only slight modifications to the design having been made by Don Breeding and Joe Wallis. E-meters once again became an essential part of Scientology's Auditing (Scientology) process, and no further mention was made of the four-year period in which Hubbard had disavowed it. Mathison authored a Science Fiction novel called Radiobuster, and also published many non-fiction books over the years on various topics, some less scientific than others:

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/index.php/Volociximab

# Volociximab Volociximab (also known as M200) is a chimeric monoclonal antibody jointly developed by PDL BioPharma and Biogen Idec for treatment of a variety of advanced solid tumors. It binds to and inhibits the functional activity of α5β1 integrin.

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/index.php/Voltage-gated_calcium_channel

# Voltage-dependent calcium channel Voltage-dependent calcium channels (VDCC) are a group of voltage-gated ion channels found in excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the ion Ca2+. At physiologic or resting membrane potential, VDCCs are normally closed. They are activated (i.e., opened) at depolarized membrane potentials and this is the source of the "voltage-dependent" epithet. Activation of particular VDCCs allows Ca2+ entry into the cell, which depending on the cell type, results in muscular contraction, excitation of neurons, up-regulation of gene expression, or release of hormones or neurotransmitters. Voltage-dependent calcium channels are formed as a complex of several different subunits: α1, α2δ, β1-4, and γ. The α1 subunit forms the ion conducting pore while the associated subunits have several functions including modulation of gating. There are several different kinds of high-voltage-gated calcium channels (HVGCCs). They are structurally homologous among varying types; they are all similar, but not structurally identical. In the laboratory, it is possible to tell them apart by studying their physiological roles and/or inhibition by specific toxins. High-voltage-gated calcium channels include the neural N-type channel blocked by ω-conotoxinGVIA, the R-type channel (R stands for Resistant to the other blockers and toxins) involved in poorly defined processes in the brain, the closely related P/Q-type channel blocked by ω-agatoxins, and the dihydropyridine-sensitive L-type channels responsible for excitation-contraction coupling of skeletal, smooth, and cardiac muscle and for hormone secretion in endocrine cells. The α1 subunit pore (~190 kDa in molecular mass) is the primary subunit necessary for channel functioning in the HVGCC, and consists of the characteristic four homologous I-IV domains containing six transmembrane α-helices each. The α1 subunit forms the Ca2+ selective pore, which contains voltage-sensing machinery and the drug/toxin-binding sites. A total of ten α1 subunits that have been identified in humans: The α2δ gene forms two subunits α2 and δ (which are both the product of the same gene). They are linked to each other via a disulfide bond and have a combined molecular weight of 170 kDa. The α2 is the extracellular glycosylated subunit that interacts the most with the α1 subunit. The δ subunit has a single transmembrane region with a short intracellular portion, which serves to anchor the protein in the plasma membrane. There are 4 α2δ genes: Co-expression of the α2δ enhances the level of expression of the α1 subunit and causes an increase in current amplitude, faster activation and inactivation kinetics and a hyperpolarizing shift in the voltage dependence of inactivation. Some of these effects are observed in the absence of the beta subunit, whereas, in other cases, the co-expression of beta is required. The α2δ-1 and α2δ-2 subunits are the binding site for at least two anticonvulsant drugs, gabapentin (Neurontin) and pregabalin (Lyrica), that also find use in treating chronic neuropathic pain. The intracellular β subunit (55 kDa) is an intracellular MAGUK-like protein (Membrane-Associated Guanylate Kinase) containing a guanylate kinase (GK) domain and an SH3 (src homology 3) domain. The guanylate kinase domain of the β subunit binds to the α1 subunit I-II cytoplasmic loop and regulates HVGCC activity. There are four known isoforms of the β subunit: It is hypothesized that the cytosolic β subunit has a major role in stabilizing the final α1 subunit conformation and delivering it to the cell membrane by its ability to mask an endoplasmic reticulum retention signal in the α1 subunit. The endoplasmic retention brake is contained in the I-II loop in the α1 subunit that becomes masked when the β subunit binds. Therefore the β subunit functions initially to regulate the current density by controlling the amount of α1 subunit expressed at the cell membrane. In addition to this trafficking role, the β subunit has the added important functions of regulating the activation and inactivation kinetics, and hyperpolarizing the voltage-dependence for activation of the α1 subunit pore, so that more current passes for smaller depolarizations. The β subunit has effects on the kinetics of the cardiac α1C in Xenopus oocytes co-expressed with β subunits. The β subunit acts as an important modulator of channel electrophysiological properties. Until very recently, the interaction between a highly conserved 18-amino acid region on the α1 subunit intracellular linker between domains I and II (the Alpha Interaction Domain, AID) and a region on the GK domain of the β subunit (Alpha Interaction Domain Binding Pocket) was thought to be solely responsible for the regulatory effects by the β subunit. Recently, it has been discovered that the SH3 domain of the β subunit also gives added regulatory effects on channel function, opening the possibility of the β subunit having multiple regulatory interactions with the α1 subunit pore. Furthermore, the AID sequence does not appear to contain an endoplasmic reticulum retention signal, and this may be located in other regions of the I-II α1 subunit linker. The γ1 subunit is known to be associated with skeletal muscle VGCC complexes, but the evidence is inconclusive regarding other subtypes of calcium channel. The γ1 subunit glycoprotein (33 kDa) is composed of four transmembrane spanning helices. The γ1 subunit does not affect trafficking, and, for the most part, is not required to regulate the channel complex. However, γ2, γ3, γ4 and γ8 are also associated with AMPA glutamate receptors. When a smooth muscle cell is depolarized, it causes opening of the voltage-gated, or L-type, calcium channels. Depolarization may be brought about by stretching of the cell, agonist-binding its G protein-coupled receptor (GPCR), or autonomic nervous system stimulation. Opening of the L-type calcium channel causes infux of extracellular Ca2+, which then binds calmodulin. The activated calmodulin molecule activates myosin light-chain kinase (MLCK), which phosphorylates the myosin in thick filaments. Phosphorylated myosin is able to form crossbridges with actin thin filaments, and the smooth muscle fiber (i.e., cell) contracts via the sliding filament mechanism. (See reference for an illustration of the signaling cascade involving L-type calcium channels in smooth muscle). L-type calcium channels are also enriched in the t-tubules of striated muscle cells, i.e., skeletal and cardiac myofibers. When these cells are depolarized, the L-type calcium channels open as in smooth muscle. In skeletal muscle, the actual opening of the channel, which is mechanically gated to a calcium-release channel (a.k.a. ryanodine receptor, or RYR) in the sarcoplasmic reticulum (SR), causes opening of the RYR. In cardiac muscle, opening of the L-type caclium channel permits influx of calcium into the cell. The calcium binds to the calcium release channels (RYRs) in the SR, opening them; this phenomenon is called "calcium-induced calcium release," or CICR. However the RYRs are opened, either through mechanical-gating or CICR, Ca2+ is released from the SR and is able to bind to troponin C on the actin filaments. The muscles then contract through the sliding filament mechanism, causing shortening of sarcomeres and muscle contraction.

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/index.php/Voltage-gated_ion_channel

# Voltage-gated ion channel Voltage-gated ion channels are a class of transmembrane ion channels that are activated by changes in electrical potential difference near the channel; these types of ion channels are especially critical in neurons, but are common in many types of cells. All voltage gates contain repeating sequences of arginine that are responsible for the charged portion of the domain. They have a crucial role in excitable neuronal and muscle tissues, allowing a rapid and coordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. They generally are composed of several subunits arranged in such a way that there is a central pore through which ions can travel down their electrochemical gradients. The channels tend to be quite ion-specific, although similarly sized and charged ions may also travel through them to some extent. From crystallographic structural studies of a potassium channel, assuming that this structure remains intact in the corresponding plasma membrane, it is possible to surmise that when a potential difference is introduced over the membrane, the associated electromagnetic field induces a conformational change in the potassium channel. The conformational change distorts the shape of the channel proteins sufficiently such that the cavity, or channel, opens to admit ion influx or efflux to occur across the membrane, down its electrochemical gradient. This subsequently generates an electrical current sufficient to depolarise the cell membrane. Voltage-gated sodium channels and calcium channels are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning alpha helices. One of these helices, S4, is the voltage sensing helix. It has many positive charges such that a high positive charge outside the cell repels the helix - inducing a conformational change such that ions may flow through the channel. Potassium channels function in a similar way, with the exception that they are composed of four separate polypeptide chains, each comprising one domain. The voltage-sensitive protein domain of these channels (the "voltage sensor") generally contains a region composed of S3b and S4 helices, known as the "paddle" due to its shape, which appears to be a conserved sequence, interchangable across a wide variety of cells and species. Genetic engineering of the paddle region from a species of volcano-dwelling archaebacteria into rat brain potassium channels results in a fully functional ion channel, as long as the whole intact paddle is replaced. This "modularity" allows use of simple and inexpensive model systems to study the function of this region, its role in disease, and pharmaceutical control of its behavior rather than being limited to poorly characterized, expensive, and/or difficult to study preparations.

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/index.php/Voltage-gated_potassium_channel

# Voltage-gated potassium channel Voltage-gated potassium channels are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. They play a crucial role during action potentials in returning the depolarized cell to a resting state. Alpha subunits form the actual conductance pore. Based on sequence homology of the hydrophobic transmembrane cores, the alpha subunits of voltage-gated potassium channels have been grouped into 12 classes labeled Kv1-12. The following is a list of the 40 known human voltage-gated potassium channel alpha subunits grouped first according to function and then subgrouped according to the Kv sequence homology classification scheme: Beta subunits are auxiliary proteins which associate with alpha subunits in a α4β4 stoichiometry. These subunits do not conduct current on their own but rather modulate the activity of Kv channels. Genetic approaches include screening for behavioral changes in animals with mutations in K+ channel genes. Such genetic methods allowed the genetic identification of the "Shaker" K+ channel gene in Drosophila before ion channel gene sequences were well known. Study of the altered properties of voltage-gated K+ channel proteins produced by mutated genes has helped reveal the functional roles of K+ channel protein domains and even individual amino acids within their structures. Voltage-gated K+ channels of vertebrates typically are tetramers of four identical subunits arranged as a ring, each contributing to the wall of the trans-membrane K+ pore. Each subunit is comprised of six membrane spanning hydrophobic α-helical sequences. A high resolution crystallographic structure of the rat Kvα1.2/β2 channel has recently been solved (Protein Databank Accession Number 2A79​). Voltage-gated K+ channels are selective for K+ over other cations such as Na+. There is a selectivity filter at the narrowest part of the transmembrane pore. Channel mutation studies revealed the parts of the subunits that are essential for ion selectivity. They include the amino acid sequence (Thr-Val-Gly-Tyr-Gly) or (Thr-Val-Gly-Phe-Gly) typical to the selectivity filter of voltage-gated K+ channels. As K+ passes through the pore, interactions between potassium ions and water molecules are prevented and the K+ interacts with specific atomic components of the Thr-Val-Gly-X-Gly sequences from the four channel subunits . Attempts continue to relate the structure of the mammalian voltage-gated K+ channel to its ability to respond to the voltage that exists across the membrane. Specific domains of the channel subunits have been identified that are important for voltage-sensing and converting between the open conformation of the channel and closed conformations. There are at least two closed conformations; in one, the channel can open if the membrane potential becomes positive inside. Voltage-gated K+ channels inactivate after opening, entering a distinctive, second closed conformation. In the inactivated conformation, the channel cannot open, even if the transmembrane voltage is favorable. A domain at one end of the K+ channel protein mediates inactivation. This end of the protein can transiently plug the inner opening of the pore, preventing ion movement through the channel.

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/index.php/Voltage_clamp

# Voltage clamp The voltage clamp is used by electrophysiologists to measure the ion currents across a neuronal membrane while holding the membrane voltage at a set level. Neuronal membranes contain many different kinds of ion channels, some of which are voltage gated. The voltage clamp allows the membrane voltage to be manipulated independently of the ionic currents, allowing the current-voltage relationships of membrane channels to be studied. The concept of the voltage clamp is due to Kenneth Cole and George Marmount in the 1940s. Cole discovered that it was possible to use two electrodes and a feedback circuit to keep the cell's membrane potential at a level set by the experimenter. Alan Hodgkin realized that, to understand ion flux across the membrane, it was necessary to eliminate differences in membrane potential. After experiments with the voltage clamp, Hodgkin and Andrew Huxley outlined the ionic causes of the action potential in 1952, for which they shared the Nobel Prize for Physiology or Medicine in 1963. The voltage clamp is a current generator with two electrodes. Transmembrane voltage is recorded through a "voltage electrode", relative to ground, and a "current electrode" passes current into the cell. The experimenter sets a "holding voltage", or "command potential", and the voltage clamp uses negative feedback to maintain the cell at this voltage. The electrodes are connected to an amplifier, which measures membrane potential and feeds the signal into a feedback amplifier. This amplifier also gets an input from the signal generator that determines the command potential, and it subtracts the membrane potential from the command potential (Vcommand - Vm), magnifies any difference, and sends an output to the current electrode. Whenever the cell deviates from the holding voltage, the operational amplifier generates an "error signal", that is the difference between the command potential and the actual voltage of the cell. The feedback circuit passes current into the cell to reduce the error signal to zero. Thus, the clamp circuit produces a current equal and opposite to the ionic current. This can be measured, giving an accurate reproduction of the currents flowing across the membrane. Cole developed the voltage clamp technique before the era of microelectrodes, so his two electrodes consisted of fine wires twisted around an insulating rod. Because this type of electrode could be inserted into only the largest cells, early electrophysiological experiments were conducted almost exclusively on squid axons. Squid squirt jets of water when they need to move quickly, as when escaping a predator. To make this escape as fast as possible, they have an axon that can reach 1 mm in diameter (signals propagate more quickly down large axons). The squid giant axon was the first preparation that could be used to voltage clamp a transmembrane current, and it was the basis of Hodgkin and Huxley's pioneering experiments on the properties of the action potential. A more detailed discussion of the below techniques can be found in the Axon Guide. The book is now out of print but can be downloaded in PDF form from Axon Instruments. This works on the same principle, but the two electrodes are glass pipettes with very fine tips (smaller than 1 micrometer), allowing for clamping of cells smaller than the squid axon. However, microelectrodes are much poorer conductors than the wires used by Cole, and sometimes cannot pass current rapidly enough to compensate for cellular current. The faster the kinetics of the current (onset and offset), the more likely it is that the clamp will be unable to "follow" it faithfully. Another disadvantage involves "space clamp" issues. Cole's voltage clamp used a long wire that clamped the squid axon uniformly along its entire length. Microelectrodes can provide only a spatial point source of current that might not uniformly affect different parts of an irregularly shaped cell. The "patch-clamp" technique allows the study of individual ion channels. It uses an electrode with a relatively large tip (> 1 micrometer) which has a smooth surface (rather than a sharp tip). This is a "patch-clamp electrode" (as distinct from a "sharp electrode" used to impale cells). This electrode is pressed against a cell membrane and suction is applied to pull the cell's membrane inside the electrode tip. The suction causes the cell to form a tight seal with the electrode (a "gigaohm seal", as the resistance is more than a gigaohm). 1) Microelectrodes are imperfect conductors; they generally have a resistance of more than a million ohms. They rectify (i.e. change their resistance with voltage, often in an irregular manner), they sometimes have unstable resistance if clogged by cell contents. Thus they will not faithfully record the voltage of the cell, especially when it is changing quickly, nor will they faithfully pass current. 2) Voltage and current errors: SEV-c circuitry does not actually measure the voltage of the cell being clamped (as does a two-electrode clamp). The patch-clamp amplifier is like a two-electrode clamp, except the voltage measuring and current passing circuits are connected (in the two-electrode clamp, they are connected through the cell). The electrode is attached to a wire that contacts the current/voltage loop inside the amplifier. Thus the electrode has only an indirect influence on the feedback circuit. The amplifier reads only the voltage at the top of the electrode, and feeds back current to compensate. But, if the electrode is an imperfect conductor, the clamp circuity has only a distorted view of the membrane potential. Similarly, when the circuit passes back current to compensate for that (distorted) voltage, the current will be distorted by the electrode before it reaches the cell. To compensate for this, the electrophysiologist uses the lowest resistance electrode possible, makes sure that the electrode characteristics don't change during an experiment (so the errors will be constant), and avoids recording currents with kinetics likely to be too fast for the clamp to follow accurately. The accuracy of SEV-c goes up the slower and smaller are the voltage changes it is trying to clamp. 3) Series resistance errors: The currents passed to the cell must go to ground to complete the circuit. The voltages are recorded by the amplifier relative to ground. When a cell is clamped at its natural resting potential, there is no problem; the clamp is not passing current and the voltage is being generated only by the cell. But when clamping at a different potential, series resistance errors become a concern; the cell will pass current across its membrane in an attempt to return to its natural resting potential. The clamp amplifier opposes this by passing current to maintain the holding potential. A problem arises because the electrode is between the amplifier and the cell, i.e. the electrode is in series with the resistor that is the cell's membrane. Thus, when passing current through the electrode and the cell, Ohm's Law tells us that this will cause a voltage to form across both the cell's and the electrode's resistance. As these resistors are in series, the voltage drops will add. If the electrode and the cell membrane have equal resistances (which they usually do not), and if the experimenter command a 40mV change from the resting potential, the amplifier will pass enough current until it reads that it has achieved that 40mV change. However, in this example, half of that voltage drop is across the electrode. The experimenter thinks he or she has moved the cell voltage by 40mV, but has moved it only by 20mV. The difference is the "series resistance error". Modern patch-clamp amplifiers have circuity to compensate for this error, but these compensate only 70-80% of it. The electrophysiologist can further reduce the error by recording at or near the cell's natural resting potential, and by using as low a resistance electrode as possible. 4) Capacitance errors. Microelectrodes are capacitors, and are particularly troublesome because they are non-linear. The capacitance arises because the electrolyte inside the electrode is separated by an insulator (glass) from the solution outside. This is, by definition and function, a capacitor. Worse, as the thickness of the glass changes the farther you get from the tip, the time constant of the capacitor will vary. This produces a distorted record of membrane voltage or current whenever they are changing. Amplifiers can compensate for this, but not entirely because the capacitance has many time-constants. The experimenter can reduce the problem by keeping the cell's bathing solution shallow (exposing less glass surface to liquid) and by coating the electrode with silicone, resin, paint, or another substance that will increase the distance between the inside and outside solutions. 5) Space clamp errors. A single electrode is a point source of current. In distant parts of the cell, the current passed through the electrode will be less influential than at nearby parts of the cell. This is particularly a problem when recording from neurons with elaborate dendritic structures. There is nothing one can do about space clamp errors except to temper the conclusions of the experiment. A single-electrode voltage clamp — discontinuous, or SEVC-d, has some advantages over SEVC-c for "whole-cell" recording. In this, a different approach is taken for passing current and recording voltage. An SEVC-d amplifier oscillates between passing current and measuring voltage. One oscillation is a "duty cycle". During a cycle, the amplifier measures the membrane potential and compares it with the holding potential. An operational amplifier measures the difference, and generates an error signal. This current is a mirror image of the current generated by the cell. The amplifier outputs feature sample and hold circuits, so each briefly sampled voltage is then held on the output until the next measurement in the next cycle. Specifically, the amplifier measures voltage in the first few milliseconds of the cycle, generates the error signal, and spends the rest of the cycle passing current to reduce that error. At the start of the next cycle, voltage is measured again, a new error signal generated, current passed etc. The experimenter sets the cycle length, and it is possible to sample every 500-333 microseconds. For this to work, the cell capacitance must be higher than the electrode capacitance by at least an order of magnitude. Capacitance slows the kinetics (the rise and fall times) of currents. If the electrode capacitance is much less than that of the cell, then when current is passed through the electrode, the electrode voltage will change faster than the cell voltage. Thus when you inject current and then turn it off (at the end of a duty cycle), the electrode voltage will decay faster than the cell voltage. As soon as the electrode voltage asymptotes to the cell voltage, the voltage can be sampled (again) and the next bolus of current applied. Thus the frequency of the duty cycle is limited to the speed at which the electrode voltage rises and decays while passing current. The lower the electrode capacitance, the faster one can cycle. SEVC-d has a major advantage over SEVC-c in allowing the experimenter to measure membrane potential, and as it obviates passing current and measuring voltage at the same time, there is never a series resistance error. The main disadvantages are that the time resolution is limited, and the amplifier is unstable. If it passes too much current, so that the goal voltage is over-shot, it reverses the polarity of the current in the next duty cycle. This causes it to undershoot the target voltage, so the next cycle reverses the polarity of the injected current again. This error can grow with each cycle until the amplifier oscillates out of control ("ringing"); this usually results in the destruction of the cell being recorded. The investigator wants a short duty cycle to improve temporal resolution; the amplifier has adjustable compensators that will make the electrode voltage decay faster, but if these are set too high the amplifier will ring, so the investigator is always trying to "tune" the amplifier as close to the edge of uncontrolled oscillation as possible, in which case small changes in recording conditions can cause ringing. There are two solutions: to "back off" the amplifier settings into a safe range, or to be alert for signs that the amplifier is about to ring.

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/index.php/Volvariella

# Volvariella Volvariella is a genus of mushrooms with pink gills and spore prints. They lack a ring, and have an Amanita-like volva at the stem base. Some species of Amanita look similar, but Amanita has white spores and often have a ring. Since the gills of young Volvariella are white at first, they are more easily mistaken for Amanita. Many sources list Volvariella as a member of the Pluteaceae family, but recent DNA studies have revealed that Pluteus and Volvareilla evolved separately and have very different DNA. These studies show that Volvariella is very closely related to "schizophylloid" mushrooms like Schizophyllum commune. Volvariella volvacea, well known as the "paddy straw mushroom," is cultured in rice straw in the Philippines and Southeast Asia. This species also favours wood chip piles. Unfortunately, it is easy to mistake the death cap mushroom (Amanita phalloides), as well as some other Amanita species, for this edible species due to similarities in appearance. This mistake is the leading cause of lethal mushroom poisoning in the United States. Volvariella and Amanita cannot be distinguished in the early "button stage", that, for many, is considered the best stage to collect Volvariella for consumption. Like Amanita, the paddy straw mushroom has a volva, or universal veil, so called because it is a membrane that encapsulates the entire mushroom when it is young. This structure breaks apart as the mushroom expands, leaving parts that can be found at the base of the stalk as a cup-like structure.

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/index.php/Volvulus

# Volvulus Synonyms and keywords:: Intestinal volvulus; Stomach volvulus; Gastric volvulus; Sigmoid volvulus; Cecal volvulus; Abdominal twisting; Colonic volvulus; Abdominal torsion; Intestinal torsion; Intestinal twisting; Colonic twisting; Stomach twisting, Volvulus neonatorum. History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X Ray | CT | Ultrasound | Other Imaging Findings | Other Diagnostic Studies

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/index.php/Volvulus_(patient_information)

# Volvulus (patient information) A volvulus is a twisting of the intestine that can occur in childhood. It causes a blockage, and may cut off blood flow and damage part of the intestine. Emergency surgery is needed to repair the volvulus. A surgical cut is made in the abdomen. The bowels are untwisted and the blood supply restored. If a small segment of bowel is dead from a lack of blood flow (necrotic), it is removed. The ends of the bowel are sewn back together. Or, they are used to form a connection of the intestines to the outside, through which bowel contents can be removed (colostomy or ileostomy).

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/index.php/Vomer

# Vomer Template:Infobox Anatomy The vomer (from Latin vomer, -ĕris, "ploughshare") is one of the unpaired facial bones of the skull. It is located in the midsagittal line, and touches the sphenoid, the ethmoid, the left and right palatine bones, and the left and right maxillary bones. The vomeronasal organ, also called Jacobson's organ, is a chemoreceptor organ named for its closeness to the vomer and nasal bones, and is particularly developed in animals such as cats (who adopt a characteristic pose called the Flehmen reaction or flehming when making use of it), and is thought to have to do with the perception of certain pheromones. It is thin, somewhat quadrilateral in shape, and forms the hinder and lower part of the nasal septum; it has two surfaces and four borders. The surfaces are marked by small furrows for blood vessels, and on each is the nasopalatine groove, which runs obliquely downward and forward, and lodges the nasopalatine nerve and vessels. The superior border, the thickest, presents a deep furrow, bounded on either side by a horizontal projecting ala of bone; the furrow receives the rostrum of the sphenoid, while the margins of the alæ articulate with the vaginal processes of the medial pterygoid plates of the sphenoid behind, and with the sphenoidal processes of the palatine bones in front. The anterior border is the longest and slopes downward and forward. Its upper half is fused with the perpendicular plate of the ethmoid; its lower half is grooved for the inferior margin of the septal cartilage of the nose. By alternately thrusting with the tongue against the roof of the mouth and pressing with one of the fingers between the two eyebrows, one can articulate the vomer bone. This process, repeated for about 20 seconds, will cause the sinuses to discharge, thus rapidly clearing a stuffy head without the use of drugs.

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/index.php/Vomeronasal_organ

# Vomeronasal organ The vomeronasal organ (VNO), or Jacobson's organ, is an auxiliary olfactory sense organ that is found in many animals and some adult humans that was discovered by Ludvig Jacobson in 1813. It develops from the nasal (olfactory) placode, at the anterior edge of the neural plate (cranial nerve zero). It is a chemoreceptor organ which is completely separated from the nasal cavity the majority of the time, being enclosed in a separate bony or cartilaginous capsule which opens into the base of the nasal cavity. It is a tubular crescent shape and split into two pairs, separated by the nasal septum. It is the first processing stage of the accessory olfactory system, after which chemical stimuli go to the accessory olfactory bulb, then to targets in the amygdala and hypothalamus. The VNO has two separate types of neuronal receptors, V1R and V2R, which are seven-transmembrane receptors that are coupled to GTP-binding proteins. The receptors are distinct from each other and from the large family of receptors in the main olfactory system. Evidence shows that the VNO responds to nonvolatile cues which stimulate the receptor neurons. Its presence in many animals has been widely studied and the importance of the vomeronasal system to the role of reproduction and social networking in animals has been shown in many studies. Its presence and functionality in humans is widely controversial. The vomeronasal organ (VNO) is found at the base of the nasal cavity. It is split into two, being divided by the nasal septum, with both sides possessing an elongated c-shaped, or crescent, lumen. It is encompassed inside a bony or cartilaginous capsule which opens into the base of the nasal cavity. The vomeronasal receptor neurons possess axons which travel from the VNO to the accessory olfactory bulb (AOB) or, as its also known, the vomeronasal bulb. These sensory receptors are located on the medial concave surface of the crescent lumen and have a density of approximately 92 x 103 mm-2. The lateral, convex surface of the lumen is covered with non sensory ciliated cells, where the basal cells are also found. At the dorsal and ventral aspect of the lumen are vomeronasal glands, which fill the vomeronasal lumen with fluid. Sitting net to the lumen are blood vessels that dilate or constrict to pump the lumen. In mammals, the sensory neurons of the vomeronasal organ detect specific chemical compounds contained within scents that are often, but not always, large non-volatile molecules. Notably by way of the vomeronasal organ, some scents act as chemical-communication signals (pheromones) from other individuals of the same species. Unlike the main olfactory bulb that sends neuronal signals to the olfactory cortex, the VNO sends neuronal signals to the accessory olfactory bulb and then to the amygdala and hypothalamus, which may explain how scents influence aggressive and mating behavior. However, it is key to note that the vomeronasal organ detects other compounds in addition to pheromones and that some pheromones are detected by the main olfactory system. The VNO is a tubular crescent shape and split into two pairs, separated by the nasal septum. The crescent lumen is lined with receptor neurons on the medial concave side and is filled with fluid from the VN glands. There VN neurons are isolated from the nasal cavity and therefore isolated from the air stream that passes during normal respiration. This means that a stimulus requires arousal of the vascular pump which is lateral to the lumen. The medial, concave area of the lumen is lined with a pseudo stratified epithelium that has tree main cell types: receptor cells, supporting cells, and basal cells. The supporting cells are located superficially on the membrane while the basal cells are found on the basement membrane near the non sensory epithelium. The vomeronasal sensory cells form in the olfactory placode along with other sensory olfaction neurons. The vomeronasal sensory neurons communicate with the hypothalamus to change neuroendocrine function. These sensory receptors are often referred to as pheromone receptors since vomeronasal receptors have been tied to detecting pheromones. The receptor cells are G-protein-coupled receptors which detect the pheromones, which are frequently referred to as pheromone receptors. The receptor neurons possess apical microvilli whose axons merge together to form VN nerves which move from the paired olfactory bulbs to the MOB, entering the posterior dorsal aspect through the AOB. There have been two different G-protein-coupled receptors identified in the VNO, each found in distinct regions. These are V1 and V2. V1 and V2 are seven transmembrane receptors which are not closely related to the main olfactory receptors. Upon stimulation activated by pheromones, IP3 production has been shown to increase in VNO membranes in many animals, while adenylyl cyclase and cyclic adenosine monophosphate (cAMP) remain unaltered. This trend has been shown in many animals, such as the hamster, the pig, the rat, and the garter snake upon introduction of vaginal or seminal secretions into the environment. V1Rs and V2Rs are suggested to be activated by distinct ligands or pheromones. The evidence that Gi and Go proteins are activated upon stimulation via different pheromones supports this. Vomeronasal sensory neurons are extremely sensitive and fire action potentials at currents as low as 1 pA. Many patch-clamp recordings have confirmed the sensitivity of the vomeronasal neurons. This sensitivity is tied to the fact that the resting potential of the vomeronasal neurons are relatively close to that of the firing threshold of these neurons. Vomeronasal sensory neurons also show remarkably slow adaptation and the firing rate increases with increasing current up to 10 pA. The main olfactory sensory neurons fire single burst action potentials and show a much quicker adaptation rate. Activating neurons that have V1 receptors, V1Rs, cause field potentials that have weak, fluctuating responses that are seen the anterior of the accessory olfactory bulb, AOB. Activation of neurons that contain V2 receptors, V2Rs, however, promote distinct oscillations in the posterior of the AOB. Some mammals, particularly felids and ungulates, use a distinctive facial movement called the flehmen response to direct inhaled compounds to this organ. The animal will lift its head after finding the odorant, wrinkle its nose while lifting its lips, and cease to breathe momentarily. Flehmen behavior is associated with "anatomical specialization", and animals that present flehmen behavior have incisive papilla and ducts, which connect the oral cavity to the VNO, that are found behind their teeth. Kudjakova et al. performed exploratory behavioral studies on non purebred rats by extirpating the VNO. The study showed that the exploratory behavior of the rats with extirpated VNO's were significantly different from both control groups of rats. These results suggest that removal of the VNO removed the experimental rats from important social information. This is seen in the reduced exploratory activity in the experimental animal and the lower number of species-specific reactions. Another study conducted by Beauchamp et al. investigated the role of the VNO in male guinea pigs social behavior. Half of the guinea pigs vomeronasal systems were removed, while the other half were put under fake surgeries with their vomeronasal systems left intact. The findings suggested that the VNO in the male domestic guinea pig is necessary for the maintenance of normal responsiveness to sex odors. However, "in its absence, other sensory systems are capable of maintaining normal sexual behavior under conditions of laboratory testing." These behavioral studies show the importance of the vomeronasal system in animals' social networks and everyday activities. The importance of the vomeronasal system to the role of reproduction and social networking has been shown in many studies. Anatomical studies demonstrate that in humans the vomeronasal organ regresses during fetal development, as is the case with some other mammals, including apes, cetaceans, and some bats. In fact, the human embryonic VNO possesses bipolar cells and luteinizing hormone releasing hormone (LHRH) producing cells, both that are characteristics of developing vomeronasal systems in other animals. The presence of a VNO in human embryos goes undisputed. It is debatable, and somewhat controversial, whether or not there is a presence of the vomeronasal system in adult humans. Many studies have been performed to find if there is an actual presence of a VNO in adult humans. Trotier et al. estimated that around 92% of their subjects that had no septal surgery had at least one intact VNO. Kajer and Hansen, on the other hand, stated that VNO structure disappeared at later stages in development. Won (2000) found evidence of a VNO in 13 of his 22 cadavers (59.1%) and in 22 of his 78 living patients (28.2%). Many studies have shown that there is a structure in adult humans in the septal mucosa inside the nasal septum that opens from the VNO pit. This structure is found in the same location of the VNO of human embryos and is thought by many to be the adult human VNO. Given these finding, many believe that there is a VNO in many adult humans, however this does not suggest that the VNO is functional in adult humans. The human VNO is absent of neurons that show characteristics of active sensory neurons that can be seen in working vomeronasal systems of other animals. Furthermore, there is no evidence to date that suggests there are nerve and axon connections between any existing sensory receptor cells that may be in the adult human VNO and the brain. Likewise, there is no evidence for any accessory olfactory bulb in the adult human. Monti-Blonch et al. in 1996 put forth data that suggested the existence of functional vomeronasal pituitary pathway in adult humans by administering vomeropherin to male subjects and measuring changes in electrodermal activity and EEG patterns. This was the first study to provide any support for the existence of a functional VNO in adult humans. Given these findings, it is unlikely, though still debatable, that the adult human VNO is functional. However, the absence of a vomeronasal system in humans does not suggest that there is no detection of pheromones since some are detected by the main olfactory system as well.

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/index.php/Vomiting_in_children

# Vomiting in children Vomiting in children is common and can range from a benign condition to a life-threatening condition. Most cases of vomiting are gastrointestinal in origin, most commonly gastroesophageal reflux disease and gastroenteritis. Vomiting, also known as emesis, is the oral expulsion of gastrointestinal content from the mouth due to the gut and thoracoabdominal wall muscles' contraction. At the same time, nausea refers to the need to vomit. Retching is used to describe the muscular event of vomiting with the expulsion of vomitus. Vomiting in children must be differentiated from other diseases that cause vomiting in children such as cyclic vomiting syndrome (CVS) , gastrointestinal disease (obstructive and inflammatory) , central nervous system (CNS) disease, pulmonary disease, renal disease, endocrine/metabolic disorders, drugs (either as side effects or in Overdose), or psychiatric disorders.

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/index.php/Vomiting_resident_survival_guide

# Vomiting resident survival guide Vomiting or Emesis means forcible emptying of the contents of stomach in which the stomach has to overcome the pressures that are normally in place to keep food and secretions within the stomach.Nausea and vomiting are most common causes for patients to seek primary care treatment, so it is very important to identify and properly manage the underlying problems causing vomiting.Though the mechanisms causing of nausea and vomiting are not completely understood, it is thought that the activation of a medullary vomiting centre by either afferent input from the gastrointestinal tract due to presence of local irritants or stimulation of the central chemoreceptor trigger zone by circulating emetogenic substances may cause vomiting.Dopamine and serotonin are the main transmitters both in central nervous system and gastrointestinal tract related vomiting. The most common causes of vomiting are Gastroenteritis, Migraine, Gastro peresis,Post operative, radiation and chemotherapy related vomiting, tumor, increased intracranial pressure,Hepatitis, Cholecystitis,Labyrithitis, Alcohol abuse, pregnancy induced vomiting. The management of most cases of nausea and vomiting depends on a good history and a detailed complete physical examination. Most episodes of vomiting that lasts for less than 48 hours have an existing triggering factor such as infection, viral illness, or food poisoning and can be managed by removing the triggering factor and by supportive therapy. Chronic and unexplained nausea and vomiting can be a difficult to treat as the cause is often obscure and requires special investigation.

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/index.php/Vomiting_resident_survival_guide_(pediatrics)

# Vomiting resident survival guide (pediatrics) Vomiting is a protective reflex mechanism that causes forceful reflux of stomach or esophageal contents outside the mouth. It is a common pediatric problem with varied etiology. It may be the presenting symptom of an underlying life-threatening illness. Management of vomiting in children usually involves treating dehydration, electrolyte imbalance, and the underlying cause. Antiemetic therapy is given in older children with persistent vomiting.

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/index.php/Vomitoxin

# Vomitoxin Vomitoxin, also known as deoxynivalenol (DON), is a type B trichothecene, an epoxy-sesquiterpeneoid. This mycotoxin occurs predominantly in grains such as wheat, barley, oats, rye, and maize, and less often in rice, sorghum, and triticale. The occurrence of deoxynivalenol is associated primarily with Fusarium graminearum (Gibberella zeae) and F. culmorum, both of which are important plant pathogens which cause Fusarium head blight in wheat and Gibberella ear rot in maize. A direct relationship between the incidence of Fusarium head blight and contamination of wheat with deoxynivalenol has been established. The incidence of Fusarium head blight is strongly associated with moisture at the time of flowering (anthesis), and the timing of rainfall, rather than the amount, is the most critical factor. F. graminearum grows optimally at a temperature of 25 °C and at a water activity above 0.88. F. culmorum grows optimally at 21 °C and at a water activity above 0.87. The geographical distribution of the two species appears to be related to temperature, F. graminearum being the commoner species and occurring in warmer climates. Deoxynivalenol has been implicated in incidents of mycotoxicoses in both humans and farm animals. Vomitoxin is rather a mild toxin compared to other toxins which can form in grains and forages. Reduced feed intake, and the accompanying decrease in performance, are the only symptoms of vomitoxin toxicity livestock producers will likely encounter. This response to vomitoxin appears to occur through the central nervous system. Vomitoxin belongs to a class of mycotoxins (tricothecenes) which are strong protein inhibitors. Inhibition of protein synthesis following exposure to vomitoxin causes the brain to increase its uptake of the amino acid tryptophan and, in turn, its synthesis of serotonin. Increased levels of serotonin are believed to be responsible for the anorexic effects of DON and other tricothecenes. Irritation of the gastrointestinal tract may also play a role in reducing feed intake... This fact may also partially explain the high incidence of pars esaughageal stomach ulcers observed in sows off feed during feed refusal.

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/index.php/Von_Braun_reaction

# Von Braun reaction The Von Braun reaction is an organic reaction in which a tertiary amine reacts with cyanogen bromide to an organocyanamide . An example is the reaction of dimethyl-α-naphthylamine : The reaction mechanism consists of two nucleophilic substitutions: the amine is the first nucleophile displacing the bromine atom which then acts as the second nucleophile .

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/index.php/Von_Hippel%E2%80%93Lindau_tumor_suppressor

# Von Hippel–Lindau tumor suppressor The von Hippel–Lindau tumor suppressor also known as pVHL is a protein that in humans is encoded by the VHL gene. Mutations of the VHL gene are associated with von Hippel–Lindau disease. Von Hippel–Lindau syndrome (VHL) is a dominantly inherited hereditary cancer syndrome predisposing to a variety of malignant and benign tumors of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands. A germline mutation of this gene is the basis of familial inheritance of VHL syndrome. Individuals with VHL syndrome inherit one mutation in the VHL protein that causes the protein's normal function to be lost or altered. Over time, sporadic mutation in the second copy of the VHL protein can lead to carcinomas, in particular hemangioblastomas affecting the liver and kidneys, renal (and vaginal) clear cell adenocarcinomas. The protein encoded by this gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity. This complex is involved in the ubiquitination and degradation of a hypoxia-inducible factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. RNA polymerase II subunit POLR2G/RPB7 is also reported to be a target of this protein. Alternatively spliced transcript variants encoding distinct isoforms have been observed. The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. HIF is necessary for tumor growth because most cancers demand high metabolic activity and are only supplied by structurally or functionally inadequate vasculature. Activation of HIF allows for enhanced angiogenesis, which in turn allows for increased glucose uptake. While HIF is mostly active in hypoxic conditions, VHL-defective renal carcinoma cells show constitutive activation of HIF even in oxygenated environments. It is clear that VHL and HIF interact closely. Firstly, all renal cell carcinoma mutations in VHL that have been tested affect the protein's ability to modify HIF. Additionally, HIF activation can be detected in the earliest events in tumorigenesis in patients with VHL syndrome. In normal cells in hypoxic conditions, HIF1A is activated with little activation of HIF2A. However, in tumors the balance of HIF1A and HIF2A is tipped towards HIF2A. While HIF1A serves as a pro-apoptotic factor, HIF2A interacts with cyclin D1. This leads to increased survival due to lower rates of apoptosis and increased proliferation due to the activation of cyclin D1. Recent genome wide analysis of HIF binding in kidney cancer showed that HIF1A binds upstream of majorly good prognosis genes, while HIF2A binds upstream to majorly poor prognosis genes. This indicates that the HIF transcription factor distribution in kidney cancer is of major importance in determining the outcome of the patients. In the normal cell with active VHL protein, HIF alpha is regulated by hydroxylation in the presence of oxygen. When iron, 2-oxoglutarate and oxygen are present, HIF is inactivated by HIF hydroxylases. Hydroxylation of HIF creates a binding site for pVHL (the protein product of the VHL gene). pVHL directs the polyubiquitylation of HIF1A, ensuring that this protein will be degraded by the proteasome. In hypoxic conditions, HIF1A subunits accumulate and bind to HIFB. This heterodimer of HIF is a transcription factor that activates genes that encode for proteins such as vascular endothelial growth factor (VEGF) and erythropoietin, proteins that are both involved in angiogenesis. Cells with abnormal pVHL are unable to disrupt the formation of these dimers, and therefore behave like they are hypoxic even in oxygenated environments. HIF can help explain the organ specific nature of VHL syndrome. It has been theorized that constitutively activating HIF in any cell could lead to cancer, but that there are redundant regulators of HIF in organs not affected by VHL syndrome. This theory has been disproved multiple times since in all cell types loss of VHL function leads to constitutive activation of HIF and its downstream effects. Another theory holds that although in all cells loss of VHL leads to activation of HIF, in most cells this leads to no advantage in proliferation or survival. Additionally, the nature of the mutation in the VHL protein leads to phenotypic manifestations in the pattern of cancer that develops. Nonsense or deletion mutations of VHL protein have been linked to type 1 VHL with a low risk of pheochromocytoma (adrenal gland tumors). Type 2 VHL has been linked to missense mutations and is linked to a high risk of pheochromocytoma. Type 2 has also been further subdivided based on risks of renal cell carcinoma. In types 1, 2A and 2B the mutant pVHL is defective in HIF regulation, while type 2C mutant are defective in protein kinase C regulation. These genotype–phenotype correlations suggest that missense mutations of pVHL lead to a 'gain of function' protein. The involvement in VHL in renal cell cancer can be rationalized via multiple characteristics of renal cells. First, they are more sensitive to the effects of growth factors created downstream of HIF activation than other cells. Secondly, the link to Cyclin D1 (as mentioned above) is only seen in renal cells. Finally, many cells in the kidney normally operate under hypoxic conditions. This may give them a proliferative advantage over other cells while in hypoxic environments. In addition to its interaction with HIF the VHL protein can also associate with tubulin. It is then capable to stabilize and thus elongate microtubules. This function plays a key role in the stabilisation of the spindle during mitosis. Deletion of VHL causes a drastic increase of misorientated and rotating spindles during mitosis. Through a not yet known mechanism, VHL also increases the concentration of MAD2, an important protein of the spindle checkpoint. Thus VHL-loss leads to a weakened checkpoint and subsequently chromosome missegregation and aneuploidy. The loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiogenic factors, including VEGF and PDGF. In turn, this leads to unregulated blood vessel growth, one of the prerequisites of a tumor. Additionally, VHL has been implicated in maintaining the differentiated phenotype in renal cells. Furthermore, cell culture experiments with VHL -/- cells have shown that the addition of pVHL can induce a mesenchymal to epithelial transition. This evidence suggests that VHL has a central role in maintaining a differentiated phenotype in the cell. Additionally, pVHL is important for extracellular matrix formation. This protein may also be important in inhibition of matrix metalloproteinases. These ideas are extremely important in the metastasis of VHL-deficient cells. In classical VHL disease a single wild-type allele in VHL appears to be sufficient to maintain normal cardiopulmonary function. Suggested targets for VHL-related cancers include targets of the HIF pathway, such as VEGF. Inhibitors of VEGF receptor sorafenib, sunitinib, pazopanib, and recently axitinib have been approved by the FDA. The mTOR inhibitor rapamycin analogs everolimus and temsirolimus or VEGF monoclonal antibody bevacizumab may also be an option. Since iron, 2-oxoglutarate and oxygen are necessary for the inactivation of HIF, it has been theorized that a lack of these cofactors could reduce the ability of hydroxlases in inactivating HIF. A recent study has shown that in cells with a high activation of HIF even in oxygenated environments was reversed by supplying the cells with ascorbate. Thus, Vitamin C may be a potential treatment for HIF induced tumors.

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/index.php/Von_Hippel-Lindau_disease

# Von Hippel-Lindau disease Von Hippel-Lindau disease (VHL) is a rare inherited genetic condition involving the abnormal growth of tumors in parts of the body which are particularly rich in blood supply. Untreated, VHL may result in blindness and permanent brain damage; death is usually caused by complications of malignant tumors in the brain or kidney, cardiovascular disease secondary to pheochromocytoma. With early detection and appropriate treatment, there is more hope today for people with VHL than ever before. VHL is an autosomal dominant disorder, but there is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from one parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development. As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. If a mutation occurs in the second copy of the VHL gene during a person's lifetime, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel-Lindau syndrome to develop. In an article appearing in the Associated Press, it has been speculated by a Vanderbilt University endocrinologist that the hostility underlying the Hatfield-McCoy feud may have been partly due to the consequences of Von Hippel-Landau disease. The article suggests that the McCoy family was pre-disposed to bad tempers because many of them had a pheochomocytoma, which produced excess adrenaline and a tendency toward explosive tempers. Pheochromocytomas produce surges of adrenaline which are more often perceived as panic attacks than rage attacks. Left untreated, they will cause serious cardiovascular disease, heart attack, and stroke. Only about 20% of people with VHL get pheochromocytomas.

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/index.php/Von_Hippel-Lindau_tumor_suppressor

# Von Hippel-Lindau tumor suppressor Von Hippel-Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign tumors of the eye, brain, spinal cord, kidney, pancreas, and adrenal glands. A germline mutation of this gene is the basis of familial inheritance of VHL syndrome. The protein encoded by this gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity. This protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. RNA polymerase II subunit POLR2G/RPB7 is also reported to be a target of this protein. Alternatively spliced transcript variants encoding distinct isoforms have been observed. The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor gene. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. (However, VHL does play other roles in tumor regulation.) It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiogenic factors, including VEGF and PDGF. In turn, this leads to unregulated blood vessel growth, one of the prerequisites of a tumour.

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/index.php/Voodoo_pharmacology

# Voodoo pharmacology Voodoo pharmacology is the belief that any drug, be it legal or illicit, robs the user of free will by creating an uncontrollable urge of craving and compulsion. The term is coined by Jacob Sullum in his book, Saying Yes: In Defence of Drug Use , where he alleges that this viewpoint is touted in governmental anti-drug propaganda which deliberately misleads the public about the actual dangers of taking recreational drugs, such as cocaine, marijuana, etc. Such claims on the danger of these drugs is not discussed vigorously in peer-reviewed research, and there appears to be a move in public health to demonize certain drugs while the most widely used drugs of nicotine and alcohol contribute more deaths.

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/index.php/Vorticella_convallaria

# Vorticella convallaria Vorticella convallaria is a protozoan, the type species of the genus Vorticella. It resembles V. campanula, but differs in being somewhat narrow in the anterior end and usually having no refractile granules in the endoplasm. The cell body of this species is 50-95 μm long and 35-53 μm wide. The peristome ranges from 55-75 μm in diameter. The rod-like, contractile stalk is 25-300 μm long and 4 μm wide. It can collapse into a tightly coiled helix in under 1/60th of a second.

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/index.php/Vosol

# Vosol Vosol is an antiseptic used to treat otitis externa, a problem of the ear canal. The active ingredient in this antiseptic is acetic acid. Acetic acid is anti-bacterial and anti-fungal; propylene glycol is hydrophilic and provides a low surface tension; benzethonium chloride is a surface active agent that promotes contact of the solution with tissues.

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/index.php/Voxel-based_morphometry

# Voxel-based morphometry Voxel based morphometry (VBM) is a neuroimaging analysis technique that allows investigation of focal differences in brain volume. It can be regarded as a form of so-called statistical parametric mapping. Traditionally, brain volume is measured by drawing regions of interest (ROIs) and calculating the volume enclosed. However, this is time consuming and can only provide measures of large areas. Smaller differences in volume may be overlooked. VBM registers every brain to a template, which gets rid of most of the large differences in brain anatomy among people. Then the brain images are smoothed so that each voxel represents the average of itself and its neighbors. Finally, volume is compared across brains at every voxel. One of the first VBM studies and one that came to attention in main stream media was a study on the hippocampus brain structure of London taxi drivers . The VBM analysis showed the back part of the hippocampus was on average larger in the taxi drivers compared to control subjects while the frontal part was smaller. London taxi drivers need good spatial navigational skills and scientists have usually associated hippocampus with this particular skill.

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/index.php/Vulture_bee

# Vulture bee Vulture bees are a small group of three closely-related American stingless bee species in the genus Trigona which feed on rotting meat rather than pollen or nectar. These are the only known bees which do not rely on plant products for food. This unusual behavior was only discovered in 1982, nearly two centuries after the bees were first classified. The three species in this group are:

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/index.php/Vulva

# Vulva The vulva (from Latin, vulva, plural vulvae or vulvas; see etymology) is the region of the external genital organs of the female, including the labia majora, mons pubis, labia minora, clitoris, bulb of the vestibule, vestibule of the vagina, greater and lesser vestibular glands, and vaginal orifice. The vulva has many major and minor anatomical structures. Its development occurs during several phases, chiefly the fetal and pubertal periods. The vulva protects the vaginal opening by a "double door": the labia majora and the labia minora as well as a vulval vestibule, and a normal microbial flora that flows from the inside out. Normal external cleanliness is usually sufficient to assure good vulvovaginal health, without recourse to any internal cleansing. The vulva is more susceptible to infections than the penis. These external body structures also have a sexual function; they are richly innervated and provide pleasure during sexual intercourse when properly stimulated. Since the origin of human society, in various branches of art the vulva has been depicted as the organ that has the power both "to give life" (i.e., often confused and associated with the vagina in pre-historic periods and antiquity, decreasingly as science has progressed), and to give sexual pleasure to humankind. In common speech, the term vagina is often used to refer to the vulva or female genitals generally, although, strictly speaking, the vagina is a specific internal structure, whereas the vulva is the exterior genitalia. The word "vulva" was taken from Middle Latin volva or vulva "womb, female genitals", probably from Latin volvere "to roll" (lit. "wrapper"). Similar to Sanskrit ulva "womb". As with nearly any aspect of the human body that is involved in sexual or excretory functions, there are many slang words for the vulva. Most male and female sex organs originate from the same tissues in the development of a foetus. The vulva is no different. The anatomy of the vulva is related to the anatomy of the male genitalia by a shared developmental biology. Organs that have a common developmental ancestry in this way are said to be homologous. The clitoral glans is homologous to the glans penis in males, and the clitoral body and the clitoral crura are homologous to the corpora cavernosa of the penis. The labia majora, labia minora and clitoral hood are homologous to the scrotum, shaft skin of the penis, and the foreskin, respectively. The vestibular bulbs beneath the skin of the labia minora are homologous to the corpus spongiosum, the tissue of the penis surrounding the urethra. The Bartholin's glands are homologous to Cowper's glands in males. The soft mound at the front of the vulva is formed by fatty tissue covering the pubic bone, and is called the mons pubis. The term mons pubis is Latin for "pubic mound", and is gender non-specific. In human females, the mons pubis is often referred to as the mons veneris, Latin for "mound of Venus" or "mound of love". The mons pubis separates into two folds of skin called the labia majora, literally "major (or large) lips". The cleft between the labia majora is called the pudendal cleft, or cleft of Venus, and it contains and protects the other, more delicate structures of the vulva. The labia majora meet again at a flat area between the pudendal cleft and the anus called the perineum. The colour of the outside skin of the labia majora is usually close to the overall skin colour of the individual, although there is considerable variation. The inside skin and mucus membrane are often pink or brownish. After the onset of puberty, the mons pubis and the labia majora become covered by pubic hair. This hair sometimes extends to the inner thighs and perineum, but the density, texture, and extent of pubic hair coverage varies considerably. The practice of cosmetic trimming and shaping the edge of the so-called "bikini line" is common, but a trend toward the severe reduction, or even complete removal, of pubic hair has gained popularity in recent years. The labia minora are two soft folds of skin within the labia majora. While labia minora translates as "minor (or small) lips", often the "minora" are of considerable size, and protrude outside the "majora". Much of the variation between vulvae lies in the significant variation in the size, shape, and color of the labia minora. The clitoris is located at the front of the vulva, where the labia minora meet. The visible portion of the clitoris is the clitoral glans. Typically, the clitoral glans is roughly the size and shape of a pea, although it can be significantly larger or smaller. The clitoral glans is highly sensitive, containing as many nerve endings as the analogous organ in males, the glans penis. The point where the labia minora attach to the clitoris is called the frenulum clitoridis. A prepuce, the clitoral hood, normally covers and protects the clitoris, however in women with particularly large clitorises or small prepuces, the clitoris may be partially or wholly exposed at all times. Often the clitoral hood is only partially hidden inside of the pudendal cleft. The area between the labia minora is called the vulval vestibule, and it contains the vaginal and urethral openings. The urethral opening (meatus) is located below the clitoris and just in front of the vagina. This is where urine passes from the bladder to the outside of the body. The opening of the vagina is located at the bottom of the vulval vestibule, towards the perineum. The term introitus is more technically correct than "opening", since the vagina is collapsed, with the opening closed, unless something is inserted into it. The introitus is sometimes partly covered by a membrane called the hymen. The hymen will rupture during the first episode of vigorous sex, and the blood produced by this rupture is often used as a sign of virginity. However, the hymen may also rupture spontaneously during exercise, or be stretched by normal activities such as the use of tampons, or be so minor as to not be noticeable. In some rare cases, the hymen may completely cover the vaginal opening, requiring surgical separation. Slightly below and to the left and right of the vaginal opening are two Bartholin glands which produce a waxy, pheromone-containing substance, the purpose of which is not fully known. The appearance of the vulva and the size of the various parts varies a great deal from one female to another, and it is common for the left and right sides to differ in appearance. During the first eight weeks of life, both male and female fetuses have the same rudimentary reproductive and sexual organs, and maternal hormones control their development. Male and female organs begin to become distinct when the fetus is able to begin producing its own hormones, although visible determination of the sex is difficult until after the twelfth week. During the sixth week, the genital tubercle develops in front of the cloacal membrane. The tubercle contains a groove termed the urethral groove. The urogenital sinus (forerunner of the bladder) opens into this groove. On either side of the grove are the urogenital folds. Beside the tubercle are a pair of ridges called the labioscrotal swellings. Beginning in the third month of development, the genital tubercle becomes the clitoris. The urogenital folds become the labia minora, and the labioscrotal swellings become the labia majora. At birth, the neonate's vulva (and breasts) may be swollen or enlarged as a result of having been exposed, via the placenta, to her mother's increased levels of hormones. The clitoris is proportionally larger than it is likely to be later in life. Within a short period of time as these hormones wear off, the vulva will shrink in size. From one year of age until the onset of puberty, the vulva does not undergo any change in appearance, other than growing in proportion with the rest of the body. The onset of puberty produces a number of changes. The structures of the vulva become proportionately larger and may become more pronounced. Coloration may change and pubic hair develops, first on the labia majora, and later spreading to the mons pubis, and sometimes the inner thighs and perineum. In pre-adolescent girls, the vulva appears to be positioned further forward than in adults, showing a larger percentage of the labia majora and pudendal cleft when standing. During puberty the mons pubis enlarges, pushing the forward portion of the labia majora away from the pubic bone, and parallel to the ground (when standing). Variations in body fat levels affect the extent to which this occurs. During childbirth, the vagina and vulva must stretch to accommodate the baby's head (approximately 9.5 cm or 3.7 in). This can result in tears in the vaginal opening, labia, and clitoris. An episiotomy (surgical pre-emptive cutting of the perineum) is sometimes performed to limit tearing, but its appropriateness as a routine procedure is under debate. During menopause, hormone levels decrease, and along with them tissues sensitive to these hormones also decrease. The mons pubis, labia, and clitoris may reduce in size, although not usually to pre-puberty proportions. Sexual arousal results in a number of physical changes in the vulva. Arousal may be broken up into four somewhat arbitrary phases: Excitement, Plateau, Orgasm, and Resolution. Vaginal lubrication begins first. This is caused as a result of the vasocongestion of the vaginal walls. Increased blood pooling there causes moisture to seep from the walls. These droplets collect together and flow out of the vagina, moistening the vulva. The labia majora flatten and spread apart, and the clitoris and labia minora increase in size. Unlike in men, where sexual excitement produces large and readily apparent changes, namely an erection, women are not necessarily aware that vaginal lubrication and blood engorgement of their vulva has occurred. Increased vasocongestion in the vagina causes it to swell, decreasing the size of the vaginal opening by about 30%. The clitoris becomes increasingly erect, and the glans moves towards the pubic bone, becoming concealed by the hood. The labia minora increase considerably in thickness, approximately 2–3 times, causing them to spread apart, displaying the vaginal opening. The labia minora change considerably in color, (in Caucasians) going from pink to red in women who have not borne a child, or red to wine in those that have. Immediately prior to orgasm, the clitoris becomes exceptionally engorged, causing the glans to appear to retract into the clitoral hood. This is thought to protect the sensitive glans during orgasm. However, there is some doubt that this is the case, since the same engorgement prior to orgasm occurs in the male homologous structure, the penis, the function of which is thought to be to extend the penis as close to the cervix as possible prior to ejaculation. Rhythmic muscle contractions occur in the outer third of the vagina, as well as the uterus and anus. They occur initially at a rate of about one every 0.8 seconds, becoming less intense and more randomly spaced as the orgasm continues. An orgasm may have as few as one or as many as 15 or more contractions, depending on intensity. Orgasm may be accompanied by female ejaculation, causing liquid from either the Skene's gland or bladder to be expelled through the urethra. The pooled blood begins to dissipate, although at a much slower rate if orgasm has not occurred. The vagina and vaginal opening return to their normal relaxed state, and the rest of the vulva returns to its normal size, position and color. There are a number of different secretions associated with the vulva, including urine, sweat, menses, skin oils (sebum), Bartholin's and Skene's gland secretions, and vaginal wall secretions. These secretions contain a mix of chemicals, including pyridine, squalene, urea, acetic acid, lactic acid, complex alcohols, glycols, ketones, and aldehydes. A secretion associated with ovulation is known as "spinnbarkeit". Smegma is a white substance formed from a combination of dead cells, skin oils, moisture and naturally occurring bacteria, that forms in mammalian genitalia. In females it collects around the clitoris and labial folds. Approximately one third of women produce aliphatic acids. These acids are a pungent class of chemicals which other primate species produce as sexual-olfactory signals. While there is some debate, researchers often refer to them as human pheromones. These acids are produced by natural bacteria resident on the skin. The acid content varies with the menstrual cycle, rising from one day after menstruation, and peaking mid-cycle, just before ovulation. Gynaecology is the branch of medicine dealing with the diagnosis and treatment of the diseases and disorders associated with the vulva. Regular examinations are necessary to detect any abnormal changes in the vulvar region. Several pathologies are defined, a complete descriptive listing may be found in Chapter XIV of the list of ICD-10 codes; the most significant disorders include: Symptoms of vulvar cancer include itching, a lump or sore on the vulva which doesn't heal and/or goes larger, and sometimes discomfort/pain/swelling in the vulval area. Treatments include vulvectomy – removal of all or part of the vulva. The most prevalent form of genital alteration in some countries is female genital cutting: removal of any part of the female genitalia for cultural, religious or other non-medical reasons. This practice is highly controversial as it is often done to non-consenting minors and for debatable (often misogynistic) reasons. In some cases, people elect to have their genitals pierced, tattooed or otherwise altered for aesthetic or other reasons. Female genital enhancement surgery includes laser resurfacing of the labia to remove wrinkles, clitoral repositioning for those not achieving optimum stimulation, labiaplasty (reducing the size of the labia) and vaginal tightening. Many peoples have no or few taboos on exposure of the breasts, but the vulva and pubic triangle are always the first areas to be covered. Saartjie Baartman, the so-called "Hottentot Venus" who was exhibited in London at the beginning of the nineteenth century, was paid to display her large buttocks, but she never revealed her vulva. Khoisan women were said to have elongated labia, leading to questions about, and requests to exhibit, their sinus pudoris, "curtain of shame", or tablier (the French word for "apron"). To quote Stephen Jay Gould, "The labia minora, or inner lips, of the ordinary female genitalia are greatly enlarged in Khoi-San women, and may hang down three or four inches below the vagina when women stand, thus giving the impression of a separate and enveloping curtain of skin". Saartjie never allowed this trait to be exhibited while she was alive. In some cultures, including modern Western culture, some women have shaved or otherwise depilated part or all of the vulva. This is a fairly recent phenomenon in the United States, Canada, and western Europe, but has been prevalent, usually in the form of waxing, in many eastern European and Middle Eastern cultures for centuries, usually for the belief that it is more hygienic. High-cut swimsuits compelled their wearers to shave the sides of their pubic triangles. Shaving may include all or nearly all of the hair. Some styles retain a "racing stripe" (on either side of the labia) or "landing strip" (directly above and in line with the vulva). See the article on pubic hair. Since the early days of Islam, Muslim women and men have followed a tradition to "pluck the armpit hairs and shave the pubic hairs". This is a preferred practice rather than an obligation, and could be carried out by shaving, waxing, cutting, clipping or any other method. This is a regular practice that is considered in some more devout Muslim cultures as a form of worship, not a shameful practice, while in other less devout regions it is a practice for the purpose of good hygiene. The reasons behind removing this hair could also be applied to the hair on the scrotum and around the anus, because the purpose is to be completely clean and pure and keep away from anything that may cause dirt and impurities.

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/index.php/Vulvectomy

# Vulvectomy Vulvectomy refers to a gynecological procedure in which the vulva is partly or completely removed. Usually this is performed as a last resort in certain cases of cancer, vulvar dysplasia or Human Papilloma Virus (genital warts). The patient experiences severe pain in the groin area for a couple of weeks after the procedure. Sexual function is generally still possible but limited. A simple vulvectomy means removal of all external tissue, and a radical vulvectomy is the same but also includes lymph node removal, clitoris, and nearby tissue is also removed. A partial vulvectomy is the least severe, only removing the affected portion of the vulva. Skinning vulvectomy involves the removal of the top layer of vulvar skin (the external female genital organs,incluiding the clitoris, vaginal lips and the opening of the vagina) where the cancer is found. Skin grafts from other parts of the body may be needed to cover the area. There are 2 types of Skinning Vulvectomy, the Partial skinning vulvectomy and the Total skinning vulvectomy. The objective of the first one is the preservation of the cosmetic and functional integrity of the vulva in younger and sexually active patients in whom a steady increase in the incidence of vulvar intraepithelial neoplasia has been observed in the last decade meanwhile the objective of the Total skinning vulvectomy is to remove the entire vulva with total skin graft replacement in patients with an entire vulva cancer involvement. Modified radical vulvectomy involves the removal of vulva containing cancer and some of the normal tissue around it.

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/index.php/Vytorin

# Vytorin Ezetimibe/simvastatin /ɛˈzɛt[invalid input: 'ɨ']mɪb ˌsɪmvəˈstæt[invalid input: 'ɨ']n/ is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe (known as Zetia in the United States and Ezetrol elsewhere) and the statin drug simvastatin (known as Zocor in the U.S.). The combination preparation is marketed by Merck & Co. under the trade names Vytorin and Inegy. Ezetimibe reduces blood cholesterol by acting at the brush border of the small intestine and inhibiting the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Even though ezetimibe decreases cholesterol levels, as of 2009 it has not been found to lead to improvement in real world outcomes. The combination of simvastatin and ezetimibe has not been found to be any better than simvastatin alone. A panel of experts thus concluded in 2008 that it should "only be used as a last resort". Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. VYTORIN contains ezetimibe and simvastatin, two lipid-lowering compounds with complementary mechanisms of action. VYTORIN reduces elevated total-C, LDL-C, Apo B, TG, and non-HDL-C, and increases HDL-C through dual inhibition of cholesterol absorption and synthesis. Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols. In a 2-week clinical study in 18 hypercholesterolemic patients, ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E and did not impair adrenocortical steroid hormone production. Ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins[see Clinical Studies (14)]. Simvastatin is a prodrug and is hydrolyzed to its active β-hydroxyacid form, simvastatin acid, after administration. Simvastatin is a specific inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, simvastatin reduces very-low-density lipoproteins (VLDL) and TG and increases HDL-C.

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/index.php/Vytorin_detailed_information

# Vytorin detailed information Ezetimibe/simvastatin (IPA: Template:IPA) is a drug combination used for the treatment of dyslipidemia. It is a combination of ezetimibe (best known as Zetia in the United States) and the statin drug simvastatin (best known as Zocor in the U.S.). The combination preparation is marketed by Merck & Co./Schering-Plough Pharmaceuticals (joint venture) under the trade names Vytorin and Inegy.

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/index.php/Vytorin_drug_interactions

# Vytorin drug interactions Strong CYP3A4 inhibitors: The risk of myopathy is increased by reducing the elimination of the simvastatin component of VYTORIN. Hence when VYTORIN is used with an inhibitor of CYP3A4 (e.g., as listed below), elevated plasma levels of HMG-CoA reductase inhibitory activity increases the risk of myopathy and rhabdomyolysis, particularly with higher doses of VYTORIN. [See Warnings and Precautions (5.1) and Clinical Pharmacology (12.3).] Concomitant use of drugs labeled as having a strong inhibitory effect on CYP3A4 is contraindicated [see Contraindications (4)]. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with VYTORIN must be suspended during the course of treatment. Cyclosporine or Danazol: The risk of myopathy, including rhabdomyolysis is increased by concomitant administration of cyclosporine or danazol. Therefore, concomitant use of these drugs is contraindicated [see Contraindications (4), Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)]. The risk of myopathy, including rhabdomyolysis, is increased by concomitant administration of amiodarone, dronedarone, ranolazine, or calcium channel blockers such as verapamil, diltiazem or amlodipine [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) and Table 6 in Clinical Pharmacology (12.3)]. Cases of myopathy/rhabdomyolysis have been observed with simvastatin coadministered with lipid-modifying doses (≥1 g/day niacin) of niacin-containing products. The benefits of the combined use of VYTORIN with niacin should be carefully weighed against the potential risks of myopathy/rhabdomyolysis. In particular, caution should be used when treating Chinese patients with VYTORIN doses exceeding 10/20 mg/day coadministered with lipid-modifying doses of niacin-containing products. Because the risk for myopathy is dose-related, Chinese patients should not receive VYTORIN 10/80 mg coadministered with lipid-modifying doses of niacin-containing products. [SeeWarnings and Precautions (5.1).] Concomitant cholestyramine administration decreased the mean AUC of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding VYTORIN to cholestyramine may be reduced by this interaction. In one study, concomitant administration of digoxin with simvastatin resulted in a slight elevation in plasma digoxin concentrations. Patients taking digoxin should be monitored appropriately when VYTORIN is initiated. The safety and effectiveness of VYTORIN administered with fibrates have not been established. Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of fibrates, VYTORIN should be administered with caution when used concomitantly with fibrates (other than gemfibrozil, which is contraindicated) [see Contraindications (4) and Warnings and Precautions (5.1)]. Fibrates may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile [seeAnimal Toxicology and/or Pharmacology (13.2)]. Simvastatin 20-40 mg/day modestly potentiated the effect of coumarin anticoagulants: the prothrombin time, reported as International Normalized Ratio (INR), increased from a baseline of 1.7 to 1.8 and from 2.6 to 3.4 in a normal volunteer study and in a hypercholesterolemic patient study, respectively. With other statins, clinically evident bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly. In such patients, prothrombin time should be determined before starting VYTORIN and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of VYTORIN is changed or discontinued, the same procedure should be repeated. Simvastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants. Concomitant administration of ezetimibe (10 mg once daily) had no significant effect on bioavailability of warfarin and prothrombin time in a study of twelve healthy adult males. There have been post-marketing reports of increased INR in patients who had ezetimibe added to warfarin. Most of these patients were also on other medications.

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