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You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare.

I've encountered the term 'VACTERL association' while reading about medical topics. What does it refer to exactly?

The VACTERL association (also VATER association, and less accurately VACTERL syndrome) refers to a recognized group of birth defects which tend to co-occur (see below). This pattern is a recognized association, as opposed to a syndrome, because there is no known pathogenetic cause to explain the grouped incidence. Each child with this condition can be unique. At present this condition is treated after birth with issues being approached one at a time. Some infants are born with symptoms that cannot be treated and they do not survive. Also, VACTERL association can be linked to other similar conditions such as Klippel Feil and Goldenhar syndrome including crossovers of conditions. No specific genetic or chromosome problem has been identified with VACTERL association. VACTERL can be seen with some chromosomal defects such as Trisomy 18 and is more frequently seen in babies of diabetic mothers. VACTERL association, however, is most likely caused by multiple factors.VACTERL association specifically refers to the abnormalities in structures derived from the embryonic mesoderm. Signs and symptoms The following features are observed with VACTERL association: V - Vertebral anomalies A - Anorectal malformations C - Cardiovascular anomalies T - Tracheoesophageal fistula E - Esophageal atresia R - Renal (Kidney) and/or radial anomalies L - Limb defectsAlthough it was not conclusive whether VACTERL should be defined by at least two or three component defects, it is typically defined by the presence of at least three of the above congenital malformations. Spine Vertebral anomalies, or defects of the spinal column, usually consist of small (hypoplastic) vertebrae or hemivertebra where only one half of the bone is formed. About 80 percent of patients with VACTERL association will have vertebral anomalies. In early life these rarely cause any difficulties, although the presence of these defects on a chest x-ray may alert the physician to other defects associated with VACTERL. Later in life these spinal column abnormalities may put the child at risk for developing scoliosis, or curvature of the spine. Anal defects Anal atresia or imperforate anus is seen in about 55 to 90 percent of patients with VACTERL association. These anomalies are usually noted at birth. It often require surgery in the first days of life. Sometimes babies will require several surgeries to fully reconstruct the intestine and anal canal. Cardiac defects Up to 75 percent of patients with VACTERL association have been reported to have congenital heart disease. The most common heart defects seen with VACTERL association are ventricular septal defect (VSD), atrial septal defects and tetralogy of Fallot. Less common defects are truncus arteriosus and transposition of the great arteries. It is subsequently thought that cardiac defects should be considered an extension of VACTERL. Trachea and oesophagus Oesophageal atresia with tracheoesophageal fistula (TO fistula or TOF) is seen in about 70 percent of patients with VACTERL association, although it can frequently occur as an isolated defect. 15 to 33 percent of patients with TO fistulas will also have congenital heart disease. However these babies usually have uncomplicated heart defects, like a ventricular septal defect, which may not require any surgery. Kidneys Kidney defects are seen in approximately 50 percent of patients with VACTERL association. In addition, up to 35 percent of patients with VACTERL association have a single umbilical artery (there are usually two arteries and one vein) which is often associated with additional kidney or urologic problems. Renal abnormalities in VACTERL association can be severe, with incomplete formation of one or both kidneys or urologic abnormalities such as obstruction of outflow of urine from the kidneys or severe reflux (backflow) of urine into the kidneys from the bladder. These problems can cause kidney failure early in life and may require kidney transplant. Many of these problems can be corrected surgically before any damage can occur. Limbs Limb defects occur in up to 70 percent of babies with VACTERL association and include a displaced or hypoplastic thumb, extra digits (polydactyly), fusion of digits (syndactyly) and forearm defects such as radial aplasia. Babies with limb defects on both sides tend to have kidney or urologic defects on both sides, while babies with limb defects on only one side of the body tend to have kidney problems on that same side. Extension Features secondary to VACTERL components are frequent enough to be considered an extension of VACTERL. These include: single umbilical artery, ambiguous genitalia, abdominal wall defects, diaphragmatic hernia, intestinal and respiratory anomalies, and oligohydramnios sequence defects. Cardiac defects are thought to fit in this category. Growth Many babies with VACTERL are born small and have difficulty with gaining weight. Babies with VACTERL association, however, do tend to have normal development and normal intelligence. Pathology Patients with abnormal cardiac and kidney function may be more at risk for hemolytic uremic syndrome Diagnosis Differential diagnosis Baller–Gerold syndrome CHARGE syndrome Currarino syndrome DiGeorge syndrome Fanconi anemia Feingold syndrome Fryns syndrome MURCS association Oculo-auriculo-vertebral syndrome Opitz G/BBB syndrome Holt–Oram syndrome Pallister–Hall syndrome Townes–Brocks syndrome VACTERL with hydrocephalus Management Epidemiology The incidence of VACTERL association is estimated to be approximately 1 in 10,000 to 1 in 40,000 live-born infants. It is seen more frequently in infants born to diabetic mothers. While most cases are sporadic, there are clearly families who present with multiple involved members. History The acronym VATER association was first described by Linda Quan, an emergency room physician, and David Smith, a man who was considered the father of dysmorphology in 1972, to define a non-random co-occurrence of the listed defects. Years later, research revealed that cardiac and renal abnormalities were common in the association, and the acronym was changed to VACTERL. However, no single cause was identified that links all these conditions together. Therefore, this VACTERL is termed as "association" instead of a "syndrome". The differentiation of the acronyms VACTERL and VATER is due to the variation in defects determined at or prior to birth. VACTERL contains vertebral, anal, cardiac, trachea-esophageal, renal/kidney, and limb defects where as VATER only has vertebral, anal, trachea-esophogeal, and renal defects. The "R" in VATER represented radial dysplasia. Though the differences are clear, the physical defects vary from case to case. See also 22q11 deletion syndrome Absent radius CHARGE Association Holt–Oram syndrome Feingold syndrome Pallister–Hall syndrome Townes–Brocks syndrome References Further reading McMullen, KP; Karnes, PS; Moir, CR; Michels, VV (Jun 28, 1996). "Familial recurrence of tracheoesophageal fistula and associated malformations". American Journal of Medical Genetics. 63 (4): 525–8. doi:10.1002/(sici)1096-8628(19960628)63:4<525::aid-ajmg3>3.0.co;2-n. PMID 8826429. == External links ==

You are a guide to medical language. Please provide in-depth and understandable explanations of medical terms, highlighting their significance in healthcare.

The term 'Bempedoic acid/ezetimibe' keeps coming up in medical discussions. What does it stand for?

Bempedoic acid/ezetimibe, sold under the brand name Nexlizet among others, is a fixed-dose combination medication used for the treatment of high cholesterol. It is a combination of bempedoic acid and ezetimibe.The most common side effects are hyperuricemia (high blood levels of uric acid) and constipation.Bempedoic acid is an adenosine triphosphate-citrate lyase (ACL) inhibitor and ezetimibe is a cholesterol absorption inhibitor. Bempedoic acid works by blocking an enzyme in the liver called adenosine triphosphate citrate lyase, which is involved in making cholesterol. Ezetimibe works by binding to a gut protein called Niemann-Pick C1 Like 1, preventing cholesterol from being absorbed into the blood from the gut.The combination was approved for medical use in the United States in February 2020, and in the European Union in March 2020. Medical uses In the US bempedoic acid/ezetimibe is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C.In the EU bempedoic acid/ezetimibe is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet: in combination with a statin in people unable to reach LDL-C goals with the maximum tolerated dose of a statin in addition to ezetimibe alone in people who are either statin-intolerant or for whom a statin is contraindicated, and are unable to reach LDL-C goals with ezetimibe alone, in people already being treated with the combination of bempedoic acid and ezetimibe as separate tablets with or without statin. Contraindications It the European Union it must not be used in pregnant or breast-feeding women. Use during pregnancy is not recommended in the US. History The European Medicines Agency (EMA) recommended approval of bempedoic acid/ezetimibe (Nustendi) in the EU in January 2020.Bempedoic acid/ezetimibe was approved in the United States in February 2020, and in the European Union in March 2020.Two studies showed that bempedoic acid and ezetimibe effectively reduced LDL cholesterol levels in participants with hypercholesterolemia and heart disease or who were at high risk of heart disease. High cholesterol is a risk factor for heart disease.The first study involved 382 participants also taking the maximum tolerated doses of statins. After three months, LDL cholesterol levels were reduced by 36% in participants taking bempedoic acid and ezetimibe compared with a reduction of 23% with ezetimibe alone, 17% with bempedoic acid alone and an increase of around 2% with placebo (a dummy treatment).The second study involved 269 participants with high cholesterol levels who were not able to take a statin or were taking a low dose of a statin. All the participants were also taking ezetimibe. After three months, LDL cholesterol levels were reduced by 23% in participants taking bempedoic acid in addition to ezetimibe compared with an increase of around 5% in participants taking placebo and ezetimibe. References External links "Bempedoic acid". Drug Information Portal. U.S. National Library of Medicine. "Ezetimibe". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03337308 for "A Study Evaluating the Safety and Efficacy of Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination Compared to Bempedoic Acid, Ezetimibe, and Placebo in Patients Treated With Maximally Tolerated Statin Therapy" at ClinicalTrials.gov

You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience.

Could you provide a brief overview of 'Trifluridine/tipiracil' in a medical context?

Trifluridine/tipiracil, sold under the brand name Lonsurf, is a fixed-dose combination medication that is used as a third- or fourth-line treatment of metastatic colorectal cancer or gastric cancer, after chemotherapy and targeted therapeutics have failed. It is a combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil, a thymidine phosphorylase inhibitor. Tipiracil prevents rapid metabolism of trifluridine, increasing the bioavailability of trifluridine.The most common side effects include neutropenia (low levels of neutrophils, a type of white blood cell that fights infection), feeling sick, tiredness and anemia (low red blood cell counts). Medical uses It is used as a third- or fourth-line treatment for metastatic colorectal cancer or gastric cancer, after chemotherapy and biologic therapy. Contraindications The combination caused harm to the fetus of pregnant animals, and it was not tested in pregnant women. Pregnant women should not take it, and women should not become pregnant while taking it. Adverse effects The combination severely suppresses bone marrow function, resulting in fewer red blood cells, white blood cells, and platelets, so many people taking it are at risk for infections, anemia, and blood loss from lack of clotting. It also causes digestive problems, with more than 10% of people experiencing loss of appetite, diarrhea, nausea, and vomiting. More than 10% of people experience fatigue and fever.Between 1 and 10% of people have skin and mucosa issues, like rashes and itchiness, or mouth sores, as well as skin sloughing, numbness, redness, and swelling of their palms and soles. Dizziness and confusion are common as well. Interactions Only in vitro interaction studies are available. In these, trifluridine used the concentrative nucleoside transporter 1 (CNT1) and equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), and tipiracil was transported by the solute carrier proteins SLC22A2 and SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of trifluridine and tipiracil. Trifluridine, being a thymidine phosphorylase inhibitor, could also interact with substrates of this enzyme such as zidovudine. Pharmacology Mechanism of action The drug consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP; TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzymes activity. TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, thymidine triphosphate (dTTP). Inhibition of TS depletes the cell of dTTP and causes accumulation of deoxyuridine monophosphate (dUMP), which increases the likelihood that uracil gets misincorporated into the DNA. Also, subsequent phosphorylations of TF-TMP cause an increased level of TF-TTP within the cell, which results in it being incorporated into DNA. Even though the exact mechanism of how TFT causes DNA damage is not completely understood, it is hypothesized that the incorporation TF-TTP in DNA leads to DNA strand break formation.Tipiracil prevents the degradation of trifluridine via thymidine phosphorylase (TP) when taken orally and also has antiangiogenic properties. History Since the synthesis of 5-fluorouracil (5-FU) in 1957, fluoropyrimidines have been used to treat many types of cancer. Due to the drawbacks of 5-FU therapy, such as having to be administered over long periods of time via intravenous infusion and the development of resistance in tumors, more convenient and efficacious fluoropyrimidine therapy has been desired. The fluoropyrimidine component of this drug, trifluridine, was first synthesized in 1964 by Heidelberger et al.By the late 1960s, Phase I and Phase II clinical trials of intravenous trifluridine alone initially proved to be disappointing. Its pharmacokinetic profile during these clinical trials showed that the drug exhibited a very short half-life while in serum (12 minutes post-injection). Adjustments in the dosing regimen improved its effects in small studies, but the effect was short-lived.Researchers later found out that trifluridine, when taken orally, was broken down into the inactive metabolites 5-trifluoromethyluracil and 5-trifluoromethyl-2,4(1H,3,H)-pyrimidinedione (FTY) during its extensive first pass metabolism in the liver via the enzyme thymidine phosphorylase. It was then hypothesized that orally administered FTD concentrations could be increased and maintained if the drug was given with a thymidine phosphorylase inhibitor.Trifluridine/tipiracil was approved by the U.S. FDA in September 2015, and by the European Medicines Agency in April 2016. References External links "Tipiracil hydrochloride mixture with trifluridine". Drug Information Portal. U.S. National Library of Medicine.

You are an expert in medical terminology. Explain medical terms in a way that is both precise and easy to understand for non-medical audiences.

I'm seeking clarification on the medical term 'Variant Creutzfeldt–Jakob disease.' Could you explain it?

Variant Creutzfeldt–Jakob disease (vCJD), commonly referred to as "mad cow disease" or "human mad cow disease" to distinguish it from its BSE counterpart, is a fatal type of brain disease within the transmissible spongiform encephalopathy family. Initial symptoms include psychiatric problems, behavioral changes, and painful sensations. In the later stages of the illness, patients may exhibit poor coordination, dementia and involuntary movements. The length of time between exposure and the development of symptoms is unclear, but is believed to be years to decades. Average life expectancy following the onset of symptoms is 13 months.It is caused by prions, which are misfolded proteins. Spread is believed to be primarily due to eating bovine spongiform encephalopathy (BSE)-infected beef. Infection is also believed to require a specific genetic susceptibility. Spread may potentially also occur via blood products or contaminated surgical equipment. Diagnosis is by brain biopsy but can be suspected based on certain other criteria. It is different from typical Creutzfeldt–Jakob disease, though both are due to prions.Treatment for vCJD involves supportive care. As of 2020, 178 cases of vCJD have been recorded in the United Kingdom, due to a 1990s outbreak, and 50 cases in the rest of the world. The disease has become less common since 2000. The typical age of onset is less than 30 years old. It was first identified in 1996 by the National CJD Surveillance Unit in Edinburgh, Scotland. Signs and symptoms Initial symptoms include psychiatric problems, behavioral changes, and painful sensations. In the later stages of the illness, patients may exhibit poor coordination, dementia and involuntary movements. The length of time between exposure and the development of symptoms is unclear, but is believed to be years. Average life expectancy following the onset of symptoms is 13 months. Cause Tainted beef In the UK, the primary cause of vCJD has been eating beef tainted with bovine spongiform encephalopathy. A 2012 study by the Health Protection Agency showed that around 1 in 2,000 people in the UK show signs of abnormal prion accumulation.Jonathan Quick, instructor of medicine at the Department of Global Health and Social Medicine at Harvard Medical School, stated that bovine spongiform encephalopathy or BSE is the first man-made epidemic, or "Frankenstein" disease, because a human decision to feed meat and bone meal to previously herbivorous cattle (as a source of protein) caused what was previously an animal pathogen to enter into the human food chain, and from there to begin causing humans to contract vCJD. Blood products As of 2018, evidence suggests that while there may be prions in the blood of individuals with vCJD this is not the case in individuals with sporadic CJD.In 2004, a report showed that vCJD can be transmitted by blood transfusions. The finding alarmed healthcare officials because a large epidemic of the disease could result in the near future. A blood test for vCJD infection is possible but is not yet available for screening blood donations. Significant restrictions exist to protect the blood supply. The UK government banned anyone who had received a blood transfusion since January 1980 from donating blood. Since 1999 there has been a ban in the UK for using UK blood to manufacture fractional products such as albumin. Whilst these restrictions may go some way to preventing a self-sustaining epidemic of secondary infections, the number of infected blood donations is unknown and could be considerable. In June 2013 the government was warned that deaths, then at 176, could rise five-fold through blood transfusions.On 28 May 2002, the United States Food and Drug Administration instituted a policy that excludes from blood donation anyone having spent at least six months in certain European countries (or three months in the United Kingdom) from 1980 to 1996. Given the large number of U.S. military personnel and their dependents residing in Europe, it was expected that over 7% of donors would be deferred due to the policy. Later changes to this policy have relaxed the restriction to a cumulative total of five years or more of civilian travel in European countries (six months or more if military). The three-month restriction on travel to the UK, however, has not been changed.In New Zealand, the New Zealand Blood Service (NZBS) in 2000 introduced measures to preclude permanently donors having resided in the United Kingdom (including the Isle of Man and the Channel Islands) for a total of six months or more between January 1980 and December 1996. The measure resulted in ten percent of New Zealands active blood donors at the time becoming ineligible to donate blood. In 2003, the NZBS further extended restrictions to permanently preclude donors having received a blood transfusion in the United Kingdom since January 1980, and in April 2006, restrictions were further extended to include the Republic of Ireland and France.Similar regulations are in place where anyone having spent more than six months for Germany or one year for France living in the UK between January 1980 and December 1996 is permanently banned from donating blood.In Canada, individuals are not eligible to donate blood or plasma if they have spent a cumulative total of three months or more in the UK, or France from 1 January 1980 to December 31, 1996. They are also ineligible if they have spent a cumulative total of five years or more in the Republic of Ireland since January 1, 1980 through 31 December 2001 or spent a cumulative total of six months or more in Saudi Arabia from January 1, 1980, through December 31, 1996 or if they have had a blood transfusion in the UK, France or Western Europe since 1980.In Poland, anyone having spent cumulatively six months or longer between 1 January 1980 and 31 December 1996 in the UK, Ireland, or France is permanently barred from donating.In France, anyone having lived or stayed in the United Kingdom a total of over one year between 1 January 1980 and 31 December 1996 is permanently barred from donating.In the Czech Republic, anyone having spent more than six months in the UK or France between the years 1980 and 1996 or received transfusion in the UK after the year 1980 is not allowed to donate blood.In Finland, anyone having lived or stayed in the British Isles a total of over six months between 1 January 1980 and 31 December 1996 is permanently barred from donating. Sperm donation In the U.S., the FDA has banned import of any donor sperm, motivated by a risk of variant Creutzfeldt-Jakob disease, inhibiting the once popular import of Scandinavian sperm. Despite this, the scientific consensus is that the risk is negligible, as there is no evidence Creutzfeldt–Jakob is sexually transmitted. Occupational contamination In France, the last two victims of variant Creutzfeldt-Jakob disease, who died in 2019 and 2021, were research technicians at the National Research Institute for Agriculture, Food and the Environment (INRAE). Emilie Jaumain, who died in 2019, at the age of 33, had been the victim of a work accident in 2010, during which she had pricked herself with a tool contaminated with infected brain. The efficacy of this route of contamination has been unambiguously demonstrated in primates. Pierrette C., who died in 2021, had been victim of the same type of work accident. After her diagnosis, a moratorium was initiated in all French laboratories on research activities on infectious prions. In March 2022, INRAE recognized the occupational cause of these two deaths. This raises serious questions about the safety of personnel in these laboratories. Indeed, inspections have noted serious failures in the protection of agents in the face of this deadly risk, and the long incubation period of this disease leads to fears of new cases in the future, hence great concern. Other causes Eating other types of brains such as those from squirrels is not recommended as one person contracted vCJD from eating the brain of a squirrel. Mechanism Despite the consumption of contaminated beef in the UK being high, vCJD has infected a small number of people. One explanation for this can be found in the genetics of people with the disease. The human PRNP protein which is subverted in prion disease can occur with either methionine or valine at amino acid 129, without any apparent physiological difference. Of the overall Caucasian population, about 40% have two methionine-containing alleles, 10% have two valine-containing alleles, and the other 50% are heterozygous at this position. Only a single person with vCJD tested was found to be heterozygous; most of those affected had two copies of the methionine-containing form. It is not yet known whether those unaffected are actually immune or only have a longer incubation period until symptoms appear. Diagnosis Definitive Examination of brain tissue is required to confirm a diagnosis of variant CJD. The following confirmatory features should be present: Numerous widespread kuru-type amyloid plaques surrounded by vacuoles in both the cerebellum and cerebrum – florid plaques. Spongiform change and extensive prion protein deposition shown by immunohistochemistry throughout the cerebellum and cerebrum. Suspected Current age or age at death less than 55 years (a brain autopsy is recommended, however, for all physician-diagnosed CJD cases). Psychiatric symptoms at illness onset and/or persistent painful sensory symptoms (frank pain and/or dysesthesia). Dementia, and development ≥4 months after illness onset of at least two of the following five neurologic signs: poor coordination, myoclonus, chorea, hyperreflexia, or visual signs. (If persistent painful sensory symptoms exist, ≥4 months delay in the development of the neurologic signs is not required). A normal or an abnormal EEG, but not the diagnostic EEG changes often seen in classic CJD. Duration of illness of over 6 months. Routine investigations do not suggest an alternative, non-CJD diagnosis. No history of getting human pituitary growth hormone or a dura mater graft from a cadaver. No history of CJD in a first degree relative or prion protein gene mutation in the person. Classification vCJD is a separate condition from classic Creutzfeldt–Jakob disease (though both are caused by PrP prions). Both classic and variant CJD are subtypes of Creutzfeldt–Jakob disease. There are three main categories of CJD disease: sporadic CJD, hereditary CJD, and acquired CJD, with variant CJD being in the acquired group along with iatrogenic CJD. The classic form includes sporadic and hereditary forms. Sporadic CJD is the most common type.ICD-10 has no separate code for vCJD and such cases are reported under the Creutzfeldt–Jakob disease code (A81.0). Epidemiology The Lancet in 2006 suggested that it may take more than 50 years for vCJD to develop, from their studies of kuru, a similar disease in Papua New Guinea. The reasoning behind the claim is that kuru was possibly transmitted through cannibalism in Papua New Guinea when family members would eat the body of a dead relative as a sign of mourning. In the 1950s, cannibalism was banned in Papua New Guinea. In the late 20th century, however, kuru reached epidemic proportions in certain Papua New Guinean communities, therefore suggesting that vCJD may also have a similar incubation period of 20 to 50 years. A critique to this theory is that while mortuary cannibalism was banned in Papua New Guinea in the 1950s, that does not necessarily mean that the practice ended. Fifteen years later Jared Diamond was informed by Papuans that the practice continued.These researchers noticed a genetic variation in some people with kuru that has been known to promote long incubation periods. They have also proposed that individuals having contracted CJD in the early 1990s represent a distinct genetic subpopulation, with unusually short incubation periods for bovine spongiform encephalopathy (BSE). This means that there may be many more people with vCJD with longer incubation periods, which may surface many years later.Prion protein is detectable in lymphoid and appendix tissue up to two years before the onset of neurological symptoms in vCJD. Large scale studies in the UK have yielded an estimated prevalence of 493 per million, higher than the actual number of reported cases. This finding indicates a large number of asymptomatic cases and the need to monitor. Society and culture In 1997, a number of people from Kentucky developed CJD. It was discovered that all had consumed squirrel brains. A coincidental relationship between the disease and this dietary practice may have been involved. In 2008, UK scientists expressed concern over the possibility of a second wave of human cases due to the wide exposure and long incubation of some cases of vCJD. In 2015, a man from New York developed vCJD after eating squirrel brains. From November 2017 to April 2018, four suspected cases of the disease arose in Rochester. United Kingdom Researchers believe one in 2,000 people in the UK is a carrier of the disease, linked to eating contaminated beef. The survey provides the most robust prevalence measure to date—and identifies abnormal prion protein across a wider age group than found previously and in all genotypes, indicating "infection" may be relatively common. This new study examined over 32,000 anonymous appendix samples. Of these, 16 samples were positive for abnormal prion protein, indicating an overall prevalence of 493 per million population, or one in 2,000 people are likely to be carriers. No difference was seen in different birth cohorts (1941–1960 and 1961–1985), in both sexes, and there was no apparent difference in abnormal prion prevalence in three broad geographical areas. Genetic testing of the 16 positive samples revealed a higher proportion of valine homozygous (VV) genotype on the codon 129 of the gene encoding the prion protein (PRNP) compared with the general UK population. This also differs from the 176 people with vCJD, all of whom to date have been methionine homozygous (MM) genotype. The concern is that individuals with this VV genotype may be susceptible to developing the condition over longer incubation periods. Human BSE foundation In 2000 a voluntary support group was formed by families of people who had died from vCJD. The goal was to support other families going through a similar experience. This support was provided through a National Helpline, a Carers Guide, a website and a network of family befriending. The support groups had an internet presence at the turn of the 21st century. The driving force behind the foundation was Lester Firkins, whose young son had died from the disease.In October 2000 the report of the government inquiry into BSE chaired by Lord Phillips was published. The BSE report criticised former Conservative Party Agriculture Ministers John Gummer, John MacGregor and Douglas Hogg. The report concluded that the escalation of BSE into a crisis was the result of intensive farming, particularly with cows being fed with cow and sheep remains. Furthermore, the report was critical of the way the crisis had been handled. There was a reluctance to consider the possibility that BSE could cross the species barrier. The government assured the public that British beef was safe to eat, with agriculture minister John Gummer famously feeding his daughter a burger. The British government were reactive more than proactive in response; the worldwide ban on all British beef exports in March 1996 was a serious economic blow.The foundation had been calling for compensation to include a care package to help relatives look after those with vCJD. There have been widespread complaints of inadequate health and social services support. Following the Phillips Report in October 2001, the government announced a compensation scheme for British people affected with vCJD. The multi-million-pound financial package was overseen by the vCJD Trust. A memorial plaque for those who have died due to vCJD was installed in central London in approximately 2000. It is located on the boundary wall of St Thomas Hospital in Lambeth facing the Riverside Walk of Albert Embankment. See also Jonathan Simms, a person who died from vCJD Mepacrine == References ==

You are a medical advisor. Your role is to break down medical terminology into clear, detailed explanations for a general audience.

Could you please explain the term 'Adenosine deaminase deficiency' in simple language?

Adenosine deaminase deficiency (ADA deficiency) is a metabolic disorder that causes immunodeficiency. It is caused by mutations in the ADA gene. It accounts for about 10–15% of all cases of autosomal recessive forms of severe combined immunodeficiency (SCID) among non-inbred populations.ADA deficiency can present in infancy, childhood, adolescence, or adulthood. Age of onset and severity is related to some 29 known genotypes associated with the disorder. It occurs in fewer than one in 100,000 live births worldwide. Signs and symptoms The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes. Affected children also grow much more slowly than healthy children and some have developmental delay. Most individuals with ADA deficiency are diagnosed with SCID in the first 6 months of life.An association with polyarteritis nodosa has been reported. Genetics The enzyme adenosine deaminase is encoded by the ADA gene on chromosome 20. ADA deficiency is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome (chromosome 20 is an autosome), and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.Age of onset and severity is related to some 29 known genotypes associated with the disorder. Pathophysiology ADA deficiency is due to a lack of the enzyme adenosine deaminase. This deficiency results in an accumulation of deoxyadenosine, which, in turn, leads to: a buildup of dATP in all cells, which inhibits ribonucleotide reductase and prevents DNA synthesis, so cells are unable to divide. Since developing T cells and B cells are some of the most mitotically active cells, they are highly susceptible to this condition. an increase in S-adenosylhomocysteine since the enzyme adenosine deaminase is important in the purine salvage pathway; both substances are toxic to immature lymphocytes, which thus fail to mature.Because T cells undergo proliferation and development in the thymus, affected individuals typically have a small, underdeveloped thymus. As a result, the immune system is severely compromised or completely lacking. Diagnosis The diagnosis is based on clinical features, with a concomitant decreased blood adenosine deaminase level supporting the diagnosis. Treatment Treatments include: bone marrow transplant ADA enzyme in PEG vehicle Gene therapy In September 1990, the first gene therapy to combat this disease was performed by Dr. William French Anderson on a four-year-old girl, Ashanti DeSilva, at the National Institutes of Health, Bethesda, Maryland, U.S.A. In April 2016 the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed and recommended for approval a stem cell gene therapy called Strimvelis, for children with ADA-SCID for whom no matching bone marrow donor is available. History ADA deficiency was discovered in 1972 by Eloise Giblett, a professor at the University of Washington. The ADA gene was used as a marker for bone marrow transplants. A lack of ADA activity was discovered by Giblett in an immunocompromised transplant candidate. After discovering a second case of ADA deficiency in an immunocompromised patient, ADA deficiency was recognized as the first immunodeficiency disorder. References Further reading Adenosine deaminase deficiency - Genetics Home Reference == External links ==

You function as a medical explainer. Your task is to convey the meanings of medical terms in a detailed, yet easy-to-understand manner.

I'm curious about the meaning of the medical term 'Olanzapine.' Can you give me some insights?

Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.Common side effects include weight gain, movement disorders, dizziness, feeling tired, constipation, and dry mouth. Other side effects include low blood pressure with standing, allergic reactions, neuroleptic malignant syndrome, high blood sugar, seizures, and tardive dyskinesia. In older people with dementia, its use increases the risk of death. Use in the later part of pregnancy may result in a movement disorder in the baby for some time after birth. Although how it works is not entirely clear, it blocks dopamine and serotonin receptors.Olanzapine was patented in 1991 and approved for medical use in the United States in 1996. It is available as a generic medication. In 2019, it was the 185th most commonly prescribed medication in the United States, with more than 3 million prescriptions. Lilly also markets olanzapine in a fixed-dose combination with fluoxetine as olanzapine/fluoxetine (Symbyax). Medical uses Schizophrenia The first-line psychiatric treatment for schizophrenia is antipsychotic medication, with olanzapine being one such medication. Olanzapine appears to be effective in reducing symptoms of schizophrenia, treating acute exacerbations, and treating early-onset schizophrenia. The usefulness of maintenance therapy, however, is difficult to determine, as more than half of people in trials quit before the 6-week completion date. Treatment with olanzapine (like clozapine) may result in increased weight gain and increased glucose and cholesterol levels when compared to most other second-generation antipsychotic drugs used to treat schizophrenia. Comparison The National Institute for Health and Care Excellence, the British Association for Psychopharmacology, and the World Federation of Societies for Biological Psychiatry suggest that little difference in effectiveness is seen between antipsychotics in prevention of relapse, and recommend that the specific choice of antipsychotic be chosen based on a persons preference and the drugs side-effect profile. The U.S. Agency for Healthcare Research and Quality concludes that olanzapine is not different from haloperidol in the treatment of positive symptoms and general psychopathology, or in overall assessment, but that it is superior for the treatment of negative and depressive symptoms. It has a lower risk of causing movement disorders than typical antipsychotics.In a 2013 comparison of fifteen antipsychotic drugs in schizophrenia, olanzapine was ranked third in efficacy. It was 5% more effective than risperidone (fourth), 24-27% more effective than haloperidol, quetiapine, and aripiprazole, and 33% less effective than clozapine (first). A 2013 review of first-episode schizophrenia concluded that olanzapine is superior to haloperidol in providing a lower discontinuation rate, and in short-term symptom reduction, response rate, negative symptoms, depression, cognitive function, discontinuation due to poor efficacy, and long-term relapse, but not in positive symptoms or on the clinical global impressions (CGI) score. In contrast, pooled second-generation antipsychotics showed superiority to first-generation antipsychotics only against the discontinuation, negative symptoms (with a much larger effect seen among industry- compared to government-sponsored studies), and cognition scores. Olanzapine caused less extrapyramidal side effects and less akathisia, but caused significantly more weight gain, serum cholesterol increase, and triglyceride increase than haloperidol.A 2012 review concluded that among ten atypical antipsychotics, only clozapine, olanzapine, and risperidone were better than first-generation antipsychotics. A 2011 review concluded that neither first- nor second-generation antipsychotics produce clinically meaningful changes in CGI scores, but found that olanzapine and amisulpride produce larger effects on the PANSS and BPRS batteries than five other second-generation antipsychotics or pooled first-generation antipsychotics. A 2010 Cochrane systematic review found that olanzapine may have a slight advantage in effectiveness when compared to aripiprazole, quetiapine, risperidone, and ziprasidone. No differences in effectiveness were detected when comparing olanzapine to amisulpride and clozapine. A 2014 meta-analysis of nine published trials having minimum duration six months and median duration 52 weeks concluded that olanzapine, quetiapine, and risperidone had better effects on cognitive function than amisulpride and haloperidol. Bipolar disorder Olanzapine is recommended by the National Institute for Health and Care Excellence as a first-line therapy for the treatment of acute mania in bipolar disorder. Other recommended first-line treatments are haloperidol, quetiapine, and risperidone. It is recommended in combination with fluoxetine as a first-line therapy for acute bipolar depression, and as a second-line treatment by itself for the maintenance treatment of bipolar disorder.The Network for Mood and Anxiety Treatments recommends olanzapine as a first-line maintenance treatment in bipolar disorder and the combination of olanzapine with fluoxetine as second-line treatment for bipolar depression.A review on the efficacy of olanzapine as maintenance therapy in patients with bipolar disorder was published by Dando & Tohen in 2006. A 2014 meta-analysis concluded that olanzapine with fluoxetine was the most effective among nine treatments for bipolar depression included in the analysis. Other uses Olanzapine may be useful in promoting weight gain in underweight adult outpatients with anorexia nervosa. However, no improvement of psychological symptoms was noted.Olanzapine has been shown to be helpful in addressing a range of anxiety and depressive symptoms in individuals with schizophrenia and schizoaffective disorders, and has since been used in the treatment of a range of mood and anxiety disorders. Olanzapine is no less effective than lithium or valproate and more effective than placebo in treating bipolar disorder. It has also been used for Tourette syndrome and stuttering.Olanzapine has been studied for the treatment of hyperactivity, aggressive behavior, and repetitive behaviors in autism.Olanzapine is frequently prescribed off-label for the treatment of insomnia, including difficulty falling asleep and staying asleep, even though such use is not recommended. The daytime sedation experienced with olanzapine is generally comparable to quetiapine and lurasidone, which is a frequent complaint in clinical trials. In some cases, the sedation due to olanzapine impaired the ability of people to wake up at a consistent time every day. Some evidence of efficacy for treating insomnia is seen; however, side effects such as dyslipidemia and neutropenia, which may possibly be observed even at low doses, outweigh any potential benefits for insomnia that is not due to an underlying mental health condition.Olanzapine has been recommended to be used in antiemetic regimens in people receiving chemotherapy that has a high risk for vomiting. Specific populations Pregnancy and lactation Olanzapine is associated with the highest placental exposure of any atypical antipsychotic. Despite this, the available evidence suggests it is safe during pregnancy, although the evidence is insufficiently strong to say anything with a high degree of confidence. Olanzapine is associated with weight gain, which according to recent studies, may put olanzapine-treated patients offspring at a heightened risk for neural tube defects (e.g. spina bifida). Breastfeeding in women taking olanzapine is advised against because olanzapine is secreted in breast milk, with one study finding that the exposure to the infant is about 1.8% that of the mother. Elderly Citing an increased risk of stroke, in 2004, the Committee on the Safety of Medicines in the UK issued a warning that olanzapine and risperidone, both atypical antipsychotic medications, should not be given to elderly patients with dementia. In the U.S., olanzapine comes with a black box warning for increased risk of death in elderly patients. It is not approved for use in patients with dementia-related psychosis. A BBC investigation in June 2008 found that this advice was being widely ignored by British doctors. Evidence suggested that the elderly are more likely to experience weight gain on olanzapine compared to aripiprazole and risperidone. Adverse effects The principal side effect of olanzapine is weight gain, which may be profound in some cases and/or associated with derangement in blood-lipid and blood-sugar profiles (see section metabolic effects). A 2013 meta-analysis of the efficacy and tolerance of 15 antipsychotic drugs (APDs) found that it had the highest propensity for causing weight gain out of the 15 APDs compared with an SMD of 0.74. Extrapyramidal side effects, although potentially serious, are infrequent to rare from olanzapine, but may include tremors and muscle rigidity. Aripiprazole, asenapine, clozapine, quetiapine and olanzapine, in comparison to other antipsychotic drugs, are less frequently associated with hyperprolactinaemia. Although these drugs can cause transient or sustained hyperprolactinaemia, the risk is much lower. Owing to its partial dopaminergic agonist effect, aripiprazole is likely to reduce prolactin levels and, in some patients, can cause hypoprolactinaemia. Although olanzapine causes an early dose-related rise in prolactin, this is less frequent and less marked than that seen with haloperidol, and is usually transient. A rise in prolactin is seen in about half of patients on olanzapine compared to over 90% of those taking risperidone, and enduring increases were less frequent in those taking olanzapine.It is not recommended to be used by IM injection in acute myocardial infarction, bradycardia, recent heart surgery, severe hypotension, sick sinus syndrome, and unstable angina.Several patient groups are at a heightened risk of side effects from olanzapine and antipsychotics in general. Olanzapine may produce nontrivial high blood sugar in people with diabetes mellitus. Likewise, the elderly are at a greater risk of falls and accidental injury. Young males appear to be at heightened risk of dystonic reactions, although these are relatively rare with olanzapine. Most antipsychotics, including olanzapine, may disrupt the bodys natural thermoregulatory systems, thus permitting excursions to dangerous levels when situations (exposure to heat, strenuous exercise) occur.Other side effects include galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction (impotence). Paradoxical effects Olanzapine is used therapeutically to treat serious mental illness. Occasionally, it can have the opposite effect and provoke serious paradoxical reactions in a small subgroup of people, causing unusual changes in personality, thoughts, or behavior; hallucinations and excessive thoughts about suicide have also been linked to olanzapine use. Drug-induced OCD Many different types of medication can create or induce pure obsessive-compulsive disorder (OCD) in patients who have never had symptoms before. A new chapter about OCD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (2013) now specifically includes drug-induced OCD. Metabolic effects The US Food and Drug Administration (FDA) requires all atypical antipsychotics to include a warning about the risk of developing hyperglycemia and diabetes, both of which are factors in the metabolic syndrome. These effects may be related to the drugs ability to induce weight gain, although some reports have been made of metabolic changes in the absence of weight gain. Studies have indicated that olanzapine carries a greater risk of causing and exacerbating diabetes than another commonly prescribed atypical antipsychotic, risperidone. Of all the atypical antipsychotics, olanzapine is one of the most likely to induce weight gain based on various measures. The effect is dose dependent in humans and animal models of olanzapine-induced metabolic side effects. There are some case reports of olanzapine-induced diabetic ketoacidosis. Olanzapine may decrease insulin sensitivity, though one 3-week study seems to refute this. It may also increase triglyceride levels.Despite weight gain, a large multicenter, randomized National Institute of Mental Health study found that olanzapine was better at controlling symptoms because patients were more likely to remain on olanzapine than the other drugs. One small, open-label, nonrandomized study suggests that taking olanzapine by orally dissolving tablets may induce less weight gain, but this has not been substantiated in a blinded experimental setting. Post-injection delirium/sedation syndrome Postinjection delirium/sedation syndrome (PDSS) is a rare syndrome that is specific to the long-acting injectable formulation of olanzapine, olanzapine pamoate. The incidence of PDSS with olanzapine pamoate is estimated to be 0.07% of administrations, and is unique among other second-generation, long-acting antipsychotics (e.g. paliperidone palmitate), which do not appear to carry the same risk. PDSS is characterized by symptoms of delirium (e.g. confusion, difficulty speaking, and uncoordinated movements) and sedation. Most people with PDSS exhibit both delirium and sedation (83%). Although less specific to PDSS, a majority of cases (67%) involved a feeling of general discomfort. PDSS may occur due to accidental injection and absorption of olanzapine pamoate into the bloodstream, where it can act more rapidly, as opposed to slowly distributing out from muscle tissue. Using the proper, intramuscular-injection technique for olanzapine pamoate helps to decrease the risk of PDSS, though it does not eliminate it entirely. This is why the FDA advises that people who are injected with olanzapine pamoate be watched for 3 hours after administration, in the event that PDSS occurs. Animal toxicology Olanzapine has demonstrated carcinogenic effects in multiple studies when exposed chronically to female mice and rats, but not male mice and rats. The tumors found were in either the liver or mammary glands of the animals. Discontinuation The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly, vertigo, numbness, or muscle pains may occur. Symptoms generally resolve after a short time.Tentative evidence indicates that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely, tardive dyskinesia can occur when the medication is stopped. Overdose Symptoms of an overdose include tachycardia, agitation, dysarthria, decreased consciousness, and coma. Death has been reported after an acute overdose of 450 mg, but also survival after an acute overdose of 2000 mg. Fatalities generally have occurred with olanzapine plasma concentrations greater than 1000 ng/mL post mortem, with concentrations up to 5200 ng/mL recorded (though this might represent confounding by dead tissue, which may release olanzapine into the blood upon death). No specific antidote for olanzapine overdose is known, and even physicians are recommended to call a certified poison control center for information on the treatment of such a case. Olanzapine is considered moderately toxic in overdose, more toxic than quetiapine, aripiprazole, and the SSRIs, and less toxic than the monoamine oxidase inhibitors and tricyclic antidepressants. Interactions Drugs or agents that increase the activity of the enzyme CYP1A2, notably tobacco smoke, may significantly increase hepatic first-pass clearance of olanzapine; conversely, drugs that inhibit CYP1A2 activity (examples: ciprofloxacin, fluvoxamine) may reduce olanzapine clearance. Carbamazepine, a known enzyme inducer, has decreased the concentration/dose ration of olanzapine by 33% compared to olanzapine alone. Another enzyme inducer, ritonavir, has also been shown to decrease the bodys exposure to olanzapine, due to its induction of the enzymes CYP1A2 and uridine 5-diphospho-glucuronosyltransferase (UGT).Probenecid increases the total exposure (area under the curve) and maximum plasma concentration of olanzapine. Although olanzapines metabolism includes the minor metabolic pathway of CYP2D6, the presence of the CYP2D6 inhibitor fluoxetine does not have a clinically significant effect on olanzapines clearance. Pharmacology Pharmacodynamics Olanzapine was first discovered while searching for a chemical analog of clozapine that would not require hematological monitoring. Investigation on a series of thiophene isosteres on 1 of the phenyl rings in clozapine, a thienobenzodiazepine analog (olanzapine) was discovered.Olanzapine has a higher affinity for 5-HT2A serotonin receptors than D2 dopamine receptors, which is a common property of most atypical antipsychotics, aside from the benzamide antipsychotics such as amisulpride along with the nonbenzamides aripiprazole, brexpiprazole, blonanserin, cariprazine, melperone, and perospirone. Olanzapine had the highest affinity of any second-generation antipsychotic towards the P-glycoprotein in one in vitro study. P-glycoprotein transports a myriad of drugs across a number of different biological membranes (found in numerous body systems) including the blood-brain barrier (a semipermeable membrane that filters the contents of blood prior to it reaching the brain); P-GP inhibition could mean that less brain exposure to olanzapine results from this interaction with the P-glycoprotein. A relatively large quantity of commonly encountered foods and medications inhibit P-GP, and pharmaceuticals fairly commonly are either substrates of P-GP, or inhibit its action; both substrates and inhibitors of P-GP effectively increase the permeability of the blood-brain barrier to P-GP substrates and subsequently increase the central activity of the substrate, while reducing the local effects on the GI tract. The mediation of olanzapine in the central nervous system by P-GP means that any other substance or drug that interacts with P-GP increases the risk for toxic accumulations of both olanzapine and the other drug.Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetogenic side effects. Additionally, it also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites.The antagonistic effects of olanzapine at 5-HT2c, histaminergic H1, and muscarinic M3 receptors have been implicated in weight gain.The mode of action of olanzapines antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia (TD), and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation; in addition, it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, but it offers no protection against the development of TD. In common with other second-generation (atypical) antipsychotics, olanzapine poses a relatively low risk of extrapyramidal side effects including TD, due to its higher affinity for the 5HT2A receptor over the D2 receptor.Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation. Pharmacokinetics Metabolism Olanzapine is metabolized by the cytochrome P450 (CYP) system; principally by isozyme 1A2 (CYP1A2) and to a lesser extent by CYP2D6. By these mechanisms, more than 40% of the oral dose, on average, is removed by the hepatic first-pass effect. Clearance of olanzapine appears to vary by sex; women have roughly 25% lower clearance than men. Clearance of olanzapine also varies by race; in self-identified African Americans or Blacks, olanzapines clearance was 26% higher. A difference in the clearance is not apparent between individuals identifying as Caucasian, Chinese, or Japanese. Routine, pharmacokinetic monitoring of olanzapine plasma levels is generally unwarranted, though unusual circumstances (e.g. the presence of drug-drug interactions) or a desire to determine if patients are taking their medicine may prompt its use. Chemistry Olanzapine is unusual in having four well-characterised crystalline polymorphs and many hydrated forms. Chemical synthesis The preparation of olanzapine was first disclosed in a series of patents from Eli Lilly & Co. in the 1990s. In the final two steps, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile was reduced with stannous chloride in ethanol to give the substituted thienobenzodiazepine ring system, and this was treated with methylpiperazine in a mixture of dimethyl sulfoxide and toluene as solvent to produce the drug. Society and culture Regulatory status Olanzapine is approved by the US FDA for: Treatment—in combination with fluoxetine—of depressive episodes associated with bipolar disorder (December 2003).Long-term treatment of bipolar I disorder (January 2004). Long-term treatment—in combination with fluoxetine—of resistant depression (March 2009) Oral formulation: acute and maintenance treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder (monotherapy and in combination with lithium or sodium valproate) Intramuscular formulation: acute agitation associated with schizophrenia and bipolar I mania in adults Oral formulation combined with fluoxetine: treatment of acute depressive episodes associated with bipolar I disorder in adults, or treatment of acute, resistant depression in adults Treatment of the manifestations of psychotic disorders (September 1996 – March 2000).Short-term treatment of acute manic episodes associated with bipolar I disorder (March 2000) Short-term treatment of schizophrenia instead of the management of the manifestations of psychotic disorders (March 2000) Maintaining treatment response in schizophrenic patients who had been stable for about eight weeks and were then followed for a period of up to eight months (November 2000)The drug became generic in 2011. Sales of Zyprexa in 2008 were $2.2 billion in the US and $4.7 billion worldwide. Controversy and litigation Eli Lilly has faced many lawsuits from people who claimed they developed diabetes or other diseases after taking Zyprexa, as well as by various governmental entities, insurance companies, and others. Lilly produced a large number of documents as part of the discovery phase of this litigation, which started in 2004; the documents were ruled to be confidential by a judge and placed under seal, and later themselves became the subject of litigation.In 2006, Lilly paid $700 million to settle around 8,000 of these lawsuits, and in early 2007, Lilly settled around 18,000 suits for $500 million, which brought the total Lilly had paid to settle suits related to the drug to $1.2 billion.A December 2006 New York Times article based on leaked company documents concluded that the company had engaged in a deliberate effort to downplay olanzapines side effects. The company denied these allegations and stated that the article had been based on cherry-picked documents. The documents were provided to the Times by Jim Gottstein, a lawyer who represented mentally ill patients, who obtained them from a doctor, David Egilman, who was serving as an expert consultant on the case. After the documents were leaked to online peer-to-peer, file-sharing networks by Will Hall and others in the psychiatric survivors movement, who obtained copies, in 2007 Lilly filed a protection order to stop the dissemination of some of the documents, which Judge Jack B. Weinstein of the Brooklyn Federal District Court granted. Judge Weinstein also criticized the New York Times reporter, Gottstein, and Egilman in the ruling. The Times of London also received the documents and reported that as early as 1998, Lilly considered the risk of drug-induced obesity to be a "top threat" to Zyprexa sales. On October 9, 2000, senior Lilly research physician Robert Baker noted that an academic advisory board to which he belonged was "quite impressed by the magnitude of weight gain on olanzapine and implications for glucose."Lilly had threatened Egilman with criminal contempt charges regarding the documents he took and provided to reporters; in September 2007, he agreed to pay Lilly $100,000 in return for the companys agreement to drop the threat of charges.In September 2008, Judge Weinstein issued an order to make public Lillys internal documents about the drug in a different suit brought by insurance companies, pension funds, and other payors.In March 2008, Lilly settled a suit with the state of Alaska, and in October 2008, Lilly agreed to pay $62 million to 32 states and the District of Columbia to settle suits brought under state consumer protection laws.In 2009, Eli Lilly pleaded guilty to a US federal criminal misdemeanor charge of illegally marketing Zyprexa for off-label use and agreed to pay $1.4 billion. The settlement announcement stated "Eli Lilly admits that between September 1999 and March 31, 2001, the company promoted Zyprexa in elderly populations as treatment for dementia, including Alzheimer’s dementia. Eli Lilly has agreed to pay a $515 million criminal fine and to forfeit an additional $100 million in assets."The outcomes described here, and their legal ramifications, were fueled by motions and appeals that were not resolved until 2010. In 2021, Gottstein summarized this tangle of legal activities, and their impact on the political landscape of psychiatry and antipsychiatry in the US, in The Zyprexa Papers. Trade names Olanzapine is generic and available under many trade names worldwide. Dosage forms Olanzapine is marketed in a number of countries, with tablets ranging from 2.5 to 20 mg. Zyprexa (and generic olanzapine) is available as an orally disintegrating "wafer", which rapidly dissolves in saliva. It is also available in 10-mg vials for intramuscular injection. Research Olanzapine has been studied as an antiemetic, particularly for the control of chemotherapy-induced nausea and vomiting (CINV).In general, olanzapine appears to be about as effective as aprepitant for the prevention of CINV, though some concerns remain for its use in this population. For example, concomitant use of metoclopramide or haloperidol increases the risk for extrapyramidal symptoms. Otherwise, olanzapine appears to be fairly well tolerated for this indication, with somnolence being the most common side effect.Olanzapine has been considered as part of an early psychosis approach for schizophrenia. The Prevention through Risk Identification, Management, and Education study, funded by the National Institute of Mental Health and Eli Lilly, tested the hypothesis that olanzapine might prevent the onset of psychosis in people at very high risk for schizophrenia. The study examined 60 patients with prodromal schizophrenia, who were at an estimated risk of 36–54% of developing schizophrenia within a year, and treated half with olanzapine and half with placebo. In this study, patients receiving olanzapine did not have a significantly lower risk of progressing to psychosis. Olanzapine was effective for treating the prodromal symptoms, but was associated with significant weight gain. References External links "Olanzapine". Drug Information Portal. U.S. National Library of Medicine. Alex B (5 January 2007). "Lilly Settles With 18,000 Over Zyprexa". The New York Times.

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I'm seeking clarification on the medical term 'Esophageal candidiasis.' Could you explain it?

Esophageal candidiasis is an opportunistic infection of the esophagus by Candida albicans. The disease usually occurs in patients in immunocompromised states, including post-chemotherapy and in AIDS. However, it can also occur in patients with no predisposing risk factors, and is more likely to be asymptomatic in those patients. It is also known as candidal esophagitis or monilial esophagitis. Signs and symptoms People with esophageal candidiasis typically present with difficult or painful swallowing. Longstanding esophageal candidiasis can result in weight loss. There is often concomitant thrush in the mouth. Some patients present with esophageal candidiasis as a first presentation of systemic candidiasis. Diagnosis In most cases, the diagnosis is established based on response to therapy. Patients in whom esophageal candidiasis is suspected should receive a brief course of antifungal therapy with fluconazole. If the infection resolves after treatment with fluconazole, then the diagnosis of esophageal candidiasis is made and no further investigation is needed. However, if the infection persists or if there are other factors involved which may warrant further investigation, then patient will undergo an esophagogastroduodenoscopy if it is safe to do so. Endoscopy often reveals classic diffuse raised plaques that characteristically can be removed from the mucosa by the endoscope. Brushing or biopsy of the plaques shows yeast and pseudohyphae by histology that are characteristic of Candida species. Treatment The current first-line treatment is fluconazole, 200 mg. on the first day, followed by daily dosing of 100 mg. for at least 21 days total. Treatment should continue for 14 days after relief of symptoms. Other therapy options include: Nystatin is an effective treatment for mild esophageal candidiasis. It can be used as (swish, do not swallow) treatment for oral candidiasis that occurs with the use of asthma pumps. Oral fluconazole can be used for moderate to severe esophageal candidiasis (and oropharyngeal candidiasis). Other oral triazoles, such as itraconazole Caspofungin, used in refractory or systemic cases Amphotericin, used in refractory or systemic cases Mimidis, K; Papadopoulos, V; Margaritis, V; Thomopoulos, K; Gatopoulou, A; Nikolopoulou, V; Kartalis, G (February 2005). "Predisposing factors and clinical symptoms in HIV-negative patients with Candida oesophagitis: are they always present?". International Journal of Clinical Practice. 59 (2): 210–3. doi:10.1111/j.1742-1241.2004.00249.x. PMID 15854199. References == External links ==

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I'm encountering the term 'Primary sclerosing cholangitis' in medical literature. What's its definition?

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as yellow discoloration of the skin and eyes, itching, and abdominal pain. The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the intestines. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma. The underlying cause of PSC is unknown. Genetic susceptibility, immune system dysfunction, and abnormal composition of the gut flora may play a role. This is further suggested by the observation that around 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis.No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a liver transplant, but it can recur after transplantation. Many people affected by PSC require a liver transplant. PSC is a rare disease and most commonly affects people with IBD. About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD. Diagnosis usually occurs in people in their 30s or 40s. Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent. Men are affected more often than women. The disease was initially described in the mid-1800s, but was not fully characterized until the 1970s with the advent of improved medical-imaging techniques such as endoscopic retrograde cholangiopancreatography. Signs and symptoms Nearly half of people with PSC do not have symptoms, and are often incidentally discovered to have PSC due to abnormal liver function tests; however, a substantial proportion have debilitating signs and symptoms of the disease. Signs and symptoms of PSC may include severe itching and nonspecific fatigue. Yellowing of the skin and white portion of the eyes may also be seen. Enlargement of the liver and spleen are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC.Multiple episodes of life-threatening acute cholangitis (infection within the bile ducts) can be seen due to impaired drainage of the bile ducts, which increases the risk of infection. Dark urine due to excess conjugated bilirubin, which is water-soluble and excreted by the kidneys (i.e. choluria) Malabsorption, especially of fat, and steatorrhea (fatty stool), due to an inadequate amount of bile reaching the small intestine, leading to decreased levels of the fat-soluble vitamins, A, D, E, and K. Portal hypertension, a complication of cirrhosis, which can manifest with esophageal and parastomal varices as well as hepatic encephalopathy (mental status alteration/disturbance caused by liver dysfunction and shunting of blood away from the scarred liver; such that ammonia detoxification is reduced with concomitant encephalopathy) or ascites. Cause The exact cause of primary sclerosing cholangitis is unknown, and its pathogenesis is improperly understood. Although PSC is thought to be caused by autoimmune disease, it does not demonstrate a clear response to immunosuppressants. Thus, many experts believe it to be a complex, multifactorial (including immune-mediated) disorder and perhaps one that encompasses several different hepatobiliary diseases.Data have provided novel insights suggesting: an important association between the intestinal microbiota and PSC and a process referred to as cellular senescence and the senescence-associated secretory phenotype in the pathogenesis of PSC.In addition, longstanding, well-recognized associations are seen between PSC and human leukocyte antigen alleles (A1, B8, and DR3). Pathophysiology PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening (sclerosis) of these ducts due to scar formation, be it inside and/or outside the liver. The resulting scarring of the bile ducts obstructs the flow of bile, which further perpetuates bile duct and liver injury. Chronic impairment of bile flow due to blockage and dysfunctional bile transport (cholestasis) causes progressive biliary fibrosis and ultimately biliary cirrhosis and liver failure.The primary physiological function of bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K).Liver enlargement is seen due to portal hypertension caused by compression of portal veins by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain. Diagnosis PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out: serum alkaline phosphatase (ALP) > 1.5x the upper limit of normal for longer than 6 months cholangiography demonstrating biliary strictures or irregularity consistent with PSC liver biopsy consistent with PSC (if available)Historically, a cholangiogram would be obtained via endoscopic retrograde cholangiopancreatography (ERCP), which typically reveals "beading" (alternating strictures and dilation) of the bile ducts inside and/or outside the liver. Currently, the preferred option for diagnostic cholangiography, given its noninvasive yet highly accurate nature, is magnetic resonance cholangiopancreatography (MRCP), a magnetic resonance imaging technique. MRCP has unique strengths, including high spatial resolution, and can even be used to visualize the biliary tract of small animal models of PSC.Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels. For example, approximately 80% of people with PSC have perinuclear antineutrophil cytoplasmic antibodies (P-ANCA); however, this and other immunoglobulin findings are not specific to those with PSC and are of unclear clinical significance/consequence. Antinuclear antibodies and anti-smooth muscle antibody are found in 20-50% of PSC patients, and likewise are not specific for the disease,but may identify a subgroup of PSC patients who also have autoimmune hepatitis (i.e. PSC-AIH overlap syndrome).The differential diagnosis can include primary biliary cholangitis (formerly referred to as primary biliary cirrhosis), drug-induced cholestasis, cholangiocarcinoma, IgG4-related disease, post-liver transplantation nonanastomotic biliary strictures, and HIV-associated cholangiopathy. Primary sclerosing cholangitis and primary biliary cholangitis are distinct entities and exhibit important differences, including the site of tissue damage within the liver, associations with IBD, which includes ulcerative colitis and Crohns disease, response to treatment, and risks of disease progression. Classification Primary sclerosing cholangitis is typically classified into three subgroups based on whether the small and/or large bile ducts are affected. The subgroups of PSC include: Classic PSC Small-duct PSC PSC associated with autoimmune hepatitis Management No pharmacologic treatment has been approved by the U.S. Food and Drug Administration for PSC. Some experts recommend a trial of ursodeoxycholic acid (UDCA), a bile acid occurring naturally in small quantities in humans, as it has been shown to lower elevated liver enzyme numbers in patients with PSC and has proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clearly lead to improved liver histology and survival. Guidelines from the American Association for the Study of Liver Diseases and the American College of Gastroenterology do not support the use of UDCA but guidelines from the European Association for the Study of the Liver do endorse the use of moderate doses (13-15 milligrams per kilogram) of UDCA for PSC.Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with antipruritics (e.g. bile acid sequestrants such as cholestyramine); antibiotics to treat episodes of ascending cholangitis; and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (A, D, E, and K).ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile-duct cancer (cholangiocarcinoma).Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial ascending cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some experience disease recurrence afterward. The reasons why some patients develop recurrent PSC remains largely obscure, but surprisingly, those without recurrence of disease (hence protected from recurrence) are characterized by an increased presence of the potentially pathogenic Shigella species. Prognosis Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 years. Various models have been developed to help predict survival, but their use is generally best suited for research and not clinical purposes. A serum alkaline phosphatase less than 1.5 times the upper limit of normal has been associated with better outcomes, but its use in predicting long-term outcomes is unclear. An IgA isotype autoantibody to the pancreatic GP2 protein (anti-GP2 IgA antibody) is the first verified prognostic biomarker in PSC. The role of anti-GP2 IgA in PSC was simultaneously investigated and reported by two research groups, and later confirmed by others. Association was demonstrated between anti-GP2 IgA and progressive liver fibrosis, cholangiocarcinoma development and shorter transplantation free survival in PSC patients.Other markers which may be measured and monitored are a complete blood count, serum liver enzymes, bilirubin levels (usually grossly elevated), kidney function, and electrolytes. Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g., gross steatorrhea) are prominent. Related diseases The development of any of the cancers associated with PSC predicts a poor prognosis. Complications from PSC-associated cancers account for 40% of deaths from PSC. Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma, a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%. This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population. Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers, although consensus regarding the modality and interval has yet to be established. Similarly, a screening colonoscopy is recommended in people who receive a new diagnosis of primary sclerosing cholangitis since their risk of colorectal cancer is 10 times higher than that of the general population.PSC is strongly associated with IBD, in particular ulcerative colitis (UC) and to a lesser extent Crohns disease. As many as 5% of patients with IBD are co-diagnosed with PSC, and approximately 70% of people with PSC have IBD. Of note, the presence of colitis appears to be associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma) development, although this relationship remains poorly understood. Close monitoring of PSC patients is vital. Various forms of gallbladder disease such as gallstones and gallbladder polyps are also common in those with PSC. Approximately 25% of people with PSC have gallstones. Ultrasound surveillance of the gallbladder every year is recommended for people with PSC. Any person with PSC who is found to have a mass in the gallbladder should undergo surgical removal of the gallbladder due to the high risk of cholangiocarcinoma. Osteoporosis (hepatic osteodystrophy) and hypothyroidism are also associated with PSC.A 2–3:1 male-to-female predilection occurs in primary sclerosing cholangitis. PSC can affect men and women at any age, although it is commonly diagnosed in the fourth decade of life, most often in the presence of IBD. PSC progresses slowly and is often asymptomatic, so it can be present for years before it is diagnosed and before it causes clinically significant consequences. Relatively few data are available on the prevalence and incidence of PSC, with studies in different countries showing annual incidence of 0.068–1.3 per 100,000 people and prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with ulcerative colitis, the risk is likely higher in populations where UC is more common. In the United States, an estimated 29,000 individuals have PSC. Research Although no curative treatment is known, several clinical trials are underway that aim to slow progression of this liver disease. Obeticholic acid is being investigated as a possible treatment for PSC due to its antifibrotic effects. Simtuzumab is a monoclonal antibody against the profibrotic enzyme LOXL2 that is being developed as a possible therapy for PSC. Notable cases Chris Klug – professional snowboarder with PSC who had liver transplant Chris LeDoux – professional rodeo rider and country musician with PSC who died of cholangiocarcinoma Elena Baltacha – British professional tennis player, diagnosed with PSC at age 19 and died five months after being diagnosed with PSC-associated liver cancer (specifically cholangiocarcinoma) at the age of 30 Walter Payton – died of complications of PSC Kieron Dyer – professional footballer James Redford – director and son of Robert Redford who underwent two liver transplants due to PSC References External links Patient support organizations: www.pscpartners.org—based in the US www.pscpartners.ca—based in Canada www.pscsupport.org.au—based in Australia www.pscsupport.org.uk—based in the UK

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Could you please explain the term 'Werner syndrome' in simple language?

Werner syndrome (WS) or Werners syndrome, also known as "adult progeria", is a rare, autosomal recessive disorder which is characterized by the appearance of premature aging.Werner syndrome is named after the German scientist Otto Werner. He identified the syndrome in four siblings observed with premature aging, which he explored as the subject of his dissertation of 1904.It has a global incidence rate of less than 1 in 100,000 live births (although incidence in Japan and Sardinia is higher, affecting 1 in 20,000–40,000 and 1 in 50,000, respectively). 1,300 cases had been reported as of 2006. Affected individuals typically grow and develop normally until puberty; the mean age of diagnosis is twenty-four, often realized when the adolescent growth spurt is not observed. The youngest person diagnosed was six years old. The median and mean ages of death are 47–48 and 54 years, respectively. The main causes of death are cardiovascular disease and cancer. Presentation Werner syndrome patients exhibit growth retardation, short stature, premature graying of hair, alopecia (hair loss), wrinkling, prematurely aged faces with beaked noses, skin atrophy (wasting away) with scleroderma-like lesions, lipodystrophy (loss of fat tissues), abnormal fat deposition leading to thin legs and arms, and severe ulcerations around the Achilles tendon and malleoli (around ankles). Other symptoms include change in voice (weak, hoarse, high-pitched), atrophy of gonads leading to reduced fertility, bilateral cataracts (clouding of lens), premature arteriosclerosis (thickening and loss of elasticity of arteries), calcinosis (calcium deposits in blood vessels), atherosclerosis (blockage of blood vessels), type 2 diabetes, osteoporosis (loss of bone mass), telangiectasia, and malignancies. The prevalence of rare cancers, such as meningiomas, are increased in individuals with Werner syndrome. Gene expression Gene transcription changes found in WS cells are strikingly similar to those observed in normal aging. At the level of gene expression, WRN protein deficiency causes changes in the pattern of gene expression that markedly resemble those of normal old age. DNA methylation The blood of WS patients exhibits accelerated DNA methylation changes that are similar to those observed in normal aging according to a molecular biomarker of aging known as epigenetic clock. Diagnosis and clinical symptoms The mutation in the WRN gene that causes Werner syndrome is autosomal and recessive, meaning that sufferers must inherit a copy of the gene from each parent. Patients display rapid premature aging beginning in young adulthood, usually in their early twenties. Diagnosis is based on six cardinal symptoms: premature graying of the hair or hair loss, presence of bilateral cataracts, atrophied or tight skin, soft tissue calcification, sharp facial features, and an abnormal, high-pitched voice. Patients are generally short-statured due to absence of the adolescent growth spurt. Patients also display decreased fertility. The most common symptom of the six is premature graying and loss of hair. This is also generally the earliest observed symptom, with hair loss occurring first on the scalp and the eyebrows.Werner syndrome patients often have skin that appears shiny and tight, and may also be thin or hardened. This is due to atrophy of the subcutaneous tissue and dermal fibrosis. Over time, the characteristic facial features may be more apparent due to these skin conditions. Other associated skin conditions include ulcers, which are very difficult to treat in Werner syndrome patients, and are caused in part by decreased potential of skin cells for replication.WS cataracts are distinctly different from those of normal aging. They are associated with problems in the lens posterior cortex and subcapsular regions. These cataracts are generally treatable with cataract surgery, which should restore normal vision.Symptoms become apparent in the late teens and early twenties and continue to progress. Most patients live to about fifty years of age. The most common causes of death for people are associated diseases and complications, especially atherosclerosis and cancer. Associated diseases Werner syndrome patients are at increased risk for several other diseases, many associated with aging. Atherosclerosis, the thickening of artery walls due to cholesterol buildup, is one common complication. While normal atherosclerosis generally involves the major arteries, smaller arterioles are more likely to be affected. It is possible nervous system disorders are associated. Brain atrophy is present in 40% of patients. Osteoporosis, the loss of bone mineral density common in post-menopausal women, is another common symptom. In contrast with the normal population, the rate of osteoporosis is especially high for male patients. Diabetes mellitus is another common accompaniment. Skin ulcers occur in about 75% of patients – and can be difficult to treat. If skin ulcers become badly infected or develop gangrene, they often require amputation. Unlike most other related diseases and complications, these ulcers are not associated with normal aging.Patients are also at an increased risk of cancer, especially malignant melanoma. Soft-tissue sarcomas are the most common cancer types. Other types of skin cancer, other epithelial cancers such as thyroid and liver cancers, MDS (myelodysplastic syndrome), and MFH (malignant fibrous histiocytoma) are also prevalent among. Mutations in the WRN gene, especially single-nucleotide polymorphisms (SNPs), are associated with many of the cancers and other associated diseases. WRN SNPs correlate with cancers such as sarcomas and non-Hodgkin lymphomas, as well as diabetes and cardiovascular problems including atherosclerosis. Causes Approximately 90% of individuals presenting Werner syndrome have any of a range of mutations in the gene, WRN, the only gene currently attributed to cause Werner syndrome. WRN, which lies on chromosome 8 in humans, encodes the WRNp protein, a 1432 amino acid protein with a central domain resembling members of the RecQ helicases. RecQ helicases are a special type of helicase that function at unique times during DNA repair of doubled stranded breaks, which are a form of DNA damage that results in a break of both strands of DNA. Thus, RecQ helicases are important for maintaining DNA stability, and loss of function of these helicases has important implications in the development of Werner syndrome. In addition to the central domain, there are three exonuclease domains at the N-terminus and a Helicase and Ribonuclease D C-terminal (HRDC) domain at the C-terminus.When functioning normally, the WRN gene and its associated protein (WRNp) are important for maintaining genome stability. WRNp is active in unwinding DNA, a step necessary in DNA repair and DNA replication. Specifically, it has an important role in responding to replication malfunctions, particularly double-stranded breaks, and stalled replication machinery. WRNp may reactivate replication by preventing unwanted recombination processes from occurring or by promoting recombination, depending on the type of DNA damage. In addition, WRNp physically interacts with or binds to several other proteins that are involved in processing DNA. For example, when WRNp binds to RPA, its helicase activity is stimulated. WRNp also physically interacts with p53, a tumor suppressor gene that stops the formation of tumors and the progression of cancers, which inhibits the exonuclease activity of the WRNp. Since WRNps function depends on DNA, it is only functional when localized to the nucleus.Surprisingly, complete loss of WRN helicase activity does not cause clinical Werner syndrome. DNA repair processes The finding that WRN protein interacts with DNA-PKcs and the Ku protein complex, combined with evidence that WRN deficient cells produce extensive deletions at sites of joining of non-homologous DNA ends, suggests a role for WRN protein in the DNA repair process of non-homologous end joining (NHEJ). WRN protein also physically interacts with the major NHEJ factor X4L4 (XRCC4-DNA ligase 4 complex). X4L4 stimulates WRN exonuclease activity that likely facilitates DNA end processing prior to final ligation by X4L4.WRN protein appears to play a role in resolving recombination intermediate structures during homologous recombinational repair (HRR) of DNA double-strand breaks.WRN protein participates in a complex with RAD51, RAD54, RAD54B and ATR proteins in carrying out the recombination step during inter-strand DNA cross-link repair.Evidence was presented that WRN protein plays a direct role in the repair of methylation induced DNA damage. This process likely involves the helicase and exonuclease activities of WRN protein that operate together with DNA polymerase beta in long patch base excision repair. Effects on cell structure and function Mutations which cause Werner syndrome all occur at the regions of the gene which encode for protein, and not at non-coding regions. There are 35 different known mutations of WRN, which correspond to stop codons, insertions, or deletions that result in a frameshift mutation. These mutations can have a range of effects. They may decrease the stability of the transcribed messenger RNA (mRNA), which increases the rate at which they are degraded. With less mRNA, less is available to be translated into the WRNp protein. Mutations may also lead to the truncation (shortening) of the WRNp protein, leading to the loss of its nuclear localization signal sequence, thus it is no longer transported into the nucleus where it interacts with the DNA. This leads to a reduction in DNA repair. Furthermore, mutated proteins are more likely to be degraded than normal WRNp. Apart from causing defects in DNA repair, its aberrant association with p53 down-regulates the function of p53, leading to a reduction in p53-dependent apoptosis and increasing the survival of these dysfunctional cells. Cells of affected individuals also have reduced lifespan in culture, have more chromosome breaks and translocations and have extensive deletions.Patients with Werner syndrome lose the RecQ helicase activity in the WRN protein because of the loss of its C-terminus region, but the mechanism by which this happens is unclear. The loss of the helicase activity can have far-reaching consequences in terms of cell stability and mutation. One instance of these consequences involves telomeres. It is thought that the WRN helicase activity is important not only for DNA repair and recombination, but also for maintaining telomere length and stability. Thus, WRN helicase is important for preventing catastrophic telomere loss during DNA replication. In a normal cell, the telomeres (the ends of chromosomes) undergo repeated shortening during the cell cycle, which can prevent the cell from dividing and multiplying. This event can be counteracted by telomerase, an enzyme that extends the ends of the chromosomes by copying the telomeres and synthesizing an identical, but new end that can be added to the existing chromosome. However, patients with Werner syndrome often exhibit accelerated telomere shortening, indicating that there may be a connection between the loss of the WRN helicase activity and telomere and cell instability. While evidence shows that telomere dysfunction is consistent with the premature aging in WS, it has yet to be determined if it is the actual cause of the genomic instability observed in cells and the high rate of cancer in WS patients.Without the WRN protein, the interwoven pathways of DNA repair and telomere maintenance fail to suppress cancer and the aging symptoms seen in patients with WS. Events such as rapid telomere shortening cause Werner syndrome cells to exhibit low responses to overall cellular stress. In addition to telomere dysfunction, over-expression of oncogenes and oxidation can induce this type of response. High stress causes a synergistic effect, where WS cells become even more sensitive to agents that increase cell stress and agents that damage DNA. As a result, WS cells show a drastic reduction in replicative lifespan and enter into a stage of aging prematurely. The accumulation of these damaged cells due to telomere shortening over many years may be indicative of why Werner syndrome symptoms only appear after an individual is about twenty years old. Protection of DNA against oxidative damage WRN protein was found to have a specific role in preventing or repairing DNA damages resulting from chronic oxidative stress, particularly in slowly replicating cells. This finding suggested that WRN may be important in dealing with oxidative DNA damage that underlies normal aging (see DNA damage theory of aging). Diagnosis Treatment A cure for Werner syndrome has not yet been discovered. It is often treated by managing the associated diseases and relieving symptoms to improve quality of life. The skin ulcers that accompany WS can be treated in several ways, depending on the severity. Topical treatments can be used for minor ulcers, but are not effective in preventing new ulcers from occurring. In the most severe cases, surgery may be required to implant a skin graft or amputate a limb if necessary. Diseases commonly associated with Werner syndrome such as diabetes and cancer are treated in generally the same ways as they would be for a non-Werner syndrome individual. A change in diet and exercise can help prevent and control arteriosclerosis, and regular cancer screenings can allow for early detection of cancer.There is evidence that suggests that the cytokine-suppressive anti-inflammatory drug SB203580 may be a possible therapeutic option for patients with Werners syndrome. This drug targets the p38 signaling pathway, which may become activated as a result of genomic instability and stalled replication forks that are characteristic mutations in WS. This activation of p38 may play a role in the onset of premature cell aging, skin aging, cataracts, and graying of the hair. The p38 pathway has also been implicated in the inflammatory response that causes atherosclerosis, diabetes, and osteoporosis, all of which are associated with Werners syndrome. This drug has shown to revert the aged characteristics of young WS cells to those seen in normal, young cells and improve the lifespan of WS cells in vitro. SB203580 is in the clinical trial stages, and the same results have not yet been seen in vivo.In 2010, vitamin C supplementation was found to reverse the premature aging and several tissue dysfunctions in a genetically modified mouse model of the disease. Vitamin C supplementation also appeared to normalize several age-related molecular markers such as the increased levels of the transcription factor NF-κB. In addition, it decreases activity of genes activated in human Werner syndrome and increases gene activity involved in tissue repair. Supplementation of vitamin C is suspected to be beneficial in the treatment of human Werner syndrome, although there was no evidence of anti-aging activity in nonmutant mice. In general, treatments are available for only the symptoms or complications and not for the disease itself. History Otto Werner was the first to observe Werner syndrome in 1904 as a part of his dissertation research. As a German ophthalmologist, Werner described several progeria-like features and juvenile cataracts in many of his patients. He noticed these symptoms particularly in a family with four sequential children who all showed the characteristics of the syndrome at around the same age. He assumed the cause to be genetic, though most of his evidence was clinical. Between 1934 and 1941, two internists from New York, Oppenheimer and Kugel, coined the term "Werner Syndrome," igniting a wave of interest and research on the disease. During that time, Agatson and Gartner suggested a possible link between Werners syndrome and cancer. However, it was not until 1966 that there was a general consensus on the autosomal recessive mode of inheritance for the syndrome. By 1981, geneticists had located the WRN gene on chromosome 8, leading to its cloning in 1996. This cloning of the WRN was significant because it revealed the predicted WRN protein was made from a family of DNA helicases. Prior to 1996, Werner syndrome was thought to be a model for accelerated aging. Since the discovery of the gene, it has become clear that the premature aging displayed in Werner syndrome is not the same, on a cellular level, as normal aging. The role of WRN in DNA repair and its exonuclease and helicase activities have been the subject of many studies in recent years.Since the initial discovery in 1904, several other cases of Werner syndrome have been recorded. Many of these cases have occurred in Japan, where a founder effect has caused a higher incidence rate than in other populations. The incidence rate of Werner syndrome in Japan is approximately 1 case per 100 thousand people (1:100,000), a large contrast with the rate of incidence for the rest of the world, which is between 1:1,000,000 and 1:10,000,000. A founder effect is also apparent in Sardinia, where there have been 18 recorded cases of Werner syndrome. Society and culture On the episode "Stargazer in a Puddle" from the television series Bones, the victim has Werner syndrome. The team discovers in the course of the investigation that her mother killed her because she was dying of another disease, and worried that her daughter would have nobody to look after her afterwards, with the tragic twist that the mother began to recover from her disease after her daughters death.Werner syndrome is featured in the 1989 film The Fly II, starring Eric Stoltz, in which his character is born as a 2 year old baby. He never sleeps and grows 5 times his normal age due to his biological father having half fly genes from the first 1986 film The Fly.Werner syndrome is also featured in the 1996 film Jack, starring Robin Williams, in which his character ages four times faster than normal.In an early cutscene from the game Metal Gear Solid 4, Otacon cites "classic Werner syndrome" as the most likely cause of Solid Snakes premature aging, though he goes on to say that testing had been inconclusive. It is however later said that Solid Snakes body, created as a genetically engineered clone, had been designed to break down quickly.In season 3 episode 9, "The Ballad of Kevin and Tess", of the TV series The 4400, Kevin is said to have Werner syndrome to hide his real condition from the public.In The Invisible Man season 1 episode 6, "Impetus", the new character Gloria has an experimentally altered type of Werner syndrome that causes it to become contagious.The central character in Gail Tsukiyamas novel DREAMING WATER (2002) has Werners syndrome.In season 1 episode 8 "Cold Comfort" from TV series Dark Angel, a character has a "form of progeria, similar to Werner syndrome", due to genetic manipulation. With an appropriate treatment, her condition seems to be stabilized.In Resident Evil: The Final Chapter (2016), the deadly "T-Virus", which causes the viral pandemic in the Resident Evil film series, is revealed to be the cure for "adult progeria". James Marcus originally develops the virus to cure his young daughter Alicia Marcus.Ratsasan (2018), a Tamil movie (as well as its Telugu remake Rakshasudu), features a young man born with Werners and is a victim of childhood bullying due to his appearance and has bad experience proposing to a girl, who turns into serial killer and hunts down and kills school girls. See also References External links This article incorporates public domain text from The U.S. National Library of Medicine Werner Syndrome from GeneReviews, contains extensive information on the disorder

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The term 'Treprostinil' keeps coming up in medical discussions. What does it stand for?

Treprostinil, sold under the brand names Remodulin for infusion, Orenitram for oral, and Tyvaso for inhalation, is a vasodilator that is used for the treatment of pulmonary arterial hypertension. Treprostinil is a synthetic analog of prostacyclin (PGI2). Treprostinil was approved for use in the United States in May 2002.The drug can be given in various forms: IV, subcutaneous injection, oral inhalation, as well as oral extended-release tablets. The subcutaneous administration tends to be very painful. Medical uses Treprostinil is indicated for the treatment of pulmonary arterial hypertension in people with NYHA Class II-IV symptoms to diminish symptoms associated with exercise. It may be administered as a continuous subcutaneous infusion or continuous intravenous infusion; however, because of the risks associated with chronic indwelling central venous catheters, including serious blood stream infections, continuous intravenous infusion should be reserved for patients who are intolerant of the subcutaneous route, or in whom these risks are considered warranted. This medication is also available in inhaled and tablet forms. In people with pulmonary arterial hypertension requiring transition from epoprostenol sodium (Flolan), treprostinil is indicated to diminish the rate of clinical deterioration. The risks and benefits of each drug should be carefully considered prior to transition. Treprostinil therapy may be effective in treating Degos disease. Adverse effects Since treprostinil is a vasodilator, its antihypertensive effect may be compounded by other medications that affect the blood pressure, including calcium channel blockers, diuretics, and other vasodilating agents. Because of treprostinils inhibiting effect on platelet aggregation, there is an increased risk of bleeding, especially among patients who are also taking anticoagulants. It is not known whether treprostinil is excreted in breast milk. Caution is advised when administering this medication to nursing women. Caution is advised when administering treprostinil to patients who have impaired kidney or liver function.Common side effects depending on route of administration: 85% of patients report pain or other reaction at the infusion site. Other side effects may include headache, cough, throat irritation, diarrhea, nausea, rash, jaw pain, vasodilatation, dizziness, edema (swelling), pruritus (itching), and hypotension.Warnings: Abrupt interruption of the treprostinil infusion can lead to worsening of pulmonary hypertension symptoms, and should be avoided. Pharmacology Mechanism of action Treprostinil binds to the IP receptor in the lung tissue which will cause G protein activation and lead to three major effects: vasodilation, decreased cell proliferation and inhibition of platelet aggregation. Pharmacokinetics The pharmacokinetics of continuous subcutaneous treprostinil are linear over the dose range of 1.25 to 125 ng/kg/min (corresponding to plasma concentrations of about 15 pg/mL to 18,250 pg/m) and can be described by a two-compartment model. Dose proportionality at infusion rates greater than 125 ng/kg/min has not been studied. Treprostinil is substantially metabolized by the liver, but the involved enzymes are not currently known. Five metabolites (HU1 through HU5) have been described thus far. Based on the results of in vitro human hepatic cytochrome P450 studies, Remodulin does not inhibit CYP-1A2, 2C9, 2C19, 2D6, 2E1, or 3A. Whether Remodulin induces these enzymes has not been studied. Dosage and administration For infusion Treprostinil may be administered as a continuous subcutaneous infusion or continuous intravenous infusion via a small infusion pump that the patient must wear at all times. Treprostinil can be given subcutaneously by continuous infusion using an infusion set connected to an infusion pump, but also may be given intravenously via a central venous catheter if the patient is unable to tolerate subcutaneous administration because of severe site pain or reaction. Remodulin is supplied in 20 mL vials, containing treprostinil in concentrations of 1 mg/mL, 2.5 mg/mL, 5 mg/mL, and 10 mg/mL. Treprostinil can be administered subcutaneously as supplied. It must be diluted for intravenous infusion with either sterile water or a 0.9% sodium chloride solution prior to administration. The infusion rate is normally initiated at 1.25 ng/kg/min for new patients, but may be reduced to 0.625 ng/kg/min if the normal rate provokes unwanted side effects in the patient. The infusion rate of treprostinil should be increased no more than 1.25 ng/kg/min per week for the first month, then 2.5 ng/kg/min per week for the remaining duration of infusion. The infusion rate should ideally be high enough to improve symptoms of pulmonary hypertension, while minimizing unpleasant side effects (headache, nausea, emesis, restlessness, anxiety and infusion site pain or reaction). Dosage adjustments may be undertaken more often if tolerated. There is little experience with doses >40 ng/kg/min. Abrupt cessation of infusion should be avoided. Restarting a Remodulin infusion within a few hours after an interruption can be done using the same dose rate. Interruptions for longer periods may require the dose of Remodulin to be re-titrated. In patients with mild or moderate liver dysfunction, the initial dose of Remodulin should be decreased to 0.625 ng/kg/min ideal body weight and should be increased cautiously. Remodulin has not been studied in patients with severe liver dysfunction. No studies have been performed in patients with kidney dysfunction. No specific advice about dosing in patients with renal impairment can be given. Inhaled form The inhaled form of treprostinil was approved by the FDA in July 2009 and is marketed as the trade name Tyvaso. The inhaled form is used with a proprietary inhalation device supplied by the manufacturer. Patients use one ampule with inhalation solution a day, four times a day at least four hours apart. Oral form The oral form of treprostinil was approved by the FDA in December 2013 and is marketed as the trade name Orenitram. Orenitram is taken 2 or 3 times daily with food. History During the 1960s a U.K. research team, headed by Professor John Vane began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Working with a team from the Royal College of Surgeons, Vane discovered that aspirin and other oral anti-inflammatory drugs worked by inhibiting the synthesis of prostaglandins. This finding opened the door to a broader understanding of the role of prostaglandins in the body. Vane and a team from the Wellcome Foundation had identified a lipid mediator they called “PG-X,” which inhibited platelet aggregation. PG-X, which later would become known as prostacyclin, was 30 times more potent than any other known anti-aggregatory agent.By 1976, Vane and fellow researcher Salvador Moncada published the first paper on prostacyclin, in the scientific journal Nature. The collaboration produced a synthetic molecule which was given the name epoprostenol. But like native prostacyclin, the structure of the epoprostenol molecule proved to be unstable in solution, prone to rapid degradation. This presented a challenge for both in vitro experiments and clinical applications. To overcome this challenge, the research team that discovered prostacyclin was determined to continue the research in an attempt to build upon the success they had seen with the prototype molecule. The research team synthesized nearly 1,000 analogs.Remodulin was approved for use in the United States in May 2002, and again in July 2018. Tyvaso, the inhaled form of treprostinil, was approved for use in the United States in July 2009. Orenitram was approved in December 2013.Trepulmix was approved for use in the European Union in April 2020. Effect on PPARs Treprostinil has demonstrated an effect on PPAR-γ, a transcription factor important in vascular pathogenesis as a mediator of proliferation, inflammation and apoptosis. Through a complementary, yet cyclic AMP-independent pathway, treprostinil activates PPARs, another mechanism that contributes to the anti-growth benefits of the prostacyclin class. References Further reading External links "Treprostinil". Drug Information Portal. U.S. National Library of Medicine.

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I'm encountering the term 'Burning mouth syndrome' in medical literature. What's its definition?

Burning mouth syndrome (BMS) is a burning, tingling or scalding sensation in the mouth, lasting for at least four to six months, with no underlying known dental or medical cause. No related signs of disease are found in the mouth. People with burning mouth syndrome may also have a subjective xerostomia (dry mouth sensation where no cause can be found such as reduced salivary flow), paraesthesia (altered sensation such as tingling in the mouth), or an altered sense of taste or smell.A burning sensation in the mouth can be a symptom of another disease when local or systemic factors are found to be implicated; this is not considered to be burning mouth syndrome, which is a syndrome of medically unexplained symptoms. The International Association for the Study of Pain defines burning mouth syndrome as "a distinctive nosological entity characterized by unremitting oral burning or similar pain in the absence of detectable mucosal changes" and "burning pain in the tongue or other oral mucous membranes", and the International Headache Society defines it as "an intra-oral burning sensation for which no medical or dental cause can be found". To ensure the correct diagnosis of burning mouth syndrome, Research Diagnostic Criteria (RDC/BMS) have been developed.Insufficient evidence leaves it unclear if effective treatments exist. Signs and symptoms By definition, BMS has no signs. Sometimes affected persons will attribute the symptoms to sores in the mouth, but these are in fact normal anatomic structures (e.g. lingual papillae, varices). Symptoms of BMS are variable, but the typical clinical picture is given below, considered according to the Socrates pain assessment method (see table). If clinical signs are visible, then another explanation for the burning sensation may be present. Erythema (redness) and edema (swelling) of papillae on the tip of the tongue may be a sign that the tongue is being habitually pressed against the teeth. The number and size of filiform papillae may be reduced. If the tongue is very red and smooth, then there is likely a local or systemic cause (e.g. eythematous candidiasis, anemia). Causes Theories In about 50% of cases of burning mouth sensation no identifiable cause is apparent; these cases are termed (primary) BMS. Several theories of what causes BMS have been proposed, and these are supported by varying degrees of evidence, but none is proven. As most people with BMS are postmenopausal women, one theory of the cause of BMS is of estrogen or progesterone deficit, but a strong statistical correlation has not been demonstrated. Another theory is that BMS is related to autoimmunity, as abnormal antinuclear antibody and rheumatoid factor can be found in the serum of more than 50% of persons with BMS, but these levels may also be seen in elderly people who do not have any of the symptoms of this condition. Whilst salivary flow rates are normal and there are no clinical signs of a dry mouth to explain a complaint of dry mouth, levels of salivary proteins and phosphate may be elevated and salivary pH or buffering capacity may be reduced.Depression and anxiety are strongly associated with BMS. It is not known if depression is a cause or result of BMS, as depression may develop in any setting of constant unrelieved irritation, pain, and sleep disturbance. It is estimated that about 20% of BMS cases involve psychogenic factors, and some consider BMS a psychosomatic illness, caused by cancerophobia, concern about sexually transmitted infections, or hypochondriasis.Chronic low-grade trauma due to parafunctional habits (e.g. rubbing the tongue against the teeth or pressing it against the palate), may be involved. BMS is more common in persons with Parkinsons disease, so it has been suggested that it is a disorder of reduced pain threshold and increased sensitivity. Often people with BMS have unusually raised taste sensitivity, termed hypergeusia ("super tasters"). Dysgeusia (usually a bitter or metallic taste) is present in about 60% of people with BMS, a factor which led to the concept of a defect in sensory peripheral neural mechanisms. Changes in the oral environment, such as changes in the composition of saliva, may induce neuropathy or interruption of nerve transduction. The onset of BMS is often spontaneous, although it may be gradual. There is sometimes a correlation with a major life event or stressful period in life. In women, the onset of BMS is most likely three to twelve years following menopause. Other causes of an oral burning sensation Several local and systemic factors can give a burning sensation in the mouth without any clinical signs, and therefore may be misdiagnosed as BMS. Some sources state that where there is an identifiable cause for a burning sensation, this can be termed "secondary BMS" to distinguish it from primary BMS. However, the accepted definitions of BMS hold that there are no identifiable causes for BMS, and where there are identifiable causes, the term BMS should not be used.Some causes of a burning mouth sensation may be accompanied by clinical signs in the mouth or elsewhere on the body. For example, burning mouth pain may be a symptom of allergic contact stomatitis. This is a contact sensitivity (type IV hypersensitivity reaction) in the oral tissues to common substances such as sodium lauryl sulfate, cinnamaldehyde or dental materials. However, allergic contact stomatitis is accompanied by visible lesions and gives positive response with patch testing. Acute (short term) exposure to the allergen (the substance triggering the allergic response) causes non-specific inflammation and possibly mucosal ulceration. Chronic (long term) exposure to the allergen may appear as chronic inflammatory, lichenoid (lesions resembling oral lichen planus), or plasma cell gingivitis, which may be accompanied by glossitis and cheilitis. Apart from BMS itself, a full list of causes of an oral burning sensation is given below: Deficiency of iron, folic acid or various B vitamins (glossitis e.g. due to anemia), or zinc Neuropathy, e.g. following damage to the chorda tympani nerve. Hypothyroidism. Medications ("scalded mouth syndrome", unrelated to BMS) - protease inhibitors and angiotensin-converting-enzyme inhibitors (e.g. captopril). Type 2 diabetes True xerostomia, caused by hyposalivation e.g. Sjögrens syndrome Parafunctional activity, e.g. nocturnal bruxism or a tongue thrusting habit. Restriction of the tongue by poorly constructed dentures. Geographic tongue. Oral candidiasis. Herpetic infection (herpes simplex virus). Fissured tongue. Lichen planus. Allergies and contact sensitivities to foods, metals, and other substances (see table). Hiatal hernia. Human immunodeficiency virus. Multiple myeloma Diagnosis BMS is a diagnosis of exclusion, i.e. all other explanations for the symptoms are ruled out before the diagnosis is made. There are no clinically useful investigations that would help to support a diagnosis of BMS (by definition all tests would have normal results), but blood tests and / or urinalysis may be useful to rule out anemia, deficiency states, hypothyroidism and diabetes. Investigation of a dry mouth symptom may involve sialometry, which objectively determines if there is any reduction of the salivary flow rate (hyposalivation). Oral candidiasis can be tested for with use of a swabs, smears, an oral rinse or saliva samples. It has been suggested that allergy testing (e.g., patch test) is inappropriate in the absence of a clear history and clinical signs in people with a burning sensation in the mouth. The diagnosis of a people with a burning symptom may also involve psychologic screening e.g. depression questionnaires.The second edition of the International Classification of Headache Disorders lists diagnostic criteria for "Glossodynia and Sore Mouth": A. Pain in the mouth present daily and persisting for most of the day, B. Oral mucosa is of normal appearance, C. Local and systemic diseases have been excluded. Classification A burning sensation in the mouth may be primary (i.e. burning mouth syndrome) or secondary to systemic or local factors. Other sources refer to a "secondary BMS" with a similar definition, i.e. a burning sensation which is caused by local or systemic factors, or "where oral burning is explained by a clinical abnormality". However this contradicts the accepted definition of BMS which specifies that no cause can be identified. "Secondary BMS" could therefore be considered a misnomer. BMS is an example of dysesthesia, or a distortion of sensation.Some consider BMS to be a variant of atypical facial pain. More recently, BMS has been described as one of the 4 recognizable symptom complexes of chronic facial pain, along with atypical facial pain, temporomandibular joint dysfunction and atypical odontalgia. BMS has been subdivided into three general types, with type two being the most common and type three being the least common. Types one and two have unremitting symptoms, whereas type three may show remitting symptoms. Type 1 - Symptoms not present upon waking, and then increase throughout the day Type 2 - Symptoms upon waking and through the day Type 3 - No regular pattern of symptomsSometimes those terms specific to the tongue (e.g. glossodynia) are reserved for when the burning sensation is located only on the tongue. Treatment If a cause can be identified for a burning sensation in the mouth, then treatment of this underlying factor is recommended. If symptom persist despite treatment a diagnosis of BMS is confirmed. BMS has been traditionally treated by reassurance and with antidepressants, anxiolytics or anticonvulsants. A 2016 Cochrane review of treatment for burning mouth syndrome concluded that strong evidence of an effective treatment was not available, however, a systematic review in 2018 found that the use of antidepressants and alpha-lipoic acids gave promising results.Other treatments which have been used include atypical antipsychotics, histamine receptor antagonists, and dopamine agonists. Supplementation with vitamin complexes and cognitive behavioral therapy may be helpful in the management of burning mouth syndrome. Prognosis BMS is benign (importantly, it is not a symptom of oral cancer), but as a cause of chronic pain which is poorly controlled, it can detriment quality of life, and may become a fixation which cannot be ignored, thus interfering with work and other daily activities. Two thirds of people with BMS have a spontaneous partial recovery six to seven years after the initial onset, but in others the condition is permanent. Recovery is often preceded by a change in the character of the symptom from constant to intermittent. No clinical factors predicting recovery have been noted.If there is an identifiable cause for the burning sensation, then psychologic dysfunctions such as anxiety and depression often disappear if the symptom is successfully treated. Epidemiology BMS is fairly uncommon worldwide, affecting up to five individuals per 100,000 general population. People with BMS are more likely to be middle aged or elderly, and females are three to seven times more likely to have BMS than males. Some report a female to male ratio of as much as 33 to 1. BMS is reported in about 10-40% of women seeking medical treatment for menopausal symptoms, and BMS occurs in about 14% of postmenopausal women. Males and younger individuals of both sexes are sometimes affected.Asian and Native American people have considerably higher risk of BMS. Notable cases Sheila Chandra, a singer of Indian heritage, retired due to this condition. References Scala A; Checchi L; Montevecchi M; Marini I; Giamberardino MA (2003). "Update on burning mouth syndrome: overview and patient management". Crit Rev Oral Biol Med. 14 (4): 275–91. doi:10.1177/154411130301400405. PMID 12907696. == External links ==

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I'm seeking clarification on the medical term 'Isocarboxazid.' Could you explain it?

Isocarboxazid (Marplan, Marplon, Enerzer) is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class used as an antidepressant. Along with phenelzine and tranylcypromine, it is one of only three classical MAOIs still available for clinical use in the treatment of psychiatric disorders in the United States, though it is not as commonly employed in comparison to the others.Isocarboxazid is primarily used to treat mood and anxiety disorders. It has also been investigated in the treatment of schizophrenia, Parkinsons disease and other dementia-related disorders. Isocarboxazid, as well as other MAOIs, increase the levels of the monoamine neurotransmitters serotonin, dopamine, and norepinephrine in the brain.Classical MAOIs, including isocarboxazid, are used only rarely due to prominent food and drug interactions and have been largely superseded by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs). The cause of the interactions is because MAOIs inhibit the metabolism of dietary amines (e.g., tyramine) and the monoamine neurotransmitters. In combination with other drugs that increase the levels of the monoamine neurotransmitters such as the SSRIs, or with certain foods high in dietary amines such as aged cheeses, MAOIs can produce dangerous elevations of monoamine neurotransmitters resulting in potentially life-threatening syndromes such as hypertensive crisis and serotonin syndrome. See also Hydrazine (antidepressant) == References ==

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I've encountered the term 'Terbinafine' while reading about medical topics. What does it refer to exactly?

Terbinafine, sold under the brand name Lamisil among others, is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athletes foot. It is either taken by mouth or applied to the skin as a cream or ointment. The cream and ointment are not effective for nail infections.Common side effects when taken by mouth include nausea, diarrhea, headache, cough, rash, and elevated liver enzymes. Severe side effects include liver problems and allergic reactions. Liver injury is, however, unusual. Use during pregnancy is not typically recommended. The cream and ointment may result in itchiness but are generally well tolerated. Terbinafine is in the allylamines family of medications. It works by decreasing the ability of fungi to synthesize sterols. It appears to result in fungal cell death.Terbinafine was discovered in 1991. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 307th most commonly prescribed medication in the United States, with more than one million prescriptions. Medical uses Terbinafine is mainly effective on fungi of the group Onygenales and some yeasts in the genus Candida (e.g. Candida glabrata) As a cream or powder, it is used topically for superficial skin infections such as jock itch (tinea cruris), athletes foot (tinea pedis), and other types of ringworm (tinea corporis).Tablets by mouth are often prescribed for the treatment of onychomycosis, a fungal nail infection, typically by a dermatophyte or Candida species. Fungal nail infections are located deep under the nail in the cuticle to which topically applied treatments are unable to penetrate in sufficient amounts. The tablets may, rarely, cause hepatotoxicity, so patients are warned of this and may be monitored with liver function tests. Alternatives to oral administration have been studied. Terbinafine may induce or exacerbate subacute cutaneous lupus erythematosus. Persons with lupus erythematosus should first discuss possible risks with their doctor before initiation of therapy. Side effects Many side effects and adverse drug reactions have been reported with oral terbinafine hydrochloride possibly due to its extensive biodistribution and the often extended durations involved in antifungal treatment (longer than two months). A comprehensive list of adverse events associated with terbinafine use includes: Gastrointestinal problems: Diarrhea, constipation, nausea, fullness, abdominal pain, indigestion, dyspepsia, gastritis, cholestasis, flatulence, altered stool colour, abdominal muscular pain Central nervous system or neurological problems: Headaches, dizziness, vertigo, light-headedness, decreased concentration levels, paraesthesia (pins and needles) Hepatic problems: Raised liver enzyme levels, liver inflammation (hepatitis), liver damage, liver failure Immune system problems: Decreased white blood cell counts including pancytopenia, leukopenia, lymphopenia, thrombocytopenia, agranulocytosis, and neutropenia, autoimmune reactions such as lupus erythematosus Psychological problems: Depression, anxiety, insomnia, increased or unusual dream activity, malaise Sensory problems: Complete loss of taste (ageusia), decreased taste (hypogeusia) and distorted taste (dysgeusia), often involving a metallic taste sensation and dry mouth, visual disturbances including blurred vision, green vision and double vision. In extremely rare cases, the loss or impairment of taste is permanent Skin problems: Rashes, hives (urticaria), skin irritation, itching, jaundice, Stevens–Johnson syndrome Other side effects: Fatigue, increased heart rate (tachycardia), hair loss (alopecia), decreased red blood cell count (anemia), muscle pain (myalgia), joint pain (arthralgia)In 2015 physicians reported that a patient with an MTHFR enzyme mutation (specifically the C677T variant) had developed an adverse reaction to Lamisil (headache, fatigue, and dizziness). Genetic testing revealed the MTHFR C677T mutation. It was noted that Lamisil interferes with the methylation cycle and that this can cause side effects in individuals with the MTHFR C677T mutation. Pharmacology Like other allylamines, terbinafine inhibits ergosterol synthesis by inhibiting squalene epoxidase, an enzyme that catalyzes the conversion of squalene to lanosterol. In fungi, lanosterol is then converted to ergosterol; in humans, lanosterol becomes cholesterol. However, as fungi and animals diverged around 1.1 billion years ago - there is enough difference in this enzyme that terbinafine preferentially binds fungal squalene epoxidase, making it selective for inhibiting ergosterol production in fungi without significantly affecting cholesterol production in mammals. This is thought to fatally disrupt the fungal cell membrane. Terbinafine is highly lipophilic and tends to accumulate in hair, skin, nails, and fat cells. This accumulation results in therapeutic levels of terbinafine even after 80 days following one week treatment of 250 mg/day. Different dosing schedules have been proposed such as 500 mg/day for one week or 250 mg/day for two weeks each followed by a drug-free period of three or two weeks, totaling 3 months of treatment including the drug-free periods. Such intermittent dosing schedules appear to be as effective as continuous regimes. Chemistry Terbinafine hydrochloride is a white crystalline powder that is freely soluble in methanol and dichloromethane, soluble in ethanol, and slightly soluble in water.Terbinafine is produced from olefin metathesis of 1,3-dichloropropene and neohexene followed by reaction with N-methyl-1-naphthalenemethanamine.Despite its name it does not contain terbium. History Terbinafine first became available in Europe in 1991 and in the United States in 1996. The U.S. Food and Drug Administration has approved the first generic versions of prescription Lamisil (terbinafine hydrochloride) tablets. The remaining patent or exclusivity for Lamisil expired on June 30, 2007. On September 28, 2007, the FDA stated that terbinafine is a new treatment approved for use by children age four and up. The antifungal granules can be sprinkled on a childs food to treat ringworm of the scalp, tinea capitis.In the United States the price in 1999 was $547 for a 12-week course; this fell to $10 by 2015, after the patent had expired. Society and culture Brand names Terbinafine is sold in India as Terboderm by Omega Pharma and Tyza (Abbott Healthcare). Lamisil in Argentina, Australia, Bangladesh, Belgium, Brazil, Canada, Chile, Colombia, Croatia, Egypt, the Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Mexico, the Netherlands, New Zealand, Norway, Pakistan (لیمسل), Peru, the Philippines, Romania, Russia, Slovakia, Slovenia, South Africa, Sweden, Thailand, the United Kingdom, the United States, and Venezuela Corbinal and Terbisil in Turkey, Pakistan, Undofen in Poland, and Terbistad (Stada Arzneimittel). As a generic oral medication, it is sold as Sebifin, Tinasil, Terbisil, Terbicor, and Tamsil in Australia, whilst the generic topical medication is sold there as SolvEasyTinea and Tamsil. It is also available as a generic medication in the United States, the United Kingdom, Belgium, Switzerland, Brazil, Mexico, Canada and France. In India, terbinafine hydrochloride is available in topical form under the brand names Triabin by Medley Pharmaceuticals, Sebifin (Sun Pharma), Zimig (GSK Pharma) and mycoCeaze (Progreś Laboratories). MycoVa, developed by Apricus Biosciences, is a topical nail solution of terbinafine and DDAIP, which has completed three phase-III studies for the treatment of onychomycosis. Other names include Terbinaforce (Mankind Pharma) and Tafine (Deurali Janta Pharmaceuticals Pvt Ltd.) Turbo (Apex Pharmaceuticals Pvt Ltd) in Nepal. The topical form is sold as Lamisil AT in the United States. References External links "Terbinafine". Drug Information Portal. U.S. National Library of Medicine.

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I'm not familiar with the medical term 'High-altitude cerebral edema.' Could you provide some insights?

High-altitude cerebral edema (HACE) is a medical condition in which the brain swells with fluid because of the physiological effects of traveling to a high altitude. It generally appears in patients who have acute mountain sickness and involves disorientation, lethargy, and nausea among other symptoms. It occurs when the body fails to acclimatize while ascending to a high altitude. It appears to be a vasogenic edema (fluid penetration of the blood–brain barrier), although cytotoxic edema (cellular retention of fluids) may play a role as well. Individuals with the condition must immediately descend to a lower altitude or coma and death can occur. Patients are usually given supplemental oxygen and dexamethasone as well. HACE can be prevented by ascending to heights slowly to allow the body more time to acclimatize. Acetazolamide also helps prevent the condition. Untreated patients usually die within 48 hours. Those who receive treatment may take weeks to fully recover. It is a rare condition, occurring in less than one percent of people who ascend to 4,000 metres (13,000 ft). Although it was first described in 1913, little was known about the cause of the condition until MRI studies were performed in the 1990s. Signs and symptoms Early symptoms of HACE generally correspond with those of moderate to severe acute mountain sickness (AMS). Initial symptoms of HACE commonly include confusion, loss of consciousness, fever, ataxia, photophobia, rapid heart beat, lassitude, and an altered mental state. Those affected generally attempt to cease physical activities, regardless of their necessity for survival. Severe headaches develop and people lose the ability to sit up. Retinal venous dilation occurs in 59% of people with HACE. Rarer symptoms include brisk deep tendon reflexes, retinal hemorrhages, blurred vision, extension plantar reflexes, and ocular paralysis. Cranial nerve palsies occur in some unusual cases.In the bestselling 1996 non-fiction book Into Thin Air: A Personal Account of the Mt. Everest Disaster, Jon Krakauer describes the effects of HACE upon Dale Kruse, a forty-four-year-old dentist and one of the members of Scott Fischers team: Kruse was having an incredibly difficult time simply trying to dress himself. He put his climbing harness on inside out, threaded it through the fly of his wind suit, and failed to fasten the buckle; fortunately, Fischer and Neal Beidleman noticed the screwup before Kruse started to descend. "If hed tried to rappel down the ropes like that," says Beidleman, "he would have immediately popped out of his harness and fallen to the bottom of the Lhotse Face." "It was like I was very drunk," Kruse recollects. "I couldnt walk without stumbling, and completely lost the ability to think or speak. It was a really strange feeling. Id have some word in my mind, but I couldnt figure out how to bring it to my lips. So Scott and Neal had to get me dressed and make sure my harness was on correctly, then Scott lowered me down the fixed ropes." By the time Kruse arrived in Base Camp, he says, "it was still another three or four days before I could walk from my tent to the mess tent without stumbling all over the place." Patients with HACE have an elevated white blood cell count, but otherwise their blood count and biochemistry are normal. If a lumbar puncture is performed, it will show normal cerebral spinal fluid and cell counts but an increase in pressure. In one study, CT scans of patients with HACE exhibited ventricle compression and low density in the cerebellum. Only a few autopsies have been performed on fatal cases of HACE; they showed swollen gyri, spongiosis of white matter, and compressed sulci. There was some variation between individuals, and the results may not be typical of HACE deaths. Mechanism Most people who travel to high altitudes acclimatize. Acclimatization precludes the development of HACE by maintaining adequate levels of cerebral oxygen. The primary cause of HACE is hypoxia (oxygen deprivation). This occurs after the body is exposed to a low-oxygen environment and before it acclimatizes. The rate of change from a normal oxygen environment and how little oxygen is in the new environment can be used to predict the chance of developing HACE. Prolonged exertion in low oxygen also causes serious hypocapnia, lower carbon dioxide in the bloodstream, which may play a role in HACE. These factors cause the brain to swell with fluid, resulting in severe impairment. If the swelling is untreated, it causes death by brain herniation.The brain swelling is likely a result of vasogenic edema, the penetration of the blood–brain barrier by fluids. This process has been observed in MRI studies. Hypoxia increases extracellular fluid, which passes through the vasogenic endothelium in the brain. The leaking may be caused by increased pressure, or it may be caused by inflammation that makes the endothelium vulnerable to leaking. An MRI study found microhemorrhages in the corpus callosum of HACE patients, and hypoxia may also cause microvascular permeability. It has been hypothesized that vascular endothelial growth factor may cause the vascular permeability at the root of HACE. MRI scans of patients with HACE showed increased T2 in the corpus callosum, although grey matter was unchanged. This demonstrated that the blood-brain barrier was broken by cerebral blood vessels, thus interfering with white matter metabolism. Another study looked at the brains of people with HACE several months after their recovery; it showed hemosiderin deposits in the corpus callosum, evidence of vascular permeability.While there is strong evidence that vasogenic edema plays a major role in HACE, cytotoxic edema, cellular retention of fluids, may contribute as well. Cytotoxic edema may be caused by the failure of cellular ion pumps, which results from hypoxia. Then intracellular sodium and osmolarity increase, and there is an influx of water that causes cellular swelling. After the failure of the ATPase pumps, free radicals form and cause damage that complicates the edema. Evidence against cytotoxic edema includes the high levels of hypoxemia (low bloodstream oxygen) needed to cause it.It is not known why some are more vulnerable to HACE than others. One theory is that variations in brain size play a role, but the increase in brain volume from edema does not likely cause cranial vault impingement. The presence of large sulci indicate the condition may be influenced by the brain tightly fitting. Elevated intracranial pressure is generally accepted to be a late effect of HACE. High central venous pressure may also occur late in the conditions progression.One study demonstrated that normal autorelation of cerebral blood flow does not cause HACE. What role the sympathetic nervous system plays in determining who gets HACE is unclear, but it may have an effect.Another theory about the cause of HACE is that hypoxia may induce nitrous oxide synthase. Vasodilation is caused by the release of nitric oxide and adenosine. This in turn can increase vascular permeability and causes edema. This may combine with low levels of cytokines to cause HACE. Diagnosis Generally, high-altitude pulmonary edema (HAPE) or AMS precede HACE. In patients with AMS, the onset of HACE is usually indicated by vomiting, headache that does not respond to non-steroidal anti-inflammatory drugs, hallucinations, and stupor. In some situations, however, AMS progresses to HACE without these symptoms. HACE must be distinguished from conditions with similar symptoms, including stroke, intoxication, psychosis, diabetic symptoms, meningitis, or ingestion of toxic substances. It should be the first diagnosis ruled out when sickness occurs while ascending to a high altitude. Prevention HACE is generally preventable by ascending gradually with frequent rest days while climbing or trekking. Not ascending more than 1,000 metres (3,300 ft) daily and not sleeping at a greater height than 300 metres (980 ft) more than the previous night is recommended. The risk of developing HACE is diminished if acetazolamide or dexamethasone are administered. Generally, the use of acetazolamide is preferred, but dexamethasone can be used for prevention if there are side effects or contraindications. Some individuals are more susceptible to HACE than others, and physical fitness is not preventive. Age and sex do not by themselves affect vulnerability to HACE. Treatment Patients with HACE should be brought to lower altitudes and provided supplemental oxygen, and rapid descent is sometimes needed to prevent mortality. Early recognition is important because as the condition progresses patients are unable to descend without assistance. Dexamethasone should also be administered, although it fails to ameliorate some symptoms that can be cured by descending to a lower altitude. It can also mask symptoms, and they sometimes resume upon discontinuation. Dexamethasones prevention of angiogenesis may explain why it treats HACE well. Three studies that examined how mice and rat brains react to hypoxia gave some credence to this idea.If available, supplemental oxygen can be used as an adjunctive therapy, or when descent is not possible. FiO2 should be titrated to maintain arterial oxygen saturation of greater than 90%, bearing in mind that oxygen supply is often limited in high altitude clinics/environments.In addition to oxygen therapy, a portable hyperbaric chamber (Gamow bag) can by used as a temporary measure in the treatment of HACE. These devices simulate a decrease in altitude of up to 7000 ft, but they are resource intensive and symptoms will often return after discontinuation of the device. Portable hyperbaric chambers should not be used in place of descent or evacuation to definitive care.Diuretics may be helpful, but pose risks outside of a hospital environment. Sildenafil and tadalafil may help HACE, but there is little evidence of their efficacy. Theophylline is also theorized to help the condition.Although AMS is not life-threatening, HACE is usually fatal within 24 hours if untreated. Without treatment, the patient will enter a coma and then die. In some cases, patients have died within a few hours, and a few have survived for two days. Descriptions of fatal cases often involve climbers who continue ascending while experiencing the conditions symptoms. Prognosis Recovery varies between days and weeks, but most recover in a few days. After the condition is successfully treated, it is possible for climbers to reascend. Dexamethesone should be discontinued, but continual acetazolamide is recommended. In one study, it took patients between one week and one month to display a normal CT scan following HACE. Epidemiology HACE occurs in 0.5% to 1% of people who climb or trek between 4,000 metres (13,000 ft) and 5,000 metres (16,000 ft). In some unusual cases, up to 30% of members of expeditions have had the condition. The condition is seldom seen below 3,000 metres (9,800 ft), but in some rare cases it has developed as low as 2,500 metres (8,200 ft). The condition generally does not occur until an individual has spent 48 hours at an altitude of 4,000 metres (13,000 ft). History HACE was first described by a medical officer stationed in Chile in 1913, but few took note of it. Later, access to air travel made the condition more common because it allowed more people access to high mountains, such as those in the Himalayas. One early description of HACE may have been published in 1969 after a group of Indian soldiers made a rapid ascent to almost 6,000 metres (20,000 ft). It is not definitely established whether they had HACE or acute decompression sickness. MRI has been used to study the effects of high altitude on the brain, providing the best evidence about the condition. A 1998 MRI study of nine climbers with HACE clearly demonstrated vasogenic edema.Data about HACE are lacking because it generally occurs in remote areas, far from hospitals and is generally rare. It is uncommon for doctors to be able to study victims within six days of the conditions development. Animal models of HACE have not been developed. Several genes are being examined for the role they may play in the development of the condition.Increased education and helicopter capabilities have combined to cut the number of deaths from the condition. Symptoms of HACE have been reported in many cases of deaths while descending Mount Everest, although HACE may not be the only problem they experienced. HACE also posed a threat to workers on the Qinghai–Tibet Railway. References Bibliography Bärtsch, Peter; Swenson, Erik (2013). "Acute High-Altitude Illnesses". The New England Journal of Medicine. 368 (24): 2294–302. doi:10.1056/NEJMcp1214870. PMID 23758234. Imray, Chris; Wright, Alex; Subudhi, Andrew; Roach, Robert (2010). "Acute Mountain Sickness: Pathophysiology, Prevention, and Treatment". Progress in Cardiovascular Diseases. 52 (6): 467–484. doi:10.1016/j.pcad.2010.02.003. PMID 20417340. Rosenberg, Gary (2012). Molecular Physiology and Metabolism of the Nervous System (5 ed.). Oxford University Press. ISBN 978-0-19-539427-6. Schoene, Robert (2008). "Illnesses at High Altitude". Chest. 134 (2): 402–16. doi:10.1378/chest.07-0561. PMID 18682459. Schoene, Robert; Milledge, James; Luks, Andrew; West, John (2012). High Altitude Medicine and Physiology. CRC Press. ISBN 978-1-4441-5432-0. Wilson, Mark; Newman, Stanton; Imray, Chris (2009). "The Cerebral Effects of Ascent to High Altitudes". Lancet Neurology. 8 (2): 175–91. doi:10.1016/S1474-4422(09)70014-6. PMID 19161909. S2CID 268646. == External links ==

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The term 'White sponge nevus' keeps coming up in medical discussions. What does it stand for?

White sponge nevus (WSN) is an autosomal dominant condition of the oral mucosa (the mucous membrane lining of the mouth). It is caused by a mutations in certain genes coding for keratin, which causes a defect in the normal process of keratinization of the mucosa. This results in lesions which are thick, white and velvety on the inside of the cheeks within the mouth. Usually, these lesions are present from birth or develop during childhood. The condition is entirely harmless, and no treatment is required. Signs and symptoms It presents itself in the mouth, most frequently as a thick, bilateral, symmetrical white plaques with a spongy, corrugated or velvety texture. Most usually, the lesions are on the buccal mucosa, but sometimes on the labial mucosa, alveolar ridge, floor of the mouth, ventral surface of the tongue or soft palate. The gingival margin and dorsum of the tongue are almost never affected. Less commonly, sites outside the mouth are affected, including the nasal, esophageal, laryngeal, anal and genital mucosae. It usually is present from birth, or develops during childhood. Rarely, the lesions may develop during adolescence. Apart from the appearance of the affected areas, there are usually no other signs or symptoms. Pathophysiology WSN is caused by a mutation of the keratin 4 or keratin 13 genes, located respectively at human chromosomes 12q13 and 17q21-q22. The condition is inherited in an autosomal dominant manner. This indicates that the defective gene responsible for a disorder is located on an autosome (chromosomes 12 and 17 are autosomes), and only one copy of the defective gene is sufficient to cause the disorder, when inherited from a parent who has the disorder. Diagnosis Differential diagnosis It is often mistaken for leukoplakia.The differential diagnosis also includes hyperplastic candidiasis and frictional keratosis Classification The ICD-10 lists WSN under "other congenital malformations of mouth". It could be classified as a skin condition, or more precisely as a genodermatosis (a genetically determined skin disorder). Treatment There is no treatment, but because this is a benign condition with no serious clinical complications, prognosis is excellent. See also Oral melanosis List of cutaneous conditions caused by mutations in keratins Hereditary benign intraepithelial dyskeratosis References External links White sponge nevus of cannon; Leukokeratosis, hereditary mucosal at NIHs Office of Rare Diseases

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What does the medical term 'Migraine' encompass?

Migraine (UK: , US: ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hours to three days. Non-headache symptoms may include nausea, vomiting, and sensitivity to light, sound, or smell. The pain is generally made worse by physical activity during an attack, although regular physical exercise may prevent future attacks. Up to one-third of people affected have aura: typically, it is a short period of visual disturbance that signals that the headache will soon occur. Occasionally, aura can occur with little or no headache following, but not everyone has this symptom.Migraine is believed to be due to a mixture of environmental and genetic factors. About two-thirds of cases run in families. Changing hormone levels may also play a role, as migraine affects slightly more boys than girls before puberty and two to three times more women than men. The risk of migraine usually decreases during pregnancy and after menopause. The underlying mechanisms are not fully known. They are, however, believed to involve the nerves and blood vessels of the brain.Initial recommended treatment is with simple pain medication such as ibuprofen and paracetamol (acetaminophen) for the headache, medication for the nausea, and the avoidance of triggers. Specific medications such as triptans or ergotamines may be used in those for whom simple pain medications are not effective. Caffeine in combination with other analgesics is safe and effective in treatment of acute migraine. A number of medications are useful to prevent attacks including metoprolol, valproate, and topiramate.Globally, approximately 15% of people are affected by migraine. In the Global Burden of Disease Study of 2010, it was ranked as the third most prevalent disorder in the world. It most often starts at puberty and is worst during middle age. As of 2016, it is one of the most common causes of disability. An early description consistent with migraines is contained in the Ebers papyrus, written around 1500 BC in ancient Egypt. The word migraine is from the Greek ἡμικρᾱνίᾱ (hēmikrāníā), pain in half of the head, from ἡμι- (hēmi-), half and κρᾱνίον (krāníon), skull. Signs and symptoms Migraine typically presents with self-limited, recurrent severe headache associated with autonomic symptoms. About 15–30% of people living with migraine experience episodes with aura, and they also frequently experience episodes without aura. The severity of the pain, duration of the headache, and frequency of attacks are variable. A migraine attack lasting longer than 72 hours is termed status migrainosus. There are four possible phases to a migraine attack, although not all the phases are necessarily experienced: The prodrome, which occurs hours or days before the headache The aura, which immediately precedes the headache The pain phase, also known as headache phase The postdrome, the effects experienced following the end of a migraine attackMigraine is associated with major depression, bipolar disorder, anxiety disorders, and obsessive–compulsive disorder. These psychiatric disorders are approximately 2–5 times more common in people without aura, and 3–10 times more common in people with aura. Prodrome phase Prodromal or premonitory symptoms occur in about 60% of those with migraines, with an onset that can range from two hours to two days before the start of pain or the aura. These symptoms may include a wide variety of phenomena, including altered mood, irritability, depression or euphoria, fatigue, craving for certain food(s), stiff muscles (especially in the neck), constipation or diarrhea, and sensitivity to smells or noise. This may occur in those with either migraine with aura or migraine without aura. Neuroimaging indicates the limbic system and hypothalamus as the origin of prodromal symptoms in migraine. Aura phase Aura is a transient focal neurological phenomenon that occurs before or during the headache. Aura appears gradually over a number of minutes (usually occurring over 5–60 minutes) and generally lasts less than 60 minutes. Symptoms can be visual, sensory or motoric in nature, and many people experience more than one. Visual effects occur most frequently: they occur in up to 99% of cases and in more than 50% of cases are not accompanied by sensory or motor effects.Visual disturbances often consist of a scintillating scotoma (an area of partial alteration in the field of vision which flickers and may interfere with a persons ability to read or drive). These typically start near the center of vision and then spread out to the sides with zigzagging lines which have been described as looking like fortifications or walls of a castle. Usually the lines are in black and white but some people also see colored lines. Some people lose part of their field of vision known as hemianopsia while others experience blurring.Sensory aura are the second most common type; they occur in 30–40% of people with auras. Often a feeling of pins-and-needles begins on one side in the hand and arm and spreads to the nose–mouth area on the same side. Numbness usually occurs after the tingling has passed with a loss of position sense. Other symptoms of the aura phase can include speech or language disturbances, world spinning, and less commonly motor problems. Motor symptoms indicate that this is a hemiplegic migraine, and weakness often lasts longer than one hour unlike other auras. Auditory hallucinations or delusions have also been described. Pain phase Classically the headache is unilateral, throbbing, and moderate to severe in intensity. It usually comes on gradually and is aggravated by physical activity during a migraine attack. However, the effects of physical activity on migraine are complex, and some researchers have concluded that, while exercise can trigger migraine attacks, regular exercise may have a prophylactic effect and decrease frequency of attacks. The feeling of pulsating pain is not in phase with the pulse. In more than 40% of cases, however, the pain may be bilateral (both sides of the head), and neck pain is commonly associated with it. Bilateral pain is particularly common in those who have migraine without aura. Less commonly pain may occur primarily in the back or top of the head. The pain usually lasts 4 to 72 hours in adults; however, in young children frequently lasts less than 1 hour. The frequency of attacks is variable, from a few in a lifetime to several a week, with the average being about one a month.The pain is frequently accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound, sensitivity to smells, fatigue and irritability. Many thus seek a dark and quiet room. In a basilar migraine, a migraine with neurological symptoms related to the brain stem or with neurological symptoms on both sides of the body, common effects include a sense of the world spinning, light-headedness, and confusion. Nausea occurs in almost 90% of people, and vomiting occurs in about one-third. Other symptoms may include blurred vision, nasal stuffiness, diarrhea, frequent urination, pallor, or sweating. Swelling or tenderness of the scalp may occur as can neck stiffness. Associated symptoms are less common in the elderly. Silent migraine Sometimes, aura occurs without a subsequent headache. This is known in modern classification as a typical aura without headache, or acephalgic migraine in previous classification, or commonly as a silent migraine. However, silent migraine can still produce debilitating symptoms, with visual disturbance, vision loss in half of both eyes, alterations in color perception, and other sensory problems, like sensitivity to light, sound, and odors, and aura sudden outbreak without headache can be scary. It can last from 15 to 30 minutes, usually no longer than 60 minutes, and it can recur or appear as an isolated event. Postdrome The migraine postdrome could be defined as that constellation of symptoms occurring once the acute headache has settled. Many report a sore feeling in the area where the migraine was, and some report impaired thinking for a few days after the headache has passed. The person may feel tired or "hung over" and have head pain, cognitive difficulties, gastrointestinal symptoms, mood changes, and weakness. According to one summary, "Some people feel unusually refreshed or euphoric after an attack, whereas others note depression and malaise." For some individuals this can vary each time. Cause The underlying causes of migraines are unknown. However, they are believed to be related to a mix of environmental and genetic factors. They run in families in about two-thirds of cases and rarely occur due to a single gene defect. While migraines were once believed to be more common in those of high intelligence, this does not appear to be true. A number of psychological conditions are associated, including depression, anxiety, and bipolar disorder, as are many biological events or triggers. Genetics Studies of twins indicate a 34% to 51% genetic influence of likelihood to develop migraine. This genetic relationship is stronger for migraine with aura than for migraines without aura. A number of specific variants of genes increase the risk by a small to moderate amount.Single gene disorders that result in migraines are rare. One of these is known as familial hemiplegic migraine, a type of migraine with aura, which is inherited in an autosomal dominant fashion. Four genes have been shown to be involved in familial hemiplegic migraine. Three of these genes are involved in ion transport. The fourth is an axonal protein associated with the exocytosis complex. Another genetic disorder associated with migraine is CADASIL syndrome or cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. One meta-analysis found a protective effect from angiotensin converting enzyme polymorphisms on migraine. The TRPM8 gene, which codes for a cation channel, has been linked to migraines. Triggers Migraine may be induced by triggers, with some reporting it as an influence in a minority of cases and others the majority. Many things such as fatigue, certain foods, alcohol, and weather have been labeled as triggers; however, the strength and significance of these relationships are uncertain. Most people with migraines report experiencing triggers. Symptoms may start up to 24 hours after a trigger. Physiological aspects Common triggers quoted are stress, hunger, and fatigue (these equally contribute to tension headaches). Psychological stress has been reported as a factor by 50 to 80% of people. Migraine has also been associated with post-traumatic stress disorder and abuse. Migraine episodes are more likely to occur around menstruation. Other hormonal influences, such as menarche, oral contraceptive use, pregnancy, perimenopause, and menopause, also play a role. These hormonal influences seem to play a greater role in migraine without aura. Migraine episodes typically do not occur during the second and third trimesters of pregnancy, or following menopause. Dietary aspects Between 12 and 60% of people report foods as triggers.There are many reports that tyramine – which is naturally present in chocolate, alcoholic beverages, most cheeses, processed meats, and other foods – can trigger migraine symptoms in some individuals. Likewise, monosodium glutamate (MSG) is frequently reported as a trigger for migraine symptoms. Environmental aspects A 2009 review on potential triggers in the indoor and outdoor environment concluded that while there were insufficient studies to confirm environmental factors as causing migraine, "migraineurs worldwide consistently report similar environmental triggers". The article suggests that people living with migraine take some preventive measures related to indoor air quality and lighting. Pathophysiology Migraine is believed to be primarily a neurological disorder, while others believe it to be a neurovascular disorder with blood vessels playing the key role, although current evidence does not support this completely. Others believe both are likely important. One theory is related to increased excitability of the cerebral cortex and abnormal control of pain neurons in the trigeminal nucleus of the brainstem. Aura Cortical spreading depression, or spreading depression according to Leão, is a burst of neuronal activity followed by a period of inactivity, which is seen in those with migraines with aura. There are a number of explanations for its occurrence, including activation of NMDA receptors leading to calcium entering the cell. After the burst of activity, the blood flow to the cerebral cortex in the area affected is decreased for two to six hours. It is believed that when depolarization travels down the underside of the brain, nerves that sense pain in the head and neck are triggered. Pain The exact mechanism of the head pain which occurs during a migraine episode is unknown. Some evidence supports a primary role for central nervous system structures (such as the brainstem and diencephalon), while other data support the role of peripheral activation (such as via the sensory nerves that surround blood vessels of the head and neck). The potential candidate vessels include dural arteries, pial arteries and extracranial arteries such as those of the scalp. The role of vasodilatation of the extracranial arteries, in particular, is believed to be significant. Neuromodulators Adenosine, a neuromodulator, may be involved. Released after the progressive cleavage of adenosine triphosphate (ATP), adenosine acts on adenosine receptors to put the body and brain in a low activity state by dilating blood vessels and slowing the heart rate, such as before and during the early stages of sleep. Adenosine levels have been found to be high during migraine attacks. Caffeines role as an inhibitor of adenosine may explain its effect in reducing migraine. Low levels of the neurotransmitter serotonin, also known as 5-hydroxytryptamine (5-HT), are also believed to be involved.Calcitonin gene-related peptides (CGRPs) have been found to play a role in the pathogenesis of the pain associated with migraine, as levels of it become elevated during an attack. Diagnosis The diagnosis of a migraine is based on signs and symptoms. Neuroimaging tests are not necessary to diagnose migraine, but may be used to find other causes of headaches in those whose examination and history do not confirm a migraine diagnosis. It is believed that a substantial number of people with the condition remain undiagnosed.The diagnosis of migraine without aura, according to the International Headache Society, can be made according to the following criteria, the "5, 4, 3, 2, 1 criteria": Five or more attacks—for migraine with aura, two attacks are sufficient for diagnosis. Four hours to three days in duration Two or more of the following: Unilateral (affecting one side of the head) Pulsating Moderate or severe pain intensity Worsened by or causing avoidance of routine physical activity One or more of the following: Nausea and/or vomiting Sensitivity to both light (photophobia) and sound (phonophobia)If someone experiences two of the following: photophobia, nausea, or inability to work or study for a day, the diagnosis is more likely. In those with four out of five of the following: pulsating headache, duration of 4–72 hours, pain on one side of the head, nausea, or symptoms that interfere with the persons life, the probability that this is a migraine attack is 92%. In those with fewer than three of these symptoms, the probability is 17%. Classification Migraine was first comprehensively classified in 1988. The International Headache Society updated their classification of headaches in 2004. A third version was published in 2018. According to this classification, migraine is a primary headache disorder along with tension-type headaches and cluster headaches, among others.Migraine is divided into seven subclasses (some of which include further subdivisions): Migraine without aura, or "common migraine", involves migraine headaches that are not accompanied by aura. Migraine with aura, or "classic migraine", usually involves migraine headaches accompanied by aura. Less commonly, aura can occur without a headache, or with a nonmigraine headache. Two other varieties are familial hemiplegic migraine and sporadic hemiplegic migraine, in which a person has migraine with aura and with accompanying motor weakness. If a close relative has had the same condition, it is called "familial", otherwise it is called "sporadic". Another variety is basilar-type migraine, where a headache and aura are accompanied by difficulty speaking, world spinning, ringing in ears, or a number of other brainstem-related symptoms, but not motor weakness. This type was initially believed to be due to spasms of the basilar artery, the artery that supplies the brainstem. Now that this mechanism is not believed to be primary, the symptomatic term migraine with brainstem aura (MBA) is preferred. Childhood periodic syndromes that are commonly precursors of migraine include cyclical vomiting (occasional intense periods of vomiting), abdominal migraine (abdominal pain, usually accompanied by nausea), and benign paroxysmal vertigo of childhood (occasional attacks of vertigo). Retinal migraine involves migraine headaches accompanied by visual disturbances or even temporary blindness in one eye. Complications of migraine describe migraine headaches and/or auras that are unusually long or unusually frequent, or associated with a seizure or brain lesion. Probable migraine describes conditions that have some characteristics of migraines, but where there is not enough evidence to diagnose it as a migraine with certainty (in the presence of concurrent medication overuse). Chronic migraine is a complication of migraines, and is a headache that fulfills diagnostic criteria for migraine headache and occurs for a greater time interval. Specifically, greater or equal to 15 days/month for longer than 3 months. Abdominal migraine The diagnosis of abdominal migraine is controversial. Some evidence indicates that recurrent episodes of abdominal pain in the absence of a headache may be a type of migraine or are at least a precursor to migraines. These episodes of pain may or may not follow a migraine-like prodrome and typically last minutes to hours. They often occur in those with either a personal or family history of typical migraine. Other syndromes that are believed to be precursors include cyclical vomiting syndrome and benign paroxysmal vertigo of childhood. Differential diagnosis Other conditions that can cause similar symptoms to a migraine headache include temporal arteritis, cluster headaches, acute glaucoma, meningitis and subarachnoid hemorrhage. Temporal arteritis typically occurs in people over 50 years old and presents with tenderness over the temple, cluster headache presents with one-sided nose stuffiness, tears and severe pain around the orbits, acute glaucoma is associated with vision problems, meningitis with fevers, and subarachnoid hemorrhage with a very fast onset. Tension headaches typically occur on both sides, are not pounding, and are less disabling.Those with stable headaches that meet criteria for migraines should not receive neuroimaging to look for other intracranial disease. This requires that other concerning findings such as papilledema (swelling of the optic disc) are not present. People with migraines are not at an increased risk of having another cause for severe headaches. Prevention Preventive treatments of migraine include medications, nutritional supplements, lifestyle alterations, and surgery. Prevention is recommended in those who have headaches more than two days a week, cannot tolerate the medications used to treat acute attacks, or those with severe attacks that are not easily controlled. Recommended lifestyle changes include stopping tobacco use and reducing behaviors that interfere with sleep.The goal is to reduce the frequency, painfulness, and duration of migraine episodes, and to increase the effectiveness of abortive therapy. Another reason for prevention is to avoid medication overuse headache. This is a common problem and can result in chronic daily headache. Medication Preventive migraine medications are considered effective if they reduce the frequency or severity of the migraine attacks by at least 50%. Due to few medications being approved specifically for the preventative treatment of migraine headaches; many medications such as beta-blockers, anticonvulsive agents such as topiramate or sodium valproate, antidepressants such as amitriptyline and calcium channel blockers such as flunarizine are used off label for the preventative treatment of migraine headaches. Guidelines are fairly consistent in rating the anticonvulsants topiramate and divalproex/sodium valproate, and the beta blockers propranolol and metoprolol as having the highest level of evidence for first-line use for migraine prophylaxis in adults. Propranolol and topiramate have the best evidence in children; however, evidence only supports short-term benefit as of 2020.The beta blocker timolol is also effective for migraine prevention and in reducing migraine attack frequency and severity. While beta blockers are often used for first-line treatment, other antihypertensives also have a proven efficiency in migraine prevention, namely the calcium channel blocker verapamil and the angiotensin receptor blocker candesartan.Tentative evidence also supports the use of magnesium supplementation. Increasing dietary intake may be better. Recommendations regarding effectiveness varied for the anticonvulsants gabapentin and pregabalin. Frovatriptan is effective for prevention of menstrual migraine.The antidepressants amitriptyline and venlafaxine are probably also effective. Angiotensin inhibition by either an angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist may reduce attacks.Medications in the anti-calcitonin gene-related peptide, including eptinezumab, erenumab, fremanezumab, and galcanezumab, appear to decrease the frequency of migraines by one to two per month. They are, however, expensive: a year of erenumab costs $6,900 as of 2019. Alternative therapies Acupuncture has a small effect in reducing migraine frequency, compared to sham acupuncture, a practice where needles are placed randomly or do not penetrate the skin. Physiotherapy, massage and relaxation, and chiropractic manipulation might be as effective as propranolol or topiramate in the prevention of migraine headaches; however, the research had some problems with methodology. Another review, however, found evidence to support spinal manipulation to be poor and insufficient to support its use.Tentative evidence supports the use of stress reduction techniques such as cognitive behavioral therapy, biofeedback, and relaxation techniques. Regular physical exercise may decrease the frequency. Numerous psychological approaches have been developed that are aimed at preventing or reducing the frequency of migraine in adults including educational approaches, relaxation techniques, assistance in developing coping strategies, strategies to change the way one thinks of a migraine attack, and strategies to reduce symptoms. The medical evidence supporting the effectiveness of these types of psychological approaches is very limited.Among alternative medicines, butterbur has the best evidence for its use. However, unprocessed butterbur contains chemicals called pyrrolizidine alkaloids (PAs) which can cause liver damage, however there are versions that are PA free. In addition, butterbur may cause allergic reactions in people who are sensitive to plants such as ragweed. There is tentative evidence that coenzyme Q10 reduces migraine frequency.Feverfew has traditionally been used as a treatment for fever, headache and migraine, womens conditions such as difficulties in labour and regulation of menstruation, relief of stomach ache, toothache and insect bites. During the last decades, it has mainly been used for headache and as a preventive treatment for migraine. The plant parts used for medicinal use are the dried leaves or the dried aerial parts. Several historical data supports feverfews traditional medicinal uses. In addition, several clinical studies have been performed assessing the efficacy and safety of feverfew monotherapy in the prevention of migraine. The majority of the clinical trials favoured feverfew over placebo. The data also suggest that feverfew is associated with only mild and transient adverse effects. The frequency of migraine was positively affected after treatment with feverfew. Reduction of migraine severity was also reported after intake of feverfew and incidence of nausea and vomiting decreased significantly. No effect of feverfew was reported in one study.There is tentative evidence for melatonin as an add-on therapy for prevention and treatment of migraine. The data on melatonin are mixed and certain studies have had negative results. The reasons for the mixed findings are unclear but may stem from differences in study design and dosage. Melatonins possible mechanisms of action in migraine are not completely clear, but may include improved sleep, direct action on melatonin receptors in the brain, and anti-inflammatory properties. Devices and surgery Medical devices, such as biofeedback and neurostimulators, have some advantages in migraine prevention, mainly when common anti-migraine medications are contraindicated or in case of medication overuse. Biofeedback helps people be conscious of some physiological parameters so as to control them and try to relax and may be efficient for migraine treatment. Neurostimulation uses noninvasive or implantable neurostimulators similar to pacemakers for the treatment of intractable chronic migraine with encouraging results for severe cases. A transcutaneous electrical nerve stimulator and a transcranial magnetic stimulator are approved in the United States for the prevention of migraines. There is also tentative evidence for transcutaneous electrical nerve stimulation decreases the frequency of migraines. Migraine surgery, which involves decompression of certain nerves around the head and neck, may be an option in certain people who do not improve with medications. Management There are three main aspects of treatment: trigger avoidance, acute symptomatic control, and medication for prevention. Medications are more effective if used earlier in an attack. The frequent use of medications may result in medication overuse headache, in which the headaches become more severe and more frequent. This may occur with triptans, ergotamines, and analgesics, especially opioid analgesics. Due to these concerns simple analgesics are recommended to be used less than three days per week at most. Analgesics Recommended initial treatment for those with mild to moderate symptoms are simple analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) or the combination of paracetamol (also known as acetaminophen), aspirin, and caffeine. Several NSAIDs, including diclofenac and ibuprofen have evidence to support their use. Aspirin (900 to 1000 mg) can relieve moderate to severe migraine pain, with an effectiveness similar to sumatriptan. Ketorolac is available in intravenous and intramuscular formulations.Paracetamol, either alone or in combination with metoclopramide, is another effective treatment with a low risk of adverse effects. Intravenous metoclopramide is also effective by itself. In pregnancy, paracetamol and metoclopramide are deemed safe as are NSAIDs until the third trimester.Naproxen by itself may not be effective as a stand-alone medicine to stop a migraine headache as it is only weakly better than a placebo medication in clinical trials. Antiemetics Triptans Triptans such as sumatriptan are medications used to stop an active migraine headache (an abortive medication). Triptans are the initially recommended treatments for those with moderate to severe pain from an acute migraine headache or those with milder symptoms who do not respond to simple analgesics. Triptans have been shown to be effective for both pain and nausea in up to 75% of people. There are different methods or routes of administration to take sumatriptan including oral (by mouth), injectable (subcutaneous), rectal, nasal spray, and oral dissolving tablets. For people with migraine symptoms such as nausea or vomiting, taking the abortive medicine by mouth or through the nose may be difficult. All route of administration have been shown to be effective at reducing migraine symptoms, however, nasal and injectable subcutaneous administration may result in more side effects. The adverse effects associated with rectal administration have not been well studied. Some people may find that they respond to one type of sumatriptan better than another.Most side effects are mild, including flushing; however, rare cases of myocardial ischemia have occurred. They are thus not recommended for people with cardiovascular disease, who have had a stroke, or have migraines that are accompanied by neurological problems. In addition, triptans should be prescribed with caution for those with risk factors for vascular disease. While historically not recommended in those with basilar migraines there is no specific evidence of harm from their use in this population to support this caution. Triptans are not addictive, but may cause medication-overuse headaches if used more than 10 days per month.Sumatriptan does not prevent other migraine headaches from starting in the future. For increased effectiveness at stopping migraine symptoms, a combined therapy that includes sumatriptan and naproxen may be suggested. CGRP receptor antagonists CGRP receptor antagonists target calcitonin gene-related peptide or its receptor to prevent migraine headaches or reduce their severity. CGRP is a signaling molecule as well as a potent vasodilator that is involved in the development of a migraine headache. There are four injectable monoclonal antibodies that target CGRP or its receptor (eptinezumab, erenumab, fremanezumab and galcanezumab) and the medications have demonstrated efficacy in the preventative treatment of episodic and chronic migraine headaches in phase 3 randomized clinical trials. Eptinezumab is available as an infusion every three months, Erenumab and galcanezumab are once monthly injections and fremanezumab is a monthly or quarterly injection. Ergotamines Ergotamine and dihydroergotamine are older medications still prescribed for migraines, the latter in nasal spray and injectable forms. They appear equally effective to the triptans and experience adverse effects that typically are benign. In the most severe cases, such as those with status migrainosus, they appear to be the most effective treatment option. They can cause vasospasm including coronary vasospasm and are contraindicated in people with coronary artery disease. Magnesium Magnesium is recognized as an inexpensive, over-the-counter supplement which some studies have shown to be effective in both preventing and treating migraine in intravenous form. Other Intravenous metoclopramide, intravenous prochlorperazine, or intranasal lidocaine are other potential options. Metoclopramide or prochlorperazine are the recommended treatment for those who present to the emergency department. Haloperidol may also be useful in this group. A single dose of intravenous dexamethasone, when added to standard treatment of a migraine attack, is associated with a 26% decrease in headache recurrence in the following 72 hours. Spinal manipulation for treating an ongoing migraine headache is not supported by evidence. It is recommended that opioids and barbiturates not be used due to questionable efficacy, addictive potential, and the risk of rebound headache. There is tentative evidence that propofol may be useful if other measures are not effective.Occipital nerve stimulation, may be effective but has the downsides of being cost-expensive and has a significant amount of complications.There is modest evidence for the effectiveness of non-invasive neuromodulatory devices, behavioral therapies and acupuncture in the treatment of migraine headaches. There is little to no evidence for the effectiveness of physical therapy, chiropractic manipulation and dietary approaches to the treatment of migraine headaches. Behavioral treatment of migraine headaches may be helpful for those who may not be able to take medications (for example pregnant women).Feverfew is registered as a traditional herbal medicine in the Nordic countries under the brand name Glitinum, only powdered feverfew is approved in the Herbal community monograph issued by European Medicines Agency (EMA). Sexual activity, particularly orgasm, may provide relief for some migraineurs. Children Ibuprofen helps decrease pain in children with migraines and is the initially recommended treatment. Paracetamol does not appear to be effective in providing pain relief. Triptans are effective, though there is a risk of causing minor side effects like taste disturbance, nasal symptoms, dizziness, fatigue, low energy, nausea, or vomiting. Ibuprofen should be used less than half the days in a month and triptans less than a third of the days in a month to decrease the risk of medication overuse headache. Chronic migraine Topiramate and botulinum toxin (Botox) have evidence in treating chronic migraine. Botulinum toxin has been found to be useful in those with chronic migraine but not those with episodic ones. The anti-CGRP monoclonal antibody erenumab was found in one study to decrease chronic migraines by 2.4 days more than placebo. Prognosis "Migraine exists on a continuum of different attack frequencies and associated levels of disability." For those with occasional, episodic migraine, a "proper combination of drugs for prevention and treatment of migraine attacks" can limit the diseases impact on patients personal and professional lives. But fewer than half of people with migraine seek medical care and more than half go undiagnosed and undertreated. "Responsive prevention and treatment of migraine is incredibly important" because evidence shows "an increased sensitivity after each successive attack, eventually leading to chronic daily migraine in some individuals." Repeated migraine results in "reorganization of brain circuitry," causing "profound functional as well as structural changes in the brain." "One of the most important problems in clinical migraine is the progression from an intermittent, self-limited inconvenience to a life-changing disorder of chronic pain, sensory amplification, and autonomic and affective disruption. This progression, sometimes termed chronification in the migraine literature, is common, affecting 3% of migraineurs in a given year, such that 8% of migraineurs have chronic migraine in any given year." Brain imagery reveals that the electrophysiological changes seen during an attack become permanent in people with chronic migraine; "thus, from an electrophysiological point of view, chronic migraine indeed resembles a never-ending migraine attack." Severe migraine ranks in the highest category of disability, according to the World Health Organization, which uses objective metrics to determine disability burden for the authoritative annual Global Burden of Disease report. The report classifies severe migraine alongside severe depression, active psychosis, quadriplegia, and terminal-stage cancer.Migraine with aura appears to be a risk factor for ischemic stroke doubling the risk. Being a young adult, being female, using hormonal birth control, and smoking further increases this risk. There also appears to be an association with cervical artery dissection. Migraine without aura does not appear to be a factor. The relationship with heart problems is inconclusive with a single study supporting an association. Migraine does not appear to increase the risk of death from stroke or heart disease. Preventative therapy of migraines in those with migraine with aura may prevent associated strokes. People with migraine, particularly women, may develop higher than average numbers of white matter brain lesions of unclear significance. Epidemiology Worldwide, migraine affects nearly 15% or approximately one billion people. It is more common in women at 19% than men at 11%. In the United States, about 6% of men and 18% of women experience a migraine attack in a given year, with a lifetime risk of about 18% and 43% respectively. In Europe, migraines affect 12–28% of people at some point in their lives with about 6–15% of adult men and 14–35% of adult women getting at least one yearly. Rates of migraine are slightly lower in Asia and Africa than in Western countries. Chronic migraine occurs in approximately 1.4 to 2.2% of the population.These figures vary substantially with age: onset of migraine is most commonly between 15 and 24 years of age, and occur most frequently in those 35 to 45 years of age. In children, about 1.7% of 7 year olds and 3.9% of those between 7 and 15 experience migraine, with the condition being slightly more common in boys before puberty. Children as young as two years may be affected. During adolescence, migraine becomes more common among women and this persists for the rest of the lifespan, being twice as common among elderly females than males. In women migraine without aura are more common than migraine with aura; however in men the two types occur with similar frequency.During perimenopause symptoms often get worse before decreasing in severity. While symptoms resolve in about two thirds of the elderly, in 3 to 10% they persist. History An early description consistent with migraine is contained in the Ebers papyrus, written around 1500 BCE in ancient Egypt. In 200 BCE, writings from the Hippocratic school of medicine described the visual aura that can precede the headache and a partial relief occurring through vomiting.A second-century description by Aretaeus of Cappadocia divided headaches into three types: cephalalgia, cephalea, and heterocrania. Galen of Pergamon used the term hemicrania (half-head), from which the word migraine was eventually derived. He also proposed that the pain arose from the meninges and blood vessels of the head. Migraine was first divided into the two now used types – migraine with aura (migraine ophthalmique) and migraine without aura (migraine vulgaire) in 1887 by Louis Hyacinthe Thomas, a French Librarian. The mystical visions of Hildegard von Bingen, which she described as “reflections of the living light", are consistent with the visual aura experienced during migraines. Trepanation, the deliberate drilling of holes into a skull, was practiced as early as 7,000 BCE. While sometimes people survived, many would have died from the procedure due to infection. It was believed to work via "letting evil spirits escape". William Harvey recommended trepanation as a treatment for migraines in the 17th century.While many treatments for migraine have been attempted, it was not until 1868 that use of a substance which eventually turned out to be effective began. This substance was the fungus ergot from which ergotamine was isolated in 1918. Methysergide was developed in 1959 and the first triptan, sumatriptan, was developed in 1988. During the 20th century with better study-design, effective preventive measures were found and confirmed. Society and culture Migraine is a significant source of both medical costs and lost productivity. It has been estimated that migraine is the most costly neurological disorder in the European Community, costing more than €27 billion per year. In the United States, direct costs have been estimated at $17 billion, while indirect costs — such as missed or decreased ability to work — is estimated at $15 billion. Nearly a tenth of the direct cost is due to the cost of triptans. In those who do attend work during a migraine attack, effectiveness is decreased by around a third. Negative impacts also frequently occur for a persons family. Research Potential prevention mechanisms Transcranial magnetic stimulation shows promise as does transcutaneous supraorbital nerve stimulation. There is preliminary evidence that a ketogenic diet may help prevent episodic and long-term migraine. Potential gender dependency While no definitive proof has been found linking migraine to gender, statistical data indicates that women may be more prone to having migraine, showing migraine incidence three times higher among women than men. The Society for Womens Health Research has also mentioned hormonal influences, mainly estrogen, as having a considerable role in provoking migraine pain. Studies and research related to the gender dependencies of migraine are still ongoing, and conclusions have yet to be achieved. References Notes Olesen J (2006). The headaches (3 ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 9780781754002. Further reading Ashina M (November 2020). Ropper AH (ed.). "Migraine". The New England Journal of Medicine. 383 (19): 1866–1876. doi:10.1056/nejmra1915327. PMID 33211930. S2CID 227078662. Oskoui M, Pringsheim T, Billinghurst L, Potrebic S, Gersz EM, Gloss D, et al. (September 2019). "Practice guideline update summary: Pharmacologic treatment for pediatric migraine prevention: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society". Neurology. 93 (11): 500–509. doi:10.1212/WNL.0000000000008105. PMC 6746206. PMID 31413170. Oskoui M, Pringsheim T, Holler-Managan Y, Potrebic S, Billinghurst L, Gloss D, et al. (September 2019). "Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society". Neurology. 93 (11): 487–499. doi:10.1212/WNL.0000000000008095. PMID 31413171. S2CID 199662718. External links Migraine at Curlie

You act as a medical communicator. Your goal is to translate medical terms into comprehensive, yet straightforward language for all readers.

Please help me grasp the concept behind the medical term 'Lathosterolosis.'

Lathosterolosis is a defect in cholesterol biosynthesis. See also SC5DL Lathosterol References == External links ==