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https://en.wikipedia.org/wiki/Pneumonic_plague	disease	Pneumonic plague	Pneumonic plague is a severe lung infection caused by the bacterium Yersinia pestis. Symptoms include fever, headache, shortness of breath, chest pain, and cough. They typically start about three to seven days after exposure. It is one of three forms of plague, the other two being septicemic plague and bubonic plague. The pneumonic form may occur following an initial bubonic or septicemic plague infection. It may also result from breathing in airborne droplets from another person or cat infected with pneumonic plague. The difference between the forms of plague is the location of infection; in pneumonic plague the infection is in the lungs, in bubonic plague the lymph nodes, and in septicemic plague within the blood. Diagnosis is by testing the blood, sputum, or fluid from a lymph node. While vaccines are being worked on, in most countries they are not yet commercially available. Prevention is generally by avoiding contact with rodents. It is recommended that those infected be isolated from others. Treatment of pneumonic plague is with antibiotics. Plague is present among rodents in Africa, the Americas, and Asia. Pneumonic plague is more serious and less common than bubonic plague. The total reported number of all types of plague in 2013 was 783. Untreated pneumonic plague has a mortality of nearly 100%. Some hypothesize that the pneumonic version of the plague was mainly responsible for the Black Death that resulted in approximately 50 million deaths in the 1300s.	The most apparent symptom of pneumonic plague is coughing, often with hemoptysis (coughing up blood). With pneumonic plague, the first signs of illness are fever, headache, weakness and rapidly developing pneumonia with shortness of breath, chest pain, cough and sometimes bloody or watery sputum. The pneumonia progresses for two to four days and may cause respiratory failure and shock. Patients will die without early treatment, some within 36 hours. Initial pneumonic plague symptoms can often include the following: - Fever - Weakness - Headaches - Nausea Rapidly developing pneumonia with: - Shortness of breath - Chest pain - Cough - Bloody or watery sputum (saliva and discharge from respiratory passages). Pneumonic plague can be caused in two ways: primary, which results from the inhalation of aerosolised plague bacteria, or secondary, when septicaemic plague spreads into lung tissue from the bloodstream. Pneumonic plague is not exclusively vector-borne like bubonic plague; instead it can be spread from person to person. There have been cases of pneumonic plague resulting from the dissection or handling of contaminated animal tissue. This is one type of the plague formerly known as the Black Death. Pneumonic plague is a very aggressive infection requiring early treatment. Antibiotics must be given within 24 hours of first symptoms to reduce the risk of death. Streptomycin, gentamicin, tetracyclines and chloramphenicol are all effective against pneumonic plague. Antibiotic treatment for seven days will protect people who have had direct, close contact with infected patients. Wearing a close-fitting surgical mask also protects against infection. The mortality rate from untreated pneumonic plague approaches 100%. Since 2002, the World Health Organization (WHO) has reported seven plague outbreaks, though some may go unreported because they often happen in remote areas. Between 1998 and 2009, nearly 24,000 cases have been reported, including about 2,000 deaths, in Africa, Asia, the Americas, and Eastern Europe. Ninety-eight percent of the world's cases occur in Africa. In September 1994, India experienced an outbreak of plague that killed 50 and caused travel to New Delhi by air to be suspended until the outbreak was brought under control. The outbreak was feared to be much worse because the plague superficially resembles other common diseases such as influenza and bronchitis; over 200 people that had been quarantined were released when they did not test positive for the plague. All but two of the deaths occurred around the city of Surat. The People's Republic of China has eradicated the pneumonic plague from most parts of the country, but still reports occasional cases in remote Western areas where the disease is carried by rats and the marmots that live across the Himalayan plateau. Outbreaks can be caused when a person eats an infected marmot or comes into contact with fleas carried by rats. A 2006 WHO report from an international meeting on plague cited a Chinese government disease expert as saying that most cases of the plague in China's northwest occur when hunters are contaminated while skinning infected animals. The expert said at the time that due to the region's remoteness, the disease killed more than half the infected people. The report also said that since the 1990s, there was a rise in plague cases in humans—from fewer than 10 in the 1980s to nearly 100 cases in 1996 and 254 in 2000. Official statistics posted on the Chinese Health Ministry's Web site showed no cases of plague in 2007 and 2008. In September 2008, two people in east Tibet died of pneumonic plague. An outbreak of the disease in China began in August 2009 in Ziketan Town located in Qinghai Province. The town was sealed off and several people died as a result of the disease. According to spokesperson Vivian Tan of the WHO office in Beijing, "In cases like this [in August 2009], we encourage the authorities to identify cases, to investigate any suspicious symptoms among close contacts, and to treat confirmed cases as soon as possible. So far, they have done exactly that. There have been sporadic cases reported around the country in the last few years so the authorities do have the experience to deal with this." In September 2010, five cases of pneumonic plague were reported in Tibet. In July 17, 2014, Chinese media reported one case found in Gansu. In August 2010, Peru's health minister Oscar Ugarte announced that an outbreak of plague had killed a 14-year-old boy and had infected at least 31 people in a northern coastal province. The boy died of bubonic plague on 26 July 2010. Ugarte stated that authorities were screening sugar and fish meal exports from Ascope Province, located about 325 miles (520 km) northwest of Lima, not far from popular Chicama beach. Most of the infections in Peru were bubonic plague, with four cases of pneumonic plague. The first recorded plague outbreak in Peru was in 1903. The last, in 1994, killed 35 people. An outbreak of plague in November 2013, occurred in the African island nation of Madagascar. As of 16 December, at least 89 people were infected, with 39 deaths with at least two cases involving pneumonic plague. However, as many as 90% of cases were later reported to have involved pneumonic plague. From 23 August to 30 September 2017, a total of 73 suspected, probable, and confirmed cases of pneumonic plague, including 17 deaths, were reported in Madagascar.The diagnosis was confirmed by the Institut Pasteur de Madagascar by polymerase chain reaction test or using rapid diagnostic test. The WHO and Institut Pasteur were both involved in administering antibiotic compounds and attempting to stop the spread of the disease. By mid-October there were an estimated 684 confirmed cases of plague with 474 pneumonic, 156 bubonic and one septicaemic. The remainder were not classified. At least 74 deaths have been ascribed to pneumonic plague. On November 2, 2007, wildlife biologist Eric York died of pneumonic plague in Grand Canyon National Park. York was exposed to the bacteria while conducting a necropsy on a mountain lion carcass. In 2014, the Colorado Department of Public Health and Environment confirmed that a Colorado man had been diagnosed with pneumonic plague, the first confirmed human case in Colorado in more than ten years, and one of only 60 cases since 1957. The man was found to have the disease after the family dog died unexpectedly and a necropsy revealed that the dog had died from the disease. Three additional pneumonic plague cases were confirmed in Colorado before the outbreak ended. The outbreak was caused by a pit bull.	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https://en.wikipedia.org/wiki/Bagassosis	disease	Bagassosis	Bagassosis, an interstitial lung disease, is a type of hypersensitivity pneumonitis attributed to exposure to moldy molasses (bagasse).	Some symptoms and signs of Bagassosis include breathlessness, cough, haemoptysis, slight fever. Acute diffuse bronchiolitis may also occur. An xray may show mottling of lungs or a shadow. Bagassosis has been shown to be due to a thermophilic actinomycetes for which the name thermoactinomycetes sacchari was suggested. The following are precautionary measures that can be taken to avoid the spread of bagassosis: 1. Dust control-prevention /suppression of dust such as wet process, enclosed apparatus, exhaust ventilation etc. should be used 2. Personal protection- masks/ respirators 3. Medical control- initial medical examination & periodical checkups of workers 4. Bagasse control- keep moisture content above 20% and spray bagasse with 2% propionic acid Bagassosis was first reported in India by Ganguly and Pal in 1955, in a cardboard manufacturing plant near Kolkata. India has a large cane sugar industry. The sugarcane fibre which, until recently, went to waste, is now utilised in the manufacture of cardboard, paper and rayon.	[ { "begin": 0, "class": "SectionAnnotation", "length": 188, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 188, "class": "SectionAnnotation", "length": 131, "sectionHeading": "Cause", "sectionLabel": "disease.cause" }, { "begin": 319, "class": "SectionAnnotation", "length": 440, "sectionHeading": "Prevention", "sectionLabel": "disease.prevention" }, { "begin": 759, "class": "SectionAnnotation", "length": 279, "sectionHeading": "History", "sectionLabel": "disease.history" } ]
https://en.wikipedia.org/wiki/Baastrup's_sign	disease	Baastrup's sign	Baastrup's sign, or kissing spine, is an orthopedic and radiographic disorder that often occurs in elderly humans. It is characterized by enlargement of the posterior spinous projections of the lumbar spine, with normal intervertebral disc height and neuroforamina. The reason it is referred to as kissing spine is because the posterior spinous processes 'kiss' and touch one another as the individual goes into lumbar extension, for example when flat on their stomach. The condition has been seen in humans, canines, particularly with boxer breeds, and certain breeds of horses. This disorder is named after Christian Ingerslev Baastrup.	The salient feature of the disorder is the exuberant osteophytosis that occurs at posterior lumbar spinous processes. Osteophytes are coarse calcifications at the edges of bone that form due to repetitive stress and trauma. There is also atrophy and fatty replacement of paraspinal musculature, which can be detected by CT or MRI. The malpositioning seen on radiography may not cause any symptoms at all. If there are related symptoms, however, therapeutic options include chiropractic care, physical therapy and nerve block injections. As a last resort, decompressive laminectomy may be attempted to relieve pain symptoms and remove the abnormally enlarged portions of bone.	[ { "begin": 0, "class": "SectionAnnotation", "length": 331, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 331, "class": "SectionAnnotation", "length": 345, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Cystinuria	disease	Cystinuria	Cystinuria is an inherited autosomal recessive disease that is characterized by high concentrations of the amino acid cystine in the urine, leading to the formation of cystine stones in the kidneys, ureter, and bladder. It is a type of aminoaciduria.	Cystinuria is a cause of persistent kidney stones. It is a disease involving the defective transepithelial transport of cystine and dibasic amino acids in the kidney and intestine, and is one of many causes of kidney stones. If not treated properly, the disease could cause serious damage to the kidneys and surrounding organs, and in some rare cases death. The stones may be identified by a positive nitroprusside cyanide test. The crystals are usually hexagonal, translucent, white. Upon removal, the stones may be pink or yellow in color, but later they turn to greenish due to exposure to air. Cystinuria is usually asymptomatic when no stone is formed. However, once a stone is formed, or if stone production is severe or frequent, symptoms may be present: - Nausea/vomiting - Dull ache or "colicky" pain - Chronic pain - Hematuria - Obstructive syndromes like hydronephrosis - Infective syndromes like pyelonephritis Cystinurics can also experience chronic pain in one, or both, kidneys due to the scars that the jagged edges of the stones can leave or damage from multiple stone removal surgeries. This can leave a cystinuric in constant pain which often requires medical intervention, such as long-term use of analgesics or surgical procedures, including T11, T12 or T13 nerve blocks (although, these procedures are often not successful, they can provide some relief). Aside from the chronic pain, a cystinuric will often have severe breakthrough pain from passing stones. People with cystinuria pass stones monthly, weekly, or daily, and need ongoing care. Cystinurics have an increased risk for chronic kidney disease and since kidney damage or poor function is often present in cystinurics, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or over the counter (OTC) medications should be used with caution. Cystine stones are often not visible on most x-rays, CT's, and ultrasounds. This does not mean the cystinuric doesn't have a stone. It takes a trained eye and experience to spot a cystine stone. It is not unusual for a cystinuric to pass a stone, or stones, after being released from the hospital with a CT or x-ray result of no stones in the kidneys. Urine odor in cystinuria has a smell of rotten eggs due to the increase in cystine. Cystinuria is an autosomal recessive disease, which means that the defective gene responsible for the disease is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disease. The parents of an individual with an autosomal recessive disease both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disease. Although signs and symptoms are rare, there are some directly and indirectly associated with cystinuria. These sign and symptoms consist of 1) hematuria- blood in the urine, 2) flank pain – pain in the side due to kidney pain, 3) renal colic – intense, cramping pain due to stones in the urinary tract, 4) obstructive uropathy- urinary tract disease due to obstruction, and 5) urinary tract infections. Cystinuria is caused by mutations in the SLC3A1 and SLC7A9 genes. These defects prevent proper reabsorption of basic, or positively charged, amino acids: Cystine, lysine, ornithine, arginine. Under normal circumstances, this protein allows certain amino acids, including cystine, to be reabsorbed into the blood from the filtered fluid that will become urine. Mutations in either of these genes disrupt the ability of this transporter protein to reabsorb these amino acids, allowing them to become concentrated in the urine. As the levels of cystine in the urine increase, the crystals typical of cystinuria are able to form, resulting in kidney stones. Cystine crystals form hexagonal-shaped crystals that can be viewed upon microscopic analysis of the urine. The other amino acids that are not reabsorbed do not create crystals in urine. The overall prevalence of cystinuria is approximately 1 in 7,000 neonates (from 1 in 2,500 neonates in Libyan Jews to 1 in 100,000 among Swedes). Cystinuria is characterized by the inadequate reabsorption of cystine in the proximal convoluted tubules after the filtering of the amino acids by the kidney's glomeruli, thus resulting in an excessive concentration of this amino acid in the urine. Cystine may precipitate out of the urine, if the urine is neutral or acidic, and form crystals or stones in the kidneys, ureters, or bladder. It is one of several inborn errors of metabolism included in the Garrod's tetrad. The disease is attributed to deficiency in transport and metabolism of amino acids. Regular X-rays often fail to show the cystine stones, however they can be visualized in the diagnostic procedure that is called intravenous pyelogram (or IVP for short). Stones may show up on XR with a fuzzy gray appearance. They are radioopaque due to sulfur content, though more difficult to visualize than calcium oxalate stones. Initial treatment is with adequate hydration, alkalization of the urine with citrate supplementation or acetazolamide, and dietary modification to reduce salt and protein intake (especially methionine). If this fails then patients are usually started on chelation therapy with an agent such as penicillamine. Tiopronin is another agent. Once renal stones have formed, however, the first-line treatment is ESWL (Extracorporeal shock wave lithotripsy). If ESWL do not work efficiently surgery can be necessary. Both endoscopic surgery and conventional open-abdominal surgery have proven to be effective treatment modalities for patients with more advanced disease. Adequate hydration is the foremost aim of treatment to prevent cysteine stones. The goal is to increase the urine volume because the concentration of cystine in the urine is reduced which prevents cystine from precipitating from the urine and forming stones. People with cystine stones should consume 5 to 7 liters a day. The rationale behind alkalizing the urine is that cystine tends to stay in solution and causes no harm. In order to alkalize the urine, sodium biocarbonate has been used. One must be careful in alkalizing their urine because it could lead to other forms of stones in process of preventing cystine stones. Penicillamine is a drug that acts to form a complex with cystine that is 50 times more soluble than cystine itself. Percutaneous nephrolithotripsy (PNL) is performed via a port created by puncturing the kidney through the skin and enlarging the access port to 1 cm in diameter. Most of the time, cystine stones are too dense to be broken up by shock (ESWL) so PNL is needed. Videos of surgery are available on various websites that show stone removal by percutaneous nephrolithotomy. In February 2017, an article was published in Nature Medicine entitled 'Alpha lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria', suggesting that a high dose of the readily available antioxidant, alpha-lipoic acid at 2,700 mg/67 kg body weight daily reduced the incidence of stones. The effects were dose dependent. The results are unprecedented for cystinuria. A clinical trial is underway based on this mouse model. This disease is known to occur in at least four mammalian species: humans, domestic canines, domestic ferrets and a wild canid, the maned wolf of South America. Cystine uroliths have been demonstrated, usually in male dogs, from approximately 70 breeds including the Australian cattle dog, Australian shepherd, Basenji, Basset, Bullmastiff, Chihuahua, Scottish deerhound, Scottish terrier, Staffordshire terrier, Welsh corgi, and both male and female Newfoundland dogs.	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https://en.wikipedia.org/wiki/Fibroadenoma	disease	Fibroadenoma	Fibroadenomas, are benign breast tumours characterized by an admixture of stromal and epithelial tissue. Breasts are made of lobules (milk producing glands) and ducts (tubes that carry the milk to the nipple). These are surrounded by glandular, fibrous and fatty tissues. Fibroadenomas develop from the lobules. The glandular tissue and ducts grow over the lobule to form a solid lump. Since both fibroadenomas, and breast lumps as a sign of breast cancer can appear similar, it is recommended to perform ultrasound analyses and possibly tissue sampling with subsequent histopathologic analysis in order to make a proper diagnosis. Unlike typical lumps from breast cancer, fibroadenomas are easy to move, with clearly defined edges. Fibroadenomas are sometimes called breast mice or a breast mouse owing to their high mobility in the breast.	The typical case is the presence of a painless, firm, solitary, mobile, slowly growing lump in the breast of a woman of child-bearing years. In the male breast, fibroepithelial tumors are very rare, and are mostly phyllodes tumors. Exceptionally rare case reports exist of fibroadenomas in the male breast, however these cases may be associated with antiandrogen treatment. Fibroadenomas are partially hormone-related and frequently regress after menopause. Higher intake of fruits and vegetables, higher number of live births, lower use of oral contraceptives and moderate exercise are associated with lower frequency of fibroadenomas. The diagnostic findings on needle biopsy consist of abundant stromal cells, which appear as bare bipolar nuclei, throughout the aspirate; sheets of fairly uniform-size epithelial cells that are typically arranged in either an antler-like pattern or a honeycomb pattern. These epithelial sheets tend to show typical metachromatic blue on Diff-Quik staining. Foam cells and apocrine cells may also be seen, although these are less diagnostic features. The gallery images below demonstrate these features. Cellular fibroadenoma, also known as juvenile fibroadenoma, is a variant type of fibroadenoma with increased stromal cellularity. Approximately 90% of fibroadenomas are less than 3 cm in diameter. However, these tumors have the potential to grow reaching a remarkable size, particularly in young individuals. The tumor is round or ovoid, elastic, and nodular, and has a smooth surface. The cut surface usually appears homogenous and firm, and is grey-white or tan in colour. The pericanalicular type (hard) has a whorly appearance with a complete capsule, while the intracanalicular type (soft) has an incomplete capsule. Fibroadenoma of the breast is a benign tumor composed of a biphasic proliferation of both stromal and epithelial components that can be arranged in two growth patterns: pericanalicular (stromal proliferation around epithelial structures) and intracanalicular (stromal proliferation compressing the epithelial structures into clefts). These tumors characteristically display hypovascular stroma compared to malignant neoplasms. Furthermore, the epithelial proliferation appears in a single terminal ductal unit and describes duct-like spaces surrounded by a fibroblastic stroma. The basement membrane is intact. Up to 66% of fibroadenomas harbor mutations in the exon (exon 2) of the mediator complex subunit 12 (MED12) gene. In particular, these mutations are restricted to the stromal component. A fibroadenoma is usually diagnosed through clinical examination, ultrasound or mammography, and often a needle biopsy sample of the lump. Most fibroadenomas are simply monitored. Some are treated by surgical excision. They are removed with a small margin of normal breast tissue if the preoperative clinical investigations are suggestive of the necessity of this procedure. A small amount of normal tissue must be removed in case the lesion turns out to be a phyllodes tumour on microscopic examination. Because needle biopsy is often a reliable diagnostic investigation, some doctors may decide not to operate to remove the lesion, and instead opt for clinical follow-up to observe the lesion over time using clinical examination and mammography to determine the rate of growth, if any, of the lesion. A growth rate of less than sixteen percent per month in women under fifty years of age, and a growth rate of less than thirteen percent per month in women over fifty years of age have been published as safe growth rates for continued non-operative treatment and clinical observation. Some fibroadenomas respond to treatment with ormeloxifene. Fibroadenomas have not been shown to recur following complete excision or transform into phyllodes tumours following partial or incomplete excision. The FDA has approved cryoablation of a fibroadenoma as a safe, effective and minimally-invasive alternative to open surgical removal in 2001. In the procedure, ultrasound imaging is used to guide a probe into the mass of breast tissue. Extremely cold temperatures are then used to destroy the abnormal cells, and over time the cells are reabsorbed into the body. The procedure can be performed as an outpatient surgery using local anesthesia only, and leaves substantially less scarring than open surgical procedures and no breast tissue deformation. The American Society of Breast Surgeons recommends the following criteria to establish a patient as a candidate for cryoablation of a fibroadenoma: 1. The lesion must be sonographically visible. 2. The diagnosis of a fibroadenoma must be confirmed histologically. 3. The lesion should be less than 4 cm in diameter. They are the most common breast tumor in adolescent women. They also occur in a small number of post-menopausal women. Their incidence declines with increasing age, and, in general, they appear before the age of thirty years.	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https://en.wikipedia.org/wiki/New_daily_persistent_headache	disease	New daily persistent headache	New daily persistent headache (NDPH) is a primary headache syndrome which can mimic chronic migraine and chronic tension-type headache. The headache is daily and unremitting from very soon after onset (within 3 days at most), usually in a person who does not have a history of a primary headache disorder. The pain can be intermittent, but lasts more than 3 months. Headache onset is abrupt and people often remember the date, circumstance and, occasionally, the time of headache onset. One retrospective study stated that over 80% of patients could state the exact date their headache began. The cause of NDPH is unknown, and it may have more than one etiology. NDPH onset is commonly associated with an infection or flu-like illness, stressful life event, minor head trauma, and extra cranial surgery. Infection or flu-like illness and stressful life event are most often cited. The pathophysiology of NDPH is poorly understood. The syndrome is difficult to treat and may persist for years. The age of onset ranges from 6 to greater than 70 years old, with a mean of 35 years. It is found to be more common in females in both the adult and pediatric populations. NDPH is rare. The Akershus study of chronic headache, a population based cross sectional study of 30,000 persons aged 30–44 years in Norway, found a one-year prevalence of 0.03 percent in the population. In 1986, Vanast was the first author to describe the new daily-persistent headache (NDPH) as a benign form of chronic daily headache (CDH). The criteria for the diagnosis of NDPH were proposed in 1994 (the Silberstein–Lipton criteria) but not included in the International Classification of Headache Disorders (ICHD) until 2004.	The headaches can vary greatly in their clinical presentation and duration. Quality of the headache has been described as dull and/or pressure-like sensation, and throbbing and/or pulsating sensation. The pain is usually on both sides of the head (in 88–93% of people with NDPH), but may be unilateral, and may be localized to any head region. The pain can fluctuate in intensity and duration, is daily, and lasts more than 3 months. There may be accompanying photophobia, phonophobia, lightheadedness or mild nausea. Co-morbidity with mood disorders has been reported in a subset of patients. Cranial autonomic nervous symptoms occur with painful exacerbations in 21%, and cutaneous allodynia may be present in 26%. In 2002, Li and Rozen conducted a study of 56 patients at the Jefferson Headache Center in Philadelphia and published the following results: - 82% of patients were able to pinpoint the exact day their headache started. - 30% of the patients, the onset of the headache occurred in correlation with an infection or flu-like illness. - 38% of the patients had a prior personal history of headache. - 29% of the patients had a family history of headache. - 68% reported nausea. - 66% reported photophobia. - 61% reported phonophobia. - 55% reported lightheadedness. Imaging and laboratory testing were unremarkable except for an unusually high number of patients who tested positive for a past Epstein-Barr virus infection. Although NDPH is classified as a primary headache syndrome, it must be remembered that a number of important conditions can present with a new-onset persisting headache, and these must be excluded prior to making a diagnosis of a primary headache disorder. The diagnosis is one of excluding the many secondary types or NDPH mimics, which is especially critical early in the course of the disease when a secondary etiology is more likely. NDPH mimics include but are not limited to: - neoplasms - subarachnoid hemorrhage - idiopathic intracranial hypertension - temporal arteritis - chronic subdural hematoma - post-traumatic headaches - sphenoid sinusitis - hypertension - spontaneous cerebrospinal fluid leak - cervical artery dissections - pseudotumor cerebri without papilledema - cerebral venous thrombosis - Chiari malformation - NDPH with medication overuse headache Many doctors state that the condition is best viewed as a syndrome rather than a diagnosis. Once a diagnosis of NDPH is made, clinicians argue that patients are best managed according to the more detailed pathophysiology-based diagnosis than lumped together into a single group, since a single disorder is unlikely to exist. NDPH It is classified as a Primary Headache Disorder by the ICHD-2 classification system (by the IHS) using number 4.8. It is one of the types of primary headache syndromes that present as a chronic daily headache, which is a headache present for more than 15 days a month for more than 3 months. The ICHD Diagnostic Criteria is: 1. Headache that, within 3 days of onset, fulfils criteria 2-4 2. Headache is present daily, and is unremitting, for > 3 months 3. At least two of the following pain characteristics: 1. bilateral location 2. pressing/tightening (non-pulsating) quality 3. mild or moderate intensity 4. not aggravated by routine physical activity such as walking or climbing 4. Both of the following: 1. no more than one of photophobia, phonophobia or mild nausea 2. neither moderate or severe nausea nor vomiting 5. Not attributed to another disorder Notes: 1. Headache may be unremitting from the moment of onset or very rapidly build up to continuous and unremitting pain. Such onset or rapid development must be clearly recalled and unambiguously described by the patient. Otherwise it is coded as 2.3 Chronic tension-type headache. 2. History and physical and neurological examinations do not suggest any of the disorders listed in groups 5-12 (including 8.2 medication overuse headaches and its subforms), or history and/or physical and/or neurological examinations do suggest such disorder but it is ruled out by appropriate investigations, or such disorder is present but headache does not occur for the first time in close temporal relation to the disorder. Although the original Silberstein–Lipton criteria and the original description by Vanast make no suggestion for the exclusion of migrainous features in NDPH, the current ICHD criteria exclude patients with migrainous features. When migraine features are present, classification thus becomes problematic. It has been reported that migraine symptoms may be present in over 50% of NDPH patients. The current criteria definition thus excludes more than half of patients with new onset of daily headache. This exclusion due to migrainous features could have adverse scientific, diagnostic, and treatment consequences. One proposal for reclassification of the criteria is from a study conducted on retrospective analysis of the records of 1348 patients regularly treated at the headache clinic of the Department of Neurology of Santa Casa de São Paulo, Brazil, and would be the following subdivision: NDPH with migraine features and without migraine features that would allow the inclusion of all individuals present who has a daily and persistent headache from the beginning. Another proposed reclassification of the criteria is from a study conducted as a retrospective chart review of patients seen at the Headache Center at Montefiore Medical Center in Bronx, New York, from September 2005 to April 2009. The revised criteria for NDPH definition does not exclude migraine features (NDPH-R), and three subdivisions were created and described based on prognosis: Persisting, remitting, and relapsing–remitting. Additionally, this revised criteria would not include parts C or D currently required by the ICHD diagnostic criteria for NDPH. The pathophysiology of NDPH is poorly understood. Research points to an immune-mediated, inflammatory process. Cervical joint hypermobility and defective internal jugular venous drainage have also been suggested as causes. In 1987, Vanast first suggested autoimmune disorder with a persistent viral trigger for CDH (now referred to as NDPH). Post-infectious origins have been approximated to make up anywhere between 30–80% of NDPH patients in different studies. Viruses that have been implicated include Epstein-Barr virus, herpes simplex virus and cytomegalovirus. Non-specific upper respiratory infections including rhinitis and pharyngitis are most often cited by patients. In one study, 46.5% patients recalled a specific trigger with a respiratory tract illness being the most common. In children, almost half report headache onset during an infection. A study by Rozen and Swindan in 2007 found elevated levels of tumor necrosis factor alpha, a proinflammatory cytokine, in the cerebrospinal fluid but not the blood of patients with NDPH, chronic migraine, and post-traumatic headaches suggesting inflammation as the cause of the headaches. NDPH as an inflammatory, post-infectious manifestation indicates a potential meningoencephalitis event in NDPH patients. Tissue specificity is a general feature of post-infectious, immune-mediated conditions, and the meninges are a type of connective tissue membrane. Inflammation of the meninges was first proposed as a possible pathophysiology for migraine in the 1960s and has recently been explored again. This hypothesis is based on meningeal mast cell activation. Reactive arthritis (ReA) is a post-infectious disease entity of synovium/joints with connective tissue membrane (synovial membrane of the joints) which provides a corollary. NDPH has been reported in Hashimoto's encephalopathy, an immune-mediated type of encephalitis. A mean 5-year retrospective analysis of 53 patients with a history of viral meningitis and 17 patients with a history of bacterial meningitis showed an increased onset of subsequent new onset headache and increased severity of those with prior primary headaches. There is no specific treatment for NDPH. Often they are treated similar to migraines. A number of medications have been used including amitriptyline, gabapentin, pregabalin, propranolol, and topiramate. There are no prospective placebo controlled trials of preventive treatment. In those with migrainous features treatment may be similar to migraines. Opiates, or narcotics, tend to be avoided because of their side effects, including the development of medication overuse headaches and potential for dependency. NDPH is often associated with medication overuse. To avoid the development of medication overuse headaches, it is advised not to use pain relievers for more than nine days a month. NDPH, like other primary headaches, has been linked to comorbid psychiatric conditions, mainly mood and anxiety and panic disorders. The spectrum of anxiety disorders, particularly panic disorder, should be considered in NDPH patients presenting with psychiatric symptoms. Simultaneous treatment of both disorders may lead to good outcomes. Medications within the tetracycline family, mexiletine, corticosteroids and nerve blocks are being studied. Occipital nerve block have been reported to be helpful for some people. 23/71 people had undergone a nerve block for their severe headache. The NDPH-ICHD group responded to the nerve block much more often (88.9%) than the NDPH with migraine features (42.9% responded to nerve block). Most patients have persistent headaches, although about 15% will remit, and 8% will have a relapsing-remitting type. It is not infrequent for NDPH to be an intractable headache disorder that is unresponsive to standard headache therapies.	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https://en.wikipedia.org/wiki/Adrenoleukodystrophy	disease	Adrenoleukodystrophy	Adrenoleukodystrophy is a disease linked to the X chromosome. It is a result of fatty acid buildup caused by the relevant enzymes not functioning properly, which then causes damage to the myelin sheath of the nerves, resulting in seizures and hyperactivity. Other side effects include problems with speaking, listening, and understanding verbal instructions. In more detail, it is a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very long chain fatty acids in tissues throughout the body. The most severely affected tissues are the myelin in the central nervous system, the adrenal cortex, and the Leydig cells in the testes. Clinically, ALD is a heterogeneous disorder, presenting with several distinct phenotypes, and no clear pattern of genotype-phenotype correlation. As an X-linked disorder, ALD presents most commonly in males, however approximately 50% of heterozygote females show some symptoms later in life. Approximately two-thirds of ALD patients will present with the childhood cerebral form of the disease, which is the most severe form. It is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state. The other forms of ALD vary in terms of onset and clinical severity, ranging from adrenal insufficiency to progressive paraparesis in early adulthood (this form of the disease is typically known as adrenomyeloneuropathy). ALD is caused by mutations in ABCD1, a gene located on the X chromosome that codes for ALD, a peroxisomal membrane transporter protein. The exact mechanism of the pathogenesis of the various forms of ALD is not known. Biochemically, individuals with ALD show very high levels of unbranched, saturated, very long chain fatty acids, particularly cerotic acid (26:0). The level of cerotic acid in plasma does not correlate with clinical presentation. Treatment options for ALD are limited. Dietary treatment is with Lorenzo's oil. For the childhood cerebral form, stem cell transplant and gene therapy are options if the disease is detected early in the clinical course. Adrenal insufficiency in ALD patients can be successfully treated. ALD is the most common peroxisomal inborn error of metabolism, with an incidence estimated between 1:18,000 and 1:50,000. It does not have a significantly higher incidence in any specific ethnic groups.	ALD can present in different ways. The different presentations are complicated by the pattern of X-linked recessive inheritance. There have been seven phenotypes described in males with ABCD1 mutations and five in females. Initial symptoms in boys affected with the childhood cerebral form of ALD include emotional instability, hyperactivity and disruptive behavior at school. Older patients affected with the cerebral form will present with similar symptoms. Untreated, cerebral ALD is characterized by progressive demyelination leading to a vegetative state and death. Adult males with an adrenomyeloneuropathy presentation typically present initially with muscle stiffness, paraparesis and sexual dysfunction. All patients with clinically recognized ALD phenotypes are at risk for adrenal insufficiency. There is no reliable way to predict which form of the disease an affected individual will develop, with multiple phenotypes being demonstrated within families. Onset of adrenal insufficiency is often the first symptom, appearing as early as two years of age. ALD is caused by mutations in ABCD1, located at Xq28 and demonstrates X-linked recessive inheritance. The gene ABCD1 encodes a peroxisomal membrane transporter which is responsible for transporting very long chain fatty acid substrate into the peroxisomes for degradation. Mutations in this gene that interfere with this process cause this syndrome. Males with an ABCD1 mutation are hemizygous, as they only have a single X chromosome. Female carriers will typically avoid the most severe manifestations of the disease, but often become symptomatic later in life. Although, the detection of an ABCD1 mutation identifies an individual who is affected with a form of ALD, there is no genotype - phenotype correlation. Within a family, there will often be several different phenotypes, despite the presence of the same causative mutation. In one case, a family with six affected members displayed five different phenotypes. There are no common mutations that cause ALD, most are private or familial. Almost 600 different mutations have been identified, approximately half are missense mutations, one quarter are frameshifts, with in-frame deletions and splicing defects making up the remainder. The incidence of new mutations in ALD (those occurring spontaneously, rather than being inherited from a carrier parent) is estimated at approximately 4.1%, with the possibility that these are due to germline mosaicism. The exact cause for the varied collection of symptoms found in the different ALD phenotypes is not clear. The white matter of the brain, the Leydig cells of the testes and the adrenal cortex are the most severely affected systems. The excess VLCFA can be detected in almost all tissues of the body, despite the localization of symptoms. The lack of Coenzyme A does not permit the disintegration of the VLCFA, accumulating the same in the white matter, adrenal glands, and the testes more specifically in the Leydig cells not allowing the proper function of this organs. Successful treatment of the demyelination process that affects the brain with either stem cell transplant or gene therapy does not immediately normalize the VLCFA levels in body tissues. The levels of VLCFA can be normalized by treatment with Lorenzo's oil, but this does not alter the progression of the disease. It is unclear whether the accumulation of VLCFA is associated with the pathogenesis of the disease in a specific way, or if it is a biochemical phenotype, useful for identification. The clinical presentation of ALD can vary greatly, making diagnosis difficult. With the variety of phenotypes, clinical suspicion of ALD can result from a variety of different presentations. Symptoms vary based on the disease phenotype, and even within families or between twins. When ALD is suspected based on clinical symptoms, the initial testing usually includes plasma very long chain fatty acid (VLCFA) determination using gas chromatography-mass spectrometry. The concentration of unsaturated VLCFA, particularly 26 carbon chains is significantly elevated in males with ALD, even prior to the development of other symptoms. Confirmation of ALD after positive plasma VLCFA determination usually involves molecular genetic analysis of ABCD1. In females, where plasma VLCFA measurement is not always conclusive (some female carriers will have normal VLCFA in plasma), molecular analysis is preferred, particularly in cases where the mutation in the family is known. Although the clinical phenotype is highly variable among affected males, the elevations of VLCFA are present in all males with an ABCD1 mutation. Because the characteristic elevations associated with ALD are present at birth, well before any symptoms are apparent, there have been methods developed in the interests of including it in newborn screening programs. One of the difficulties with ALD as a disease included in universal newborn screening is the difficulty in predicting the eventual phenotype that an individual will express. The accepted treatment for affected boys presenting with the cerebral childhood form of the disease is a bone marrow transplant, a procedure which carries significant risks. However, because most affected males will demonstrate adrenal insufficiency, early discovery and treatment of this symptom could potentially prevent complications and allow these patients to be monitored for other treatment in the future, depending on the progression of their disease. The Loes score is a rating of the severity of abnormalities in the brain found on MRI. It ranges from 0 to 34, based on a point system derived from the location and extent of disease and the presence of atrophy in the brain, either localized to specific points or generally throughout the brain. A Loes score of 0.5 or less is classified as normal, while a Loes score of 14 or greater is considered severe. It was developed by neuroradiologist Daniel J. Loes MD and is an important tool in assessing disease progression and the effectiveness of therapy. Initial attempts at dietary therapy in ALD involved restricting the intake of very-long chain fatty acids (VLCFA). Dietary intake is not the only source for VLCFA in the body, as they are also synthesized endogenously. This dietary restriction did not impact the levels of VLCFA in plasma and other body tissues. After the realization that endogenous synthesis was an important contribution to VLCFA in the body, efforts at dietary therapy shifted to inhibiting these synthetic pathways in the body. The parents of Lorenzo Odone, a boy with ALD, spearheaded efforts to develop a dietary treatment to slow the progression of the disease. They developed a mixture of unsaturated fatty acids (glycerol trioleate and glyceryl trierucate in a 4:1 ratio), known as Lorenzo's oil that inhibits elongation of saturated fatty acids in the body. Supplementation with Lorenzo's oil has been found to normalize the VLCFA concentrations in the body, although its effectiveness at treating the cerebral manifestations of the disease is still controversial and unproven. Trials with Lorenzo's oil have shown that it does not stop the neurological degradation in symptomatic patients, nor does it improve adrenal function. While dietary therapy has been shown to be effective to normalize the very-long chain fatty acid concentrations in the plasma of individuals with ALD, allogeneic hematopoietic stem cell transplants is the only treatment that can stop demyelination that is the hallmark of the cerebral forms of the disease. In order to be effective, the transplant must be done at an early stage of the disease; if the demyelination has progressed, transplant can worsen the outcome, and increase the rate of decline. While transplants have been shown to be effective at halting the demyelination process in those presenting with the childhood cerebral form of ALD, follow-up of these patients has shown that it does not improve adrenal function. For patients where an appropriate match for a transplant cannot be found, there have been investigations into the use of gene therapy. Appropriate vectors are selected and modified to express wild type ABCD1, which is then transplanted into the patients using a similar procedure as for a bone marrow or stem cell transplant. Gene therapy has only been tried on a small number of patients, mainly in France. These patients were only considered for gene therapy after there was no HLA match for a traditional transplant. In two reported cases, the gene therapy was successful, with a resolution of the demyelination process up to two years after the procedure. Although the gene therapy was successful in resolving the neurological symptoms, plasma VLCFA levels remained elevated. Treatment of the adrenal insufficiency that can accompany any of the common male phenotypes of ALD does not resolve any of the neurological symptoms. Hormone replacement is standard for ALD patients demonstrating adrenal insufficiency. Adrenal insufficiency does not resolve with successful transplant; most patients still require hormone replacement. ALD has not been shown to have an increased incidence in any specific country or ethnic group. In the United States, the incidence of affected males is estimated at 1:21,000. Overall incidence of hemizygous males and carrier females is estimated at 1:16,800. The reported incidence in France is estimated at 1:22,000.	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https://en.wikipedia.org/wiki/Endodermal_sinus_tumor	disease	Endodermal sinus tumor	Endodermal sinus tumor (EST), also known as yolk sac tumor (YST), is a member of the germ cell tumor group of cancers. It is the most common testicular tumor in children under 3, and is also known as infantile embryonal carcinoma. This age group has a very good prognosis. In contrast to the pure form typical of infants, adult endodermal sinus tumors are often found in combination with other kinds of germ cell tumor, particularly teratoma and embryonal carcinoma. While pure teratoma is usually benign, endodermal sinus tumor is malignant.	The histology of EST is variable, but usually includes malignant endodermal cells. These cells secrete alpha-fetoprotein (AFP), which can be detected in tumor tissue, serum, cerebrospinal fluid, urine and, in the rare case of fetal EST, in amniotic fluid. When there is incongruence between biopsy and AFP test results for EST, the result indicating presence of EST dictates treatment. This is because EST often occurs as small "malignant foci" within a larger tumor, usually teratoma, and biopsy is a sampling method; biopsy of the tumor may reveal only teratoma, whereas elevated AFP reveals that EST is also present. GATA-4, a transcription factor, also may be useful in the diagnosis of EST. Diagnosis of EST in pregnant women and in infants is complicated by the extremely high levels of AFP in those two groups. Tumor surveillance by monitoring AFP requires accurate correction for gestational age in pregnant women, and age in infants. In pregnant women, this can be achieved simply by testing maternal serum AFP rather than tumor marker AFP. In infants, the tumor marker test is used, but must be interpreted using a reference table or graph of normal AFP in infants. EST can have a multitude of morphologic patterns including: reticular, endodermal sinus-like, microcystic, papillary, solid, glandular, alveolar, polyvesicular vitelline, enteric and hepatoid. Schiller-Duval bodies on histology are pathognomonic and seen in the context of the endodermal sinus-like pattern. Most treatments involve some combination of surgery and chemotherapy. Treatment with cisplatin, etoposide, and bleomycin has been described. Before modern chemotherapy, this type of neoplasm was highly lethal, but the prognosis has significantly improved since. When endodermal sinus tumors are treated promptly with surgery and chemotherapy, fatal outcomes are exceedingly rare.	[ { "begin": 0, "class": "SectionAnnotation", "length": 1177, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 1177, "class": "SectionAnnotation", "length": 309, "sectionHeading": "Diagnosis \| Pathology", "sectionLabel": "disease.diagnosis" }, { "begin": 1486, "class": "SectionAnnotation", "length": 380, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Neonatal_infection	disease	Neonatal infection	Neonatal infections are infections of the neonate (newborn) during the neonatal period or first four weeks after birth. Neonatal infections may be contracted by transplacental transfer in utero, in the birth canal during delivery (perinatal), or by other means after birth. Some neonatal infections are apparent soon after delivery, while others may develop postpartum within the first week or month. Some infections acquired in the neonatal period do not become apparent until much later such as HIV, hepatitis B and malaria. There is a higher risk of infection for preterm or low birth weight neonates. Respiratory tract infections contracted by preterm neonates may continue into childhood or possibly adulthood with long-term effects that limit one's ability to engage in normal physical activities, decreasing one's quality of life and increasing health care costs. In some instances, neonatal respiratory tract infections may increase one's susceptibility to future respiratory infections and inflammatory responses related to lung disease. Antibiotics can be effective treatments for neonatal infections, especially when the pathogen is quickly identified. Instead of relying solely on culturing techniques, pathogen identification has improved substantially with advancing technology; however, neonate mortality has not kept pace and remains 20% to 50%. While preterm neonates are at a particularly high risk, full term and post-term infants can also develop infection. Neonatal infection may also be associated with premature rupture of membranes (breakage of the amniotic sac) which substantially increases the risk of neonatal sepsis by allowing passage for bacteria to enter the womb prior to the birth of the infant. Neonatal infection can be distressing to the family and it initiates concentrated effort to treat it by clinicians.Research to improve treatment of infections and prophylactic treatment of the mother to avoid infections of the infant is ongoing.	In industrialized countries, treatment for neonatal infections takes place in the neonatal intensive care unit. The causes and reasons for neonatal infection are many. The origin of infectious bacteria and some other pathogens is often the maternal gastrointestinal and genitourinary tract. Many of the maternal infections with these organisms are asymptomatic in the mother. Other maternal infections that may be transmitted to the infant in utero or during birth are bacterial and viral sexually transmitted infections. The infant's ability to resist infection is complicated by its immature immune system. The causative agents of neonatal infection are bacteria, viruses, and fungi. In addition, the immune system of the neonate may respond in ways that can create problems that complicate treatment, such as the release of inflammatory chemicals. Congenital defects of the immune system also affect the infants ability to fight off the infection. Group B streptococcus are typically identified as the cause of the majority of early-onset infections in the neonate. This pathogen is vertically transmitted (transmitted directly from the mother) to the infant. Enteric bacilli that originate from the digestive system of the mother have become as prevalent as the group B streptococcus pathogens and are currently as likely to cause infection. With the advances in preventing group B streptococcus infections, β-lactam-resistant Escherichia coli infections have increased in causing neonatal deaths in very low birthweight and premature infants. Infections with Staphylococcus aureus are also diagnosed, but not as frequently as group B streptococcus infections. Listeria monocytogenes can also cause infection acquired from tainted food and present in the mother. The presence of this pathogen can sometimes be determined by the symptoms that appear as a gastrointestinal illness in the mother. The mother acquires infection from ingesting food that contains animal products such as hot dogs, unpasteurized milk, delicatessen meats, and cheese. Neonatal infection can also occur in term and post-term infants. Infections that develop one month after the birth of the infant are more likely due to Gram-positive bacteria and coagulase positive staphylococci. Acquired maternal infection and subsequent inflammation from Ureaplasma urealyticum is accompanied by a strong immune response and is correlated with the need for prolonged mechanical ventilation. Other bacterial pathogens include Streptococcus agalactiae, Streptococcus pyogenes, Viridans streptococci, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa". Human immunodeficiency virus type I (HIV) infection can occur during labor and delivery, in utero through mother-to-child transmission or postnatally by way of breastfeeding. Transmission can occur during pregnancy, delivery or breastfeeding. Most transmission occurs during delivery. In women with low detectable levels of the virus, the incidence of transmission is lower. Transmission risk can be reduced by: - providing antiretroviral therapy during pregnancy and immediately after birth - delivery by caesarean section - not breastfeeding - antiretroviral prophylaxis in infants born to mothers with HIV. A low number of women whose HIV status are unknown until after the birth, do not benefit from interventions that could help lower the risk of mother-to-child HIV transmission. Sixty percent of mothers of preterm infants are infected with cytomegalovirus (CMV). Infection is asymptomatic in most instances but 9% to 12% of postnatally infected low birth weight, preterm infants have severe, sepsis-like infection. CMV infection duration can be long and result in pneumonitis in association with fibrosis. CMV infection in infants has an unexpected effect on the white blood cells of the immune system causing them to prematurely age. This leads to a reduced immune response similar to that found in the elderly. Herpes simplex virus (HSV) can infect the infant during birth. Most women with HVS genital herpes develop asymptomatic infection during pregnancy. HVS inoculation from mother to fetus has a high likelihood of occurring. Mothers who are treated with antiviral prophylaxis are less prone to have an active, symptomatic case at the time of birth. Mothers who have received prophylactic antiviral medication have been shown to be less likely to require a cesarean section. At delivery, mothers treated with antiviral medication are less likely to have a viral shedding at the time of birth. Zika fever is caused by a virus that is acquired by the mother and then transmitted to the infant in utero. The CDC is concerned with the potential that this viral infection may cause microcephaly in newborns. Congential rubella is still a risk with higher risk among immigrant women from countries without adequate vaccination programs. Other viral infections such as respiratory syncytial virus (RSV), metapneumovirus (hMPV), rhinovirus, parainfluenza (PIV), and human coronavirus in the neonatal period are associated with recurrent wheezing in later childhood. RSV infections can be prolonged. Premature infants born at less than 32 weeks gestation have more days of cough and wheeze at 1 year of age than those uninfected with RSV. In very low birth weight infants (VLBWI), systemic fungus infection is a hospital-acquired infection with serious consequences. The pathogens are usually Candida albicans and Candida parapsilosis. A small percentage of fungal infections are caused by Aspergillus, Zygomycetes, Malassezia, and Trichosporon. Infection is usually late-onset. Up to 9% of VLBWI with birth weights of <1,000 g develop these fungus infections leading to sepsis or meningitis. As many as one-third of these infants can die. Candidiasis is associated with retinopathy, prematurity and negative neurodevelopmental consequences. Candida can colonize the gastrointestinal tract of low birthweight infants (LBI). This gastrointestinal colonization is often a precursor to a more serious invasive infection. The risk of serious candida infection increases when multiple factors are present. These are: thrombocytopenia, the presence of candidal dermatitis, the use of systemic steroids, birth weights of <1,000 g, presence of a central catheter, postponing enteral feeding, vaginal delivery, and the amount of time broad-spectrum antibiotics were given. Infants born with malaria can be infected with a variety of species; Plasmodium vivax, Plasmodium malariae, Plasmodium ovale, and Plasmodium falciparum. In most instances of congenital marlaria is caused by P. vivax and P. falciparum. Women living in areas where malaria is prevalent and common are repeatedly exposed to malaria. In response to maternal infection, mothers develop antimalarial antibodies. It is probable that the antibodies present in the mother offers protection for the baby. Bacterial infection can develop with malaria. Infants that are infected by the protozoanToxoplasma gondii in utero can be born with chorioretinitis or ocular toxoplasmosis. Globally, it is the most common cause of infections of the back of the eye. (posterior segment). The most common sign is decreased vision in one eye. Other signs and symptoms may appear after the neonatal period and include: miscarriage, stillbirth, chorioretinitis development later in life, intracranial calcification hydrocephalus or central nervous system abnormalities. Risk factors are those conditions which increase the likelihood that an infant will be born with or develop an infection. The risk for developing catheter-related infections is offset by the increased survival rate of premature infants that have early onset sepsis. Intravenous administration of prophylactic immunoglobin enhances immunity of the immature infant and is used for treatment. Inflammation accompanies infection and is likely to complicate treatment and recovery. Inflammation is linked to reduced growth of the lungs of the premature baby. The recent identification of the presence of microorganisms in maternal-infant body fluids that were previously thought to be sterile has provided one explanation for the presence of the inflammatory response in both the mother and infant. Sixty-one percent of pregnant women with chorioamnionitis, or inflammation of the amniotic fluid, were found to be infected by microorganisms. Often, more than one pathogen was present. In fifteen percent of pregnant women inflammation was still evident even though there was no evidence of pathogens. This may indicate that there are other causes. A high percentage, 51% to 62%, of pregnant women who had chorioamnionitis also had inflammation of the placenta. Diagnosis of infection is based upon the recovery of the pathogen or pathogens from the typically sterile sites in the mother or the baby. Unfortunately, as many half of pregnant women are asymptomatic with a gonorrhea infection and other sexually transmitted infections. Samples are obtained from urine, blood or cerebrospinal fluid. Diagnosis of infection can also be aided by the use of more nonspecific tests such as determining the total white blood cell count, cytokine levels and other blood tests and signs. Symptoms and the isolation of the virus pathogen the upper respiratory tract is diagnostic. Virus identification is specific immunologic methods and PCR. The presence of the virus can be rapidly confirmed by the detection of the virus antigen. The methods and materials used for identifying the RSV virus has a specificity and sensitivity approaching 85% to 95%. Not all studies confirm this sensitivity. Antigen detection has comparatively lower sensitivity rates that approach 65% to 75%. Neonatal sepsis of the newborn is an infection that has spread through the entire body. The inflammatory response to this systematic infection can be as serious as the infection itself. In infants that weigh under 1500 g, sepsis is the most common cause of death. Three to four percent of infants per 1000 births contract sepsis. The mortality rate from sepsis is near 25%. Infected sepsis in an infant can be identified by culturing the blood and spinal fluid and if suspected, intravenous antibiotics are usually started. Lumbar puncture is controversial because in some cases it has found not to be necessary while concurrently, without it estimates of missing up to one third of infants with meningitis is predicted. To reduce neonatal infection, routine screening of pregnant women for HIV, hepatitis B, syphilis, and rubella susceptibility is required in the UK. Treatment with an vaginal antibiotic wash prior to birth does not prevent infection with group B streptococcus bacteria. Breast milk protects against necrotizing enterocolitis. Because GBS bacteria can colonize the lower reproductive tract of 30% of women, typically pregnant women are tested for this pathogen from 35 to 37 weeks of pregnancy. Before delivery treatment of the mother with antibiotics reduces the rate of neonatal infection. Prevention of the infection of the baby is done by treating the mother with penicillin. Since the adoption of this prophylatic treatment, infant mortality from GBS infection has decreased by 80%. Mothers with symptomatic HSV and who are treated with antiviral prophylaxis are less prone to have an active, symptomatic case at the time of birth and it may be able to reduce the risk of passing on HSV during birth. Cesarean delivery reduces the risk of infection of the infant. Neonatal infection treatment is typically started before the diagnosis of the cause can be confirmed. Neonatal infection can be prophylactically treated with antibiotics. Maternal treatment with antibiotics is primarily used to protect against group B streptococcus. Women with a history of HSV, can be treated with antiviral drugs to prevent symptomatic lesions and viral shedding that could infect the infant at birth. The antiviral medications used include acyclovir, penciclovir, valacyclovir, and famciclovir. Only very small amounts of the drug can be detected in the fetus. There are no increases in drug-related abnormalities in the infant that could be attributed to acyclovir. Long-term effects of antiviral medications have not been evaluated for their effects after growth and development of the child occurs. Neutropenia can be a complication of acyclovir treatment of neonatal HSV infection, but is usually transient. Treatment with immunoglobulin therapy has not been proven to be effective. Up to 3.3 million newborns die each year and 23.4% of these die of neonatal infection. About half of the deaths caused by sepsis or pneumonia happen in the first week postpartum. In industrialized countries, prophylactic antibiotic treatment of the mothers identified with group B streptococcus, early identification of sepsis in the newborn, and administration of antibiotics to the newborn has reduced mortality. Neonatal herpes in North America is estimated to be from 5 – 80 per 100,000 live births. HSV has a lower prevalence in mothers outside the United States. In the United Kingdom the incidence is much lower and estimated to be 1.6 per 100,000 live births. Approximately 70% to 80% of infected infants are born to mothers with no reported history of HSV infection. Regions with low neonatal mortality include Europe, the Western Pacific, and the Americas, which have sepsis rates that account for 9.1% to 15.3% of the total neonatal deaths worldwide. This is in contrast with the 22.5 to 27.2% percentage of total deaths in resource-poor countries such as Nigeria, the Democratic Republic of the Congo, India, Pakistan, and China. In the UK, the proportions of pregnant women who are newly screened positive for hepatitis B, syphilis, and HIV have remained constant since 2010 at about 0.4%, 0.14% and 0.15%, respectively. Estimated prevalence levels among pregnant women for hepatitis B and HIV, including previous diagnoses, were higher at 0.67% and 0.27%. Pregnant women evaluated as susceptible to rubella due to low antibody levels have increased by over 60%, to about 7.2%. However, this increase is probably due to changes in testing methods and evaluation criteria. In North America, prior to the 1950s, group A β-hemolytic streptococcus (GAS) was the most common pathogen associated with neonatal sepsis prior to the 1960s. In the past twenty years, the most common pathogen causing sepsis is coagulase-negative staphylococci that exist as biofilms associated with infected central venous or arterial catheters. Infections can be fatal and contribute to long-term morbidity and disability among the infants who survive into childhood. Neonatal sepsis effects 128 cases per 1000 live births. Meningitis can occur in the septic infant. Expectant mothers with HVS have a 75% chance of at least one flare-up during their pregnancy. In limited studies it was found that infants in Africa born to mothers with malaria have a 7% of acquiring congenital malaria. Early onset sepsis can occur in the first week of life. It usually is apparent on the first day after birth. This type of infection is usually acquired before the birth of the infant. Premature rupture of membranes and other obstetrical complications can add to the risk of early-onset sepsis. If the amniotic membrane has been ruptured greater than 18 hours before delivery the infant may be at more risk for this complication. Prematurity, low birth weight, chorioamnionitis, maternal urinary tract infection and/or maternal fever are complications that increase the risk for early-onset sepsis. Early onset sepsis is indicated by serious respiratory symptoms. The infant usually suffers from pneumonia, hypothermia, or shock. The mortality rate is 30 to 50%. Infections that occur after the first week of life but before the age of 30 days are considered late onset infections. Obstetrical and maternal complications are not typically the cause of these late onset infections; they are usually acquired by the infant in the hospital neonatal intensive care unit. The widespread use of broad-spectrum antibiotics in the nursery intensive care unit can cause a higher prevalence of invasive antibiotic resistant bacteria. Meconium aspiration syndrome has a mortality rate just over 4%. This accounts for 2% for all neonatal deaths. The susceptibility to risk of infection and immune deficiencies are active areas of research. Studies regarding the role of viruses in neonatal infections are lacking. Research also continues into the role and protective effect of gut, skin and other human microbiomes and the colonization during the neonatal period. The comparison between resource rich countries and resource poor countries makes it somewhat difficult to compare the diagnosis success since industrialized regions are able to confirm the diagnosis and presence of pathogens in the clinical laboratory. Clinical testing may not be available in all settings and clinicians must rely on the signs of infection in the newborn. Research data from Africa and Southeast Asia is scarce. The result of some research has been the identification of diagnostic tools and procedures that could identify mothers with group B streptococcus infection in resource-poor regions. These procedures would be easy and inexpensive to use. Those mothers who are identified as being infected could then be prophylactly treated prior to the birth of the baby. Probiotic administration of Lactobacillus species has shown some success. A GBS vaccine is currently being tested but not currently available. Vaccination is estimated to being able to prevent 4% of GBS infections for preterm births and 60–70% for neonatal GBS infections in the US. The projected benefits of maternal vaccination is the prevention of 899 cases of GBS disease and 35 deaths among infants. The cost savings in the prevention of GBS may be over 43 million dollars. Vaccination may be especially beneficial in low to middle income countries where screening and prophylactic treatment is not possible. Analysts project that GBS vaccination would prevent 30–54% of infant GBS cases. Screening, prophylactic antibiotics and vaccine would prevent 48% of infection.	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https://en.wikipedia.org/wiki/Ciliopathy	disease	Ciliopathy	A ciliopathy is a genetic disorder of the cellular cilia or the cilia anchoring structures, the basal bodies, or of ciliary function. Although ciliopathies are usually considered to involve proteins that localize to motile and/or immotile (primary) cilia or centrosomes, it is possible for ciliopathies to be associated with proteins such as XPNPEP3, which localizes to mitochondria but is believed to affect ciliary function through proteolytic cleavage of ciliary proteins. Significant advances in understanding the importance of cilia were made beginning in the mid-1990s. However, the physiological role that this organelle plays in most tissues remains elusive. Additional studies of how ciliary dysfunction can lead to such severe disease and developmental pathologies is a subject of current research.	A wide variety of symptoms are potential clinical features of ciliopathy. - Chemosensation abnormalities, typically via ciliated epithelial cellular dysfunction. - Defective thermosensation or mechanosensation, often via ciliated epithelial cellular dysfunction. - Cellular motility dysfunction - Issues with displacement of extracellular fluid - Paracrine signal transduction abnormalities In organisms of normal health, cilia are critical for: - development - homeostasis - reproduction "In effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Cilia "function as mechano- or chemosensors and as a cellular global positioning system to detect changes in the surrounding environment." For example, ciliary signaling plays a role in the initiation of cellular replacement after cell damage. In addition to this sensory role mediating specific signaling cues, cilia play "a secretory role in which a soluble protein is released to have an effect downstream of the fluid flow" in epithelial cells, and can of course mediate fluid flow directly in the case of motile cilia. Primary cilia in the retina play a role in transferring nourishment to the non-vascularized rod and cone cells from the vascularized cells several micrometres behind the surface of the retina. Signal transduction pathways involved include the Hedgehog signaling pathway and the Wnt signaling pathway. "Just as different genes can contribute to similar diseases, so the same genes and families of genes can play a part in a range of different diseases." For example, in just two of the diseases caused by malfunctioning cilia, Meckel-Gruber syndrome and Bardet-Biedl syndrome, patients who carry mutations in genes associated with both diseases "have unique symptoms that are not seen in either condition alone." The genes linked to the two different conditions "interact with each other during development." Systems biologists are endeavoring to define functional modules containing multiple genes and then look at disorders whose phenotypes fit into such modules. A particular phenotype can overlap "considerably with several conditions (ciliopathies) in which primary cilia are also implicated in pathogenicity. One emerging aspect is the wide spectrum of ciliopathy gene mutations found within different diseases." "The phenotypic parameters that define a ciliopathy may be used to both recognize the cellular basis of a number of genetic disorders and to facilitate the diagnosis and treatment of some diseases of unknown" cause. Although non-motile or primary cilia were first described in 1898, they were largely ignored by biologists. However, microscopists continued to document their presence in the cells of most vertebrate organisms. The primary cilium was long considered—with few exceptions—to be a largely useless evolutionary vestige, a vestigial organelle. Recent research has revealed that cilia are essential to many of the body's organs. These primary cilia play important roles in chemosensation, mechanosensation, and thermosensation. Cilia may thus be "viewed as sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation." Recent advances in mammalian genetic research have made possible the understanding of a molecular basis for a number of dysfunctional mechanisms in both motile and primary cilia structures of the cell. A number of critical developmental signaling pathways essential to cellular development have been discovered. These are principally but not exclusively found in the non-motile or primary cilia. A number of common observable characteristics of mammalian genetic disorders and diseases are caused by ciliary dysgenesis and dysfunction. Once identified, these characteristics thus describe a set of hallmarks of a ciliopathy. Cilia have recently been implicated in a wide variety of human genetic diseases by "the discovery that numerous proteins involved in mammalian disease localize to the basal bodies and cilia." For example, in just a single area of human disease physiology, cystic renal disease, cilia-related genes and proteins have been identified to have causal effect in polycystic kidney disease, nephronophthisis, Senior-Loken syndrome type 5, orofaciodigital syndrome type 1 and Bardet-Biedl syndrome.	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https://en.wikipedia.org/wiki/Granular_corneal_dystrophy	disease	Granular corneal dystrophy	Granular corneal dystrophy is a slowly progressive corneal dystrophy that most often begins in early childhood. Granular corneal dystrophy has two types: - Granular corneal dystrophy type I , also corneal dystrophy Groenouw type I, is a rare form of human corneal dystrophy. It was first described by German ophthalmologist Arthur Groenouw in 1890. - Granular corneal dystrophy type II, also called Avellino corneal dystrophy or combined granular-lattice corneal dystrophy is also a rare form of corneal dystrophy. The disorder was first described by Folberg et al. in 1988. The name Avellino corneal dystrophy comes from the first four patients in the original study each tracing their family origin to the Italian province of Avellino.	Granular corneal dystrophy is caused by a mutation in the TGFBI gene, located on chromosome 5q31. The disorder is inherited in an autosomal dominant manner. This indicates that the defective gene responsible for the disorder is located on an autosome (chromosome 5 is an autosome), and only one copy of the gene is sufficient to cause the disorder, when inherited from a parent who has the disorder. The gene TGFBI encodes the protein keratoepithelin. Granular corneal dystrophy is diagnosed during an eye examination by an ophthalmologist or optometrist. The lesions consist of central, fine, whitish granular lesions in the cornea. Visual acuity is slightly reduced. Corneal transplant is not needed except in very severe and late cases. Light sensitivity may be overcome by wearing tinted glassess.	[ { "begin": 0, "class": "SectionAnnotation", "length": 452, "sectionHeading": "Genetics", "sectionLabel": "disease.genetics" }, { "begin": 452, "class": "SectionAnnotation", "length": 217, "sectionHeading": "Clinical presentation", "sectionLabel": "disease.symptom" }, { "begin": 669, "class": "SectionAnnotation", "length": 133, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Fungal_meningitis	disease	Fungal meningitis	Fungal meningitis refers to meningitis caused by a fungal infection.	Symptoms of fungal meningitis are generally similar to those of other types of meningitis, and include: a fever, stiff neck, severe headache, photophobia (sensitivity to light), nausea and vomiting, and altered mental status (drowsiness or confusion). Fungal meningitis may be caused by the following (and also other) types of fungi: - Candida - C. albicans is the most common Candida species causing CNS infection. - Coccidioides - it is endemic to southwestern United States and Mexico. A third of patients presenting with disseminated coccidioidomycosis have developed meningitis. - Histoplasma - occurs in bird and bat droppings and is endemic in parts of the United States, South, and Central America. CNS involvement occurs in 10-20% of disseminated histoplasmosis cases. - Blastomyces - occurs in soil rich in decaying organic matter in the Midwest United States. Meningitis is an unusual manifestation of blastomycosis and can be very difficult to diagnose. - Cryptococcus (Cryptococcal meningitis) - it is thought to be acquired through inhalation of soil contaminated with bird droppings. C. neoformans is the most common pathogen to cause fungal meningitis. - Aspergillus - Aspergillus infections account for 5% of CNS fungal infections. Individuals with a weak immune system are most at risk. This includes individuals taking immunosuppressive medication, cancer patients, HIV patients, premature babies with very low birth weight, the elderly, etc. People who are at an increased risk of acquiring particular fungal infections in general may also be at an increased risk of developing fungal meningitis, as the infection may in some cases spread to the CNS. People residing in the Midwestern United States, and Southwestern United States and Mexico are at an increased risk of infection with Histoplasma and Coccidioides, respectively. If suspected, fungal meningitis is diagnosed by testing blood and CSF samples for pathogens. Identifying the specific pathogen is necessary to determine the proper course of treatment and the prognosis. Measurement of opening pressure, cell count with differential, glucose and protein concentrations, Gram's stain, India ink, and culture tests should be preformed on CSF samples when fungal meningitis is suspected. Fungal meningitis is treated with long courses of high dose antifungal medications. The duration of treatment is dependent upon the causal pathogen and the patient's ability to stave off the infection; for patients with a weaker immune system or diabetes, treatment will often take longer. Prognosis depends on the pathogen responsible for the infection and risk group. Overall mortality for Candida meningitis is 10-20%, 31% for patients with HIV, and 11% in neurosurgical cases (when treated). Prognosis for Aspergillus and coccidioidal infections is poor. As of November 5, 2012, the CDC reported that 409 patients had laboratory-confirmed fungal meningitis caused by injections with contaminated medication.There had been 30 fatalities. A black mold, Exserohilum rostratum, was found in 45 of these cases. Aspergillus fumigatus was found in one case, and a Cladosporium species was found in one case. Aspergillus has been very rarely associated with meningitis while cases caused explicitly by Exserohilum in otherwise healthy individuals have not been previously reported.	[ { "begin": 0, "class": "SectionAnnotation", "length": 252, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 252, "class": "SectionAnnotation", "length": 997, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 1249, "class": "SectionAnnotation", "length": 600, "sectionHeading": "Risk factors", "sectionLabel": "disease.risk" }, { "begin": 1849, "class": "SectionAnnotation", "length": 418, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 2267, "class": "SectionAnnotation", "length": 290, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 2557, "class": "SectionAnnotation", "length": 269, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" }, { "begin": 2826, "class": "SectionAnnotation", "length": 520, "sectionHeading": "Outbreaks", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Laurence–Moon_syndrome	disease	Laurence–Moon syndrome	Laurence–Moon syndrome (LMS) is a rare autosomal recessive genetic disorder associated with retinitis pigmentosa, spastic paraplegia, and mental disabilities.	LMS is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on 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. It is named after the physicians John Zachariah Laurence and Robert Charles Moon who provided the first formal description of the condition in a paper published in 1866. In the past, LMS has also been referred to as Laurence–Moon–Bardet–Biedl or Laurence–Moon–Biedl–Bardet syndrome, but Bardet–Biedl syndrome (BBS) is now usually recognized as a separate entity. Recent advances in genetic typing of the phenotypically-wide variation in patients clinically diagnosed with either Bardet-Biedl Syndrome (BBS) or Laurence-Moon Syndrome (LMS) have questioned whether LMS and BBS are genetically distinct. For example, a 1999 epidemiological study of BBS and LMS reported that "BBS proteins interact and are necessary for the development of many organs." "Two patients [in the study] were diagnosed clinically as LMS but both had mutations in a BBS gene. The features in this population do not support the notion that BBS and LMS are distinct." A more recent 2005 paper also suggests that the two conditions are not distinct.	[ { "begin": 0, "class": "SectionAnnotation", "length": 437, "sectionHeading": "Genetics", "sectionLabel": "disease.genetics" }, { "begin": 437, "class": "SectionAnnotation", "length": 1021, "sectionHeading": "Eponym and nomenclature", "sectionLabel": "disease.etymology" } ]
https://en.wikipedia.org/wiki/Alveolar_soft_part_sarcoma	disease	Alveolar soft part sarcoma	Alveolar soft part sarcoma, abbreviated ASPS, is a very rare type of soft-tissue sarcoma, that grows slowly and whose cell of origin is unknown. It arises mainly in children and young adults. ASPS can migrate (metastasize) into other parts of the body, typically the lungs and the brain. ASPS is a sarcoma, and that indicates that this cancer initially arises from tissue of embryonic mesenchymal origin. (The fertilized egg divides and redivides forming a sphere. Early in embryogenesis, dimples appear in the poles of the sphere and burrow through the sphere forming an inner passage that will ultimately form the gut. Malignancies arising from cells that were originally part of the outer layer of the sphere and those that were part of the embryonic tunnel are termed carcinomas; malignancies arising from the cells between the outer layer and the inner burrow are termed sarcomas.) Typically, ASPS arises in muscles and deep soft tissue of the thigh or the leg (lower extremities), but can also appear in the upper extremities (hands, neck, and head). While ASPS is a soft tissue sarcoma, it can also spread and grow inside the bones. The term alveolar comes from the microscopic pattern, visible during the analysis of slides of ASPS under the microscope in histopathology. The tumor cells seem to be arranged in the same pattern as the cells of the small air sacks (alveoli) in the lungs. However, this is just a structural similarity. ASPS was first described and characterized in 1952.	Chromosomal analysis of ASPS shows the breaking and joining of two chromosomes in the tumor cells. A piece of chromosome X breaks and is joined to chromosome 17. This translocation creates a fusion between two genes named ASPL and TFE3, which results in the formation of an aberrant protein (termed fusion protein) that is not found in normal cells. Two sorts of fusions between chromosome X and chromosome 17 are found in different ASPS tumors: Type one, and type two. Dr. Ladanyi at Memorial Sloan-Kettering Cancer Center, in New York City, has pioneered this work. The first xenograft model of ASPS (for type one) was established in mice by David Vistica at the National Cancer Institute in Frederick, MD in 2009. ASPS may exist in the patient’s body for a long time before being diagnosed. It can grow large and push aside surrounding tissues for a long time before causing any discomfort. Therefore, ASPS symptoms may either be a painless swelling, or a soreness caused by compressed nerves or muscles, affecting the range of motion in the area. The definitive diagnosis of ASPS is based on its appearance under the microscope, i.e. its histomorphology, and presence of the characteristic chromosomal translocation. ASPS' histomorphologic features include an alveolar-like pattern at low magnification and the presence of large cells with abundant eosinophilic cytoplasm and eccentric nuclei. Calcifications are commonly present, as may be seen with slow growing neoplasms. Although ASPS displays a relatively indolent course, the ultimate prognosis is poor and is often characterized by late metastases. ASPS is an extremely rare cancer. While sarcomas comprise about 1% of all newly diagnosed cancers, and 15% of all childhood cancers, ASPS comprises less than 1% of sarcomas. According to the American Cancer Society, about 9530 new cases of soft tissue sarcoma will be diagnosed in the USA in 2006. This predicts under 100 new cases of ASPS. Such low numbers of occurrence seriously impede the search for a cure by making it hard to gather any meaningful statistics about the disease. As a result, finding the best treatment option often involves making a lot of educated guesses. Work out of Huntsman Cancer Institute (HCI) in Utah has demonstrated that ASPS might be driven in part by lactate both being used as a fuel and driving angiogenesis.	[ { "begin": 0, "class": "SectionAnnotation", "length": 717, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 717, "class": "SectionAnnotation", "length": 334, "sectionHeading": "Primary diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 1051, "class": "SectionAnnotation", "length": 428, "sectionHeading": "Primary diagnosis \| Pathology", "sectionLabel": "disease.diagnosis" }, { "begin": 1479, "class": "SectionAnnotation", "length": 131, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" }, { "begin": 1610, "class": "SectionAnnotation", "length": 580, "sectionHeading": "Epidemiology", "sectionLabel": "disease.epidemiology" }, { "begin": 2190, "class": "SectionAnnotation", "length": 166, "sectionHeading": "Research", "sectionLabel": "disease.research" } ]
https://en.wikipedia.org/wiki/Viral_hepatitis	disease	Viral hepatitis	Viral hepatitis is liver inflammation due to a viral infection. It may present in acute (recent infection, relatively rapid onset) or chronic forms. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses hepatitis A, hepatitis B, hepatitis C, hepatitis D, and hepatitis E. In addition to the nominal hepatitis viruses, other viruses that can also cause liver inflammation include cytomegalovirus, Epstein–Barr virus, and yellow fever. Up to 1997 there has been also 52 cases of viral hepatitis caused by herpes simplex virus. There is the opportunity to prevent or treat the most common types. Hepatitis A and hepatitis B can be prevented by vaccination. Effective treatments for hepatitis C are available but expensive. In 2013 about 1.5 million people died from viral hepatitis. Most deaths are due to hepatitis B and hepatitis C. East Asia is the region of the world most affected.	The most common cause of hepatitis is viral. Although they are classified under the disease hepatitis, these viruses are not all related. Hepatitis A or infectious jaundice is caused by hepatitis A virus (HAV), a picornavirus transmitted by the fecal-oral route often associated with ingestion of contaminated food. It causes an acute form of hepatitis and does not have a chronic stage. The patient's immune system makes antibodies against HAV that confer immunity against future infection. People with hepatitis A are advised to rest, stay hydrated and avoid alcohol. A vaccine is available that will prevent HAV infection for up to 10 years. Hepatitis A can be spread through personal contact, consumption of raw sea food, or drinking contaminated water. This occurs primarily in third world countries. Strict personal hygiene and the avoidance of raw and unpeeled foods can help prevent an infection. Infected people excrete HAV with their feces two weeks before and one week after the appearance of jaundice. The time between the infection and the start of the illness averages 28 days (ranging from 15 to 50 days), and most recover fully within 2 months, although approximately 15% of sufferers may experience continuous or relapsing symptoms from six months to a year following initial diagnosis. Hepatitis B is caused by hepatitis B virus, a hepadnavirus that can cause both acute and chronic hepatitis. Chronic hepatitis develops in the 15% of adults who are unable to eliminate the virus after an initial infection. Identified methods of transmission include blood (blood transfusion, now rare), unsanitary tattoos, sexually (through sexual intercourse or through contact with blood or bodily fluids), or via mother to child by breast feeding (minimal evidence of transplacental crossing). However, in about half of cases the source of infection cannot be determined. Blood contact can occur by sharing syringes in intravenous drug use, shaving accessories such as razor blades, or touching wounds on infected persons. Needle-exchange programmes have been created in many countries as a form of prevention. Patients with chronic hepatitis B have antibodies against hepatitis B, but these antibodies are not enough to clear the infection of the affected liver cells. The continued production of virus combined with antibodies is a likely cause of the immune complex disease seen in these patients. A vaccine is available that will prevent infection from hepatitis B for life. Hepatitis B infections result in 500,000 to 1,200,000 deaths per year worldwide due to the complications of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatitis B is endemic in a number of (mainly South-East Asian) countries, making cirrhosis and hepatocellular carcinoma big killers. There are six treatment options approved by the U.S. Food and Drug Administration (FDA) available for persons with a chronic hepatitis B infection: alpha-interferon, pegylated interferon, adefovir, entecavir, telbivudine, and lamivudine. About 65% of persons on treatment achieve a sustained response. Hepatitis C (originally "non-A non-B hepatitis") is caused by hepatitis C virus (HCV), an RNA virus that is a member of the Flaviviridae family. HCV can be transmitted through contact with blood (including through sexual contact if the two parties' blood is mixed) and can also cross the placenta. Hepatitis C usually leads to chronic hepatitis, culminating in cirrhosis in some people. It usually remains asymptomatic for decades. Patients with hepatitis C are susceptible to severe hepatitis if they contract either hepatitis A or B, so all persons with hepatitis C should be immunized against hepatitis A and hepatitis B if they are not already immune, and avoid alcohol. HCV viral levels can be reduced to undetectable levels by a combination of interferon and the antiviral drug ribavirin. The genotype of the virus is the primary determinant of the rate of response to this treatment regimen, with genotype 1 being the most resistant. Hepatitis C is the most common chronic blood-borne infection in the United States. The Hepatitis D virus (HDV) or hepatitis delta agent belongs to the Deltavirus genus, is similar to a viroid as it can only propagate in the presence of the hepatitis B virus. HDV is a defective virus as it depends on the helper function of HBV for its replication and expression. HDV causes Type D Hepatitis & has no independent existence and can survive and replicate as long as HBV infection persists in the host body. The Hepatitis E virus (HEV), from the Hepeviridae family, produces symptoms similar to hepatitis A, although it can take a fulminant course in some patients, particularly pregnant women; chronic infections may occur in immune-compromised patients. It is more prevalent in the Indian subcontinent. Hepatitis F virus (HFV) is a hypothetical virus linked to hepatitis. Several hepatitis F virus candidates emerged in the 1990s; none of these reports have been substantiated. The GB virus C is another potential viral cause of hepatitis that is probably spread by blood and sexual contact. It was initially identified as Hepatitis G virus. There is very little evidence that this virus causes hepatitis, as it does not appear to replicate primarily in the liver. It is now classified as GB virus C. The first virus capable of causing hepatitis was the yellow fever virus a mosquito borne flavivirus. Other viruses than can cause hepatitis include: - Adenoviruses - Arenaviruses: Guanarito virus, Junín virus, Lassa fever virus, Machupo virus, and Sabiá virus - Bunyaviruses: Crimean-Congo hemorrhagic fever virus, Dobrava virus, Hantaan virus, Puumala virus, Rift Valley fever virus, and Seoul virus - Coronavirus: severe acute respiratory syndrome virus - Erythrovirus: Parvovirus B19 - Filoviruses: Ebola virus and Marburg virus - Flaviviruses: dengue, Lujo virus, Kyasanur Forest disease virus, Omsk hemorrhagic fever virus, and yellow fever virus - Herpesviruses: cytomegalovirus,Epstein–Barr virus, varicella-zoster virus, human herpesvirus 6, human herpesvirus 7, and human herpesvirus 8 - Orthomyxoviruses: influenza - Picornaviruses: echovirus - Reovirus: Colorado tick fever virus, reovirus 3 KIs-V is a virus isolated in 2011 from four patients with raised serum alanine transferases without other known cause. A causal role is suspected.	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https://en.wikipedia.org/wiki/Lichen_planus	disease	Lichen planus	Lichen planus (LP) is a disease characterized by itchy reddish-purple polygon-shaped skin lesions on the lower back, wrists, and ankles. It may also present with a burning sensation in the mouth, and a lattice-like network of white lines near sites of erosion (Wickham striae). The cause is unknown, but it is thought to be the result of an autoimmune process with an unknown initial trigger. There is no cure, but many different medications and procedures have been used in efforts to control the symptoms. The term lichenoid reaction (or lichenoid lesion) refers to a lesion of similar or identical histopathologic and clinical appearance to lichen planus (i.e. an area which looks the same as lichen planus, both to the naked eye and under a microscope). Sometimes dental materials or certain medications can cause a lichenoid reaction. They can also occur in association with graft versus host disease.	Lichen planus (LP) is a chronic inflammatory disease of the skin, mucous membranes and nails. Lichen planus lesions are so called because of their "lichen-like" appearance and can be classified by the site they involve, or by their morphology. Lichen planus may be categorized as affecting mucosal or cutaneous surfaces. - Cutaneous forms are those affecting the skin, scalp, and nails. - Mucosal forms are those affecting the lining of the gastrointestinal tract (mouth, pharynx, esophagus, stomach, anus), larynx, and other mucosal surfaces including the genitals, peritoneum, ears, nose, bladder and conjunctiva of the eyes. Occasionally, lichen planus is known to occur with other conditions. For example: - Lupus erythematosus overlap syndrome. Lesions of this syndrome share features of both lupus erythematosus and lichen planus. Lesions are usually large and hypopigmented, atrophic, and with a red to blue colour and minimal scaling. Telangectasia may be present. - Lichen sclerosus overlap syndrome, sharing features of lichen planus and lichen sclerosus. Although lichen planus can present with a variety of lesions, the most common presentation is as a well defined area of purple-coloured, itchy, flat-topped papules with interspersed lacy white lines (Wickham's striae). This description is known as the characteristic "6 Ps" of lichen planus: planar (flat-topped), purple, polygonal, pruritic, papules, and plaques. This rash, after regressing, is likely to leave an area of hyperpigmentation that slowly fades. That said, a variety of other lesions can also occur. Variants of cutaneous lichen planus are distinguished based upon the appearance of the lesions and/or their distribution. Lesions can affect the: - Extremities (face, dorsal hands, arms, and nape of neck). This is more common in Middle Eastern countries in spring and summer, where sunlight appears to have a precipitating effect. - Palms and soles - Intertriginous areas of the skin. This is also known as "Inverse lichen planus." - Nails characterized by irregular longitudinal grooving and ridging of the nail plate, thinning of the nail plate, pterygium formation, shedding of the nail plate with atrophy of the nail bed, subungual keratosis, longitudinal erthronychia (red streaks), and subungual hyperpigmentation. A sand-papered appearance is present in around 10% of individuals with nail lichen planus. - Hair and Scalp. The scalp is rarely affected by a condition known as lichen planopilaris, acuminatus, follicular lichen planus, and peripilaris, characterised by violaceous, adherent follicular scale with progressive scarring alopecia. While lichen planus and lichen planopilaris may occur together, aside from sharing the term ‘lichen’ and revealing inflammation on skin biopsy, there is neither established data on their co-occurrence nor data to suggest a common etiology. Lichen planopilaris is considered an orphan disease with no definitive prevalence data and no proven effective treatments. Other variants may include: - Lichen planus pemphigoides characterized by the development of tense blisters atop lesions of lichen planus or the development vesicles de novo on uninvolved skin. - Keratosis lichenoides chronica (also known as "Nekam's disease") is a rare dermatosis characterized by violaceous papular and nodular lesions, often arranged in a linear or reticulate pattern on the dorsal hands and feet, extremities, and buttock, and some cases manifest by sorrheic dermatitis-like eruption on the scalp and face; also palmo plantar keratosis has been reported. - Lichenoid keratoses (also known as "Benign lichenoid keratosis," and "Solitary lichen planus") is a cutaneous condition characterized by brown to red scaling maculopapules, found on sun-exposed skin of extremities. Restated, this is a cutaneous condition usually characterized by a solitary dusky-red to violaceous papular skin lesion. - Lichenoid dermatitis represents a wide range of cutaneous disorders characterized by lichen planus-like skin lesions. Lichen planus affecting mucosal surfaces may have one lesion or be multifocal. Examples of lichen planus affecting mucosal surfaces include: - Esophageal lichen planus, affecting the esophageal mucosa. This can present with difficulty or pain when swallowing due to oesophageal inflammation, or as the development of an esophageal stricture. It has also been hypothesized that it is a precursor to squamous cell carcinoma of the esophagus. - Genital lichen planus, which may cause lesions on the glans penis or skin of the scrotum in males, and the vulva or vagina in females. Symptoms may include lower urinary tract symptoms associated with stenosis of the urethra, painful sexual intercourse, and itching. In females, Vulvovaginal-gingival syndrome, is severe and distinct variant affecting the vulva, vagina, and gums, with complications including scarring, vaginal stricture formation, or vulva destruction. The corresponding syndrome in males, affecting the glans penis and gums, is the peno-gingival syndrome. It is associated with HLA-DQB1. Oral lichen planus (also termed oral mucosal lichen planus), is a form of mucosal lichen planus, where lichen planus involves the oral mucosa, the lining of the mouth. This may occur in combination with other variants of lichen planus. Six clinical forms of oral lichen planus are recognized: - Reticular, the most common presentation of oral lichen planus, is characterised by the net-like or spider web-like appearance of lacy white lines, oral variants of Wickham's straiae. This is usually asymptomatic. - Erosive/ulcerative, the second most common form of oral lichen planus, is characterised by oral ulcers presenting with persistent, irregular areas of redness, ulcerations and erosions covered with a yellow slough. This can occur in one or more areas of the mouth. In 25% of people with erosive oral lichen planus, the gums are involved, described as desquamative gingivitis (a condition not unique to lichen planus). This may be the initial or only sign of the condition. - Papular, with white papules. - Plaque-like appearing as a white patch which may resemble leukoplakia. - Atrophic, appearing as areas. Atrophic oral lichen planus may also manifest as desquamative gingivitis. - Bullous, appearing as fluid-filled vesicles which project from the surface. These types often coexist in the same individual. Oral lichen planus tends to present bilaterally as mostly white lesions on the inner cheek, although any mucosal site in the mouth may be involved. Other sites, in decreasing order of frequency, may include the tongue, lips, gingivae, floor of the mouth, and very rarely, the palate. Generally, oral lichen planus tends not to cause any discomfort or pain, although some people may experience soreness when eating or drinking acidic or spicy foodstuffs or beverages. When symptoms arise, they are most commonly associated with the atrophic and ulcerative subtypes. These symptoms can include a burning sensation to severe pain. Lichen planus, particularly when concomitant oral or genital lesions occur, significantly affects patients’ quality of life. The cause of lichen planus is unknown, but it is not contagious and does not involve any known pathogen. It is thought to be a T cell mediated autoimmune reaction (where the body's immune system targets its own tissues). This autoimmune process triggers apoptosis of the epithelial cells. Several cytokines are involved in lichen planus, including tumor necrosis factor alpha, interferon gamma, interleukin-1 alpha, interleukin 6, and interleukin 8. This autoimmune, T cell mediated, process is thought to be in response to some antigenic change in the oral mucosa, but a specific antigen has not been identified. Where a causal or triggering agent is identified, this is termed a lichenoid reaction rather than lichen planus. These may include: - Drug reactions, with the most common inducers including gold salts, beta blockers, traditional antimalarials (e.g. quinine), thiazide diuretics, furosemide, spironolactone, metformin and penicillamine. - Reactions to amalgam (metal alloys) fillings (or when they are removed/replaced), - Graft-versus-host disease lesions, which chronic lichenoid lesions seen on the palms, soles, face and upper trunk after several months. - Hepatitis, specifically hepatitis B and hepatitis C infection, and primary biliary cirrhosis. It has been suggested that lichen planus may respond to stress, where lesions may present during times of stress. Lichen planus can be part of Grinspan's syndrome. It has also been suggested that mercury exposure may contribute to lichen planus. Lichen planus lesions are diagnosed clinically by their "lichen-like" appearance. A biopsy can be used to rule out conditions that may resemble lichen planus, and can pick up any secondary malignancies. Lichen planus has a unique microscopic appearance that is similar between cutaneous, mucosal and oral. A Periodic acid-Schiff stain of the biopsy may be used to visualise the specimen. Histological features seen include: - thickening of the stratum corneum both with nuclei present (parakeratosis) and without (orthokeratosis). Parakeratosis is more common in oral variants of lichen planus. - thickening of the stratum granulosum - thickening of the stratum spinosum (acanthosis) with formation of colloid bodies (also known as Civatte bodies, Sabouraud bodies) that may stretch down to the lamina propria. - liquefactive degeneration of the stratum basale, with separation from the underlying lamina propria, as a result of desmosome loss, creating small spaces (Max Joseph spaces). - Infiltration of T cells in a band-like pattern into the dermis "hugging" the basal layer. - Development of a "saw-tooth" appearance of the rete pegs, which is much more common in non-oral forms of lichen planus. The differential diagnosis for OLP includes: - Other oral vesiculo-ulcerative conditions such as Pemphigus vulgaris and Benign mucous membrane pemphigoid - Lupus erythematosus, with lesions more commonly occur on the palate and appear as centrally ulcerated or erythematous with radiating white striae. In contrast, OLP and lichenoid reactions rarely occur on the palate, and the striae are randomly arranged rather than radial. - Chronic ulcerative stomatitis - Frictional keratosis and Morsicatio buccarum (chronic cheek biting) - Oral leukoplakia - Oral candidiasis There is no cure for lichen planus, and so treatment of cutaneous and oral lichen planus is for symptomatic relief or due to cosmetic concerns. When medical treatment is pursued, first-line treatment typically involves corticosteroids, and removal of any triggers. Without treatment, most lesions will spontaneously resolve within 6–9 months for cutaneous lesions, and longer for mucosal lesions. Many different treatments have been reported for cutaneous lichen planus, however there is a general lack of evidence of efficacy for any treatment. Treatments tend to be prolonged, partially effective and disappointing. The mainstay of localized skin lesions is topical steroids. Additional treatments include retinoids, such as acitretin, or sulfasalazine. Narrow band UVB phototherapy or systemic PUVA therapy are known treatment modalities for generalized disease. Reassurance that the condition is benign, elimination of precipitating factors and improving oral hygiene are considered initial management for symptomatic OLP, and these measures are reported to be useful. Treatment usually involves topical corticosteroids (such as betamethasone, clobetasol, dexamethasone, and triamcinolone) and analgesics, or if these are ineffective and the condition is severe, the systemic corticosteroids may be used. Calcineurin inhibitors (such as pimecrolimus, tacrolimus or cyclosporin) are sometimes used. In contrast to cutaneous LP, which is self limited, lichen planus lesions in the mouth may persist for many years, and tend to be difficult to treat, with relapses being common. Atrophic/erosive lichen planus is associated with a small risk of cancerous transformation, and so people with OLP tend to be monitored closely over time to detect any potential change early. Sometimes OLP can become secondarily infected with Candida organisms. The overall prevalence of lichen planus in the general population is about 0.1–4.0%. It generally occurs more commonly in females, in a ratio of 3:2, and most cases are diagnosed between the ages of 30 and 60, but it can occur at any age. Oral lichen planus is relatively common, It is one of the most common mucosal diseases. The prevalence in the general population is about 1.27–2.0%, and it occurs more commonly in middle aged people. OLP in children is rare. About 50% of females with oral lichen planus were reported to have undiagnosed vulvar lichen planus. In 2016, interferon gamma/CXCL10 axis was hypothesized to be a target for treatments that reverse inflammation. Apremilast is undergoing investigation as a potential treatment .	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https://en.wikipedia.org/wiki/Athetoid_cerebral_palsy	disease	Athetoid cerebral palsy	Athetoid cerebral palsy or dyskinetic cerebral palsy (sometimes abbreviated ADCP) is a type of cerebral palsy primarily associated with damage, like other forms of CP, to the basal ganglia in the form of lesions that occur during brain development due to bilirubin encephalopathy and hypoxic-ischemic brain injury. Unlike spastic or ataxic cerebral palsies, ADCP is characterized by both hypertonia and hypotonia, due to the affected individual's inability to control muscle tone. Clinical diagnosis of ADCP typically occurs within 18 months of birth and is primarily based upon motor function and neuroimaging techniques. While there are no cures for ADCP, some drug therapies as well as speech, occupational therapy, and physical therapy have shown capacity for treating the symptoms. Classification of cerebral palsy can be based on severity, topographic distribution, or motor function. Severity is typically assessed via the Gross Motor Function Classification System (GMFCS) or the International Classification of Functioning, Disability and Health (described further below). Classification based on motor characteristics classifies CP as occurring from damage to either the corticospinal pathway or extrapyramidal regions. Athetoid dyskinetic cerebral palsy is a non-spastic, extrapyramidal form of cerebral palsy (spastic cerebral palsy, in contrast, results from damage to the brain’s corticospinal pathways). Non-spastic cerebral palsy is divided into two groups, ataxic and dyskinetic. Dyskinetic cerebral palsy is separated further into two different groups; choreoathetoid and dystonic. Choreo-athetotic CP is characterized by involuntary movements most predominantly found in the face and extremities. Dystonic ADCP is characterized by slow, strong contractions, which may occur locally or encompass the whole body. Clinically, physicians have also classified cerebral palsy according to the topographic distribution of muscle spasticity. This method classifies children as diplegic, (bilateral involvement with leg involvement greater than arm involvement), hemiplegic (unilateral involvement), or quadriplegic (bilateral involvement with arm involvement equal to or greater than leg involvement).	ADCP is often characterized by slow, uncontrolled movements of the extremities and trunk. Small, rapid, random and repetitive, uncontrolled movements known as chorea may also occur. Involuntary movements often increase during periods of emotional stress or excitement and disappear when the patient is sleeping or distracted. Patients experience difficulty in maintaining posture and balance when sitting, standing, and walking due to these involuntary movements and fluctuations in muscle tone. Coordinated activities such as reaching and grasping may also be challenging. Muscles of the face and tongue can be affected, causing involuntary facial grimaces, expressions, and drooling. Speech and language disorders, known as dysarthria, are common in athetoid CP patients. In addition, ADCP patients may have trouble eating. Hearing loss is a common co-occurring condition, and visual disabilities can be associated with Athetoid Cerebral Palsy. Squinting and uncontrollable eye movements may be initial signs and symptoms. Children with these disabilities rely heavily on visual stimulation, especially those who are also affected by sensory deafness. Cognitive impairment occur in 30% of cases. Epilepsy occur in 25% of cases. CP in general is a non-progressive, neurological condition that results from brain injury and malformation occurring before cerebral development is complete. ADCP is associated with injury and malformations to the extrapyramidal tracts in the basal ganglia or the cerebellum. Lesions to this region principally arise via hypoxic ischemic brain injury (HIBI) or bilirubin encephalopathy. Hypoxic-ischemic brain injury (HIBI) is a form of cerebral hypoxia in which oxygen cannot perfuse to cells in the brain. Lesions in the putamen and thalamus caused by HIBI are primary causes of ADCP and can occur during the prenatal period and shortly after. Lesions that arise after this period typically occur as a result of injury or infections of the brain. 40~50% will have intellectual disability. Bilirubin encephalopathy, also known as kernicterus, is the accumulation of bilirubin in the grey matter of the central nervous system. The main accumulation targets of hyperbilirubinemia are the basal ganglia, ocular movement nucleus, and acoustic nucleus of the brainstem. Pathogenesis of bilirubin encephalopathy involves several factors, including the transport of bilirubin across the blood-brain barrier and into neurons. Mild disruption results in left cognition impairment, while severe disruption results in ADCP. Lesions caused by accumulation of bilirubin occur mainly in the global pallidus and hypothalamus. Disruption of the blood-brain barrier by disease or a hypoxic ischemic injury can also contribute to an accumulation of bilirubin in the brain. Bilirubin encephalopathy leading to cerebral palsy has been greatly reduced by effective monitoring and treatment for hyperbilirubinemia in preterm infants. As kernicterus has decreased due to improvements in care, over the last 50 years the proportion of children developing athetoid CP has decreased. Usually normal intelligence and 40% will have IQ over 100. Movement and posture limitations are aspects of all CP types and as a result, CP has historically been diagnosed based on parental reporting of developmental motor delays such as failure to sit upright, reach for objects, crawl, stand, or walk at the appropriate age. Diagnosis of ADCP is also based on clinical assessment used in conjunction with milestone reporting. The majority of ADCP assessments now use the Gross Motor Function Classification System (GMFCS) or the International Classification of Functioning, Disability and Health (formerly the International Classification of Impairments Disease, and Handicaps), measures of motor impairment that are effective in assessing severe CP. ADCP is typically characterized by an individual’s inability to control their muscle tone, which is readily assessed via these classification systems. Magnetic resonance imaging (MRI) is used to detect morphological brain abnormalities associated with ADCP in patients that are either at risk for ADCP or have shown symptoms thereof. The abnormalities chiefly associated with ADCP are lesions that appear in the basal ganglia. The severity of the disease is proportional to the severity and extent of these abnormalities, and is typically greater when additional lesions appear elsewhere in the deep grey matter or white matter. MRI also has the ability to detect brain malformation, periventricular leukomalacia (PVL), and areas affected by hypoxia-ischemia, all of which may play a role in the development of ADCP. The MRI detection rate for ADCP is approximately 54.5%, however this statistic varies depending on the patient’s age and the cause of the disease and has been reported to be significantly higher. Physical therapy and Occupational Therapy are staple treatments of ADCP. Physical therapy is initiated soon after diagnosis and typically focuses on trunk strength and maintaining posture. Physical therapy helps to improve mobility, range of motion, functional ability, and quality of life. Specific exercises and activities prescribed by a therapist help to prevent muscles from deteriorating or becoming locked in position and help to improve coordination. Occupational therapy interventions for children with CP can include feeding, dressing, bathing, toileting, grooming, pencil grasp and handwriting skills, play, and use of adaptive equipment. Speech impairment is common in ADCP patients. Speech therapy is the treatment of communication diseases, including disorders in speech production, pitch, intonation, respiration and respiratory disorders. Exercises advised by a speech therapist or speech-language pathologist help patients to improve oral motor skills, restore speech, improve listening skills, and use communication aids or sign language if necessary. Medications that impede the release of excitatory neurotransmitters have been used to control or prevent spasms. Treatment with intrathecal baclofen, a gamma-aminobutyric acid (GABA) agonist, decreases muscle tone and has been shown to decrease the frequency of muscle spasms in ADCP patients. Tetrabenazine, a drug commonly used in the treatment of Huntington's disease, has been shown to be effective treating chorea. Deep brain stimulation (DBS) is a technique that uses electrodes placed in the brain to modify brain activity by sending a constant electrical signal to the nearby nuclei. Treatment of muscle tone issues via deep brain stimulation typically targets the global pallidus and has shown to significantly improve symptoms associated with ADCP. The specific mechanism by which DBS affects ADCP is unclear. DBS of the globus pallidus interna improves dystonia in people with dyskinetic CP in 40% of cases, perhaps due to variation in basal ganglia injuries. The severity of impairment and related prognosis is dependent on the location and severity of brain lesions. Up to 50% of patients will achieve some degree of ambulation. Speech problems, such as dysarthria, are common to these patients.	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https://en.wikipedia.org/wiki/Barrett's_esophagus	disease	Barrett's esophagus	Barrett's esophagus refers to an abnormal change (metaplasia) in the cells of the lower portion of the esophagus. It is characterized by the replacement of the normal stratified squamous epithelium lining of the esophagus by simple columnar epithelium with goblet cells (which are usually found lower in the gastrointestinal tract). The medical significance of Barrett's esophagus is its strong association (0.1 per 1 cm Prague C>M> total segment length per patient-year) with esophageal adenocarcinoma, a very often deadly cancer, because of which it is considered to be a premalignant condition. The main cause of Barrett's esophagus is thought to be an adaptation to chronic acid exposure from reflux esophagitis. The incidence of esophageal adenocarcinoma has increased substantially in the Western world in recent years. The condition is found in 5–15% of patients who seek medical care for heartburn (gastroesophageal reflux disease), although a large subgroup of patients with Barrett's esophagus do not have symptoms. Diagnosis requires endoscopy (more specifically, esophagogastroduodenoscopy, a procedure in which a fibreoptic cable is inserted through the mouth to examine the esophagus, stomach, and duodenum) and biopsy. The cells of Barrett's esophagus, after biopsy, are classified into four general categories: nondysplastic, low-grade dysplasia, high-grade dysplasia, and frank carcinoma. High-grade dysplasia and early stages of adenocarcinoma can be treated by endoscopic resection and new endoscopic therapies such as radiofrequency ablation, whereas advanced stages (submucosal) are generally advised to undergo surgical treatment. Nondysplastic and low-grade patients are generally advised to undergo annual observation with endoscopy, with radiofrequency ablation as a therapeutic option. In high-grade dysplasia, the risk of developing cancer might be at 10% per patient-year or greater. The condition is named after the Australian-born British thoracic surgeon Norman Barrett (1903–1979), who described it in 1950. Those with the eating disorder bulimia are more likely to develop Barrett’s esophagus because bulimia can cause severe acid reflux, and because purging also floods the esophagus with acid.	The change from normal to premalignant cells that indicate Barrett's esophagus does not cause any particular symptoms. Barrett's esophagus, however, is associated with these symptoms: - frequent and longstanding heartburn - trouble swallowing (dysphagia) - vomiting blood (hematemesis) - pain under the sternum where the esophagus meets the stomach - unintentional weight loss because eating is painful (odynophagia) The risk of developing Barrett's esophagus is increased by central obesity (vs. peripheral obesity). The exact mechanism is unclear. The difference in distribution of fat among men (more central) and women (more peripheral) may explain the increased risk in males. Barrett's esophagus occurs due to chronic inflammation. The principal cause of the chronic inflammation is gastroesophageal reflux disease, GERD (UK: GORD). In this disease, acidic stomach, bile, and small intestine and pancreatic contents cause damage to the cells of the lower esophagus. Recently, bile acids were shown to be able to induce intestinal differentiation, in gastroesophageal junction cells, through inhibition of the epidermal growth factor receptor (EGFR) and the protein kinase enzyme Akt. This results in the eventual up-regulation of the p50 subunit of protein complex NF-κB (NFKB1), and ultimately activation of the homeobox gene CDX2, which is responsible for the expression of intestinal enzymes such as guanylate cyclase 2C. This mechanism also explains the selection of HER2/neu (also called ERBB2) and the overexpressing (lineage-addicted) cancer cells during the process of carcinogenesis, and the efficacy of targeted therapy against the Her-2 receptor with trastuzumab (Herceptin) in the treatment of adenocarcinomas at the gastroesophageal junction. Researchers are unable to predict who with heartburn will develop Barrett's esophagus. While no relationship exists between the severity of heartburn and the development of Barrett's esophagus, a relationship does exist between chronic heartburn and the development of Barrett's esophagus. Sometimes, people with Barrett's esophagus have no heartburn symptoms at all. In rare cases, damage to the esophagus may be caused by swallowing a corrosive substance such as lye. Both macroscopic (from endoscopy) and microscopic positive findings are required to make a diagnosis. Barrett's esophagus is marked by the presence of columnar epithelia in the lower esophagus, replacing the normal squamous cell epithelium—an example of metaplasia. The secretory columnar epithelium may be more able to withstand the erosive action of the gastric secretions; however, this metaplasia confers an increased risk of adenocarcinoma. Screening endoscopy is recommended among males over the age of 60 who have reflux symptoms that are of long duration and not controllable with treatment. Among those not expected to live more than 5 years screening is not recommended. The presence of goblet cells, called intestinal metaplasia, is necessary to make a diagnosis of Barrett's esophagus. This frequently occurs in the presence of other metaplastic columnar cells, but only the presence of goblet cells is diagnostic. The metaplasia is grossly visible through a gastroscope, but biopsy specimens must be examined under a microscope to determine whether cells are gastric or colonic in nature. Colonic metaplasia is usually identified by finding goblet cells in the epithelium and is necessary for the true diagnosis. Many histologic mimics of Barrett's esophagus are known (i.e. goblet cells occurring in the transitional epithelium of normal esophageal submucosal gland ducts, "pseudogoblet cells" in which abundant foveolar [gastric] type mucin simulates the acid mucin true goblet cells). Assessment of relationship to submucosal glands and transitional-type epithelium with examination of multiple levels through the tissue may allow the pathologist to reliably distinguish between goblet cells of submucosal gland ducts and true Barrett's esophagus (specialized columnar metaplasia). Use of the histochemical stain Alcian blue pH 2.5 is also frequently used to distinguish true intestinal-type mucins from their histologic mimics. Recently, immunohistochemical analysis with antibodies to CDX-2 (specific for mid and hindgut intestinal derivation) has also been used to identify true intestinal-type metaplastic cells. The protein AGR2 is elevated in Barrett's esophagus and can be used as a biomarker for distinguishing Barrett epithelium from normal esophageal epithelium. The presence of intestinal metaplasia in Barrett's esophagus represents a marker for the progression of metaplasia towards dysplasia and eventually adenocarcinoma. This factor combined with two different immunohistochemical expression of p53, Her2 and p16 leads to two different genetic pathways that likely progress to dysplasia in Barrett's esophagus. After the initial diagnosis of Barrett's esophagus is rendered, affected persons undergo annual surveillance to detect changes that indicate higher risk to progression to cancer: development of epithelial dysplasia (or "intraepithelial neoplasia"). Considerable variability is seen in assessment for dysplasia among pathologists. Recently, gastroenterology and GI pathology societies have recommended that any diagnosis of high-grade dysplasia in Barrett be confirmed by at least two fellowship-trained GI pathologists prior to definitive treatment for patients. For more accuracy and reproductibility, it is also recommended to follow international classification system as the "Vienna classification" of gastrointestinal epithelial neoplasia (2000). Many people with Barrett's esophagus do not have dysplasia. Medical societies recommend that if a patient has Barrett's esophagus, and if the past two endoscopy and biopsy examinations have confirmed the absence of dysplasia, then the patient should not have another endoscopy within three years. Endoscopic surveillance of people with Barrett's esophagus is often recommended, although little direct evidence supports this practice. Treatment options for high-grade dysplasia include surgical removal of the esophagus (esophagectomy) or endoscopic treatments such as endoscopic mucosal resection or ablation (destruction). The risk of malignancy is highest in the U.S. in Caucasian men over fifty years of age with more than five years of symptoms. Current recommendations include routine endoscopy and biopsy (looking for dysplastic changes). Although in the past physicians have taken a watchful waiting approach, newly published research supports consideration of intervention for Barrett's esophagus. Balloon-based radiofrequency ablation, invented by Ganz, Stern, and Zelickson in 1999, is a new treatment modality for the treatment of Barrett's esophagus and dysplasia, and has been the subject of numerous published clinical trials. The findings demonstrate radiofrequency ablation has an efficacy of 90% or greater with respect to complete clearance of Barrett's esophagus and dysplasia with durability up to five years and a favorable safety profile. Proton pump inhibitor drugs have not been proven to prevent esophageal cancer. Laser treatment is used in severe dysplasia, while overt malignancy may require surgery, radiation therapy, or systemic chemotherapy. Additionally, a recent five-year random-controlled trial has shown that photodynamic therapy using photofrin is statistically more effective in eliminating dysplastic growth areas than sole use of a proton pump inhibitor. There is presently no reliable way to determine which patients with Barrett esophagus will go on to develop esophageal cancer, although a recent study found the detection of three different genetic abnormalities was associated with as much as a 79% chance of developing cancer in six years. Endoscopic mucosal resection has also been evaluated as a management technique. Additionally an operation known as a Nissen fundoplication can reduce the reflux of acid from the stomach into the esophagus. In a variety of studies, nonsteroidal anti-inflammatory drugs (NSAIDS), like aspirin, have shown evidence of preventing esophageal cancer in people with Barrett's esophagus. However, none of these studies have been randomized, placebo-controlled trials, which are considered the gold standard for evaluating a medical intervention. In addition, the best dose of NSAIDs for cancer prevention is not yet known. Barrett's esophagus is a premalignant condition. Its malignant sequela, oesophagogastric junctional adenocarcinoma, has a mortality rate of over 85%. The risk of developing esophageal adenocarcinoma in people who have Barrett's esophagus has been estimated to be 6–7 per 1000 person-years, however a cohort study of 11,028 patients from Denmark published in 2011 showed an incidence of only 1.2 per 1000 person-years (5.1 per 1000 person-years in patients with dysplasia, 1.0 per 1000 person-years in patients without dysplasia). The relative risk of esophageal adenocarcinoma is approximately 10 in those with Barret's esophagus, compared to the general population. Most patients with esophageal carcinoma survive less than one year. The incidence in the United States among Caucasian men is eight times the rate among Caucasian women and five times greater than African American men. Overall, the male to female ratio of Barrett's esophagus is 10:1. Several studies have estimated the prevalence of Barrett's esophagus in the general population to be 1.3% to 1.6% in two European populations (Italian and Swedish), and 3.6% in a Korean population. Barrett first described the columnar metaplasia in 1950. An association with gastroesophageal reflux was made in 1953. An association with adenocarcinoma was made in 1975.	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https://en.wikipedia.org/wiki/Tonsillitis	disease	Tonsillitis	Tonsillitis is inflammation of the tonsils, typically of rapid onset. It is a type of pharyngitis. Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, and large lymph nodes around the neck. Complications include peritonsillar abscess. Tonsillitis is most commonly caused by a viral infection, with about 5% to 40% of cases caused by a bacterial infection. When caused by the bacterium group A streptococcus, it is referred to as strep throat. Rarely bacteria such as Neisseria gonorrhoeae, Corynebacterium diphtheriae, or Haemophilus influenzae may be the cause. Typically the infection is spread between people through the air. A scoring system, such as the Centor score, may help separate possible causes. Confirmation may be by a throat swab or rapid strep test. Treatment efforts involve improving symptoms and decreasing complications. Paracetamol (acetaminophen) and ibuprofen may be used to help with pain. If strep throat is present the antibiotic penicillin by mouth is generally recommended. In those who are allergic to penicillin, cephalosporins or macrolides may be used. In children with frequent episodes of tonsillitis, tonsillectomy modestly decreases the risk of future episodes. About 7.5% of people have a sore throat in any three-month period and 2% of people visit a doctor for tonsillitis each year. It is most common in school aged children and typically occurs in the fall and winter months. The majority of people recover with or without medication. In 40% of people, symptoms resolve within three days, and in 80% symptoms resolve within one week, regardless of if streptococcus is present. Antibiotics decrease symptom duration by approximately 16 hours.	Common signs and symptoms include: - sore throat - red, swollen tonsils - pain when swallowing - high temperature (fever) - headache - tiredness - chills - a general sense of feeling unwell (malaise) - white pus-filled spots on the tonsils - swollen lymph nodes (glands) in the neck - pain in the ears or neck - weight loss - difficulty ingesting and swallowing meal/liquid intake - difficulty sleeping Less common symptoms include: - nausea - fatigue - stomach ache - vomiting - furry tongue - bad breath (halitosis) - voice changes - difficulty opening the mouth (trismus) - loss of appetite - Anxiety/fear of choking In cases of acute tonsillitis, the surface of the tonsil may be bright red and with visible white areas or streaks of pus. Tonsilloliths occur in up to 10% of the population frequently due to episodes of tonsillitis. The most common cause is viral infection and includes adenovirus, rhinovirus, influenza, coronavirus, and respiratory syncytial virus. It can also be caused by Epstein-Barr virus, herpes simplex virus, cytomegalovirus, or HIV. The second most common cause is bacterial infection of which the predominant is Group A β-hemolytic streptococcus (GABHS), which causes strep throat. Less common bacterial causes include: Staphylococcus aureus (including methicillin resistant Staphylococcus aureus or MRSA ),Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis, Fusobacterium sp., Corynebacterium diphtheriae, Treponema pallidum, and Neisseria gonorrhoeae. Anaerobic bacteria have been implicated in tonsillitis and a possible role in the acute inflammatory process is supported by several clinical and scientific observations. Under normal circumstances, as viruses and bacteria enter the body through the nose and mouth, they are filtered in the tonsils. Within the tonsils, white blood cells of the immune system destroy the viruses or bacteria by producing inflammatory cytokines like phospholipase A2, which also lead to fever. The infection may also be present in the throat and surrounding areas, causing inflammation of the pharynx. Sometimes, tonsillitis is caused by an infection of spirochaeta and treponema, in this case called Vincent's angina or Plaut-Vincent angina. The diagnosis of group A beta-hemolytic streptococcus (GABHS) tonsillitis can be confirmed by culture of samples obtained by swabbing both tonsillar surfaces and the posterior pharyngeal wall and plating them on sheep blood agar medium. The isolation rate can be increased by incubating the cultures under anaerobic conditions and using selective growth media. A single throat culture has a sensitivity of 90–95% for the detection of GABHS (which means that GABHS is actually present 5–10% of the time culture suggests that it is absent). This small percentage of false-negative results are part of the characteristics of the tests used but are also possible if the patient has received antibiotics prior to testing. Identification requires 24 to 48 hours by culture but rapid screening tests (10–60 minutes), which have a sensitivity of 85–90%, are available. Older antigen tests detect the surface Lancefield group A carbohydrate. Newer tests identify GABHS serotypes using nucleic acid (DNA) probes or polymerase chain reaction. Bacterial culture may need to be performed in cases of a negative rapid streptococcal test. True infection with GABHS, rather than colonization, is defined arbitrarily as the presence of >10 colonies of GABHS per blood agar plate. However, this method is difficult to implement because of the overlap between carriers and infected patients. An increase in antistreptolysin O (ASO) streptococcal antibody titer 3–6 weeks following the acute infection can provide retrospective evidence of GABHS infection and is considered definitive proof of GABHS infection. Increased values of secreted phospholipase A2 and altered fatty acid metabolism in patients with tonsillitis may have diagnostic utility. Treatments to reduce the discomfort from tonsillitis include: - pain and fever reducing medications such as paracetamol (acetaminophen) and ibuprofen - warm salt water gargle, lozenges, or warm liquids When tonsillitis is caused by a virus, the length of illness depends on which virus is involved. Usually, a complete recovery is made within one week; however, symptoms may last for up to two weeks. If the tonsillitis is caused by group A streptococcus, then antibiotics are useful, with penicillin or amoxicillin being primary choices. Cephalosporins and macrolides are considered good alternatives to penicillin in the acute setting. A macrolide such as erythromycin is used for people allergic to penicillin. Individuals who fail penicillin therapy may respond to treatment effective against beta-lactamase producing bacteria such as clindamycin or amoxicillin-clavulanate. Aerobic and anaerobic beta lactamase producing bacteria that reside in the tonsillar tissues can "shield" group A streptococcus from penicillins. Chronic cases may be treated with tonsillectomy (surgical removal of tonsils) as a choice for treatment. Children have had only a modest benefit from tonsillectomy for chronic cases of tonsillitis. Since the advent of penicillin in the 1940s, a major preoccupation in the treatment of streptococcal tonsillitis has been the prevention of rheumatic fever, and its major effects on the nervous system (Sydenham's chorea) and heart. Recent evidence would suggest that the rheumatogenic strains of group A beta hemolytic strep have become markedly less prevalent and are now only present in small pockets such as in Salt Lake City, USA. This brings into question the rationale for treating tonsillitis as a means of preventing rheumatic fever. Complications may rarely include dehydration and kidney failure due to difficulty swallowing, blocked airways due to inflammation, and pharyngitis due to the spread of infection. An abscess may develop lateral to the tonsil during an infection, typically several days after the onset of tonsillitis. This is termed a peritonsillar abscess (or quinsy). Rarely, the infection may spread beyond the tonsil resulting in inflammation and infection of the internal jugular vein giving rise to a spreading septicaemia infection (Lemierre's syndrome). In chronic/recurrent cases (generally defined as seven episodes of tonsillitis in the preceding year, five episodes in each of the preceding two years or three episodes in each of the preceding three years), or in acute cases where the palatine tonsils become so swollen that swallowing is impaired, a tonsillectomy can be performed to remove the tonsils. Patients whose tonsils have been removed are still protected from infection by the rest of their immune system. In strep throat, very rarely diseases like rheumatic fever or glomerulonephritis can occur. These complications are extremely rare in developed nations but remain a significant problem in poorer nations. Tonsillitis associated with strep throat, if untreated, is hypothesized to lead to pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS).	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https://en.wikipedia.org/wiki/Flail_chest	disease	Flail chest	Flail chest is a life-threatening medical condition that occurs when a segment of the rib cage breaks due to trauma and becomes detached from the rest of the chest wall. Two of the symptoms of flail chest are chest pain and shortness of breath. It occurs when multiple adjacent ribs are broken in multiple places, separating a segment, so a part of the chest wall moves independently. The number of ribs that must be broken varies by differing definitions: some sources say at least two adjacent ribs are broken in at least two places, some require three or more ribs in two or more places. The flail segment moves in the opposite direction to the rest of the chest wall: because of the ambient pressure in comparison to the pressure inside the lungs, it goes in while the rest of the chest is moving out, and vice versa. This so-called "paradoxical breathing" is painful and increases the work involved in breathing. Flail chest is usually accompanied by a pulmonary contusion, a bruise of the lung tissue that can interfere with blood oxygenation. Often, it is the contusion, not the flail segment, that is the main cause of respiratory problems in people with both injuries. Surgery to fix the fractures appears to result in better outcomes.	Two of the symptoms of flail chest are chest pain and shortness of breath. The characteristic paradoxical motion of the flail segment occurs due to pressure changes associated with respiration that the rib cage normally resists: - During normal inspiration, the diaphragm contracts and intercostal muscles pull the rib cage out. Pressure in the thorax decreases below atmospheric pressure, and air rushes in through the trachea. The flail segment will be pulled in with the decrease in pressure while the rest of the rib cage expands. - During normal expiration, the diaphragm and intercostal muscles relax increasing internal pressure, allowing the abdominal organs to push air upwards and out of the thorax. However, a flail segment will also be pushed out while the rest of the rib cage contracts. The constant motion of the ribs in the flail segment at the site of the fracture is extremely painful, and, untreated, the sharp broken edges of the ribs are likely to eventually puncture the pleural sac and lung, possibly causing a pneumothorax. The concern about "mediastinal flutter" (the shift of the mediastinum with paradoxical diaphragm movement) does not appear to be merited. Pulmonary contusions are commonly associated with flail chest and that can lead to respiratory failure. This is due to the paradoxical motions of the chest wall from the fragments interrupting normal breathing and chest movement. Typical paradoxical motion is associated with stiff lungs, which requires extra work for normal breathing, and increased lung resistance, which makes air flow difficult. The respiratory failure from the flail chest requires mechanical ventilation and a longer stay in an intensive care unit. It is the damage to the lungs from the flail segment that is life-threatening. The most common causes of flail chest injuries are vehicle collisions, which account for 76% of flail chest injuries. Another main cause of flail chest injuries is falling. This mainly occurs in the elderly, who are more impacted by the falls as a result of their weak and frail bones, unlike their younger counterparts who can fall without being impacted as severely. Falls account for 14% of flail chest injuries. Flail chest typically occurs when three or more adjacent ribs are fractured in two or more places, allowing that segment of the thoracic wall to displace and move independently of the rest of the chest wall. Flail chest can also occur when ribs are fractured proximally in conjunction with disarticulation of costal cartilages distally. For the condition to occur, generally there must be a significant force applied over a large surface of the thorax to create the multiple anterior and posterior rib fractures. Rollover and crushing injuries most commonly break ribs at only one point, whereas for flail chest to occur a significant impact is required, breaking the ribs in two or more places. This can be caused by forceful accidents such as the aforementioned vehicle collisions or significant falls. In the elderly, it can be caused by deterioration of bone, although rare. In children, the majority of flail chest injuries result from common blunt force traumas or metabolic bone diseases, including a group of genetic disorders known as osteogenesis imperfecta. Diagnosis is by medical imaging with either plain X ray or CT scan. Treatment of the flail chest initially follows the principles of advanced trauma life support. Further treatment includes: - Good pain management includes intercostal blocks and avoiding opioid pain medication as much as possible. This allows much better ventilation, with improved tidal volume, and increased blood oxygenation. - Positive pressure ventilation, meticulously adjusting the ventilator settings to avoid pulmonary barotrauma. - Chest tubes as required. - Adjustment of position to make the person most comfortable and provide relief of pain. - Aggressive pulmonary toilet Surgical fixation can help in significantly reducing the duration of ventilatory support and in conserving the pulmonary function. A person may be intubated with a double lumen tracheal tube. In a double lumen endotracheal tube, each lumen may be connected to a different ventilator. Usually one side of the chest is affected more than the other, so each lung may require drastically different pressures and flows to adequately ventilate. In order to begin a rehabilitation program for a flail chest it is important to treat the person's pain so they are able to perform the proper exercises. Due the underlying conditions that the flail segment has caused onto the respiratory system, chest physiotherapy is important to reduce further complications. Proper positioning of the body is key, including postural alignment for proper drainage of mucous secretions. The therapy will consist of a variety of postural positioning and changes in order to increase normal breathing. Along with postural repositioning, a variety of breathing exercises are also very important in order to allow the chest wall to reposition itself back to normal conditions. Breathing exercises will also include coughing procedures. Furthermore, range of motion exercises are given to reduce the atrophy of the musculature. With progression, resistance exercises are added to the regimen to the shoulder and arm of the side containing the injury. Moreover, trunk exercises will be introduced while sitting and will progress to during standing. Hip flexion exercises can be done to expand the thorax. This is done by lying supine on a flat surface, flexing the knees and hips and bringing them in toward the chest. The knees should come in toward the chest while the person inhales, and exhale when the knees are lowered. This exercise can be done in 3 sets of 6-8 repetitions with a pause in between sets. The person should always make sure to maintain controlled breaths. Eventually, the person will be progressed to walking and posture correction while walking. Before, the person is discharged from the hospital the person should be able to perform mobility exercises to the core and should have attained good posture. The death rate of people with flail chest depends on the severity of their condition, ranging from 10 to 25%. Approximately 1 out of 13 people admitted to the hospital with fractured ribs are found to have flail chest.	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https://en.wikipedia.org/wiki/Neurogenic_inflammation	disease	Neurogenic inflammation	Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). TRPA1 channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. Neurogenic inflammation appears to play an important role in the pathogenesis of numerous diseases including migraine, psoriasis, asthma, vasomotor rhinitis, fibromyalgia, eczema, rosacea, dystonia, and multiple chemical sensitivity. In migraine, stimulation of the trigeminal nerve causes neurogenic inflammation via release of neuropeptides including Substance P, nitric oxide, vasoactive intestinal polypeptide, 5-HT, Neurokinin A and CGRP. leading to a "sterile neurogenic inflammation."	Magnesium deficiency causes neurogenic inflammation in a rat model. Researchers have theorized that since substance P which appears at day five of induced magnesium deficiency, is known to stimulate in turn the production of other inflammatory cytokines including IL-1, Interleukin 6 (IL-6), and TNF-alpha (TNFα), which begin a sharp rise at day 12, substance P is a key in the path from magnesium deficiency to the subsequent cascade of neuro-inflammation. In a later study, researchers provided rats dietary levels of magnesium that were reduced but still within the range of dietary intake found in the human population, and observed an increase in substance P, TNF alpha (TNFα) and Interleukin-1 beta (IL-1β), followed by exacerbated bone loss. These and other data suggest that deficient dietary magnesium intake, even at levels not uncommon in humans, may trigger neurogenic inflammation and lead to an increased risk of osteoporosis. Anticipating later botox therapy for migraine, early work by Jancsó et al. found some success in treatment using denervation or pretreatment with capsaicin to prevent uncomfortable symptoms of neurogenic inflammation. A recent (2010) study of the treatment of migraine with CGRP blockers shows promise. In early trials, the first oral nonpeptide CGRP antagonist, MK-0974 (Telcagepant), was shown effective in the treatment of migraine attacks, but elevated liver enzymes in two participants were found. Other therapies and other links in the neurogenic inflammatory pathway for interruption of disease are under study, including migraine therapies. Noting that botulinum toxin has been shown to have an effect on inhibiting neurogenic inflammation, and evidence suggesting the role of neurogenic inflammation in the pathogenesis of psoriasis, the University of Minnesota has a pilot clinical trial underway to follow up on the observation that patients treated with botulinum toxin for dystonia had dramatic improvement in psoriasis. Astelin (Azelastine) "is indicated for symptomatic treatment of vasomotor rhinitis including rhinorrhea, nasal congestion, and post nasal drip in adults and children 12 years of age and older." Statins appear to "decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons," and so might be of use in treating diseases presenting with predominant neurogenic inflammation. In a 2012 article in Nature Neuroscience Chiu et al. discuss the development of science related to neurogenic inflammation and provide a graphic illustrating key discoveries leading toward the current understanding of neurogenic inflammation, its mechanisms, and the conditions caused by its disorder.	[ { "begin": 0, "class": "SectionAnnotation", "length": 941, "sectionHeading": "Prevention", "sectionLabel": "disease.prevention" }, { "begin": 941, "class": "SectionAnnotation", "length": 1470, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 2411, "class": "SectionAnnotation", "length": 302, "sectionHeading": "Research", "sectionLabel": "disease.research" } ]
https://en.wikipedia.org/wiki/Squamous_cell_skin_cancer	disease	Squamous cell skin cancer	Squamous-cell skin cancer, also known as cutaneous squamous-cell carcinoma (cSCC), is one of the main types of skin cancer along with basal cell cancer, and melanoma. It usually presents as a hard lump with a scaly top but can also form an ulcer. Onset is often over months. Squamous-cell skin cancer is more likely to spread to distant areas than basal cell cancer. The greatest risk factor is high total exposure to ultraviolet radiation from the Sun. Other risks include prior scars, chronic wounds, actinic keratosis, lighter skin, Bowen's disease, arsenic exposure, radiation therapy, poor immune system function, previous basal cell carcinoma, and HPV infection. Risk from UV radiation is related to total exposure, rather than early exposure. Tanning beds are becoming another common source of ultraviolet radiation. It begins from squamous cells found within the skin. Diagnosis is often based on skin examination and confirmed by tissue biopsy. Decreasing exposure to ultraviolet radiation and the use of sunscreen appear to be effective methods of preventing squamous-cell skin cancer. Treatment is typically by surgical removal. This can be by simple excision if the cancer is small otherwise Mohs surgery is generally recommended. Other options may include application of cold and radiation therapy. In the cases in which distant spread has occurred chemotherapy or biologic therapy may be used. As of 2015, about 2.2 million people have cSCC at any given time. It makes up about 20% of all skin cancer cases. About 12% of males and 7% of females in the United States developed cSCC at some point in time. While prognosis is usually good, if distant spread occurs five-year survival is ~34%. In 2015 it resulted in about 51,900 deaths globally. The usual age at diagnosis is around 66. Following the successful treatment of one case of cSCC people are at high risk of developing further cases.	SCC of the skin begins as a small nodule and as it enlarges the center becomes necrotic and sloughs and the nodule turns into an ulcer. - The lesion caused by SCC is often asymptomatic - Ulcer or reddish skin plaque that is slow growing - Intermittent bleeding from the tumor, especially on the lip - The clinical appearance is highly variable - Usually the tumor presents as an ulcerated lesion with hard, raised edges - The tumor may be in the form of a hard plaque or a papule, often with an opalescent quality, with tiny blood vessels - The tumor can lie below the level of the surrounding skin, and eventually ulcerates and invades the underlying tissue - The tumor commonly presents on sun-exposed areas (e.g. back of the hand, scalp, lip, and superior surface of pinna) - On the lip, the tumor forms a small ulcer, which fails to heal and bleeds intermittently - Evidence of chronic skin photodamage, such as multiple actinic keratoses (solar keratoses) - The tumor grows relatively slowly Squamous cell carcinoma is the second-most common cancer of the skin (after basal-cell carcinoma but more common than melanoma). It usually occurs in areas exposed to the sun. Sunlight exposure and immunosuppression are risk factors for SCC of the skin, with chronic sun exposure being the strongest environmental risk factor. There is a risk of metastasis starting more than 10 years after diagnosable appearance of squamous cell carcinoma, but the risk is low, though much higher than with basal-cell carcinoma. Squamous cell cancers of the lip and ears have high rates of local recurrence and distant metastasis (20–50%). In a recent study, it has also been shown that the deletion or severe down-regulation of a gene titled Tpl2 (tumor progression locus 2) may be involved in the progression of normal keratinocytes into becoming squamous cell carcinoma. SCCs represent about 20% of the non-melanoma skin cancers, but due to their more obvious nature and growth rates, they represent 90% of all head and neck cancers that are initially presented. The vast majority of SCCs are those of the skin, and like all skin cancers, are the result of ultraviolet exposure. SCCs usually occur on portions of the body commonly exposed to the Sun; the face, ears, neck, hands, or arm. The main symptom is a growing bump that may have a rough, scaly surface and flat reddish patches. Unlike basal-cell carcinomas, SCCs carry a significant risk of metastasis, often spreading to local nerves or the lymph nodes, During its earliest stages, it is sometimes known as Bowen's disease. Squamous cell carcinoma are generally treated by surgical , Mohs surgery or electrodessication and curettage. Non-surgical options for the treatment of cutaneous SCC include topical chemotherapy, topical immune response modifiers, photodynamic therapy (PDT), radiotherapy, and systemic chemotherapy. The use of topical therapy, such as Imiquimod cream and PDT is generally limited to premalignant (i.e., actinic keratoses) and in situ lesions. Radiation therapy is a primary treatment option for patients in whom surgery is not feasible and is an adjuvant therapy for those with metastatic or high-risk cutaneous SCC. At this time, systemic chemotherapy is used exclusively for patients with metastatic disease. People who have received solid organ transplants are at a significantly increased risk of developing squamous cell carcinoma due to the use of chronic immunosuppressive medication. While the risk of developing all skin cancers increases with these medications, this effect is particularly severe for SCC, with hazard ratios as high as 250 being reported, versus 40 for basal cell carcinoma. The incidence of SCC development increases with time posttransplant. Heart and lung transplant recipients are at the highest risk of developing SCC due to more intensive immunosuppressive medications used. Squamous cell cancers of the skin in individuals on immunotherapy or suffering from lymphoproliferative disorders (i.e. leukemia) tend to be much more aggressive, regardless of their location. The risk of SCC, and non-melanoma skin cancers generally, varies with the immunosuppressive drug regimen chosen. The risk is greatest with calcineurin inhibitors like cyclosporine and tacrolimus, and least with mTOR inhibitors, such as sirolimus and everolimus. The antimetabolites azathioprine and mycophenolic acid have an intermediate risk profile. Diagnosis is confirmed via biopsy of the tissue(s) suspected to be affected by SCC. For the skin, look under skin biopsy. The pathological appearance of a squamous cell cancer varies with the depth of the biopsy. For that reason, a biopsy including the subcutaneous tissue and basalar epithelium, to the surface is necessary for correct diagnosis. The performance of a shave biopsy (see skin biopsy) might not acquire enough information for a diagnosis. An inadequate biopsy might be read as actinic keratosis with follicular involvement. A deeper biopsy down to the dermis or subcutaneous tissue might reveal the true cancer. An excision biopsy is ideal, but not practical in most cases. An incisional or punch biopsy is preferred. A shave biopsy is least ideal, especially if only the superficial portion is acquired. Appropriate sun-protective clothing, use of broad-spectrum (UVA/UVB) sunscreen with at least SPF 50, and avoidance of intense sun exposure may prevent skin cancer. Most squamous cell carcinomas are removed with surgery. A few selected cases are treated with topical medication. Surgical excision with a free margin of healthy tissue is a frequent treatment modality. Radiotherapy, given as external beam radiotherapy or as brachytherapy (internal radiotherapy), can also be used to treat squamous cell carcinomas. Mohs surgery is frequently utilized; considered the treatment of choice for squamous cell carcinoma of the skin, physicians have also utilized the method for the treatment of squamous cell carcinoma of the mouth, throat, and neck. An equivalent method of the CCPDMA standards can be utilized by a pathologist in the absence of a Mohs-trained physician. Radiation therapy is often used afterward in high risk cancer or patient types. Electrodessication and curettage or EDC can be done on selected squamous cell carcinoma of the skin. In areas where SCC's are known to be non-aggressive, and where the patient is not immunosuppressed, EDC can be performed with good to adequate cure rate. High-risk squamous cell carcinoma, as defined by those occurring around the eye, ear, or nose, is of large size, is poorly differentiated, and grows rapidly, requires more aggressive, multidisciplinary management. Nodal spread: 1. Surgical block dissection if palpable nodes or in cases of Marjolin's ulcers but the benefit of prophylactic block lymph node dissection with Marjolin's ulcers is not proven. 2. Radiotherapy 3. Adjuvant therapy may be considered in those with high-risk SCC even in the absence of evidence for local mestastasis. Imiquimod (Aldara) has been used with success for squamous cell carcinoma in situ of the skin and the penis, but the morbidity and discomfort of the treatment is severe. An advantage is the cosmetic result: after treatment, the skin resembles normal skin without the usual scarring and morbidity associated with standard excision. Imiquimod is not FDA-approved for any squamous cell carcinoma. In general, squamous cell carcinomas have a high risk of local recurrence, and up to 50% do recur. Frequent skin exams with a dermatologist is recommended after treatment. The long-term outcome of squamous cell carcinomas is dependent upon several factors: the sub-type of the carcinoma, available treatments, location(s) and severity, and various patient health-related variables (accompanying diseases, age, etc.). Generally, the long-term outcome is positive, as less than 4% of Squamous cell carcinoma cases are at risk of metastasis. Some particular forms of squamous cell carcinomas have a higher mortality rate. One study found squamous cell carcinoma of the penis had a much greater rate of mortality than some other forms of squamous cell carcinoma, that is, about 23%, although this relatively high mortality rate may be associated with possibly latent diagnosis of the disease due to patients avoiding genital exams until the symptoms are debilitating, or refusal to submit to a possibly scarring operation upon the genitalia. Squamous cell carcinoma occurring in the organ transplant population is also associated with a higher risk of mortality. The incidence of squamous cell carcinoma continues to rise around the world. A recent study estimated that there are between 180,000 and 400,000 cases of SCC in the United States in 2013. Risk factors for squamous cell carcinoma varies with age, gender, race, geography, and genetics. The incidence of SCC increases with age and the peak incidence is usually around 60 years old. Males are affected with SCC at a ratio of 2:1 in comparison to females. Caucasians are more likely to be affected, especially those with fair Celtic skin and chronically exposed to UV radiation. Squamous cell carcinoma of the skin is the most common among all sites of the body. Solid organ transplant recipients (heart, lung, liver, pancreas, among others) are also at a heightened risk of developing aggressive, high-risk SCC. There are also a few rare congenital diseases predisposed to cutaneous malignancy. In certain geographic locations, exposure to arsenic in well water or from industrial sources may significantly increase the risk of SCC.	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https://en.wikipedia.org/wiki/Necrobiosis_lipoidica	disease	Necrobiosis lipoidica	Necrobiosis lipoidica is a necrotising skin condition that usually occurs in patients with diabetes mellitus but can also be associated with rheumatoid arthritis. In the former case it may be called necrobiosis lipoidica diabeticorum (NLD). NLD occurs in approximately 0.3% of the diabetic population, with the majority of sufferers being women (approximately 3:1 females to males affected). The severity or control of diabetes in an individual does not affect who will or will not get NLD. Better maintenance of diabetes after being diagnosed with NLD will not change how quickly the NLD will resolve.	NL/NLD most frequently appears on the patient's shins, often on both legs, although it may also occur on forearms, hands, trunk, and, rarely, nipple, penis, and surgical sites. The lesions are often asymptomatic but may become tender and ulcerate when injured. The first symptom of NL is often a "bruised" appearance (erythema) that is not necessarily associated with a known injury. The extent to which NL is inherited is unknown. NLD appears as a hardened, raised area of the skin. The center of the affected area usually has a yellowish tint while the area surrounding it is a dark pink. It is possible for the affected area to spread or turn into an open sore. When this happens the patient is at greater risk of developing ulcers. If an injury to the skin occurs on the affected area, it may not heal properly or it will leave a dark scar. Although the exact cause of this condition is not known, it is an inflammatory disorder characterised by collagen degeneration, combined with a granulomatous response. It always involves the dermis diffusely, and sometimes also involves the deeper fat layer. Commonly, dermal blood vessels are thickened (microangiopathy). It can be precipitated by local trauma, though it often occurs without any injury. NL is diagnosed by a skin biopsy, demonstrating superficial and deep perivascular and interstitial mixed inflammatory cell infiltrate (including lymphocytes, plasma cells, mononucleated and multinucleated histiocytes, and eosinophils) in the dermis and subcutis, as well as necrotising vasculitis with adjacent necrobiosis and necrosis of adnexal structures. Areas of necrobiosis are often more extensive and less well defined than in granuloma annulare. Presence of lipid in necrobiotic areas may be demonstrated by Sudan stains. Cholesterol clefts, fibrin, and mucin may also be present in areas of necrobiosis. Depending on the severity of the necrobiosis, certain cell types may be more predominant. When a lesion is in its early stages, neutrophils may be present, whereas in later stages of development lymphocytes and histiocytes may be more predominant. There is no clearly defined cure for necrobiosis. NLD may be treated with PUVA therapy and improved therapeutic control. Although there are some techniques that can be used to diminish the signs of necrobiosis such as low dose aspirin orally, a steroid cream or injection into the affected area, this process may be effective for only a small percentage of those treated.	[ { "begin": 0, "class": "SectionAnnotation", "length": 845, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 845, "class": "SectionAnnotation", "length": 406, "sectionHeading": "Pathophysiology", "sectionLabel": "disease.pathophysiology" }, { "begin": 1251, "class": "SectionAnnotation", "length": 862, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 2113, "class": "SectionAnnotation", "length": 372, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Paraphimosis	disease	Paraphimosis	Paraphimosis is an uncommon medical condition in which the foreskin of a penis becomes trapped behind the glans penis, and cannot be reduced (pulled back to its normal flaccid position covering the glans). If this condition persists for several hours or there is any sign of a lack of blood flow, paraphimosis should be treated as a medical emergency, as it can result in gangrene.	Paraphimosis is usually caused by medical professionals or parents who handle the foreskin improperly: The foreskin may be retracted during penile examination, penile cleaning, urethral catheterization, or cystoscopy; if the foreskin is left retracted for a long period, some of the foreskin tissue may become edematous (swollen with fluid), which makes subsequent reduction of the foreskin difficult. Paraphimosis can be avoided by bringing the foreskin back into its normal, forward, non-retracted position after retraction is no longer necessary (for instance, after cleaning the glans penis or placing a Foley catheter). Phimosis (both pathologic and normal childhood physiologic forms) is a risk factor for paraphimosis; physiologic phimosis resolves naturally as a child matures, but it may be advisable to treat pathologic phimosis via long-term stretching or elective surgical techniques (such as preputioplasty to loosen the preputial orifice or circumcision to amputate the foreskin tissue partially or completely). The foreskin responds to the application of tension to cause expansion by creating new skin cells though the process of mitosis. The tissue expansion is permanent. Non-surgical stretching of the foreskin may be used to widen a narrow, non-retractable foreskin. Stretching may be combined with the use of a steroid cream. Beaugé recommends manual stretching for young males in preference to circumcision as a treatment for non-retractile foreskin because of the preservation of sexual sensation. Paraphimosis can often be effectively treated by manual manipulation of the swollen foreskin tissue. This involves compressing the glans and moving the foreskin back to its normal position, perhaps with the aid of a lubricant, cold compression, and local anesthesia as necessary. If this fails, the tight edematous band of tissue can be relieved surgically with a dorsal slit or circumcision. An alternative method, the Dundee technique, entails placing multiple punctures in the swollen foreskin with a fine needle, and then expressing the edema fluid by manual pressure. According to Ghory and Sharma, treatment by circumcision may be elected as "a last resort, to be performed by a urologist". Other experts recommend delaying elective circumcision until after paraphimosis has been resolved.	[ { "begin": 0, "class": "SectionAnnotation", "length": 402, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 402, "class": "SectionAnnotation", "length": 1916, "sectionHeading": "Prevention and treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Auto-brewery_syndrome	disease	Auto-brewery syndrome	Auto-brewery syndrome, also known as gut fermentation syndrome, is a rare medical condition in which intoxicating quantities of ethanol are produced through endogenous fermentation within the digestive system. One gastrointestinal organism, Saccharomyces cerevisiae, a type of yeast, has been identified as a pathogen for this condition. Claims of endogenous fermentation of this type have been used as a defense against drunk driving charges. One case went undetected for 20 years. It has also been investigated, but eliminated, as a possible cause of sudden infant death syndrome. A variant occurs in persons with liver abnormalities that prevent them from excreting or breaking down alcohol normally. Patients with this condition can develop symptoms of auto-brewery syndrome even when the gut yeast produces a quantity of alcohol that is too small to intoxicate a healthy individual.	The effects of the disease can have profound effects on everyday life. As well, the recurring side effects of excessive belching, dizziness, dry mouth, hangovers, disorientation, irritable bowel syndrome, and chronic fatigue syndrome can lead to other health problems such as depression, anxiety and poor productivity in employment. The random state of intoxication can lead to personal difficulties, and the relative obscurity of the condition can also make it hard to seek treatment. The treatment for auto-brewery syndrome is a change in diet requiring low carbohydrates and high protein. Sugar is fermented into alcohol, and a diet that effectively lowers sugars also lowers the alcohol that can be fermented from it. Anything that causes an imbalance between the beneficial and harmful bacteria in the gut can help increase the chance that fermentation in the gut will develop. This can include not only antibiotics, but also overindulgence in sugars and carbohydrates. Watching what you eat could lower the risk of gut fermentation syndrome, and taking probiotics could further protect you by increasing the number of good bacteria in your system.	[ { "begin": 0, "class": "SectionAnnotation", "length": 486, "sectionHeading": "Symptoms", "sectionLabel": "disease.symptom" }, { "begin": 486, "class": "SectionAnnotation", "length": 668, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Oral_candidiasis	disease	Oral candidiasis	Oral candidiasis, also known as oral thrush among other names, is candidiasis that occurs in the mouth. That is, oral candidiasis is a mycosis (yeast/fungal infection) of Candida species on the mucous membranes of the mouth. Candida albicans is the most commonly implicated organism in this condition. C. albicans is carried in the mouths of about 50% of the world's population as a normal component of the oral microbiota. This candidal carriage state is not considered a disease, but when Candida species become pathogenic and invade host tissues, oral candidiasis can occur. This change usually constitutes an opportunistic infection by normally harmless micro-organisms because of local (i.e., mucosal) or systemic factors altering host immunity.	Oral candidiasis is a mycosis (fungal infection). Traditionally, oral candidiasis is classified using the Lehner system, originally described in the 1960s, into acute and chronic forms (see table). Some of the subtypes almost always occur as acute (e.g., acute pseudomembranous candidiasis), and others chronic. However, these typical presentations do not always hold true, which created problems with this system. A more recently proposed classification of oral candidiasis distinguishes primary oral candidiasis, where the condition is confined to the mouth and perioral tissues, and secondary oral candidiasis, where there is involvement of other parts of the body in addition to the mouth. The global human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pandemic has been an important factor in the move away from the traditional classification since it has led to the formation of a new group of patients who present with atypical forms of oral candidiasis. Three main clinical appearances of candidiasis are generally recognized: pseudomembranous, erythematous (atrophic) and hyperplastic. Most often, affected individuals display one clear type or another, but sometimes there can be more than one clinical variant in the same person. Acute pseudomembranous candidiasis is a classic form of oral candidiasis, commonly referred to as thrush. Overall, this is the most common type of oral candidiasis, accounting for about 35% of oral candidiasis cases. It is characterized by a coating or individual patches of pseudomembranous white slough that can be easily wiped away to reveal erythematous (reddened), and sometimes minimally bleeding, mucosa beneath. These areas of pseudomembrane are sometimes described as "curdled milk", or "cottage cheese". The white material is made up of debris, fibrin, and desquamated epithelium that has been invaded by yeast cells and hyphae that invade to the depth of the stratum spinosum. Due to the fact that an erythematous surface is revealed beneath the pseudomembranes, some consider pseudomembranous candidiasis and erythematous candidiasis stages of the same entity. Some sources state that if there is bleeding when the pseudomembrane is removed, then the mucosa has likely been affected by an underlying process such as lichen planus or chemotherapy. Pseudomembraneous candidiasis can involve any part of the mouth, but usually it appears on the tongue, buccal mucosae or palate. It is classically an acute condition, appearing in infants, people taking antibiotics or immunosuppressant medications, or immunocompromising diseases. However, sometimes it can be chronic and intermittent, even lasting for many years. Chronicity of this subtype generally occurs in immunocompromised states, (e.g., leukemia, HIV) or in persons who use corticosteroids topically or by aerosol. Acute and chronic pseudomembranous candidiasis are indistinguishable in appearance. Erythematous (atrophic) candidiasis is when the condition appears as a red, raw-looking lesion. Some sources consider denture-related stomatitis, angular stomatitis, median rhombiod glossitis, and antiobiotic-induced stomatitis as subtypes of erythematous candidiasis, since these lesions are commonly erythematous/atrophic. It may precede the formation of a pseudomembrane, be left when the membrane is removed, or arise without prior pseudomembranes. Some sources state that erythematous candidiasis accounts for 60% of oral candidiasis cases. Where it is associated with inhalation steroids (often used for treatment of asthma), erythematous candidiasis commonly appears on the palate or the dorsum of the tongue. On the tongue, there is loss of the lingual papillae (depapillation), leaving a smooth area. Acute erythematous candidiasis usually occurs on the dorsum of the tongue in persons taking long term corticosteroids or antibiotics, but occasionally it can occur after only a few days of using a topical antibiotic. This is usually termed "antibiotic sore mouth", "antibiotic sore tongue", or "antibiotic-induced stomatitis" because it is commonly painful as well as red. Chronic erythematous candidiasis is more usually associated with denture wearing (see denture-related stomatitis). This variant is also sometimes termed "plaque-like candidiasis" or "nodular candidiasis". The most common appearance of hyperplastic candidiasis is a persistent white plaque that does not rub off. The lesion may be rough or nodular in texture. Hyperplastic candidiasis is uncommon, accounting for about 5% of oral candidiasis cases, and is usually chronic and found in adults. The most common site of involvement is the commissural region of the buccal mucosa, usually on both sides of the mouth. Another term for hyperplastic candidiasis is "candidal leukoplakia". This term is a largely historical synonym for this subtype of candidiasis, rather than a true leukoplakia. Indeed, it can be clinically indistinguishable from true leukoplakia, but tissue biopsy shows candidal hyphae invading the epithelium. Some sources use this term to describe leukoplakia lesions that become colonized secondarily by Candida species, thereby distinguishing it from hyperplastic candidiasis. It is known that Candida resides more readily in mucosa that is altered, such as may occur with dysplasia and hyperkeratosis in an area of leukoplakia. Candida-associated lesions are primary oral candidiases (confined to the mouth), where the causes are thought to be multiple. For example, bacteria as well as Candida species may be involved in these lesions. Frequently, antifungal therapy alone does not permanently resolve these lesions, but rather the underlying predisposing factors must be addressed, in addition to treating the candidiasis. Angular cheilitis is inflammation at the corners (angles) of the mouth, very commonly involving Candida species, when sometimes the terms "Candida-associated angular cheilitis", or less commonly "monilial perlèche" are used. Candida organisms alone are responsible for about 20% of cases, and a mixed infection of C. albicans and Staphylococcus aureus for about 60% of cases. Signs and symptoms include soreness, erythema (redness), and fissuring of one, or more commonly both the angles of the mouth, with edema (swelling) seen intraorally on the commissures (inside the corners of the mouth). Angular cheilitis generally occurs in elderly people and is associated with denture related stomatitis. This term refers to a mild inflammation and erythema of the mucosa beneath a denture, usually an upper denture in elderly edentulous individuals (with no natural teeth remaining). Some report that up to 65% of denture wearers have this condition to some degree. About 90% of cases are associated with Candida species, where sometimes the terms "Candida-associated denture stomatitis", or "Candida-associated denture-induced stomatitis" (CADIS), are used. Some sources state that this is by far the most common form of oral candidiasis. Although this condition is also known as "denture sore mouth", there is rarely any pain. Candida is associated with about 90% of cases of denture related stomatitis. This is an elliptical or rhomboid lesion in the center of the dorsal tongue, just anterior (in front) of the circumvallate papillae. The area is depapillated, reddened (or red and white) and rarely painful. There is frequently Candida species in the lesion, sometimes mixed with bacteria. This is a localized or generalized, linear band of erythematous gingivitis (inflammation of the gums). It was first observed in HIV infected individuals and termed "HIV-gingivitis", but the condition is not confined to this group. Candida species are involved, and in some cases the lesion responds to antifungal therapy, but it is thought that other factors exist, such as oral hygiene and human herpesviruses. This condition can develop into necrotizing ulcerative periodontitis. This is an uncommon form of chronic (more than one month in duration) candidal infection involving multiple areas in the mouth, without signs of candidiasis on other mucosal or cutaneous sites. The lesions are variably red and/or white. Unusually for candidal infections, there is an absence of predisposing factors such as immunosuppression, and it occurs in apparently healthy individuals, normally elderly males. Smoking is a known risk factor. This refers to a group of rare syndromes characterized by chronic candidal lesions on the skin, in the mouth and on other mucous membranes (i.e., a secondary oral candidiasis). These include Localized chronic mucocutaneous candidiasis, diffuse mucocutaneous candidiasis (Candida granuloma), candidiasis–endocrinopathy syndrome and candidiasis thymoma syndrome. About 90% of people with chronic mucocutaneous candidiasis have candidiasis in the mouth. Signs and symptoms are dependent upon the type of oral candidiasis. Often, apart from the appearance of the lesions, there are usually no other signs or symptoms. Most types of oral candidiasis are painless, but a burning sensation may occur in some cases. Candidiasis can therefore sometimes be misdiagnosed as burning mouth syndrome. A burning sensation is more likely with erythematous (atrophic) candidiasis, whilst hyperplastic candidiasis is normally entirely asymptomatic. Acute atrophic candidiasis may feel like the mouth has been scalded with a hot liquid. Another potential symptom is a metallic, acidic, salty or bitter taste in the mouth. The pseudomembranous type rarely causes any symptoms apart from possibly some discomfort or bad taste due to the presence of the membranes. Sometimes the patient describes the raised pseudomembranes as "blisters." Occasionally there can be dysphagia (difficulty swallowing), which indicates that the candidiasis involves the oropharynx or the esophagus, as well as the mouth. The trachea and the larynx may also be involved where there is oral candidiasis, and this may cause hoarseness of the voice. The causative organism is usually Candida albicans, or less commonly other Candida species such as (in decreasing order of frequency) Candida tropicalis, Candida glabrata, Candida parapsilosis, Candida krusei, or other species (Candida stellatoidea, Candida pseudotropicalis, Candida famata, Candida rugosa, Candida geotrichium, Candida dubliniensis, and Candida guilliermondii). C. albicans accounts for about 50% of oral candidiasis cases, and together C. albicans, C. tropicalis and C. glabrata account for over 80% of cases. Candidiasis caused by non-C. albicans Candida (NCAC) species is associated more with immunodeficiency. For example, in HIV/AIDS, C. dubliniensis and C. geotrichium can become pathogenic. About 35-50% of humans possess C. albicans as part of their normal oral microbiota. With more sensitive detection techniques, this figure is reported to rise to 90%. This candidal carrier state is not considered a disease, since there are no lesions or symptoms of any kind. Oral carriage of Candida is pre-requisite for the development of oral candidiasis. For Candida species to colonize and survive as a normal component of the oral microbiota, the organisms must be capable of adhering to the epithelial surface of the mucous membrane lining the mouth. This adhesion involves adhesins (e.g., hyphal wall protein 1), and extracellular polymeric materials (e.g., mannoprotein). Therefore, strains of Candida with more adhesion capability have more pathogenic potential than other strains. The prevalence of Candida carriage varies with geographic location, and many other factors. Higher carriage is reported during the summer months, in females, in hospitalized individuals, in persons with blood group O and in non-secretors of blood group antigens in saliva. Increased rates of Candida carriage are also found in people who eat a diet high in carbohydrates, people who wear dentures, people with xerostomia (dry mouth), in people taking broad spectrum antibiotics, smokers, and in immunocompromised individuals (e.g., due to HIV/AIDS, diabetes, cancer, Down syndrome or malnutrition). Age also influences oral carriage, with the lowest levels occurring in newborns, increasing dramatically in infants, and then decreasing again in adults. Investigations have quantified oral carriage of Candida albicans at 300-500 colony forming units in healthy persons. More Candida is detected in the early morning and the late afternoon. The greatest quantity of Candida species are harbored on the posterior dorsal tongue, followed by the palatal and the buccal mucosae. Mucosa covered by an oral appliance such as a denture harbors significantly more candida species than uncovered mucosa. When Candida species cause lesions - the result of invasion of the host tissues - this is termed candidiasis. Some consider oral candidiasis a change in the normal oral environment rather than an exposure or true "infection" as such. The exact process by which Candida species switch from acting as normal oral commensals (saprophytic) state in the carrier to acting as a pathogenic organism (parasitic state) is not completely understood. Several Candida species are polymorphogenic, that is, capable of growing in different forms depending on the environmental conditions. C. albicans can appear as a yeast form (blastospores), which is thought to be relatively harmless; and a hyphal form associated with invasion of host tissues. Apart from true hyphae, Candida can also form pseudohyphae — elongated filamentous cells, lined end to end. As a general rule, candidiasis presenting with white lesions is mainly caused by Candida species in the hyphal form and red lesions by yeast forms. C. albicans and C. dubliniensis are also capable of forming germ tubes (incipient hyphae) and chlamydospores under the right conditions. C. albicans is categorized serologically into A or B serotypes. The prevalence is roughly equal in healthy individuals, but type B is more prevalent in immunocompromised individuals. The host defenses against opportunistic infection of candida species are - The oral epithelium, which acts both as a physical barrier preventing micro-organisms from entering the tissues, and is the site of cell mediated immune reactions. - Competition and inhibition interactions between candida species and other micro-organisms in the mouth, such as the many hundreds of different kinds of bacteria. - Saliva, which possesses both mechanical cleansing action and immunologic action, including salivary immunoglobulin A antibodies, which aggregate candida organisms and prevent them adhering to the epithelial surface; and enzymatic components such as lysozyme, lactoperoxidase and antileukoprotease. Disruption to any of these local and systemic host defense mechanisms constitutes a potential susceptibility to oral candidiasis, which rarely occurs without predisposing factors. It is often described as being "a disease of the diseased", occurring in the very young, the very old, or the very sick. Immunodeficiency is a state of reduced function of the immune system, which can be caused by medical conditions or treatments. Acute pseudomembranous candidiasis occurs in about 5% of newborn infants. Candida species are acquired from the mother's vaginal canal during birth. At very young ages, the immune system is yet to develop fully and there is no individual immune response to candida species, an infants antibodies to the fungus are normally supplied by the mother's breast milk. Other forms of immunodeficiency which may cause oral candidiasis include HIV/AIDS, active cancer and treatment, chemotherapy or radiotherapy. Corticosteroid medications may contribute to the appearance of oral candidiasis, as they cause suppression of immune function either systemically or on a local/mucosal level, depending on the route of administration. Topically administered corticosteroids in the mouth may take the form of mouthwashes, dissolving lozenges or mucosal gels; sometimes being used to treat various forms of stomatitis. Systemic corticosteroids may also result in candidiasis. Inhaled corticosteroids (e.g., for treatment of asthma or chronic obstructive pulmonary disease), are not intended to be administered topically in the mouth, but inevitably there is contact with the oral and oropharyngeal mucousa as it is inhaled. In asthmatics treated with inhaled steroids, clinically detectable oral candidiasis may occur in about 5-10% of adults and 1% of children. Where inhaled steroids are the cause, the candidal lesions are usually of the erythematous variety. Candidiasis appears at the sites where the steroid has contacted the mucosa, typically the dorsum of the tongue (median rhomboid glossitis) and sometimes also on the palate. Candidal lesions on both sites are sometimes termed "kissing lesions" because they approximate when the tongue is in contact with the palate. Denture wearing and poor denture hygiene, particularly wearing the denture continually rather than removing it during sleep, is another risk factor for both candidal carriage and oral candidiasis. Dentures provide a relative acidic, moist and anaerobic environment because the mucosa covered by the denture is sheltered from oxygen and saliva. Loose, poorly fitting dentures may also cause minor trauma to the mucosa, which is thought to increase the permeability of the mucosa and increase the ability of C. albicans to invade the tissues. These conditions all favor the growth of C. albicans. Sometimes dentures become very worn, or they have been constructed to allow insufficient lower facial height (occlusal vertical dimension), leading to over-closure of the mouth (an appearance sometimes described as "collapse of the jaws"). This causes deepening of the skin folds at the corners of the mouth (nasolabial crease), in effect creating intertriginous areas where another form of candidiasis, angular cheilitis, can develop. Candida species are capable of adhering to the surface of dentures, most of which are made from polymethylacrylate. They exploit micro-fissures and cracks in the surface of dentures to aid their retention. Dentures may therefore become covered in a biofilm, and act as reservoirs of infection, continually re-infecting the mucosa. For this reason, disinfecting the denture is a vital part of treatment of oral candidiasis in persons who wear dentures, as well as correcting other factors like inadequate lower facial height and fit of the dentures. Both the quantity and quality of saliva are important oral defenses against candida. Decreased salivary flow rate or a change in the composition of saliva, collectively termed salivary hypofunction or hyposalivation is an important predisposing factor. Xerostomia is frequently listed as a cause of candidiasis, but xerostomia can be subjective or objective, i.e., a symptom present with or without actual changes in the saliva consistency or flow rate. Malnutrition, whether by malabsorption, or poor diet, especially hematinic deficiencies (iron, vitamin B12, folic acid) can predispose to oral candidiasis, by causing diminished host defense and epithelial integrity. For example, iron deficiency anemia is thought to cause depressed cell-mediated immunity. Some sources state that deficiencies of vitamin A or pyridoxine are also linked. There is limited evidence that a diet high in carbohydrates predisposes to oral candidiasis. In vitro and studies show that Candidal growth, adhesion and biofilm formation is enhanced by the presence of carbohydrates such as glucose, galactose and sucrose. Smoking, especially heavy smoking, is an important predisposing factor but the reasons for this relationship are unknown. One hypothesis is that cigarette smoke contains nutritional factors for C. albicans, or that local epithelial alterations occur that facilitate colonization of candida species. Broad-spectrum antibiotics (e.g. tetracycline) eliminate the competing bacteria and disrupt the normally balanced ecology of oral microorganisms, which can cause antibiotic-induced candidiasis. Endocrine disorders, e.g., diabetes (when poorly controlled). Presence of certain other mucosal lesions, especially those that cause hyperkeratosis and/or dysplasia, e.g., lichen planus. Such changes in the mucosa predispose it to secondary infection with candidiasis. Other physical mucosal alterations are sometimes associated with candida overgrowth, such as Fissured tongue (rarely), or Tongue piercing. Women undergoing hormonal changes, like pregnancy or those on birth control pills. Atopy. Hospitalization. Lupus. The diagnosis can typically be made from the clinical appearance alone, but not always. As candidiasis can be variable in appearance, and present with white, red or combined white and red lesions, the differential diagnosis can be extensive. In pseudomembraneous candidiasis, the membranous slough can be wiped away to reveal an erythematous surface underneath. This is helpful in distinguishing pseudomembraneous candidiasis from other white lesions in the mouth that cannot be wiped away, such as lichen planus, oral hairy leukoplakia. Erythematous candidiasis can mimic geographic tongue. Erythematous candidiasis usually has a diffuse border that helps distinguish it from erythroplakia, which normally has a sharply defined border. Special investigations to detect the presence of candida species include oral swabs, oral rinse or oral smears. Smears are collected by gentle scraping of the lesion with a spatula or tongue blade and the resulting debris directly applied to a glass slide. Oral swabs are taken if culture is required. Some recommend that swabs be taken from 3 different oral sites. Oral rinse involves rinsing the mouth with phosphate-buffered saline for 1 minute and then spitting the solution into a vessel that examined in a pathology laboratory. Oral rinse technique can distinguish between commensal candidal carriage and candidiasis. If candidal leukoplakia is suspected, a biopsy may be indicated. Smears and biopsies are usually stained with periodic acid-Schiff, which stains carbohydrates in fungal cell walls in magenta. Gram staining is also used as Candida stains are strongly Gram positive. Sometimes an underlying medical condition is sought, and this may include blood tests for full blood count and hematinics. If a biopsy is taken, the histopathologic appearance can be variable depending upon the clinical type of candidiasis. Pseudomembranous candidiasis shows hyperplastic epithelium with a superficial parakeratotic desquamating (i.e., separating) layer. Hyphae penetrate to the depth of the stratum spinosum, and appear as weakly basophilic structures. Polymorphonuclear cells also infiltrate the epithelium, and chronic inflammatory cells infiltrate the lamina propria. Atrophic candidiasis appears as thin, atrophic epithelium, which is non-keratinized. Hyphae are sparse, and inflammatory cell infiltration of the epithelium and the lamina propria. In essence, atrophic candidiasis appears like pseudomembranous candidiasis without the superficial desquamating layer. Hyperplastic candidiasis is variable. Usually there is hyperplastic and acanthotic epithelium with parakeratosis. There is an inflammatory cell infiltrate and hyphae are visible. Unlike other forms of candidiasis, hyperplastic candidiasis may show dysplasia. Oral candidiasis can be treated with topical anti-fungal drugs, such as nystatin, miconazole, Gentian violet or amphotericin B. Underlying immunosuppression may be medically manageable once it is identified, and this helps prevent recurrence of candidal infections. Patients who are immunocompromised, either with HIV/AIDS or as a result of chemotherapy, may require systemic treatment with oral or intravenous administered anti-fungals. If candidiasis is secondary to corticosteroid or antibiotic use, then use may be stopped, although this is not always a feasible option. Candidiasis secondary to the use of inhaled steroids may be treated by rinsing out the mouth with water after taking the steroid. Use of a spacer device to reduce the contact with the oral mucosa may greatly reduce the risk of oral candidiasis. In recurrent oral candidiasis, the use of azole antifungals risks selection and enrichment of drug-resistant strains of candida organisms. Drug resistance is increasingly more common and presents a serious problem in persons who are immunocompromised. Prophylactic use of antifungals is sometimes employed in persons with HIV disease, during radiotherapy, during immunosuppressive or prolonged antibiotic therapy as the development of candidal infection in these groups may be more serious. The candidal load in the mouth can be reduced by improving oral hygiene measures, such as regular toothbrushing and use of anti-microbial mouthwashes. Since smoking is associated with many of forms of oral candidiasis, cessation may be beneficial. Good denture hygiene involves regular cleaning of the dentures, and leaving them out of the mouth during sleep. This gives the mucosa a chance to recover, while wearing a denture during sleep is often likened to sleeping in one's shoes. In oral candidiasis, the dentures may act as a reservoir of Candida species, continually reinfecting the mucosa once antifungal medication is stopped. Therefore, they must be disinfected as part of the treatment for oral candidiasis. There are commercial denture cleaner preparations for this purpose, but it is readily accomplished by soaking the denture overnight in a 1:10 solution of sodium hypochlorite (Milton, or household bleach). Bleach may corrode metal components, so if the denture contains metal, soaking it twice daily in chlorhexidine solution can be carried out instead. An alternative method of disinfection is to use a 10% solution of acetic acid (vinegar) as an overnight soak, or to microwave the dentures in 200mL water for 3 minutes at 650 watts. Antifungal medication can also be applied to the fitting surface of the denture before it is put back in the mouth. Other problems with the dentures, such as inadequate occlusal vertical dimension may also need to be corrected in the case of angular cheilitis. The severity of oral candidiasis is subject to great variability from one person to another and in the same person from one occasion to the next. The prognosis of such infection is usually excellent after the application of topical or systemic treatments. However, oral candidiasis can be recurrent. Individuals continue to be at risk of the condition if underlying factors such as reduced salivary flow rate or immunosuppression are not rectifiable. Candidiasis can be a marker for underlying disease, so the overall prognosis may also be dependent upon this. For example, a transient erythematous candidiasis that developed after antiobiotic therapy usually resolves after antibiotics are stopped (but not always immediately), and therefore carries an excellent prognosis—but candidiasis may occasionally be a herald of a more sinister undiagnosed pathology, such as HIV/AIDS or leukemia. It is possible for candidiasis to spread to/from the mouth, from sites such as the pharynx, esophagus, lungs, liver, anogenital region, skin or the nails. The spread of oral candidiasis to other sites usually occurs in debilitated individuals. It is also possible that candidiasis is spread by sexual contact. Rarely, a superficial candidal infection such as oral candidiasis can cause invasive candidiasis, and even prove fatal. The observation that Candida species are normally harmless commensals on the one hand, but are also occasionally capable of causing fatal invasive candidiases has led to the description "Dr Jekyll and Mr Hyde". The role of thrush in the hospital and ventilated patients is not entirely clear however there is a theoretical risk of positive interaction of candida with topical bacteria that could increase the risk for Ventilator Associated Pneumonia and other diseases. In humans, oral candidiasis is the most common form of candidiasis, by far the most common fungal infection of the mouth, and it also represents the most common opportunistic oral infection in humans with lesions only occurring when the environment favors pathogenic behavior. Oropharyngeal candidiasis is common during cancer care, and it is a very common oral sign in individuals with HIV. Oral candidiasis occurs in about two thirds of people with concomitant AIDS and esophageal candidiasis. The incidence of all forms of candidiasis have increased in recent decades. This is due to developments in medicine, with more invasive medical procedures and surgeries, more widespread use of broad spectrum antibiotics and immunosuppression therapies. The HIV/AIDs global pandemic has been the greatest factor in the increased incidence of oral candidiasis since the 1980s. The incidence of candidiasis caused by NCAC species is also increasing, again thought to be due to changes in medical practise (e.g., organ transplantation and use of indwelling catheters). Oral candidiasis has been recognized throughout recorded history. The first description of this condition is thought to have occurred in the 4th century B.C. in "Epidemics" (a treatise that is part of the hippocratic corpus), where descriptions of what sounds like oral candidiasis are stated to occur with severe underlying disease. The colloquial term "thrush" refers to the resemblance of the white flecks present in some forms of candidiasis (e.g., pseudomembranous candidiasis), with the breast of the bird of the same name. Many pseudoscientific claims by proponents of alternative medicine surround the topic of candidiasis. Oral candidiasis is sometimes presented in this manner as a symptom of a widely prevalent systemic candidiasis, candida hypersensitivity syndrome, yeast allergy, or gastrointestinal candida overgrowth, which are medically unrecognized conditions. (See: Alternative medicine in Candidiasis)	[ { "begin": 0, "class": "SectionAnnotation", "length": 985, "sectionHeading": "Classification", "sectionLabel": "disease.classification" }, { "begin": 985, "class": "SectionAnnotation", "length": 279, "sectionHeading": "Classification \| By appearance", "sectionLabel": "disease.symptom" }, { "begin": 1264, "class": "SectionAnnotation", "length": 1666, "sectionHeading": "Classification \| By appearance \| Pseudomembranous", "sectionLabel": "disease.symptom" }, { "begin": 2930, "class": "SectionAnnotation", "length": 1298, "sectionHeading": "Classification \| By appearance \| Erythematous", "sectionLabel": "disease.symptom" }, { "begin": 4228, "class": "SectionAnnotation", "length": 1130, "sectionHeading": "Classification \| By appearance \| Hyperplastic", "sectionLabel": "disease.symptom" }, { "begin": 5358, "class": "SectionAnnotation", "length": 397, "sectionHeading": "Classification \| Associated lesions", "sectionLabel": "disease.classification" }, { "begin": 5755, "class": "SectionAnnotation", "length": 699, "sectionHeading": "Classification \| Associated lesions \| Angular cheilitis", "sectionLabel": "disease.classification" }, { "begin": 6454, "class": "SectionAnnotation", "length": 702, "sectionHeading": "Classification \| Associated lesions \| Denture-related stomatitis", "sectionLabel": "disease.classification" }, { "begin": 7156, "class": "SectionAnnotation", "length": 289, "sectionHeading": "Classification \| Associated lesions \| Median rhomboid glossitis", "sectionLabel": "disease.classification" }, { "begin": 7445, "class": "SectionAnnotation", "length": 482, "sectionHeading": "Classification \| Associated lesions \| Linear gingival erythema", "sectionLabel": "disease.classification" }, { "begin": 7927, "class": "SectionAnnotation", "length": 448, "sectionHeading": "Classification \| Others \| Chronic multifocal oral candidiasis", "sectionLabel": "disease.classification" }, { "begin": 8375, "class": "SectionAnnotation", "length": 451, "sectionHeading": "Classification \| Others \| Chronic mucocutaneous candidiasis", "sectionLabel": "disease.classification" }, { "begin": 8826, "class": "SectionAnnotation", "length": 1153, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 9979, "class": "SectionAnnotation", "length": 4011, "sectionHeading": "Causes \| Species", "sectionLabel": "disease.cause" }, { "begin": 13990, "class": "SectionAnnotation", "length": 1004, "sectionHeading": "Causes \| Predisposing factors", "sectionLabel": "disease.cause" }, { "begin": 14994, "class": "SectionAnnotation", "length": 1889, "sectionHeading": "Causes \| Predisposing factors \| Immunodeficiency", "sectionLabel": "disease.cause" }, { "begin": 16883, "class": "SectionAnnotation", "length": 1580, "sectionHeading": "Causes \| Predisposing factors \| Denture wearing", "sectionLabel": "disease.cause" }, { "begin": 18463, "class": "SectionAnnotation", "length": 454, "sectionHeading": "Causes \| Predisposing factors \| Dry mouth", "sectionLabel": "disease.cause" }, { "begin": 18917, "class": "SectionAnnotation", "length": 645, "sectionHeading": "Causes \| Predisposing factors \| Diet", "sectionLabel": "disease.cause" }, { "begin": 19562, "class": "SectionAnnotation", "length": 299, "sectionHeading": "Causes \| Predisposing factors \| Smoking", "sectionLabel": "disease.cause" }, { "begin": 19861, "class": "SectionAnnotation", "length": 194, "sectionHeading": "Causes \| Predisposing factors \| Antibiotics", "sectionLabel": "disease.cause" }, { "begin": 20055, "class": "SectionAnnotation", "length": 524, "sectionHeading": "Causes \| Predisposing factors \| Other factors", "sectionLabel": "disease.cause" }, { "begin": 20579, "class": "SectionAnnotation", "length": 2774, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 23353, "class": "SectionAnnotation", "length": 1560, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 24913, "class": "SectionAnnotation", "length": 1267, "sectionHeading": "Treatment \| Denture hygiene", "sectionLabel": "disease.treatment" }, { "begin": 26180, "class": "SectionAnnotation", "length": 1792, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" }, { "begin": 27972, "class": "SectionAnnotation", "length": 1061, "sectionHeading": "Epidemiology", "sectionLabel": "disease.epidemiology" }, { "begin": 29033, "class": "SectionAnnotation", "length": 531, "sectionHeading": "History", "sectionLabel": "disease.history" }, { "begin": 29564, "class": "SectionAnnotation", "length": 392, "sectionHeading": "Society and culture", "sectionLabel": "disease.culture" } ]
https://en.wikipedia.org/wiki/Thyroid_lymphoma	disease	Thyroid lymphoma	Thyroid lymphoma is a rare malignant tumor constituting 1% to 2% of all thyroid malignancies and less than 2% of lymphomas. Thyroid lymphomas are classified as non–Hodgkin's B-cell lymphomas in a majority of cases, although Hodgkin's lymphoma of the thyroid has also been identified.	The majority of thyroid lymphomas are non–Hodgkin's B-cell lymphomas; the rest exhibit properties of T-cell lymphomas . - Diffuse large B-cell lymphoma with marginal zone - Diffuse large B-cell lymphoma without marginal zone - Marginal zone В-cell lymphoma of mucosa-associated lymphoid tissue (MALT) - Follicular lymphoma As other thyroid lesions, thyroid lymphoma affects predominantly females over 70 years of age with a history of Hashimoto's thyroiditis. Thus, Hashimoto's thyroiditis is considering as risk factor for thyroid lymphoma development. The thyroid lymphoma manifests as rapidly enlarging neck mass causing respiratory difficulty. On physical examination, patients usually exhibit a firm thyroid and lymphadenopathy. Thyroid lymphoma shows a diagnostic and therapeutic challenge in many cases, because some manifestation patterns are similar to anaplastic thyroid cancer (ATC). Performance of fine-needle aspiration (FNA) has helped to distinguish these between two entities preoperatively. Combined modality therapy is the most common approach for the initial treatment of thyroid lymphomas. The CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) has been shown high effectiveness for many types of thyroid lymphoma. However, it is suggested to perform radiation therapy only for MALT resulting a 96% complete response, with only a 30% relapse rate. Surgical treatment might be performed for patients with thyroid lymphoma in addition to chemotherapy and radiation, particularly for MALT lymphomas. The factors of poor prognosis for patients with thyroid lymphoma are advanced stage of the tumor, large size (>10 cm) as well as spreading to mediastinum. The overall survival for primary thyroid lymphoma is 50% to 70%, ranging from 80% in stage IE to less than 36% in stage IIE and IVE in 5 years.	[ { "begin": 0, "class": "SectionAnnotation", "length": 323, "sectionHeading": "Histopathology", "sectionLabel": "disease.pathology" }, { "begin": 323, "class": "SectionAnnotation", "length": 411, "sectionHeading": "Clinical presentation", "sectionLabel": "disease.symptom" }, { "begin": 734, "class": "SectionAnnotation", "length": 274, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 1008, "class": "SectionAnnotation", "length": 531, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 1539, "class": "SectionAnnotation", "length": 299, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" } ]
https://en.wikipedia.org/wiki/Persistent_cloaca	disease	Persistent cloaca	A persistent cloaca is a symptom of a complex anorectal congenital disorder, in which the rectum, vagina, and urinary tract meet and fuse, creating a cloaca, a single common channel.	Diagnosis of a female with cloaca should be suspected in a female born with an imperforate anus and small looking genitalia. The diagnosis can be made clinically. Failure to identify a cloaca as being present in a newborn may be dangerous, as more than 90% have associated urological problems. The goal for treatment of a female born with cloaca is to achieve bowel control, urinary control, and sexual function, which includes menstruation, sexual intercourse, and possibly pregnancy. Cloacas probably occur in 1 in 20,000 live births. Cloacas appear in a wide spectrum of variation in females born with the malformation. The single orifice, called a common channel, may occur varying in length from 1 to 10 cm. The length of the common channel can be used to judge prognostic outcomes and technical challenges during surgical repair. A common channel less than 3 cm in length usually has good sphincter muscles and a well-developed sacrum. The prognostic outcomes for this type of cloaca are good for bowel control and urinary function. The surgical repair for this type of cloaca can usually be done by performing posterior sagittal approach without opening of the abdomen. A common channel longer than 3 cm in length usually has poor sphincter muscles and a poor sacrum, suggesting a prognostic outcome for bowel control and urinary function to be less likely. Common channels longer than 3 cm are generally considered more complex and more technically challenging in surgical repair.	[ { "begin": 0, "class": "SectionAnnotation", "length": 537, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 537, "class": "SectionAnnotation", "length": 405, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 942, "class": "SectionAnnotation", "length": 547, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Cephalic_disorder	disease	Cephalic disorder	Cephalic disorders (from the Greek word κεφάλι, meaning "head") are congenital conditions that stem from damage to, or abnormal development of, the budding nervous system. Cephalic means "head" or "head end of the body." Cephalic disorders are not necessarily caused by a single factor, but may be influenced by hereditary or genetic conditions, nutritional deficiencies, or by environmental exposures during pregnancy, such as medication taken by the mother, maternal infection, or exposure to radiation. Some cephalic disorders occur when the cranial sutures (the fibrous joints that connect the bones of the skull) join prematurely. Most cephalic disorders are caused by a disturbance that occurs very early in the development of the fetal nervous system. The human nervous system develops from a small, specialized plate of cells on the surface of the embryo. Early in development, this plate of cells forms the neural tube, a narrow sheath that closes between the third and fourth weeks of pregnancy to form the brain and spinal cord of the embryo. Four main processes are responsible for the development of the nervous system: cell proliferation, the process in which nerve cells divide to form new generations of cells; cell migration, the process in which nerve cells move from their place of origin to the place where they will remain for life; cell differentiation, the process during which cells acquire individual characteristics; and cell death, a natural process in which cells die. Damage to the developing nervous system is a major cause of chronic, disabling disorders and, sometimes, death in infants, children, and even adults. The degree to which damage to the developing nervous system harms the mind and body varies enormously. Many disabilities are mild enough to allow those afflicted to eventually function independently in society. Others are not. Some infants, children, and adults die, others remain totally disabled, and an even larger population is partially disabled, functioning well below normal capacity throughout life. The National Institute of Neurological Disorders and Stroke (NINDS) is currently "conducting and supporting research on normal and abnormal brain and nervous system development."	Where known, the ICD-10 code is listed below. - Anencephaly (Q00.0) - Colpocephaly (ICD10 unknown) - Holoprosencephaly (Q04.2) - Ethmocephaly (ICD10 unknown) - Hydranencephaly (Q04.3) - Iniencephaly (Q00.2) - Lissencephaly (Q04.3) - Megalencephaly (Q04.5) - Microcephaly (Q02) - Porencephaly (Q04.6) - Schizencephaly (Q04.6)	[ { "begin": 0, "class": "SectionAnnotation", "length": 325, "sectionHeading": "More common cephalic disorders", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Creatine_transporter_defect	disease	Creatine transporter defect	Creatine transporter defect (CTD) is an inborn error of creatine metabolism in which creatine is not properly transported to the brain and muscles due to defective creatine transporters. CTD is an X-linked disorder caused by mutations in the SLC6A8 gene. The SLC6A8 gene is located on the short arm of the sex chromosome, Xq28. Hemizygous males with CTD express speech and behavior abnormalities, intellectual disabilities, development delay, seizures, and autistic behavior. Heterozygous females with CTD generally express fewer, less severe symptoms. CTD is one of three different types of cerebral creatine deficiency (CCD). The other two types of CCD are guanidinoacetate methyltransferase (GAMT) deficiency and deficiency. Clinical presentation of CTD is similar to that of GAMT and AGAT deficiency. CTD was first identified in 2001 with the presence of a hemizygous nonsense mutation in the SLC6A8 gene in a male patient.	Generally, the majority of individuals with creatine transporter defect express the following symptoms with varying levels of severity: developmental delay and regression, mental retardation, and abnormalities in expressive and cognitive speech. However, several studies have shown a wider variety of symptoms including, but not limited to attention deficit and hyperactivity with impulsivity, myopathy, hypotonia, semantic-pragmatic language disorder, oral dyspraxia, extrapyramidal movement disorder, constipation, absent speech development, seizures, and epilepsy. Furthermore, symptoms can significantly vary between hemizygous males and heterozygous females, although, symptoms are generally more severe in hemizygous males. Hemizygous males more commonly express seizures, growth deficiency, severe mental retardation, and severe expressive language impairment. Heterozygous females more commonly express mild retardation, impairments to confrontational naming and verbal memory, and learning and behavior problems. CTD is caused by mutations in the SLC6A8 gene, located at Xq28. The SLC6A8 gene contains 13 exons and spreads across 8.5 kb of genomic DNA (gDNA). The presence of hemizygous mutations in males and heterozygous mutations in females on the SLC6A8 gene provides evidence that CTD is inherited in an X-linked recessive manner. This usually results in hemizygous males having severe symptoms, while heterozygous female carriers tend to have less severe and more varying symptoms. The creatine phosphate system is needed for the storage and transmission of phosphate-bound energy in the brain and muscle. The brain and muscle have particularly high metabolic demands, therefore, making creatine a necessary molecule in ATP homeostasis. In regard to the brain, in order for creatine to reach the brain, it must first pass through the blood–brain barrier (BBB). The BBB separates blood from brain interstitial fluid and is, therefore, able to regulate the transfer of nutrients to the brain from the blood. In order to pass through the BBB, creatine utilizes creatine transporter (CRT). When present at the BBB, CRT mediates the passage of creatine from the blood to the brain. When being transported from the blood to the brain, creatine has to constantly move against the creatine concentration gradient that is present at the border between the brain and circulating blood. The diagnosis of CTD is usually suspected based on the clinical presentation of mental retardation, abnormalities in cognitive and expressive speech, and developmental delay. Furthermore, a family history of X-linked intellectual disability, developmental coordination disorder, and seizures is strongly suggestive. Initial screening of CTD involves obtaining a urine sample and measuring the ratio of creatine to creatinine. If the ratio of creatine to creatinine is greater than 1.5, then the presence of CTD is highly likely. This is because a large ratio indicates a high amount of creatine in the urine. This, in turn, indicates inadequate transport of creatine into the brain and muscle. However, the urine screening test often fails in diagnosing heterozygous females. Studies have demonstrated that as a group heterozygous females have significantly decreased cerebral creatine concentration, but that individual heterozygous females often have normal creatine concentrations found in their urine. Therefore, urine screening tests are unreliable as a standard test for diagnosing CTD. A more reliable and sophisticated manner of testing for cerebral creatine concentrations is through in vivo proton magnetic resonance spectroscopy (1H MRS). In vivo 1H MRS uses proton signals to determine the concentration of specific metabolites. This method of testing is more reliable because it provides a fairly accurate measurement of the amount of creatine inside the brain. Similar to urine testing, a drawback of using 1H MRS as a test for CTD is that the results of the test could be attributed to any of the cerebral creatine deficiencies. The most accurate and reliable method of testing for CTD is through DNA sequence analysis of the SLC6A8 gene. DNA analysis of SLC6A8 allows the identification of the location and type of mutation causing the cerebral creatine deficiency. Furthermore, DNA analysis of SLC6A8 is able to prove that a cerebral creatine deficiency is due to CTD and not GAMT or AGAT deficiency. CTD is difficult to treat because the actual transporter responsible for transporting creatine to the brain and muscles is defective. Studies in which oral creatine monohydrate supplements were given to patients with CTD found that patients did not respond to treatment. However, similar studies conducted in which patients that had GAMT or AGAT deficiency were given oral creatine monohydrate supplements found that patient’s clinical symptoms improved. Patients with CTD are unresponsive to oral creatine monohydrate supplements because regardless of the amount of creatine they ingest, the creatine transporter is still defective, and therefore creatine is incapable of being transported across the BBB. Given the major role that the BBB has in the transport of creatine to the brain and unresponsiveness of oral creatine monohydrate supplements in CTD patients, future research will focus on working with the BBB to deliver creatine supplements. However, given the limited number of patients that have been identified with CTD, future treatment strategies must be more effective and efficient when recognizing individuals with CTD.	[ { "begin": 0, "class": "SectionAnnotation", "length": 1022, "sectionHeading": "Signs and Symptoms", "sectionLabel": "disease.symptom" }, { "begin": 1022, "class": "SectionAnnotation", "length": 475, "sectionHeading": "Genetics", "sectionLabel": "disease.genetics" }, { "begin": 1497, "class": "SectionAnnotation", "length": 894, "sectionHeading": "Mechanism", "sectionLabel": "disease.mechanism" }, { "begin": 2391, "class": "SectionAnnotation", "length": 2018, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 4409, "class": "SectionAnnotation", "length": 1136, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Muenke_syndrome	disease	Muenke syndrome	Muenke syndrome, also known as FGFR3-related craniosynostosis, is a human specific condition characterized by the premature closure of certain bones of the skull during development, which affects the shape of the head and face. First described by Maximilian Muenke, the syndrome occurs in about 1 in 30,000 newborns. This condition accounts for an estimated 8 percent of all cases of craniosynostosis.	Many people with this disorder have a premature fusion of skull bones along the coronal suture. Not every case has had craniosynostosis however. Other parts of the skull may be malformed as well. This will usually cause an abnormally shaped head, wide-set eyes, low set ears and flattened cheekbones in these patients. About 5 percent of affected individuals have an enlarged head (macrocephaly). There may also be associated hearing loss in 10-33% of cases and it is important for affected individuals to have hearing tests to check on the possibility of a problem. They can lose about 33-100% of hearing. Most people with this condition have normal intellect, but developmental delay and learning disabilities are possible. The signs and symptoms of Muenke syndrome vary among affected people, and some findings overlap with those seen in other craniosynostosis syndromes. Between 6 percent and 7 percent of people with the gene mutation associated with Muenke syndrome do not have any of the characteristic features of the disorder. Apart from craniosynostosis, it has been suggested that hearing loss, and learning difficulties are common in Muenke syndrome. According to Ulster Medical Journal, most individuals with Muenke syndrome may have limb findings. The most common ocular finding in Muenke syndrome is strabismus as studied by Agochukwu and his researching team. Muenke syndrome is caused by a specific gene mutation in the FGFR3 gene. The mutation arises randomly; there is no full understanding for what causes this mutation. This mutation causes the FGFR3 protein to be overly active; it interferes with normal bone growth, and allows skull bones to fuse prematurely. There is no connection between anything mother did (or did not do) to activate the syndrome. If neither of the parents have Muenke syndrome, chances of having another child with the syndrome are minimal. This condition is inherited in an autosomal dominant pattern. This means if a parent has Muenke syndrome, every newborn has a 50% chance of inheriting the syndrome. Muenke syndrome is inherited in an autosomal dominant pattern. In some cases, an affected person inherits the mutation from one affected parent. If a patient is shown to have Muenke, they have a 50/50 chance of passing it on to their children. Not all cases of Muenke however is obvious. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family. A single mutation in the FGFR3 gene cause this syndrome. The FGFR3 gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. This mutation causes the FGFR3 protein to be overly active, which interferes with normal bone growth and allows the bones of the skull to fuse before they should. As stated by researchers at the University of Washington, Muenke syndrome is inherited in an autosomal dominant manner with incomplete penetrance and variable expressivity.” Prenatal diagnosis for pregnancies at increased risk is possible if the defining mutation has been identified in the family (Agochukwu et.al. 2006). According to the article Craniosynostosis: Molecular Genetics, penetrance is higher in females (87%) than in males (76%). Muenke syndrome is estimated to account for 25%-30% of all genetic causes of craniosynostosis according to the Journal of Anatomy. The diagnosis of Muenke syndrome is suspected bases on abnormal skull shape and a diagnosis of coronal craniosynostosis. In 2006, Agochukwu and her colleagues concluded that “A distinct Muenke syndrome phenotype includes: uni or bilateral coronal synostosis, midface hypoplasia, broad toes, and brachydactyly.” Due to phenotypic overlap and/or mild phenotypes, clinical differentiation of this syndrome may be difficult. The suspected diagnosis is confirmed by a blood test to check for gene mutation. To establish the extent of disease in an individual diagnosed with Muenke syndrome, various evaluations are recommended. The treatment of Muenke syndrome is focused on the correction of the abnormal skull shape and mirrors the treatment of coronal craniosynostosis. The abnormal growth patterns continue throughout the growing years; therefore, intervention, accurate diagnosis, and a customized, expertly carried-out treatment plan should be a primary concern. The treatment of Muenke syndrome is focused on correction of the abnormal skull shape and mirrors the treatment of non-syndromic coronal craniosynostosis. Although the timing of surgery can be highly individualized, surgical correction of the bicoronal craniosynostosis is most often done between 6 and 12 months of age. Surgery is usually performed through a scalp incision that lies concealed within the hair of the head. Your craniofacial surgeon will work in concert with a pediatric neurosurgeon in order to safely remove the bones of the skull. Then, the craniofacial surgeon reshapes and repositions those bones to give a more normal skull shape.	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https://en.wikipedia.org/wiki/Taijin_kyofusho	disease	Taijin kyofusho	Taijin kyofusho (対人恐怖症 taijin kyōfushō, TKS, for taijin kyofusho symptoms) is a Japanese culture-specific syndrome. The term taijin kyofusho translates into the disorder (sho) of fear (kyofu) of interpersonal relations (taijin). Those who have taijin kyofusho are likely to be extremely embarrassed of themselves or fearful of displeasing others when it comes to the functions of their bodies or their appearances. These bodily functions and appearances include their faces, odor, actions, or even looks. They do not want to embarrass other people with their presence. This culture-bound syndrome is a social phobia based on fear and anxiety. The symptoms of this disorder include avoiding social outings and activities, rapid heartbeat, shortness of breath, panic attacks, trembling, and feelings of dread and panic when around people. The causes of this disorder are mainly from emotional trauma or psychological defense mechanism. It is more common in men than women. Lifetime prevalence is estimated at 3–13%.	Taijin kyofusho is commonly described as a form of social anxiety (social phobia), with the person dreading and avoiding social contact, and as a subtype of shinkeishitsu (anxiety disorder). However, instead of a fear of embarrassing themselves or being harshly judged by others because of their social ineptness, sufferers of taijin kyofusho report a fear of offending or harming other people. The focus is thus on avoiding harm to others rather than to oneself. In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), variants of taijin kyofusho (shubo-kyofu and jikoshu-kyofu) are listed under 300.3 (F42) "Other Specified Obsessive-Compulsive and Related Disorders". One source even breaks taijin kyofusho into two different subtypes: neurotic and offensive. The first subtype can be broken into two parts that are classical type and avoidant type. The classical type being afraid of being judged negatively because of physical signs of anxiety and feeling shame due to anxiety. The physical signs that can cause fear of being judged include sweating and tremors. The second subtype deals with people thinking something about them is offensive. Some of their fears include body odor, gas, excessive or insufficient eye contact, blushing, etc. In the official Japanese diagnostic system, taijin kyofusho is subdivided into the following categories: - Sekimen-kyofu ( ), the phobia of blushing (ereuthophobia) - Shubo-kyofu ( ), the phobia of a deformed body, similar to body dysmorphic disorder - Jikoshisen-kyofu ( ), the phobia of eye contact - Jikoshu-kyofu ( ), the phobia of having foul body odor (also termed olfactory reference syndrome, osmophobia or bromidrosiphobia) Japan psychology also recognizes additional types of taijin kyofusho based on severity: - Transient: This type of taijin kyofusho is short-lived and moderately severe. It most commonly appears in teens, but may occur at any time. - Delusional: This is the most common type of taijin kyofusho and is the most similar to social phobia. It is chronic, often begins before the age of 30, and varies in severity from moderate to severe. - Phobic with schizophrenia: This is a more complicated disorder. In such cases, rather than a phobia, taijin kyofusho is a manifestation of schizophrenic symptoms. Typically, this disease is presaged by a childhood history of social inhibition and shyness. It is possible that it could result from a humiliating traumatic experience, or it could emerge from a lifelong onset of the illness that only comes to the surface after time. Clinical data indicates that more males have the condition than females, despite the fact that females scored higher on a social phobia scale than men, and report higher scores on proclivity towards feelings of embarrassment. This differs from Western society where the prevalence of females with social phobias is to some extent greater than that of males. The lifetime prevalence of the disorder falls anywhere between 3% and 13% with changes in severity occurring throughout one's lifetime. It is estimated that about 17% of individuals with taijin kyofusho have fears of releasing foul body odor. A person may be diagnosed with taijin kyofusho if they feel as if their attitudes, behavior, and physical characteristics are inadequate in social situations. As a result of these feelings, they also experience persistent suffering in the form of emotional distress through shame, embarrassment, anxiety, fear, and other tense feelings that occur when confronted with social circumstances. In addition, individuals also worry about being unable to maintain healthy relationships with others. When it comes to socializing, taijin kyofusho sufferers avoid painful social and interpersonal situations, while simultaneously being averse to doing so. Those likely to develop taijin kyofusho have more of a temperamental characteristic of being hypochondriacal. The balance between introversion and extroversion in hypochondriacal temperament is geared more towards introversion. The introversion causes sufferers to focus on themself and problems they have, and by fixating on their weaknesses they become more anxious and depressed. A problem with culture-bound syndromes is that they are resistant to Western-style medicine.} The standard Japanese treatment for taijin kyofusho is Morita therapy, developed by Shoma Morita in the 1910s as a treatment for the Japanese mental disorders taijin kyofusho and shinkeishitsu (nervousness). The original regimen involved patient isolation, enforced bed rest, diary writing, manual labor, and lectures on the importance of self-acceptance and positive endeavor. Since the 1930s, the treatment has been modified to include out-patient and group treatments. This modified version is known as neo-Morita therapy. Medications have also gained acceptance as a treatment option for taijin kyofusho. Other treatments include systematic desensitization, which includes slowly exposing one self to the fear, and learning relaxation skills, to extinguish fear and anxiety. Milnacipran, a serotonin–norepinephrine reuptake inhibitor (SNRI), is currently used in the treatment of taijin kyofusho and has been shown to be efficacious for the related social anxiety disorder. The primary aspect of treating this disorder is getting patients to focus their attention on their body parts and sensations.	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https://en.wikipedia.org/wiki/Clavicle_fracture	disease	Clavicle fracture	A clavicle fracture, also known as a broken collarbone, is a bone fracture of the clavicle. Symptoms typically include pain at the site of the break and a decreased ability to move the affected arm. Complications can include a collection of air in the pleural space surrounding the lung (pneumothorax), injury to the nerves or blood vessels in the area, and an unpleasant appearance. It is often caused by a fall onto a shoulder, outstretched arm, or direct trauma. The fracture can also occur in a baby during childbirth. The middle section of the clavicle is most often involved. Diagnosis is typically based on symptoms and confirmed with X-rays. Clavicle fractures are typically treated by putting the arm in a sling for one or two weeks. Pain medication such as paracetamol (acetaminophen) may be useful. It can take up to five months for the strength of the bone to return to normal. Reasons for surgical repair include an open fracture, involvement of the nerves or blood vessels, or shortening of the clavicle by more than 1.5 cm in a young person. Clavicle fractures most commonly occur in people under the age of 25 and those over the age of 70. Among the younger group males are more often affected than females. In adults they make up about 5% of all fractures while in children they represent about 13% of fractures.	Clavicle fractures are commonly known as a breaking of the collarbone, and they are usually a result of injury or trauma. The most common type of fracture occurs when a person falls horizontally on the shoulder or with an outstretched hand. A direct hit to the collarbone can also cause a break. In most cases, the direct hit occurs from the lateral side towards the medial side of the bone. The muscles involved in clavicle fractures include the deltoid, trapezius, subclavius, sternocleidomastoid, sternohyoid, and pectoralis major muscles. The ligaments involved include the conoid ligament and trapezoid ligament. Incidents that may lead to a clavicle fracture include automobile accidents, biking accidents (especially common in mountain biking), horizontal falls on the shoulder joint, or contact sports such as football, rugby, hurling, or wrestling. It is most often fractured in the middle third of its length which is its weakest point. The lateral fragment is depressed by the weight of the arm and is pulled medially and forward by the strong adductor muscles of the shoulder joint, especially the pectoralis major. The part of the clavicle near the center of the body is tilted upwards by the sternocleidomastoid muscle. Children and infants are particularly prone to it. Newborns often present clavicle fractures following a difficult delivery. After fracture of the clavicle, the sternocleidomastoid muscle elevates the medial fragment of the bone. The trapezius muscle is unable to hold up the distal fragment owing to the weight of the upper limb, thus the shoulder droops. The adductor muscles of the arm, such as the pectoralis major, may pull the distal fragment medially, causing the bone fragments to override. The clavicle is the bone that connects the trunk of the body to the arm, and it is located directly above the first rib. A clavicle is located on each side of the front, upper part of the chest. The clavicle consists of a medial end, a shaft, and a lateral end. The medial end connects with the manubrium of the sternum and gives attachments to the fibrous capsule of the sternoclavicular joint, articular disc, and interclavicular ligament. The lateral end connects at the acromion of the scapula which is referred to as the acromioclavicular joint. The clavicle forms a slight S-shaped curve where it curves from the sternal end laterally and anteriorly for near half its length, then forming a posterior curve to the acromion of the scapula. The basic method to check for a clavicle fracture is by an X-ray of the clavicle to determine the fracture type and extent of injury. In former times, X-rays were taken of both clavicle bones for comparison purposes. Due to the curved shape in a tilted plane X-rays are typically oriented with ~15° upwards facing tilt from the front. In more severe cases, a computerized tomography (CT) or magnetic resonance imaging (MRI) scan is taken. However, the standard method of diagnosis through ultrasound imaging performed in the emergency room may be equally accurate in children. Medication can be prescribed to ease the pain. Antibiotics and tetanus vaccination may be used if the bone breaks through the skin. Often, they are treated without surgery. In severe cases, surgery may be done. The arm must be supported by use of a splint or sling to keep the joint stable and decrease the risk of further damage. Usually, a figure-of-eight splint that wraps the shoulders to keep them forced back is used and the arm is placed in a clavicle strap for comfort. Current practice is generally to provide a sling, and pain relief, and to allow the bone to heal itself, monitoring progress with X-rays every week or few weeks. Surgery is employed in 5–10% of cases. However, a recent study supports primary plate fixation of completely displaced midshaft clavicular fractures in active adult patients. If the fracture is at the lateral end, the risk of nonunion is greater than if the fracture is of the shaft. The evidence for different types of surgery for breaks of the middle part of the clavicle is poor as of 2015. Surgery is considered when one or more of the following conditions presents. - Comminution with separation (bone is broken into multiple pieces) - Significant foreshortening of the clavicle (indicated by shoulder forward) - Skin penetration (open fracture) - Associated nervous and vascular trauma (brachial plexus or supraclavicular nerves) - Nonunion after several months (3–6 months, typically) - Distal third fractures (high risk of nonunion) A discontinuity in the bone shape often results from a clavicular fracture, visible through the skin, if not treated with surgery. Surgical procedures often call for open reduction internal [plate] fixation where an anatomically shaped titanium or steel plate is affixed along the superior aspect of the bone by several screws. In some cases, the plate may be removed after healing, but this is very rarely required (based on nerve interaction or tissue aggravation), and typically considered an elective procedure. In cases when surgery is indicated, the surgery of choice is elastic TEN intramedullary nailing. These devices are implanted within the clavicle's canal to support the bone from the inside. Typical surgical complications are infection, neurological symptoms distal the incision (sometimes to the extremity), and nonunion of the bone (failure of the bone to properly fuse together). Healing time varies based on age, health, complexity, and location of the break, as well as the bone displacement. For adults, a minimum of 2–6 weeks of sling immobilization is normally employed to allow initial bone and soft tissue healing; teenagers require slightly less, while children can often achieve the same level in two weeks. During this period, patients may remove the sling to practice passive pendulum range of motion exercises to reduce atrophy in the elbow and shoulder, but they are minimized to 15–20° off vertical. Depending on the severity of fracture, a person can begin to use the arm if comfortable with movement and no pain results. The final goal is to be able to have full range of motion with no pain; therefore, if any pain occurs, allowing for more recovery time is best. Depending on severity of the fracture, athletes involved in contact sports may need a longer period of rest to heal to avoid refracturing bone. A person should be able to return unrestricted to any sports or work by 3 months after the injury. Clavicle fractures occur at 30–64 cases per 100,000 a year and are responsible for 2.6–5.0% of all fractures. This type of fracture occurs more often in males. About half of all clavicle fractures occur in children under the age of seven and is the most common pediatric fracture. Clavicle fractures involve roughly 5% of all fractures seen in hospital emergency admissions. Clavicles are the most commonly broken bone in the human body. Hippocrates, 4th century BC: When, then, a [clavicle] fracture has recently taken place, the patients attach much importance to it, as supposing the mischief greater than it really is, and the physicians bestow great pains in order that it may be properly bandaged; but in a little time the patients, having no pain, nor finding any impediment to their walking or eating, become negligent; and the physicians finding they cannot make the parts look well, take themselves off, and are not sorry at the neglect of the patient, and in the meantime the callus is quickly formed. The management of skeletal injuries in ancient Egypt – Collar bone: "If thou examinest a man having a break in his collar bone and shouldst thou find his collar bone short and separated from its fellow, I will treat. Place him prostrate on his back with something folded between his shoulder blades; thou shouldst spread out with his two shoulders to stretch apart his collar bone until the break falls in its place."	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https://en.wikipedia.org/wiki/Uterine_fibroid	disease	Uterine fibroid	Uterine fibroids, also known as uterine leiomyomas or fibroids, are benign smooth muscle tumors of the uterus. Most women have no symptoms while others may have painful or heavy periods. If large enough, they may push on the bladder causing a frequent need to urinate. They may also cause pain during sex or lower back pain. A woman can have one uterine fibroid or many. Occasionally, fibroids may make it difficult to become pregnant, although this is uncommon. The exact cause of uterine fibroids is unclear. However, fibroids run in families and appear to be partly determined by hormone levels. Risk factors include obesity and eating red meat. Diagnosis can be performed by pelvic examination or medical imaging. Treatment is typically not needed if there are no symptoms. NSAIDs, such as ibuprofen, may help with pain and bleeding while paracetamol (acetaminophen) may help with pain. Iron supplements may be needed in those with heavy periods. Medications of the gonadotropin releasing hormone agonist class may decrease the size of the fibroids but are expensive and associated with side effects. If greater symptoms are present, surgery to remove the fibroid or uterus may help. Uterine artery embolization may also help. Cancerous versions of fibroids are very rare and are known as leiomyosarcomas. They do not appear to develop from benign fibroids. About 20% to 80% of women develop fibroids by the age of 50. In 2013, it was estimated that 171 million women were affected. They are typically found during the middle and later reproductive years. After menopause, they usually decrease in size. In the United States, uterine fibroids are a common reason for surgical removal of the uterus.	Some women with uterine fibroids do not have symptoms. Abdominal pain, anemia and increased bleeding can indicate the presence of fibroids. There may also be pain during intercourse, depending on the location of the fibroid. During pregnancy, they may also be the cause of miscarriage, bleeding, premature labor, or interference with the position of the fetus. A uterine fibroid can cause rectal pressure. The abdomen can grow larger mimicking the appearance of pregnancy. Some large fibroids can extend out through the cervix and vagina. While fibroids are common, they are not a typical cause for infertility, accounting for about 3% of reasons why a woman may not be able to have a child. The majority of women with uterine fibroids will have normal pregnancy outcomes. In cases of intercurrent uterine fibroids in infertility, a fibroid is typically located in a submucosal position and it is thought that this location may interfere with the function of the lining and the ability of the embryo to implant. Some risk factors associated with the development of uterine fibroids are modifiable. Fibroids are more common in obese women. Fibroids are dependent on estrogen and progesterone to grow and therefore relevant only during the reproductive years. Diets high in fruits and vegetables tend to lower the risk of developing fibroids. Fruits, especially citrus, have a greater protective benefit than vegetables. Normal dietary levels of vitamin D is shown to reduce the risk of developing fibroids. No protective benefit has been found with the consumption of folate, whole grains, soy products, or fiber. No association between the consumption of fat, eggs, dairy products has been shown to increase the risk of fibroids. Fifty percent of uterine fibroids demonstrate a genetic abnormality. Often a translocation is found on some chromosomes. Fibroids are partly genetic. If a mother had fibroids, risk in the daughter is about three times higher than average. Researchers have completed profiling of global gene expression for uterine fibroids. They found that only a few specific genes or cytogenetic deviations are associated with fibroids. 80-85% of fibroids have a mutation in the mediator complex subunit 12 (MED12) gene. A syndrome (Reed's syndrome) that causes uterine leiomyomata along with cutaneous leiomyomata and renal cell cancer has been reported. This is associated with a mutation in the gene that produces the enzyme fumarate hydratase, located on the long arm of chromosome 1 (1q42.3-43). Inheritance is autosomal dominant. Fibroids are a type of uterine leiomyoma. Fibroids grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the abdominal wall. Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus) and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active. The appearance of prominent nucleoli with perinucleolar halos should alert the pathologist to investigate the possibility of the extremely rare hereditary leiomyomatosis and renal cell cancer (Reed) syndrome. Growth and location are the main factors that determine if a fibroid leads to symptoms and problems. A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows: - Intramural fibroids are located within the muscular wall of the uterus and are the most common type. Unless they are large, they may be asymptomatic. Intramural fibroids begin as small nodules in the muscular wall of the uterus. With time, intramural fibroids may expand inwards, causing distortion and elongation of the uterine cavity. - Subserosal fibroids are located on the surface of the uterus. They can also grow outward from the surface and remain attached by a small piece of tissue and then are called pedunculated fibroids. These pedunculated growths can actually detach from the uterus to become a parasitic leiomyoma. - Submucosal fibroids are located in the muscle beneath the endometrium of the uterus and distort the uterine cavity; even small lesions in this location may lead to bleeding and infertility. A pedunculated lesion within the cavity is termed an intracavitary fibroid and can be passed through the cervix. - Cervical fibroids are located in the wall of the cervix (neck of the uterus). Rarely, fibroids are found in the supporting structures (round ligament, broad ligament, or uterosacral ligament) of the uterus that also contain smooth muscle tissue. Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes. They tend to calcify after menopause. If the uterus contains too many to count, it is referred to as diffuse uterine leiomyomatosis. Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizing leiomyoma. They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with an increased risk of this complication. There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location. - In leiomyoma with vascular invasion, an ordinary-appearing fibroid invades into a vessel but there is no risk of recurrence. - In intravenous leiomyomatosis, leiomyomata grow in veins with uterine fibroids as their source. Involvement of the heart can be fatal. - In benign metastasizing leiomyoma, leiomyomata grow in more distant sites such as the lungs and lymph nodes. The source is not entirely clear. Pulmonary involvement can be fatal. - In disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on the peritoneal and omental surfaces, with uterine fibroids as their source. This can simulate a malignant tumor but behaves benignly. Fibroids are monoclonal tumors and approximately 40 to 50% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids. The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth. It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signaling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signaling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1. Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium. TGIF is a potential repressor of TGF-β pathways in myometrial cells. Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that fibroids can convert circulating androstenedione into estradiol. Similar mechanism of action has been elucidated in endometriosis and other endometrial diseases. Aromatase inhibitors are currently considered for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is particularly pronounced in African-American women. Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy compared to dizygotic twins. Expansion of uterine fibroids occurs by a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix. A small population of the cells in a uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor α and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signaling. The presence of a uterine fibroid versus an adnexal tumor is made. Fibroids can be mistaken for ovarian neoplasms. An uncommon tumor which may be mistaken for a fibroid is Sarcoma botryoides. It is more common in children and adolescents. Like a fibroid, it can also protrude from the vagina and is distinguished from fibroids. While palpation used in a pelvic examination can typically identify the presence of larger fibroids, gynecologic ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. The location can be determined and dimensions of the lesion measured. Also, magnetic resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the uterus. Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine leiomyosarcoma, however, the latter is quite rare. Fast growth or unexpected growth, such as enlargement of a lesion after menopause, raise the level of suspicion that the lesion might be a sarcoma. Also, with advanced malignant lesions, there may be evidence of local invasion. A biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis after ultrasounds and MRI imaging, surgery is generally indicated. Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine cavity are hysterosalpingography or sonohysterography. Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects gastrointestinal problems such as constipation and bloatedness are possible. Compression of the ureter may lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause infertility. Adenomyosis may be mistaken for or coexist with fibroids. In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop. In extremely rare cases uterine fibroids may present as part or early symptom of the hereditary leiomyomatosis and renal cell cancer syndrome. Most fibroids do not require treatment unless they are causing symptoms. After menopause fibroids shrink and it is unusual for them to cause problems. Symptomatic uterine fibroids can be treated by: - medication to control symptoms - medication aimed at shrinking tumors - ultrasound fibroid destruction - myomectomy or radio frequency ablation - hysterectomy - uterine artery embolization In those who have symptoms uterine artery embolization and surgical options have similar outcomes with respect to satisfaction. A number of medications may be used to control symptoms. NSAIDs can be used to reduce painful menstrual periods. Oral contraceptive pills may be prescribed to reduce uterine bleeding and cramps. Anemia may be treated with iron supplementation. Levonorgestrel intrauterine devices are effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically few as the levonorgestrel (a progestin) is released in low concentration locally. While most levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported good results specifically for women with fibroids including a substantial regression of fibroids. Cabergoline in a moderate and well-tolerated dose has been shown in two studies to shrink fibroids effectively. The mechanism of action responsible for how cabergoline shrinks fibroids is unclear. Ulipristal acetate is a synthetic selective progesterone receptor modulator (SPRM) that has tentative evidence to support its use for presurgical treatment of fibroids with low side-effects. Long-term UPA-treated fibroids have shown volume reduction of about 70%. In some cases UPA alone is used to relieve symptoms without surgery. Danazol is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing. Gonadotropin-releasing hormone analogs cause temporary regression of fibroids by decreasing estrogen levels. Because of the limitations and side effects of this medication, it is rarely recommended other than for preoperative use to shrink the size of the fibroids and uterus before surgery. It is typically used for a maximum of 6 months or less because after longer use they could cause osteoporosis and other typically postmenopausal complications. The main side effects are transient postmenopausal symptoms. In many cases the fibroids will regrow after cessation of treatment, however, significant benefits may persist for much longer in some cases. Several variations are possible, such as GnRH agonists with add-back regimens intended to decrease the adverse effects of estrogen deficiency. Several add-back regimes are possible, tibolone, raloxifene, progestogens alone, estrogen alone, and combined estrogens and progestogens. Progesterone antagonists such as mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting. Fibroid growth has recurred after antiprogestin treatment was stopped. Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids. However, fibroid growth has recurred after treatment was stopped. Experience from experimental aromatase inhibitor treatment of endometriosis indicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor. Uterine artery embolization (UAE) is a noninvasive procedure that blocks of blood flow to fibroids and thus can treat them. Long term outcomes with respect to how happy people are with the procedure are similar to that of surgery. There is tentative evidence that traditional surgery may result in better fertility. One review found that UAE doubles the future risk of miscarriage. UAE also appears to require more repeat procedures than if surgery was done initially. A person will usually recover from the procedure within a few days. Uterine artery ligation, sometimes also laparoscopic occlusion of uterine arteries are minimally invasive methods to limit blood supply of the uterus by a small surgery that can be performed transvaginally or laparoscopically. The principal mechanism of action may be similar like in UAE but is easier to perform and fewer side effects are expected. Myomectomy is a surgery to remove one or more fibroids. It is usually recommended when more conservative treatment options fail for women who want fertility preserving surgery or who want to retain the uterus. There are three types of myomectomy: - In a hysteroscopic myomectomy (also called transcervical resection), the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device. - A laparoscopic myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy leads to lower morbidity rates and faster recovery than does laparotomic myomectomy. - A laparotomic myomectomy (also known as an open or abdominal myomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus. Laparoscopic myomectomy has less pain and shorter time in hospital than open surgery. Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US. Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids. Radiofrequency ablation is a minimally invasive treatments for fibroids. In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy. Magnetic resonance guided focused ultrasound, is a non-invasive intervention (requiring no incision) that uses high intensity focused ultrasound waves to destroy tissue in combination with magnetic resonance imaging (MRI), which guides and monitors the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using MR thermal imaging. Patients who have symptomatic fibroids, who desire a non-invasive treatment option and who do not have contraindications for MRI are candidates for MRgFUS. About 60% of patients qualify. It is an outpatient procedure and takes one to three hours depending on the size of the fibroids. It is safe and about 75% effective. Symptomatic improvement is sustained for two plus years. Need for additional treatment varies from 16-20% and is largely dependent on the amount of fibroid that can be safely ablated; the higher the ablated volume, the lower the re-treatment rate. There are currently no randomized trial between MRgFUS and UAE. A multi-center trial is underway to investigate the efficacy of MRgFUS vs. UAE. About 1 out of 1000 lesions are or become malignant, typically as a leiomyosarcoma on histology. A sign that a lesion may be malignant is growth after menopause. There is no consensus among pathologists regarding the transformation of leiomyoma into a sarcoma. There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location. See extrauterine fibroids. About 20% to 80% of women develop fibroids by the age of 50. Globally in 2013 it was estimated that 171 million women were affected. They are typically found during the middle and later reproductive years. After menopause they usually decrease in size. Surgery to remove uterine fibroids occurs more frequently in women in "higher social classes". Adolescents develop unterine fibroids much less frequently than older women. Up to 50% of women with uterine fibroids have no symptoms. The prevalence of uterine fibroids among teenagers is 0.4%. The incidence of uterine fibroids in Europe is thought to be lower than the incidence in the US. Eighty percent of African-American women will develop benign uterine fibroid tumors by their late 40s, according to the National Institute of Environmental Health Sciences. African-American women are two to three times more likely to get fibroids than Caucasian women. In African-American women fibroids seem to occur at a younger age, grow more quickly, and are more likely to cause symptoms. This leads to higher rates of surgery for African Americans, both myomectomy, and hysterectomy. Increased risk of fibroids in African- Americans causes them to fare worse in in-vitro fertility treatments and raises their risk of premature births and delivery by Cesarean section. It is unclear why fibroids are more common in African American women. Some studies suggest that black women who are obese and who have high blood pressure are more likely to have fibroids. Other suggested causes include the tendency of African American women to consume food with less than the daily requirements for vitamin D. The 2005 S.1289 bill was read twice and referred to the committee on Health, Labor, and Pensions but never passed for a Senate or House vote. The proposed Uterine Fibroid Research and Education Act of 2005 mentioned that $5 billion is spent annually on hysterectomy surgeries each year, which affect 22% of African Americans and 7% of Caucasian women. The bill also called for more funding for research and educational purposes. It also states that of the $28 billion issued to NIH, $5 million was allocated for uterine fibroids in 2004. Uterine fibroids are rare in other mammals, although they have been observed in certain dogs and Baltic grey seals. Selective progesterone receptor modulators, such as progenta, have been under investigation. Another selective progesterone receptor modulator asoprisnil is being tested with promising results as a possible use as a treatment for fibroids, intended to provide the advantages of progesterone antagonists without their adverse effects. Low dietary intake of vitamin D is associated with the development of uterine fibroids.	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https://en.wikipedia.org/wiki/Paroxysmal_extreme_pain_disorder	disease	Paroxysmal extreme pain disorder	Paroxysmal extreme pain disorder (PEPD), originally named familial rectal pain syndrome, is a rare disorder whose most notable features are pain in the mandibular, ocular and rectal areas as well as flushing. PEPD often first manifests at the beginning of life, perhaps even in utero, with symptoms persisting throughout life. PEPD symptoms are reminiscent of primary erythromelalgia, as both result in flushing and episodic pain, though pain is typically present in the extremities for primary erythromelalgia. Both of these disorders have recently been shown to be allelic, both caused by mutations in the voltage-gated sodium channel Na1.7 encoded by the gene SCN9A. A different mutation in "SCN9A" causes congenital insensitivity to pain.	The most distinctive feature of PEPD is episodic burning pain of the rectum, ocular, and mandibular regions. It should be stressed that while pain often originates or is centered in these areas it can also spread or be diffuse in nature. Pain experienced by patients with this disorder should not be underestimated as women with the disorder who have also given birth describe PEPD pain as worse than labor pain. Concomitant with this pain is typically flushing, often in an area associated with the pain. During attacks in infants, the child often looks startled or terrified and can scream inconsolably. These attacks can be precipitated by injections, defecation, wiping of the perineum, eating, or the consumption of oral medication. When attacks occur due to such precipitation, pain and flushing are often present in the area of attack precipitation, though symptoms may also be diffuse in nature. Other symptoms may include hypersalivation when attacks are localized in the mandibular region, or leg weakness after foot trauma. A prominent non-physical symptom are tonic non-epileptic seizures. Such seizures are more common in infancy and childhood than during adulthood. In older children, inconsolable screaming usually precedes such attack, followed by apnea, paleness, and stiffness. Such stiffness can last from seconds to a few minutes. Attack precipitants are usually physical in nature, such as defecation, eating, or taking medicine. Some less common precipitants are micturition, coitus, and painful stimuli. There are also non-physical precipitants, such as the thought or sight of food. In general attacks tend to occur in the precipitated area, though this is not always the case. While some individuals have described a build-up to attacks, in general they tend to be abrupt. The duration of these attacks can be from a few seconds to two hours. Patients are largely normal between attacks. The only notable interictal problem is constipation, likely due to apprehension of precipitating an attack. This symptom often decreases with age, likely due to coping mechanisms such as the use of stool softeners. The voltage-gated sodium channel Na1.7 is expressed in nociceptive and sympathetic neurons, where it aids in action potential creation and regulation. The mutations in this gene that have received study all alter the channel's ability to inactivate. Sodium channel inactivation is vital for the proper cessation of action potentials. The decreased inactivation caused by these mutations, then, is expected to cause prolonged action potentials and repetitive firing. Such altered firing will cause increased pain sensation and increased sympathetic nervous system activity, producing the phenotype observed in patients with PEPD. There are a total of 8 mutations that account for the disorder in 8 of 14 studied families. These mutations are clustered in four regions throughout the channel: the linker between domains 2 and 3 (D2-3), the intracellular segment linking segments 4 and 5 in domain 3 (D3S4-5), the linker between domains 3 and 4 (D3-4) and the intracellular segment linking segments 4 and 5 in domain 4 (D4S4-5). The mutations in the D3S4-5 region (I1461T, F1462V and T1461I) are located in or next to an IFM motif that is conserved across all voltage-gated sodium channels. Mutagenesis studies of this region have shown that it acts as part of the inactivation gate, pivoting to block the central pore. Not surprisingly then, the two of these mutations that have received further study show incomplete inactivation. When the IFM motif pivots to block the central pore it interacts with residues in the D3S4-5 region. There are three mutations in this region (V1298F, F1298D and V1299F) that are believed to alter the interaction with the inactivation gate. While this region has been studied by mutagenesis these specific mutations have not all received attention, though they are expected to produce changes similar to the aforementioned IFM region mutations. The M1627K mutation in the D4S4-5 region may also affect a residue involved in interacting with the IFM inactivation motif. This would explain the observed alteration of inactivation and the broadening of a window current. One of the affected families with the R996C mutation, pedigree 12, has a single individual who also has the V1298D mutation. The individual in this family with the compound mutation is the most severely affected, suggesting that the R996C mutation may cause a less severe phenotype. The less severe phenotype of the pedigree 4 family is in concordance with this theory. It is unclear how the R996C mutation affects channel function. Hematological, biochemical and metabolic investigations on blood and urine between attacks are normal, as are karyotyping and EKG recordings. EKG recordings during attacks show sinus tachycardia. CT, MRI, EMG and nerve conduction studies produce normal results. EEG recordings are normal between attacks but show early-onset tachycardia during attacks. On the Neuropathic Pain Questionnaire patients indicated that pain during attacks is extremely unpleasant and typically felt deep, though also superficial on occasion. Aside from presentation of typical symptoms (see Signs and symptoms above) mutation of the gene SCN9A aids in appropriate diagnosis as this gene is mutated in 8 of 14 studied families. Carbamazepine is at least partly effective at reducing the number or severity of attacks in the majority of PEPD patients. High doses of this drug may be required, perhaps explaining the lack of effect in some individuals. While other anti-epileptic drugs, gabapentin and topiramate, have limited effect in some patients, they have not been shown to be generally effective. Opiate derived analgesics are also largely ineffective, with only sporadic cases of beneficial effect. PEPD is an extremely rare disorder with only 15 known affected families. There are some cases, however, of individuals originally diagnosed with epilepsy who are later determined to have PEPD. This suggests that rates of PEPD may be higher than currently believed. PEPD was originally described by Hayden and Grossman in 1959. At that time it was not given a specific name. A later report, by Dugan in 1972, labeled this disorder as familial rectal pain syndrome. This name was used for 33 years, until a consortium of patients and clinicians was formed in the hopes of discovering the genetic cause of PEPD. During this process a number of patients expressed dissatisfaction with the name and after considerable discussion between patients and clinicians the name paroxysmal extreme pain disorder was agreed upon in 2005.	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https://en.wikipedia.org/wiki/Seminoma	disease	Seminoma	Seminoma (also known as pure seminoma or classical seminoma) is a germ cell tumor of the testicle or, more rarely, the mediastinum or other extra-gonadal locations. It is a malignant neoplasm and is one of the most treatable and curable cancers, with a survival rate above 95% if discovered in early stages. Testicular seminoma originates in the germinal epithelium of the seminiferous tubules. About half of germ cell tumors of the testicles are seminomas. Treatment usually requires removal of one testicle. However, fertility usually isn't affected. All other sexual functions will remain intact.	The average age of diagnosis is between 15 and 35 years. This is about 5 to 10 years older than men with other germ cell tumors of the testes. In most cases, they produce masses that are readily felt on testicular self-examination; however, in up to 11 percent of cases, there may be no mass able to be felt, or there may be testicular atrophy. Testicular pain is reported in up to one fifth of cases. Low back pain may occur after metastasis to the retroperitoneum. Some cases of seminoma can present as a primary tumour outside the testis, most commonly in the mediastinum. In the ovary, the tumor is called a dysgerminoma, and in non-gonadal sites, particularly the central nervous system, it is called a germinoma. Blood tests may detect the presence of placental alkaline phosphatase (PLAP) in fifty percent of cases. However, PLAP cannot usefully stand alone as a marker for seminoma and contributes little to follow-up, due to its rise with smoking. Human chorionic gonadotropin (hCG) may be elevated in some cases, but this correlates more to the presence of trophoblast cells within the tumour than to the stage of the tumour. A classical or pure seminoma by definition do not cause an elevated serum alpha fetoprotein . Lactate dehydrogenase (LDH) may be the only marker that is elevated in some seminomas. The degree of elevation in the serum LDH has prognostic value in advanced seminoma. The cut surface of the tumour is fleshy and lobulated, and varies in colour from cream to tan to pink. The tumour tends to bulge from the cut surface, and small areas of hemorrhage may be seen. These areas of hemorrhage usually correspond to trophoblastic cell clusters within the tumour. Microscopic examination shows that seminomas are usually composed of either a sheet-like or lobular pattern of cells with a fibrous stromal network. The fibrous septa almost always contain focal lymphocyte inclusions, and granulomas are sometimes seen. The tumour cells themselves typically have abundant clear to pale pink cytoplasm containing abundant glycogen, which is demonstrable with a periodic acid-Schiff (PAS) stain. The nuclei are prominent and usually contain one or two large nucleoli, and have prominent nuclear membranes. Foci of syncytiotrophoblastic cells may be present in varied amounts. The adjacent testicular tissue commonly shows intratubular germ cell neoplasia, and may also show variable spermatocytic maturation arrest. POU2AF1 and PROM1 have been proposed as possible markers. Intratesticular masses that appear suspicious on an ultrasound should be treated with an inguinal orchiectomy. The pathology of the removed testicle and spermatic cord indicate the presence of the seminoma and assist in the staging. Tumors with both seminoma and nonseminoma elements or that occur with the presence of AFP should be treated as nonseminomas. Abdominal CT or MRI scans as well as chest imaging are done to detect for metastasis. The analysis of tumor markers also helps in staging. The preferred treatment for most forms of stage 1 seminoma is active surveillance. Stage 1 seminoma is characterized by the absence of clinical evidence of metastasis. Active surveillance consists of periodic history and physical examinations, tumor marker analysis, and radiographic imaging. Around 85-95% of these cases will require no further treatment. Modern radiotherapy techniques as well as one or two cycles of single-agent carboplatin have been shown to reduce the risk of relapse, but carry the potential of causing delayed side effects. Regardless of treatment strategy, stage 1 seminoma has nearly a 100% cure rate. Stage 2 seminoma is indicated by the presence of retroperitoneal metastasis. Cases require radiotherapy or, in advanced cases, combination chemotherapy. Large residual masses found after chemotherapy may require surgical resection. Second-line treatment is the same as for nonseminomas. Stage 3 seminoma is characterized by the presence of metastasis outside the retroperitoneum—the lungs in "good risk" cases or elsewhere in "intermediate risk" cases. This is treated with combination chemotherapy. Second-line treatment follows nonseminoma protocols. Spermatocytic seminomas are not considered a subtype of seminoma and unlike other germ cell tumours do not arise from intratubular germ cell neoplasia.	[ { "begin": 0, "class": "SectionAnnotation", "length": 719, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 719, "class": "SectionAnnotation", "length": 1776, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 2495, "class": "SectionAnnotation", "length": 1679, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 4174, "class": "SectionAnnotation", "length": 152, "sectionHeading": "Relation to spermatocytic seminoma", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Dactylitis	disease	Dactylitis	Dactylitis or sausage digit is inflammation of an entire digit (a finger or toe), and can be painful. The word dactyl comes from the Greek word "daktylos" meaning "finger". In its medical term, it refers to both the fingers and the toes.	Dactylitis can occur in seronegative arthropathies, such as psoriatic arthritis and ankylosing spondylitis, and in sickle-cell disease as result of a vasoocclusive crisis with bone infarcts, and in infectious conditions including tuberculosis and leprosy. In reactive arthritis, sausage fingers occur due to synovitis. In sickle-cell disease it is manifested for the first time between 6-9 month old infants (as their protective fetal hemoglobin, HbF, is replaced with adult hemoglobin and the disease manifests) and is very often the presenting sign of the disorder.	[ { "begin": 0, "class": "SectionAnnotation", "length": 569, "sectionHeading": "Associated conditions", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Neuromyelitis_optica	disease	Neuromyelitis optica	Neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is a heterogeneous condition consisting of the simultaneous inflammation and demyelination of the optic nerve (optic neuritis) and the spinal cord (myelitis). It can be monophasic or recurrent. Currently at least two different causes are proposed based on the presence of autoantibodies against AQP4. AQP4+ NMO is currently considered an autoimmune disease (autoimmune astrocytopathy, or autoimmune astrocytic channelopathy) in which a person's own immune system attacks the astrocytes of the optic nerves and spinal cord. The cause of the AQP4− variants is unknown. Although inflammation may also affect the brain, the lesions are different from those observed in the related condition, multiple sclerosis. Spinal cord lesions lead to varying degrees of weakness or paralysis in the legs or arms, loss of sensation (including blindness), and/or bladder and bowel dysfunction. Devic's disease is now studied along a collection of similar diseases called "Neuromyelitis optica spectrum diseases". Some cases of this spectrum resemble multiple sclerosis (MS) in several ways, but require a different course of treatment for optimal results. In 2004, NMO-IgG (currently known as Anti-AQP IgG) was first described leading to the distinction between positive and negative cases. In Anti-AQP positive variants, CNS astrocytes, which are the basis for the glymphatic system are the target of the autoimmune attack. NMO-IgG-negative cases are less understood. It seems currently that astrocytes are spared in these IgG negative cases.	The main symptoms of Devic's disease are loss of vision and spinal cord function. Optic neuritis may manifest as visual impairment with decreased visual acuity, although visual field defects, or loss of color vision may occur in isolation or prior to formal loss of acuity. Spinal cord dysfunction can lead to muscle weakness, reduced sensation, or loss of bladder and bowel control. The typical patient has an acute and severe spastic weakness of the legs (paraparesis) or all four limbs (quadriparesis) with sensory signs, often accompanied by loss of bladder control. Devic's disease has been associated with many systemic diseases, based on anecdotal evidence of some Devic's disease patients with a comorbid condition. Such conditions include: collagen vascular diseases, autoantibody syndromes, infections with varicella-zoster virus, Epstein–Barr virus, and HIV, and exposure to clioquinol and antituberculosis drugs. The discovery of NMO-IgG has opened a new way into the research for the causes. Currently two principal causes are accepted: - In NMO-IgG positive patients, the cause of the neuromyelitis optica (understood as the syndrome) is an autoimmune aquaporin-4 channelopathy, due to these specific autoantibodies. In these cases, astrocytes are the victims of the autoimmune attack. - In NMO-IgG negative patients, or at least a subset of them, the cause is an antiMOG associated encephalomyelitis, About the presence of NMO-IgG, some researchers have pointed out that some other cases could be paraneoplastic. It seems also clear that lupus can produce NMO-IgG autoantibodies sometimes, leading to some cases of lupus-derived NMO. In any case, the IgG generation is produced mainly intrathecally. Devic's disease is similar to MS in that the body's immune system attacks the myelin surrounding nerve cells. Unlike standard MS, the attacks are not believed to be mediated by the immune system's T cells, but rather by antibodies called NMO-IgG, or simply NMO antibodies. These antibodies target the protein aquaporin 4 in the cell membranes of astrocytes which acts as a channel for the transport of water across the cell membrane. Aquaporin 4 is found in the astrocytes that surround the blood–brain barrier (BBB), a system responsible for preventing substances in the blood from crossing into the brain. The blood–brain barrier is weakened in Devic's disease, but it is currently unknown how the auto-antibodies cross the BBB. Some reports point to the metalloproteinase-2 and interleukin-6 as culprits for the BBB failure. Most research into the pathology of Devic's disease has focused on the spinal cord. The damage can range from inflammatory demyelination to necrotic damage of the white and grey matters. The inflammatory lesions in Devic's disease have been classified as type II lesions (complement-mediated demyelinization), but they differ from MS pattern II lesions in their prominent perivascular distribution. Therefore, the pattern of inflammation is often quite distinct from that seen in MS. The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic's disease in 2006. Those new guidelines require two absolute criteria plus at least two of three supportive criteria. In 2015 a new review was published by an international panel refining the previous clinical case definition but leaving the main criteria unmodified: Absolute criteria: 1. Optic neuritis 2. Acute myelitis Supportive criteria: 1. Brain MRI not meeting criteria for MS at disease onset 2. Spinal cord MRI with continuous T2-weighted signal abnormality extending over three or more vertebral segments, indicating a relatively large lesion in the spinal cord 3. NMO-IgG seropositive status (The NMO-IgG test checks the existence of antibodies against the aquaporin 4 antigen.) After the development of the NMO-IgG test, the spectrum of disorders comprising Devic's disease was expanded. The spectrum is now believed to consist of: - Standard Devic's disease, according to the diagnostic criteria described above - Limited forms of Devic's disease, such as single or recurrent events of longitudinally extensive myelitis, and bilateral simultaneous or recurrent optic neuritis - Asian optic-spinal MS—this variant can present brain lesions like MS. - Longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease - Optic neuritis or myelitis associated with lesions in specific brain areas such as the hypothalamus, periventricular nucleus, and brainstem - NMO-IgG negative NMO: AQP4 antibody-seronegative NMO poses a diagnostic challenge. Some cases could be related to anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies. Whether Devic's disease is a distinct disease or part of the wide spectrum of multiple sclerosis is debated. Devic's disease differs in that it usually has more severe sequelae after an acute episode than standard MS, MS infrequently presents as transverse myelitis, and oligoclonal bands in the CSF, as well as white matter lesions on brain MRI, are uncommon in Devic's disease, but occur in over 90% of MS patients. Recently, AQP4 has been found to distinguish standard multiple sclerosis from neuromyelitis optica, but as MS is a heterogeneous condition, and some MS cases are reported to be Kir4.1 channelopathies (autoimmunity against the potassium channels) it is still possible to consider NMO as part of the MS spectrum. Besides, some NMO-AQP(−) variants are not astrocytopathic, but demyelinating. Tumefactive demyelinating lesions in NMO are not usual, but they have been reported to appear in several cases mistakenly treated with interferon beta. AQP4-Ab-negative NMO presents problems for diagnosis. The behavior of the oligoclonal bands respect MS can help to establish a more accurate diagnosis. Oligoclonal bands in NMO are rare and they tend to disappear after the attacks, while in MS they are nearly always present and persistent. It is important to notice for differential diagnosis that, though uncommon, it is possible to have longitudinal lesions in MS Other problem for diagnosis is that AQP4ab in MOGab levels can be too low to be detected. Some additional biomarkers have been proposed. Currently, there is no cure for Devic's disease, but symptoms can be treated. Some patients recover, but many are left with impairment of vision and limbs, which can be severe. Attacks are treated with short courses of high dosage intravenous corticosteroids such as methylprednisolone IV. Plasmapheresis can be an effective treatment when attacks progress or do not respond to corticosteroid treatment. Clinical trials for these treatments contain very small numbers, and most are uncontrolled, though some report high success percentage. No controlled trials have established the effectiveness of treatments for the prevention of attacks. Many clinicians agree that long term immunosuppression is required to reduce the frequency and severity of attacks, while others argue the exact opposite. Commonly used immunosuppressant treatments include azathioprine (Imuran) plus prednisone, mycophenolate mofetil plus prednisone, mitoxantrone, intravenous immunoglobulin (IVIG), and cyclophosphamide. Though the disease is known to be auto-antibodies mediated, B-cell depletion has been tried with the monoclonal antibody rituximab, showing good results. Several other disease modifying therapies are being tried. In 2007, Devic's disease was reported to be responsive to glatiramer acetate and to low-dose corticosteroids. Use of Mycophenolate mofetil is also currently under research. Normally, some measure of improvement appears in a few weeks, but residual signs and disability may persist, sometimes severely. The disease can be monophasic, i.e. a single episode with permanent remission. However, at least 85% of patients have a relapsing form of the disease with repeated attacks of transverse myelitis and/or optic neuritis. In patients with the monophasic form, the transverse myelitis and optic neuritis occur simultaneously or within days of each other. On the other hand, patients with the relapsing form are more likely to have weeks or months between the initial attacks, and to have better motor recovery after the initial transverse myelitis event. Relapses usually occur early, with about 55% of patients having a relapse in the first year and 90% in the first five years. It is possible that the relapsing form is related to the antiAQP4+ seropositive status and the monophasic form related to its absence Unlike multiple sclerosis, Devic's disease rarely has a secondary progressive phase in which patients have increasing neurologic decline between attacks without remission. Instead, disabilities arise from the acute attacks. Approximately 20% of patients with monophasic Devic's disease have permanent visual loss, and 30% have permanent paralysis in one or both legs. Among patients with relapsing Devic's disease, 50% have paralysis or blindness within five years. In some patients (33% in one study), transverse myelitis in the cervical spinal cord resulted in respiratory failure and subsequent death. However, the spectrum of Devic's disease has widened due to improved diagnostic criteria, and the options for treatment have improved; as a result, researchers believe these estimates will be lowered. The prevalence and incidence of Devic's disease has not been established, partly because the disease is underrecognized and often confused with MS. Devic's disease is more common in women than men, with women comprising over two-thirds of patients and more than 80% of those with the relapsing form of the disease. A retrospective study found that prevalence of NMOsd was 1.5% inside a random sample of neurological patients, with a MS:NMOsd ratio of 42.7. Among 13 NMOsd patients, 77% had long spinal cord lesions, 38% had severe optic neuritis and 23% had brain or brainstem lesions. Only 56% had clinically definite NMO at follow-up. According to the Walton Centre in England, "NMO seems to be present across the world unlike MS, which has a higher incidence in temperate climates and white races. Africans and Asians especially in Far East may have a higher risk of NMO, although the exact incidence of this disease is unknown, making specific conclusions difficult". Although many people who have Devic's disease were initially misdiagnosed with MS, 35% of African Americans are often misdiagnosed with MS when they really have NMO. Devic's disease is more common in Asians than Caucasians. In fact, Asian optic-spinal MS (which constitutes 30% of the cases of MS in Japan) has been suggested to be identical to Devic's disease (differences between optic-spinal and classic MS in Japanese patients). In the indigenous populations of tropical and subtropical regions, MS is rare, but when it appears, it often takes the form of optic-spinal MS. The majority of Devic's disease patients have no affected relatives, and it is generally regarded as a nonfamilial condition. Since the discovery of AQP4 autoantibody, it has been found that it appears also in patients with NMO-like symptoms that do not fulfill the clinical requirements to be diagnosed NMO (Recurrent and simultaneous optic nerve and spinal cord inflammation). The term NMOSD (NMO Spectrum Disorders) has been designed to allow incorporation of cases associated a non-AQP4 biomarkers. Therefore, it includes all the clinical variants due to anti-AQP4 plus other non-related but clinically similar syndromes like antiMOG associated encephalomyelitis. Some cases with MOG+ and AQP4+ antibodies have been found The collection of these condition has been named "neuromyelitis optica spectrum disorders" (NMSD) and they are expected to respond to the same treatments as standard NMO. Some authors propose to use the name "autoimmune aquaporin-4 channelopathy" for these diseases, while others prefer a more generic term "AQP4-astrocytopathy" that includes also problems in AQP4 with a non-autoimmune origin. First reports on an association of spinal cord and optic nerve disorders appeared in the early 19th century. However, only an 1870 report by Sir Thomas Clifford Allbutt created sustained interest of neurologists and ophthalmologists in this rare syndrome. In 1894, Eugène Devic and his PhD student Fernand Gault described 16 patients who had lost vision in one or both eyes and within weeks developed severe spastic weakness of the limbs, loss of sensation and often bladder control. They recognized these symptoms were the result of inflammation of the optic nerve and spinal cord, respectively. Similar instances of optic neuritis and myelitis were reported, and many believed it constituted a distinct clinical entity. However, some patients had pathology in other parts of the brain, a feature which was more suggestive of acute disseminated encephalomyelitis or MS. In 2002, Mayo Clinic researchers identified an humoral mechanism, targeting a perivascular protein, as the culprit for NMO and in 2004 an unknown specific autoantibody was found. In 2005 they identified the aquaporin 4 protein as the target of the disease, and developed a test to aid in the diagnosis of Devic's disease by detection of an antibody, NMO-IgG, in the blood. Some patients with NMO may be seronegative for NMO-IgG, whilst some patients with NMO-IgG may still not fulfill clinical criteria for NMO thus serological testing is now an important part of the diagnostic procedure and seropositive and seronegative cases are described in a manner similar to myasthenia gravis. According to the Mayo Clinic report, this was the first time a molecular target had been identified for a type of demyelinating inflammatory disease. Since the discovery of AQP-4 involvement, some research studies have focused on targeted treatment aimed at anti-aquaporin 4 antibodies. The most established method for antibody removal is plasmapheresis. A number of drugs are being studied: aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). There is little research into the primary causes of the Anti-AQP4 auto-antibodies. It has been noticed that some cases could be paraneoplastic. In addition, several NMO variants have been discovered with antibodies other than those for AQP4. Six different patterns of damage have been reported in NMO, raising the possibility of five different types of AQP4-negative variants. Currently, the most promising non-aquaporin biomarker is the presence of the anti-MOG autoantibody, which together with the anti-AQP4 can classify the NMO cases in four classes, according to the presence or absence of any of the two antibodies. MOG antibodies are currently considered mostly absent in multiple sclerosis. Therefore, it can be said that anti-MOG is a group contained inside AQP-Negative NMO. The clinical course and the response to therapy is different for these groups, showing a better prognosis for those in the NMO-Ab(−)/MOG-Ab(−) group, and a worse prognosis for those in the NMO-Ab(+)/MOG-Ab(+) group. The MOG-related neuromyelitis optica can be radiologically identified by the conus involvement. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging. Other auto-antibody under research is flotillin. It has been found in seronegative NMO and some MS patients Finally, other proteins under study are Connexin 43 and anti-AQP1 though, as of 2015, there are only initial reports about the involvement of these proteins The group AQP+/MOG+ is very small and it can be considered a coincidence of two independent problems in the same person. Assuming these cases could be verified, currently five different kinds of NMO are being considered: - NMO derived from an autoimmune channelopathy (AQP4-Ab+), around 80% of the cases - NMO derived from an antiMOG associated encephalomyelitis, around 10% of the cases - Connexin-43 NMO - Aquaporin-1 associated NMO - Idiopatic NMO, defined by the absence of all previous antibodies	[ { "begin": 0, "class": "SectionAnnotation", "length": 572, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 572, "class": "SectionAnnotation", "length": 1144, "sectionHeading": "Pathophysiology \| Causes", "sectionLabel": "disease.cause" }, { "begin": 1716, "class": "SectionAnnotation", "length": 1312, "sectionHeading": "Pathophysiology \| Mechanism", "sectionLabel": "disease.mechanism" }, { "begin": 3028, "class": "SectionAnnotation", "length": 765, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 3793, "class": "SectionAnnotation", "length": 1697, "sectionHeading": "Diagnosis \| Variants", "sectionLabel": "disease.diagnosis" }, { "begin": 5490, "class": "SectionAnnotation", "length": 152, "sectionHeading": "Diagnosis \| Tumefactive lesions", "sectionLabel": "disease.diagnosis" }, { "begin": 5642, "class": "SectionAnnotation", "length": 554, "sectionHeading": "Diagnosis \| Differential diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 6196, "class": "SectionAnnotation", "length": 177, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 6373, "class": "SectionAnnotation", "length": 363, "sectionHeading": "Treatment \| Attacks", "sectionLabel": "disease.treatment" }, { "begin": 6736, "class": "SectionAnnotation", "length": 842, "sectionHeading": "Treatment \| Secondary prevention", "sectionLabel": "disease.prevention" }, { "begin": 7578, "class": "SectionAnnotation", "length": 1744, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" }, { "begin": 9322, "class": "SectionAnnotation", "length": 1676, "sectionHeading": "Epidemiology", "sectionLabel": "disease.epidemiology" }, { "begin": 10998, "class": "SectionAnnotation", "length": 995, "sectionHeading": "Neuromyelitis optica spectrum disorders", "sectionLabel": "disease.tomography" }, { "begin": 11993, "class": "SectionAnnotation", "length": 1707, "sectionHeading": "History", "sectionLabel": "disease.history" }, { "begin": 13700, "class": "SectionAnnotation", "length": 769, "sectionHeading": "Research directions", "sectionLabel": "disease.research" }, { "begin": 14469, "class": "SectionAnnotation", "length": 864, "sectionHeading": "Research directions \| MOG-associated NMO", "sectionLabel": "disease.research" }, { "begin": 15333, "class": "SectionAnnotation", "length": 767, "sectionHeading": "Research directions \| Other AQP4-negative variants", "sectionLabel": "disease.research" } ]
https://en.wikipedia.org/wiki/Niemann–Pick_disease,_type_C	disease	Niemann–Pick disease, type C	Niemann–Pick type C is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.	Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications. Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood. Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia). Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with in turning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor. In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia. Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes. Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically. Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein. - Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network. - Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form. - Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1. - Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation. Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2. The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997. - The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes. - The NPC2 gene encodes a protein that binds and transports cholesterol. It has been shown to closely interact with NPC1. Type D Niemann–Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann–Pick type C. Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant. Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterfication and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab and the Mayo Clinic. There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment. Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, psychiatrist, orthopedics, nutrition, physical therapy and occupational therapy. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube). An observational study is underway at the National Institutes of Health to better characterize the natural history of NPC and to attempt to identify markers of disease progression. In 2014 the European Medicines Agency (EMA) granted orphan drug designation to arimoclomol for the treatment of Niemann-Pick type C. This was followed in 2015 by the U.S. Food & Drug Administration (FDA). Dosing in a placebo-controlled phase II/III clinical trial to investigate treatment for Niemann-Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016. Arimoclomol, which is orally administered, induces the heat shock response in cells and is well tolerated in humans. In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel, identical twin girls suffering from Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins' chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice and feline models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy suffering from severe hypervitaminosis A. On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease. On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Children's Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010. On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND through Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both have since begun intrathecal treatments beginning in January 2012. In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients. On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease. On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012. Due to unprecedented collaboration between individual physicians and parents of children afflicted with NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy. On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann–Pick disease, type C was announced by scientists from the NIH's National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). A Phase I clinical trial is currently being conducted at the NIH Clinical Center. One drug that has been tried is Miglustat. Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC. Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone, rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent. The pregnane X receptor has been identified as a potential target. Neural stem cells have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown. Low cholesterol diets are often used, but there is no evidence of efficacy. The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years. Loss of myelin in the central nervous system is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann-Pick disease, e.g. a mutation in the NPC1 gene Niemann-Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased. MRF is a transcription factor of critical importance in the development and maintenance of myelin sheaths. A perturbation of oligodendrocyte maturation and the myelination process might therefore be an underlying mechanism of the neurological deficits. Recent neuroimaging studies have shown patients with Niemann-Pick, type C to have a corpus callosum with microstructural abnormalities. Clear reductions in corpus callosum mean thickness and surface area have been shown when compared to age-matched controls. Also, studies using diffusion tensor imaging have shown marked reductions in callosal fractional anisotropy, which suggests architectural abnormalities based on the directional flow of water. These conclusions suggest that the corpus callosum plays an important role in the disease and should be explored for use as a biomarker of disease progression. Parents of children with NPC are being studied in an attempt to gain insight into the Ebola virus, which uses the protein encoded by NPC1 to enter cells. Researchers have found that mice with one normal copy of the NPC1 gene are more likely to survive Ebola infection than mice with normal two copies of the gene. Mice lacking any normal copy of NPC1 all survived. Studying cells from parents who are NPC disease carriers may allow for better understanding of how changes to the NPC1 gene affect Ebola risk.	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https://en.wikipedia.org/wiki/Primary_aldosteronism	disease	Primary aldosteronism	Primary aldosteronism, also known as primary hyperaldosteronism or Conn's syndrome, is excess production of the hormone aldosterone by the adrenal glands resulting in low renin levels. Often it produces few symptoms. Most people have high blood pressure which may cause poor vision or headaches. Occasionally there may be muscular weakness, muscle spasms, tingling sensations, or excessive urination. Complications include cardiovascular disease such as stroke, myocardial infarction, kidney failure, and abnormal heart rhythms. Primary hyperaldosteronism has a number of causes. About 66% of cases are due to enlargement of both adrenal glands and 33% of cases are due to an adrenal adenoma that produces aldosterone. Other uncommon causes include adrenal cancer and an inherited disorder called familial hyperaldosteronism. Some recommend screening people with high blood pressure who are at increased risk while others recommend screening all people with high blood pressure for the disease. Screening is usually done by measuring the aldosterone-to-renin ratio in the blood with further testing used to confirm positive results. While low blood potassium is classically described this is only present in about a quarter of people. To determine the underlying cause medical imaging is carried out. Some cases may be cured by removing the adenoma by surgery. A single adrenal gland may also be removed in cases where only one is enlarged. In cases due to enlargement of both glands treatment is typically with medications known as aldosterone antagonists such as spironolactone or eplerenone. Other medications for high blood pressure and a low salt diet may also be needed. Some people with familial hyperaldosteronism may be treated with the steroid dexamethasone. Primary aldosteronism is present in about 10% of people with high blood pressure. It occurs more often in women than men. Often it begins in those between 30 and 50 years of age. Conn's syndrome is named after Jerome W. Conn (1907–1994), the American endocrinologist who first described adenomas as a cause of the condition in 1955.	People often have few or no symptoms. They may get occasional muscular weakness, muscle spasms, tingling sensations, or excessive urination. High blood pressure, manifestations of muscle cramps (due to hyperexcitability of neurons secondary to low blood calcium), muscle weakness (due to hypoexcitability of skeletal muscles secondary to hypokalemia), and headaches (due to low blood potassium or high blood pressure) may be seen. Secondary hyperaldosteronism is often related to decreased cardiac output which is associated with elevated renin levels. The condition is due to: - Bilateral idiopathic (micronodular) adrenal hyperplasia (66%) - Adrenal adenoma (Conn's syndrome) (33%) - Primary (unilateral) adrenal hyperplasia—2% of cases - Aldosterone-producing adrenocortical carcinoma—<1% of cases - Familial Hyperaldosteronism (FH) - Glucocorticoid-remediable aldosteronism (FH type I)—<1% of cases - FH type II (APA or IHA)—<2% of cases - Ectopic aldosterone-producing adenoma or carcinoma—< 0.1% of cases 40% of people with an adrenal aldosterone producing adenoma have somatic gain-of-function mutations in a single gene (KCNJ5). This gene is mutated in inherited cases albeit less frequently. These mutations tend to occur in young women with the adenoma in the cortisol secreting zona fasciculata. Adenomas without this mutation tend to occur in older men with resistant hypertension. Aldosterone has effects on most or all cells of the body but, clinically, the most important actions are in the kidney, on cells of the late distal convoluted tubule and medullary collecting duct. In the principal cells aldosterone increases activity of basolateral membrane sodium-potassium ATPase and apical epithelial sodium channels, ENaC, as well as potassium channels, ROMK. These actions increase sodium reabsorption and potassium secretion. Since more sodium is reabsorbed than potassium secreted, it also makes the lumen more electrically negative, causing chloride to follow sodium. Water then follows sodium and chloride by osmosis. In Conn syndrome, these actions cause increased extracellular sodium and fluid volume and reduced extracellular potassium. Aldosterone also acts on intercalated cells to stimulate an apical proton ATPase, causing proton secretion that acidifies urine and alkalizes extracellular fluid. In summary, hyperaldosteronism causes hypernatremic, hypokalemic, metabolic alkalosis. Finer notes on aldosterone include the fact that it stimulates sodium-potassium ATPase in muscle cells, increasing intracellular potassium and also increases sodium reabsorption all along the intestine and nephron, possibly due to widespread stimulation of sodium-potassium ATPase. Finally, epithelial cells of sweat gland ducts and distal colon surface respond exactly the same as the principal cells of the nephron. These responses are important in climate adaptation and as a cause of constipation with elevated aldosterone. The sodium retention leads to plasma volume expansion and elevated blood pressure. The increased blood pressure will lead to increased glomerular filtration rate and cause a decrease in renin release from the granular cells of the juxtaglomerular apparatus in the kidney decreasing sodium reabsorption and returning sodium renal excretion to near normal levels allowing sodium to 'escape' the effect of mineralocorticoids (also known as Aldosterone escape mechanism in primary hyperaldosteronism also contributed to by increased ANP level). If there is a primary hyperaldosteronism, the decreased renin (and subsequent decreased angiotensin II) will not lead to a decrease in aldosterone levels (a very helpful clinical tool in diagnosis of primary hyperaldosteronism). Screening may be considered in people with high blood pressure presenting with low blood potassium, high blood pressure that is difficult to treat, other family members with the same condition, or a mass on the adrenal gland. Measuring aldosterone alone is not considered adequate to diagnose primary hyperaldosteronism. Rather, both renin and aldosterone are measured, and a resultant aldosterone-to-renin ratio is used for case detection. A high aldosterone-to-renin ratio suggests the presence of primary hyperaldosteronism. The diagnosis is made by performing a saline suppression test, ambulatory salt loading test, or fludrocortisone suppression test. If primary hyperaldosteronism is confirmed biochemically, CT scanning or other cross-sectional imaging can confirm the presence of an adrenal abnormality, possibly an adrenal cortical adenoma (aldosteronoma), adrenal carcinoma, bilateral adrenal hyperplasia, or other less common changes. Imaging findings may ultimately lead to other necessary diagnostic studies, such as adrenal venous sampling, to clarify the cause. It is not uncommon for adults to have bilateral sources of aldosterone hypersecretion in the presence of a nonfunctioning adrenal cortical adenoma, making adrenal venous sampling mandatory in cases where surgery is being considered. The diagnosis is best accomplished by an appropriately-trained subspecialist, though primary care providers are critical in recognizing clinical features of primary aldosteronism and obtaining the first blood tests for case detection. Some people only use Conn's syndrome for when it occurs due to an adrenal adenoma (a type of benign tumor). In practice, however, the terms are often used interchangeably, regardless of the underlying physiology. Primary hyperaldosteronism can be mimicked by Liddle syndrome, and by ingestion of licorice and other foods containing glycyrrhizin. In one case report, hypertension and quadriparesis resulted from intoxication with a non-alcoholic pastis (an anise-flavored aperitif containing glycyrrhizinic acid). The treatment for hyperaldosteronism depends on the underlying cause. In people with a single benign tumor (adenoma), surgical removal (adrenalectomy) may be curative. This is usually performed laparoscopically, through several very small incisions. For people with hyperplasia of both glands, successful treatment is often achieved with spironolactone or eplerenone, drugs that block the effect of aldosterone. With its antiandrogen effect, spironolactone drug therapy may have a range of effects in males, including sometimes gynecomastia. These symptoms usually do not occur with eplerenone drug therapy. In the absence of treatment, individuals with hyperaldosteronism often have poorly controlled high blood pressure, which may be associated with increased rates of stroke, heart disease, and kidney failure. With appropriate treatment, the prognosis is excellent. Conn's syndrome is named after Jerome W. Conn (1907–1994), the American endocrinologist who first described the condition at the University of Michigan in 1955.	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https://en.wikipedia.org/wiki/Amusia	disease	Amusia	Amusia is a musical disorder that appears mainly as a defect in processing pitch but also encompasses musical memory and recognition. Two main classifications of amusia exist: acquired amusia, which occurs as a result of brain damage, and congenital amusia, which results from a music-processing anomaly present since birth. Studies have shown that congenital amusia is a deficit in fine-grained pitch discrimination and that 4% of the population suffers from this disorder. Acquired amusia, on the other hand, may take several forms. Patients with brain damage may experience the loss of ability to produce musical sounds while sparing speech, much like aphasics lose speech selectively but can sometimes still sing. Other forms of amusia may affect specific sub-processes of music processing. Current research has demonstrated dissociations between rhythm, melody, and emotional processing of music, and amusia may include impairment of any combination of these skill sets.	Neurologically intact individuals appear to be born musical. Even before they are able to talk, infants show remarkable musical abilities that are similar to those of adults in that they are sensitive to musical scales and a regular tempo. Also, infants are able to differentiate between consonant and dissonant intervals. These perceptual skills indicate that music-specific predispositions exist. Prolonged exposure to music develops and refines these skills. Extensive musical training does not seem to be necessary in the processing of chords and keys. The development of musical competence most likely depends on the encoding of pitch along musical scales and maintaining a regular pulse, both of which are key components in the structure of music and aid in perception, memory, and performance. Also, the encoding of pitch and temporal regularity are both likely to be specialized for music processing. Pitch perception is absolutely crucial to processing music. The use of scales and the organization of scale tones around a central tone (called the tonic) assign particular importance to notes in the scale and cause non-scale notes to sound out of place. This enables the listener to ascertain when a wrong note is played. However, in individuals with amusia, this ability is either compromised or lost entirely. Music-specific neural networks exist in the brain for a variety of music-related tasks. It has been shown that Broca's area is involved in the processing of musical syntax. Furthermore, brain damage can disrupt an individual's ability to tell the difference between tonal and atonal music and detect the presence of wrong notes, but can preserve the individual's ability to assess the distance between pitches and the direction of the pitch. The opposite scenario can also occur, in which the individual loses pitch discrimination capabilities, but can sense and appreciate the tonal context of the work. Distinct neural networks also exist for music memories, singing, and music recognition. Neural networks for music recognition are particularly intriguing. A patient can undergo brain damage that renders him/her unable to recognize familiar melodies that are presented without words. However, the patient maintains the ability to recognize spoken lyrics or words, familiar voices, and environmental sounds. The reverse case is also possible, in which the patient cannot recognize spoken words, but can still recognize familiar melodies. These situations overturn previous claims that speech recognition and music recognition share a single processing system. Instead, it is clear that there are at least two distinct processing modules: one for speech and one for music. Symptoms of amusia are generally categorized as receptive, clinical, or mixed. Symptoms of receptive amusia, sometimes referred to as "musical deafness", include the inability to recognize familiar melodies, the loss of ability to read musical notation, and the inability to detect wrong or out-of tune notes. Clinical, or expressive, symptoms include the loss of ability to sing, write musical notation, and/or play an instrument. A mixed disorder would be a combination of expressive and receptive impairment. Clinical symptoms of acquired amusia are much more variable than those of congenital amusia and are determined by the location and nature of the lesion. Brain injuries may afflict motor or expressive functioning, including the ability to sing, whistle, or hum a tune (oral-expressive amusia), the ability to play an instrument (instrumental amusia or musical apraxia), and the ability to write music (musical agraphia). Additionally, brain damage to the receptive dimension affects the faculty to discriminate tunes (receptive or sensorial amusia), the ability to read music (musical alessia), and the ability to identify songs that were familiar prior to the brain damage (amnesic amusia). Research suggests that patients with amusia also have difficulty when it comes to spatial processing. Amusics performed more quickly than normal individuals on a combined task of both spatial and musical processing tasks, which is most likely due to their deficit. Normal individuals experience interference due to their intact processing of both musical and spatial tasks, while amusics do not. Pitch processing normally depends on the cognitive mechanisms that are usually used to process spatial representations. Those with congenital amusia show impaired performance on discrimination, identification and imitation of sentences with intonational differences in pitch direction in their final word. This suggests that amusia can in subtle ways impair language processing. The diagnosis of amusia requires individuals to detect out-of-key notes in conventional but unfamiliar melodies. A behavioral failure on this test is diagnostic because there is typically no overlap between the distributions of the scores of amusics and controls. Such scores are generally obtained through the Montreal Battery of Evaluation of Amusia (MBEA), which involves a series of tests that evaluate the use of musical characteristics known to contribute to the memory and perception of conventional music. The battery comprises six subtests which assess the ability to discriminate pitch contour, musical scales, pitch intervals, rhythm, meter, and memory. An individual is considered amusic if he/she performs two standard deviations below the mean obtained by musically-competent controls. This musical pitch disorder represents a phenotype that serves to identify the associated neuro-genetic factors. Both MRI-based brain structural analyses and electroencephalography (EEG) are common methods employed to uncover brain anomalies associated with amusia (See Neuroanatomy). Additionally, voxel-based morphometry (VBM) is used to detect anatomical differences between the MRIs of amusic brains and musically intact brains, specifically with respect increased and/or decreased amounts of white and grey matter. There are two general classifications of amusia: congenital amusia and acquired amusia. Congenital amusia, commonly known as tone deafness, refers to a musical disability that cannot be explained by prior brain lesion, hearing loss, cognitive defects, or lack of environmental stimulation, and it affects about 4% of the population. Individuals who suffer from congenital amusia seem to lack the musical predispositions with which most people are born. They are unable to recognize or hum familiar tunes even if they have normal audiometry and above-average intellectual and memory skills. Also, they do not show sensitivity to dissonant chords in a melodic context, which, as discussed earlier, is one of the musical predispositions exhibited by infants. The hallmark of congenital amusia is a deficit in fine-grained pitch discrimination, and this deficit is most apparent when congenital amusics are asked to pick out a wrong note in a given melody. If the distance between two successive pitches is small, congenital amusics are not able to detect a pitch change. As a result of this defect in pitch perception, a lifelong musical impairment may emerge due to a failure to internalize musical scales. A lack of fine-grained pitch discrimination makes it extremely difficult for amusics to enjoy and appreciate music, which consists largely of small pitch changes. Tone-deaf people seem to be disabled only when it comes to music as they can fully interpret the prosody or intonation of human speech. Tone deafness has a strong negative correlation with belonging to societies with tonal languages. This could be evidence that the ability to reproduce and distinguish between notes may be a learned skill; conversely, it may suggest that the genetic predisposition towards accurate pitch discrimination may influence the linguistic development of a population towards tonality. A correlation between allele frequencies and linguistic typological features has been recently discovered, supporting the latter hypothesis. Tone deafness is also associated with other musical-specific impairments such as the inability to keep time with music (beat deafness, or the lack of rhythm), or the inability to remember or recognize a song. These disabilities can appear separately, but some research shows that they are more likely to appear in tone-deaf people. Experienced musicians, such as W. A. Mathieu, have addressed tone deafness in adults as correctable with training. Acquired amusia is a musical disability that shares the same characteristics as congenital amusia, but rather than being inherited, it is the result of brain damage. It is also more common than congenital amusia. While it has been suggested that music is processed by music-specific neural networks in the brain, this view has been broadened to show that music processing also encompasses generic cognitive functions, such as memory, attention, and executive processes. A recent study was conducted to investigate the neural and cognitive mechanisms that underlie acquired amusia and contribute to its recovery. The study was performed on 53 stroke patients with a left or right hemisphere middle cerebral artery (MCA) infarction one week, three months, and six months after the stroke occurred. Amusic subjects were identified one week following their stroke, and over the course of the study, amusics and non-amusics were compared in both brain lesion location and their performances on neuropsychological tests. Results showed that there was no significant difference in the distribution of left and right hemisphere lesions between amusic and non-amusic groups, but that the amusic group had a significantly higher number of lesions to the frontal lobe and auditory cortex. Temporal lobe lesions were also observed in patients with amusia. Amusia is a common occurrence following an ischemic MCA stroke, as evidenced by the 60% of patients who were found to be amusic at the one-week post-stroke stage. While significant recovery takes place over time, amusia can persist for long periods of time. Test results suggest that acquired amusia and its recovery in the post-stroke stage are associated with a variety of cognitive functions, particularly attention, executive functioning, and working memory. Many research studies of individuals with amusia show that a number of cortical regions appear to be involved in processing music. Some report that the primary auditory cortex, secondary auditory cortex, and limbic system are responsible for this faculty, while more recent studies suggest that lesions in other cortical areas, abnormalities in cortical thickness, and deficiency in neural connectivity and brain plasticity may contribute to amusia. While various causes of amusia exist, some general findings that provide insight to the brain mechanisms involved in music processing are discussed below. Studies suggest that the analysis of pitch is primarily controlled by the right temporal region of the brain. The right secondary auditory cortex processes pitch change and manipulation of fine tunes; specifically, this region distinguishes the multiple pitches that characterize melodic tunes as contour (pitch direction) and interval (frequency ratio between successive notes) information. The right superior temporal gyrus recruits and evaluates contour information, while both right and left temporal regions recruit and evaluate interval information. In addition, the right anterolateral part of Heschl's gyrus (primary auditory cortex) is also concerned with processing pitch information. The brain analyzes the temporal (rhythmic) components of music in two ways: (1) it segments the ongoing sequences of music into temporal events based on duration, and (2) it groups those temporal events to understand the underlying beat to music. Studies on rhythmic discrimination reveal that the right temporal auditory cortex is responsible for temporal segmenting, and the left temporal auditory cortex is responsible for temporal grouping. Other studies suggest the participation of motor cortical areas in rhythm perception and production. Therefore, a lack of involvement and networking between bilateral temporal cortices and neural motor centers may contribute to both congenital and acquired amusia. Memory is required in order to process and integrate both melodic and rhythmic aspects of music. Studies suggest that there is a rich interconnection between the right temporal gyrus and frontal cortical areas for working memory in music appreciation. This connection between the temporal and frontal regions of the brain is extremely important since these regions play critical roles in music processing. Changes in the temporal areas of the amusic brain are most likely associated with deficits in pitch perception and other musical characteristics, while changes in the frontal areas are potentially related to deficits in cognitive processing aspects, such as memory, that are needed for musical discrimination tasks. Memory is also concerned with the recognition and internal representation of tunes, which help to identify familiar songs and confer the ability to sing tunes in one's head. The activation of the superior temporal region and left inferior temporal and frontal areas is responsible for the recognition of familiar songs, and the right auditory cortex (a perceptual mechanism) is involved in the internal representation of tunes. These findings suggest that any abnormalities and/or injuries to these regions of the brain could facilitate amusia. In 1825, F. Gall mentioned a "musical organ" in a specific region of the human brain that could be spared or disrupted after a traumatic event resulting in brain damage. In 1865, Jean-Baptiste Bouillaud described the first series of cases that involved the loss of music abilities that were due to brain injury. Later, during the late nineteenth-century, several influential neurologists studied language in an attempt to construct a theory of cognition. While not studied as thoroughly as language, music and visual processing were also studied. In 1888-1890, August Knoblauch produced a cognitive model for music processing and termed it amusia. This model for music processing was the earliest produced. While the possibility that certain individuals may be born with musical deficits is not a new notion, the first documented case of congenital amusia was published relatively recently. The study was conducted with a female volunteer, referred to as Monica, who declared herself to be musically impaired in response to an advertisement in the newspaper. Monica had no psychiatric or neurological history, nor did she have any hearing loss. MRI scans showed no abnormalities. Monica also scored above average on a standard intelligence test, and her working memory was evaluated and found to be normal. However, Monica suffers from a lifelong inability to recognize or perceive music, which has persisted even after involvement with music through church choir and band during her childhood and teenage years. Monica even admits that she does not enjoy listening to music because, to her, it sounds like noise and evokes a stressful response. In order to determine if Monica's disorder is amusia, she was subjected to the MBEA series of tests. One of the tests dealt with Monica's difficulties in discriminating pitch variations in sequential notes. In this test, a pair of melodies was played, and Monica was asked if the second melody in the pair contained a wrong note. Monica's score on this test was well below the average score generated by the control group. Further tests showed that Monica struggles with recognizing highly familiar melodies, but that she has no problems in recognizing the voices of well-known speakers. Thus, it appears that Monica's deficit seems limited to music. Interestingly, a later study showed that not only do amusics experience difficulty in discriminating variations in pitch, but they also exhibit deficits in perceiving patterns in pitch. This finding led to another test that was designed to assess the presence of a deficiency in pitch perception. In this test, Monica heard a sequence of five piano tones of constant pitch followed by a comparison sequence of five piano tones in which the fourth tone could be the same pitch as the other notes in the sequence or a completely different pitch altogether. Monica was asked to respond "yes" if she detected a pitch change on the fourth tone or respond "no" if she could not detect a pitch change. Results show that Monica could barely detect a pitch change as large as two semitones (whole tone), or half steps. While this pitch-processing deficit is extremely severe, it does not seem to include speech intonation. This is because pitch variations in speech are very coarse compared with those used in music. In conclusion, Monica's learning disability arises from a basic problem in pitch discrimination, which is viewed as the origin of congenital amusia. Another interesting question posed about congenital amusia is if it has a genetic origin. A study was conducted to test for the presence of a genetic origin by studying family aggregation of congenital amusia. Family members of amusics were studied, as well as family members of a control group. The study yielded interesting results. Amusia cannot be attributed solely to family environment due to the presence of at least one unaffected sibling in each tested family in the amusic group. Also, music was found to be present to a lesser extent, but not absent, in the environment of the amusic subjects than in that of the musically intact control group. This supports the claim that the occurrence of congenital amusia cannot be explained by a lack of environmental stimulation. Another interesting finding was that the next generation, or the offspring of those with congenital amusia, was more musical. A reason for this might be that musical stimulation for the offspring probably started early in life when their brains were more plastic. Overall, test results support the view that congenital amusia is hereditary. It is likely to be influenced by several genes that interact to increase an individual's susceptibility to its development. However, the fact that the offspring have a lower risk of developing congenital amusia shows that it can be less prevalent when the musical environment is enriched. This stresses the importance that experience-dependent tuning has in the musical pitch system. While it is known that congenital amusia is a disorder characterized by poor pitch perception, a recent study sought to discover to what extent this pitch deficit may compromise singing. In this study, eleven amusic individuals and eleven controls were asked to sing a familiar song using the lyrics first, and then using the syllable "la". Results showed that individuals with congenital amusia were poor singers. They could not maintain a stable pitch, nor could they sing the correct pitch intervals that were written in the music. However, many of the amusic testing subjects were able to sing with the correct rhythm. The results confirmed that the amusics' ability to detect pitch changes influences their level of singing proficiency. The subjects who struggled the most with pitch perception were the most unstable in producing the correct pitch and made several pitch interval and contour errors. However, there were some remarkable exceptions. A couple of amusic individuals were able to sing proficiently despite extremely impaired pitch perception. It is also interesting to compare the results of singing with the lyrics and singing on the syllable "la". Although most of the amusic subjects struggled with maintaining the correct pitch when singing with lyrics, they were able to complete the task. However, when singing the same song on the syllable "la", more than half of the amusic subjects could only sing a few notes. This is due to a poor memory of the musical component of songs. Overall, it was concluded that singing deficiency in amusic individuals might be a result of their pitch perception deficit. However, the existence of amusic individuals who are able to sing proficiently suggests that there may be separate neural pathways for auditory perception and action. Amusia has recently been classified as a learning disability that affects musical abilities. Research suggests that in congenital amusia, younger subjects can be taught tone differentiation techniques. This finding leads researchers to believe that amusia is related to dyslexia and other similar disorders. Research has been shown that amusia may be related to an increase in size of the cerebral cortex, which may be a result of a malformation in cortical development. Diseases such as dyslexia and epilepsy are due to a malformation in cortical development and also lead to an increase in cortical thickness, which leads researchers to believe that congenital amusia may be caused by the identical phenomenon in a different area of the brain. Amusia is also similar to aphasia in that they affect similar areas of the brain near the temporal lobe. Most cases of those with amusia do not show any symptoms of aphasia. However, a number of cases have shown that those who have aphasia can exhibit symptoms of amusia, especially in acquired aphasia. The two are not mutually exclusive and having one does not imply possession of the other. In acquired amusia, inability to perceive music correlates with an inability to perform other higher-level functions. As musical ability improves, so too do the higher cognitive functions which suggests that musical ability is closely related to these higher-level functions, such as memory and learning, mental flexibility, and semantic fluency. Amusia can also be related to aprosody, a disorder in which the sufferer's speech is affected, becoming extremely monotonous. It has been found that both amusia and aprosody can arise from seizures occurring in the non-dominant hemisphere. They can also both arise from lesions to the brain, as can Broca's aphasia come about simultaneously with amusia from injury. There is a relation between musical abilities and the components of speech, however, they are not understood very well. Other than their inability to hear music, which is most likely due to a genetic defect, the rest of an amusic's brain remains normal. The only effect is on the ability to tell different notes apart due to the separation of two key areas in the brain. Most sufferers of amusia describe music as unpleasant. Others simply refer to it as noise and find it annoying. This can have social implications because amusics often try to avoid music, which in many social situations is not an option. In China and other countries in which identical words have different meanings based on pitch, amusia may have a much more pronounced social and emotional impact: difficulty in speaking and understanding the language. Currently, no forms of treatment have proven effective in treating amusia. One study has shown tone differentiation techniques to have some success, however future research on treatment of this disorder will be necessary to verify this technique as an appropriate treatment. Over the past decade, much has been discovered about amusia. However, there remains a great deal more to learn. While a method of treatment for people with amusia has not been defined, tone differentiation techniques have been used on amusic patients with some success. It was found with this research that children reacted positively to these tone differentiation techniques, while adults found the training annoying. However, further research in this direction would aid in determining if this would be a viable treatment option for people with amusia. Additional research can also serve to indicate which processing component in the brain is essential for normal music development. Also, it would be extremely beneficial to investigate musical learning in relation to amusia since this could provide valuable insights into other forms of learning disabilities such as dysphasia and dyslexia.	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https://en.wikipedia.org/wiki/Supernumerary_body_part	disease	Supernumerary body part	Supernumerary body parts are most commonly a congenital disorder involving the growth of an additional part of the body and a deviation from the body plan. Body parts may be easily visible or hidden away, such as internal organs. Many additional body parts form by the same process as conjoined twins: the zygote begins to split but fails to completely separate. This condition may also be a symptom of repeated occurrences of continuous inbreeding in a genetic line.	Specific types of additional body parts include: - Accessory breast – one or more additional breasts - Accessory spleen – one or more additional spleens - Cervical rib – an additional rib - Diphallia - Having two penes/penises. - Hermaphroditism – having both sexes' sex organs - Hyperdontia – additional teeth - Pelvic digit – a bony growth in the soft tissue of the pelvic region - Polycephaly – an extra head - Polydactyly – additional fingers or toes - Polymelia — an extra arm or leg. - Polyorchidism – having three or more testicles - Supernumerary bones – these additional bones are fairly common, particularly in the feet, and are frequently mistaken for fractures on x-rays. - Supernumerary kidney – a third kidney - Supernumerary nipples – an additional nipple - Supernumerary phantom limbs – where the brain acts as though a limb were there, but it is not. - Syndactyly – webbing between the fingers or toes - Uterus didelphys – two vaginal canals and/or uteri Vestigial structures are anatomical structures of organisms in a species which are considered to have lost much or all of their original function through evolution. These body parts can be classed as additional to the required functioning of the body. In human anatomy the vermiform appendix is sometimes classed as a vestigial remnant. Prosthesis is an artificial extension that replaces a body part, and cybernetics is the study of computer technology in relation to organisms which can include replacement or additional body parts. Body integrity identity disorder (BIID) is a psychiatric disorder in which a person thinks that they have one or more additional limbs than they should, despite having two arms and two legs. People with this condition often wish to amputate what they see as additional body parts. A phantom limb is the sensation that a missing limb is still attached to the body. A supernumerary phantom limb is the sensation of having an extra limb or body part despite no such limb actually existing. It is an uncommon syndrome, usually due to some kind of brain injuries in the somatosensory cortex or in some parts of the right hemisphere of the brain, usually due to a stroke in the brain. A chimera is an animal or plant that has two or more different populations of genetically distinct cells that originated in different zygotes that have merged; anatomical structures are typically mixed depending on which cells are prevalent in different body parts, for example plants can have two different types of flowers. A mosaic is a genetic anomaly similar in nature and effects to a chimera: genetically different populations of cells within one organism, originated from some propagated mutation of a single cell rather than from outside sources. In Hindu mythology additional limbs and heads are considered a sign of power. In Greek mythology, Artemis, the goddess of fertility, was sometimes represented as having numerous breasts. This was particularly notable in the cult of Artemis (Diana) celebrated in the ancient city of Ephesus, in modern Turkey. In Japanese mythology, the God of the sea and storms, Susanoo, is sometimes depicted as having a third arm. In Hungarian mythology, six fingers on a hand (polydactyly) is held to be the sign of innate supernatural power (see táltos). In the Bible, Goliath has brothers that have six fingers and six toes.	[ { "begin": 0, "class": "SectionAnnotation", "length": 972, "sectionHeading": "Specific types of occurrence", "sectionLabel": "disease.classification" }, { "begin": 972, "class": "SectionAnnotation", "length": 1770, "sectionHeading": "Related conditions and concepts", "sectionLabel": "disease.other" }, { "begin": 2742, "class": "SectionAnnotation", "length": 614, "sectionHeading": "Mythology", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Nail_disease	disease	Nail disease	A nail disease or onychosis is a disease or deformity of the nail. Although the nail is a structure produced by the skin and is a skin appendage, nail diseases have a distinct classification as they have their own signs and symptoms which may relate to other medical conditions. Some nail conditions that show signs of infection or inflammation may require medical assistance.	Nail inspection can give hints to the internal condition of the body as well. Nail disease can be very subtle and should be evaluated by a dermatologist with a focus in this particular area of medicine. A nail technician may be the first to note a subtle change in nail health. In approximately half of suspected nail fungus cases there is actually no fungal infection, but only some nail dystrophy. Before beginning oral antifungal therapy the health care provider should confirm a fungal infection. Administration of treatment to persons without an infection is unnecessary health care and causes needless exposure to side effects.	[ { "begin": 0, "class": "SectionAnnotation", "length": 279, "sectionHeading": "Nail changes and conditions associated with them", "sectionLabel": "disease.other" }, { "begin": 279, "class": "SectionAnnotation", "length": 356, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Korsakoff's_syndrome	disease	Korsakoff's syndrome	Korsakoff's syndrome is an amnestic disorder caused by thiamine deficiency usually associated prolonged ingestion of alcohol. It is rare among other people but some cases have been observed after bariatric surgeries, when deficiency was not prevented by use of nutritional supplements. This neurological disorder is caused by a lack of thiamine (vitamin B) in the brain, and is also often exacerbated by the neurotoxic effects of alcohol. When Wernicke's encephalopathy accompanies Korsakoff's psychosis the combination is called the Wernicke–Korsakoff syndrome; however, a recognized episode of Wernicke's is not always obvious. The syndrome and psychosis are named after Sergei Korsakoff, a Russian neuropsychiatrist who discovered the syndrome during the late 19th century.	There are seven major symptoms of Korsakoff's syndrome (amnestic-confabulatory syndrome): 1. anterograde amnesia, memory loss for events after the onset of the syndrome 2. retrograde amnesia, memory loss extends back for some time before the onset of the syndrome 3. amnesia of fixation, also known as fixation amnesia (loss of immediate memory, a person being unable to remember events of the past few minutes) 4. confabulation, that is, invented memories which are then taken by the patient as true due to gaps in memory, with such gaps sometimes associated with blackouts 5. minimal content in conversation 6. lack of insight 7. apathy – the patients lose interest in things quickly, and generally appear indifferent to change. Benon R. and LeHuché R. (1920) described the characteristic signs of Korsakoff syndrome with some additional features: confabulation (false memories), fixation amnesia, paragnosia or false recognition of places, mental excitation, euphoria, etc. Thiamine is essential for the decarboxylation of pyruvate, and deficiency during this metabolic process is thought to cause damage to the medial thalamus and mammillary bodies of the posterior hypothalamus, as well as generalized cerebral atrophy. These brain regions are all parts of the limbic system, which is heavily involved in emotion and memory. Korsakoff's involves neuronal loss, that is, damage to neurons; gliosis, which is a result of damage to supporting cells of the central nervous system, and hemorrhage or bleeding also occurs in mammillary bodies. Damage to the dorsomedial nucleus or anterior group of the thalamus (limbic-specific nuclei) is also associated with this disorder. Cortical dysfunction may have arisen from thiamine deficiency, alcohol neurotoxicity, and/or structural damage in the diencephalon. Originally, it was thought that a lack of initiative and a flat affect were important characteristics of emotional presentation in sufferers. Studies have questioned this, proposing that neither is necessarily a symptom of Korsakoff's. Research suggesting that Korsakoff's patients are emotionally unimpaired has made this a controversial topic. It can be argued that apathy, which usually characterizes Korsakoff's patients, reflects a deficit of emotional expressions, without affecting the experience or perception of emotion. Korsakoff's Syndrome causes deficits in declarative memory in most patients, but leaves implicit spatial, verbal, and procedural memory functioning intact. People who have Korsakoff's syndrome have deficits in the processing of contextual information. Context memories refers to the where and when of experiences, and is an essential part of recollection. The ability to store and retrieve this information, such as spatial location or temporal order information, is impaired. Research has also suggested that Korsakoff patients have impaired executive functions, which can lead to behavioral problems and interfere with daily activities. It is unclear, however, which executive functions are affected most. Nonetheless, IQ is usually not affected by the brain damage associated with Korsakoff's syndrome. At first it was thought that Korsakoff's patients used confabulation to fill in memory gaps. However, it has been found that confabulation and amnesia do not necessarily co-occur. Studies have shown that there is dissociation between provoked confabulation, spontaneous confabulation (which is unprovoked), and false memories. That is, patients could be led to believe certain things had happened which actually had not, but so could people without Korsakoff’s syndrome. Conditions resulting in thiamine deficiency and its effects include chronic alcoholism and severe malnutrition. Alcoholism may co-occur with poor nutrition, which in addition to inflammation of the stomach lining, causes thiamine deficiency. Other causes include dietary deficiencies, prolonged vomiting, eating disorders, and the effects of chemotherapy. It can also occur in pregnant women who have a form of extreme morning sickness known as hyperemesis gravidarum. Mercury poisoning can also lead to Korsakoff's syndrome. Korsakoff's syndrome has also been caused by centipede (mukade) bites in Japan. Though it does not always co-occur, this disorder can emerge frequently as a consequential result of Wernicke’s encephalopathy. PET scans show that there is a decrease of glucose metabolism in the frontal, parietal and cingulated regions of the brain in Korsakoff's patients. This may contribute to memory loss and amnesia. Structural neuroimaging has also shown the presence of midline diencephalic lesions and cortical atrophy. Structural lesions of the central nervous system, though rare, can also contribute to symptoms of Korsakoff's syndrome. Severe damage to the medial dorsal nucleus inevitably results in memory deficit. Additionally, autopsies of patients with Korsakoff's have showed lesions in both the midline and anterior thalamus, and thalamic infarctions. Bilateral infarctions to the thalamus can result in Korsakoff-induced amnesia as well. These findings imply damage to anterior thalamic nuclei can result in disruptive memory. A number of factors may increase a person's risk to develop Korsakoff’s syndrome. These factors are often related to patients’ general health and their food intake habits. - Age - Alcoholism - Chemotherapy - Dialysis - Extreme dieting - Genetic factors The prevalence varies from country to country, but is estimated to be around 12.5% of heavy drinkers. It was once assumed that anyone suffering from Korsakoff's syndrome would eventually need full-time care. This is still often the case, but rehabilitation can help regain some, albeit often limited, level of independence. Treatment involves the replacement or supplementation of thiamine by intravenous (IV) or intramuscular (IM) injection, together with proper nutrition and hydration. However, the amnesia and brain damage caused by the disease does not always respond to thiamine replacement therapy. In some cases, drug therapy is recommended. Treatment of the patient typically requires taking thiamine orally for 3 to 12 months, though only about 20 percent of cases are reversible. If treatment is successful, improvement will become apparent within two years, although recovery is slow and often incomplete. As an immediate form of treatment, a pairing of IV or IM thiamine with a high concentration of B-complex vitamins can be administered three times daily for period of 2–3 days. In most cases, an effective response from patients will be observed. A dose of 1 gram of thiamine can also be administered to achieve a clinical response. In patients who are seriously malnourished, the sudden availability of glucose without proper bodily levels of thiamine to metabolize is thought to cause damage to cells. Thus, the administration of thiamine along with an intravenous form of glucose is often good practice. Treatment for the memory aspect of Korsakoff's syndrome can also include domain-specific learning, which when used for rehabilitation is called the method of vanishing cues. Such treatments aim to use patients' intact memory processes as the basis for rehabilitation. Patients who used the method of vanishing cues in therapy were found to learn and retain information more easily. People diagnosed with Korsakoff's are reported to have a normal life expectancy, presuming that they abstain from alcohol and follow a balanced diet. Empirical research has suggested that good health practices have beneficial effects in Korsakoff's syndrome. The most effective method of preventing Korsakoff's syndrome is to avoid B vitamin/thiamine deficiency. In Western nations, the most common causes of such a deficiency are alcoholism and eating disorders. Because these are behavioral-induced causes, Korsakoff's syndrome is essentially considered a preventable disease. Thus, fortifying foods with thiamine, or requiring companies that sell alcoholic beverages to supplement them with B vitamins in general or thiamine in particular, could avert many cases of Korsakoff's Syndrome. In a case of a non-alcoholic 63-year-old man with severe right hippocampal hemorrhage, neuropsychological assessments showed that he displayed severe anterograde amnesia, loss of recall, impaired recognition, and overall disorientation. He knew his birthday and could recall genuine memories of his childhood, but consistently asked about his parents who had died 25 years earlier. Thalamic damage is thought to have been the trigger for the amnestic syndrome.	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https://en.wikipedia.org/wiki/Lymphatic_filariasis	disease	Lymphatic filariasis	Lymphatic filariasis, also known as elephantiasis, is a human disease caused by parasitic worms known as filarial worms. Most cases of the disease have no symptoms. Some people, however, develop a syndrome called elephantiasis, which is marked by severe swelling in the arms, legs, breasts, or genitals. The skin may become thicker as well, and the condition may become painful. The changes to the body may harm the affected person's social and economic situation. The worms are spread by the bites of infected mosquitoes. Three types of worms are known to cause the disease: Wuchereria bancrofti, Brugia malayi, and Brugia timori, with Wuchereria bancrofti being the most common. These worms damage the lymphatic system. The disease is diagnosed by microscopic examination of blood collected during the night. The blood is typically examined as a smear after being stained with Giemsa stain. Testing the blood for antibodies against the disease may also permit diagnosis. Other roundworms from the same family are responsible for river blindness. Prevention can be achieved by treating entire groups in which the disease exists, known as mass deworming. This is done every year for about six years, in an effort to rid a population of the disease entirely. Medications used include antiparasitics such as albendazole with ivermectin, or albendazole with diethylcarbamazine. The medications do not kill the adult worms but prevent further spread of the disease until the worms die on their own. Efforts to prevent mosquito bites are also recommended, including reducing the number of mosquitoes and promoting the use of bed nets. In 2015 about 38.5 million people were infected. About 950 million people are at risk of the disease in 54 countries. It is most common in tropical Africa and Asia. Lymphatic filariasis is classified as a neglected tropical diseases and one of the four main worm infections. The disease results in economic losses of many billions of dollars a year.	The most spectacular symptom of lymphatic filariasis is elephantiasis, a stage 3 lymphedema with thickening of the skin and underlying tissues. This was the first mosquito-borne disease to be discovered. Elephantiasis results when the parasites lodge in the lymphatic system and cause blockages to the flow of lymph. Infections usually begin in childhood. The skin condition the disease causes is called "elephantiasis tropica" (also known as "elephantiasis arabum"). Elephantiasis mainly affects the lower extremities; the ears, mucous membranes, and amputation stumps are affected less frequently. However, various species of filarial worms tend to affect different parts of the body: Wuchereria bancrofti can affect the arms, breasts, legs, scrotum, and vulva (causing hydrocele formation), while Brugia timori rarely affects the genitals. Those who develop the chronic stages of elephantiasis are usually amicrofilaraemic and often have adverse immunological reactions to the microfilariae as well as the adult worms. The subcutaneous worms present with skin rashes, urticarial papules, and arthritis, as well as hyper- and hypopigmentation macules. Onchocerca volvulus manifests itself in the eyes, causing "river blindness" (onchocerciasis), one of the leading causes of blindness in the world. Serous cavity filariasis presents with symptoms similar to subcutaneous filariasis, in addition to abdominal pain, because these worms are also deep-tissue dwellers. Elephantiasis leads to marked swelling of the lower half of the body. Elephantiasis occurs in the presence of microscopic, thread-like parasitic worms such as Wuchereria bancrofti (the most common), Brugia malayi, and Brugia timori (also known as B. timori), all of which are transmitted by bites from infected mosquitoes. It is a type of helminth infection. Three types of worm cause the disease and damage the lymphatic system: The disease itself is a result of a complex interplay between several factors: the worm, the endosymbiotic Wolbachia bacteria within the worm, the host’s immune response, and the numerous opportunistic infections and disorders that arise. The adult worms only live in the human lymphatic system. The parasite infects the lymph nodes and blocks the flow of lymph throughout the body; this results in chronic lymphedema, most often noted in the lower torso (typically in the legs and genitals). The standard method for diagnosing active infection is by finding the microfilariae via microscopic examination. This may be difficult, as in most parts of the world, microfilariae only circulate in the blood at night. For this reason, the blood has to be collected nocturnally. The blood sample is typically in the form of a thick smear and stained with Giemsa stain. Testing the blood serum for antibodies against the disease may also be used. The World Health Organization recommends mass deworming—treating entire groups of people who are at risk with a single annual dose of two medicines, namely albendazole in combination with either ivermectin or diethylcarbamazine citrate. With consistent treatment, since the disease needs a human host, the reduction of microfilariae means the disease will not be transmitted, the adult worms will die out, and the cycle will be broken. In sub-Saharan Africa, albendazole (donated by GlaxoSmithKline) is being used with ivermectin (donated by Merck & Co.) to treat the disease, whereas elsewhere in the world, albendazole is used with diethylcarbamazine. Transmission of the infection can be broken when a single dose of these combined oral medicines is consistently maintained annually for a duration of four to six years. Using a combination of treatments better reduces the number of microfilariae in blood. Avoiding mosquito bites, such as by using insecticide-treated mosquito bed nets, also reduces the transmission of lymphatic filariasis. The Carter Center's International Task Force for Disease Eradication declared lymphatic filariasis one of six potentially eradicable diseases. According to medical experts, the worldwide effort to eliminate lymphatic filariasis is on track to potentially succeed by 2020. For similar-looking but causally unrelated podoconiosis, international awareness of the disease will have to increase before elimination is possible. In 2011, podoconiosis was added to the World Health Organization's Neglected Tropical Diseases list, which was an important milestone in raising global awareness of the condition. The efforts of the Global Programme to Eliminate LF are estimated to have prevented 6.6 million new filariasis cases from developing in children between 2000 and 2007, and to have stopped the progression of the disease in another 9.5 million people who had already contracted it. Dr. Mwele Malecela, who chairs the programme, said: "We are on track to accomplish our goal of elimination by 2020." In 2010, the WHO published a detailed progress report on the elimination campaign in which they assert that of the 81 countries with endemic LF, 53 have implemented mass drug administration, and 37 have completed five or more rounds in some areas, though urban areas remain problematic. Treatments for lymphatic filariasis differ depending on the geographic location of the endemic area. In sub-Saharan Africa, albendazole is being used with ivermectin to treat the disease, whereas elsewhere in the world, albendazole is used with diethylcarbamazine. Geo-targeting treatments is part of a larger strategy to eventually eliminate lymphatic filariasis by 2020. Additionally, surgical treatment may be helpful for issues related to scrotal elephantiasis and hydrocele. However, surgery is generally ineffective at correcting elephantiasis of the limbs. A vaccine is not yet available but in 2013 the University of Illinois was reporting 95% efficacity in testing against B. malayi in mice. Treatment for podoconiosis consists of consistent shoe-wearing (to avoid contact with the irritant soil) and hygiene - daily soaking in water with an antiseptic (such as bleach) added, washing the feet and legs with soap and water, application of ointment, and in some cases, wearing elastic bandages. Antibiotics are used in cases of infection. The antibiotic doxycycline is effective in treating lymphatic filariasis. Its drawbacks are that it requires 4 to 6 weeks of treatment and should not be used in young children and pregnant women, which limits its use for mass prevention. The parasites responsible for elephantiasis have a population of endosymbiotic bacteria, Wolbachia, that live inside the worm. When the symbiotic bacteria of the adult worms are killed by the antibiotic, they no longer provide chemicals which the nematode larvae need to develop, which either kills the larvae or prevents their normal development. This permanently sterilizes the adult worms, which additionally die within 1 to 2 years instead of their normal 10 to 14 year lifespan. Elephantiasis caused by lymphatic filariasis is one of the most common causes of disability in the world. A 2012 report noted that lymphatic filariasis affected 120 million people and one billion people at risk for infection. About 40 million people were disfigured or incapacitated by the disease in 2015. It is considered endemic in tropical and subtropical regions of Africa, Asia, Central and South America, and Pacific Island nations. In areas endemic for podoconiosis, prevalence can be 5% or higher. In communities where lymphatic filariasis is endemic, as many as 10% of women can be afflicted with swollen limbs, and 50% of men can suffer from mutilating genital symptoms. Filariasis is considered endemic in 73 countries; 37 of these are in Africa. - In the Americas, it is present in Brazil, Costa Rica, the Dominican Republic, Guyana, Haiti, Suriname, and Trinidad and Tobago. - In Asia, it is present in Bangladesh, Cambodia, India, Indonesia, Laos, Malaysia, Maldives, the Philippines, Sri Lanka, Thailand, Timor-Leste, and Vietnam. - In the Middle East, it is present only in Yemen. - In the Pacific region, it is endemic in American Samoa, the Cook Islands, Fiji, French Polynesia, Micronesia, Niue, Papua New Guinea, Samoa, Tonga, Tuvalu, and Vanuatu. In many of these countries, considerable progress has been made towards elimination of filariasis. In July 2017, the World Health Organization (WHO) announced that the disease had been eliminated in Tonga. Elimination of the disease has also occurred in Cambodia, China, the Cook Islands, Niue, the Marshall Islands, South Korea, and Vanuatu, according to the WHO. Lymphatic filariasis is thought to have affected humans for about 4000 years. Artifacts from ancient Egypt (2000 BC) and the Nok civilization in West Africa (500 BC) show possible elephantiasis symptoms. The first clear reference to the disease occurs in ancient Greek literature, wherein scholars differentiated the often similar symptoms of lymphatic filariasis from those of leprosy. The first documentation of symptoms occurred in the 16th century, when Jan Huyghen van Linschoten wrote about the disease during the exploration of Goa. Similar symptoms were reported by subsequent explorers in areas of Asia and Africa, though an understanding of the disease did not begin to develop until centuries later. In 1866, Timothy Lewis, building on the work of and Otto Henry Wucherer, made the connection between microfilariae and elephantiasis, establishing the course of research that would ultimately explain the disease. In 1876, Joseph Bancroft discovered the adult form of the worm. In 1877, the lifecycle involving an arthropod vector was theorized by Patrick Manson, who proceeded to demonstrate the presence of the worms in mosquitoes. Manson incorrectly hypothesized that the disease was transmitted through skin contact with water in which the mosquitoes had laid eggs. In 1900, George Carmichael Low determined the actual transmission method by discovering the presence of the worm in the proboscis of the mosquito vector. Researchers at the University of Illinois at Chicago (UIC) have developed a novel vaccine for the prevention of lymphatic filariasis. This vaccine has been shown to elicit strong, protective immune responses in mouse models of lymphatic filariasis infection. The immune response elicited by this vaccine has been demonstrated to be protective against both W. bancrofti and B. malayi infection in the mouse model and may prove useful in the human. On September 20, 2007, geneticists published the first draft of the complete genome (genetic content) of Brugia malayi, one of the roundworms which causes lymphatic filariasis. This project had been started in 1994 and by 2000, 80% of the genome had been determined. Determining the content of the genes might lead to the development of new drugs and vaccines.	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https://en.wikipedia.org/wiki/Normal_pressure_hydrocephalus	disease	Normal pressure hydrocephalus	Normal pressure hydrocephalus (NPH), also termed Hakim's syndrome and symptomatic hydrocephalus, is a type of brain malfunction caused by expansion of the lateral cerebral ventricles and distortion of the fibers in the corona radiata. Its typical symptoms are urinary incontinence, dementia, and gait disturbance. CSF pressure is usually normal. Ventricles are chronically dilated. The name “normal pressure” came out of a 1965 medical paper describing cases of hydrocephalus where the symptoms occurred in the presence of supposedly normal cerebrospinal-fluid pressure. The paper was published before continuous pressure-recording techniques were available. We now know that “normal pressure” is a misnomer. The usual treatment is surgical installation of a ventriculoperitoneal shunt to drain excess CSF into the lining of the abdomen where the CSF will eventually be absorbed.	NPH may exhibit a classic triad of clinical findings (known as the Adams triad or Hakim's triad) of urinary incontinence, gait disturbance, and dementia (commonly referred to as "wet, wacky and wobbly" or "weird walking water"). - Gait disturbance is typically the initial and most prominent symptom of the triad and may be progressive, due to expansion of the ventricular system, particularly at the level of the lateral ventricles, leading to traction on the corticospinal tract motor fibers descending to the lumbosacral spinal cord. The gait disturbance can be classified as mild (cautious gait or difficulty with tandem gait), marked (evident difficulty walking or considerable unstable gait) or severe (unaided gait not possible) In the early stages, most often this gait disturbance occurs in the form of unsteadiness and impaired balance, especially when encountering stairs and curbs. Weakness and tiredness of the legs may also be part of the complaint, although examination discloses no paresis or ataxia. Often a mobility aid is used for added stability, once the patient has reached the mild to marked stage. Such aids may include a quad cane or wheeled walker. The patient's gait at the marked stage will often show a decrease in step height and foot-floor clearance, as well as a decrease in walking speed. This style is often referred to as a magnetic gait, in which the feet appear to be stuck to the walking surface, and is considered the characteristic gait disturbance of NPH. The gait may begin to mimic a Parkinsonian gait, with short shuffling steps and stooped, forward-leaning posture, but there is no rigidity or tremor. An increased tendency to fall backwards is also seen, and a broad-based gait may be employed by the patient in order to increase their base of support and thereby their stability. In the very late stages, the patient can progress from an inability to walk, to an inability to stand, sit, rise from a chair or turn over in bed; this advanced stage is referred to as "hydrocephalic astasia-abasia". - Dementia is predominantly frontal lobe in nature and of the subcortical type of dementia. It presents in the form of abulia, forgetfulness, inertia, inattention, decreased speed of complex information procession (also described as a dullness in thinking and actions), and disturbed manipulation of acquired knowledge, which is reflective of the loss of integrity of the frontal lobes. Memory problems are usually a component of the overall problem and have been predominant in some cases, which can lead to the misdiagnosis of Alzheimer's disease. However, in NPH there may be an obvious discrepancy between (often severely) impaired recall and intact or much less impaired recognition. The dementia is thought to result from traction on frontal and limbic fibers that also run in the periventricular region. - Urinary incontinence appears late in the illness, and is found to be of the spastic hyperreflexic, increased-urgency type associated with decreased inhibition of bladder contractions and detrusor instability. In the most severe cases, bladder hyperreflexia is associated with a lack of concern for micturition due to the severe frontal lobe cognitive impairment. This is also known as "frontal lobe incontinence", where the patient becomes indifferent to their recurrent urinary symptoms. NPH is caused by an increase in intracranial pressure (ICP) due to an abnormal accumulation of CSF in the ventricles of the brain, leading to ventriculomegaly. The intracranial pressure gradually falls but still remains slightly elevated, and the CSF pressure reaches a high normal level of 150 to 200 mm HO. Measurements of ICP, therefore, are not usually elevated. Because of this, patients do not exhibit the classic signs that accompany increased intracranial pressure such as headache, nausea, vomiting, or altered consciousness, although some studies have shown pressure elevations to occur intermittently. However, enlarged ventricles put increased pressure on the adjacent cortical tissue and cause myriad effects in the patient. The classic symptom triad (gait disturbance, urinary incontinence, and dementia) was first described by Hakim and Adams in 1965. NPH is often misdiagnosed as Parkinson's disease, Alzheimer's disease, or dementia, due to its chronic nature and nonspecific presenting symptoms. Diagnosis of NPH is usually first led by brain imaging, either CT or MRI, to rule out any mass lesions in the brain. This is then followed by lumbar puncture and evaluation of clinical response to removal of CSF. This can be followed by continuous external lumbar CSF drainage during 3 or 4 days. - CT scan may show enlarged ventricles without convolutional atrophy. - MRI may show some degree of transependymal migration of CSF surrounding the ventricles on T2/FLAIR sequence. Imaging however cannot differentiate between pathologies with similar clinical picture like Alzheimer's dementia, vascular dementia or Parkinson's disease. - Following imaging, lumbar puncture is usually the first step in diagnosis and the CSF opening pressure is measured carefully. In most cases, CSF pressure is usually above 155 mmHO. Clinical improvement after removal of CSF (30 mL or more) has a high predictive value for subsequent success with shunting. This is called the "lumbar tap test" or Miller Fisher test. On the contrary, a "negative" test has a very low predictive accuracy, as many patients may improve after a shunt in spite of lack of improvement after CSF removal. - Infusion test is a test that may have higher sensitivity and specificity than a lumbar puncture, but is not performed in most centers. The outflow conductance (Cout) of the cerebrospinal fluid (CSF) system is a parameter considered by some centers to be predictive in selection for hydrocephalus surgery. Cout can be determined through an infusion test. This is not a test that is normally performed prior to shunting, but may become more accepted. - In some centers, External lumbar drainage has been shown to have the highest sensitivity and specificity with regards to predicting a successful outcome following surgery. There are two types of normal pressure hydrocephalus: idiopathic and secondary. The secondary type of NPH can be due to a subarachnoid hemorrhage, head trauma, tumor, infection in the central nervous system, or a complication of cranial surgery. Patients with dementia who are confined to a nursing home and may have undiagnosed NPH can possibly become independent again once treated. So far only one study was able to evaluate the prevalence of NPH, both diagnosed and undiagnosed, among residents of assisted-living facilities, showing a prevalence in 9 to 14% of the residents. NPH may be relieved by surgically implanting a ventriculoperitoneal shunt to drain excess cerebrospinal fluid to the abdomen where it is absorbed. Once the shunt is in place, the ventricles usually diminish in size in 3 to 4 days, regardless of the duration of the hydrocephalus. Even though the ventricular swelling diminishes, only 21% of patients show a marked improvement in symptoms. The most likely patients to show improvement are those that show only gait disturbance, mild or no incontinence, and mild dementia. A more recent study (2004) found better outcomes, concluding that if patients with idiopathic normal pressure hydrocephalus are correctly identified, shunt insertion yielded beneficial outcomes in 86% of patients, in either gait disturbance (81%), improved continence (70%), or both. They also observed that measurements in the diagnostic clinical triad, the cortical sulci size, and periventricular lucencies were related to outcome. However, other factors such as age of the patient, symptom duration, dilation of ventricles, and the degree of presurgical dementia were unrelated to outcome. Recent population-based studies have estimated the prevalence of NPH to be about 0.5% in those over 65 years old, with an incidence of about 5.5 patients per 100,000 of people per year. This is in accordance with comparable findings stating that although normal pressure hydrocephalus can occur in both men and women of any age, it is found more often in the elderly population, with a peak onset generally in the sixth to seventh decades.	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https://en.wikipedia.org/wiki/Distal_18q-	disease	Distal 18q-	Distal 18q- is a genetic condition caused by a deletion of genetic material within one of the two copies of chromosome 18. The deletion involves the distal section of 18q and typically extends to the tip of the long arm of chromosome 18.	Distal 18q- causes a wide range of medical and developmental concerns, with significant variation in severity due to the variation in breakpoints reported in individuals with distal 18q-. Current research is focused on establishing genotype-phenotype correlations to enable predictive genotyping. Heart abnormalities are present in 25–35% of people with distal 18q-. The majority of these defects are septal. Congenital orthopedic anomalies are also relatively common, particularly rocker-bottom feet or clubfoot. Cleft lip and palate are relatively common in people with distal 18q-. Kidney abnormalities have also been reported and include horseshoe kidney, hydronephrosis, polycystic kidney, and absent kidney. Boys with distal 18q- may have genital anomalies, the most frequent being cryptorchidism and hypospadias. Hypotonia is a common finding. Around 10% of people with distal 18q- have seizures. Dysmyelination is a common finding in people with distal 18q-, present in about 95%. Hypoplasia of the corpus callosum is also a common finding. Strabismus and nystagmus are prevalent in distal 18q-. Changes in the optic nerve, as well as colobomas, are also fairly common. Myopia has been reported in some individuals. Due to changes in facial structures, infants, toddlers, and children with distal 18q- often have poor drainage from the middle ears, leading to a build-up of fluid. This can in turn lead to recurrent ear and sinus infections. Antibiotics are typically required to treat these infections. In addition, the diagnosis of ear infections in children with 18q- is frequently complicated by stenosis or atresia of the ear canals, a common finding in people with distal 18q-. People with distal 18q- frequently have conductive and/or sensorineural hearing loss. The degree of hearing loss may vary from a mild to a severe loss. Individuals with distal 18q- may have problems with reflux. Hernias have also been reported. As mentioned above, males with distal 18q- may have cryptorchidism. Hypospadias and chordee have also been reported. Also, a variety of kidney malformations have been reported in infants with distal 18q-, as noted above. Additionally, vesicouretereral reflux has been diagnosed in several people with distal 18q-. As mentioned above, distal 18q- is associated with an increased incidence of clubfoot and rocker bottom feet. Also, a significant chance of developing pes planus or pes cavus exists. People with distal 18q- frequently have overlapping toes. Scoliosis and genu varum are also known orthopedic complications in children and adults with distal 18q-. Children and adults with distal 18q- are often small for their age. Many people with distal 18q- have an abnormal response to growth hormone stimulation. Those who have been treated with growth hormone have responded well to the treatment. Microcephaly is also common in people with distal 18q-. Hypothyroidism has been reported in some people with distal 18q-. Several people with distal 18q- have been diagnosed with low IgA levels, resulting in an increased incidence of infections. An increased incidence of psychiatric conditions occurs within the distal 18q- population. In one study, nearly 60% had depressive symptoms, 60% had symptoms of an anxiety disorder, 25% had manic symptoms, and 25% had psychotic symptoms. However, this study included young patients, many of whom were too young to exhibit signs of certain psychiatric conditions. The typical age of onset for many of these conditions appears to be during the teen years. Thus, the results of this study may actually underestimate the true incidence of psychiatric conditions within this population. Outbursts, or anger issues, such as temper tantrums are also common. 97% of individuals possess some form of mental retardation, ranging from moderate to severe cases. The intellectual development of individuals with distal 18q- vary quite widely. In one study of 46 individuals with distal 18q-, IQ ranged from 49 to 113, with most individuals falling in the mild to moderate range of intellectual disability. Some of those with IQ scores on the lower end of the spectrum probably actually had deletions encompassing the TCF4 gene. An increased incidence of autism is seen within the distal 18q- population. In a recent study, 45 of 105 individuals evaluated fell into the "possible" or "very likely" levels of risk for autism. Adaptive skills may also be delayed in people with distal 18q-. Common facial features include midfacial hypoplasia, short and downward- or upward-slanting palpebral fissures, epicanthic folds, and low-set ears with a prominent antihelix. Distal 18q- is a deletion of the long arm of chromosome 18. The majority of deletions have breakpoints between 45,405,887 and the tip of the chromosome. There are no common breakpoints, thus the size of the deletions vary widely. The largest deletion reported is 30.076 Mb, while the smallest deletion reported to cause a clinical phenotype is 3.78 Mb. Suspicion of a chromosome abnormality is typically raised due to the presence of developmental delays or birth defects. Diagnosis of distal 18q- is usually made from a blood sample. A routine chromosome analysis, or karyotype, is usually used to make the initial diagnosis, although it may also be made by microarray analysis. Increasingly, microarray analysis is also being used to clarify breakpoints. Prenatal diagnosis is possible using amniocentesis or chorionic villus sampling. At present, treatment for distal 18q- is symptomatic, meaning the focus is on treating the signs and symptoms of the conditions as they arise. To ensure early diagnosis and treatment, people with distal 18q- are suggested to undergo routine screenings for thyroid, hearing, and vision problems. Distal 18q- was first described in 1964. Originally, it was called "De Grouchy syndrome" or "De Grouchy syndrome 2". Today, the preferred nomenclature for this condition is 18q-. Since this condition was originally described, researchers have clarified the size and nature of these deletions. In general, deletions of 18q fall into one of two categories: interstitial deletions, which typically have breakpoints between 18q11.2 (18.9 Mb) to 18q21.1 (43.8 Mb), and terminal deletions, which typically have a breakpoint distal to 18q21.1 (45.4 Mb) and extend to the end of the chromosome. If possible, it is preferable to indicate the general location of the deletion with the phrases "proximal 18q-" and "distal 18q-". Currently, research is focusing on identifying the role of the genes on 18q in causing the signs and symptoms associated with distal deletions of 18q. TCF4 – In 2007, deletions of or point mutations in this gene were identified as the cause of Pitt-Hopkins syndrome. This is the first gene that has been definitively shown to directly cause a clinical phenotype when deleted. If a deletion includes the TCF4 gene (located at 55,222,331-55,664,787), features of Pitt-Hopkins may be present, including abnormal corpus callosum, short neck, small penis, accessory and wide-spaced nipples, broad or clubbed fingers, and sacral dimple. Those with deletions inclusive of TCF4 have a significantly more severe cognitive phenotype. TSHZ1 - Point mutations and deletions of this gene are linked with congenital aural atresia. Individuals with deletions inclusive of this gene have a 78% chance of having aural atresia. Critical regions – Recent research has narrowed the critical regions for four features of the distal 18q- phenotype down to a small segment of distal 18q, although the precise genes responsible for those features remain to be identified. The table below shows the established critical regions for four features of distal 18q-, as well as the penetrance for each of those features. The penetrance figure represents the likelihood a person would have the feature given the critical region is deleted. Haplolethal regions - Two regions on chromosome 18 have never been found to be deleted. They are located between the centromere and 22,826,284 bp (18q11.2) and between 43,832,732 and 45,297,446 bp (18q21.1). The genes in these regions are thought to be lethal when deleted.	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https://en.wikipedia.org/wiki/Shot_hole_disease	disease	Shot hole disease	Shot hole disease (also called Coryneum blight) is a serious fungal disease that creates BB-sized holes in leaves, rough areas on fruit, and concentric lesions on branches. The pathogen that causes shot hole disease is Wilsonomyces carpophilus.	The fungal pathogen Wilsonomyces carpophilus affects members of the Prunus genera. Almond, apricot, nectarine, peach, prune and cherry trees can be affected. Both edible and ornamental varieties are vulnerable to infection. Shot hole disease produces small (1/10-1/4”) reddish or purplish-brown spots. There may be a light green or yellow ring around these spots. Damaged areas become slightly larger and then dry up and fall away, leaving BB-sized holes in leaves. As the fungus spreads, more leaf tissue is damaged until the leaf falls. Significant infections can reduce the amount of photosynthesis that can occur, weakening the plant, and decreasing fruit production. The fungi can also affect fruit, beginning as small purple spots that develop into gray to white lesions. Gummosis may occur. These lesions leave toughened spots on the skin, and in some cases the fruit may be lost. Infected buds may appear darker than normal. Branches may develop concentric lesions when infected. These lesions may girdle a twig and kill it. W. carpophilus overwinters in infected buds and in twig cankers. Asexual spores (conidia) are dispersed in spring when moisture levels increase or as a result of overhead watering. Spores are pigmented and remain viable, in a dormant state, for months. Infection can occur any time moisture is present for at least 24 hours, as long as temperatures are above 36 °F. At higher temperatures, infection occurs more quickly. W. carpophilus infection takes only 6 hours at 77 °F. W. carpophilus can remain viable for several months and spores are often airborne. Since the fungi thrive in wet conditions, overhead watering should be avoided. Remove and dispose of any infected buds, leaves, fruit and twigs. In fall, fixed copper or Bordeaux mixture can be applied. Shot hole disease is a major concern of the stone fruit industry. It is estimated that 80% of the California almond crop may be infested with shot hole disease, resulting in a potential yield loss of 50-75%. In the 1930s, it was found that applications of Bordeaux mixture reduces shot hole disease on peaches from 80% to 9%.	[ { "begin": 0, "class": "SectionAnnotation", "length": 1033, "sectionHeading": "Hosts and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 1033, "class": "SectionAnnotation", "length": 475, "sectionHeading": "Disease cycle", "sectionLabel": "disease.other" }, { "begin": 1508, "class": "SectionAnnotation", "length": 286, "sectionHeading": "Management", "sectionLabel": "disease.management" }, { "begin": 1794, "class": "SectionAnnotation", "length": 326, "sectionHeading": "Importance", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Langer_mesomelic_dysplasia	disease	Langer mesomelic dysplasia	Langer mesomelic dysplasia (LMD) is a rare congenital disorder characterized by an altered bone formation that causes a severe short and disproportionate stature.	It's part of the mesomelic and rhizomelic skeletal dysplasias, primary bone diseases in which the short stature is due to a lack of complete bone development of the limb's long bones. It's strictly related to another disease, the Léri–Weill dyschondrosteosis, of which it seems to be the homozygothic variant, clinically more severe (it differs from this disorder for the absence, in some cases, of the Madelung deformity too). The incidence is less than 1/1.000.000. Fewer than 50 cases have been reported so far. At the core of the disorder there is a homozygous or compound heterozygous mutation or deletion of the SHOX (Short Stature Homeobox), SHOXY (Short Stature Homeobox Y-linked) or PAR1 (where SHOX enhancer elements are located) genes, which is inherited in a pseudosomal recessive manner. Clinically and radiologically the disease is characterized by severe shortening of long bones (limb's both proximal and median segments are affected), aplasia or severe hypoplasia of ulna and fibula, thickened and curved radius and tibia. These anomalies can cause deformities of the hands and feet. Hypoplasia of the mandible can also be present. Diagnosis may be suspected on the basis of the clinical and radiologic findings, and can supported by molecular analysis of the SHOX, SHOXY and PAR1 genes. May also be suspected by ultrasound during the second trimester of gestation. There is no known cure. In selected patients orthopaedic surgery may be helpful to try to gain some functionality of severely impaired joints.	[ { "begin": 0, "class": "SectionAnnotation", "length": 428, "sectionHeading": "Classification", "sectionLabel": "disease.classification" }, { "begin": 428, "class": "SectionAnnotation", "length": 87, "sectionHeading": "Epidemiology", "sectionLabel": "disease.epidemiology" }, { "begin": 515, "class": "SectionAnnotation", "length": 286, "sectionHeading": "Pathogenesis", "sectionLabel": "disease.mechanism" }, { "begin": 801, "class": "SectionAnnotation", "length": 348, "sectionHeading": "Symptoms and signs", "sectionLabel": "disease.symptom" }, { "begin": 1149, "class": "SectionAnnotation", "length": 234, "sectionHeading": "Symptoms and signs \| Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 1383, "class": "SectionAnnotation", "length": 143, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Bing–Neel_syndrome	disease	Bing–Neel syndrome	Bing–Neel syndrome (BNS) is an extremely rare neurologic complication of Waldenström macroglobulinemia (WM), which is a chronic lymphoproliferative disorder. There's no clear definition of BNS but what is known so far is that unlike WM, It involves the central nervous system (CNS), infiltrated by differentiated malignant B cells and by having hyperglobulinemia. This infiltration increases blood viscosity, which impairs blood circulation through small blood vessels of the brain and the eye. Some scientists proposed that a person diagnosed with BNS is typically classified into Group A and Group B depending on whether or not plasma cells are present within the brain parenchyma, leptomeninges, dura, and/or the cerebral spinal fluid (CSF). Symptoms are diverse and nonspecific, and they can vary depending on which aspect of the CNS is being affected. Symptoms can include a range of severity of nausea and seizures. Since the symptoms vary, there are multiple treatment options to treat the symptoms for this non-curable disease. Although there is no specific set of diagnosis for BNS, different combinations of diagnostic tools are used to narrow down and conclude the presence of BNS.	Symptoms of BNS gradually progress over the span of a week or even a month, and there is typically a delay in diagnosis after the initial symptoms arise. Although BNS arises due to complications from WM, some individuals may experience symptoms of BNS without having a past history of WM. Given that BNS is so rare, the symptoms are diverse and nonspecific. Symptoms range in severity from nausea to seizures and are characterized by how they interfere with the function of the CNS. Where certain symptoms are present depends on which branch of the CNS is being affected by plasma B-cells. People diagnosed with BNS experience some sensory symptoms as well. Some sensory symptoms include a pin and needles sensation experienced in the lower limbs, the hands, and in the arms, along with pain and extreme numbness. There is no clear-cut route to diagnosing BNS, meaning just one diagnostic tool alone is not conclusive in diagnosing BNS. But through the utilization of several different tools cooperatively, a diagnosis can be reached through the elimination of other CNS pathologies. Infiltration of malignant, differentiated B-cells linked to WM into the nervous system precipitates BNS. Histological practices that entail a biopsy of the cerebrum and/or the meninges look for the presence of lymphoplasmacytic lymphomas (Mature B-cells). Though a biopsy alone is not indicative of BNS, it is a necessary step that ensures that at the very least, the CNS has been infiltrated by some sort of lymphoma. Analysis entails analyzing several different aspects of the cerebrospinal fluid (CSF) to identify characteristics linked to WM and BNS. Quantification of leukocytes and their differentiation, as well as a morphological analysis of any detected malignant lymphomas found in the CSF are some parameters assed by CSF analysis. Flow cytometry, used to identify cell biomarkers, is an auxiliary tool used in CSF analysis. With respect to diagnosing BNS, flow cytometry analyzes CSF contents for B-cells expressing the pan antigens CD19 and CD20, commonly found in WM; it should be noted, not all cases of BNS show conclusive findings in CSF analysis. MRI with gadolinium contrast is the primary radiologic tool used to diagnose ailments of the central nervous system, BNS included. MRI’s effect is twofold in that it is able to identify brain and spine abnormalities, as well as identifying tissues appropriate for biopsy. MRI with gadolinium contrast can also discern which form of BNS has formed. Where the tumoral form of BNS is highlighted by tumor growth in the subcortical hemispheric regions, the diffuse form of BNS is characterized by leptomeningeal and perivascular infiltration by lymphoid cells. Other characteristics of BNS identified via MRI are abnormal enhancement of cranial and spinal nerves, as well as thickening and enhancement of the cauda equina. The MYD88 L2659 is a gene mutation found in the majority of WM cases. During CSF analysis, PCR amplification of genomic DNA found in the fluid, followed by sequencing, can determine if the mutation is present within the CNS; if so, this would be indicative of, though not conclusive, of BNS. Treatment for BNS has a multitude of options. If people with BNS are asymptomatic, physicians will watch for progression of the disease using MRI. If any signs of further disease is shown, they will take action to alleviate the symptoms. Because this disease is non-curative and rather rare, treatment is only used to get rid of symptoms. Even so, due to the lack of regeneration of the nervous system, some symptoms may not be reversible and stay with the person with BNS. There are some costs, along with the benefits, of treating the symptoms depending on the type, which may include lesions or brain damage. Doctors will make a risk assessment and monitor by MRI to validate that complications do not occur. There are a few options when it comes to treatment so the type one will choose is completely individualized, taking into consideration the person's state or condition and liking. Steroids are mostly used for short term and quick use. The use provides improvement, but should not be considered a long term plan. Physicians would normally prescribe steroids after a biopsy and after further analysis has been completed. Treatment also involves central nervous system penetrating chemotherapy. Options include intrathecal, intraventricular, and systemic chemotherapy. These must penetrate the blood-brain barrier in order to be effective. Sometimes mixing multiple forms of treatment with chemotherapy seems to be the best route. For example, some significant improvement has been shown as a result of cranial radiation treatment preceding a brief course of intrathecal chemotherapy. Although this is an effective treatment to do, penetrating the blood-brain barrier can cause side effects due to the toxicity in the nervous system. These would include dizziness, confusion, and changes in mental status. Another form could be the use of pharmaceuticals, which have all shown positive results for treatment but should always be consulted with a physician to asses risks. Autologous stem-cell transplants are shown to be an effective treatment. However, this should be only considered for certain people due to toxicity concerns. It is possible that the transplant may cause problems like septic shock. Lastly, radiation is normally used as a rescue type treatment and is not recommended as a first line treatment. The doctor would perform localized radiation therapy at a dose of 30 to 40 Gy on the lesions. This is to limit the amount of radiation and prevent further damage to the nervous system, which could happen due to the toxicity of radiation therapy. Bing–Neel syndrome was first described by Jens Bing and Axel Valdemar Neel, who observed a case of 2 women, 56 and 39 years old, presenting with rapid neurodegeneration in the setting of hyperglobulinemia. This discovery was reported eight years before the first report on WM, which was discovered and described by Jan Waldenström. From the first publication, there was never a clear consensus and guideline to the diagnosis and treatment of BNS. It was only 80 years later that there was a meeting with a group of people at the 8th International Workshop on WM to come up with broad diagnostic criteria for BNS. This group of people included radiologists, immunologists, hematologists, and neurologists from all over the world using PubMed as their source for the guideline. The first draft was reviewed by a multidisciplinary team of experts in WM.	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https://en.wikipedia.org/wiki/Bartholin's_cyst	disease	Bartholin's cyst	A Bartholin's cyst occurs when a Bartholin's gland is blocked and the gland becomes inflamed. Sizes range from that of a pea to that of an egg and form just within each side of the lower part of the opening of the vagina. An abscess may form if the cyst becomes infected. In this case it often becomes red and painful when touched. A Bartholin's cyst is not an infection, although it can be caused by an infection, inflammation, or physical blockage (mucus or other impediment) to the Bartholin's ducts (tubes which lead from the glands to the vulva). If infection sets in, the result is a Bartholin's abscess. Cysts are not sexually transmitted. There is no known reason for their development and infection is rare. With an abscess, a bacterial infection is the cause, but it is usually not an STI. Treatment depends on the severity of symptoms. If there are no symptoms, no treatment may be needed. If a cyst is causing problems, drainage is recommended. The preferred method of drainage is the insertion of a Word catheter for four weeks. Simple incision and drainage may allow the cyst to reform. A surgical procedure known as marsupialization may be used for cysts, but should not be used if they are infected. If the problems persist, the entire gland may be removed. Removal is sometimes recommended in those older than 40 to ensure cancer is not present. Antibiotics are not generally needed. Bartholin's cysts only occur in women and most likely those of childbearing age. About two percent of women have the problem at some point in their life.	Most Bartholin's cysts do not cause any symptoms, although some may cause pain during walking, sitting, or sexual intercourse (dyspareunia). They are usually between 1 and 4 cm, and are located just medial to the labia minora. Most Bartholin's cysts only affect the left or the right side (unilateral). Small cysts are usually not painful, but very large cysts can cause significant pain. A Bartholin's gland cyst develops when the duct that drains the gland becomes blocked. Blockage may be caused by an infection or a mucus plug. The secretions from the Bartholin's gland are retained, forming a cyst. Other conditions that may present similarly include hidradenoma papilliferum, lipomas, epidermoid cysts and Skene's duct cysts among others. In those who are more than 40 years of age a biopsy may be recommended to ensure cancer is not present. Treatment may not be necessary when Bartholin's cysts cause no symptoms. Small, asymptomatic cysts should simply be observed over time to see whether they grow. In cases that require intervention, a catheter may be placed to drain the cyst, or the cyst may be surgically opened to create a permanent pouch (marsupialization). Intervention has a success rate of 85%, regardless of the method used, for the achievement of absence of swelling and discomfort and the appearance of a freely draining duct. Catheterization is a minor procedure that can be performed in an office setting. A small tube with a balloon on the end (known as a Word catheter) may be inserted into the cyst. The balloon is then inflated to keep it in place. The catheter stays in place for 2 to 4 weeks, draining the fluid and causing a normal gland opening to form, after which the catheter is removed. The catheters do not generally impede normal activity, but sexual intercourse is generally abstained from while the catheter is in place. Cysts may also be opened permanently, a procedure called marsupialization, in which an opening to the gland is formed with stitches to hold the secretion channel open. If a cyst is infected, it may break open and start to heal on its own after 3 to 4 days. Nonprescription pain medication such as ibuprofen relieves pain, and a sitz bath may increase comfort. Warm compresses can speed healing. If a Bartholin gland abscess comes back several times, the gland and duct can be surgically removed. While Bartholin cysts can be quite painful, they are not life-threatening. New cysts cannot absolutely be prevented from forming, but surgical or laser removal of a cyst makes it less likely that a new one will form at the same site. Those with a cyst are more likely than those without a cyst to get one in the future. They can recur every few years or more frequently. Many women who have marsupialization done find that the recurrences may slow, but do not actually stop. Two percent of women will have a Bartholin's gland cyst at some point in their lives. They occur at a rate of 0.55 per 1000 person-years and in women aged 35–50 years at a rate of 1.21 per 1000 person-years. The incidence of Bartholin duct cysts increases with age until menopause, and decreases thereafter. Hispanic women may be more often affected than white women and black women. The risk of developing a Bartholin's gland cyst increases with the number of childbirths.	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https://en.wikipedia.org/wiki/Retrograde_amnesia	disease	Retrograde amnesia	Retrograde amnesia (RA) is a loss of memory-access to events that occurred, or information that was learned, before an injury or the onset of a disease. It tends to negatively affect episodic, autobiographical, and declarative memory while usually keeping procedural memory intact with no difficulty for learning new knowledge. RA can be temporally graded or more permanent based on the severity of its cause and is usually consistent with Ribot's Law: where subjects are more likely to lose memories closer to the traumatic incident than more remote memories. The type of information that is forgotten can be very specific, like a single event, or more general, resembling generic amnesia. It is not to be confused with anterograde amnesia, which deals with the inability to form new memories following the onset of an injury or disease.	The most commonly affected areas are associated with episodic and declarative memory such as the hippocampus, the diencephalon, and the temporal lobes. - The hippocampus deals largely with memory consolidation, where information from the working memory and short-term memory is encoded into long-term storage for future retrieval. Amnesic patients with damage to the hippocampus are able to demonstrate some degree of unimpaired semantic memory, despite a loss of episodic memory, due to spared parahippocampal cortex. In other words, retrograde amnesics "know" an information or skill, but cannot "remember" how they do. - The diencephalon and the surrounding areas' role in memory is not well understood. However, this structure appears to be involved in episodic memory recall. - The temporal lobes are essential for semantic and factual memory processing. Aside from helping to consolidate memory with the hippocampus, the temporal lobes are extremely important for semantic memory. Damage to this region of the brain can result in the impaired organization and categorization of verbal material, disturbance of language comprehension, and impaired long-term memory. The right frontal lobe is critical for the retrieval of episodic information, while the left frontal region is more active for the retrieval of semantic information. [56] Lesions in the right hemisphere and right frontal lobes result in the impaired recall of non-verbal material, such as music and drawings. Difficulties in studying this region of the brain extends to its duties in comprehension, naming objects, verbal memory, and other language functions. Brain plasticity has helped explain the recovery process of brain damage induced retrograde amnesia, where neuro-structures use different neural pathways to avoid the damaged areas while still performing their tasks. Thus, the brain can learn to be independent of the impaired hippocampus, but only to a certain extent. For example, older memories are consolidated over time and in various structures of the brain, including Wernicke's area and the neocortex, making retrieval through alternate pathways possible. As previously mentioned, RA commonly results from damage to the brain regions most closely associated with episodic and declarative memory, including autobiographical information. In extreme cases, individuals may completely forget who they are. Generally, this is a more severe type of amnesia known as global or generalized amnesia. However, memory loss can also be selective or categorical, manifested by a person's inability to remember events related to a specific incident or topic. Patients also differ in durations of RA (how long they can't recall information) and durations of what is forgotten (past time frame for which information is unavailable). In temporally graded retrograde amnesia, victims eventually recover most memories following the onset of RA. This suggests that the hippocampal formation is only used in systematic consolidation for temporary, and short periods of time, until long-term consolidation takes place in other brain structures. Here, the fact that damage to the hippocampal formation can eventually overcome RA suggests that other brain structures are able to take over the jobs of the malfunctioning regions. RA can also progress and further deteriorate memory recollection, as in the case of Korsakoff syndrome and Alzheimer's disease, due to the ongoing nature of the damage caused by the illnesses. The degree to which different patients recover from RA differs in time (some take a few days while others a few decades) and content (some will only remember certain specific instances while others more). These terms are used to describe a pure form of RA, with an absence of anterograde amnesia (AA). In addition, Focal RA in particular, has also been used to describe a RA situation in which there is a lack of observable physical deficit as well. This could be described as a psychogenic form of amnesia with mild anterograde and retrograde loss. A case study of DH revealed that the patient was unable to provide personal or public information, however there was no parahippocampal or entorhinal damage found. Individuals with focal brain damage have minimal RA. Isolated RA is associated with a visible thalamic lesion. Consistent with other forms of RA, the isolated form is marked by a profound inability to recall past information. Pure retrograde amnesia (PRA) refers to the behavioral syndrome that is characterized by the inability to retrieve remote information in the face of a normal ability to learn new information, with no other ecological or psychometric evidence of cognitive impairment. It should not be confused with the brief periods of peritraumatic amnesia that are common in mild concussive head traumas. The findings of pure retrograde amnesia have helped form the dissociation between mechanisms for RA and AA. Several studies have found numerous causes for PRA like vascular diseases, head traumas ranging from mild to severe, encephalitis, as well as purely psychological conditions and totally unidentifiable aetiologies. Most people who suffer from PRA can function normally and learn new information and therefore are not severely set back in life. [57] (Lucchelli, Muggia, & Spinnler, 1998). A pure form of RA is rare as most cases of RA co-occur with AA. A famous example is that of patient ML. The patient's MRI revealed damage to the right ventral frontal cortex and underlying white matter, including the uncinate fasciculus, a band of fibres previously thought to mediate retrieval of specific events from one's personal past. The causal explanation of retrograde amnesia is still under investigation. The three main models used to explain RA assume that the hippocampus is one of the main areas of the brain used in memory consolidation. During consolidation, the hippocampus acts as an intermediate tool that quickly stores new information until it is transferred to the neocortex for the long-term. The temporal lobe, which holds the hippocampus, entorhinal, perirhinal and parahippocampal cortices, has a reciprocal connection with the neocortex. The temporal lobe is temporarily needed when consolidating new information; as the learning becomes stronger, the neocortex becomes more independent of the temporal lobe. Studies on specific cases demonstrate how particular impaired areas of the hippocampus are associated with the severity of RA. Damage can be limited to the CA1 field of the hippocampus, causing very limited RA for about 1 to 2 years. More extensive damage limited to the hippocampus causes temporally graded amnesia for 15 to 25 years. Another study also suggests that large medial temporal lobe lesions, that extend laterally to include other regions, produce more extensive RA, covering 40 to 50 years. These findings suggest that density of RA becomes more severe and long-term as the damage extends beyond the hippocampus to surrounding structures. The common studied causes of RA do not always lead to the onset of RA. It may even be that in some cases both conscious feigning and unconscious processes are at play. Traumatic brain injury (TBI), also known as post-traumatic amnesia, occurs from an external force that causes structural damage to the brain, such as a sharp blow to the head, a diffuse axonal injury, or childhood brain damage (e.g., shaken baby syndrome). In cases of sudden rapid acceleration, the brain continues moving around in the skull, harming brain tissue as it hits internal protrusions. TBI varies according to impact of external forces, location of structural damage, and severity of damage ranging from mild to severe. Retrograde amnesia can be one of the many consequences of brain injury but it is important to note that it is not always the outcome of TBI. An example of a subgroup of people who are often exposed to TBI are individuals who are involved in high-contact sports. Research on football players takes a closer look at some of the implications to their high-contact activities. Enduring consistent head injuries can have an effect on the neural consolidation of memory. Specific cases, such as that of patient ML, support the evidence that severe blows to the head can cause the onset of RA. In this specific case there was an onset of isolated RA following a severe head injury. The brain damage did not affect the person's ability to form new memories. Therefore, the idea that specific sections of retrograde memory are independent of anterograde is supported. Normally, there is a very gradual recovery, however, a dense period of amnesia immediately preceding the trauma usually persists. RA can occur without any anatomical damage to the brain, lacking an observable neurobiological basis. Primarily referred to as psychogenic amnesia or psychogenic fugue, it often occurs due to a traumatic situation that individuals wish to consciously or unconsciously avoid through intrapsychic conflicts or unconscious repressions. The onset of psychogenic amnesia can be either global (i.e., individual forgets all history) or situation specific (i.e., individual is unable to retrieve memories of specific situations). People experiencing psychogenic amnesia have impaired episodic memory, instances of wandering and traveling, and acceptance of a new identity as a result of inaccessible memories pertaining to their previous identity. Recent research has begun to investigate the effects of stress and fear-inducing situations with the onset of RA. Long-term potentiation (LTP) is the process by which there is a signal transmission between neurons after the activation of a neuron, which has been known to play a strong role in the hippocampus in learning and memory. Common changes in the hippocampus have been found to be related to stress and induced LTP. The commonalities support the idea that variations of stress can play a role in producing new memories as well as the onset of RA for other memories. Also, the amygdala plays a crucial role in memory and can be affected by emotional stimuli, evoking RA. Studies of specific cases, such as 'AMN', support evidence of traumatic experiences as a plausible cause of RA. AMN escaped a small fire in his house, did not inhale any smoke, and had no brain damage. Surprisingly, the next day, he was unable to recall autobiographical based knowledge. This case shows that RA can occur in the absence of structural brain damage. After a traumatic head injury, emotional disturbances can occur at three different levels: neurological, reactionary, and long-term disturbances. Neurological disturbances can change emotional and motivational responses. Reactionary disturbances effect emotional and motivational responses as well, but they reflect failure to cope with environmental demands. Someone with this might withdraw from the environment that they are placed in because they no longer know how to handle the cognitive resources. RA has been found among alcohol-dependent patients who suffer from Korsakoff's syndrome. Korsakoff's syndrome patients suffer from retrograde amnesia due to a thiamine deficiency (lack of vitamin B1). Also, chronic alcohol use disorders are associated with a decrease in volume of the left and right hippocampus. These patients' regular diet consists mostly of hard alcohol intake, which lacks the necessary nutrients for healthy development and maintenance. Therefore, after a prolonged time consuming primarily alcohol, these people undergo memory difficulties and ultimately suffer from RA. However, some of the drawback of using Korsakoff patients to study RA is the progressive nature of the illness and the unknown time of onset. Infections that pass the blood–brain barrier can cause brain damage (encephalitis), sometimes resulting in the onset of RA. In the case of patient 'SS', the infection led to focal or isolated retrograde amnesia where there was an absence of or limited AA. Brain scans show abnormalities in the bilateral medial temporal lobes, including two thirds of the hippocampal formation and the posterior part of the amygdala. Henry Molaison suffered from epilepsy that progressed and worsened by his late twenties. The severity of his condition caused him to undergo surgery in an effort to prevent his seizures. Unfortunately, due to a lack of overall known neurological knowledge, Molaison's surgeons removed his bilateral medial temporal lobe, causing profound AA and RA. The removed brain structures included the hippocampus, the amygdala, and the parahippocampal gyrus, now called the medial temporal lobe memory system. HM was one of the most studied memory cases to date and started the examination of neurological structures in relation to memory. Other patients who suffered RA due to surgery are 'P.B.' and 'F.C.' who had unilateral removal of the medial areas in the left temporal lobe. Clinically induced RA has been achieved using different forms of electrical induction. - Electroconvulsive therapy (ECT), used as a depression therapy, can cause impairments in memory. Tests show that information of days and weeks before the ECT can be permanently lost. The results of this study also show that severity of RA is more extreme in cases of bilateral ECT rather than unilateral ECT. Impairments can also be more intense if ECT is administered repetitively (sine wave simulation) as opposed to a single pulse (brief-pulse stimulation). - Electroconvulsive shock (ECS): The research in this field has been advanced by using animals as subjects. Researchers induce RA in rats, for example, by giving daily ECS treatments. This is done to further understand RA. As previously mentioned, RA can affect people's memories in different degrees, but testing is required to help determine if someone is experiencing RA. Several tests exist, for example, testing for factual knowledge such as known public events. A problem with this form of testing is that people generally differ in their knowledge of such subjects. Other ways to test someone is via autobiographical knowledge using the Autobiographical Memory Interview (AMI), comprising names of relatives, personal information, and job history. This information could help determine if someone is experiencing RA and the degree of memory affected. However, due to the nature of the information being tested, it is often difficult to verify the accuracy of the memories being recalled, especially if they are from a distant past. Some researchers have found that the time interval after the head injury occurred did not seem to matter. The effect of the memory loss was the same no matter how long it had been after from the injury. Brain abnormalities can be measured using magnetic resonance imaging (MRI), computed tomography scan (CT) and electroencephalography (EEG), which can provide detailed information about specific brain structures. In many cases, an autopsy helps identify the exact brain region affected and the extent of the damage that caused RA once the patient has died. There are some aspects essential to the patient that remain unaffected by RA. In many patients, their personality remains the same. Also, semantic memory, that is general knowledge about the world, is usually unaffected. However, episodic memory, which refers to one's life experiences, is impaired. Another real life problem with RA is malingering, which is conceived as the rational output of a neurologically normal brain aiming at the surreptitious achievement of a well identified gain. Since it is common for people who have committed a crime to report having RA for that specific event in order to avoid their punishment, the legal system has pushed for the creation of a standardized test of amnesia. However, since most cases differ in onset, duration, and content forgotten, this task has shown to be a rather complex one. When someone is suffering from RA, their memory cannot be recovered from simply being told personal experiences and their identity. This is called reminder effect or reminder treatment. The reminder effect consists of re-exposing the patient to past personal information, which cannot reverse RA. Thus, reminding the patient details of their life has no scientific bearings on recovering memory. Fortunately, memory can be and usually is recovered due to spontaneous recovery and plasticity. Since researchers are interested in examining the effects of disrupted brain areas and conducting experiments for further understanding of an unaffected, normal brain, many individuals with brain damage have volunteered to undergo countless tests to advance our scientific knowledge of the human brain. For example, Henry Molaison (HM) was someone with significant brain damage and participated in a lot of neurological research. Furthermore, he was also the most tested person in neuropsychology. All living people who participate are referred to in literature using only their initials to protect privacy. Each case of RA has led to different symptoms and durations, where some patients have exhibited an inability to describe future plans, whether in the near future (e.g., this afternoon) or in the distant future (e.g., next summer) because of their inability to consolidate memories. Furthermore, researchers have also found that some patients can identify themselves and loved ones in photographs, but cannot determine the time or place the photo was taken. It has also been found that patients with RA greatly differ from the general population in remembering past events. A few case examples are: - After a head injury, AB had to relearn personal information. Many of AB’s habits had also changed. - Patient CD, reported disorientation of place and time following his injuries as well as relearning previously learned information and activities (e.g., using a razor). - EF was examined and found to be very confused about social norms (e.g., appropriate attire outside his home). EF exhibited memory loss of his personal experiences (e.g., childhood), and the impaired ability to recognize his wife and parents. - JG is the first recorded patient suffering from isolated RA. - GH, a mother and a wife, had surgery in August 2002. When GH woke up after the surgery, she believed it was May 1989. Due to her amnesia, GH experienced great difficulty in her social environment, being overwhelmed by relationships to others. - DH, a learning disabilities instructor and husband, suffered a closed head injury. He did not show any normal signs of memory loss but he could not recall anything prior to the accident. - CDA is 20-year-old man who fell and experienced head trauma after being unconscious for a little less than an hour. He had a self-identity loss and a retrograde deficit limited to the autobiographical events 5 years before the trauma. He often showed signs of spontaneous speech that was iterative and sometimes incoherent. When he saw his family and friends, he was shocked at how old they looked because he remembered them from 5 years earlier. This case also included amnesia for procedural skills like the fear of shaving or driving, which ultimately was overcome. There were no psychological, neuropsychological, or brain damage problems. His recovery of memory was progressive and spontaneous, where after several months the amnesia was limited to the two years preceding the trauma. This was a classic case of PRA. [57] - GC was a 38 year old accountant that was found in a town square unable to remember anything about himself and unaware of where he was and how he got there. He was eventually able to recall basic information about himself and his family, but could not recall emotionally charged autobiographical events pertaining to the last 7 years of his life. Within 3–4 days, it was determined that his autobiographical amnesia was clearly and strictly selective for professional events, as he could remember everything that was not related to his job. It was ultimately learned that the job had created severe emotional stress and anxiety due to the extreme hours that triggered a sudden fugue state. He was eventually able to recover most of his memories minus a single work event where he had stolen money from the company. This was a classic case of psychogenic amnesia. [57] - AF is a 15-year-old boy who hit his head and lost consciousness. He could not remember anything but was able to play songs on the piano, showing that his procedural memory was still intact. He gradually recovered some memories within the first 2–3 days but had autobiographical amnesia as well as significant memory loss for famous public facts and events for the 2 years prior to the injury. [57] Although it may seem that people living with brain damage have great difficulty continuing the usual day-to-day aspects, they still can accomplish many feats. People with RA are able to lead a normal life. For instance, KC is a man who has many functional aspects intact; normal intelligence, unaffected perceptual and linguistic skills, short-term memory, social skills, and reasoning abilities. All of these things are necessary in everyday life and contribute to normal living. KC also is fully capable of scripted activities (e.g., making reservations or changing a flat tire). In addition, patient HC successfully graduated high school and continued into post-secondary studies, an obvious accomplishment despite her condition. DH relearned his childhood memories from his parents and can retell the stories, but cannot recall specifics other than what has been told to him. Other forms of amnesia exist and may be confused with RA. For instance, anterograde amnesia (AA) is the inability to learn new information. This describes a problem encoding, storing, or retrieving information that can be used in the future. It is important to note that these two conditions can, and often do both occur in the same patient simultaneously, but are otherwise separate forms of amnesia. RA can also be an inherent aspect of other forms of amnesia, namely transient global amnesia (TGA). TGA is the sudden onset of AA and RA caused by a traumatic event, however it is short lived, typically lasting only 4 to 8 hours. TGA is very difficult to study because of the patients' quick recovery. This form of amnesia, like AA, remains distinct from RA. Post-traumatic amnesia (PTA) is a state of confusion that occurs immediately following a traumatic brain injury in which the injured person is disoriented and unable to remember events that occur after the injury. Psychogenic amnesia, or dissociative amnesia, is a memory disorder characterized by sudden retrograde autobiographical memory loss, said to occur for a period of time ranging from hours to years.	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https://en.wikipedia.org/wiki/Iron_overload	disease	Iron overload	Iron overload, also known as haemochromatosis, indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.	Organs commonly affected by haemochromatosis are the liver, heart, and endocrine glands. Haemochromatosis may present with the following clinical syndromes: - Cirrhosis of the liver: Varies from zonal iron deposition to fibrosis (cirrhosis). - Diabetes due to selective iron deposition in pancreatic islet beta cells leading to functional failure and cell death. - Cardiomyopathy - Arthritis, from calcium pyrophosphate deposition in joints. The most commonly affected joints are those of the hands, particularly the knuckles of the second and third fingers. - Testicular failure - Bronzing of the skin. This deep tan color, in concert with insulin insufficiency due to pancreatic damage, is the source of a nickname for this condition: "bronze diabetes". - Joint pain and bone pain The causes can be distinguished between primary cases (hereditary or genetically determined) and less frequent secondary cases (acquired during life). People of Celtic (Irish, Scottish, Welsh, Cornish, Breton etc.), English, and Scandinavian origin have a particularly high incidence of whom about 10% are carriers of the C282Y mutation on the HFE gene associated with HLA-A3 and 1% have the condition. Although it was known most of the 20th century that most cases of haemochromatosis were inherited, they were incorrectly assumed to depend on a single gene. The overwhelming majority depend on mutations of the HFE gene discovered in 1996, but since then others have been discovered and sometimes are grouped together as "non-classical hereditary haemochromatosis", "non-HFE related hereditary haemochromatosis", or "non-HFE haemochromatosis". Most types of hereditary haemochromatosis have autosomal recessive inheritance, while type 4 has autosomal dominant inheritance. There are several methods available for diagnosing and monitoring iron loading including: - Serum ferritin: In males and postmenopausal females, a serum ferritin value of over 300 ng/mL (670 pmol/L) indicates iron overload. In premenopausal females, a serum ferritin value of over 150 or 200 ng/mL (330 or 440 pmol/L) indicates iron overload. - Liver biopsy - HFE - MRI Serum ferritin testing is a low-cost, readily available, and minimally invasive method for assessing body iron stores. However, the major problem with using it as an indicator of iron overload is that it can be elevated in a range of other medical conditions unrelated to iron levels including infection, inflammation, fever, liver disease, kidney disease, and cancer. Also, total iron binding capacity may be low, but can also be normal. The standard of practice in diagnosis of haemochromatosis was recently reviewed by Pietrangelo. Positive HFE analysis confirms the clinical diagnosis of haemochromatosis in asymptomatic individuals with blood tests showing increased iron stores, or for predictive testing of individuals with a family history of haemochromatosis. The alleles evaluated by HFE gene analysis are evident in ~80% of patients with haemochromatosis; a negative report for HFE gene does not rule out haemochromatosis. In a patient with negative HFE gene testing, elevated iron status for no other obvious reason, and family history of liver disease, additional evaluation of liver iron concentration is indicated. In this case, diagnosis of haemochromatosis is based on biochemical analysis and histologic examination of a liver biopsy. Assessment of the hepatic iron index (HII) is considered the "gold standard" for diagnosis of haemochromatosis. Magnetic resonance imaging (MRI) is emerging as a noninvasive alternative to accurately estimate iron deposition levels in the liver as well as heart, joints, and pituitary gland. First degree relatives of those with primary haemochromatosis should be screened to determine if they are a carrier or if they could develop the disease. This can allow preventive measures to be taken. Screening the general population is not recommended. Routine treatment in an otherwise-healthy person consists of regularly scheduled phlebotomies (bloodletting or erythrocytapheresis). When first diagnosed, the phlebotomies may be fairly frequent, until iron levels can be brought to within normal range. Once iron and other markers are within the normal range, treatments may be scheduled every other month or every three months depending upon the underlying cause of the iron overload and the person's iron load. A phlebotomy session typically draws between 450 to 500 cc whole blood. For those unable to tolerate routine blood draws, there is a chelating agent available for use. The drug deferoxamine binds with iron in the bloodstream and enhances its elimination in urine and faeces. Typical treatment for chronic iron overload requires subcutaneous injection over a period of 8–12 hours daily. Two newer iron chelating drugs that are licensed for use in patients receiving regular blood transfusions to treat thalassaemia (and, thus, who develop iron overload as a result) are deferasirox and deferiprone. Affected individuals over age 40 or who have high serum ferritin levels are at risk for developing cirrhosis. Iron overload increases the risk of hepatocellular carcinoma. This risk is greater in those with cirrhosis but is still present in those without cirrhosis. Significant problems occur in around one in ten. It is most common in certain European populations (such as the Irish and Norwegians) and occurs in 0.6% of the population. Men with the disease are 24 times more likely to experience symptoms than affected women. Historically, the term haemochromatosis (spelled hemochromatosis in American English) was initially used to refer to what is now more specifically called haemochromatosis type 1 (or HFE-related hereditary haemochromatosis). Currently, haemochromatosis (without further specification) is mostly defined as iron overload with a hereditary or primary cause, or originating from a metabolic disorder. However, the term is currently also used more broadly to refer to any form of iron overload, thus requiring specification of the cause, for example, hereditary haemochromatosis. Hereditary haemochromatosis is an autosomal recessive disorder with estimated prevalence in the population of 1 in 200 among patients with European ancestry, with lower incidence in other ethnic groups. The gene responsible for hereditary haemochromatosis (known as HFE gene) is located on chromosome 6; the majority of hereditary haemochromatosis patients have mutations in this HFE gene. Hereditary haemochromatosis is characterized by an accelerated rate of intestinal iron absorption and progressive iron deposition in various tissues. This typically begins to be expressed in the third to fifth decades of life, but may occur in children. The most common presentation is hepatic (liver) cirrhosis in combination with hypopituitarism, cardiomyopathy, diabetes, arthritis, or hyperpigmentation. Because of the severe sequelae of this disorder if left untreated, and recognizing that treatment is relatively simple, early diagnosis before symptoms or signs appear is important. In general, the term haemosiderosis is used to indicate the pathological effect of iron accumulation in any given organ, which mainly occurs in the form of the iron-storage complex haemosiderin. Sometimes, the simpler term siderosis is used instead. Other definitions distinguishing haemochromatosis or haemosiderosis that are occasionally used include: - Haemosiderosis is haemochromatosis caused by excessive blood transfusions, that is, haemosiderosis is a form of secondary haemochromatosis. - Haemosiderosis is haemosiderin deposition within cells, while haemochromatosis is haemosiderin within cells and interstitium. - Haemosiderosis is iron overload that does not cause tissue damage, while haemochromatosis does. - Haemosiderosis is arbitrarily differentiated from haemochromatosis by the reversible nature of the iron accumulation in the reticuloendothelial system.	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https://en.wikipedia.org/wiki/Anaplastic_astrocytoma	disease	Anaplastic astrocytoma	Anaplastic astrocytoma is a rare WHO grade III type of astrocytoma, which is a type of cancer of the brain. In the United States, the annual incidence rate for Anaplastic astrocytoma is 0.44 per 100,000 persons	Anaplastic astrocytomas fall under the category of high grade gliomas (WHO grade III-IV), which are pathologically undifferentiated gliomas that carry a poor clinical prognosis. Unlike glioblastomas (WHO grade IV), anaplastic astrocytomas lack vascular proliferation and necrosis on pathologic evaluation. Compared to grade II tumors, anaplastic astrocytomas are more cellular, demonstrate more atypia, and mitoses are seen. Initial presenting symptoms most commonly are headache, depressed mental status, focal neurological deficits, and/or seizures. The growth rate and mean interval between onset of symptoms and diagnosis is approximately 1.5–2 years but is highly variable, being intermediate between that of low-grade astrocytomas and glioblastomas. Seizures are less common among patients with anaplastic astrocytomas compared to low-grade lesions. Most high-grade gliomas occur sporadically or without identifiable cause. However, a small proportion (less than 5%) of persons with malignant astrocytoma has a definite or suspected hereditary predisposition. The main hereditary predispositions are mainly neurofibromatosis type I, Li-Fraumeni syndrome, hereditary nonpolyposis colorectal cancer and tuberous sclerosis. Anaplastic astrocytomas have also been associated with previous exposure to vinyl chloride and to high doses of radiation therapy to the brain. The standard initial treatment is to remove as much of the tumor as possible without worsening neurologic deficits. Radiation therapy has been shown to prolong survival and is a standard component of treatment. There is no proven benefit to adjuvant chemotherapy or supplementing other treatments for this kind of tumor. Although temozolomide is effective for treating recurrent anaplastic astrocytoma, its role as an adjuvant to radiation therapy has not been fully tested. Quality of life after treatment depends heavily on the area of the brain that housed the tumor. In many cases, patients with anaplastic astrocytoma may experience various types of paralysis, speech impediments, difficulties planning and skewed sensory perception. Most cases of paralysis and speech difficulties can be rehabilitated with speech, occupational, physical, and vision therapy. The age-standardized 5-year relative survival rate is 23.6%. Patients with this tumor are 46 times more likely to die than matched members of the general population. It is important to note that prognosis across age groups is different especially during the first three years post-diagnosis. When the elderly population is compared with young adults, the excess hazard ratio (a hazard ratio that is corrected for differences in mortality across age groups) decreases from 10.15 to 1.85 at 1 to 3 years, meaning that the elderly population are much more likely to die in the first year post-diagnosis when compared to young adults (aged 15 to 40), but after three years, this difference is reduced markedly. Typical median survival for anaplastic astrocytoma is 2–3 years. Secondary progression to glioblastoma multiforme is common. Radiation, younger age, female sex, treatment after 2000, and surgery were associated with improved survival in AA patients.	[ { "begin": 0, "class": "SectionAnnotation", "length": 425, "sectionHeading": "Pathology", "sectionLabel": "disease.pathology" }, { "begin": 425, "class": "SectionAnnotation", "length": 431, "sectionHeading": "Symptoms", "sectionLabel": "disease.symptom" }, { "begin": 856, "class": "SectionAnnotation", "length": 515, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 1371, "class": "SectionAnnotation", "length": 865, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 2236, "class": "SectionAnnotation", "length": 958, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" } ]
https://en.wikipedia.org/wiki/Riedel's_thyroiditis	disease	Riedel's thyroiditis	Riedel's thyroiditis, also called Riedel's struma is a chronic form of thyroiditis. It is now believed that Riedel's thyroiditis is one manifestation of a systemic disease that can affect many organ systems called IgG4-related disease. It is often a multi-organ disease affecting pancreas, liver, kidney, salivary and orbital tissues and retroperitoneum. The hallmarks of the disease are fibrosis and infiltration by IgG4 secreting plasma cells.	Riedel's thyroiditis is characterized by a replacement of the normal thyroid parenchyma by a dense fibrosis that invades adjacent structures of the neck and extends beyond the thyroid capsule. This makes the thyroid gland stone-hard (woody) and fixed to adjacent structures. The inflammatory process infiltrates muscles and causes symptoms of tracheal compression. Surgical treatment is required to relieve tracheal or esophageal obstruction. Therapy usually consists of prednisolone, nonetheless some cases may require surgery. Tamoxifen has been proposed as part of a treatment plan. Treatment is directed to surgical relief of compressive symptoms. Tamoxifen may also be beneficial. -Harrison's principle of internal medicine, 17th The type of surgery which is indicated here is isthmectomy. Riedel's thyroiditis is classified as rare. Most patients remain euthyroid, but approximately 30% of patients become hypothyroid and very few patients are hyperthyroid. It is most seen in women. It is named for Bernhard Riedel. He first recognized the disease In 1883 and published its description in 1896.	[ { "begin": 0, "class": "SectionAnnotation", "length": 443, "sectionHeading": "Pathophysiology", "sectionLabel": "disease.pathophysiology" }, { "begin": 443, "class": "SectionAnnotation", "length": 353, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 796, "class": "SectionAnnotation", "length": 195, "sectionHeading": "Prevalence", "sectionLabel": "disease.epidemiology" }, { "begin": 991, "class": "SectionAnnotation", "length": 112, "sectionHeading": "Eponym", "sectionLabel": "disease.etymology" } ]
https://en.wikipedia.org/wiki/MOMO_syndrome	disease	MOMO syndrome	MOMO syndrome is an extremely rare genetic disorder which belongs to the overgrowth syndromes and has been diagnosed in only six cases around the world, and occurs in 1 in 100 million births. The name is an acronym of the four primary aspects of the disorder: Macrosomia (excessive birth weight), Obesity, Macrocephaly (excessive head size) and Ocular abnormalities. It is unknown if it is a life-limiting condition. MOMO syndrome was first diagnosed in 1993 by Professor Célia Priszkulnik Koiffmann, a Brazilian researcher in the Genetic and Clinical Studies of neurodevelopmental disorders. This syndrome's acronym is an intended pun. It refers to the traditionally tall and obese king of Carnivals, Momus—Rei Momo in Portuguese.	Along with the four aspects of the disorder that give it its name, there are also other common symptoms: - A downward slant of the forehead - Delayed bone maturation - Mental retardation The ocular abnormalities are generally retinal coloboma and nystagmus. Because MOMO is such a rare disorder, very few studies have been conducted into its causes. Current research suggests that it is linked to a de novo (new) autosomal dominant mutation. Archie Thompson was born in 2002 in Icklesham, England and weighed 8 lb 4 oz (3740 g). By 15 months his weight had increased to 4 stone (56 lb; 25 kg) and by 24 months it was up to 6 stone (84 pounds; 38 kg). The condition placed a large strain on his heart and lungs. The Thompson family were featured in a documentary for Five first shown on 3 October 2004. It has since aired on Discovery Fit & Health in the United States. Danielle Falan, from São Paulo, Brazil, is one of the oldest surviving sufferers of MOMO syndrome. At age 17 she was featured in the Archie Thompson documentary as her mother traveled to visit her in Brazil. Falan attended school as normal, and hopes to attend college. Five other cases have been diagnosed, in Italy, in Brazil , two in Germany, and in Poland. An additional case was reported in 2010.	[ { "begin": 0, "class": "SectionAnnotation", "length": 258, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 258, "class": "SectionAnnotation", "length": 184, "sectionHeading": "Pathophysiology", "sectionLabel": "disease.pathophysiology" }, { "begin": 442, "class": "SectionAnnotation", "length": 829, "sectionHeading": "Confirmed cases", "sectionLabel": "disease.research" } ]
https://en.wikipedia.org/wiki/T-cell_lymphoma	disease	T-cell lymphoma	The T-cell lymphomas are four types of lymphoma that affect T cells. These account for about one in ten cases of non-Hodgkin lymphoma. They can be associated with Epstein Barr virus and Human T-cell leukemia virus-1.	The four classes are: - Extranodal T cell lymphoma - Cutaneous T cell lymphomas: Sézary syndrome and Mycosis fungoides - Anaplastic large cell lymphoma - Angioimmunoblastic T cell lymphoma More information on various classification schemes is in the main lymphoma article. Of all cancers involving the same class of blood cell, 8% of cases are mature T cell lymphomas. Of such cases, 2% are precursor T lymphoblastic and 2% are cutaneous T cell lymphomas.	[ { "begin": 0, "class": "SectionAnnotation", "length": 273, "sectionHeading": "Types", "sectionLabel": "disease.classification" }, { "begin": 273, "class": "SectionAnnotation", "length": 183, "sectionHeading": "Epidemiology", "sectionLabel": "disease.epidemiology" } ]
https://en.wikipedia.org/wiki/Nasolacrimal_duct_obstruction	disease	Nasolacrimal duct obstruction	Nasolacrimal duct obstruction (NLDO) is the obstruction of nasolacrimal duct and may be either congenital or acquired. Obstruction of the nasolacrimal duct leads to the excess overflow of tears called epiphora.	Excessive tearing is the most common complaint of patients with NLDO, followed by acute or chronic infections. Pain at the side of the nose suggests dacryocystitis. NLDO is found to be more common with increasing age and more common in females. Involutional stenosis is probably the most common cause of NLD obstruction in older persons. It affects women twice as frequently as men. Although the inciting event in this process is unknown, clinicopathologic study suggests that compression of the lumen of the NLD is caused by inflammatory infiltrates and edema. This may be the result of an unidentified infection or possibly an autoimmune disease. Dacryoliths or cast formation, within the lacrimal sac can also produce obstruction of the NLD. Sinus disease often occurs in conjunction with, and in other instances may contribute to the development of NLD obstruction. Patients should be asked about previous sinus surgery, as the NLD is sometimes damaged when the maxillary sinus ostium is being enlarged anteriorly. Naso-orbital fractures may involve the NLD. Early treatment by fracture reduction with stenting of the entire lacrimal drainage system should be considered. However, such injuries are often not recognized or are initially neglected as more serious injuries are managed. In such cases, late treatment of persistent epiphora usually requires DCR. Granulomatous disease, including sarcoidosis, granulomatosis with polyangiitis, and midline granuloma, may also lead to NLD obstruction. As with similar cases of canalicular obstruction, dislodged punctal and canalicular plugs can migrate to and occlude the NLD. Neoplasm should be considered in any patient presenting with NLD obstruction.In patients with an atypical presentation, including younger age and male gender, further workup is appropriate. Bloody punctal discharge or lacrimal sac distension above the medial canthal tendon is also highly suggestive of neoplasm. Congenital nasolacrimal duct obstruction, or dacryostenosis, occurs when the lacrimal duct has failed to open at the time of birth, most often due to an imperforate membrane at the valve of Hasner. Around 6% of infants have CLDO, usually experiencing a persistent watery eye even when not crying. If a secondary infection occurs (Dacryocystitis), purulent (yellow / green) discharge may be present. Most cases resolve spontaneously, with antibiotics reserved only if conjunctivitis occurs. Lacrimal sac massage has been proposed as helping to open the duct, though this is not always successful. The aim of massage is to generate enough hydrostatic pressure (downward, toward the nose) to "pop" open any obstruction. Additional massage may then be performed up toward the lacrimal punctum, in order to express any infectious material out of the nasolacrimal sac. When discharge or crusting is present, the lids should be gently cleaned using cooled pre-boiled water or saline. Referral to an ophthalmologist is indicated if symptoms are still present at 12 months, or sooner if significant symptoms or recurrent infections occur. Nasolacrimal duct probing may be performed in the office setting (usually from 4 to 8 months of age) or under general anesthesia in an operating room for older patients. The success rate of probing is higher for younger children. A silastic tube or stent may be employed along with probing to maintain tear duct patency. A systematic review comparing immediate probing with deferred probing found that in children with unilateral NLDO, immediate probing resulted in a higher success rate of treatment compared to deferred probing. Evaluation is in the form of a dye disappearance test followed by irrigation test. By using this sequence (with modifications) as a guide, the physician can frequently streamline diagnostic testing. The dye disappearance test (DDT) is useful for assessing the presence or absence of adequate lacrimal outflow, especially in unilateral cases. It is more heavily relied upon in children, in whom lacrimal irrigation is impossible without deep sedation. Using a drop of sterile 2% fluorescein solution or a moistened fluorescein strip, the examiner instills fluorescein into the conjunctival fornices of each eye and then observes the tear film, preferably with the cobalt blue filter of the slit lamp. Persistence of significant dye and, particularly asymmetric clearance of the dye from the tear meniscus over a 5-minute period indicate an obstruction. If the DDT result is normal, severe lacrimal drainage dysfunction is highly unlikely. Variations of the DDT are the Jones tests. In irrigation test, a lacrimal irrigation cannula is passed into the punctum and advanced through the canaliculus to the lacrimal fossa. Clear water or saline is then irrigated through the cannula. If fluid passes into the nose without reflux out of the opposite canaliculus, the system is patent. If no fluid passes but it all comes back through either punctum, nasolacrimal duct obstruction is present. Some clinicians believe that partial stenosis of the NLD with symptomatic epiphora sometimes responds to surgical intubation of the entire lacrimal drainage system. This procedure should be performed only if the tubes can be passed easily. In complete NLD obstruction, intubation alone is not effective, and a DCR should be considered. A DCR is the treatment of choice for most patients with acquired NLD obstruction. Surgical indications include recurrent dacryocystitis, chronic mucoid reflux, painful distension of the lacrimal sac, and bothersome epiphora. For patients with dacryocystitis, active infection should be cleared, if possible, before DCR is performed.	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https://en.wikipedia.org/wiki/Gastroesophageal_reflux_disease	disease	Gastroesophageal reflux disease	Gastroesophageal reflux disease (GERD), also known as acid reflux, is a long-term condition where stomach contents come back up into the esophagus resulting in either symptoms or complications. Symptoms include the taste of acid in the back of the mouth, heartburn, bad breath, chest pain, vomiting, breathing problems, and wearing away of the teeth. Complications include esophagitis, esophageal strictures, and Barrett's esophagus. Risk factors include obesity, pregnancy, smoking, hiatus hernia, and taking certain medicines. Medications involved include antihistamines, calcium channel blockers, antidepressants, and sleeping medication. It is due to poor closure of the lower esophageal sphincter (the junction between the stomach and the esophagus). Diagnosis among those who do not improve with simpler measures may involve gastroscopy, upper GI series, esophageal pH monitoring, or esophageal manometry. Treatment is typically via lifestyle changes, medications, and sometimes surgery. Lifestyle changes include not lying down for three hours after eating, losing weight, avoiding certain foods, and stopping smoking. Medications include antacids, H receptor blockers, proton pump inhibitors, and prokinetics. Surgery may be an option in those who do not improve with other measures. In the Western world, between 10 and 20% of the population are affected by GERD. Gastroesophageal reflux (GER) once in a while, without significant symptoms or complications, is more common. The condition was first described in 1935 by the American gastroenterologist Asher Winkelstein. The classic symptoms had been described earlier in 1925.	The most common symptoms of GERD in adults are an acidic taste in the mouth, regurgitation, and heartburn. Less common symptoms include pain with swallowing/sore throat, increased salivation (also known as water brash), nausea, chest pain, and coughing. GERD sometimes causes injury of the esophagus. These injuries may include one or more of the following: - Reflux esophagitis – inflammation of esophageal epithelium which can cause ulcers near the junction of the stomach and esophagus - Esophageal strictures – the persistent narrowing of the esophagus caused by reflux-induced inflammation - Barrett's esophagus – intestinal metaplasia (changes of the epithelial cells from squamous to intestinal columnar epithelium) of the distal esophagus - Esophageal adenocarcinoma – a form of cancer Some researchers have proposed that recurrent ear infections, and idiopathic pulmonary fibrosis might be tied, in some cases, to GERD; however, a causative role has not been established. GERD does not appear to be linked to chronic sinusitis. GERD may be difficult to detect in infants and children, since they cannot describe what they are feeling and indicators must be observed. Symptoms may vary from typical adult symptoms. GERD in children may cause repeated vomiting, effortless spitting up, coughing, and other respiratory problems, such as wheezing. Inconsolable crying, refusing food, crying for food and then pulling off the bottle or breast only to cry for it again, failure to gain adequate weight, bad breath, and burping are also common. Children may have one symptom or many; no single symptom is universal in all children with GERD. Of the estimated 4 million babies born in the US each year, up to 35% of them may have difficulties with reflux in the first few months of their lives, known as 'spitting up'. One theory for this is the "fourth trimester theory" which notes most animals are born with significant mobility, but humans are relatively helpless at birth, and suggests there may have once been a fourth trimester, but children began to be born earlier, evolutionarily, to accommodate the development of larger heads and brains and allow them to pass through the birth canal and this leaves them with partially undeveloped digestive systems. Most children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition. This is particularly true when a family history of GERD is present. GERD may lead to Barrett's esophagus, a type of intestinal metaplasia, which is in turn a precursor condition for esophageal cancer. The risk of progression from Barrett's to dysplasia is uncertain, but is estimated at about 20% of cases. Due to the risk of chronic heartburn progressing to Barrett's, EGD every five years is recommended for people with chronic heartburn, or who take drugs for chronic GERD. GERD is caused by a failure of the lower esophageal sphincter. In healthy patients, the "Angle of His"—the angle at which the esophagus enters the stomach—creates a valve that prevents duodenal bile, enzymes, and stomach acid from traveling back into the esophagus where they can cause burning and inflammation of sensitive esophageal tissue. Factors that can contribute to GERD: - Hiatal hernia, which increases the likelihood of GERD due to mechanical and motility factors. - Obesity: increasing body mass index is associated with more severe GERD. In a large series of 2,000 patients with symptomatic reflux disease, it has been shown that 13% of changes in esophageal acid exposure is attributable to changes in body mass index. - Zollinger-Ellison syndrome, which can be present with increased gastric acidity due to gastrin production. - A high blood calcium level, which can increase gastrin production, leading to increased acidity. - Scleroderma and systemic sclerosis, which can feature esophageal dysmotility. - The use of medicines such as prednisolone. - Visceroptosis or Glénard syndrome, in which the stomach has sunk in the abdomen upsetting the motility and acid secretion of the stomach. GERD has been linked to a variety of respiratory and laryngeal complaints such as laryngitis, chronic cough, pulmonary fibrosis, earache, and asthma, even when not clinically apparent. These atypical manifestations of GERD are commonly referred to as laryngopharyngeal reflux (LPR) or as extraesophageal reflux disease (EERD). Factors that have been linked with GERD, but not conclusively: - Obstructive sleep apnea - Gallstones, which can impede the flow of bile into the duodenum, which can affect the ability to neutralize gastric acid In 1999, a review of existing studies found that, on average, 40% of GERD patients also had H. pylori infection. The eradication of H. pylori can lead to an increase in acid secretion, leading to the question of whether H. pylori-infected GERD patients are any different than non-infected GERD patients. A double-blind study, reported in 2004, found no clinically significant difference between these two types of patients with regard to the subjective or objective measures of disease severity. The diagnosis of GERD is usually made when typical symptoms are present. Reflux can be present in people without symptoms and the diagnosis requires both symptoms or complications and reflux of stomach content. Other investigations may include esophagogastroduodenoscopy (EGD). Barium swallow X-rays should not be used for diagnosis. Esophageal manometry is not recommended for use in diagnosis, being recommended only prior to surgery. Ambulatory esophageal pH monitoring may be useful in those who do not improve after PPIs and is not needed in those in whom Barrett's esophagus is seen. Investigation for H. pylori is not usually needed. The current gold standard for diagnosis of GERD is esophageal pH monitoring. It is the most objective test to diagnose the reflux disease and allows monitoring GERD patients in their response to medical or surgical treatment. One practice for diagnosis of GERD is a short-term treatment with proton-pump inhibitors, with improvement in symptoms suggesting a positive diagnosis. Short-term treatment with proton-pump inhibitors may help predict abnormal 24-hr pH monitoring results among patients with symptoms suggestive of GERD. Endoscopy, the looking down into the stomach with a fibre-optic scope, is not routinely needed if the case is typical and responds to treatment. It is recommended when people either do not respond well to treatment or have alarm symptoms, including dysphagia, anemia, blood in the stool (detected chemically), wheezing, weight loss, or voice changes. Some physicians advocate either once-in-a-lifetime or 5- to 10-yearly endoscopy for people with longstanding GERD, to evaluate the possible presence of dysplasia or Barrett's esophagus. Biopsies performed during gastroscopy may show: - Edema and basal hyperplasia (nonspecific inflammatory changes) - Lymphocytic inflammation (nonspecific) - Neutrophilic inflammation (usually due to reflux or Helicobacter gastritis) - Eosinophilic inflammation (usually due to reflux): The presence of intraepithelial eosinophils may suggest a diagnosis of eosinophilic esophagitis (EE) if eosinophils are present in high enough numbers. Less than 20 eosinophils per high-power microscopic field in the distal esophagus, in the presence of other histologic features of GERD, is more consistent with GERD than EE. - Goblet cell intestinal metaplasia or Barrett's esophagus - Elongation of the papillae - Thinning of the squamous cell layer - Dysplasia - Carcinoma Reflux changes may not be erosive in nature, leading to "nonerosive reflux disease". Severity may be documented with the Johnson-DeMeester's scoring system: 0 - None 1 - Minimal - occasional episodes 2 - Moderate - medical therapy visits 3 - Severe - interfere with daily activities Other causes of chest pain such as heart disease should be ruled out before making the diagnosis. Another kind of acid reflux, which causes respiratory and laryngeal signs and symptoms, is called laryngopharyngeal reflux (LPR) or "extraesophageal reflux disease" (EERD). Unlike GERD, LPR rarely produces heartburn, and is sometimes called silent reflux. The treatments for GERD include lifestyle modifications, medications, and possibly surgery. Initial treatment is frequently with a proton-pump inhibitor such as omeprazole. Certain foods and lifestyle are considered to promote gastroesophageal reflux, but most dietary interventions have little supporting evidence. Avoidance of specific foods and of eating before lying down should be recommended only to those in which they are associated with the symptoms. Foods that have been implicated include coffee, alcohol, chocolate, fatty foods, acidic foods, and spicy foods. Weight loss and elevating the head of the bed are generally useful. A wedge pillow that elevates the head may inhibit gastroesophageal reflux during sleep. Stopping smoking and not drinking alcohol do not appear to result in significant improvement in symptoms. Although moderate exercise may improve symptoms in people with GERD, vigorous exercise may worsen them. The primary medications used for GERD are proton-pump inhibitors, H receptor blockers and antacids with or without alginic acid. Proton-pump inhibitors (PPIs), such as omeprazole, are the most effective, followed by H receptor blockers, such as ranitidine. If a once daily PPI is only partially effective they may be used twice a day. They should be taken one half to one hour before a meal. There is no significant difference between agents in this class. When these medications are used long term, the lowest effective dose should be taken. They may also be taken only when symptoms occur in those with frequent problems. H receptor blockers lead to roughly a 40% improvement. The evidence for antacids is weaker with a benefit of about 10% (NNT=13) while a combination of an antacid and alginic acid (such as Gaviscon) may improve symptoms 60% (NNT=4). Metoclopramide (a prokinetic) is not recommended either alone or in combination with other treatments due to concerns around adverse effects. The benefit of the prokinetic mosapride is modest. Sucralfate has a similar effectiveness to H receptor blockers; however, sucralfate needs to be taken multiple times a day, thus limiting its use. Baclofen, an agonist of the GABA receptor, while effective, has similar issues of needing frequent dosing in addition to greater adverse effects compared to other medications. The standard surgical treatment for severe GERD is the Nissen fundoplication. In this procedure, the upper part of the stomach is wrapped around the lower esophageal sphincter to strengthen the sphincter and prevent acid reflux and to repair a hiatal hernia. It is recommended only for those who do not improve with PPIs. Quality of life is improved in the short term compared to medical therapy, but there is uncertainty in the benefits over surgery versus long-term medical management with proton pump inhibitors. When comparing different fundoplication techniques, partial posterior fundoplication surgery is more effective than partial anterior fundoplication surgery, and partial fundoplication has better outcomes than total fundoplication. In 2012 the FDA approved a device called the LINX, which consists of a series of metal beads with magnetic cores that are placed surgically around the lower esophageal sphincter, for those with severe symptoms that do not respond to other treatments. Improvement of GERD symptoms is similar to those of the Nissen fundoplication, although there is no data regarding long-term effects. Compared to Nissen fundoplication procedures, the procedure has shown a reduction in complications such as gas bloat syndrome that commonly occur. Adverse responses include difficulty swallowing, chest pain, vomiting, and nausea. Contraindications that would advise against use of the device are patients who are or may be allergic to titanium, stainless steel, nickel, or ferrous iron materials. A warning advises that the device should not be used by patients who could be exposed to, or undergo, magnetic resonance imaging (MRI) because of serious injury to the patient and damage to the device. In those with symptoms that do not improve with PPIs surgery known as transoral incisionless fundoplication may help. Benefits may last for up to six years. In pregnancy, dietary modifications and lifestyle changes may be attempted, but often have little effect. Calcium-based antacids are recommended if these changes are not effective. Aluminum- and magnesium-based antacids are also safe, as is ranitidine and PPIs. Infants may see relief with changes in feeding techniques, such as smaller, more frequent feedings, changes in position during feedings, or more frequent burping during feedings. They may also be treated with medicines such as ranitidine or proton pump inhibitors. Proton pump inhibitors however have not been found to be effective in this population and there is a lack of evidence for safety. The use of acid suppression therapy is a common response to GERD symptoms and many patients get more of this kind of treatment than their individual case merits. The overuse of this treatment is a problem because of the side effects and costs which the patient will have from undergoing unnecessary therapy, and patients should not take more treatment than they need. In some cases, a person with GERD symptoms can manage them by taking over-the-counter drugs and making lifestyle changes. This is often safer and less expensive than taking prescription drugs. Some guidelines recommend trying to treat symptoms with an H antagonist before using a proton-pump inhibitor because of cost and safety concerns. In Western populations, GERD affects approximately 10% to 20% of the population and 0.4% newly develop the condition. For instance, an estimated 3.4 million to 6.8 million Canadians are GERD sufferers. The prevalence rate of GERD in developed nations is also tightly linked with age, with adults aged 60 to 70 being the most commonly affected. In the United States 20% of people have symptoms in a given week and 7% every day. No data support sex predominance with regard to GERD. An obsolete treatment is vagotomy ("highly selective vagotomy"), the surgical removal of vagus nerve branches that innervate the stomach lining. This treatment has been largely replaced by medication. Vagotomy by itself tended to worsen contraction of the pyloric sphincter of the stomach, and delayed stomach emptying. Historically, vagotomy was combined with pyloroplasty or gastroenterostomy to counter this problem. A number of endoscopic devices have been tested to treat chronic heartburn. - Endocinch, puts stitches in the lower esophogeal sphincter (LES) to create small pleats to help strengthen the muscle. However, long-term results were disappointing, and the device is no longer sold by Bard. - Stretta procedure, uses electrodes to apply radio-frequency energy to the LES. A 2015 systematic review and meta-analysis in response to the systematic review (no meta-analysis) conducted by SAGES did not support the claims that Stretta was an effective treatment for GERD. A 2012 systematic review found that it improves GERD symptoms. - NDO Surgical Plicator creates a plication, or fold, of tissue near the gastroesophageal junction, and fixates the plication with a suture-based implant. The company ceased operations in mid-2008, and the device is no longer on the market. - Transoral incisionless fundoplication, which uses a device called Esophyx, may be effective.	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https://en.wikipedia.org/wiki/Trench_foot	disease	Trench foot	Trench foot is a medical condition caused by prolonged exposure of the feet to damp, unsanitary, and cold conditions. It is one of many immersion foot syndromes. The use of the word trench in the name of this condition is a reference to trench warfare, mainly associated with World War I, which started in 1914.	Affected feet may become numb, by erythema (turning red) or cyanosis (turning blue) as a result of poor blood supply, and may begin emanating a decaying odor if the early stages of necrosis (tissue death) set in. As the condition worsens, feet may also begin to swell. Advanced trench foot often involves blisters and open sores, which lead to fungal infections; this is sometimes called tropical ulcer (jungle rot). If left untreated, trench foot usually results in gangrene, which may require amputation. If trench foot is treated properly, complete recovery is normal, though it is marked by severe short-term pain when feeling returns. Unlike frostbite, trench foot does not require freezing temperatures; it can occur in temperatures up to 16° Celsius (about 60° Fahrenheit) and within as little as 13 hours. Exposure to these environmental conditions causes deterioration and destruction of the capillaries and leads to morbidity of the surrounding flesh. Excessive sweating (hyperhidrosis) has long been regarded as a contributory cause; unsanitary, cold, and wet conditions can also cause trench foot. Trench foot can be prevented by keeping the feet clean, warm, and dry. It was also discovered in World War I that a key preventive measure was regular foot inspections; soldiers would be paired and each made responsible for the feet of the other, and they would generally apply whale oil to prevent trench foot. If left to their own devices, soldiers might neglect to take off their own boots and socks to dry their feet each day, but if it were the responsibility of another, this became less likely. Later on in the war, instances of trench foot began to decrease, probably as a result of the introduction of the aforementioned measures; of wooden duckboards to cover the muddy, wet, cold ground of the trenches; and of the increased practice of troop rotation, which kept soldiers from prolonged time at the front. The mainstay of treatment, like the treatment of gangrene, is surgical debridement, and often includes amputation. Trench foot was first documented by Napoleon's army in 1812. It became prevalent during the retreat from Russia and was first described by French army surgeon Dominique Jean Larrey. It was also a problem for soldiers engaged in trench warfare during the winters of World War I (hence the name). Trench foot made a reappearance in the British Army, during the Falklands War in 1982. Some people were even reported to have developed trench foot at the 1998 and 2007 Glastonbury Festivals, the 2009 and 2013 Leeds Festivals, as well as the 2012 Download Festival, as a result of the sustained cold, wet, and muddy conditions at the events.	[ { "begin": 0, "class": "SectionAnnotation", "length": 640, "sectionHeading": "Signs and symptoms", "sectionLabel": "disease.symptom" }, { "begin": 640, "class": "SectionAnnotation", "length": 470, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 1110, "class": "SectionAnnotation", "length": 819, "sectionHeading": "Prevention", "sectionLabel": "disease.prevention" }, { "begin": 1929, "class": "SectionAnnotation", "length": 115, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 2044, "class": "SectionAnnotation", "length": 637, "sectionHeading": "History", "sectionLabel": "disease.history" } ]
https://en.wikipedia.org/wiki/Thrombocytopenia	disease	Thrombocytopenia	Thrombocytopenia is a condition characterized by abnormally low levels of thrombocytes, also known as platelets, in the blood. A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease. One common definition of thrombocytopenia requiring emergency treatment is a platelet count below 50,000 per microliter.	Thrombocytopenia usually has no symptoms and is picked up on a routine full blood count (or complete blood count). Some individuals with thrombocytopenia may experience external bleeding such as nosebleeds, and/or bleeding gums. Some women may have heavier or longer periods or breakthrough bleeding. Bruising, particularly purpura in the forearms and petechiae in the feet, legs, and mucous membranes, may be caused by spontaneous bleeding under the skin. Eliciting a full medical history is vital to ensure the low platelet count is not secondary to another disorder. It is also important to ensure that the other blood cell types, such as red blood cells and white blood cells, are not also suppressed. Painless, round and pinpoint (1 to 3 mm in diameter) petechiae usually appear and fade, and sometimes group to form ecchymoses. Larger than petechiae, ecchymoses are purple, blue or yellow-green areas of skin that vary in size and shape. They can occur anywhere on the body. A person with this disease may also complain of malaise, fatigue and general weakness (with or without accompanying blood loss). Acquired thrombocytopenia may be associated with a history of drug use. Inspection typically reveals evidence of bleeding (petechiae or ecchymoses), along with slow, continuous bleeding from any injuries or wounds. Adults may have large, blood-filled bullae in the mouth. If the person's platelet count is between 30,000 and 50,000/mm, bruising with minor trauma may be expected; if it is between 15,000 and 30,000/mm, spontaneous bruising will be seen (mostly on the arms and legs). Abnormally low platelet production may be caused by: - Dehydration, Vitamin B or folic acid deficiency - Leukemia or myelodysplastic syndrome or aplastic anemia - Decreased production of thrombopoietin by the liver in liver failure - Sepsis, systemic viral or bacterial infection - Leptospirosis - Hereditary syndromes - Congenital amegakaryocytic thrombocytopenia - Thrombocytopenia absent radius syndrome - Fanconi anemia - Bernard-Soulier syndrome, (associated with large platelets) - May-Hegglin anomaly, - Grey platelet syndrome - Alport syndrome - Wiskott–Aldrich syndrome Abnormally high rates of platelet destruction may be due to immune or non-immune conditions, including: - Immune thrombocytopenic purpura - Thrombotic thrombocytopenic purpura - Hemolytic-uremic syndrome - Disseminated intravascular coagulation - Paroxysmal nocturnal hemoglobinuria - Antiphospholipid syndrome - Systemic lupus erythematosus - Post-transfusion purpura - Neonatal alloimmune thrombocytopenia - Hypersplenism - Dengue fever - Gaucher's disease - Zika virus The following medications can induce thrombocytopenia through direct myelosuppression. - Valproic acid - Methotrexate - Carboplatin - Interferon - Isotretinoin - Panobinostat - H blockers and proton-pump inhibitors Laboratory tests for thrombocytopenia might include full blood count, liver enzymes, kidney function, vitamin B levels, folic acid levels, erythrocyte sedimentation rate, and peripheral blood smear. If the cause for the low platelet count remains unclear, a bone marrow biopsy is usually recommended to differentiate cases of decreased platelet production from cases of peripheral platelet destruction. Thrombocytopenia in hospitalized alcoholics may be caused by spleen enlargement, folate deficiency, and, most frequently, the direct toxic effect of alcohol on production, survival time, and function of platelets. Platelet count begins to rise after 2 to 5 days' abstinence from alcohol. The condition is generally benign, and clinically significant hemorrhage is rare. In severe thrombocytopenia, a bone marrow study can determine the number, size and maturity of the megakaryocytes. This information may identify ineffective platelet production as the cause of thrombocytopenia and rule out a malignant disease process at the same time. Treatment is guided by the severity and specific cause of the disease. Treatment focuses on eliminating the underlying problem, whether that means discontinuing drugs suspected to cause it or treating underlying sepsis. Diagnosis and treatment of serious thrombocytopenia is usually directed by a hematologist. Corticosteroids may be used to increase platelet production. Lithium carbonate or folate may also be used to stimulate platelet production in the bone marrow. Treatment of thrombotic thrombocytopenic purpura (TTP) is a medical emergency, since the associated hemolytic anemia and platelet activation can lead to renal failure and changes in the level of consciousness. Treatment of TTP was revolutionized in the 1980s with the application of plasmapheresis. According to the Furlan-Tsai hypothesis, this treatment works by removing antibodies against the von Willebrand factor-cleaving protease ADAMTS-13. The plasmapheresis procedure also adds active ADAMTS-13 protease proteins to the patient, restoring a normal level of von Willebrand factor multimers. Patients with persistent antibodies against ADAMTS-13 do not always manifest TTP, and these antibodies alone are not sufficient to explain how plasmapheresis treats TTP. Many cases of ITP can be left untreated, and spontaneous remission (especially in children) is not uncommon. However, counts of under 50,000 are usually monitored with regular blood tests, and those with counts of under 10,000 are usually treated, as the risk of serious spontaneous bleeding is high with such a low platelet count. Any patient experiencing severe bleeding symptoms is also usually treated. The threshold for treating ITP has decreased since the 1990s; hematologists recognize that patients rarely spontaneously bleed with platelet counts greater than 10,000, although there are documented exceptions to this observation. Thrombopoetin analogues have been tested extensively for the treatment of ITP. These agents had previously shown promise but had been found to stimulate antibodies against endogenous thrombopoietin or lead to thrombosis. Romiplostim (trade name Nplate, formerly AMG 531) was found to be safe and effective for the treatment of ITP in refractory patients, especially those who relapsed following splenectomy. Discontinuation of heparin is critical in a case of heparin-induced thrombocytopenia (HIT). Beyond that, however, clinicians generally treat to avoid a thrombosis, often by starting patients directly on warfarin. For this reason, patients are usually treated with a direct thrombin inhibitor, such as lepirudin or argatroban, which are approved by the FDA for this use. Other blood thinners sometimes used in this setting that are not FDA-approved for treatment of HIT include bivalirudin and fondaparinux. Platelet transfusions are not routinely used to treat HIT because thrombosis, not bleeding, is the primary problem. Bone marrow/stem cell transplants are the only known cures for this genetic disease. Frequent platelet transfusions are required to keep the patient from bleeding to death before the transplant can be performed, although this is not always the case. Thrombocytopenia affects a few percent of newborns, and its prevalence in neonatal intensive care units (NICU) is high. Normally, it is mild and resolves without consequences. Most cases affect preterm birth infants and result from placental insufficiency and/or fetal hypoxia. Other causes, such as alloimmunity, genetics, autoimmunity, and infection, are less frequent. Thrombocytopenia that starts after the first 72 hours since birth is often the result of underlying sepsis or necrotizing enterocolitis (NEC). In the case of infection, PCR tests may be useful for rapid pathogen identification and detection of antibiotic resistance genes. Possible pathogens include viruses (e.g. Cytomegalovirus (CMV), rubella virus, HIV), bacteria (e.g. Staphylococcus sp., Enterococcus sp., Streptococcus agalactiae (GBS), Listeria monocytogenes, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Yersinia enterocolitica), fungi (e.g. Candida sp.), and Toxoplasma gondii. The severity of thrombocytopenia may be correlated with pathogen type; some research indicates that the most severe cases are related to fungal or gram-negative bacterial infection. The pathogen may be transmitted during or before birth, by breast feeding, or during transfusion. Interleukin-11 is being investigated as a drug for managing thrombocytopenia, especially in cases of sepsis or necrotizing enterocolitis (NEC).	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https://en.wikipedia.org/wiki/Keratoacanthoma	disease	Keratoacanthoma	Keratoacanthoma (KA) is a common low-grade (unlikely to metastasize or invade) skin tumour that is believed to originate from the neck of the hair follicle. The defining characteristic of KA is that it is dome-shaped, symmetrical, surrounded by a smooth wall of inflamed skin, and capped with keratin scales and debris. It grows rapidly, reaching a large size within days or weeks, and if untreated for months will almost always starve itself of nourishment, necrose (die), slough, and heal with scarring. KA is commonly found on sun-exposed skin, often face, forearms and hands. Under the microscope, keratoacanthoma very closely resembles squamous cell carcinoma. In order to differentiate between the two, almost the entire structure needs to be removed and examined. While some pathologists classify KA as a distinct entity and not a malignancy, about 6% of clinical and histological keratoacanthomas do progress to invasive and aggressive squamous cell cancers; some pathologists may label KA as "well-differentiated squamous cell carcinoma, keratoacanthoma variant", and prompt definitive surgery may be recommended.	Keratoacanthomas (molluscum sebaceum) may be divided into the following types: - Giant keratoacanthomas are a variant of keratoacanthoma, which may reach dimensions of several centimeters. - Keratoacanthoma centrifugum marginatum is a cutaneous condition, a variant of keratoacanthomas, which is characterized by multiple tumors growing in a localized area. - Multiple keratoacanthomas (also known as "Ferguson–Smith syndrome," "Ferguson-Smith type of multiple self-healing keratoacanthomas,") is a cutaneous condition, a variant of keratoacanthomas, which is characterized by the appearance of multiple, sometimes hundreds of keratoacanthomas. - A solitary keratoacanthoma (also known as "Subungual keratoacanthoma") is a benign, but rapidly growing, locally aggressive tumor which sometimes occur in the nail apparatus. - Generalized eruptive keratoacanthoma (also known as "Generalized eruptive keratoacanthoma of Grzybowski") is a cutaneous condition, a variant of keratoacanthomas, characterized by hundreds to thousands of tiny follicular keratotic papules over the entire body. Treatments are not successful for many patients with Generalized eruptive keratoacanthoma. Use of emollients and anti-itch medications can ease some symptoms. Improvement or complete resolutions of the condition has occurred with the application of the following medications: Acitretin, Isotretinoin, Fluorouracil, Methotrexate, Cyclophosphamide. Keratoacanthoma usually occurs in older individuals. As with squamous cell cancer, it seems likely that ultraviolet light from the sun causes the development of KA. As with squamous cell cancer, sporadic cases have been found co-infected with the human papilloma virus (HPV). Many new treatments for Melanoma are also known to increase the rate of Keratoacanthoma, such as the B-Raf inhibitor drugs Vemurafenib and Dabrafenib. Keratoacanthoma presents as a fleshy, elevated and nodular lesion with an irregular crater shape and a characteristic central hyperkeratotic core. Usually the patient will notice a rapidly growing dome-shaped tumor on sun-exposed skin. If the entire lesion is removed, the pathologist will probably be able to differentiate between keratoacanthoma and squamous cell carcinoma. If only part of the lesion is removed, confident diagnosis may be impossible. Excision of the entire lesion, with adequate margin, will remove the lesion, allow full tissue diagnosis, and leave a planned surgical wound which can usually be repaired with a good cosmetic result. However, removing the entire lesion (especially on the face) may present difficult problems of plastic reconstruction. (On the nose and face, Mohs surgery may allow for good margin control with minimal tissue removal, but many insurance companies require the definitive diagnosis of a malignancy before they are prepared to pay the extra costs of Mohs surgery.) Especially in more cosmetically-sensitive areas, and where the clinical diagnosis is reasonably certain, alternatives to surgery may include no treatment (awaiting spontaneous resolution). On the trunk, arms, and legs, electrodesiccation and curettage often suffice to control keratoacanthomas until they regress. Other modalities of treatment include cryosurgery and radiotherapy; intralesional injection of methotrexate or of 5-fluorouracil have also been used. Recurrence after electrodesiccation and curettage can occur; it can usually be identified and treated promptly with either further curettage or surgical excision.	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https://en.wikipedia.org/wiki/Dubowitz_syndrome	disease	Dubowitz syndrome	Dubowitz syndrome is a rare genetic disorder characterized by microcephaly, stunted growth, and a receding chin. Symptoms vary among patients, but other characteristics include a soft, high-pitched voice; partial webbing of the fingers and toes; palate deformations; genital abnormalities; language difficulties; and an aversion to crowds. The pathogenesis of the disease is yet to be identified, and no medical tests can definitively diagnose the disease. The primary method of diagnosis is to identify facial phenotypes. Since it was first described in 1965 by English physician Victor Dubowitz, over 140 cases have been reported worldwide. Although the majority of cases have been reported from the United States, Germany, and Russia, the disorder appears to affect both genders and all ethnicities equally.	Microcephaly is a characteristic in which the circumference of the head is smaller than normal due to improper development of the brain. It is caused by genetic disorders, infections, radiation, medications or alcohol abuse during pregnancy. Defects in the growth of the cerebral cortex lead to many of the features associated with microcephaly. There is currently no known method of correcting microcephaly. However, there are a variety of symptomatic treatments that help to counter some of its adverse effects, such as speech and occupational therapies, as well as medication to control seizures and hyperactivity. Microcephaly has a vast range of prognoses: some patients experience little to very mental retardation and can reach regular age-appropriate milestones. Others may experience severe mental retardation and neuromuscular side effects. Although the exact pathology of Dubowitz syndrome is not known yet, it is heritable and classified as an autosomal recessive disease. Furthermore, there is an occasional parental consanguinity. Several cases point to Dubowitz syndrome occurring in monozygotic twins, siblings, and cousins. There is considerable phenotypic variability between cases, especially in regards to intelligence. Although substantial evidence points to the genetic basis of this disorder, the phenotypic similarity is found in fetal alcohol syndrome. Further studies need to be done to determine whether this environmental agent effects the expression of the genotype. Breakdown of chromosomes is known to occur. Dubowitz syndrome is accompanied by a deficiency in growth hormone. Individuals with this disorder have stunted growth, and growth hormones are secreted by the anterior pituitary of the brain. The main function of the anterior pituitary is to increase the height of an individual during development. The anterior pituitary also plays a role in regulating the immune function, increasing calcium retention, increasing muscle mass and stimulating gluconeogenesis. A deficiency in growth hormone may be caused by gene mutations, malformations of the hypothalamus or pituitary gland during development or damage to the pituitary. In Dubowitz syndrome, the cause is likely due to the gene mutations or disruption of brain structures during development. Growth hormone deficiency also correlates with low levels of IgG, a condition found in Dubowitz patients. Researchers are also investigating the genetic similarities between Dubowitz Syndrome and Smith-Lemli-Opitz syndrome (SLOS). Patients with SLOS and Dubowitz syndromes experience many of the same abnormalities, and the two disorders are hypothesized to be linked. A characteristic of SLOS is a low cholesterol level and a high 7-dehydrocholesterol level. Cholesterol is essential for several key functions of the body, including cell membrane structure, embryogenesis, and steroid and sex hormone synthesis. Impaired cholesterol biosynthesis or transport possibly accounts for most of the symptoms of both SLOS and Dubowitz. Although only a few patients with Dubowitz Syndrome have been identified with altered cholesterol levels, researchers are exploring whether Dubowitz Syndrome, like SLOS, carries a link to a defect in the cholesterol biosynthetic pathway. The exact biochemical pathology of the disease is still under research because of the low prevalence of the disease and the wide array of symptoms associated with it. Several studies have focused on different aspects of the disease to try to find its exact cause and expression. One study examined the specific oral features in one patient. Another found abnormalities in the brain, such as corpus callosum dysgenesis, an underdeveloped anterior pituitary and a brain stalk with an ectopic neurohypophysis.	[ { "begin": 0, "class": "SectionAnnotation", "length": 851, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 851, "class": "SectionAnnotation", "length": 689, "sectionHeading": "Genetics", "sectionLabel": "disease.genetics" }, { "begin": 1540, "class": "SectionAnnotation", "length": 854, "sectionHeading": "Genetics \| Growth hormone", "sectionLabel": "disease.genetics" }, { "begin": 2394, "class": "SectionAnnotation", "length": 1369, "sectionHeading": "Genetics \| Relation to SLOS", "sectionLabel": "disease.genetics" } ]
https://en.wikipedia.org/wiki/Raspberry_spur_blight	disease	Raspberry spur blight	Raspberry Spur Blight is caused by the fungus Didymella applanata. This plant pathogen is most problematic on red raspberries (Rubus idaeus) than on black or purple raspberries. The fungus infects the leaves first and then spreads to the cane. It causes necrotic spots on the cane near the base of the petiole attachment. Raspberry Spur Blight can cause a significant reduction in yield, fruit blight, premature leaf drop, and weak bud and cane growth. The magnitude of damage is not clearly understood in the United States, however, studies from Scotland suggest damage to the cane itself is limited. The disease has minor economic impacts by reducing leaves in the summer or killing buds. Major economic damage occurs if the disease manages to kill the entire cane. In the United States, this disease is found in Oregon and Washington.	In the late summer, the bark of infected areas split and the lesions produce fruiting bodies called pycnidia. Pycnidia appear as small black dots to the naked eye and can be seen as flask-shaped structures under a microscope. Perithecia, another fruiting body, forms after the pycnidia. Perithecia appear as medium, black, erupting dots. In the spring, spur blight can be mistaken for winter injury therefore it is important to scout for these signs in September to assess the potential damage that will be done in the following season. Infection generally occurs in the late spring when the environment is wet and optimal for fungus to proliferate. Symptoms do not become visible until mid to late summer. Visible symptoms include purple and brown expansive lesions appearing below buds, leaves and the lower portion of the stem. leaflets that are infected have wedge-shaped brown patches. Infected leaflets may fall, leaving only the petiole and canes behind. During the next season, branch growth from diseased canes will often be weak and wilted. The raspberry spur blight fungus spreads through the pycniospores that are released from the pycnidia. The spores are released and infect other raspberry plants with the help of rain through open wounds or natural openings. The fungus will then spread throughout the plant and will live in lesions during the winter to survive. After winter there are two spore types that are formed pycniospores and ascospores. The pycniospores come from conidia and the ascospores come from the perithecia that was formed. Both of these spores will spread through rainfall onto new plants and start the process over again. The environments that are favorable for Raspberry spur blight are conditions that usually favor spore production. Infection generally occurs in late spring when the environment is wet and moist. Thick and dense patches of raspberries also increase infection. Methods of controlling this disease include improving air circulation to allow fast drying of the plant, removing weeds that slow air flow, reducing the number of wet periods the plant is exposed to, avoiding the use of fertilizers because it promotes growth of susceptible tissue targeted by the pathogen, thinning plants for better light exposure and removing possible sources of inoculum. Removing sources of inoculum can be completed by destroying wild brambles that may carry the disease, removing and destroying all previously infected material and using special fungicide in certain situations. Other methods include starting with disease free plants, buying cultivars that are less susceptible to Raspberry Spur Blight such as Brandywine, Killarney, Latham and Newburgh, and avoiding cultivars that have greater susceptibility such as Royalty, Titan, Canby, Skeena, Willamette, Reveille, and Sentry. Willamette readily infects with spur blight but is tolerant to the disease and still produces satisfactory yields. It is important to minimize plant wounding and maintain proper soil nutrition. If you plan on pruning, always allow four to five days for healing before exposing the plants to water. Chemicals can be used in some cases. However, the spraying of chemicals is only efficient if it is sprayed on the entire raspberry plant. These include lime sulfur or copper application, captan/fenhexamid mixture (Captevate 68WDG) applied when 8-10” shoot growth, and Strobilurins. Recent research indicates that chitinases may effectively control against Raspberry Spur Blight. Specifically, chitinases, when applied, were found to reduce lesion size, and control infection of internal tissues. Notably, the application of Phytoverm, a Streptomyces avermitilis metabolite, had a similar inhibitory effect on disease growth. Other plant pathogens have also been found to reduce the growth rate of casual agent D. applanata such as entornopathogenic fungi (Hyphomycetes). The United States is the third largest country in producing raspberries. Raspberries are grown all over the country, but the majority are produced in Washington, California and Oregon. However, in the United States the magnitude of damage is not clearly understood.	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https://en.wikipedia.org/wiki/Aspergillosis	disease	Aspergillosis	Aspergillosis is the name given to a wide variety of diseases caused by infection by fungi of the genus Aspergillus. The majority of cases occur in people with underlying illnesses such as tuberculosis or chronic obstructive pulmonary disease (COPD), but with otherwise healthy immune systems. Most commonly, aspergillosis occurs in the form of chronic pulmonary aspergillosis (CPA), aspergilloma or allergic bronchopulmonary aspergillosis (ABPA). Some forms are intertwined; for example ABPA and simple aspergilloma can progress to CPA. Other, non-invasive manifestations include fungal sinusitis (both allergic in nature and with established fungal balls), otomycosis (ear infection), keratitis (eye infection) and onychomycosis (nail infection). In most instances these are less severe, and curable with effective antifungal treatment. People with deficient immune systems—such as patients undergoing hematopoietic stem cell transplantation, chemotherapy for leukaemia, or AIDS—are at risk of more disseminated disease. Acute invasive aspergillosis occurs when the immune system fails to prevent Aspergillus spores from entering the bloodstream via the lungs. Without the body mounting an effective immune response, fungal cells are free to disseminate throughout the body and can infect major organs such as the heart and kidneys. The most frequently identified pathogen is Aspergillus fumigatus—a ubiquitous organism that is capable of living under extensive environmental stress. It is estimated that most humans inhale thousands of Aspergillus spores daily, but they do not affect most people’s health due to effective immune responses. Taken together, the major chronic, invasive and allergic forms of aspergillosis account for around 600,000 deaths annually worldwide.	A fungus ball in the lungs may cause no symptoms and may be discovered only with a chest X-ray, or it may cause repeated coughing up of blood, chest pain, and occasionally severe, even fatal, bleeding. A rapidly invasive Aspergillus infection in the lungs often causes cough, fever, chest pain, and difficulty breathing. Poorly controlled aspergillosis can disseminate through the blood stream to cause widespread organ damage. Symptoms include fever, chills, shock, delirium, seizures and blood clots. The person may develop kidney failure, liver failure (causing jaundice), and breathing difficulties. Death can occur quickly. Aspergillosis of the ear canal causes itching and occasionally pain. Fluid draining overnight from the ear may leave a stain on the pillow. Aspergillosis of the sinuses causes a feeling of congestion and sometimes pain or discharge. It can extend beyond the sinuses. In addition to the symptoms, an X-ray or computerised tomography (CT) scan of the infected area provides clues for making the diagnosis. Whenever possible, a doctor sends a sample of infected material to a laboratory to confirm identification of the fungus. On chest X-ray and CT, pulmonary aspergillosis classically manifests as a halo sign, and, later, an air crescent sign. In hematologic patients with invasive aspergillosis, the galactomannan test can make the diagnosis in a noninvasive way. False positive Aspergillus galactomannan tests have been found in patients on intravenous treatment with some antibiotics or fluids containing gluconate or citric acid such as some transfusion platelets, parenteral nutrition or PlasmaLyte. On microscopy, Aspergillus species are reliably demonstrated by silver stains, e.g., Gridley stain or Gomori methenamine-silver. These give the fungal walls a gray-black colour. The hyphae of Aspergillus species range in diameter from 2.5 to 4.5 µm. They have septate hyphae, but these are not always apparent, and in such cases they may be mistaken for Zygomycota. Aspergillus hyphae tend to have dichotomous branching that is progressive and primarily at acute angles of about 45°. The current medical treatments for aggressive invasive aspergillosis include voriconazole and liposomal amphotericin B in combination with surgical debridement. For the less aggressive allergic bronchopulmonary aspergillosis findings suggest the use of oral steroids for a prolonged period of time, preferably for 6–9 months in allergic aspergillosis of the lungs. Itraconazole is given with the steroids, as it is considered to have a "steroid sparing" effect, causing the steroids to be more effective, allowing a lower dose., Other drugs used, such as amphotericin B, caspofungin (in combination therapy only), flucytosine (in combination therapy only), or itraconazole, are used to treat this fungal infection. However, a growing proportion of infections are resistant to the triazoles. A. fumigatus, the most commonly infecting species, is intrinsically resistant to fluconazole. Prevention of aspergillosis involves a reduction of mold exposure via environmental infection-control. Anti-fungal prophylaxis can be given to high-risk patients. Posaconazole is often given as prophylaxis in severely immunocompromised patients. Albeit relatively rare in humans, aspergillosis is a common and dangerous infection in birds, particularly in pet parrots. Mallards and other ducks are particularly susceptible, as they will often resort to poor food sources during bad weather. Captive raptors, such as falcons and hawks, are susceptible to this disease if they are kept in poor conditions and especially if they are fed pigeons, which are often carriers of "asper". It can be acute in chicks, but chronic in mature birds. Aspergillosis has been the culprit in several rapid die-offs among waterfowl. From 8 December until 14 December 2006, over 2,000 Mallards died in the Burley, Idaho area of the USA, an agricultural community approximately 150 miles southeast of Boise. Mouldy waste grain from the farmland and feedlots in the area is the suspected source. A similar aspergillosis outbreak caused by mouldy grain killed 500 Mallards in Iowa, USA, in 2005. While there is no connection between aspergillosis and the H5N1 strain of avian influenza (commonly called "bird flu"), rapid die-offs caused by aspergillosis can spark fears of bird flu outbreaks. Laboratory analysis is the only way to distinguish bird flu from aspergillosis. In dogs, aspergillosis is an uncommon disease typically affecting only the nasal passages (nasal aspergillosis). This is much more common in dolicocephalic breeds. It can also spread to the rest of the body; this is termed disseminated aspergillosis and is rare, usually affecting individuals with underlying immune disorders.	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https://en.wikipedia.org/wiki/Lymphangioma	disease	Lymphangioma	Lymphangiomas are malformations of the lymphatic system characterized by lesions that are thin-walled cysts; these cysts can be macroscopic, as in a cystic hygroma, or microscopic. The lymphatic system is the network of vessels responsible for returning to the venous system excess fluid from tissues as well as the lymph nodes that filter this fluid for signs of pathogens. These malformations can occur at any age and may involve any part of the body, but 90% occur in children less than 2 years of age and involve the head and neck. These malformations are either congenital or acquired. Congenital lymphangiomas are often associated with chromosomal abnormalities such as Turner syndrome, although they can also exist in isolation. Lymphangiomas are commonly diagnosed before birth using fetal ultrasonography. Acquired lymphangiomas may result from trauma, inflammation, or lymphatic obstruction. Most lymphangiomas are benign lesions that result only in a soft, slow-growing, "doughy" mass. Since they have no chance of becoming malignant, lymphangiomas are usually treated for cosmetic reasons only. Rarely, impingement upon critical organs may result in complications, such as respiratory distress when a lymphangioma compresses the airway. Treatment includes aspiration, surgical excision, laser and radiofrequency ablation, and sclerotherapy.	Lymphangiomas have traditionally been classified into three subtypes: capillary and cavernous lymphangiomas and cystic hygroma. This classification is based on their microscopic characteristics. A fourth subtype, the hemangiolymphangioma is also recognized. - Capillary lymphangiomas - Cavernous lymphangiomas - Cystic hygromas - Hemangiolymphangioma Lymphangiomas may also be classified into microcystic, macrocystic, and mixed subtypes, according to the size of their cysts. - Microcystic lymphangiomas - Macrocystic lymphangiomas - Mixed lymphangiomas Finally, lymphangiomas may be described in stages, which vary by location and extent of disease. In particular, stage depends on whether lymphangiomas are present above or superior to the hyoid bone (suprahyoid), below or inferior to the hyoid bone (infrahyoid), and whether the lymphangiomas are on one side of the body (unilateral) or both (bilateral). - Stage I: Unilateral infrahyoid. - Stage II: Unilateral suprahyoid. - Stage III: Unilateral suprahyoid and infrahyoid. - Stage IV: Bilateral suprahyoid. - Stage V: Bilateral suprahyoid and infrahyoid. There are three distinct types of lymphangioma, each with their own symptoms. They are distinguished by the depth and the size of abnormal lymph vessels, but all involve a malformation of the lymphic system. Lymphangioma circumscriptum can be found on the skin's surface, and the other two types of lymphangiomas occur deeper under the skin. - Lymphangioma circumscriptum, a microcystic lymphatic malformation, resembles clusters of small blisters ranging in color from pink to dark red. They are benign and do not require medical treatment, although some patients may choose to have them surgically removed for cosmetic reasons. - Cavernous lymphangiomas are generally present at birth, but may appear later in the child's life. These bulging masses occur deep under the skin, typically on the neck, tongue and lips, and vary widely in size, ranging from as small as a centimeter in diameter to several centimeters wide. In some cases, they may affect an entire extremity such as a hand or foot. Although they are usually painless, the patient may feel mild pain when pressure is exerted on the area. They come in the colors white, pink, red, blue, purple, and black; and the pain lessens the lighter the color of the bump. - Cystic hygroma shares many commonalities with cavernous lymphangiomas, and some doctors consider them to be too similar to merit separate categories. However, cystic lymphangiomas usually have a softer consistency than cavernous lymphangiomas, and this term is typically the one that is applied to lymphangiomas that develop in fetuses. They usually appear on the neck (75%), arm pit or groin areas. They often look like swollen bulges underneath the skin. The direct cause of lymphangioma is a blockage of the lymphatic system as a fetus develops, although symptoms may not become visible until after the baby is born. The cause remains unknown. Why the embryonic lymph sacs remain disconnected from the rest of the lymphatic system is also not known. Cystic lymphangioma that emerges during the first two trimesters of pregnancy is associated with genetic disorders such as Noonan syndrome and trisomies 13, 18, and 21. Chromosomal aneuploidy such as Turner syndrome or Down syndrome were found in 40% of patients with cystic hygroma. In 1976, Whimster studied the pathogenesis of lymphangioma circumscriptum, finding lymphatic cisterns in the deep subcutaneous plane are separated from the normal network of lymph vessels. They communicate with the superficial lymph vesicles through vertical, dilated lymph channels. Whimster theorized the cisterns might come from a primitive lymph sac that failed to connect with the rest of the lymphatic system during embryonic development. A thick coat of muscle fibers that cause rhythmic contractions line the sequestered primitive sacs. Rhythmic contractions increase the intramural pressure, causing dilated channels to come from the walls of the cisterns toward the skin. He suggested that the vesicles seen in lymphangioma circumscriptum are outpouchings of these dilated projecting vessels. Lymphatic and radiographic studies support Whimsters observations. Such studies reveal that big cisterns extend deeply into the skin and beyond the clinical lesions. Lymphangiomas that are deep in the dermis show no evidence of communication with the regular lymphatics. The cause for the failure of lymph sacs to connect with the lymphatic system is not known. Microscopically, the vesicles in lymphangioma circumscriptum are greatly dilated lymph channels that cause the papillary dermis to expand. They may be associated with acanthosis and hyperkeratosis. There are many channels in the upper dermis which often extend to the subcutis (the deeper layer of the dermis, containing mostly fat and connective tissue). The deeper vessels have large calibers with thick walls which contain smooth muscle. The lumen is filled with lymphatic fluid, but often contains red blood cells, lymphocytes, macrophages, and neutrophils. The channels are lined with flat endothelial cells. The interstitium has many lymphoid cells and shows evidence of fibroplasia (the formation of fibrous tissue). Nodules (A small mass of tissue or aggregation of cells) in cavernous lymphangioma are large, irregular channels in the reticular dermis and subcutaneous tissue that are lined by a single layer of endothelial cells. Also an incomplete layer of smooth muscle also lines the walls of these channels. The stroma consists of loose connective tissue with a lot of inflammatory cells. These tumors usually penetrate muscle. Cystic hygroma is indistinguishable from cavernous lymphangiomas on histology. The typical history of Lymphangioma circumscriptum shows a small number of vesicles on the skin at birth or shortly after. In subsequent years, they tend to increase in number, and the area of skin involved continues to expand. Vesicles or other skin abnormalities may not be noticed until several years after birth. Usually, lesions are asymptomatic or do not show any evidence of a disease, but, mostly, patients may have random break outs of some bleeding and major drainage of clear fluid from ruptured vesicles. Cavernous lymphangioma first appears during infancy, when a rubbery nodule with no skin changes becomes obvious in the face, trunk, or extremity. These lesions often grow at a rapid pace, similar to that of raised hemangiomas. No family history of prior lymphangiomas is described. Cystic hygroma causes deep subcutaneous cystic swelling, usually in the axilla, base of the neck, or groin, and is typically noticed soon after birth. If the lesions are drained, they will rapidly fill back up with fluid. The lesions will grow and increase to a larger size if they are not completely removed in surgery. Cases of lymphangioma are diagnosed by histopathologic inspection. In prenatal cases, cystic lymphangioma is diagnosed using an ultrasound; when confirmed amniocentesis may be recommended to check for associated genetic disorders. Treatment for cystic hygroma involves the removal of the abnormal tissue; however complete removal may be impossible without removing other normal areas. Surgical removal of the tumor is the typical treatment provided, with the understanding that additional removal procedures will most likely be required as the lymphangioma grows. Most patients need at least two procedures done for the removal process to be achieved. Recurrence is possible but unlikely for those lesions able to be removed completely via excisional surgery. Radiotherapy and chemical cauteries are not as effective with the lymphangioma than they are with the hemangioma. Draining lymphangiomas of fluid provides only temporary relief, so they are removed surgically. Cystic Hygroma can be treated with OK432 (Picibanil). The least invasive and most effective form of treatment is now performed by interventional radiologists. A sclerosing agent, such as 1% or 3% sodium tetradecyl sulfate, doxycycline, or ethanol, may be directly injected into a lymphocele. "All sclerosing agents are thought to work by ablating the endothelial cells of the disrupted lymphatics feeding into the lymphocele." Lymphangioma circumscription can be healed when treated with a flashlamp pulsed dye laser, although this can cause port-wine stains and other vascular lesions. The prognosis for lymphangioma circumscriptum and cavernous lymphangioma is generally excellent. This condition is associated with minor bleeding, recurrent cellulitis, and lymph fluid leakage. Two cases of lymphangiosarcoma arising from lymphangioma circumscriptum have been reported; however, in both of the patients, the preexisting lesion was exposed to extensive radiation therapy. In cystic hygroma, large cysts can cause dysphagia, respiratory problems, and serious infection if they involve the neck. Patients with cystic hygroma should receive cytogenetic analysis to determine if they have chromosomal abnormalities, and parents should receive genetic counseling because this condition can recur in subsequent pregnancies. Complications after surgical removal of cystic hygroma include damage to the structures in the neck, infection, and return of the cystic hygroma. Lymphangiomas are rare, accounting for 4% of all vascular tumors in children. Although lymphangioma can become evident at any age, 50% are seen at birth, and 90% of lymphangiomas are evident by 2 years of age. In 1828, Redenbacher first described a lymphangioma lesion. In 1843, Wernher gave the first case report of a cystic hygroma, from the Greek "hygro-" meaning fluid and "oma" meaning tumor. In 1965, Bill and Summer proposed that Cystic hygromas and lymphangiomas are variations of a single entity and that its location determines its classification.	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https://en.wikipedia.org/wiki/Lichen_nitidus	disease	Lichen nitidus	Lichen nitidus is a chronic inflammatory disease of unknown cause characterized by 1–2 mm, discrete and uniform, shiny, flat-topped, pale flesh-colored or reddish-brown papules that may appear as hypopigmented against dark skin. Occasionally, minimal scaling is present or can be induced by rubbing the surface of the papules. The disease usually affects children and young adults and is painless and usually nonpruritic, although protracted itching may occur in some cases. It is sometimes referred to by dermatologists as "mini lichen planus".	Linear arrangements of these papules is common (referred to as a Koebner phenomenon), especially on the forearms, but may occasionally be grouped, though not confluent, on flexural areas. Generally, the initial lesions are localized, and remain so, to the chest, abdomen, glans penis, and flexor aspects of the upper extremities; however, less commonly, the disease process can (1) be strictly isolated to the palms and soles, presenting with many hyperkeratotic, yellow papules that may coalesce into plaques that fissure or “...sometimes a non-specific keratoderma resembling chronic eczema,” or (2) become more widespread, with papules widely distributed on the body—the extensor surfaces of the elbows, wrists, and hands, folds of the neck, submammary region in females, groin, thighs, ankles, and feet—and fusing into erythematous, minimally scaled plaques, with reddness that develops tints of violet, brown, and yellow. The histology of lichen nitidus is significant for a "...localized granulomatous lymphohistiocytic infiltrate in an expanded dermal papilla with thinning of overlying epidermis and downward extension of the ridges at the lateral margin of the infiltrate, producing a typical 'claw clutching a ball' picture..." Generally, lichen nitidus is asymptomatic and self-limited; therefore, no treatment is required. However, if persistent pruritus is present, or the appearance “...interferes with daily activities or outlook...” topical glucocorticoids may be tried. If the disease process is symptomatic, generalized and extensive, oral glucocorticoids may be indicated. Other reported treatments include PUVA, UVA/UVB phototherapy, astemizole, acitretin, and etretinate. When appears with sun/humidity; air conditioning (cool dry air) reduces swelling and discomfort.	[ { "begin": 0, "class": "SectionAnnotation", "length": 927, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 927, "class": "SectionAnnotation", "length": 311, "sectionHeading": "Pathology", "sectionLabel": "disease.pathology" }, { "begin": 1238, "class": "SectionAnnotation", "length": 552, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Chronic_sclerosing_sialadenitis	disease	Chronic sclerosing sialadenitis	Chronic sclerosing sialadenitis is a chronic (long-lasting) inflammatory condition affecting the salivary gland. Relatively rare in occurrence, this condition is benign, but presents as hard, indurated and enlarged masses that are clinically indistinguishable from salivary gland neoplasms or tumors. It is now regarded as a manifestation of IgG4-related disease. Involvement of the submandibular glands is also known as Küttner's tumor, named after Hermann Küttner (1870–1932), a German Oral and Maxillofacial Surgeon, who reported four cases of submandibular gland lesions for the first time in 1896.	The inflammatory lesions in Küttner's tumor may occur on one side (unilateral) or both sides (bilateral), predominantly involving the submandibular gland, but is also known to occur in other major and minor salivary glands, including the parotid gland. Overall, salivary gland tumors are relatively rare, with approximately 2.5–3 cases per 100,000 people per year seen in the Western world; however, salivary gland malignancies account for 3–5% of all head and neck cancers. However, salivary tumors show a great deal of morphological diversity, as well as variations in the nature of the lesion (malignant vs. benign): approximately 20% to 25% of parotid tumors, 35% to 40% of submandibular tumors, and more than 90% of sublingual gland tumors are malignant. This situation underscores the diagnostic challenges in respect of Küttner's tumor; despite being benign, this condition mimics the clinical appearance of malignancy in the salivary gland. The swollen masses of Küttner's tumor are generally painful, and patients are advised surgical resection (known as 'sialadenectomy') of a part or whole of the glandular tissue upon suspicion of possible malignancy. It is only upon post-surgical histopathology of the excised mass that the diagnosis of Küttner's tumor is definitively made. The histopathological features that characterize Küttner's tumor include: - Heavy infiltration of the glandular tissue by lymphocytes (predominantly activated B-cells and helper T-cells) as well as plasma cells (collectively known as 'Lymphoplasmacytic Infiltrate'). - Presence of reactive lymphoid follicles in the infiltrate, marked by a lack of atypical lymphoid cells (this is in sharp contrast to the presentations in lymphoma). - Atrophy and loss of acini (groups of secretory cells found in the salivary glands). - Encasement of the glandular ducts in thick fibrous tissues, as a result of chronic presence of inflammatory infiltrate in that area - a condition known as periductal fibrosis. - Eventual periductal and interlobular (inside the gland) sclerosis (replacement of regular tissue with hard connective tissue). Given the difficulties of a definitive pre-operative diagnosis, the clinical entity of Küttner's tumor has so far remained significantly under-reported and under-recognized. In recent times, armed with a better understanding of the occurrences and observable features of this condition, surgeons are increasingly depending upon pre-operative ultrasonography along with Fine-needle aspiration cytological (FNAC) examinations to make an accurate presumptive diagnosis, and according to one estimate, about 44% of patients undergoing submandibular resection are found to have this condition. In the ultrasonogram, Küttner's tumor is characterized by a diffuse, heterogeneous zone of echo-shadows. The FNAC finds cells greatly reduced in number (called 'paucicellularity') along with scattered tubular ducts against a backdrop of lymphoplasmacytic infiltration and fibrous depositions. There may be a reduced but moderate number of cells and ducts enveloped in fibrous sheaths, as well as fibrous proliferation of the gland's septa. The cytologic findings by themselves may not be specific, and the diagnosis requires adjunct consideration of both the ultrasonogram and clinical presentation. Application of magnetic resonance imaging (MRI) has been tried to non-invasively examine the morphological variations in Küttner's tumor and differentiate them from those seen in malignant tumors; while MRI findings of the affected tissue and the pattern of cellular infiltration may offer some diagnostic clues for this condition, so far the results have been inconclusive. The cause and pathogenesis of this chronic condition are not very well understood. Several factors have been postulated: - Formation of a hard salivary calculus or sialolith by accumulation of calcium salts in the duct of the salivary gland (a process known as Sialolithiasis). This has been proposed as the most common cause for Küttner's tumor of the submandibular gland, with sialoliths observed in an appreciable proportion of cases. However, sialolith involvement may not be found in many cases. - Abnormalities of the salivary gland ducts leading to excessive accumulation or retention of ductal secretions, which can excite chronic inflammations. - Immune, especially autoimmune, cause - which has gained steam, given the observation that the tissue of the glands is overrun with lymphoid immune cells and fibrous connective tissue, as well as corroboration from markedly similar lesions (with histologic and immunohistochemical findings) seen elsewhere in the body. The presence of abundant Immunoglobulin G4 (IgG4) associated with Plasma cells infiltrating into the salivary glands, as well as increased serum IgG4 concentration, has been noted with patients with Küttner's tumor. This chronic condition is primarily observed in adult (40–70 years) patients. However, Küttner's tumor, with prominent immunopathological features, has been described in an 11-year-old boy in Brazil in 2012. Standard, and most effective, therapy to date is glandular sialadenectomy, which is associated with fairly low operative morbidity; however, in recent times, the administration of steroid (which can shrink the inflammatory lesion and is known to reduce serum IgG4 values) has been considered favorably, and may be useful in younger patients or those who refuse surgery.	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https://en.wikipedia.org/wiki/Blepharitis	disease	Blepharitis	Different variations of blepharitis can be classified as seborrheic, staphylococcal, mixed, posterior or meibomitis, or parasitic. In a survey of US ophthalmologists and optometrists, 37% to 47% of patients seen by those surveyed had signs of blepharitis, which can affect all ages and ethnic groups. One single-center study of 90 patients with chronic blepharitis found that the average age of patients was 50 years old.	Blepharitis is characterized by chronic inflammation of the eyelid, usually at the base of the eyelashes. Symptoms include inflammation, irritation, itchiness, a burning sensation, excessive tearing, and crusting and sticking of eyelids. Additional symptoms may include visual impairment such as photophobia and blurred vision. Symptoms are generally worse in the mornings and patients may experience exacerbation and several remissions if left untreated. It is typically caused by bacterial infection or blockage of the meibomian oil glands. Diseases and conditions that may lead to blepharitis include: rosacea, herpes simplex dermatitis, varicella-zoster dermatitis, molluscum contagiosum, allergic dermatitis, contact dermatitis, seborrheic dermatitis, staphylococcal dermatitis, demodicosis (Demodex), and parasitic infections (e.g., Demodex and Phthiriasis palpebrarum). The parasite, Demodex folliculorum (D. folliculorum), causes blepharitis when the parasite is present in excessive numbers within the dermis of the eyelids. These parasites can live for approximately 15 days. The parasites (both adult and eggs) live on the hair follicle, inhabiting the sebaceous and apocrine gland of the human lid. Direct contact allows this pathogen to spread. Factors that allow this pathogen to multiply include hypervascular tissue, poor hygienic conditions, and immune deficiency. In treating Blepharitis caused by D. folliculorum, mechanical cleaning and proper hygiene are important towards decreasing the parasites numbers. Associated Symptoms: - Watery eyes - due to excessive tearing. - Red eyes - due to dilated blood vessels on the sclera. - Swollen eyelids - due to inflammation. - Crusting at the eyelid margins/base of the eyelashes/medial canthus, generally worse on waking - due to excessive bacterial buildup along the lid margins. - Eyelid sticking - due to crusting along the eyelid margin. - Eyelid itching - due to the irritation from inflammation and epidermis scaling of the eyelid. - Flaking of skin on eyelids - due to tear film suppressed by clog meibomian glands. - Gritty/burning sensation in the eye, or foreign-body sensation - due to crusting from bacteria and clogged oil glands - Frequent blinking - due to impaired tear film from clogged oil glands unable to keep tears from evaporating. - Light sensitivity/photophobia - Misdirected eyelashes that grow abnormally - due to permanent damage to the eyelid margin - Eyelash loss - due to excessive buildup of bacteria along the base of the eyelashes. - Infection of the eyelash follicle/sebaceous gland (hordeolum) - Debris in the tear film, seen under magnification (improved contrast with use of fluorescein drops) Chronic blepharitis may result in damage of varying severity and, in the worst cases, may have a negative effect on vision. This can be resolved with a proper eyeglass prescription. Long-term untreated blepharitis can lead to eyelid scarring, excess tearing, difficulty wearing contact lenses, development of a stye (an infection near the base of the eyelashes, resulting in a painful lump on the edge of the eyelid) or a chalazion (a blockage/bacteria infection in a small oil glands at the margin of the eyelid, just behind the eyelashes, leading to a red, swollen eyelid), chronic pink eye (conjunctivitis), keratitis, and corneal ulcer or irritation. The lids may become red and may have ulcerate, non-healing areas that may lead to bleeding. Blepharitis can also cause blurred vision due to a poor tear film. Tears may be frothy or bubbly, which can contribute to mild scarring along the eyelids. Symptoms and signs of blepharitis are often erroneously ascribed by the patient as "recurrent conjunctivitis". Staphylococcal blepharitis and Posterior blepharitis or rosacea-associated blepharitis Symptoms Symptoms include a foreign body sensation, matting of the lashes, and burning. Collarette around eyelashes, a ring-like formation around the lash shaft, can be observed. Other symptoms include loss of eyelashes or broken eyelashes. The condition can sometimes lead to a chalazion or a stye. Chronic bacterial blepharitis may also lead to ectropion. Posterior blepharitis or rosacea-associated blepharitis is manifested by a broad spectrum of symptoms involving the lids including inflammation and plugging of the meibomian orifices and production of abnormal secretion upon pressure over the glands. The mechanism by which the bacteria causes symptoms of blepharitis is not fully understood and may include direct irritation of bacterial toxins and/or enhanced cell-mediated immunity to S. aureus. Staphylococcal blepharitis is caused by an infection of the anterior portion of the eyelid by Staphylococcal bacteria. In a study of ocular flora, 46% to 51% of those diagnosed with staphylococcal blepharitis had cultures positive for Staphylococcus aureus in comparison to 8% of normal patients. Staphylococcal blepharitis may start in childhood and continue into adulthood. It is commonly recurrent and it requires special medical care. The prevalence of Staphylococcus aureus in the conjunctival sac and on the lid margin varies among countries, likely due to differences in climate and environment. Seborrheic blepharitis is characterized by less inflammation than Staphylococcal blepharitis; however, it causes more excess oil or greasy scaling. Meibomian Gland Dysfunction is a result of abnormalities of the meibomian glands and altered secretion meibum, which plays an imperative role in lagging the evaporation of tear films and smoothing of the tear film to produce an even optical surface. Posterior blepharitis is an inflammation of the eyelids, secondary to dysfunction of the meibomian glands. Like anterior blepharitis, it is a bilateral chronic condition and may be associated with skin rosacea. There is growing evidence that, in some cases, it is caused by Demodex mites. Diagnosis of the condition is done via a physical examination under a slit lamp. Cultures of debris are occasionally collected for bacterial or fungal testing. In all forms of blepharitis, Optometrists or Ophthalmologists examine the tear film, which is the most efficient method in determining instability. The most frequently used method is to measure tear production via tear break-up time (TBUT), which calculates the duration interval between complete blinks. This serves as a primary indication of regional dryness in the pre-corneal tear film after fluorescein injections. If TBUT is shorter than 10 seconds, then this suggests instability. Staphylococcal blepharitis is diagnosed by examining erythema and edema of the eyelid margin. Patients may exhibit alopecia areata of eyelashes and/or growth misdirection, trichiasis. Other signs may include telangiectasia on the anterior eyelid, collarettes encircling the lash base, and corneal changes. Seborrheic blepharitis is distinguished by less erythema, edema, and telangiectasia of the eyelid margins. Posterior blepharitis and Meibomian Gland Dysfunction are frequently associated with rosacea and can be seen during an ocular examination of the posterior eyelid margin. The meibomian glands may appear caked with oil or visibly obstructed. Cultures of the eyelid margins can be a clear indicator for patients suffering from recurrent anterior blepharitis with severe inflammation, in addition to patients who are not responding to therapy. Measurements of tear osmolarity may be beneficial in diagnosing concurrent dry eye syndrome (DES), which may be responsible for overlapping symptoms and would allow the physician to decipher between conditions and move forward with the most beneficial protocol for the patient. Consequently, the measurement of tear osmolarity has various limitations in differentiating between aqueous deficiencies and evaporative dry eye. Microscopic evaluation of epilated eyelashes may reveal mites, which have been evident in cases of chronic blepharoconjunctivitis. A biopsy of the eyelid can also determine the exclusion of carcinoma, therapy resistance, or unifocal recurrent chalazia. Blepharitis is a result of bacteria and inflammation from congested meibomian oil glands at the base of each eyelash. Routine washing of the eyelids helps subdue symptoms and prevent blepharitis. Washing each eyelid for 30 seconds, twice a day, with a single drop of hypoallergenic soap (e.g. baby shampoo) and ample water is most effective. Blepharitis is a chronic condition causing frequent exacerbation, thus requires routine eyelid hygiene. Hygienic practices include warm compresses, eyelid massages generating consistent heat at body temperature (98.6 degrees F), and eyelid scrubs. A Cochrane Systematic Review of topical antibiotics was shown to be effective in providing symptomatic relief and clearing bacteria for individuals with anterior blepharitis. Topical steroids provided some symptomatic relief, but they were ineffective in clearing bacteria from the eyelids. Lid hygiene measures such as warm compresses and lid scrubs were found to be effective in providing symptomatic relief for participants with anterior and posterior blepharitis. Warm Compresses: Soften lid margin debris and oils by placing a very warm wet compress such as a clean, warm, wet washcloth over the closed eyelids for five minutes. Re-wet and reapply it as it cools. This warms, softens, and loosens crusty and oily eyelid gland deposits. Eyelid Hygiene: Remove lid margin debris immediately after the warm compresses by gently washing the eyelids with a warm, wet, soapy washcloth to remove accumulated debris. Use a diluted, hypoallergenic baby shampoo. Gently rub along the lid margins, keeping the eyes shut. Too much soap or shampoo may remove the essential oil layer of the eyes' tear film and create further stress to the eye, as well as dry eye discomfort. A moist cotton swab soaked in a cup of water and baby shampoo may be used to rub along the lid margins while tilting the lid outward with the other hand to avoid this problem. Finally, rinse the eyelid with warm water and gently dry with a towel. Eye make-up should not be used while inflammation is present. Dandruff shampoo can be helpful if dandruff is contributing to blepharitis and may relieve blepharitis symptoms. Oral Antibiotics: Ophthalmologists or optometrists may prescribe a low-dose, oral antibiotic such as Doxycycline. Topical Antibiotics: If prescribed, topical creams or ointments can be applied after the cleansing of the lid margin. A small amount of antibiotic ophthalmic ointment is spread along the lid fissure with a swab or fingertip, while the eyes are closed. It is prescribed for use prior to bedtime to avoid blurred vision. Another method to reduce side effects of blepharitis are antibiotics such as erythromycin or sulfacetamide, which are used via eye drops, creams, or ointments on the eyelid margin. blepharitis caused by Demodex mites can be treated using a diluted solution of tea tree oil, via application by a cotton swab, for 5–10 minutes per day. Steroid eyedrops/ointments: Eye drops or ointments containing corticosteroids are frequently used in conjunction with antibiotics and can reduce eyelid inflammation. Blepharitis is a chronic condition that has periods of exacerbation and remission. Patients should be informed that symptoms can frequently improve but are rarely eliminated. Infrequently, severe blepharitis can result in permanent alterations in the eyelid margin or vision loss from superficial keratopathy, corneal neovascularization, and ulceration. Patients with an inflammatory eyelid lesion that appears suspicious of malignancy should be referred to an appropriate specialist. A study conducted in November of 2017, conveyed a correlation between blepharitis and early onset metabolic syndrome (MetS). To investigate the relationship between blepharitis and MetS, researchers used the Longitudinal Health Insurance Database in Taiwan. Results indicated that hyperlipidaemia and coronary artery disease were significantly correlated with the prior development of blepharitis. Therefore, blepharitis was shown to be significantly related to MetS and can serve as an early indication of the condition. In another recent study, the presence of Demodex has been unveiled as a common cause of blepharitis. However, the pathogenesis of demodicosis is still unclear. In this study, researchers provide a diagnosis of the disease and propose diagnostic criteria of Demodex blepharitis.	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https://en.wikipedia.org/wiki/Pes_anserine_bursitis	disease	Pes anserine bursitis	Pes anserine bursitis is an inflammatory condition of the medial (inner) knee at the anserine bursa, a sub muscular bursa, just below the pes anserinus.	The pes anserinus is the insertion of the conjoined tendons sartorius, gracilis, and semitendinosus into the anteromedial proximal tibia. Theoretically, bursitis results from stress to this area (e.g. stress may result when an obese individual with anatomic deformity from arthritis ascends or descends stairs). An occurrence of pes anserine bursitis commonly is characterized by pain, especially when climbing stairs, tenderness, and local swelling. The etymology of the name relates to the insertion of the conjoined tendons into the anteromedial proximal tibia. From anterior to posterior, the pes anserinus is made up of the tendons of the sartorius, gracilis, and semitendinosus muscles. The tendon's name, which literally means "goose's foot," was inspired by the pes anserinus's webbed, footlike structure. The conjoined tendon lies superficial to the tibial insertion of the medial collateral ligament (MCL) of the knee.	[ { "begin": 0, "class": "SectionAnnotation", "length": 451, "sectionHeading": "Pathology", "sectionLabel": "disease.pathology" }, { "begin": 451, "class": "SectionAnnotation", "length": 478, "sectionHeading": "Pathology \| Pathophysiology", "sectionLabel": "disease.pathophysiology" } ]
https://en.wikipedia.org/wiki/Ménétrier's_disease	disease	Ménétrier's disease	Ménétrier disease (also known as hypoproteinemic hypertrophic gastropathy; named after a French physician Pierre Eugène Ménétrier, 1859–1935), is a rare, acquired, premalignant disease of the stomach characterized by massive gastric folds, excessive mucous production with resultant protein loss, and little or no acid production. The disorder is associated with excessive secretion of transforming growth factor alpha (TGF-α).	Individuals with the disease present with upper abdominal pain (epigastric), at times accompanied by nausea, vomiting, loss of appetite, edema, and weight loss. A small amount of gastrointestinal bleeding may occur, which is typically due to superficial mucosal erosions; large volume bleeding is rare. 20% to 100% of patients, depending on time of presentation, develop a protein-losing gastropathy accompanied by low blood albumin and edema. Symptoms and pathological features of Ménétrier disease in children are similar to those in adults, but disease in children is usually self-limited and often follows respiratory infection. The cause of Ménétrier disease is unknown, but it has been associated with HCMV infection in children and H. pylori infections in adults. Additionally, increased TGF-α has been noted in the gastric mucosa of patients with the disease. With Ménétrier disease, the stomach is characterized by large, tortuous gastric folds in the fundus and body of the stomach, with antrum generally spared, giving the mucosa a cobblestone or cerebriform (brain-like) appearance. Histologically, the most characteristic feature is massive foveolar hyperplasia (hyperplasia of surface and glandular mucous cells). The glands are elongated with a corkscrew-like appearance and cystic dilation is common. Inflammation is usually only modest, although some cases show marked intraepithelial lymphocytosis. Diffuse or patchy glandular atrophy, evident as hypoplasia of parietal and chief cells, is typical. Although ICD-10 classifies it under "Other gastritis" (K29.6), and the lamina propria may contain mild chronic inflammatory infiltrate, Ménétrier disease is not considered a form of gastritis. It is rather considered as one of the two most well understood hypertrophic gastropathies; the other being Zollinger–Ellison syndrome. Other possible causes (eg differential diagnosis) of large folds within the stomach include: Zollinger-Ellison syndrome, cancer, infection (cytomegalovirus/CMV, histoplasmosis, syphilis), and infiltrative disorders such as sarcoidosis. The large folds of the stomach, as seen in Ménétrier disease, are easily detected by x-ray imaging following a barium meal or by endoscopic methods. Endoscopy with deep mucosal biopsy (and cytology) is required to establish the diagnosis and exclude other entities that may present similarly. A non-diagnostic biopsy may lead to a surgically obtained full-thickness biopsy to exclude malignancy. CMV and helicobacter pylori serology should be a part of the evaluation. Twenty-four-hour pH monitoring reveals hypochlorhydria or achlorhydria, and a chromium-labelled albumin test reveals increased GI protein loss. Serum gastrin levels will be within normal limits. Cetuximab is the first-line therapy for Ménétrier disease. Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR), and has been shown to be effective in treating Ménétrier disease. Several medications have been used in the treatment of the condition, with variable efficacy. Such medications include: anticholinergic agents, prostaglandins, proton pump inhibitors, prednisone, and H2 receptor antagonists. Anticholinergics decrease protein loss. A high-protein diet should be recommended to replace protein loss in patients with low levels of albumin in the blood (hypoalbuminemia). Any ulcers discovered during the evaluation should be treated in standard fashion. Severe disease with persistent and substantial protein loss despite cetuximab may require total removal of the stomach. Subtotal gastrectomy is performed by some; it may be associated with higher morbidity and mortality secondary to the difficulty in obtaining a patent and long-lasting anastomosis between normal and hyperplastic tissue. In adults, there is no FDA approved treatment other than gastrectomy and a high-protein diet. Cetuximab is approved for compassionate use in the treatment of the disease. Pediatric cases are normally treated for symptoms with the disease clearing up in weeks to months. The average age of onset is 40 to 60 years, and men are affected more often than women. Adults with Ménétrier disease have a higher risk of developing gastric adenocarcinoma.	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https://en.wikipedia.org/wiki/XY_gonadal_dysgenesis	disease	XY gonadal dysgenesis	Swyer syndrome, or XY gonadal dysgenesis, is a type of hypogonadism in a person whose karyotype is 46,XY. The person is externally female with streak gonads, and if left untreated, will not experience puberty. Such gonads are typically surgically removed (as they have a significant risk of developing tumors) and a typical medical treatment would include hormone replacement therapy. The syndrome was named by Gerald Swyer, an endocrinologist, based in London, United Kingdom.	There are several forms of gonadal dysgenesis. The term “pure gonadal dysgenesis” (PGD) has been used to describe conditions with normal sets of sex chromosomes (e.g., 46,XX or 46,XY), as opposed to those whose gonadal dysgenesis results from missing all or part of the second sex chromosome. The latter group includes those with Turner syndrome (i.e., 45,X) and its variants, as well as those with mixed gonadal dysgenesis and a mixture of cell lines, some containing a Y chromosome (e.g., 46,XY/45,X). Thus Swyer syndrome is referred to as PGD, 46,XY, and XX gonadal dysgenesis as PGD, 46,XX. Patients with PGD have a normal karyotype but may have defects of a specific gene on a chromosome. The first known step of sexual differentiation of a normal XY fetus is the development of testes. The early stages of testicular formation in the second month of gestation requires the action of several genes, of which one of the earliest and most important is SRY, the sex-determining region of the Y chromosome. Mutations of SRY account for many cases of Swyer syndrome. When such a gene is defective, the indifferent gonads fail to differentiate into testes in an XY (genetically male) fetus. Without testes, no testosterone or antimüllerian hormone (AMH) is produced. Without testosterone, the wolffian ducts fail to develop, so no internal male organs are formed. Also, the lack of testosterone means that no dihydrotestosterone is formed and consequently the external genitalia fail to virilize, resulting in normal female genitalia. Without AMH, the Müllerian ducts develop into normal internal female organs (uterus, fallopian tubes, cervix, vagina). A baby who is apparently a girl is born and is normal in most anatomic respects except that the child has nonfunctional streak gonads instead of ovaries or testes. As girls' ovaries normally produce no important body changes before puberty, a defect of the reproductive system typically remains unsuspected until puberty fails to occur in people with Swyer syndrome. They appear to be normal girls and are generally considered so. Due to the inability of the streak gonads to produce sex hormones (both estrogens and androgens), most of the secondary sex characteristics do not develop. This is especially true of estrogenic changes such as breast development, widening of the pelvis and hips, and menstrual periods. As the adrenal glands can make limited amounts of androgens and are not affected by this syndrome, most of these persons will develop pubic hair, though it often remains sparse. Evaluation of delayed puberty usually reveals elevation of gonadotropins, indicating that the pituitary is providing the signal for puberty but the gonads are failing to respond. The next steps of the evaluation usually include checking a karyotype and imaging of the pelvis. The karyotype reveals XY chromosomes and the imaging demonstrates the presence of a uterus but no ovaries (the streak gonads are not usually seen by most imaging). Although an XY karyotype can also indicate a person with complete androgen insensitivity syndrome, the absence of breasts, and the presence of a uterus and pubic hair exclude the possibility. At this point it is usually possible for a physician to make a diagnosis of Swyer syndrome. Swyer syndrome represents one phenotypic result of a failure of the gonads to develop properly, and hence is part of a class of conditions termed gonadal dysgenesis. There are many forms of gonadal dysgenesis. Swyer syndrome is an example of a condition in which an externally unambiguous female body carries dysgenetic, atypical, or abnormal gonads. Other examples include complete androgen insensitivity syndrome, partial X chromosome deletions, lipoid congenital adrenal hyperplasia, and Turner syndrome. Upon diagnosis, estrogen and progesterone therapy is typically commenced, promoting the development of female characteristics. The consequences of streak gonads to a person with Swyer syndrome: 1. Gonads cannot make estrogen, so the breasts will not develop and the uterus will not grow and menstruate until estrogen is administered. This is often given transdermally. 2. Gonads cannot make progesterone, so menstrual periods will not be predictable until progestin is administered, usually as a pill. 3. Gonads cannot produce eggs so conceiving children naturally is not possible. A woman with a uterus and ovaries but without female gamete is able to become pregnant by implantation of another woman's fertilized egg (embryo transfer). 4. Streak gonads with Y chromosome-containing cells have a high likelihood of developing cancer, especially gonadoblastoma. Streak gonads are usually removed within a year or so of diagnosis since the cancer can begin during infancy.	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https://en.wikipedia.org/wiki/Anthrax	disease	Anthrax	Anthrax is an infection caused by the bacterium Bacillus anthracis. It can occur in four forms: skin, lungs, intestinal, and injection. Symptoms begin between one day and two months after the infection is contracted. The skin form presents with a small blister with surrounding swelling that often turns into a painless ulcer with a black center. The inhalation form presents with fever, chest pain, and shortness of breath. The intestinal form presents with diarrhea which may contain blood, abdominal pains, and nausea and vomiting. The injection form presents with fever and an abscess at the site of drug injection. Anthrax is spread by contact with the spores of the bacteria, which are often from infectious animal products. Contact is by breathing, eating, or through an area of broken skin. It does not typically spread directly between people. Risk factors include people who work with animals or animal products, travelers, postal workers, and military personnel. Diagnosis can be confirmed based on finding antibodies or the toxin in the blood or by culture of a sample from the infected site. Anthrax vaccination is recommended for people who are at high risk. Immunizing animals against anthrax is recommended in areas where previous infections have occurred. Two months of antibiotics, such as doxycycline or ciprofloxacin, after exposure can also prevent infection. If infection occurs treatment is with antibiotics and possibly antitoxin. The type and number of antibiotics used depends on the type of infection. Antitoxin is recommended for those with widespread infection. Anthrax among humans is most common in Africa and central and southern Asia. It also occurs fairly regularly in Southern Europe, but is uncommon in Northern Europe and North America. Globally, at least 2,000 cases occur a year with about two cases a year in the United States. Skin infections represent more than 95% of cases. Without treatment, the risk of death from skin anthrax is 24%. For intestinal infection, the risk of death is 25 to 75%, while respiratory anthrax has a mortality of 50 to 80%, even with treatment. Until the 20th century, anthrax infections killed hundreds of thousands of people and animals each year. Anthrax has been developed as a weapon by a number of countries. In plant-eating animals, infection occurs when they eat or breathe in the spores while grazing. Carnivores may become infected by eating infected animals.	Cutaneous anthrax, also known as Hide porter's disease, is when anthrax occurs on the skin. It is the most common form (>90% of anthrax cases). Cutaneous anthrax is also the least dangerous form of anthrax (less than 1% mortality rate with treatment). Cutaneous anthrax presents as a boil-like skin lesion that eventually forms an ulcer with a black center (eschar). The black eschar often shows up as a large, painless, necrotic ulcer (beginning as an irritating and itchy skin lesion or blister that is dark and usually concentrated as a black dot, somewhat resembling bread mold) at the site of infection. In general, cutaneous infections form within the site of spore penetration between two and five days after exposure. Unlike bruises or most other lesions, cutaneous anthrax infections normally do not cause pain. Nearby lymph nodes may become infected, reddened, swollen, and painful. A scab forms over the lesion soon, and falls off in a few weeks. Complete recovery may take longer. Cutaneous anthrax is typically caused when B. anthracis spores enter through cuts on the skin. This form is found most commonly when humans handle infected animals and/or animal products. Cutaneous anthrax is rarely fatal if treated, because the infection area is limited to the skin, preventing the lethal factor, edema factor, and protective antigen from entering and destroying a vital organ. Without treatment, about 20% of cutaneous skin infection cases progress to toxemia and death. Respiratory infection in humans is relatively rare and presents as two stages. It infects the lymph nodes in the chest first, rather than the lungs themselves, a condition called hemorrhagic mediastinitis, causing bloody fluid to accumulate in the chest cavity, therefore causing shortness of breath. The first stage causes cold and flu-like symptoms. Symptoms include fever, shortness of breath, cough, fatigue, and chills. This can last hours to days. Often, many fatalities from inhalational anthrax are when the first stage is mistaken for the cold or flu and the victim does not seek treatment until the second stage, which is 90% fatal. The second (pneumonia) stage occurs when the infection spreads from the lymph nodes to the lungs. Symptoms of the second stage develop suddenly after hours or days of the first stage. Symptoms include high fever, extreme shortness of breath, shock, and rapid death within 48 hours in fatal cases. Historical mortality rates were over 85%, but when treated early (seen in the 2001 anthrax attacks), observed case fatality rate dropped to 45%. Distinguishing pulmonary anthrax from more common causes of respiratory illness is essential to avoiding delays in diagnosis and thereby improving outcomes. An algorithm for this purpose has been developed. Gastrointestinal (GI) infection is most often caused by consuming anthrax-infected meat and is characterized by diarrhea, potentially with blood, abdominal pains, acute inflammation of the intestinal tract, and loss of appetite. Occasional vomiting of blood can occur. Lesions have been found in the intestines and in the mouth and throat. After the bacterium invades the gastrointestinal system, it spreads to the bloodstream and throughout the body, while continuing to make toxins. GI infections can be treated, but usually result in fatality rates of 25 to 60%, depending upon how soon treatment commences. This form of anthrax is the rarest form. Bacillus anthracis is a rod-shaped, Gram-positive, aerobic bacterium about 1 by 9 μm in size. It was shown to cause disease by Robert Koch in 1876 when he took a blood sample from an infected cow, isolated the bacteria, and put them into a mouse. The bacterium normally rests in endospore form in the soil, and can survive for decades in this state. Herbivores are often infected whilst grazing, especially when eating rough, irritant, or spiky vegetation; the vegetation has been hypothesized to cause wounds within the gastrointestinal tract permitting entry of the bacterial endospores into the tissues, though this has not been proven. Once ingested or placed in an open wound, the bacteria begin multiplying inside the animal or human and typically kill the host within a few days or weeks. The endospores germinate at the site of entry into the tissues and then spread by the circulation to the lymphatics, where the bacteria multiply. The production of two powerful exotoxins and lethal toxin by the bacteria causes death. Veterinarians can often tell a possible anthrax-induced death by its sudden occurrence, and by the dark, nonclotting blood that oozes from the body orifices. Most anthrax bacteria inside the body after death are outcompeted and destroyed by anaerobic bacteria within minutes to hours post mortem. However, anthrax vegetative bacteria that escape the body via oozing blood or through the opening of the carcass may form hardy spores. These vegetative bacteria are not contagious. One spore forms per one vegetative bacterium. The triggers for spore formation are not yet known, though oxygen tension and lack of nutrients may play roles. Once formed, these spores are very hard to eradicate. The infection of herbivores (and occasionally humans) by the inhalational route normally proceeds as follows: Once the spores are inhaled, they are transported through the air passages into the tiny air sacs (alveoli) in the lungs. The spores are then picked up by scavenger cells (macrophages) in the lungs and are transported through small vessels (lymphatics) to the lymph nodes in the central chest cavity (mediastinum). Damage caused by the anthrax spores and bacilli to the central chest cavity can cause chest pain and difficulty in breathing. Once in the lymph nodes, the spores germinate into active bacilli that multiply and eventually burst the macrophages, releasing many more bacilli into the bloodstream to be transferred to the entire body. Once in the blood stream, these bacilli release three proteins named lethal factor, edema factor, and protective antigen. The three are not toxic by themselves, but their combination is incredibly lethal to humans. Protective antigen combines with these other two factors to form lethal toxin and edema toxin, respectively. These toxins are the primary agents of tissue destruction, bleeding, and death of the host. If antibiotics are administered too late, even if the antibiotics eradicate the bacteria, some hosts still die of toxemia because the toxins produced by the bacilli remain in their system at lethal dose levels. The spores are able to survive in harsh conditions for decades or even centuries. Such spores can be found on all continents, including Antarctica. Disturbed grave sites of infected animals have been known to cause infection after 70 years. Occupational exposure to infected animals or their products (such as skin, wool, and meat) is the usual pathway of exposure for humans. Workers who are exposed to dead animals and animal products are at the highest risk, especially in countries where anthrax is more common. Anthrax in livestock grazing on open range where they mix with wild animals still occasionally occurs in the United States and elsewhere. Many workers who deal with wool and animal hides are routinely exposed to low levels of anthrax spores, but most exposure levels are not sufficient to develop anthrax infections. A lethal infection is reported to result from inhalation of about 10,000–20,000 spores, though this dose varies among host species. Little documented evidence is available to verify the exact or average number of spores needed for infection. Historically, inhalational anthrax was called woolsorters' disease because it was an occupational hazard for people who sorted wool. Today, this form of infection is extremely rare in advanced nations, as almost no infected animals remain. Anthrax can enter the human body through the intestines (ingestion), lungs (inhalation), or skin (cutaneous) and causes distinct clinical symptoms based on its site of entry. In general, an infected human will be quarantined. However, anthrax does not usually spread from an infected human to a noninfected human. But, if the disease is fatal to the person's body, its mass of anthrax bacilli becomes a potential source of infection to others and special precautions should be used to prevent further contamination. Inhalational anthrax, if left untreated until obvious symptoms occur, is usually fatal. Anthrax can be contracted in laboratory accidents or by handling infected animals or their wool or hides. It has also been used in biological warfare agents and by terrorists to intentionally infect as exemplified by the 2001 anthrax attacks. The lethality of the anthrax disease is due to the bacterium's two principal virulence factors: the poly-D-glutamic acid capsule, which protects the bacterium from phagocytosis by host neutrophils, and the tripartite protein toxin, called anthrax toxin. Anthrax toxin is a mixture of three protein components: protective antigen (PA), edema factor (EF), and lethal factor (LF). PA plus LF produces lethal toxin, and PA plus EF produces edema toxin. These toxins cause death and tissue swelling (edema), respectively. To enter the cells, the edema and lethal factors use another protein produced by B. anthracis called protective antigen, which binds to two surface receptors on the host cell. A cell protease then cleaves PA into two fragments: PA and PA. PA dissociates into the extracellular medium, playing no further role in the toxic cycle. PA then oligomerizes with six other PA fragments forming a heptameric ring-shaped structure named a prepore. Once in this shape, the complex can competitively bind up to three EFs or LFs, forming a resistant complex. Receptor-mediated endocytosis occurs next, providing the newly formed toxic complex access to the interior of the host cell. The acidified environment within the endosome triggers the heptamer to release the LF and/or EF into the cytosol. It is unknown how exactly the complex results in the death of the cell. Edema factor is a calmodulin-dependent adenylate cyclase. Adenylate cyclase catalyzes the conversion of ATP into cyclic AMP (cAMP) and pyrophosphate. The complexation of adenylate cyclase with calmodulin removes calmodulin from stimulating calcium-triggered signaling, thus inhibiting the immune response. To be specific, LF inactivates neutrophils (a type of phagocytic cell) by the process just described so they cannot phagocytose bacteria. Throughout history, lethal factor was presumed to cause macrophages to make TNF-alpha and interleukin 1, beta (IL1B). TNF-alpha is a cytokine whose primary role is to regulate immune cells, as well as to induce inflammation and apoptosis or programmed cell death. Interleukin 1, beta is another cytokine that also regulates inflammation and apoptosis. The overproduction of TNF-alpha and IL1B ultimately leads to septic shock and death. However, recent evidence indicates anthrax also targets endothelial cells that line serous cavities such as the pericardial cavity, pleural cavity, and peritoneal cavity, lymph vessels, and blood vessels, causing vascular leakage of fluid and cells, and ultimately hypovolemic shock and septic shock. Various techniques may be used for the direct identification of B. anthracis in clinical material. Firstly, specimens may be Gram stained. Bacillus spp. are quite large in size (3 to 4 μm long), they may grow in long chains, and they stain Gram-positive. To confirm the organism is B. anthracis, rapid diagnostic techniques such as polymerase chain reaction-based assays and immunofluorescence microscopy may be used. All Bacillus species grow well on 5% sheep blood agar and other routine culture media. Polymyxin-lysozyme-EDTA-thallous acetate can be used to isolate B. anthracis from contaminated specimens, and bicarbonate agar is used as an identification method to induce capsule formation. Bacillus spp. usually grow within 24 hours of incubation at 35°C, in ambient air (room temperature) or in 5% CO. If bicarbonate agar is used for identification, then the medium must be incubated in 5% CO. B. anthracis colonies are medium-large, gray, flat, and irregular with swirling projections, often referred to as having a "medusa head" appearance, and are not hemolytic on 5% sheep blood agar. The bacteria are not motile, susceptible to penicillin, and produce a wide zone of lecithinase on egg yolk agar. Confirmatory testing to identify B. anthracis includes gamma bacteriophage testing, indirect hemagglutination, and enzyme-linked immunosorbent assay to detect antibodies. The best confirmatory precipitation test for anthrax is the Ascoli test. If a person is suspected as having died from anthrax, precautions should be taken to avoid skin contact with the potentially contaminated body and fluids exuded through natural body openings. The body should be put in strict quarantine. A blood sample should then be collected and sealed in a container and analyzed in an approved laboratory to ascertain if anthrax is the cause of death. Then, the body should be incinerated. Microscopic visualization of the encapsulated bacilli, usually in very large numbers, in a blood smear stained with polychrome methylene blue (McFadyean stain) is fully diagnostic, though culture of the organism is still the gold standard for diagnosis. Full isolation of the body is important to prevent possible contamination of others. Protective, impermeable clothing and equipment such as rubber gloves, rubber apron, and rubber boots with no perforations should be used when handling the body. No skin, especially if it has any wounds or scratches, should be exposed. Disposable personal protective equipment is preferable, but if not available, decontamination can be achieved by autoclaving. Disposable personal protective equipment and filters should be autoclaved, and/or burned and buried. Anyone working with anthrax in a suspected or confirmed person should wear respiratory equipment capable of filtering particles of their size or smaller. The US National Institute for Occupational Safety and Health – and Mine Safety and Health Administration-approved high-efficiency respirator, such as a half-face disposable respirator with a high-efficiency particulate air filter, is recommended. All possibly contaminated bedding or clothing should be isolated in double plastic bags and treated as possible biohazard waste. The body of an infected person should be sealed in an airtight body bag. Dead people who are opened and not burned provide an ideal source of anthrax spores. Cremating people is the preferred way of handling body disposal. No embalming or autopsy should be attempted without a fully equipped biohazard laboratory and trained, knowledgeable personnel. Vaccines against anthrax for use in livestock and humans have had a prominent place in the history of medicine. The French scientist Louis Pasteur developed the first effective vaccine in 1881. Human anthrax vaccines were developed by the Soviet Union in the late 1930s and in the US and UK in the 1950s. The current FDA-approved US vaccine was formulated in the 1960s. Currently administered human anthrax vaccines include acellular (United States) and live spore (Russia) varieties. All currently used anthrax vaccines show considerable local and general reactogenicity (erythema, induration, soreness, fever) and serious adverse reactions occur in about 1% of recipients. The American product, BioThrax, is licensed by the FDA and was formerly administered in a six-dose primary series at 0, 2, 4 weeks and 6, 12, 18 months, with annual boosters to maintain immunity. In 2008, the FDA approved omitting the week-2 dose, resulting in the currently recommended five-dose series. New second-generation vaccines currently being researched include recombinant live vaccines and recombinant subunit vaccines. In the 20th century the use of a modern product (BioThrax) to protect American troops against the use of anthrax in biological warfare was controversial. Preventative antibiotics are recommended in those who have been exposed. Early detection of sources of anthrax infection can allow preventive measures to be taken. In response to the anthrax attacks of October 2001, the United States Postal Service (USPS) installed biodetection systems (BDSs) in their large-scale mail processing facilities. BDS response plans were formulated by the USPS in conjunction with local responders including fire, police, hospitals and public health. Employees of these facilities have been educated about anthrax, response actions, and prophylactic medication. Because of the time delay inherent in getting final verification that anthrax has been used, prophylactic antibiotic treatment of possibly exposed personnel must be started as soon as possible. Anthrax cannot be spread directly from person to person, but a person's clothing and body may be contaminated with anthrax spores. Effective decontamination of people can be accomplished by a thorough wash-down with antimicrobial soap and water. Waste water should be treated with bleach or another antimicrobial agent. Effective decontamination of articles can be accomplished by boiling them in water for 30 minutes or longer. Chlorine bleach is ineffective in destroying spores and vegetative cells on surfaces, though formaldehyde is effective. Burning clothing is very effective in destroying spores. After decontamination, there is no need to immunize, treat, or isolate contacts of persons ill with anthrax unless they were also exposed to the same source of infection. Early antibiotic treatment of anthrax is essential; delay significantly lessens chances for survival. Treatment for anthrax infection and other bacterial infections includes large doses of intravenous and oral antibiotics, such as fluoroquinolones (ciprofloxacin), doxycycline, erythromycin, vancomycin, or penicillin. FDA-approved agents include ciprofloxacin, doxycycline, and penicillin. In possible cases of pulmonary anthrax, early antibiotic prophylaxis treatment is crucial to prevent possible death. In recent years, many attempts have been made to develop new drugs against anthrax, but existing drugs are effective if treatment is started soon enough. In May 2009, Human Genome Sciences submitted a biologic license application (BLA, permission to market) for its new drug, raxibacumab (brand name ABthrax) intended for emergency treatment of inhaled anthrax. On 14 December 2012, the US Food and Drug Administration approved raxibacumab injection to treat inhalational anthrax. Raxibacumab is a monoclonal antibody that neutralizes toxins produced by B. anthracis. On March, 2016, FDA approved a second anthrax treatment using a monoclonal antibody which neutralizes the toxins produced by B. anthracis. Obiltoxaximab is approved to treat inhalational anthrax in conjunction with appropriate antibacterial drugs, and for prevention when alternative therapies are not available or appropriate. The last fatal case of natural inhalational anthrax in the United States occurred in California in 1976, when a home weaver died after working with infected wool imported from Pakistan. To minimize the chance of spreading the disease, the deceased was transported to UCLA in a sealed plastic body bag within a sealed metal container for autopsy. During December 2009, the New Hampshire Department of Health and Human Services confirmed a case of gastrointestinal anthrax in an adult female. The CDC investigated the source and the possibility that it was contracted from an African drum recently used by the woman taking part in a drum circle. The woman apparently inhaled anthrax [in spore form] from the hide of the drum. She became critically ill, but with gastrointestinal anthrax rather than inhaled anthrax, which made her unique in American medical history. The building where the infection took place was cleaned and reopened to the public and the woman recovered. Jodie Dionne-Odom, New Hampshire state epidemiologist, stated, "It is a mystery. We really don't know why it happened." In November 2008, a drum maker in the United Kingdom who worked with untreated animal skins died from anthrax. Gastrointestinal anthrax is exceedingly rare in the United States, with two cases on record, the first was reported in 1942, according to the Centers for Disease Control and Prevention. In December 2009, an outbreak of anthrax occurred amongst heroin addicts in the Glasgow and Stirling areas of Scotland, resulting in 14 deaths. The source of the anthrax is believed to be dilution of the heroin with bone meal in Afghanistan. The English name comes from anthrax ( ), the Greek word for coal, possibly having Egyptian etymology, because of the characteristic black skin lesions developed by victims with a cutaneous anthrax infection. The central, black eschar, surrounded by vivid red skin has long been recognised as typical of the disease. The first recorded use of the word "anthrax" in English is in a 1398 translation of Bartholomaeus Anglicus' work (On the Properties of Things, 1240). Anthrax has been known by a wide variety of names, indicating its symptoms, location and groups considered most vulnerable to infection. These include Siberian plague, Cumberland disease, charbon, splenic fever, malignant edema, woolsorter's disease, and even . Robert Koch, a German physician and scientist, first identified the bacterium that caused the anthrax disease in 1875 in Wolsztyn (now part of Poland). His pioneering work in the late 19th century was one of the first demonstrations that diseases could be caused by microbes. In a groundbreaking series of experiments, he uncovered the lifecycle and means of transmission of anthrax. His experiments not only helped create an understanding of anthrax, but also helped elucidate the role of microbes in causing illness at a time when debates still took place over spontaneous generation versus cell theory. Koch went on to study the mechanisms of other diseases and won the 1905 Nobel Prize in Physiology or Medicine for his discovery of the bacterium causing tuberculosis. Although Koch arguably made the greatest theoretical contribution to our understanding of anthrax, other researchers were more concerned with the practical questions of how to prevent the disease. In Britain, where anthrax affected workers in the wool, worsted, hides and tanning industries, it was viewed with fear. John Henry Bell, a doctor based in Bradford, first made the link between the mysterious and deadly "woolsorter's disease" and anthrax, showing in 1878 that they were one and the same. In the early twentieth century, Friederich Wilhelm Eurich, the German bacteriologist who settled in Bradford with his family as a child, carried out important research for the local Anthrax Investigation Board. Eurich also made valuable contributions to a Home Office Departmental Committee of Inquiry, established in 1913 to address the continuing problem of industrial anthrax. His work in this capacity, much of it collaboration with the factory inspector G. Elmhirst Duckering, led directly to the Anthrax Prevention Act (1919). Anthrax posed a major economic challenge in France and elsewhere during the nineteenth century. Horses, cattle and sheep were particularly vulnerable, and national funds were set aside to investigate the production of a vaccine. The noted French scientist Louis Pasteur was charged with the production of a vaccine, following his successful work in developing methods which helped to protect the important wine and silk industries. In May 1881, Pasteur – in collaboration with his assistants Jean-Joseph Henri Toussaint, Émile Roux and others – performed a public experiment at Pouilly-le-Fort to demonstrate his concept of vaccination. He prepared two groups of 25 sheep, one goat, and several cows. The animals of one group were injected with an anthrax vaccine prepared by Pasteur twice, at an interval of 15 days; the control group was left unvaccinated. Thirty days after the first injection, both groups were injected with a culture of live anthrax bacteria. All the animals in the unvaccinated group died, while all of the animals in the vaccinated group survived. After this apparent triumph, which was widely reported in the local, national and international press, Pasteur made strenuous efforts to export the vaccine beyond France. He used his celebrity status to establish Pasteur Institutes across Europe and Asia, and his nephew, Adrien Loir, travelled to Australia in 1888 to try and introduce the vaccine to combat anthrax in New South Wales. Ultimately the vaccine was unsuccessful in the challenging climate of rural Australia, and it was soon superseded by a more robust version developed by local researchers John Gunn and John McGarvie Smith. The human vaccine for anthrax became available in 1954. This was a cell-free vaccine instead of the live-cell Pasteur-style vaccine used for veterinary purposes. An improved cell-free vaccine became available in 1970. The virulent Ames strain, which was used in the 2001 anthrax attacks in the United States, has received the most news coverage of any anthrax outbreak. The Ames strain contains two virulence plasmids, which separately encode for a three-protein toxin, called anthrax toxin, and a polyglutamic acid capsule. Nonetheless, the Vollum strain, developed but never used as a biological weapon during the Second World War, is much more dangerous. The Vollum (also incorrectly referred to as Vellum) strain was isolated in 1935 from a cow in Oxfordshire. This same strain was used during the Gruinard bioweapons trials. A variation of Vollum, known as "Vollum 1B", was used during the 1960s in the US and UK bioweapon programs. Vollum 1B is widely believed to have been isolated from William A. Boyles, a 46-year-old scientist at the US Army Biological Warfare Laboratories at Camp (later Fort) Detrick, Maryland, (precursor to USAMRIID), who died in 1951 after being accidentally infected with the Vollum strain. The Sterne strain, named after the Trieste-born immunologist Max Sterne, is an attenuated strain used as a vaccine, which contains only the anthrax toxin virulence plasmid and not the polyglutamic acid capsule expressing plasmid. Anthrax spores can survive for very long periods of time in the environment after release. Chemical methods for cleaning anthrax-contaminated sites or materials may use oxidizing agents such as peroxides, ethylene oxide, Sandia Foam, chlorine dioxide (used in the Hart Senate Office Building), peracetic acid, ozone gas, hypochlorous acid, sodium persulfate, and liquid bleach products containing sodium hypochlorite. Nonoxidizing agents shown to be effective for anthrax decontamination include methyl bromide, formaldehyde, and metam sodium. These agents destroy bacterial spores. All of the aforementioned anthrax decontamination technologies have been demonstrated to be effective in laboratory tests conducted by the US EPA or others. A bleach solution for treating hard surfaces has been approved by the EPA. Chlorine dioxide has emerged as the preferred biocide against anthrax-contaminated sites, having been employed in the treatment of numerous government buildings over the past decade. Its chief drawback is the need for in situ processes to have the reactant on demand. To speed the process, trace amounts of a nontoxic catalyst composed of iron and tetroamido macrocyclic ligands are combined with sodium carbonate and bicarbonate and converted into a spray. The spray formula is applied to an infested area and is followed by another spray containing tert-butyl hydroperoxide. Using the catalyst method, a complete destruction of all anthrax spores can be achieved in under 30 minutes. A standard catalyst-free spray destroys fewer than half the spores in the same amount of time. Cleanups at a Senate office building, several contaminated postal facilities, and other US government and private office buildings showed decontamination to be possible, but it is time-consuming and costly. Clearing the Senate office building of anthrax spores cost $27 million, according to the Government Accountability Office. Cleaning the Brentwood postal facility in Washington cost $130 million and took 26 months. Since then, newer and less costly methods have been developed. Cleanup of anthrax-contaminated areas on ranches and in the wild is much more problematic. Carcasses may be burned, though it often takes up to three days to burn a large carcass and this is not feasible in areas with little wood. Carcasses may also be buried, though the burying of large animals deeply enough to prevent resurfacing of spores requires much manpower and expensive tools. Carcasses have been soaked in formaldehyde to kill spores, though this has environmental contamination issues. Block burning of vegetation in large areas enclosing an anthrax outbreak has been tried; this, while environmentally destructive, causes healthy animals to move away from an area with carcasses in search of fresh grass. Some wildlife workers have experimented with covering fresh anthrax carcasses with shadecloth and heavy objects. This prevents some scavengers from opening the carcasses, thus allowing the putrefactive bacteria within the carcass to kill the vegetative B. anthracis cells and preventing sporulation. This method also has drawbacks, as scavengers such as hyenas are capable of infiltrating almost any exclosure. The experimental site at Gruinard Island is said to have been decontaminated with a mixture of formaldehyde and seawater by the Ministry of Defence. It is not clear whether similar treatments had been applied to US test sites. Anthrax spores have been used as a biological warfare weapon. Its first modern incidence occurred when Nordic rebels, supplied by the German General Staff, used anthrax with unknown results against the Imperial Russian Army in Finland in 1916. Anthrax was first tested as a biological warfare agent by Unit 731 of the Japanese Kwantung Army in Manchuria during the 1930s; some of this testing involved intentional infection of prisoners of war, thousands of whom died. Anthrax, designated at the time as Agent N, was also investigated by the Allies in the 1940s. A long history of practical bioweapons research exists in this area. For example, in 1942, British bioweapons trials severely contaminated Gruinard Island in Scotland with anthrax spores of the Vollum-14578 strain, making it a no-go area until it was decontaminated in 1990. The Gruinard trials involved testing the effectiveness of a submunition of an "N-bomb" a biological weapon containing dried anthrax spores. Additionally, five million "cattle cakes" (animal feed pellets impregnated with anthrax spores) were prepared and stored at Porton Down for "Operation Vegetarian" antilivestock attacks against Germany to be made by the Royal Air Force. The plan was for anthrax-based biological weapons to be dropped on Germany in 1944. However, the edible cattle cakes and the bomb were not used; the cattle cakes were incinerated in late 1945. Weaponized anthrax was part of the US stockpile prior to 1972, when the United States signed the Biological Weapons Convention. President Nixon ordered the dismantling of US biowarfare programs in 1969 and the destruction of all existing stockpiles of bioweapons. In 1978–79, the Rhodesian government used anthrax against cattle and humans during its campaign against rebels. The Soviet Union created and stored 100 to 200 tons of anthrax spores at Kantubek on Vozrozhdeniya Island. They were abandoned in 1992 and destroyed in 2002. American military and British Army personnel are routinely vaccinated against anthrax prior to active service in places where biological attacks are considered a threat. Despite signing the 1972 agreement to end bioweapon production, the government of the Soviet Union had an active bioweapons program that included the production of hundreds of tons of weapons-grade anthrax after this period. On 2 April 1979, some of the over one million people living in Sverdlovsk (now called Ekaterinburg, Russia), about east of Moscow, were exposed to an accidental release of anthrax from a biological weapons complex located near there. At least 94 people were infected, of whom at least 68 died. One victim died four days after the release, 10 over an eight-day period at the peak of the deaths, and the last six weeks later. Extensive cleanup, vaccinations, and medical interventions managed to save about 30 of the victims. Extensive cover-ups and destruction of records by the KGB continued from 1979 until Russian President Boris Yeltsin admitted this anthrax accident in 1992. Jeanne Guillemin reported in 1999 that a combined Russian and United States team investigated the accident in 1992. Nearly all of the night-shift workers of a ceramics plant directly across the street from the biological facility (compound 19) became infected, and most died. Since most were men, some NATO governments suspected the Soviet Union had developed a sex-specific weapon. The government blamed the outbreak on the consumption of anthrax-tainted meat, and ordered the confiscation of all uninspected meat that entered the city. They also ordered all stray dogs to be shot and people not have contact with sick animals. Also, a voluntary evacuation and anthrax vaccination program was established for people from 18–55. To support the cover-up story, Soviet medical and legal journals published articles about an outbreak in livestock that caused GI anthrax in people having consumed infected meat, and cutaneous anthrax in people having come into contact with the animals. All medical and public health records were confiscated by the KGB. In addition to the medical problems the outbreak caused, it also prompted Western countries to be more suspicious of a covert Soviet bioweapons program and to increase their surveillance of suspected sites. In 1986, the US government was allowed to investigate the incident, and concluded the exposure was from aerosol anthrax from a military weapons facility. In 1992, President Yeltsin admitted he was "absolutely certain" that "rumors" about the Soviet Union violating the 1972 Bioweapons Treaty were true. The Soviet Union, like the US and UK, had agreed to submit information to the UN about their bioweapons programs, but omitted known facilities and never acknowledged their weapons program. In theory, anthrax spores can be cultivated with minimal special equipment and a first-year collegiate microbiological education. To make large amounts of an aerosol form of anthrax suitable for biological warfare requires extensive practical knowledge, training, and highly advanced equipment. Concentrated anthrax spores were used for bioterrorism in the 2001 anthrax attacks in the United States, delivered by mailing postal letters containing the spores. The letters were sent to several news media offices and two Democratic senators: Tom Daschle of South Dakota and Patrick Leahy of Vermont. As a result, 22 were infected and five died. Only a few grams of material were used in these attacks and in August 2008, the US Department of Justice announced they believed that Dr. Bruce Ivins, a senior biodefense researcher employed by the United States government, was responsible. These events also spawned many anthrax hoaxes. Due to these events, the US Postal Service installed biohazard detection systems at its major distribution centers to actively scan for anthrax being transported through the mail. In response to the postal anthrax attacks and hoaxes, the United States Postal Service sterilized some mail using gamma irradiation and treatment with a proprietary enzyme formula supplied by Sipco Industries. A scientific experiment performed by a high school student, later published in The Journal of Medical Toxicology, suggested a domestic electric iron at its hottest setting (at least ) used for at least 5 minutes should destroy all anthrax spores in a common postal envelope. Anthrax is especially rare in dogs and cats, as is evidenced by a single reported case in the United States in 2001. Anthrax outbreaks occur in some wild animal populations with some regularity. Russian researchers estimate arctic permafrost contains around 1.5 million anthrax-infected reindeer carcasses, and the spores may survive in the permafrost for 105 years. There is a risk that global warming in the Arctic can thaw the permafrost, releasing anthrax spores in the carcasses. In 2016, an anthrax outbreak in reindeer was linked to a 75-year-old carcass that defrosted during a heat wave.	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https://en.wikipedia.org/wiki/Vein_of_Galen_aneurysmal_malformations	disease	Vein of Galen aneurysmal malformations	Vein of Galen aneurysmal malformations (VGAM) and Vein of Galen aneurysmal dilations (VGAD) are the most frequent arteriovenous malformations in infants and fetuses. VGAM consist of a tangled mass of dilated vessels supplied by an enlarged artery. The malformation increases greatly in size with age, although the mechanism of the increase is unknown. Dilation of the great cerebral vein of Galen is a secondary result of the force of arterial blood either directly from an artery via an arteriovenous fistula or by way of a tributary vein that receives the blood directly from an artery. There is usually a venous anomaly downstream from the draining vein that, together with the high blood flow into the great cerebral vein of Galen causes its dilation. The right sided cardiac chambers and pulmonary arteries also develop mild to severe dilation.	Malformations often lead to cardiac failure, cranial bruits (pattern 1), hydrocephaly, and subarachnoid hemorrhage in neonates. The heart failure is due to the size of the arteriovenous shunt that can steal 80% or more of the cardiac output, with large volumes of blood under high pressure returning to the right heart and pulmonary circulation and sinus venosus atrial septal defects. It is also the most common cause of death in such patients. Non-developmental syndromes also directly or indirectly affect the Great Cerebral Vein of Galen, although they are extremely rare. These include superior vena cava syndrome (SVCS), and thrombosis of the lateral sinus, superior sagittal sinus, internal jugular vein, or of the Great Cerebral Vein of Galen itself. Testing for a malformed vein of Galen is indicated when a patient has heart failure which has no obvious cause. Diagnosis is generally achieved by signs such as cranial bruits and symptoms such as expanded facial veins. The vein of Galen can be visualized using ultrasound or Doppler. A malformed Great Cerebral Vein will be noticeably enlarged. Ultrasound is a particularly useful tool for vein of Galen malformations because so many cases occur in infancy and ultrasound can make diagnoses prenatally. Many cases are diagnosed only during autopsy as congestive heart failure occurs very early. Five patterns of Galenic arteriovenous malformations have been described: These malformations develop in utero by the persistence of fistulae between primitive pia arachnoidal arteries and pial veins that cross each other at right angles. Because the primitive Galenic system and the primitive choroidal system lie close together, an arteriovenous malformation involving the primitive choroidal system will inevitably involve the Galenic vein. Larger arteriovenous shunts correlate with greater hemodynamic effects and earlier symptom onset; small arteriovenous shunts correlate with greater local mass effect causing progressive neurological impairment. Treatment depends on the anatomy of the malformation as determined by angiography or Magnetic Resonance Imaging (MRI). Head circumference measurements should be obtained regularly and monitored carefully to detect hydrocephalus. Neurosurgical procedures to relieve hydrocephalus are important. A ventriculoperitoneal shunt may be required in some infants. A pediatric cardiologist should be consulted to manage high-output failure, if present. Often patients need to be intubated. In most cases, the fistulous arteries feeding into the Vein of Galen must be blocked, thereby reducing the blood flow into the vein. Open surgery has a high morbidity and mortality. Recent advances over the past few decades have made endovascular embolization the preferred method of treatment. These treatments are preferred because they offer little threat to the surrounding brain tissue. However, there have been several reported cases of arteriovenous malformations recurring. The young age of many patients, the complex vascular anatomy, and the sensitive location of the Vein of Galen offer considerable challenges to surgeons. Another treatment option is Radiotherapy. Radiotherapy, also called radiosurgery, involves the use of focused beams to damage the blood vessel. Radiotherapy is often not pursued as a treatment because the effects of the procedure can take months or years and there is risk of damaging adjacent brain tissue. Surgery is not always an option when the anatomy of the malformation creates too much of a risk. Recent improvements in endovascular procedures have made many cases, which were not surgically accessible, treatable. Endovascular treatments involve delivering drugs, balloons, or coils to the site of the malformation through blood vessels via catheters. These treatments work by limiting blood flow through the vein. There is, however, still risk of complications from endovascular treatments. The wall of the vein can be damaged during the procedure and, in some cases, the emboli can become dislodged and travel through the vascular system. Two-dimensional echocardiography with color-flow imaging and pulsed Doppler ultrasound was used to evaluate one fetus and five neonates with a Vein of Galen malformation. Color-flow imaging and pulsed Doppler ultrasonography provided anatomical and pathophysiological information regarding cardiac hemodynamics and intracranial blood flow; with the patient's clinical status, these methods provided a reliable, noninvasive means to evaluate the effectiveness of therapy and the need for further treatment in neonates with Vein of Galen malformations. When none of these procedures are viable, shunting can be used to ameliorate the pressure inside the varix. Seizures usually are managed with antiepileptic medications. The complications that are usually associated with vein of Galen malformations are usually intracranial hemorrhages. Over half the patients with VGAM have a malformation that cannot be corrected. Patients frequently die in the neonatal period or in early infancy. Vein of Galen malformations are devastating complications. Studies have shown that 77% of untreated cases result in mortality. Even after surgical treatment, the mortality rate remains as high as 39.4%. Most cases occur during infancy when the mortality rates are at their highest. Vein of Galen malformations are a relatively unknown affliction, attributed to the rareness of the malformations. Therefore, when a child is diagnosed with a faulty Great Cerebral Vein of Galen, most parents know little to nothing about what they are dealing with. To counteract this, support sites have been created which offer information, advice, and a community of support to the afflicted (, ).	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https://en.wikipedia.org/wiki/Dysbaric_osteonecrosis	disease	Dysbaric osteonecrosis	ischemic bone disease caused by decompression bubbles Dysbaric osteonecrosis or DON is a form of avascular necrosis where there is death of a portion of the bone that is thought to be caused by nitrogen embolism (blockage of the blood vessels by a bubble of nitrogen coming out of solution) in divers. Although the definitive pathologic process is poorly understood, there are several hypotheses: - Intra- or extravascular nitrogen in bones, "nitrogen embolism". - Osmotic gas effects due to intramedullary pressure effects. - fat embolism - hemoconcentration and increased coagulability.	The diagnosis is made by x-ray/MRI appearance and has five juxta-articular classifications and forehead, neck, and shaft classifications indicating early radiological signs. Early on there is flattening of articular surfaces, thinning of cartilage with osteophyte (spur) formation. In juxta-articular lesions without symptoms, there is dead bone and marrow separated from living bone by a line of dense collagen. Microscopic cysts form, fill with necrotic material and there is massive necrosis with replacement by cancellous bone with collapse of the lesions. The lesion begins as a random finding on x-ray without symptoms. Symptomatic lesions usually involve joint surfaces, and fracture with attempted healing occurs. This process takes place over months to years and eventually causes disabling arthritis, particularly of the femoral head (hip). The following staging system is sometimes useful when managing lesions. - Stage 0 - Intravascular coagulation - Stage 1 - Dead Bone without repair - Stage 2 - Dead Bone with repair but without collapse - Stage 3 - Dead Bone with repair and with collapse - Stage 4 - Secondary degenerative arthritis In a study of bone lesions in 281 compressed air workers done by Walder in 1969, 29% of the lesions were in the humeral head (shoulder), 16% in the femoral head (hip), 40% in the lower end of the femur (lower thigh at the knee) and 15% in the upper tibia (knee below the knee cap). Worsening of the condition from continued decompression in an asymptomatic x-ray finding may occur. Dysbaric osteonecrosis is a significant occupational hazard, occurring in 50% of commercial Japanese divers, 65% of Hawaiian fishermen and 16% of commercial and caisson divers in the UK. Its relationship to compressed air is strong in that it may follow a single exposure to compressed air, may occur with no history of DCS but is usually associated with significant compressed air exposure. The distribution of lesions differs with the type of exposure - the juxta-articular lesions being more common in caisson workers than in divers. There is a definite relationship between length of time exposed to extreme depths and the percentage of divers with bone lesions. Evidence does not suggest that dysbaric osteonecrosis is a significant risk in recreational scuba diving. Treatment is difficult, often requiring a joint replacement. Spontaneous improvement occasionally happens and some juxta-articular lesions do not progress to collapse. Other treatments include immobilization and osteotomy of the femur. Cancellous bone grafts are of little help. Prevention is a more successful strategy than treatment. By using the most conservative decompression schedule reasonably practicable, and by minimizing the number of major decompression exposures, the risk of DON may be reduced. Prompt treatment of any symptoms of decompression sickness (DCS) with recompression and hyperbaric oxygen also reduce the risk of subsequent DON. If the diver has not been exposed to excessive depth and decompression and presents as DON, there may be a predisposition for the condition. Diving should be restricted to shallow depths. Divers who have suffered from DON are at increased risk of future fracture of a juxta-articular lesion during a dive, and may face complications with future joint replacements. Because of the young age of the population normally affected, little data is available regarding joint replacement complications. There is the potential for worsening of DON for any diving where there might be a need for decompression, experimental or helium diving. Physically stressful diving should probably be restricted, both in sport diving and work diving due to the possibility of unnecessary stress to the joint. Any diving should be less than 40 feet/12 meters. These risks are affected by the degree of disability and by the type of lesion (juxta-articular or shaft).	[ { "begin": 0, "class": "SectionAnnotation", "length": 1534, "sectionHeading": "Process", "sectionLabel": "disease.other" }, { "begin": 1534, "class": "SectionAnnotation", "length": 773, "sectionHeading": "Prevalence", "sectionLabel": "disease.epidemiology" }, { "begin": 2307, "class": "SectionAnnotation", "length": 280, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 2587, "class": "SectionAnnotation", "length": 377, "sectionHeading": "Prevention", "sectionLabel": "disease.prevention" }, { "begin": 2964, "class": "SectionAnnotation", "length": 945, "sectionHeading": "Prognosis", "sectionLabel": "disease.prognosis" } ]
https://en.wikipedia.org/wiki/Stargardt_disease	disease	Stargardt disease	Stargardt disease, or fundus flavimaculatus, is the most frequent form of inherited juvenile macular degeneration. Stargardt causes progressive vision loss usually to the point of legal blindness. Several genes are associated with the disorder. Symptoms, mainly central vision loss, typically develop before age 20 (median age of onset: ~17 years old), and also include wavy vision, blind spots, blurriness, impaired color vision, and difficulty adapting to dim lighting (dark adaptation delays). Stargardt is often used to refer to any juvenile macular dystrophy; however, it properly refers to atrophic macular dystrophy with yellow, poorly-defined flecks surrounding the macula in the retinal pigment epithelium.	Patients with Stargardt disease usually develop symptoms in the mid-first to the late second decade of life, with age of onset which can be as early as ~6 years of age. The main symptom of Stargardt disease is loss of visual acuity, uncorrectable with glasses, which progresses and frequently stabilizes between 20/200 and 20/400. Other symptoms include wavy vision, blind spots (scotomata), blurriness, impaired color vision, and difficulty adapting to dim lighting (delayed dark adaptation). The disease sometimes causes sensitivity to glare; overcast days offer some relief. Vision is most noticeably impaired when the macula (center of retina and focus of vision) is damaged, leaving peripheral vision more intact. Generally, vision loss starts within the first 20 years of life. Examination with an ophthalmoscope shows few notable findings in the early stages of the disease. Eventually, however, an oval-shaped atrophy with a horizontal major axis appears in the retinal pigment epithelium, and has the appearance of beaten bronze, along with sparing of the area surrounding the optic disc (peripapillary sparing). Techniques such as fundus autofluorescence (FAF), Optical Coherence Tomography (OCT), or less frequently fluorescein angiography, can detect early signs before they are visible ophthalmoscopically. Stargardt disease is associated with several different genes: - STGD1: The most common form of Stargardt disease is the recessive form caused by mutations in the ABCA4 gene. It can also be associated with CNGB3. - STGD3: There is also a rare dominant form of Stargardt disease caused by mutations in the ELOVL4 gene. - STGD4: Associated with PROM1. The classification "STGD2" is no longer used. In STGD1, the genetic defect causes malfunction of the ATP-binding cassette transporter (ABCA4) protein of the visual phototransduction cycle. Defective ABCA4 leads to improper shuttling of vitamin A throughout the retina, and accelerated formation of toxic vitamin A dimers (also known as bisretinoids), and associated degradation byproducts. Vitamin A dimers and other byproducts are widely accepted as the cause of STGD1. As such, slowing the formation of vitamin A dimers might lead to a treatment for Stargardt. When vitamin A dimers and byproducts damage the retinal cells, fluorescent granules called lipofuscin in the retinal pigmented epithelium of the retina appear, as a reflecting such damage. In STGD4, a butterfly pattern of dystrophy is caused by mutations in a gene that encodes a membrane bound protein that is involved in the elongation of very long chain fatty acids (ELOVL4) Currently, there is no treatment for the disease. However, ophthalmologists recommend wearing sunglasses and hats outdoors and blue-light blocking glasses when exposed to artificial light sources, such as screens and lights. Tobacco smoke and second-hand smoke should be avoided. Animal studies also show that high doses of vitamin A can be detrimental by building up more lipofuscin toxin. Dietary non-supplemental vitamin A intake may not further the disease progression. Clinical trials are being conducted with promising early results. The trials may one day lead to treatments that might halt, and possibly even reverse, the effects of Stargardt disease using stem cell therapy, gene therapy, or pharmacotherapy. The Argus retinal prosthesis, an electronic retinal implant, was successfully fitted to a 67-year-old woman in Italy at the Careggi Hospital in 2016. The patient had a very advanced stage of Stargardt’s disease, and a total absence of peripheral and central visual fields. The long-term prognosis for patients with Stargardt disease is widely variable although the majority of people will progress to legal blindness. Stargardt disease has no impact on general health and life expectancy is normal. Some patients, usually those with the late onset form, can maintain excellent visual acuities for extended periods, and are therefore able to perform tasks such as reading or driving. STGD1 is the most common form of inherited juvenile macular degeneration with a prevalence of approximately 1 in 10,000 births. The disease was first reported in 1909 by Karl Stargardt, a German ophthalmologist. In 1997, it was discovered that mutations in the ABCA4 gene cause Stargardt disease. Vitamin A dimers and byproducts are thought to cause Stargardt disease, as they poison the retinal cells, leading to retinal cells death, causing vision loss. Treatment modalities currently under clinical investigation include cell therapy, gene therapy and oral therapies. Regarding cell therapy, Advanced Cell Technology, now called Ocata Therapeutics, has completed Phase I/II multicenter clinical trial using retinal cells derived from human embryonic stem cells (hESCs) to treat patients with Stargardt. After treating and collecting data on 18 patients, Advanced Cell was given approval to test its stem cell therapy on patients with 20/100 vision. In October 2014, the results of the Phase I/II clinical trial were published in the Lancet. Research at the preclinical (animal) stage include a new compound that can remove lipofuscin from retinal pigment epithelial cells.	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https://en.wikipedia.org/wiki/Kabuki_syndrome	disease	Kabuki syndrome	Kabuki syndrome (also previously known as kabuki makeup syndrome, KMS or Niikawa–Kuroki Syndrome), is a pediatric congenital disorder of suspected genetic origin with multiple congenital anomalies and intellectual disabilities. It is quite rare, affecting roughly one in 32,000 births. It was identified and described in 1981 by two Japanese groups, led by the scientists Norio Niikawa and Yoshikazu Kuroki. It is named kabuki syndrome because of the facial resemblance of affected individuals to stage makeup used in kabuki, a Japanese traditional theatrical form.	There is a wide range of congenital problems associated with kabuki syndrome with large differences between affected individuals. Some of the common problems are heart defects, urinary tract anomalies, hearing loss, hypotonia, recurrent ear infections and postnatal growth deficiency. Other characteristics include skeletal abnormality, joint laxity, short stature, and unusual dermatoglyphic patterns. In terms of development, mild to moderate intellectual disability is a common feature. Also, children with kabuki syndrome often have distinctive behavioral features. A few have normal intelligence, most of whom have learning difficulties such as struggling with fine motor, speech skills, and memory. There is no indication that the life expectancy of individuals with kabuki syndrome is shortened. Most medical issues are resolved with medical intervention. The fact that there are relatively few adults known with this syndrome is probably related to its recent discovery in 1980 in Japan and around 1990 in Europe and America. The facial appearance of individuals with this syndrome include long eyelids with turning up of the lateral third of the lower eyelid, a broad and depressed nasal tip, large prominent earlobes, and a cleft or high-arched palate. Other clinical features often include scoliosis, short fifth finger, persistence of fingerpads, and X-ray abnormalities of the vertebrae, hands, and hip joints. Kabuki syndrome is an autosomal dominant disorder and can be caused by loss-of-function mutations in two different genes. Hundreds of mutations have been identified in diagnosed kabuki syndrome patients for these genes. Most of these mutations involve a change in amino acid sequence that codes for a premature stop codon, and therefore nonfunctional, short enzymes. KMT2D, formerly known as the MLL2 gene, is located on chromosome 12 and is one of the genes involved in the development of this disorder. A mutation in the KMT2D gene results in a loss of function for the protein this gene codes for, which is a lysine (K)-specific methyltransferase 2D enzyme. KDM6A is another gene, that when mutated, can lead to kabuki syndrome. This mutation produces a nonfunctional lysine (K)-specific demethylase 6A. This gene is located on the X chromosome. These two genes belong to a family of genes called chromatin-modifying enzymes. Specifically these genes code for a histone methyltransferase (KMT2D) and a histone demethylase (KDM6A), and play a part in the regulation of gene expression. These enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. Epigenetic activation of certain developmental genes is impaired by loss of either enzyme and developmental abnormalities occur, leading to the characteristics of kabuki syndrome patients. The specific developmental genes have not been fully identified. It is seen that a majority of these cases are due to de novo mutations (those present in the subject but not in the parents). It is important to note that a percentage of patients did not exhibit a mutation in either gene; other causes are currently being researched. Kabuki syndrome can be diagnosed using whole exome or whole genome sequencing. Some patients who were initially clinically diagnosed with Kabuki syndrome were actually found to have Wiedemann-Steiner syndrome. The treatments of kabuki syndrome are still being developed due to its genetic nature. The first step to treatment is diagnosis. After diagnosis, the treatment of medical conditions can often be treated by medical intervention. There are also options in psychotherapy for young children with this disorder, as well as the family of the child. Genetic counseling is available as a preventative treatment for kabuki syndrome because it can be inherited and expressed by only having one copy of the mutated gene.	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https://en.wikipedia.org/wiki/Congenital_hearing_loss	disease	Congenital hearing loss	Congenital hearing loss is a hearing loss present at birth. It can include hereditary hearing loss or hearing loss due to other factors present either in-utero (prenatal) or at the time of birth.	Genetic factors are thought to cause more than 50% of all incidents of congenital hearing loss. Genetic hearing loss may be autosomal dominant, autosomal recessive, or X-linked (related to the sex chromosome). In autosomal dominant hearing loss, one parent who carries the dominant gene for hearing loss and typically has a hearing loss passes it on to the child. In this case there is at least a 50% probability that the child will also have a hearing loss. The probability is higher if both parents have the dominant gene (and typically both have a hearing loss) or if both grandparents on one side of the family have hearing loss due to genetic causes. Because at least one parent usually has a hearing loss, there is prior expectation that the child may have a hearing loss. Autosomal dominant congenital hearing loss can be attributed to such causes like Waardenburg Syndrome. In autosomal recessive hearing loss, both parents who typically have normal hearing, carry a recessive gene. In this case the probability of the child having a hearing loss is 25%. Because both parents usually have normal hearing, and because no other family members have hearing loss, there is no prior expectation that the child may have a hearing loss. In X-linked hearing loss, the mother carries the recessive trait for hearing loss on the sex chromosome. She can pass on the trait to males and female children, but usually only male children are affected. There are some genetic syndromes, in which hearing loss is one of the known characteristics. Some examples are Down syndrome (abnormality on a gene), Usher syndrome (autosomal recessive), Treacher Collins syndrome (autosomal dominant), Crouzon syndrome (autosomal dominant), and Alport syndrome (X-linked). Other causes of congenital hearing loss that are not hereditary in nature include prenatal infections, illnesses, toxins consumed by the mother during pregnancy or other conditions occurring at the time of birth or shortly thereafter. These conditions typically cause sensorineural hearing loss ranging from mild to profound in degree. A child with a congenital hearing loss should begin receiving treatment before 6 months of age. Studies suggest that children treated this early are usually able to develop communication skills (using spoken or sign language) that are as good as those of hearing peers. In the United States of America, because of a Federal law (the Individuals with Disabilities Education Act), children with a hearing loss between birth and 3 years of age have the right to receive interdisciplinary assessment and early intervention services at little or no cost. After age 3, early intervention and special education programs are provided through the public school system. There are a number of treatment options available, and parents will need to decide which are most appropriate for their child. They will need to consider the child’s age, developmental level and personality, the severity of the hearing loss, as well as their own preferences. Ideally a team of experts including the child’s primary care provider, an otolaryngologist, a speech-language pathologist, audiologist and an educator will work closely with the parents to create an Individualized Family Service Plan. Treatment plans can be changed as the child gets older. Children as young as 4 weeks of age can benefit from a hearing aid. These devices amplify sound, making it possible for many children to hear spoken words and develop language. However, some children with severe to profound hearing loss may not be able to hear enough sound, even with a hearing aid, to make speech audible. A behind-the-ear hearing aid is often recommended for young children because it is safer and more easily fitted and adjusted as the child grows as compared to one that fits within the ear. Parents also will need to decide how their family and child are going to communicate. If the child is going to communicate orally (speech), s/he may need assistance learning listening skills and lip reading skills to help her/him understand what others are saying. Many children with hearing loss also need speech or language therapy. A child also can learn to communicate using a form of sign language. In the United States of America, the type preferred by most deaf adults is American Sign Language (ASL), which has rules and grammar that is distinct from English. There are also several variations of sign language that can be used along with spoken English which are standard in English-speaking countries outside the United States. There is also a visual model of spoken language called cued speech. Learning to lip read is very difficult because many sounds look the same on the lips. Cued speech enables young children with hearing loss to clearly see what is being said, and learn spoken languages with normal grammar and vocabulary. It clarifies lip reading using 8 hand shapes in 4 positions and usually takes less than 20 hours to learn the entire system. Surgery may be recommended if a child has a permanent conductive hearing loss caused by malformations of the outer or middle ear, or by repeated ear infections. Although fluid in the middle ear usually results in only temporary hearing loss, chronic ear infection can cause a child to fall behind in language skills. In some cases, a doctor may suggest inserting a tube through the eardrum to allow the middle ear to drain. This procedure generally does not require an overnight hospital stay. Surgery also may be an option for some children with severe to profound sensorineural hearing loss. A device called a cochlear implant can be surgically inserted in the inner ear of children as young as 12 months of age to stimulate hearing. The surgery requires a hospital stay of one to several days. With additional language and speech therapy, children with cochlear implants may learn to understand speech and speak reasonably well, but the amount of improvement is variable. Once a child is diagnosed, the immediate and anticipated reaction of the parents and immediate family is one of the denial. Doctors or the audiologists need to counsel the family, help them cope with the situation and encourage them to look forward to solutions to overcome the problem. Often when the family is told about the excellent options available for a hearing impaired child, the chances of acceptance are much better. Once the family accepts the handicap, half the battle is over and rehabilitation can begin. The type of intervention required depends on several factors. Chief among these is the degree of impairment. When a child has a fair degree of residual hearing, the correct intervention would be fitting "optimised" hearing aids. "Optimisation" means fitting the child with a hearing aid appropriate to its degree of deafness. Today a variety of good quality hearing aids are available – analog or digital body worn (for small children) or ear level for older children. When fitting a hearing aid, a competent audiologist has to assess the child's residual hearing, look at the hearing aid's performance and fit the child with an appropriate instrument. Equally important is the ear mould, which has to be custom made to suit the shape of the child's ear. If a child has profound or total deafness, the benefits of hearing aids are limited. Depending upon the level and type of hearing loss, cochlear implants may be used instead of hearing aids.	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https://en.wikipedia.org/wiki/Fasciolosis	disease	Fasciolosis	Fasciolosis (also known as fascioliasis, fasciolasis, distomatosis and liver rot) is a parasitic worm infection caused by the common liver fluke Fasciola hepatica as well as by Fasciola gigantica. The disease is a plant-borne trematode zoonosis, and is classified as a neglected tropical disease (NTD). It affects humans, but its main host is ruminants such as cattle and sheep. The disease progresses through four distinct phases; an initial incubation phase of between a few days up to three months with little or no symptoms; an invasive or acute phase which may manifest with: fever, malaise, abdominal pain, gastrointestinal symptoms, urticaria, anemia, jaundice, and respiratory symptoms. The disease later progresses to a latent phase with less symptoms and ultimately into a chronic or obstructive phase months to years later. In the chronic state the disease causes inflammation of the bile ducts, gall bladder and may cause gall stones as well as fibrosis. While chronic inflammation is connected to increased cancer rates, it is unclear whether fasciolosis is associated with increased cancer risk. Up to half of those infected display no symptoms, and diagnosis is difficult because the worm eggs are often missed in fecal examination. The methods of detection are through fecal examination, parasite-specific antibody detection, or radiological diagnosis, as well as laparotomy. In case of a suspected outbreak it may be useful to keep track of dietary history, which is also useful for exclusion of differential diagnoses. Fecal examination is generally not helpful because the worm eggs can seldom be detected in the chronic phase of the infection. Eggs appear in the feces first between 9–11 weeks post-infection. The cause of this is unknown, and it is also difficult to distinguish between the different species of fasciola as well distinguishing them from echinostomes and Fasciolopsis. Most immunodiagnostic tests detect infection with very high sensitivity, and as concentration drops after treatment, it is a very good diagnostic method. Clinically it is not possible to differentiate from other liver and bile diseases. Radiological methods can detect lesions in both acute and chronic infection, while laparotomy will detect lesions and also occasionally eggs and live worms. Because of the size of the parasite, as adult F. hepatica: or adult F. gigantica: 25–75×12 mm, fasciolosis is a big concern. The amount of symptoms depend on how many worms and what stage the infection is in. The death rate is significant in both sheep and cattle, but generally low among humans. Treatment with triclabendazole has been highly effective against the adult worms as well as various developing stages. Praziquantel is not effective, and older drugs such as bithionol are moderately effective but also cause more side effects. Secondary bacterial infection causing cholangitis has also been a concern and can be treated with antibiotics, and toxaemia may be treated with prednisolone. Humans are infected by eating watergrown plants, primarily wild-grown watercress in Europe or morning glory in Asia. Infection may also occur by drinking contaminated water with floating young fasciola or when using utensils washed with contaminated water. Cultivated plants do not spread the disease in the same capacity. Human infection is rare, even if the infection rate is high among animals. Especially high rates of human infection have been found in Bolivia, Peru and Egypt, and this may be due to consumption of certain foods. No vaccine is available to protect people against Fasciola infection. Preventative measures are primarily treating and immunization of the livestock, which are required to host the live cycle of the worms. Veterinary vaccines are in development, and their use is being considered by a number of countries on account of the risk to human health and economic losses resulting from livestock infection. Other methods include using molluscicides to decrease the number of snails that act as vectors, but it is not practical. Educational methods to decrease consumption of wild watercress and other waterplants has been shown to work in areas with a high disease burden. In some areas special control programs are in place or have been planned. The types of control measures depend on the setting (such as epidemiologic, ecologic, and cultural factors). Strict control of the growth and sale of watercress and other edible water plants is important. Individual people can protect themselves by not eating raw watercress and other water plants, especially from endemic grazing areas. Travelers to areas with poor sanitation should avoid food and water that might be contaminated (tainted). Vegetables grown in fields, that might have been irrigated with polluted water, should be thoroughly cooked, as should viscera from potentially infected animals. Fascioliasis occurs in Europe, Africa, the Americas as well as Oceania. Recently, worldwide losses in animal productivity due to fasciolosis were conservatively estimated at over US$3.2 billion per annum. Fasciolosis is now recognized as an emerging human disease: the World Health Organization (WHO) has estimated that 2.4 million people are infected with Fasciola, and a further 180 million are at risk of infection.	The course of fasciolosis in humans has 4 main phases: - Incubation phase: from the ingestion of metacercariae to the appearance of the first symptoms; time period: few days to 3 months; depends on number of ingested metacercariae and immune status of host - Invasive or acute phase: fluke migration up to the bile ducts. This phase is a result of mechanical destruction of the hepatic tissue and the peritoneum by migrating juvenile flukes causing localized and or generalized toxic and allergic reactions. The major symptoms of this phase are: - Fever: usually the first symptom of the disease; - Abdominal pain - Gastrointestinal disturbances: loss of appetite, flatulence, nausea, diarrhea - Urticaria - Respiratory symptoms (very rare): cough, dyspnoea, chest pain, hemoptysis - Hepatomegaly and splenomegaly - Ascites - Anaemia - Jaundice - Latent phase: This phase can last for months or years. The proportion of asymptomatic subjects in this phase is unknown. They are often discovered during family screening after a patient is diagnosed. - Chronic or obstructive phase: This phase may develop months or years after initial infection. Adult flukes in the bile ducts cause inflammation and hyperplasia of the epithelium. The resulting cholangitis and cholecystitis, combined with the large body of the flukes, are sufficient to cause mechanical obstruction of the biliary duct. In this phase, biliary colic, epigastric pain, fatty food intolerance, nausea, jaundice, pruritus, right upper-quadrant abdominal tenderness, etc., are clinical manifestations indistinguishable from cholangitis, cholecystitis and cholelithiasis of other origins. Hepatic enlargement may be associated with an enlarged spleen or ascites. In case of obstruction, the gall bladder is usually enlarged and edematous with thickening of the wall (Ref: Hepatobiliary Fascioliasis: Sonographic and CT Findings in 87 Patients During the InitialPhase and Long-Term Follow-Up. Adnan Kabaalioglu, Kagan Ceken, Emel Alimoglu, Rabin Saba, Metin Cubuk, Gokhan Arslan, Ali Apaydin. AJR 2007; 189:824–828). Fibrous adhesions of the gall bladder to adjacent organs are common. Lithiasis of the bile duct or gall bladder is frequent and the stones are usually small and multiple. Clinical signs of fasciolosis are always closely associated with infectious dose (amount of ingested metacercariae). In sheep, as the most common definitive host, clinical presentation is divided into 4 types: - Acute Type I Fasciolosis: infectious dose is more than 5000 ingested metacercariae. Sheep suddenly die without any previous clinical signs. Ascites, abdominal haemorrhage, icterus, pallor of membranes, weakness may be observed in sheep. - Acute Type II Fasciolosis: infectious dose is 1000-5,000 ingested metacercariae. As above, sheep die but briefly show pallor, loss of condition and ascites. - Subacute Fasciolosis: infectious dose is 800-1000 ingested metacercariae. Sheep are lethargic, anemic and may die. Weight loss is dominant feature. - Chronic Fasciolosis: infectious dose is 200-800 ingested metacercariae. Asymptomatic or gradual development of bottle jaw and ascites (ventral edema), emaciation, weight loss. In blood, anemia, hypoalbuminemia, and eosinophilia may be observed in all types of fasciolosis. Elevation of liver enzyme activities, such a glutamate dehydrogenase (GLDH), gamma-glutamyl transferase (GGT), and lactate dehydrogenase (LDH), is detected in subacute or chronic fasciolosis from 12 to 15 weeks after ingestion of metacercariae. Economical effect of fasciolosis in sheep consists in sudden deaths of animals as well as in reduction of weight gain and wool production. In goats and cattle, the clinical manifestation is similar to sheep. However, acquired resistance to F. hepatica infection is well known in adult cattle. Calves are susceptible to disease but in excess of 1000 metacercariae are usually required to cause clinical fasciolosis. In this case the disease is similar to sheep and is characterized by weight loss, anemia, hypoalbuminemia and (after infection with 10,000 metacercariae) death. Importance of cattle fasciolosis consist in economic losses caused by condemnation of livers at slaughter and production losses especially due to reduced weight gain. In sheep and sometimes cattle, the damaged liver tissue may become infected by the Clostridium bacteria C. novyi type B. The bacteria will release toxins into the bloodstream resulting in what is known as black disease. There is no cure and death follows quickly. As C. novyi is common in the environment, black disease is found wherever populations of liver flukes and sheep overlap. Fasciolosis is caused by two digenetic trematodes F. hepatica and F. gigantica. Adult flukes of both species are localized in the bile ducts of the liver or gallbladder. F. hepatica measures 2 to 3 cm and has a cosmopolitan distribution. F. gigantica measures 4 to 10 cm in length and the distribution of the species is limited to the tropics and has been recorded in Africa, the Middle East, Eastern Europe and south and eastern Asia. In domestic livestock in Japan, diploid (2n = 20), triploid (3n = 30) and chimeric flukes (2n/3n) have been described, many of which reproduce parthenogenetically. As a result of this unclear classification, flukes in Japan are normally referred to as Fasciola spp. Recent reports based on mitochondrial genes analysis has shown that Japanese Fasciola spp. is more closely related to F. gigantica than to F. hepatica. In India, a species called F. jacksoni was described in elephants. Human F. hepatica infection is determined by the presence of the intermediate snail hosts, domestic herbivorous animals, climatic conditions and the dietary habits of man. Sheep, goats and cattle are considered the predominant animal reservoirs. While other animals can be infected, they are usually not very important for human disease transmission. On the other hand, some authors have observed that donkeys and pigs contribute to disease transmission in Bolivia. Among wild animals, it has been demonstrated that the peridomestic rat (Rattus rattus) may play an important role in the spread as well as in the transmission of the parasite in Corsica. In France, nutria (Myocastor coypus) was confirmed as a wild reservoir host of F. hepatica. Humans are infected by ingestion of aquatic plants that contain the infectious cercariae. Several species of aquatic vegetables are known as a vehicle of human infection. In Europe, Nasturtium officinale (common watercress), Nasturtium silvestris, Rorippa amphibia (wild watercress), Taraxacum dens leonis (dandelion leaves), Valerianella olitoria (lamb's lettuce), and Mentha viridis (spearmint) were reported as a source of human infections. In the Northern Bolivian Altiplano, some authors suggested that several aquatic plants such as bero-bero (watercress), algas (algae), kjosco and tortora could act as a source of infection for humans. Because F. hepatica cercariae also encyst on water surface, humans can be infected by drinking of fresh untreated water containing cercariae. In addition, an experimental study suggested that humans consuming raw liver dishes from fresh livers infected with juvenile flukes could become infected. Intermediate hosts of F. hepatica are freshwater snails from family Lymnaeidae. Snails from family Planorbidae act as an intermediate host of F. hepatica very occasionally. The development of infection in definitive host is divided into two phases: the parenchymal (migratory) phase and the biliary phase. The parenchymal phase begins when excysted juvenile flukes penetrate the intestinal wall. After the penetration of the intestine, flukes migrate within the abdominal cavity and penetrate the liver or other organs. F. hepatica has a strong predilection for the tissues of the liver. Occasionally, ectopic locations of flukes such as the lungs, diaphragm, intestinal wall, kidneys, and subcutaneous tissue can occur. During the migration of flukes, tissues are mechanically destroyed and inflammation appears around migratory tracks of flukes. The second phase (the biliary phase) begins when parasites enter the biliary ducts of the liver. In biliary ducts, flukes mature, feed on blood, and produce eggs. Hypertrophy of biliar ducts associated with obstruction of the lumen occurs as a result of tissue damage. Mechanisms of resistance have been studied by several authors in different animal species. These studies may help to better understand the immune response to F. hepatica in host and are necessary in development of vaccine against the parasite. It has been established that cattle acquire resistance to challenge infection with F. hepatica and F. gigantica when they have been sensitized with primary patent or drug-abbreviated infection. Resistance to fasciolosis was also documented in rats. On the other hand, sheep and goats are not resistant to re-infection with F. hepatica. However, there is evidence that two sheep breeds, in particular Indonesian thin tail sheep and Red maasai sheep, are resistant to F. gigantica. No reports concerning the resistance in humans are available. Most immunodiagnostic tests will detect infection and have a sensitivity above 90% during all stages of the diseases. In addition antibody concentration quickly drops post treatment and no antibodies are present one year after treatment, which makes it a very good diagnostic method. In humans, diagnosis of fasciolosis is usually achieved parasitologically by findings the fluke eggs in stool, and immunologically by ELISA and Western blot. Coprological examinations of stool alone are generally not adequate because infected humans have important clinical presentations long before eggs are found in the stools. Moreover, in many human infections, the fluke eggs are often not found in the faeces, even after multiple faecal examinations. Furthermore, eggs of F. hepatica, F. gigantica and Fasciolopsis buski are morphologically indistinguishable. Therefore, immunonological methods such ELISA and enzyme-linked immunoelectrotransfer blot, also called Western blot, are the most important methods in diagnosis of F. hepatica infection. These immunological tests are based on detection of species-specific antibodies from sera. The antigenic preparations used have been primarily derived from extracts of excretory/secretory products from adult worms, or with partially purified fractions. Recently, purified native and recombinant antigens have been used, e.g. recombinant F. hepatica cathepsin L-like protease. Methods based on antigen detection (circulating in serum or in faeces) are less frequent. In addition, biochemical and haematological examinations of human sera support the exact diagnosis (eosinophilia, elevation of liver enzymes). Ultrasonography and xray of the abdominal cavity, biopsy of liver, and gallbladder punctuate can also be used (ref: US-guided gallbladder aspiration: a new diagnostic method for biliary fascioliasis. A. Kabaalioglu, A. Apaydin, T. Sindel, E. Lüleci. Eur. Radiol. 9, 880±882 (1999) . False fasciolosis (pseudofasciolosis) refers to the presence of eggs in the stool resulting not from an actual infection but from recent ingestion of infected livers containing eggs. This situation (with its potential for misdiagnosis) can be avoided by having the patient follow a liver-free diet several days before a repeat stool examination. In animals, intravital diagnosis is based predominantly on faeces examinations and immunological methods. However, clinical signs, biochemical and haematological profile, season, climate conditions, epidemiology situation, and examinations of snails must be considered. Similarly to humans, faeces examinations are not reliable. Moreover, the fluke eggs are detectable in faeces 8–12 weeks post-infection. In spite of that fact, faecal examination is still the only used diagnostic tool in some countries. While coprological diagnosis of fasciolosis is possible from 8- to 12-week post-infection (WPI), F. hepatica specific-antibodies are recognized using ELISA or Western blot after 2-4 week post-infection. Therefore, these methods provide early detection of the infection. Several drugs are effective for fascioliasis, both in humans and in domestic animals. The drug of choice in the treatment of fasciolosis is triclabendazole, a member of the benzimidazole family of anthelmintics. The drug works by preventing the polymerization of the molecule tubulin into the cytoskeletal structures, microtubules. Resistance of F. hepatica to triclabendazole has been recorded in Australia in 1995 and Ireland in 1998. Praziquantel treatment is ineffective. There are case reports of nitazoxanide being successfully used in human fasciolosis treatment in Mexico. There are also reports of bithionol being used successfully. More recently, Mirazid, an Egyptian drug made from myrrh, has been investigated as an oral treatment of trematode-caused ailments including fascioliasis. Nitazoxanide has been found effective in trials, but is currently not recommended. The life cycle includes freshwater snails as an intermediate host of the parasite. Human and animal fasciolosis occurs worldwide. While animal fasciolosis is distributed in countries with high cattle and sheep production, human fasciolosis occurs, excepting Western Europe, in developing countries. Fasciolosis occurs only in areas where suitable conditions for intermediate hosts exist. Studies carried out in recent years have shown human fasciolosis to be an important public health problem. Human fasciolosis has been reported from countries in Europe, America, Asia, Africa and Oceania. The incidence of human cases has been increasing in 51 countries of the five continents. A global analysis shows that the expected correlation between animal and human fasciolosis only appears at a basic level. High prevalences in humans are not necessarily found in areas where fasciolosis is a great veterinary problem. For instance, in South America, hyperendemics and mesoendemics are found in Bolivia and Peru where the veterinary problem is less important, while in countries such as Uruguay, Argentina and Chile, human fasciolosis is only sporadic or hypoendemic. In Europe, human fasciolosis occur mainly in France, Spain, Portugal, and the former USSR. France is considered an important human endemic area. A total of 5863 cases of human fasciolosis were recorded from nine French hospitals from 1970 to 1982. Concerning the former Soviet Union, almost all reported cases were from the Tajik Republic. Several papers referred to human fasciolosis in Turkey. Recently, serological survey of human fasciolosis was performed in some parts of Turkey. The prevalence of the disease was serologically found to be 3.01% in Antalya Province, and between 0.9 and 6.1% in Isparta Province, Mediterranean region of Turkey. In other European countries, fasciolosis is sporadic and the occurrence of the disease is usually combined with travelling to endemic areas. In North America, the disease is very sporadic. In Mexico, 53 cases have been reported. In Central America, fasciolosis is a human health problem in the Caribbean islands, especially in zones of Puerto Rico and Cuba. Pinar del Río Province and Villa Clara Province are Cuban regions where fasciolosis was hyperendemic. In South America, human fasciolosis is a serious problem in Bolivia, Peru, and Ecuador. These Andean countries are considered to be the area with the highest prevalence of human fasciolosis in the world. Well-known human hyperendemic areas are localized predominately in the high plain called altiplano. In the Northern Bolivian Altiplano, prevalences detected in some communities were up to 72% and 100% in coprological and serological surveys, respectively. In Peru, F. hepatica in humans occurs throughout the country. The highest prevalences were reported in Arequipa, Mantaro Valley, Cajamarca Valley, and Puno Region. In other South American countries like Argentina, Uruguay, Brazil, Venezuela and Colombia, human fasciolosis appear to be sporadic, despite the high prevalences of fasciolosis in cattle. In Africa, human cases of fasciolosis, except in northern parts, have not been frequently reported. The highest prevalence was recorded in Egypt where the disease is distributed in communities living in the Nile Delta. In Asia, the most human cases were reported in Iran, especially in Gīlān Province, on the Caspian Sea. It was mentioned that more than 10,000 human cases were detected in Iran. In eastern Asia, human fasciolosis appears to be sporadic. Few cases were documented in Japan, Koreas, Vietnam, and Thailand. In Australia, human fasciolosis is very rare (only 12 cases documented). In New Zealand, F. hepatica has never been detected in humans. A number of drugs have been used in control fasciolosis in animals. Drugs differ in their efficacy, mode of action, price, and viability. Fasciolicides (drugs against Fasciola spp.) fall into five main chemical groups: - Halogenated phenols: bithionol (Bitin), hexachlorophene (Bilevon), nitroxynil (Trodax) - Salicylanilides: closantel (Flukiver, Supaverm), rafoxanide (Flukanide, Ranizole) - Benzimidazoles: triclabendazole (Fasinex), albendazole (Vermitan, Valbazen), mebendazol (Telmin), luxabendazole (Fluxacur) - Sulphonamides: clorsulon (Ivomec Plus) - Phenoxyalkanes: diamphenetide (Coriban) Triclabendazole (Fasinex) is considered as the most common drug due to its high efficacy against adult as well as juvenile flukes. Triclabendazole is used in control of fasciolosis of livestock in many countries. Nevertheless, long-term veterinary use of triclabendazole has caused appearance of resistance in F. hepatica. In animals, triclabendazole resistance was first described in Australia, later in Ireland and Scotland and more recently in the Netherlands. Considering this fact, scientists have started to work on the development of new drug. Recently, a new fasciolicide was successfully tested in naturally and experimentally infected cattle in Mexico. This new drug is called 'Compound Alpha' and is chemically very similar to triclabendazole. Countries where fasciolosis in livestock was repeatedly reported: - Europe: UK, Ireland, France, Portugal, Spain, Switzerland, Italy, Netherlands, Germany, Poland - Asia: Turkey, Russia, Thailand, Iraq, Iran, China, Vietnam, India, Nepal, Japan, Korea, Philippines - Africa: Kenya, Zimbabwe, Nigeria, Egypt, Gambia, Morocco - Australia and the Oceania: Australia, New Zealand - Americas:United States, Mexico, Cuba, Peru, Chile, Uruguay, Argentina, Jamaica, Brazil On September 8, 2007, Veterinary officials in South Cotabato, Philippines said that laboratory tests on samples from cows, carabaos, and horses in the province's 10 towns and lone city showed the level of infection at 89.5%, a sudden increase of positive cases among large livestock due to the erratic weather condition in the area. They must be treated forthwith to prevent complications with surra and hemorrhagic septicemia diseases. Surra already affected all barangays of the Surallah town.	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https://en.wikipedia.org/wiki/Salivary_gland_pathology	disease	Salivary gland pathology	Salivary gland diseases (SGD) are multiple and varied in cause. There are 3 paired major salivary glands in humans (the parotid gland, the submandibular gland, and the sublingual gland), as well as about 800-1000 minor salivary glands in the oral mucosa of the mouth. The parotid gland is located in front of the ear, and it secretes its mostly serous saliva via the parotid duct (Stenson duct) into the mouth, usually opening roughly opposite the maxillary second molar. The submandibular gland is located medial to the angle of the mandible, and it drains its mixture of serous and mucous saliva via the submandibular duct (Wharton duct) into the mouth, usually opening in a punctum located in the floor of mouth. The sublingual gland is located below the tongue, in the floor of the mouth. It drains its mostly mucous saliva into the mouth via about 8-20 ducts which open along the plica sublingualis (a fold of tissue under the tongue). The function of the salivary glands is to secrete saliva, which has a lubricating function, which protects the oral mucosa of the mouth during eating and speaking. Saliva also contains digestive enzymes (e.g. salivary amylase) and has antimicrobial action and acts as a buffer. Persons with reduced salivary flow or hyposalivation often suffer from dry mouth or xerostomia, which can result in severe dental caries (tooth decay) as a result of the loss of the protective effects of saliva. Various examples of disorders affecting the salivary glands are listed below. Some are more common than others, and they are considered according to a surgical sieve, but this list is not exhaustive. Sialadenitis is inflammation of a salivary gland, usually caused by infections, although there are other less common causes of inflammation such as irradiation, allergic reactions or trauma.	Congenital disorders of the salivary glands are rare, but may include: - Aplasia - Atresia - Ectopic salivary gland tissue - Stafne defect - an uncommon condition which some consider to be an anatomic variant rather than a true disease. It is thought to be created by an ectopic portion of salivary gland tissue which causes the bone of the mandible to remodel around the tissue, creating an apparent cyst like radiolucent area on radiographs. Classically, this lesion is discovered as a chance finding, since it causes no symptoms. It appears below the inferior alveolar nerve canal in the posterior region of the mandible. Infections involving the salivary glands can be viral or bacterial (or rarely fungal). - Mumps is the most common viral sialadenitis. It usually occurs in children, and there is preauricular pain (pain felt in front of the ear), swelling of the parotid, fever, chills, and headaches. - Bacterial sialadentitis is usually caused by ascending organisms from the oral cavity. Risk factors include reduced salivary flow rate. - Human immunodeficiency virus-associated salivary gland disease (HIV-SGD). A salivary diverticulum (plural diverticuli) is a small pouch or out-pocketing of the duct system of a major salivary gland. Such diverticuli typically cause pooling of saliva and recurrent sialadenitis, especially parotitis. A diverticulum may also cause a sialolith to form. The condition can be diagnosed by sialography. Affected individuals may "milk" the salivary gland to encourage flow of saliva through the duct.	[ { "begin": 0, "class": "SectionAnnotation", "length": 625, "sectionHeading": "Congenital", "sectionLabel": "disease.other" }, { "begin": 625, "class": "SectionAnnotation", "length": 498, "sectionHeading": "Acquired \| Infective", "sectionLabel": "disease.tomography" }, { "begin": 1123, "class": "SectionAnnotation", "length": 421, "sectionHeading": "Acquired \| Diverticulum", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Gender_dysphoria	disease	Gender dysphoria	Gender dysphoria (GD), or gender identity disorder (GID), is the distress a person experiences as a result of the sex and gender they were assigned at birth. In this case, the assigned sex and gender do not match the person's gender identity, and the person is transgender. There is evidence suggesting that twins who identify with a gender different from their assigned sex may do so not only due to psychological or behavioral causes, but also biological ones related to their genetics or exposure to hormones before birth. Estimated rates of those with a transgender identity range from a lower bound of 1:2000 (or about 0.05%) in the Netherlands and Belgium to 0.5% of Massachusetts adults to 1.2% of New Zealand high-school students. These numbers are based on those who identify as transgender. It is estimated that about 0.005% to 0.014% of people assigned male at birth and 0.002% to 0.003% of people assigned female at birth would be diagnosed with gender dysphoria, based on 2013 diagnostic criteria, though this is considered a modest underestimate. Research indicates people who transition in adulthood are up to three times more likely to be male assigned at birth, but that among people transitioning in childhood the sex ratio is close to 1:1. Gender dysphoria is classified as a disorder under dual role transvestism in the 2017 ICD-10 CM. GID was reclassified to gender dysphoria by the DSM-5. Some transgender people and researchers support declassification of GID because they say the diagnosis pathologizes gender variance, reinforces the binary model of gender, and can result in stigmatization of transgender individuals. The official reclassification as gender dysphoria in the DSM-5 may help resolve some of these issues, because the term gender dysphoria applies only to the discontent experienced by some persons resulting from gender identity issues. The American Psychiatric Association, publisher of the DSM-5, states that "gender nonconformity is not in itself a mental disorder. The critical element of gender dysphoria is the presence of clinically significant distress associated with the condition." The main psychiatric approaches to treatment for persons diagnosed with gender dysphoria are psychotherapy or supporting the individual's preferred gender through hormone therapy, gender expression and role, or surgery.	Symptoms of GD in children may include any of the following: disgust at their own genitalia, social isolation from their peers, anxiety, loneliness and depression. According to the American Psychological Association, transgender children are more likely to experience harassment and violence in school, foster care, residential treatment centers, homeless centers and juvenile justice programs than other children. Adults with GD are at increased risk for stress, isolation, anxiety, depression, poor self-esteem and suicide. Studies indicate that transgender people have an extremely high rate of suicide attempts; one study of 6,450 transgender people in the United States found 41% had attempted suicide, compared to a national average of 1.6%. It was also found that suicide attempts were less common among transgender people who said their family ties had remained strong after they came out, but even transgender people at comparatively low risk were still much more likely to have attempted suicide than the general population. Transgender people are also at heightened risk for certain mental disorders such as eating disorders. GID exists when a person suffers discontent due to gender identity, causing them emotional distress. Researchers disagree about the nature of distress and impairment in people with GID. Some authors have suggested that people with GID suffer because they are stigmatized and victimized; and that, if society had less strict gender divisions, transsexual people would suffer less. A twin study (based on seven people in a 314 sample) suggested that GID may be 62% heritable, indicating the possibility of a genetic influence or prenatal development as its origin, in these cases. The American Psychiatric Association permits a diagnosis of gender dysphoria if the criteria in the DSM-5 are met. The DSM-5 moved this diagnosis out of the sexual disorders category and into a category of its own. The DSM-5 states that at least two of the criteria for gender dysphoria must be experienced for at least six months' duration in adolescents or adults for diagnosis. The diagnosis was renamed from "Gender Identity Disorder" to "Gender Dysphoria", after criticisms that the former term was stigmatizing. Subtyping by sexual orientation was deleted. The diagnosis for children was separated from that for adults, as "gender dysphoria in children". The creation of a specific diagnosis for children reflects the lesser ability of children to have insight into what they are experiencing, or ability to express it in the event that they have insight. The International Classification of Diseases (ICD-10) list three diagnostic criteria for "transsexualism" (F64.0): Uncertainty about gender identity which causes anxiety or stress is diagnosed as sexual maturation disorder, according to the ICD-10. Treatment for a person diagnosed with GID may include psychotherapy or to support the individual's preferred gender through hormone therapy, gender expression and role, or surgery. This may include psychological counseling, resulting in lifestyle changes, or physical changes, resulting from medical interventions such as hormonal treatment, genital surgery, electrolysis or laser hair removal, chest/breast surgery, or other reconstructive surgeries. The goal of treatment may simply be to reduce problems resulting from the person's transgender status, for example, counseling the patient in order to reduce guilt associated with cross-dressing, or counseling a spouse to help them adjust to the patient's situation. Hormone treatment or surgery for gender dysphoria is somewhat controversial because of the irreversibility of physical changes. Guidelines have been established to aid clinicians. The World Professional Association for Transgender Health (WPATH) Standards of Care are used by some clinicians as treatment guidelines. Others use guidelines outlined in Gianna Israel and Donald Tarver's Transgender Care. Guidelines for treatment generally follow a "harm reduction" model. The question of whether to counsel young children to be happy with their assigned sex, or to encourage them to continue to exhibit behaviors that do not match their assigned sex—or to explore a transsexual transition—is controversial. Some clinicians report that a significant proportion of young children diagnosed with gender dysphoria later do not exhibit any dysphoria. Professionals who treat gender identity disorder in children have begun to refer and prescribe hormones, known as a puberty blocker, to delay the onset of puberty until a child is believed to be old enough to make an informed decision on whether hormonal gender reassignment leading to surgical gender reassignment will be in that person's best interest. Until the 1970s, psychotherapy was the primary treatment for gender dysphoria, and generally was directed to helping the person adjust to the gender of the physical characteristics present at birth. Psychotherapy is any therapeutic interaction that aims to treat a psychological problem. Though some clinicians still use only psychotherapy to treat gender dysphoria, it may now be used in addition to biological interventions. Psychotherapeutic treatment of GID involves helping the patient to adapt. Attempts to cure GID by changing the patient's gender identity to reflect birth characteristics have been ineffective. Biological treatments physically alter primary and secondary sex characteristics to reduce the discrepancy between an individual's physical body and gender identity. Biological treatments for GID without any form of psychotherapy is quite uncommon. Researchers have found that if individuals bypass psychotherapy in their GID treatment, they often feel lost and confused when their biological treatments are complete. Psychotherapy, hormone replacement therapy, and sex reassignment surgery together can be effective treating GID when the WPATH standards of care are followed. The overall level of patient satisfaction with both psychological and biological treatments is very high. The term gender identity disorder is an older term for the condition. Some groups, including the American Psychiatric Association (APA), use the term gender dysphoria. The APA's Diagnostic and Statistical Manual first described the condition in the third publication ("DSM-III") in 1980. In April 2011, the UK National Research Ethics Service approved prescribing monthly injection of puberty-blocking drugs to youngsters from 12 years old, in order to enable them to get older before deciding on formal sex change. The Tavistock and Portman NHS Foundation Trust (T&P) in North London has treated such children. Clinic director Dr. Polly Carmichael said, "Certainly, of the children between 12 and 14, there's a number who are keen to take part. I know what's been very hard for their families is knowing that there's something available but it's not available here." The clinic received 127 referrals for gender dysphoria in 2010. The T&P completed a three-year trial to assess the psychological, social and physical benefits and risks involved for 12- to 14-year-old patients. The trial was deemed such a success that doctors have decided to make the drugs more widely available and to children as young as 9 years of age. As recently as 2009, national guidelines stated that treatment for gender dysphoria should not start until puberty had finished. Ferring Pharmaceuticals manufactures the drug Triptorelin, marketed under the name Gonapeptyl, at £82 per monthly dose. The treatment is reversible, which means the body will resume its previous state upon discontinuation of drugs. Social "gender" characteristics are created and supported by the expectations of a culture, and are therefore only partially related to biological sex. For example, the association of particular colours with "girl" or "boy" babies begins extremely early in Western European-derived cultures. Other expectations relate to approved and allowable behaviors and emotional expression. Some cultures have three defined genders: man, woman, and effeminate man. For example, in Samoa, the fa'afafine, a group of feminine males, are entirely socially accepted. The fa'afafine do not have any of the stigma or distress typically associated in most cultures with deviating from a male/female gender role. This suggests the distress so frequently associated with GID in a Western context is not caused by the disorder itself, but by difficulties encountered from social disapproval by one's culture. However, research has found that the anxiety associated with gender dysphoria persists in cultures, Eastern or otherwise, which are more accepting of gender nonconformity. In Australia, a 2014 High Court of Australia judgment unanimously ruled in favor of a plaintiff named Norrie, who asked to be classified by a third gender category, 'non-specific', after a long court battle with the NSW Registrar of Births, Deaths and Marriages. However, the Court did not accept that gender was a social construction: it found that sex reassignment "surgery did not resolve her sexual ambiguity". The psychiatric diagnoses of gender identity disorder (now gender dysphoria) was introduced in the DSM-III in 1980. Some sources have characterized the addition as a political maneuver to re-stigmatize homosexuality. (Homosexuality was removed from the DSM-II in 1974.) By contrast, Kenneth Zucker and Robert Spitzer argue that gender identity disorder was included in the DSM-III because it "met the generally accepted criteria used by the framers of DSM-III for inclusion." Some researchers, including Robert Spitzer and Paul J. Fink, contend that the behaviors and experiences seen in transsexualism are abnormal and constitute a dysfunction. Individuals with gender dysphoria may or may not regard their own cross-gender feelings and behaviors as a disorder. Advantages and disadvantages exist to classifying gender dysphoria as a disorder. Because gender dysphoria had been classified as a disorder in medical texts (such as the previous DSM manual, the DSM-IV-TR, under the name "gender identity disorder"), many insurance companies are willing to cover some of the expenses of sex reassignment therapy. Without the classification of gender dysphoria as a medical disorder, sex reassignment therapy may be viewed as cosmetic treatment, rather than medically necessary treatment, and may not be covered. In the United States, transgender people are less likely than others to have health insurance, and often face hostility and insensitivity from healthcare providers. The DSM-IV-TR diagnostic component of distress is not inherent in the cross-gender identity; rather, it is related to social rejection and discrimination suffered by the individual. Psychology professor Darryl Hill insists that gender dysphoria is not a mental disorder, but rather that the diagnostic criteria reflect psychological distress in children that occurs when parents and others have trouble relating to their child's gender variance. Transgender people have often been harassed, socially excluded, and subjected to discrimination, abuse and violence, including murder. In December 2002, the British Lord Chancellor's office published a Government Policy Concerning Transsexual People document that categorically states, "What transsexualism is not ... It is not a mental illness." In May 2009, the government of France declared that a transsexual gender identity will no longer be classified as a psychiatric condition. In the December 2016 draft of the ICD-11, GID is reclassified as gender incongruence. Intimate relationships between lesbians and female-to-male people with GID will sometimes endure throughout the transition process, or shift into becoming supportive friendships. Intimate relationships between heterosexual women and male-to-female people with GID often suffer once the GID is known or revealed. Researchers say the fate of the relationship seems to depend mainly on the woman's adaptability. Problems often arise, with the cisgender partner becoming increasingly angry or dissatisfied, if her partner's time spent in a female role grows, if her partner's libido decreases, or if her partner is angry and emotionally cut-off when in the male role. Cisgender women sometimes also worry about social stigma and may be uncomfortable with the bodily feminization of their partner as the partner moves through transition. The cisgender women who are likeliest to accept and accommodate their partner's transition, researchers say, are those with a low sex drive or those who are equally sexually attracted to men and women. In California, Assembly Bill (AB) No. 1266, the School Success and Opportunity Act, authored by Assemblyman Tom Ammiano (D-San Francisco), was passed in May 2013 by the State Assembly: Existing law prohibits public schools from discriminating on the basis of specified characteristics, including gender, gender identity, and gender expression, and specifies various statements of legislative intent and the policies of the state in that regard. Existing law requires that participation in a particular physical education activity or sport, if required of pupils of one sex, be available to pupils of each sex. This bill would require that a pupil be permitted to participate in sex-segregated school programs, activities, including athletic teams and competitions, and use facilities consistent with his or her gender identity, irrespective of the gender listed on the pupil's records. The California Catholic Conference opposed the bill as unnecessary, as laws exist already to fight discrimination against transgender students. A spokeswoman for the conference said that the issue should be handled by school officials.	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https://en.wikipedia.org/wiki/Simultanagnosia	disease	Simultanagnosia	Simultanagnosia (or simultagnosia) is a rare neurological disorder characterized by the inability of an individual to perceive more than a single object at a time. This type of visual attention problem is one of three major components (the others being optic ataxia and optic apraxia) of Bálint's syndrome, an uncommon and incompletely understood variety of severe neuropsychological impairments involving space representation (visuospatial processing). The term "simultanagnosia" was first coined in 1924 by Wolpert to describe a condition where the affected individual could see individual details of a complex scene but failed to grasp the overall meaning of the image. Simultanagnosia can be divided into two different categories: dorsal and ventral. Ventral occipito-temporal lesions cause a mild form of the disorder, while dorsal occipito-parietal lesions cause a more severe form of the disorder.	Patients with simultanagnosia, a component of Bálint's syndrome, have a restricted spatial window of visual attention and cannot see more than one object at a time in a scene that contains more than one object. For instance, if presented with an image of a table containing both food and various utensils, a patient will report seeing only one item, such as a spoon. If the patient's attention is redirected to another object in the scene, such as a glass, the patient will report that they see the glass but no longer see the spoon. As a result of this impairment, simultanagnosic patients often fail to comprehend the overall meaning of a scene. In addition, patients note that one stationary object may spontaneously disappear from view as they become aware of another object in the scene. Simultanagnosic patients often exhibit a phenomenon known as "local capture" where they only identify the local elements of stimuli containing local and global features. However, recent studies have demonstrated that implicit processing of the global structure can occur. With the appropriate stimulus conditions, explicit processing of the global form may occur. For example, a study performed with Navon hierarchical letters, which are large letters composed of smaller ones, revealed that the use of smaller and denser Navon letters biased the patient towards global processing. There are currently no quantitative methods for diagnosing simultanagnosia. To establish the presence of simultanagnosic symptoms, patients are asked to describe complex visual displays, such as the commonly used "Boston Cookie Theft" picture, which is a component of the Boston Diagnostic Aphasia Examination. In the picture, the sink in the kitchen is overflowing as a boy and a girl attempt to steal cookies from the cookie jar without their mother noticing. Patients take a clearly piecemeal approach to interpreting the scene by reporting isolated items from the image. For instance, a patient may report seeing a "boy," "stool," and a "woman." However, when asked to interpret the overall meaning of the picture, the patient fails to comprehend the global whole. Another picture used to assess visual impairments of patients with simultanagnosia is the "Telegraph Boy" picture. Upon examination of higher nervous system functions, patients display no general intellectual impairments. Simultanagnosia can be divided into two different types: dorsal and ventral, with each taking its name from the dorsal and ventral circuits concerned with the perception of objects' shapes and locations, respectively. These two forms of simultanagnosia are associated with different symptoms as well as damage to separate areas of the brain. Dorsal simultanagnosia results from bilateral lesions to the junction between the parietal and occipital lobes. Here, perception is limited to a single object without awareness of the presence of other stimuli. Thus, being able to see only one object at a time, a patient may collide with various objects in a room being unaware of them. Additionally, objects in motion appear more difficult to perceive. Ventral simultanagnosia results from damage to the left inferior occipito-temporal junction. Ventral simultanagnosic patients are able to see several objects at once, but their recognition of objects is piecemeal, or limited to one object at a time. Thus, individuals with ventral simultanagnosic symptoms are capable of navigating through a room without bumping into furniture. Simultanagnosia results from bilateral lesions to the junction between the parietal and occipital lobes. These lesions could result from a stroke or traumatic brain injury. It is also possible for simultanagnosic symptoms to develop from degenerative disorders. For example, one study found that four patients with progressive dementia eventually developed symptoms of simultanagnosia as well as components of Gerstmann's syndrome and transcortical sensory aphasia. In addition, patients with Huntington's disease have been found to exhibit visual impairments similar to those of simultanagnosia. It is likely that damage to any of several cognitive mechanisms could result in simultanagnosia. Several theories have been proposed to account for simultanagnosic symptoms, and while some focus on the disruption of a specific process, such as the speed of attentional processing, others focus on the disruption of a representational structure. In 1909, Rezső Bálint published one of the earliest descriptions of simultanagnosia. He studied a patient who easily identified single objects, regardless of size, but claimed that he could only see one object when presented with a complex display of numerous items. This patient also exhibited ocular apraxia, an impairment of voluntary eye movements despite intact oculomotor reflexes, and optic ataxia, or the impairment of visually guided hand movements. This collection of symptoms would later be called Bálint's syndrome. Because the size of the object did not affect his patient's ability to perceive an item, Bálint argued that his patient did not have a narrowing of the sensory field. Therefore, Bálint concluded that the patient's attention would always be as narrow as the size of the item being observed. In other words, the attentional window of a simultanagnosic patient is limited to one object. In contrast to Bálint's hypothesis, Thaiss and De Bleser studied a patient who had a physical restriction of her attentional window. The patient's ability to perceive multiple objects and identify global structures significantly improved as the size of the presented image decreased. Thus, complex stimuli could be processed as wholes so long as they occupied a small visual angle. Another theory to account for simultanagnosia involves deficits in "attentional disengaging," and this impairment affects shifts of attention in any direction. When confronted with several objects, the patient's attention becomes "locked" onto one object, and he has difficulty disengaging his attention from this object to another one. As a result of this "sticky fixation," patients with simultanagnosia can perceive only one object at a time. Other studies have proposed that simultanagnosia results from slowed attentional processing. According to this view, attention is seen as filter through which one percept at time passes, and the speed with which an individual's attention can filter percepts is much slower for a patient with simultanagnosia than a person without the disorder. People without simultanagnosia are able to perceive numerous objects at once because they can shift their attention rapidly enough between stimuli so that percepts are integrated before they decay from short-term memory. However, those with simultanagnosia are incapable of shifting their attention quickly enough from one object to another, and thus, they only perceive one object at a time. In one study patients were required to read one word and then read a second word that followed the first in rapid succession. While individuals could identify the first word relatively quickly, they had significantly greater difficulty identifying the second word. Furthermore, if the second word was shown after a long delay following the first word, identification of the second word was easier. These results indicate that patients with simultanagnosia have difficulty processing objects presented in rapid succession, and the patient is unable to shift his attention rapidly enough between successive stimuli since a certain amount of time is required for the patient to shift his attention from the first word in order to be able to identify the second word. It is also possible that impairments in mechanisms that register spatial locations lead to simultanagnosia. According to the feature-integration theory of attention, features of the visual scene, such as color and orientation, are registered early and in parallel across the visual field. These features are represented by separate maps that are later integrated to form a master map of locations that specifies where things are but not what they are. In order to identify objects, focused attention is required to bind perceptual representations of objects being viewed with features in their proper locations. Parietal lesions damage the master map of locations, and as a result, a variety of deficits can occur, including simultanagnosia. If space is necessary to distinguish objects, then deficits in explicit access to spatial information located in the master map leads to the inability to perceive more than one object at a time. One study developed a computer model of high-level visual processing, which contrasts with low-level visual processing in that it involves the use of previously stored information to identify objects and navigate. When the spatiotopic mapping subsystem of the model was partially damaged, simultanagnosic symptoms resulted. In the model simulation of simultanagnosia, the same location was assigned to all stimuli, therefore preventing the model from identifying multiple objects at once. Either the model "locked" onto the first object and was unable to disengage attention, or once recognition of the first object was completed, it "disappeared" from sight to be replaced by the second object. Coslett and Saffran studied one patient who was unable to maintain location information for more than one shape. Since only a single explicit binding could occur between spatial and shape information, the patient was incapable of perceiving more than one object at a time. Another theory to account for simultanagnosia states that patients have difficulty analyzing shapes. Bilateral lesions to the parieto-occipital junction may cause the ventral circuit to slow down; as a result, patients with simultanagnosia have difficulty discriminating among visual features. According to this theory, "feature degradation" or increased "noise" occurs in the perceptual system. One study analyzed how well patients could process targets based on a feature salient from the background; it found that processing of targets was significantly impaired even though the targets were markedly different from the background. The results suggest that impairments in parsing, such as the process by which important regions are extracted from the retinal image, or difficulty in discriminating elementary visual features led to simultanagnosia. Finally, simultanagnosia may result from deficits in spatial indexing. Several studies have noted that a pre-attentive stage of processing exists during which visual features are obtained from the visual field in parallel. Once these features have been extracted, they can be indexed, which allows them to function as anchor points for additional visual routines; visual routines are sequences of elemental operations, such as visual search or texture segregation, which define the spatial relationships among objects as well as their properties. Saliency of a feature facilitates the ease with which it can be indexed. For example, the greater the difference between a specific feature and surrounding ones, the more easily it can be indexed. The indexed features, or anchor points, can serve as a "spotlight" that directs focal attention to certain objects, which can then channel visual information to specialized systems for space and shape analysis. Deficits in the spatial indexing mechanism would result in symptoms of simultanagnosia because interpretation of a complex scene requires rapid shifting of attention to various elements, and impairments in spatial indexing lead to the inability to index multiple visual features rapidly. In addition, perception is slowed, and low-level visual processing is disrupted since the patient would not be able to extract and index salient features. Currently, there is no treatment available for patients with dorsal simultanagnosia, and it is likely that the bilateral lesions resulting in simultanagnosia will not heal. However, a recent study demonstrated that recovery may be related to finding ways to expand the restricted attentional window—their global gestalt perception—that characterizes the disorder. In another study a participant showed an improvement 18 months after stroke induced ventral simultanagnosia, this "represents the usual partial recovery from an early ventral simultanagnosia/pure alexia".	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https://en.wikipedia.org/wiki/Neonatal-onset_multisystem_inflammatory_disease	disease	Neonatal-onset multisystem inflammatory disease	Neonatal-onset multisystem inflammatory disease (abbreviated NOMID, also known as chronic infantile neurologic cutaneous and articular syndrome, or CINCA) is a rare genetic periodic fever syndrome which causes uncontrolled inflammation in multiple parts of the body starting in the newborn period. Symptoms include skin rashes, severe arthritis, and chronic meningitis leading to neurologic damage. It is one of the cryopyrin-associated periodic syndromes. NOMID can result from a mutation in the CIAS1 gene (also known as NLRP3 gene), which helps control inflammation. Mutations in this gene also cause familial cold urticaria and Muckle–Wells syndrome. NOMID has been successfully treated with the drug anakinra. This syndrome is also known as the Prieur–Griscelli syndrome as it was first described by these authors in 1981.	The age of onset is almost always before 3 months of age. Many infants are born preterm (1/3 cases) and dysmature. The babies are frequently small for dates. The placenta may be abnormal with non-specific inflammation on histology. Umbilical cord anomalies have occasionally been reported. In severe cases, signs in the brain may be detected on prenatal ultrasound. The presentation is pleiomorphic , making the diagnosis difficult, but the most common features of this disease involve the skin, joints, and central nervous system. All have a maculopapular urticarial skin rash that is often present at birth (75% cases). It is probably more correctly described as an urticarial-like rash. The presence of the rash varies with time, and biopsy of these skin lesions shows a perivascular inflammatory infiltrate including granulocytes. In about 35-65% of cases, arthritis occurs. Joint signs are variably expressed and can lead to transient swelling without sequelae between crises, or to unpredictable anomalies of growth cartilage and long bones epiphyses suggestive of a pseudo-tumour. Biopsies reveal hypertrophic cartilage without inflammatory cells. This most commonly affects the large joints (knees, ankles, elbows, and wrists) but may also involve the small joints of the hands and feet. It is usually bilateral and painful. A common and characteristic feature is giant kneecaps. Severe cases may result in contractures (joint deformities). Most patients eventually have neurological problems. These manifest themselves in three principal ways: chronic meningitis, involvement of both the optic tract and eye, and sensorineural hearing loss. The chronic meningitis presents with the features of chronically raised intracranial pressure: headaches, vomiting, ventriculomegaly, hydrocephalus, macromegaly, cerebral atrophy, and optic atrophy. Some of these features may be evidenced on prenatal ultrasound. In 50% of cases, intellectual deficit occurs. Seizures occur in 25% of cases, but other manifestations are rare. Histological examination shows infiltration of the meninges with polymorphs. Ocular manifestations occur in 80% of cases and include uveitis (70%), papillary involvement, conjunctivitis, and optical neuritis. If untreated, these may result in blindness (25%). The sensorineural hearing loss occurs in 75%, and tends to be progressive leading to deafness in 20% of cases. Almost all children are remarkably short and have growth delay. Fever is extremely common but inconstant and is most often mild. Anemia is frequent. Other findings that have been reported include macrocephaly (95%), large fontanelle, prominent forehead, flattening of the nasal bridge (saddleback nose), short and thick extremities, and finger clubbing. The liver and/or spleen may be enlarged. Lymph node enlargement may also be present. Later in life, secondary amyloidosis may occur. Delayed puberty and secondary amenorrhoea are not uncommon. Hoarseness due to inflammation of the laryngeal cartilage has also been reported. The disease is caused in 60% of cases by a mutated gene called CIAS1 that is known to be involved in other syndromes that appear somewhat similar, such as Muckle–Wells syndrome and familial cold urticaria. In many patients, the parents do not have the same mutation, indicating the problem was not inherited, even though it is a genetic disease. CIAS1 is involved in controlling the immune system, which is why the mutation leads to out-of-control inflammation. The diagnosis is based on observing the patient and finding the constellation of symptoms and signs described above. A few blood tests help, by showing signs of long standing inflammation. There is no specific test for the disease, though now that the gene that causes the disease is known, that may change. Routine laboratory investigations are non specific: anaemia, increased numbers of polymorphs, an elevated erythrocyte sedimentation rate and elevated concentrations of C-reactive protein are typically all the abnormalities found. Lumbar puncture shows elevated levels of polymorphs (20-70% of cases) and occasionally raised eosinophil counts (0-30% of cases). CSF neopterin may be elevated. The X ray changes are unique and charactistic of this syndrome. These changes include bony overgrowth due to premature ossification of the patella and the long bone epiphyses in very young children and bowing of long bones with widening and shortening periosteal reaction in older ones. Audiometry shows a progressive sensineural deafness. Visual examination shows optic atrophy and an increase in the blind spot. CT is usually normal but may show enlargement of the ventricles. MRI with contrast may show enhancement of leptomeninges and cochlea consistent with chronic meningitis. EEG shows is non specific with slow waves and spike discharges. Polymorphs tend to show increased expression of CD10. Still's disease does not affect children under 6 months old. Hyperimmunoglobulin D syndrome in 50% of cases is associated with mevalonate kinase deficiency which can be measured in the leukocytes. There have been attempts to control the inflammation using drugs that work in other conditions where inflammation is a problem. The most successful of these are steroids, but they have side effects when used long term. Other medications, including methotrexate, colchicine and canakinumab, have been tried with some success. Otherwise, the treatment is supportive, or aimed solely at controlling symptoms and maximizing function. Overall, the prognosis for patients with NOMID is not good, though many (80%) live into adulthood, and a few appear to do relatively well. They are at risk for leukemia, infections, and some develop deposits of protein aggregated called amyloid, which can lead to kidney failure and other problems. The neurologic problems are most troubling. The finding that other diseases are related and a better understanding of where the disease comes from may lead to more effective treatments. This is a rare condition with an incidence estimated to be less than 1 in a million live births. About 100 cases have been reported worldwide. The bulk of cases are sporadic but familial forms with autosomal dominant transmission have also been described.	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https://en.wikipedia.org/wiki/Fucosidosis	disease	Fucosidosis	Fucosidosis is a rare lysosomal storage disorder in which the FUCA1 gene experiences mutations that severely reduce or stop the activity of the alpha-L-fucosidase enzyme. The result is a buildup of complex sugars in parts of the body, which leads to death. Fucosidosis is one of nine identified glycoprotein storage diseases. The gene encoding the alpha-fucosidase, FUCA 1, was found to be located to the short arm of chromosome 1p36 - p34, by Carrit and co-workers, in 1982.	Fucosidosis is an autosomal recessive disorder that affects many areas of the body. Mutations in the FUCA1 gene causes fucosidosis. The FUCA1 gene provides instructions for making an enzyme called alpha-L-fucosidase. The enzyme plays a role in the breakdown of complex sugars in the body. The disorder is characterized by lysosomal accumulation of a variety of glycoproteins, glycolipids, and oligosaccharides that contain fucose moieties. The deficiency of the enzyme alpha-L-fucosidase, which is used to metabolize complex compounds in the body (fucose-containing glycolipids and fucose-containing glycoproteins). With the lack of this enzyme activity, the result is incomplete breakdown of glycolipids and glycoproteins. These partially broken down compounds accumulate in various parts of the body and begin to cause malfunction in cells, and can eventually cause cell death. Brain cells are especially sensitive to this buildup. Other results are progressive neurological deterioration, skin abnormalities, growth retardation, skeletal disease, and coarsening of facial features. Fucosidosis is the consequence of faulty degradation of both sphingolipids and polysaccharides. Major accumulation of the H-antigen (a member of the ABO blood group antigens), a glycolipid, is seen primarily in the liver of fucosidosis patients. Diagnosis: A special urine test is available to check for any partially broken-down-sugars. If they are present, a skin or blood sample will be taken to test for below-normal amounts of alpha-fucosidase. - Fucosidosis is an autosomal recessive disorder, which means that both parents have to have the mutation and pass it on to the child. When both parents have the mutation, there is a 25% chance of each child having fucosidosis. Type 1 usually begins somewhere in the first three to 18 months of age and in considered the most severe of the three types. Symptoms include: - Coarse facial features - Enlarged liver, spleen, and/or heart - Intellectual disability - Seizures - Abnormal bone formation of many bones - Progressive deterioration of brain and spinal cord - Increased or decreased perspiration Patients have no vascular lesions, but have rapid psychomotor regression, severe and rapidly progressing neurologic signs, elevated sodium and chloride excretion in the sweat, and fatal outcome before the sixth year. Type 2 appears when a child is around 18 months of age and in considered milder than Type 1 but still severe. Symptoms include: - Symptoms similar to Type 1 but milder and progress more slowly. Treatment: There is no treatment or way to reverse the disease. Treatment will focus on the symptoms an individual has, such as seizure medication. - It is possible that if an individual receives a bone marrow transplant, they could receive healthy bone marrow cells which would produce normal amounts of fucosidase. But there not is enough research to prove this is an effective treatment. Fucosidosis is an extremely rare disorder first described in 1962 in two Italian siblings who showed progressive intellectual disability and neurological deterioration. The disease itself is extremely rare (less than 100 documented cases) only affecting 1:2,000,000, with most cases being occurring in Italy, Cuba, and the southwest U.S. The disease has three different types. Type 1 and 2 are considered severe, and Type 3 being a mild disease. Symptoms are highly variable with mild cases being able to live to within the third or fourth decade. Type 1 and 2 are both linked with mental retardation. Severe cases can develop life-threatening complications early in childhood. Because the major accumulating glycoconjugate in fucosidosis patients is the blood group H-antigen, it is intriguing to speculate, but the evidence is not clear at this time, that blood type may affect the course of the disease. Canine fucosidosis is found in the English Springer Spaniel. Typically affecting dogs between 18 months and four years, symptoms include: - Loss of learned behavior - Change in temperament - Blindness - Loss of balance - Deafness - Weight loss - From the onset, disease progress is quick and fatal. Just like the human version, canine fucosidosis is a recessive disorder and two copies of the gene must be present, one from each parent, in order to show symptoms of the disease.	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https://en.wikipedia.org/wiki/Progressive_retinal_atrophy	disease	Progressive retinal atrophy	Progressive retinal atrophy (PRA) is a group of genetic diseases seen in certain breeds of dogs and, more rarely, cats. Similar to retinitis pigmentosa in humans, it is characterized by the bilateral degeneration of the retina, causing progressive vision loss culminating in blindness. The condition in nearly all breeds is inherited as an autosomal recessive trait, with the exception of the Siberian Husky (inherited as an X chromosome linked trait) and the Bullmastiff (inherited as an autosomal dominant trait). There is no treatment.	In general, PRAs are characterised by initial loss of rod photoreceptor cell function followed by that of the cones and for this reason night blindness is the first significant clinical sign for most dogs affected with PRA. As other retinal disorders, PRA can be divided into either dysplastic disease, where the cells develop abnormally, and degenerative, where the cells develop normally but then degenerate during the dog's lifetime. Generalized PRA is the most common type and causes atrophy of all the neural retinal structures. Central progressive retinal atrophy (CPRA) is a different disease from PRA involving the retinal pigment epithelium (RPE), and is also known as retinal pigment epithelial dystrophy (RPED). Commonly affected breeds: - Akita - Symptoms at one to three years old and blindness at three to five years old. Selective breeding has greatly reduced the incidence of this disease in this breed. - Miniature longhaired Dachshund - Symptoms at six months old. - Papillon - Slowly progressive with blindness at seven to eight years old. - Tibetan Spaniel - Symptoms at three to five years old. - Tibetan Terrier - PRA3/RCD4 disease of middle age dogs. http://www.ttca-online.org/html/Petersen-Jones_PRA_article.pdf - Samoyed - Symptoms by three to five years old. This type of PRA has an early onset of severe vision loss. It is caused by a defect in the gene for cGMP-phosphodiesterase, which leads to retinal levels of cyclic guanosine monophosphate ten times normal. This is caused by an abnormal development of both rod and cone cells. Dogs are initially night blind and then progress to day blindness. - Miniature Schnauzer - Slowly progressive, not seen until two to five years old. - Belgian Shepherd Dog - Complete blindness by eight weeks old. This is a disease with normal rod and cone cell development but late onset degeneration of the rod cells that progresses to the cone cells. It is inherited as an autosomal recessive trait and has been linked to the ninth canine chromosome. - Poodle - Night blindness by three to five years old, blind by five to seven years old. - English Cocker Spaniel - Occurs late in life, usually at four to eight years old. - American Cocker Spaniel - Night blindness by three to five years old, blind one to two years later. - Labrador Retriever - Night blindness by four to six years old, blind at six to eight years old. - Portuguese Water Dog - Chesapeake Bay Retriever - Australian Cattle Dog - American Eskimo Dog - Nova Scotia Duck Tolling Retriever This condition is linked to the X chromosome. - Siberian Husky - Night blindness by two to four years old. - Samoyed - More severe disease than the Husky. CPRA is also known as retinal pigment epithelial dystrophy (RPED). The cause of this condition is the loss of the retinal pigment epithelium's ability to effectively process the photoreceptor outer segment (POS) and subsequent accumulation of POS material in the RPE and loss of function. The loss of function of the RPE leads to photoreceptor degeneration. Vitamin E deficiency may play a role in the development of CPRA. It is characterized by accumulation of pigment spots in the retina surrounded by retinal atrophy and a mottled appearance of the pigmented nontapetal fundus. The pigmented spots eventually coalesce and fade as the atrophy of the retina increases. It is an inherited condition (in the Labrador Retriever it is inherited as an autosomal dominant trait with variable penetrance). CPRA occurs in older dogs. Peripheral vision is retained for a long time. Vision is better in low light and better for moving or distant objects. Not all affected dogs go blind. Secondary cataracts are common. There is another retinal disease in Briards known as hereditary retinal dysplasia. These dogs are night blind from birth, and day vision varies. Puppies affected often have nystagmus. It is also known as lipid retinopathy. Progressive vision loss in any dog in the absence of canine glaucoma or cataracts can be an indication of PRA. It usually starts with decreased vision at night, or nyctalopia. Other symptoms include dilated pupils and decreased pupillary light reflex. Fundoscopy to examine the retina will show shrinking of the blood vessels, decreased pigmentation of the nontapetal fundus, increased reflection from the tapetum due to thinning of the retina, and later in the disease a darkened, atrophied optic disc. Secondary cataract formation in the posterior portion of the lens can occur late in the disease. In these cases diagnosis of PRA may require electroretinography (ERG). For many breeds there are specific genetic tests of blood or buccal mucosa for PRA. Absent a genetic test, animals of breeds susceptible to PRA can be cleared of the disease only by the passage of time—that is, by living past the age at which PRA symptoms are typically apparent in their breed. Breeds in which the PRA gene is recessive may still be carriers of the gene and pass it on to their offspring, however, even if they lack symptoms, and it is also possible for onset of the disease to be later than expected, making this an imperfect test at best.	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https://en.wikipedia.org/wiki/Coccidiosis	disease	Coccidiosis	Coccidiosis is a parasitic disease of the intestinal tract of animals caused by coccidian protozoa. The disease spreads from one animal to another by contact with infected feces or ingestion of infected tissue. Diarrhea, which may become bloody in severe cases, is the primary symptom. Most animals infected with coccidia are asymptomatic, but young or immunocompromised animals may suffer severe symptoms and death. While coccidia can infect a wide variety of animals, including humans, birds, and livestock, they are usually species-specific. One well-known exception is toxoplasmosis caused by Toxoplasma gondii. Humans may first encounter coccidia when they acquire a puppy or kitten that is infected. Other than T. gondii, the infectious organisms are canine and feline-specific and are not contagious to humans, unlike the zoonotic diseases.	Puppies are frequently infected with coccidia from the feces of their mother, and are more likely to develop coccidiosis due to their undeveloped immune systems. Stress can trigger symptoms in susceptible animals. Symptoms in young dogs include diarrhea with mucus and blood, poor appetite, vomiting, and dehydration. Untreated the disease can be fatal. Treatment is routine and effective. Diagnosis is made by low-powered microscopic examination of the feces, which is generally replete with oocysts. Readily available drugs eliminate the protozoa or reduce them enough that the animal's immune system can clear the infection. Permanent damage to the gastrointestinal system is rare, and a dog will usually suffer no long-lasting negative effects. Coccidiosis is a significant disease for chickens, especially affecting the young chicks. It can be fatal or leave the bird with compromised digestion. There are chick feed mixes that contain a coccidiostat to manage exposure levels and control disease. In an outbreak, coccidiocidal medications are given. Examples are toltrazuril (Baycox) or amprolium. After multiple infections, surviving chickens become resistant to the coccidia. Coccidiosis is one of the most important diseases in calves and youngstock both under housing conditions and when grazing. Symptoms are generally caused by the species Eimeria zuernii and Eimeria bovis and include loss of appetite, fatigue, dehydration, and watery, sometimes bloody, diarrhoea. Outbreaks are known to occur in cattle herds. The parasite can infect up to all animals in the farm and in some countries the parasite is present in all farms. Coccidiosis affect the growth and sometimes survival of the calves and consequently affect the production and the profitability of cattle livestock production. The most common medications used to treat coccidian infections are in the sulfonamide antibiotic family. Depending on the pathogen and the condition of the animal, untreated coccidiosis may clear of its own accord, or become severe and damaging, and sometimes cause death.	[ { "begin": 0, "class": "SectionAnnotation", "length": 749, "sectionHeading": "Coccidia in dogs", "sectionLabel": "disease.fauna" }, { "begin": 749, "class": "SectionAnnotation", "length": 435, "sectionHeading": "Coccidia in chickens", "sectionLabel": "disease.other" }, { "begin": 1184, "class": "SectionAnnotation", "length": 615, "sectionHeading": "Coccidia in cattle", "sectionLabel": "disease.other" }, { "begin": 1799, "class": "SectionAnnotation", "length": 273, "sectionHeading": "Genera and species that cause coccidiosis", "sectionLabel": "disease.cause" } ]
https://en.wikipedia.org/wiki/Brachymetatarsia	disease	Brachymetatarsia	Brachymetatarsia or hypoplastic metatarsal is a condition in which there is one or more abnormally short or overlapping toes metatarsals. This condition may result due to a congenital defect or it may be an acquired condition. It most frequently involves the fourth metatarsal. If it involves the first metatarsal, the condition is known as Morton's syndrome. Treatment is via a number of differing surgical procedures.	Congenital causes include: Aarskog syndrome, Albright's hereditary osteodystrophy, and Apert syndrome. Can be caused by a trauma, although the exact mechanism is not known. Symptoms may be treated by wearing wider shoes to relieve pressure, or patient can wear padding around the toes. Surgery is also an option, if the pain and discomfort cannot be treated, or for cosmetic reasons. In this procedure, the short metatarsal is typically cut and a piece of bone is grafted between the two ends. In some cases an external fixator may be attached to the metatarsal with pins. Within the external fixator is an adjustable screw that must be turned (per doctors' orders) to lengthen the gap between bone segments, so the bone will regrow to the appropriate shape. Following surgery, crutches or a knee scooter should be used to keep all weight off the surgically repaired foot for 3 months. After this period, orthopedic shoes or boots may be used. Brachymetatarsia is found to occur more frequently in women than men.	[ { "begin": 0, "class": "SectionAnnotation", "length": 173, "sectionHeading": "Diagnosis \| Differential diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 173, "class": "SectionAnnotation", "length": 771, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 944, "class": "SectionAnnotation", "length": 70, "sectionHeading": "Epidemiology", "sectionLabel": "disease.epidemiology" } ]
https://en.wikipedia.org/wiki/X-linked_ichthyosis	disease	X-linked ichthyosis	X-linked ichthyosis (XLI) (also known as ") is a skin condition caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males. XLI manifests with dry, scaly skin and is due to deletions or mutations in the STS gene. XLI can also occur in the context of larger deletions causing contiguous gene syndromes. Treatment is largely aimed at alleviating the skin symptoms. The term is from the Ancient Greek 'ichthys' meaning 'fish'.	The major symptoms of XLI include scaling of the skin, particularly on the neck, trunk, and lower extremities. The extensor surfaces are typically the most severely affected areas. The >4 mm diameter scales adhere to the underlying skin and can be dark brown or gray in color. Symptoms may subside during the summer. The STS gene is located on the X chromosome at band Xp22.3. Thus, the syndrome is an X-linked condition, and it affects males and females differently. The 23rd pair of chromosomes is typically termed the "sex chromosomes". Females have two X chromosomes and males have one X and one Y chromosome. Therefore, in normal individuals, males carry a single copy of the STS gene and females carry two copies. This gene partially escapes X-inactivation and females normally express higher amounts of the STS enzyme than males. XLI can occur through new deletions or mutations of the STS gene but is more commonly inherited from a carrier mother. A hemizygous deletion or mutation of the STS gene in a male results in complete absence of enzyme activity, while a female carrier of a mutation or deletion is heterozygous and still has a normal copy of the STS gene. Female carriers of an STS deletion or mutation still express the STS enzyme, although with decreased enzyme activity. For this reason, XLI most commonly affects males, although individuals with numeric abnormalities of the sex chromosomes (45,X and 47,XXY) who also carry STS deletions or mutations would be exceptions to this rule. In addition, a female could be affected if she were the offspring of an affected male and a carrier female and inherited a deletion or mutation of the STS gene on both X chromosomes. Since the majority of cases appear to occur through transmission of an STS deletion from a carrier mother, enzyme testing or DNA testing should be performed in the mother of any newly diagnosed simplex case (i.e. the first case in a family). In the case of an extended family with many affected individuals, carrier status can often be assigned based on pedigree analysis. - Males with XLI will transmit the X chromosome harboring the STS deletion or mutation to each of his female offspring, who will therefore be an obligate carrier. However, all male offspring will be unaffected, since they receive their father's Y chromosome. - Female carriers of an STS deletion or mutation have a 50% chance with each pregnancy of transmitting it to an offspring. Thus, each male offspring has a 50% chance of being affected by XLI, while each female offspring has a 50% chance of being a carrier for this condition. Any individual that inherits the mother's normal copy of the STS gene will be unaffected and will have an extremely low chance of having a child affected with this condition. Due to random segregation of the chromosomes during gametogenesis, each pregnancy will be subject to the same probabilities, regardless of the number of previously affected or unaffected offspring. It should be noted that the above recurrence risks are based on the assumption that an affected male or carrier female will have children with an unaffected or non-carrier individual. The risks of having affected offspring would clearly increase in the case of a union between a male with XLI and a carrier female. Aside from the skin scaling, XLI is not typically associated with other major medical problems. Corneal opacities may be present but do not affect vision. Cryptorchidism is reported in some individuals. Some individuals can also be seen to have an intellectual disability, this is thought to be due to deletions encompassing neighboring genes in addition to STS. Female carriers generally do not experience any of these problems but rarely can have difficulty during childbirth, as the STS expressed in the placenta plays a role in normal labor. For this reason carriers should ensure their obstetrician is aware of the condition. The STS enzyme (EC 3.1.6.2), also referred to as Arylsulfatase C, is expressed throughout the body, with highest expression in the skin, liver, lymph nodes, and placenta, and lower expression in breast tissue and brain STS catalyzes the hydrolysis of sulfated steroids, such as estrone sulfate and dehydroepiandrosterone sulfate (DHEAS), to non-sulfated steroids estradiol and androstenediol, respectively. Prenatally, the enzyme is involved in placental estrogen production. The enzyme is also involved in adrenal steroid production as well as conversion of sulfated steroids in other tissues. There seems to be a particularly important role for the enzyme in skin. Deficiency of the enzyme leads to the characteristic dry and scaly skin seen in ichthyosis. Recent research indicates that the skin abnormalities seen in XLI may be due to accumulation of cholesterol sulfate in the outer epidermis, leading to abnormal barrier function and corneocyte retention. XLI can be suspected based on clinical findings, although symptoms can take varying amounts of time to become evident, from a few hours after birth, up to a year in milder cases. The diagnosis is usually made by a dermatologist, who also typically formulates the treatment plan (see below). STS enzyme deficiency is confirmed using a clinically available biochemical assay. Carrier detection can be performed in mothers of affected sons using this test (see Genetics, below). Molecular testing for DNA deletions or mutations is also offered, and can be particularly useful in the evaluation of individuals with associated medical conditions (see below). Prenatal diagnosis is possible using either biochemical or molecular tests. However, the use of prenatal diagnosis for genetic conditions that are considered to be generally benign raises serious ethical considerations and requires detailed genetic counseling. Because XLI is caused by a gene mutation or deletion, there is no "cure." One of the aims of treatment is to reduce scaling by removing the excess, flaky scales, and keep the skin hydrated. This can be achieved using a variety of topical creams. - Keratolytic agents such as Ammonium lactate (Lac-Hydrin) are used to facilitate the release of retained corneocytes. - Topical isotretinoin - The topical receptor-selective retinoid tazarotene Research is ongoing with regard to the use of gene therapy to treat XLI. In the 1960s, recessive x-linked ichthyosis was distinguished clinically from other ichthyoses.	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https://en.wikipedia.org/wiki/Synovial_sarcoma	disease	Synovial sarcoma	A synovial sarcoma (also known as: malignant synovioma) is a rare form of cancer which occurs primarily in the extremities of the arms or legs, often in close proximity to joint capsules and tendon sheaths. As one of the soft tissue sarcomas, it is one of the rarest forms of soft tissue cancer. The name "synovial sarcoma" was coined early in the 20th century, as some researchers thought that the microscopic similarity of some tumors to synovium, and its propensity to arise adjacent to joints, indicated a synovial origin; however, the actual cells from which the tumor develops are unknown and not necessarily synovial. Primary synovial sarcomas are most common in the soft tissue near the large joints of the arm and leg but have been documented in most human tissues and organs, including the brain, prostate, and heart. Synovial sarcoma occurs most commonly in the young, representing about 8% of all soft tissue sarcomas but about 15–20% of cases occur in adolescents and young adults. The peak of incidence is in the third decade of life, with males being affected more often than females (ratio around 1.2:1).	Synovial sarcoma usually presents with an otherwise asymptomatic swelling or mass, although general symptoms related to malignancies can be reported such as fatigue. The diagnosis of synovial sarcoma is typically made based on histology and is confirmed by the presence of t(X;18) chromosomal translocation. Two cell types can be seen microscopically in synovial sarcoma. One fibrous type, known as a spindle or sarcomatous cell, is relatively small and uniform, and found in sheets. The other is epithelial in appearance. Classical synovial sarcoma has a biphasic appearance with both types present. Synovial sarcoma can also appear to be poorly differentiated or to be monophasic fibrous, consisting only of sheets of spindle cells. Some authorities state that, extremely rarely, there can be a monophasic epithelial form which causes difficulty in differential diagnosis. Depending on the site, there is similarity to biphenotypic sinonasal sarcoma, although the genetic findings are distinctive. Like other soft tissue sarcomas, there is no universal grading system for reporting histopathology results. In Europe, the Trojani or French system is gaining in popularity while the NCI grading system is more common in the United States. The Trojani system scores the sample, depending on tumour differentiation, mitotic index, and tumour necrosis, between 0 and 6 and then converts this into a grade of between 1 and 3, with 1 representing a less aggressive tumour. The NCI system is also a three-grade one, but takes a number of other factors into account. Most, and perhaps all, cases of synovial sarcoma are associated with a reciprocal translocation t(x;18)(p11.2;q11.2). There is some debate about whether the molecular observation itself is definitional of synovial sarcoma. The diagnosis of synovial sarcoma is typically made based on histology and is confirmed by the presence of t(X;18). This translocation event between the SS18 gene on chromosome 18 and one of 3 SSX genes (SSX1, SSX2 and SSX4) on chromosome X causes the presence of an SS18-SSX fusion gene. The resulting fusion protein brings together the transcriptional activating domain of SS18 and the transcriptional repressor domains of SSX. It also incorporates into the SWI/SNF chromatin remodeling complex, a well known tumor suppressor. SS18-SSX is thought to underlie synovial sarcoma pathogenesis through dysregulation of gene expression. There is some association between the SS18-SSX1 or SS18-SSX2 fusion type and both tumour morphology and five-year survival. Treatment is usually multimodal, involving surgery, chemotherapy and radiotherapy: - Surgery, to remove the tumor and a safety margin of healthy tissue. This is the mainstay of synovial sarcoma treatment and is curative in approximately 20–70% of patients, depending on the particular study being quoted. - Conventional chemotherapy, (for example, doxorubicin hydrochloride and ifosfamide), to reduce the number of remaining microscopic metastases. The benefit of chemotherapy in synovial sarcoma to overall survival remains unclear, although a recent study has shown that survival of patients with advanced, poorly differentiated disease marginally improves with doxorubicin/ifosfamide treatment. - Radiotherapy to reduce the chance of local recurrence. The benefit of radiotherapy in this disease is less clear than for chemotherapy.	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https://en.wikipedia.org/wiki/Köhler_disease	disease	Köhler disease	Köhler disease (also spelled "Kohler" and referred to in some texts as Kohler disease I) is a rare bone disorder of the foot found in children between six and nine years of age. The disease typically affects boys, but it can also affect girls. It was first described in 1908 by Alban Köhler (1874–1947), a German radiologist. It is caused when the navicular bone temporarily loses its blood supply. As a result, tissue in the bone dies and the bone collapses. When treated, it causes no long term problems in most cases although rarely can return in adults. As the navicular bone gets back to normal, symptoms typically abate. In February 2010, the Journal of the American Medical Association reported that the 19-year-old king Tutankhamun may well have died of complications from malaria combined with Köhler disease II.	Sufferers experience pain and swelling in the middle part of the foot and usually limp as a result. Patients that walk with a limp tend to walk with increased weight on the lateral side of the foot. Also, there can be tenderness over the navicular. Patients often complain of pain over the apex. An X-ray of both feet is used to diagnose disease. The affected foot tends to have a sclerotic and flattened navicular bone. Diagnosis is made on the basis of history and a high index of suspicion. On examination there is tenderness to palpation on navicular head. Radiographs reveal typical changes of increased density and narrowing of the navicular bone Treatment usually involves resting the affected foot, taking pain relievers and trying to avoid putting pressure on the foot. In acute cases, the patient is often fitted with a cast that stops below the knee. The cast is usually worn for 6 to 8 weeks. After the cast is taken off, some patients are prescribed arch support for about 6 months. Also, moderate exercise is often beneficial, and physical therapy may help as well. Prognosis for children with this disease is very good. It may persist for some time, but most cases are resolved within two years of the initial diagnosis. Although in most cases no permanent damage is done, some will have lasting damage to the foot. Also, later in life, Kohler's disease can spread to the hips.	[ { "begin": 0, "class": "SectionAnnotation", "length": 421, "sectionHeading": "Symptoms", "sectionLabel": "disease.symptom" }, { "begin": 421, "class": "SectionAnnotation", "length": 233, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 654, "class": "SectionAnnotation", "length": 740, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Anterior_compartment_syndrome	disease	Anterior compartment syndrome	A compartment syndrome is an increased pressure within a muscular compartment that compromises the circulation to the muscles.	Diffuse tightness and tenderness over the entire belly of the tibialis anterior that does not respond to elevation or pain medication can be early warning signs and suggestive of Anterior Compartment Syndrome. Other common symptoms include excessive swelling that causes the skin to become hot, stretched and glossy. Pain, paresthesias, and tenderness in both the ischemic muscles and the region supplied by the deep common fibular nerve are exhibited by patients suffering from this condition. Sensitivity to passive stretch and active contraction are common, and tend to increase the symptoms. A compartment space is anatomically determined by an unyielding fascial (and osseous) enclosure of the muscles. The anterior compartment syndrome of the lower leg (often referred to simply as anterior compartment syndrome), can affect any and all four muscles of that compartment: tibialis anterior, extensor hallucis longus, extensor digitorum longus, and peroneus tertius. This term is often mistakenly used to describe various related/proximal conditions, including Anterior Shin Splints. It is important to distinguish between the two, as shin splints rarely causes serious health problems, while Anterior Compartment Syndrome can lead to irreversible damage. The true compartment syndrome arises due to increased pressure within the unyielding anterior compartment of the leg. The pressure obstructs venous outflow, which causes further swelling and increased pressure. The resultant ischemia leads to necrosis (death of tissue) of the muscles and nerves. The process can begin with swelling of the tibialis anterior, extensor hallucis longus, extensor digitorum longus, and/or the peroneus tertius muscles in response to strong eccentric contractions sufficient to produce postexercise soreness. If these symptoms are observed/experienced it is important to contact a physician specializing in sports medicine (MD/DO), a doctor of podiatric medicine (DPM), or other qualified health care professional immediately so as to get the appropriate advice/treatment before serious damage occurs. The 5 Ps of Anterior Compartment Syndrome: 1. Pain 2. Pallor 3. Paresthesia 4. Pulselessness 5. Paralysis (If not treated)	[ { "begin": 0, "class": "SectionAnnotation", "length": 596, "sectionHeading": "Symptoms", "sectionLabel": "disease.symptom" }, { "begin": 596, "class": "SectionAnnotation", "length": 1202, "sectionHeading": "Pathology", "sectionLabel": "disease.pathology" }, { "begin": 1798, "class": "SectionAnnotation", "length": 416, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" } ]
https://en.wikipedia.org/wiki/Leydig_cell_tumour	disease	Leydig cell tumour	Leydig cell tumour, also Leydig cell tumor (US spelling), (testicular) interstitial cell tumour and (testicular) interstitial cell tumor (US spelling), is a member of the sex cord-stromal tumour group of ovarian and testicular cancers. It arises from Leydig cells. While the tumour can occur at any age, it occurs most often in young adults. A Sertoli-Leydig cell tumour is a combination of a Leydig cell tumour and a Sertoli cell tumour from Sertoli cells.	The majority of Leydig cell tumors are found in males, usually at 5–10 years of age or in middle adulthood (30–60 years). Children typically present with precocious puberty. Due to excess testosterone secreted by the tumour, one-third of female patients present with a recent history of progressive masculinization. Masculinization is preceded by anovulation, oligomenorrhea, amenorrhea and defeminization. Additional signs include acne and hirsutism, voice deepening, clitoromegaly, temporal hair recession, and an increase in musculature. Serum testosterone level is high. In men testicular swelling is the most common presenting feature. Other symptoms depend on their age and the type of tumour. If it is secreting androgens the tumour is usually asymptomatic, but can cause precocious puberty in pre-pubertal boys. If the tumour secretes oestrogens it can cause feminisation in young boys. In adults, this causes a number of problems including gynaecomastia, erectile dysfunction, infertility, feminine hair distribution, gonadogenital atrophy, and a loss of libido. Presence of an ovarian tumour plus hormonal disturbances suggests a Leydig cell tumour, granulosa cell tumour or thecoma. However, hormonal disturbances, in Leydig tumours, is present in only 2/3 of cases. Testicular Leydig cell tumours can be detected sonographically, ultrasound examinations may be ordered in the event of a palpable scrotal lump, however incidental identification of these lesions is also possible. A conclusive diagnosis is made via histology, as part of a pathology report made during or after surgery. Reinke crystals are classically found in these tumours and help confirm the diagnosis, although they are seen in less than half of all Leydig cell tumours. See also Sex cord-stromal tumour. Immunohistochemical markers of Leydig cell tumours include inhibin-alpha, calretinin, and melan-A. The usual chemotherapy regimen has limited efficacy in tumours of this type, although Imatinib has shown some promise. There is no current role for radiotherapy. The usual treatment is surgery. The surgery for females usually is a fertility-sparing unilateral salpingo-oophorectomy. For malignant tumours, the surgery may be radical and usually is followed by adjuvant chemotherapy, sometimes by radiation therapy. In all cases, initial treatment is followed by surveillance. Because in many cases Leydig cell tumour does not produce elevated tumour markers, the focus of surveillance is on repeated physical examination and imaging. In males, a radical inguinal orchiectomy is typically performed. However, testes-sparing surgery can be used to maintain fertility in children and young adults. This approach involves an inguinal or scrotal incision and ultrasound guidance if the tumour is non-palpable. This can be done because the tumour is typically unifocal, not associated with precancerous lesions, and is unlikely to recur. The prognosis is generally good as the tumour tends to grow slowly and usually is benign: 10% are malignant. For malignant tumours with undifferentiated histology, prognosis is poor.	[ { "begin": 0, "class": "SectionAnnotation", "length": 1073, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 1073, "class": "SectionAnnotation", "length": 814, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 1887, "class": "SectionAnnotation", "length": 1215, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Joubert_syndrome	disease	Joubert syndrome	Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination. Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pigmentosa. The syndrome was first identified in 1969 by pediatric neurologist Marie Joubert in Montreal, Quebec, Canada, while working at the Montreal Neurological Institute and McGill University.	Most of the signs and symptoms of the Joubert syndrome appear very early in infancy with most children showing delays in gross motor milestones. Although other signs and symptoms vary widely from individual to individual, they generally fall under the hallmark of cerebellum involvement or in this case, lack thereof. Consequently, the most common features include ataxia (lack of muscle control), hyperpnea (abnormal breathing patterns), sleep apnea, abnormal eye and tongue movements, and hypotonia in early childhood. Other malformations such as polydactyly (extra fingers and toes), cleft lip or palate, tongue abnormalities, and seizures may also occur. Developmental delays, including cognitive, are always present to some degree. Those suffering from this syndrome often exhibit specific facial features such as a broad forehead, arched eyebrows, ptosis (droopy eyelids), hypertelorism (widely spaced eyes), low-set ears and a triangle shaped mouth. Additionally, this disease can include a broad range of other abnormalities to other organ systems such as retinal dystrophy, kidney diseases, liver diseases, skeletal deformities and endocrine (hormonal) problems. A number of mutations have been identified in individuals with Joubert syndrome (JBTS) which allowed for classification of the disorder into subtypes. This disorder can be caused by mutations in more than 30 genes within genetic makeup. The primary cilia play an important role in the structure and function of cells. When primary cilia are mutated and defected, it can cause various genetic disorders among individuals. This mutation of primary cilia can disrupt significant signaling pathways during the development of the fetus. Mutations in these various genes are known for causing around 60-90% of Joubert Syndrome cases. The remaining cases, the cause is unknown if isn't linked to a mutation of known genes. The disorder is characterized by absence or underdevelopment of the cerebellar vermis and a malformed brain stem (molar tooth sign), both of which can be visualized on a MRI scan. Together with this sign, the diagnosis is based on the physical symptoms and genetic testing for mutations. If the gene mutations have been identified in a family member, prenatal or carrier diagnosis can be pursued. Joubert Syndrome is known to affect 1 in 80,000-100,000 newborns. Due to the variety of genes this disorder is affected by, it is likely to be under-diagnosed. It is commonly found in Ashkenazi Jewish, French-Canadians, and Hutterite ethnic populations. Most cases of Joubert syndrome are autosomal recessive - in these cases, both parents are either carriers or affected. Rarely, Joubert syndrome is inherited in an X-linked recessive pattern. In these cases, males are more commonly affected because affected males must have one X chromosome mutated, while affected females must have mutated genes on both X chromosomes. Treatment for Joubert syndrome is symptomatic and supportive. Infant stimulation and physical, occupational, speech and hearing therapy may benefit some patients. Infants with abnormal breathing patterns should be monitored. The syndrome is associated with progressive worsening for kidneys, the liver and the eyes and thus require regular monitoring. In a sample of 19 children, a 1997 study found that 3 died before the age of 3, and 2 never learned to walk. The children had various levels of delayed development with developmental quotients from 60 to 85. Research has revealed that a number of genetic disorders, not previously thought to be related, may indeed be related as to their root cause. Joubert syndrome is one such disease. It is a member of an emerging class of diseases called ciliopathies. The underlying cause of the ciliopathies may be a dysfunctional molecular mechanism in the primary cilia structures of the cell, organelles which are present in many cellular types throughout the human body. The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development and thus offer a plausible hypothesis for the often multi-symptom nature of a large set of syndromes and diseases. Currently recognized ciliopathies include Joubert syndrome, primary ciliary dyskinesia (also known as Kartagener Syndrome), Bardet-Biedl syndrome, polycystic kidney disease and polycystic liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome and some forms of retinal degeneration. Joubert syndrome type 2 is disproportionately frequent among people of Jewish descent.	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https://en.wikipedia.org/wiki/Spondylosis	disease	Spondylosis	Spondylosis is a broad term meaning degeneration of the spinal column from any cause. In the more narrow sense it refers to spinal osteoarthrosis, the age-related wear and tear of the spinal column, which is the most common cause of spondylosis. The degenerative process in osteoarthritis chiefly affects the vertebral bodies, the neural foramina and the facet joints (facet syndrome). If severe, it may cause pressure on the spinal cord or nerve roots with subsequent sensory or motor disturbances, such as pain, paresthesia, imbalance, and muscle weakness in the limbs. When the space between two adjacent vertebrae narrows, compression of a nerve root emerging from the spinal cord may result in radiculopathy (sensory and motor disturbances, such as severe pain in the neck, shoulder, arm, back, or leg, accompanied by muscle weakness). Less commonly, direct pressure on the spinal cord (typically in the cervical spine) may result in myelopathy, characterized by global weakness, gait dysfunction, loss of balance, and loss of bowel or bladder control. The patient may experience shocks (paresthesia) in hands and legs because of nerve compression and lack of blood flow. If vertebrae of the neck are involved it is labelled cervical spondylosis. Lower back spondylosis is labeled lumbar spondylosis. The term is from Ancient Greek σπόνδυλος spóndylos, "a vertebra", in plural "vertebrae – the backbone".	A severe but rare complication of this disease is vertebrobasilar insufficiency. This is a result of the vertebral artery becoming occluded as it passes up in the transverse foramen. The spinal joints become stiff in cervical spondylosis. Thus the chondrocytes which maintain the disc become deprived of nutrition and die. The weakened disc bulges and grows out as a result of incoming osteophytes. Spondylosis is caused from years of constant abnormal pressure, from joint subluxation, sports, or poor posture, being placed on the vertebrae, and the discs between them. The abnormal stress causes the body to form new bone in order to compensate for the new weight distribution. This abnormal weight bearing from bone displacement will cause spondylosis to occur. Poor postures and loss of the normal spinal curves can lead to spondylosis as well. Spondylosis can affect a person at any age; however, older people are more susceptible. There are multiple techniques used in the diagnosis of spondylosis, these are; - Cervical Compression Test, a variant of Spurling's test, is performed by laterally flexing the patient's head and placing downward pressure on it. Neck or shoulder pain on the ipsilateral side (i.e. the side to which the head is flexed) indicates a positive result for this test. However it should be noted that a positive test result is not necessarily a positive result for spondylosis and as such additional testing is required. - Lhermitte sign: feeling of electrical shock with patient neck flexion - Reduced range of motion of the neck, the most frequent objective finding on physical examination - MRI and CT scans are helpful for pain diagnosis but generally are not definitive and must be considered together with physical examinations and history. Treatment is usually conservative in nature. Patient education on lifestyle modifications, chiropractic, nonsteroidal anti-inflammatory drugs (NSAIDs), physical therapy, and osteopathic care are common forms of manual care that help manage such conditions. Other alternative therapies such as massage, trigger-point therapy, yoga and acupuncture may be of limited benefit. Surgery is occasionally performed. Many of the treatments for cervical spondylosis have not been subjected to rigorous, controlled trials. Surgery is advocated for cervical radiculopathy in patients who have intractable pain, progressive symptoms, or weakness that fails to improve with conservative therapy. Surgical indications for cervical spondylosis with myelopathy (CSM) remain somewhat controversial, but "most clinicians recommend operative therapy over conservative therapy for moderate-to-severe myelopathy" (Baron, M.E.). Physical therapy may be effective for restoring range of motion, flexibility and core strengthening. Decompressive therapies (i.e. manual mobilization, mechanical traction) may also help alleviate pain. However, physical therapy and osteopathy cannot "cure" the degeneration, and some people view that strong compliance with postural modification is necessary to realize maximum benefit from decompression, adjustments and flexibility rehabilitation. It has been argued, however, that the cause of spondylosis is simply old age, and that posture modification treatment is often practiced by those who have a financial interest (such as Worker's Compensation) in proving that it is caused by work conditions and poor physical habits. Understanding anatomy is the key to conservative management of spondylosis. Current surgical procedures used to treat spondylosis aim to alleviate the signs and symptoms of the disease by decreasing pressure in the spinal canal (decompression surgery) and/or by controlling spine movement (fusion surgery). Decompression surgery: The vertebral column can be operated on from both an anterior and posterior approach. The approach varies depending on the site and cause of root compression. Commonly, osteophytes and portions of intervertebral disc are removed. Fusion surgery: Performed when there is evidence of spinal instability or mal-alignment. Use of instrumentation (such as pedicle screws) in fusion surgeries varies across studies.	[ { "begin": 0, "class": "SectionAnnotation", "length": 399, "sectionHeading": "Presentation \| Complications", "sectionLabel": "disease.symptom" }, { "begin": 399, "class": "SectionAnnotation", "length": 538, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 937, "class": "SectionAnnotation", "length": 839, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 1776, "class": "SectionAnnotation", "length": 1715, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 3491, "class": "SectionAnnotation", "length": 664, "sectionHeading": "Treatment \| Surgery", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Glycogen_storage_disease_type_VI	disease	Glycogen storage disease type VI	Glycogen storage disease type VI (GSD VI) is a type of glycogen storage disease caused by a deficiency in liver glycogen phosphorylase or other components of the associated phosphorylase cascade system. It is also known as "Hers' disease", after Henri G. Hers, who characterized it in 1959. The scope of GSD VI now also includes glycogen storage disease type VIII, IX (caused by phosphorylase b kinase deficiency) and X (deficiency protein kinase A). The incidence of GSD VI is approximately 1 case per 65,000–85,000 births, representing approximately 30% all cases of glycogen storage disease. Approximately 75% of these GSD VI cases result from the X-linked recessive forms of phosphorylase kinase deficiency, all other forms are autosomal recessive.	Patients generally have a benign course, and typically present with hepatomegaly and growth retardation early in childhood. Mild hypoglycemia, hyperlipidemia, and hyperketosis may occur. Lactic acid and uric acid levels may be normal. However, lactic acidosis may occur during fasting.	[ { "begin": 0, "class": "SectionAnnotation", "length": 286, "sectionHeading": "Signs/symptoms", "sectionLabel": "disease.symptom" } ]
https://en.wikipedia.org/wiki/Guanidinoacetate_methyltransferase_deficiency	disease	Guanidinoacetate methyltransferase deficiency	Guanidinoacetate methyltransferase deficiency, also called GAMT deficiency, is an autosomal recessive metabolic disorder that primarily affects the nervous system and muscles. It is the first observed disorder of creatine metabolism.	This disorder usually appears in the first few months of life, when development of new motor and cognitive skills becomes delayed or stops. Eventually, affected children may lose previously acquired skills such as head control or the ability to sit unsupported. Mutations in the GAMT gene are associated with guanidinoacetate methyltransferase deficiency. This gene codes for the enzyme guanidinoacetate methyltransferase, which participates in the two-step synthesis of the compound creatine from amino acids glycine, arginine and methionine. Specifically, guanidinoacetate methyltransferase controls the second step of the sequence, in which creatine is produced from another compound called guanidinoacetate. GAMT gene mutations impair the ability of the guanidinoacetate methyltransferase enzyme to participate in creatine synthesis. Creatine is needed for many tissues in the body to be able to store and use energy properly. The effects of guanidinoacetate methyltransferase deficiency are most severe in organs and tissues that require large amounts of energy, such as the brain and muscles. This disorder is inherited in an autosomal recessive pattern, which means the defective gene is located on an autosome, and two copies of the gene - one from each parent - are required to inherit the disorder. The parents both carry one copy of the defective gene, but are usually not affected by the disorder. People with guanidinoacetate methyltransferase deficiency have a wide spectrum of neurological symptoms. In addition to developmental disability and muscle weakness, some children with this disorder experience seizures. They may also develop autistic behaviors that affect communication and social interaction. Some affected children exhibit certain involuntary movements such as tremors or facial tics. Guanidinoacetate methyltransferase deficiency is a very rare disorder. Only a few dozen affected individuals have been reported worldwide. Of these, approximately one third are of Portuguese origin. The treatment approaches focus to restore depleted brain creatine with creatine supplementation in pharmacologic doses. All patients are reported to benefit by this treatment, with improvements in muscular hypotonia, dyskinesia, social contact, alertness and behavior. Seizures appear to reduce more with dietary arginine restriction and ornithine supplementation. Despite treatment, none of the patients have been reported to return to completely normal developmental level.	[ { "begin": 0, "class": "SectionAnnotation", "length": 262, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 262, "class": "SectionAnnotation", "length": 1148, "sectionHeading": "Pathophysiology", "sectionLabel": "disease.pathophysiology" }, { "begin": 1410, "class": "SectionAnnotation", "length": 604, "sectionHeading": "Diagnosis", "sectionLabel": "disease.diagnosis" }, { "begin": 2014, "class": "SectionAnnotation", "length": 476, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" } ]
https://en.wikipedia.org/wiki/Endocrine_disease	disease	Endocrine disease	Endocrine diseases are disorders of the endocrine system. The branch of medicine associated with endocrine disorders is known as endocrinology.	Broadly speaking, endocrine disorders may be subdivided into three groups: 1. Endocrine gland hyposecretion (leading to hormone deficiency) 2. Endocrine gland hypersecretion (leading to hormone excess) 3. Tumours (benign or malignant) of endocrine glands Endocrine disorders are often quite complex, involving a mixed picture of hyposecretion and hypersecretion because of the feedback mechanisms involved in the endocrine system. For example, most forms of hyperthyroidism are associated with an excess of thyroid hormone and a low level of thyroid stimulating hormone. In endocrinology, medical emergencies include diabetic ketoacidosis, hyperosmolar hyperglycemic state, hypoglycemic coma, acute adrenocortical insufficiency, phaeochromocytoma crisis, hypercalcemic crisis, thyroid storm, myxoedema coma and pituitary apoplexy. Emergencies arising from decompensated pheochromocytomas or parathyroid adenomas are sometimes referred for emergency resection when aggressive medical therapies fail to control the patient's state, however the surgical risks are significant, especially blood pressure lability and the possibility of cardiovascular collapse after resection (due to a brutal drop in respectively catecholamines and calcium, which must be compensated with gradual normalization). It remains debated when emergency surgery is appropriate as opposed to urgent or elective surgery after continued attempts to stabilize the patient, notably in view of newer and more efficient medications and protocols.	[ { "begin": 0, "class": "SectionAnnotation", "length": 572, "sectionHeading": "Types of disease", "sectionLabel": "disease.classification" }, { "begin": 572, "class": "SectionAnnotation", "length": 942, "sectionHeading": "Endocrine emergencies", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Tracheoesophageal_fistula	disease	Tracheoesophageal fistula	A tracheoesophageal fistula (TEF, or TOF; see spelling differences) is an abnormal connection (fistula) between the esophagus and the trachea. TEF is a common congenital abnormality, but when occurring late in life is usually the sequela of surgical procedures such as a laryngectomy.	Tracheoesophageal fistula is suggested in a newborn by copious salivation associated with choking, coughing, vomiting, and cyanosis coincident with the onset of feeding. Esophageal atresia and the subsequent inability to swallow typically cause polyhydramnios in utero. Rarely it may present in an adult. Congenital TEF can arise due to failed fusion of the tracheoesophageal ridges after the fourth week of embryological development. A fistula, from the Latin meaning 'a pipe', is an abnormal connection running either between two tubes or between a tube and a surface. In tracheo-esophageal fistula it runs between the trachea and the esophagus. This connection may or may not have a central cavity; if it does, then food within the esophagus may pass into the trachea (and on to the lungs) or alternatively, air in the trachea may cross into the esophagus. TEF can also occur due to pressure necrosis by a tracheostomy tube in apposition to a nasogastric tube (NGT). Fistulae between the trachea and esophagus in the newborn can be of diverse morphology and anatomical location; however, various pediatric surgical publications have attempted a classification system based on the below specified types. Not all types include both esophageal agenesis and tracheoesophageal fistula, but the most common types do. The letter codes are usually associated with the system used by Gross, while number codes are usually associated with Vogt. An additional type, "blind upper segment only" has been described, but this type is not usually included in most classifications. It is surgically corrected, with resection of any fistula and anastomosis of any discontinuous segments. Surgical repair can sometimes result in complications, including: - Stricture, due to gastric acid erosion of the shortened esophagus - Leak of contents at the point of anastomosis - Recurrence of fistula - Gastro-esophageal reflux disease - Dysphagia - Asthma-like symptoms, such as persistent coughing/wheezing - Recurrent chest infections - Tracheomalacia Neonates with TEF or esophageal atresia are unable to feed properly. Once diagnosed, prompt surgery is required to allow the food intake. Some children do experience problems following TEF surgery; they can develop dysphagia and thoracic problems. Children with TEF can also be born with other abnormalities, most commonly those described in VACTERL association - a group of anomalies which often occur together, including heart, kidney and limb deformities. 6% of babies with TEF also have a laryngeal cleft.	[ { "begin": 0, "class": "SectionAnnotation", "length": 305, "sectionHeading": "Presentation", "sectionLabel": "disease.symptom" }, { "begin": 305, "class": "SectionAnnotation", "length": 665, "sectionHeading": "Causes", "sectionLabel": "disease.cause" }, { "begin": 970, "class": "SectionAnnotation", "length": 598, "sectionHeading": "Diagnosis \| Classification", "sectionLabel": "disease.classification" }, { "begin": 1568, "class": "SectionAnnotation", "length": 106, "sectionHeading": "Treatment", "sectionLabel": "disease.treatment" }, { "begin": 1674, "class": "SectionAnnotation", "length": 359, "sectionHeading": "Complications", "sectionLabel": "disease.complication" }, { "begin": 2033, "class": "SectionAnnotation", "length": 510, "sectionHeading": "Associations", "sectionLabel": "disease.other" } ]
https://en.wikipedia.org/wiki/Personality_disorder	disease	Personality disorder	Personality disorders (PD) are a class of mental disorders characterized by enduring maladaptive patterns of behavior, cognition, and inner experience, exhibited across many contexts and deviating markedly from those accepted by the individual's culture. These patterns develop early, are inflexible, and are associated with significant distress or disability. The definitions may vary somewhat, according to source. Official criteria for diagnosing personality disorders are listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and the of the International Classification of Diseases (ICD). The DSM-5 lists personality disorders in the same way as other mental disorders, rather than on a separate 'axis', as previously. Personality, defined psychologically, is the set of enduring behavioral and mental traits that distinguish between individual humans. Hence, personality disorders are defined by experiences and behaviors that differ from societal norms and expectations. Those diagnosed with a personality disorder may experience difficulties in cognition, emotiveness, interpersonal functioning, or impulse control. In general, personality disorders are diagnosed in 40–60% of psychiatric patients, making them the most frequent of psychiatric diagnoses. Personality disorders are characterized by an enduring collection of behavioral patterns often associated with considerable personal, social, and occupational disruption. Personality disorders are also inflexible and pervasive across many situations, largely due to the fact that such behavior may be ego-syntonic (i.e. the patterns are consistent with the ego integrity of the individual) and are therefore perceived to be appropriate by that individual. This behavior can result in maladaptive coping skills and may lead to personal problems that induce extreme anxiety, distress, or depression. These behaviour patterns are typically recognized in adolescence, the beginning of adulthood or sometimes even childhood and often have a pervasive negative impact on the quality of life. Many issues occur with classifying a personality disorder. Because the theory and diagnosis of personality disorders occur within prevailing cultural expectations, their validity is contested by some experts on the basis of inevitable subjectivity. They argue that the theory and diagnosis of personality disorders are based strictly on social, or even sociopolitical and economic considerations.	The two major systems of classification are the ICD-10 published by the World Health Organization and the DSM-5 by the American Psychiatric Association. Both have deliberately merged their diagnoses to some extent, but some differences remain. For example, ICD-10 does not include narcissistic personality disorder as a distinct category, while DSM-5 does not include enduring personality change after catastrophic experience or after psychiatric illness. ICD-10 classifies the DSM-5 schizotypal personality disorder as a form of schizophrenia rather than as a personality disorder. There are accepted diagnostic issues and controversies with regard to distinguishing particular personality disorder categories from each other. Both diagnostic systems provide a definition and six criteria for a general personality disorder. These criteria should be met by all personality disorder cases before a more specific diagnosis can be made. The ICD-10 lists these general guideline criteria: - Markedly disharmonious attitudes and behavior, generally involving several areas of functioning; e.g. affectivity, arousal, impulse control, ways of perceiving and thinking, and style of relating to others; - The abnormal behavior pattern is enduring, of long standing, and not limited to episodes of mental illness; - The abnormal behavior pattern is pervasive and clearly maladaptive to a broad range of personal and social situations; - The above manifestations always appear during childhood or adolescence and continue into adulthood; - The disorder leads to considerable personal distress but this may only become apparent late in its course; - The disorder is usually, but not invariably, associated with significant problems in occupational and social performance. The ICD adds: "For different cultures it may be necessary to develop specific sets of criteria with regard to social norms, rules and obligations." In DSM-5, any personality disorder diagnosis must meet the following criteria: - An enduring pattern of inner experience and behavior that deviates markedly from the expectations of the individual’s culture. This pattern is manifested in two (or more) of the following areas: 1. Cognition (i.e., ways of perceiving and interpreting self, other people, and events). 2. Affectivity (i.e., the range, intensity, lability, and appropriateness of emotional response). 3. Interpersonal functioning. 4. Impulse control. - The enduring pattern is inflexible and pervasive across a broad range of personal and social situations. - The enduring pattern leads to clinically significant distress or impairment in social, occupational, or other important areas of functioning. - The pattern is stable and of long duration, and its onset can be traced back at least to adolescence or early adulthood. - The enduring pattern is not better explained as a manifestation or consequence of another mental disorder. - The enduring pattern is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., head trauma). in the ICD-10 contains the mental and behavioral disorders and includes categories of personality disorder and enduring personality changes. They are defined as ingrained patterns indicated by inflexible and disabling responses that significantly differ from how the average person in the culture perceives, thinks, and feels, particularly in relating to others. The specific personality disorders are: paranoid, schizoid, dissocial, emotionally unstable (borderline type and impulsive type), histrionic, anankastic, anxious (avoidant) and dependent. Besides the ten specific PD, there are the following categories: - Other specific personality disorders (involves PD characterized as eccentric, haltlose, immature, narcissistic, passive–aggressive, or psychoneurotic.) - Personality disorder, unspecified (includes "character neurosis" and "pathological personality"). - Mixed and other personality disorders (defined as conditions that are often troublesome but do not demonstrate the specific pattern of symptoms in the named disorders). - Enduring personality changes, not attributable to brain damage and disease (this is for conditions that seem to arise in adults without a diagnosis of personality disorder, following catastrophic or prolonged stress or other psychiatric illness). In the proposed revision of ICD-11, all discrete personality disorder diagnoses will be removed and replaced by the single diagnosis "personality disorder". Instead, there will be specifiers called "prominent personality traits" and the possibility to classify degrees of severity ranging from "mild", "moderate", and "severe" based on the dysfunction in interpersonal relationships and everyday life of the patient. The most recent fifth edition of the Diagnostic and Statistical Manual of Mental Disorders stresses that a personality disorder is an enduring and inflexible pattern of long duration that leads to significant distress or impairment and is not due to use of substances or another medical condition. DSM-5 lists ten specific personality disorders: paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dependent and obsessive-compulsive personality disorder. The DSM-5 also contains three diagnoses for personality patterns that do not match these ten disorders, but nevertheless exhibit characteristics of a personality disorder: - Personality change due to another medical condition – a personality disturbance due to the direct effects of a medical condition. - Other specified personality disorder – general criteria for a personality disorder are met but fails to meet the criteria for a specific disorder, with the reason given. - Unspecified personality disorder – general criteria for a personality disorder are met but the personality disorder is not included in the DSM-5 classification. The specific personality disorders are grouped into the following three clusters based on descriptive similarities: Cluster A personality disorders are often associated with schizophrenia: in particular, schizotypal personality disorder shares some of its hallmark symptoms, e.g., acute discomfort in close relationships, cognitive or perceptual distortions, and eccentricities of behavior, with schizophrenia. However, people diagnosed with odd-eccentric personality disorders tend to have a greater grasp on reality than do those diagnosed with schizophrenia. Patients suffering from these disorders can be paranoid and have difficulty being understood by others, as they typically have odd or eccentric modes of speaking and an unwillingness and inability to form and maintain close relationships. Though their perceptions may be unusual, it is important to distinguish these anomalies from delusions or hallucinations as people suffering from these would be diagnosed with other conditions. There is significant evidence that suggests that a small proportion of people with Type A personality disorders, especially schizotypal personality disorder, have the potential to develop schizophrenia and other psychotic disorders. These disorders also have a higher probability of occurring among individuals whose first-degree relatives have either schizophrenia or a Cluster A personality disorder. - Paranoid personality disorder: characterized by a pattern of irrational suspicion and mistrust of others, interpreting motivations as malevolent. - Schizoid personality disorder: lack of interest and detachment from social relationships, apathy, and restricted emotional expression. - Schizotypal personality disorder: a pattern of extreme discomfort interacting socially, and distorted cognitions and perceptions. Some types of personality disorder were in previous versions of the diagnostic manuals but have been deleted. Examples include sadistic personality disorder (a pervasive pattern of cruel, demeaning, and aggressive behavior) and self-defeating personality disorder or masochistic personality disorder (characterised by behaviour consequently undermining the person's pleasure and goals). They were listed in the DSM-III-R appendix as "Proposed diagnostic categories needing further study" without specific criteria. The psychologist Theodore Millon and others consider some relegated diagnoses to be equally valid disorders, and may also propose other personality disorders or subtypes, including mixtures of aspects of different categories of the officially accepted diagnoses. Psychologist Theodore Millon, who has written numerous popular works on personality, proposed the following description of personality disorders: In addition to classifying by category and cluster, it is possible to classify personality disorders using additional factors such as severity, impact on social functioning, and attribution. This involves both the notion of personality difficulty as a measure of subthreshold scores for personality disorder using standard interviews and the evidence that those with the most severe personality disorders demonstrate a “ripple effect” of personality disturbance across the whole range of mental disorders. In addition to subthreshold (personality difficulty) and single cluster (simple personality disorder), this also derives complex or diffuse personality disorder (two or more clusters of personality disorder present) and can also derive severe personality disorder for those of greatest risk. There are several advantages to classifying personality disorder by severity: - It not only allows for but also takes advantage of the tendency for personality disorders to be comorbid with each other. - It represents the influence of personality disorder on clinical outcome more satisfactorily than the simple dichotomous system of no personality disorder versus personality disorder. - This system accommodates the new diagnosis of severe personality disorder, particularly "dangerous and severe personality disorder" (DSPD). Social function is affected by many other aspects of mental functioning apart from that of personality. However, whenever there is persistently impaired social functioning in conditions in which it would normally not be expected, the evidence suggests that this is more likely to be created by personality abnormality than by other clinical variables. The Personality Assessment Schedule gives social function priority in creating a hierarchy in which the personality disorder creating the greater social dysfunction is given primacy over others in a subsequent description of personality disorder. Many who have a personality disorder do not recognize any abnormality and defend valiantly their continued occupancy of their personality role. This group have been termed the Type R, or treatment-resisting personality disorders, as opposed to the Type S or treatment-seeking ones, who are keen on altering their personality disorders and sometimes clamor for treatment. The classification of 68 personality disordered patients on the caseload of an assertive community team using a simple scale showed a 3 to 1 ratio between Type R and Type S personality disorders with Cluster C personality disorders being significantly more likely to be Type S, and paranoid and schizoid (Cluster A) personality disorders significantly more likely to be Type R than others. It is generally assumed that all personality disorders are linked to impaired functioning and a reduced quality of life (QoL) because that is a basic diagnostic requirement. But research shows that this may be true only for some types of personality disorder. In several studies, higher disability and lower QoL were predicted by avoidant, dependent, schizoid, paranoid, schizotypal and antisocial personality disorder. This link is particurlarly strong for avoidant, schizotypal and borderline PD. However, obsessive-compulsive PD was not related to a compromised QoL or dysfunction. A prospective study reported that all PD were associated with significant impairment 15 years later, except for obsessive compulsive and narcissistic personality disorder. One study investigated some aspects of "life success" (status, wealth and successful intimate relationships). It showed somewhat poor functioning for schizotypal, antisocial, borderline and dependent PD, schizoid PD had the lowest scores regarding these variables. Paranoid, histrionic and avoidant PD were average. Narcissistic and obsessive compulsive PD, however, had high functioning and appeared to contribute rather positively to these aspects of life success. There is also a direct relationship between the number of diagnostic criteria and quality of life. For each additional personality disorder criteron that a person meets there is an even reduction in quality of life. Depending on the diagnosis, severity and individual, and the job itself, personality disorders can be associated with difficulty coping with work or the workplace—potentially leading to problems with others by interfering with interpersonal relationships. Indirect effects also play a role; for example, impaired educational progress or complications outside of work, such as substance abuse and co-morbid mental disorders, can plague sufferers. However, personality disorders can also bring about above-average work abilities by increasing competitive drive or causing the sufferer to exploit his or her co-workers. In 2005 and again in 2009, psychologists Belinda Board and Katarina Fritzon at the University of Surrey, UK, interviewed and gave personality tests to high-level British executives and compared their profiles with those of criminal psychiatric patients at Broadmoor Hospital in the UK. They found that three out of eleven personality disorders were actually more common in executives than in the disturbed criminals: - Histrionic personality disorder: including superficial charm, insincerity, egocentricity and manipulation - Narcissistic personality disorder: including grandiosity, self-focused lack of empathy for others, exploitativeness and independence. - Obsessive-compulsive personality disorder: including perfectionism, excessive devotion to work, rigidity, stubbornness and dictatorial tendencies. According to leadership academic Manfred F.R. Kets de Vries, it seems almost inevitable that some personality disorders will be present in a senior management team. Early stages and preliminary forms of personality disorders need a multi-dimensional and early treatment approach. Personality development disorder is considered to be a childhood risk factor or early stage of a later personality disorder in adulthood. In addition, in Robert F. Krueger's review of their research indicates that some children and adolescents do suffer from clinically significant syndromes that resemble adult personality disorders, and that these syndromes have meaningful correlates and are consequential. Much of this research has been framed by the adult personality disorder constructs from Axis II of the Diagnostic and Statistical Manual. Hence, they are less likely to encounter the first risk they described at the outset of their review: clinicians and researchers are not simply avoiding use of the PD construct in youth. However, they may encounter the second risk they described: under-appreciation of the developmental context in which these syndromes occur. That is, although PD constructs show continuity over time, they are probabilistic predictors; not all youths who exhibit PD symptomatology become adult PD cases. The disorders in each of the three clusters may share with each other underlying common vulnerability factors involving cognition, affect and impulse control, and behavioral maintenance or inhibition, respectively. But they may also have a spectrum relationship to certain syndromal mental disorders: - Paranoid, schizoid or schizotypal personality disorders may be observed to be premorbid antecedents of delusional disorders or schizophrenia. - Borderline personality disorder is seen in association with mood and anxiety disorders, with impulse control disorders, eating disorders, ADHD, or a substance use disorder. It is sometimes seen as a mild form of bipolar disorder. - Avoidant personality disorder is seen with social anxiety disorder. The issue of the relationship between normal personality and personality disorders is one of the important issues in personality and clinical psychology. The personality disorders classification (DSM 5 and ICD-10) follows a categorical approach that views personality disorders as discrete entities that are distinct from each other and from normal personality. In contrast, the dimensional approach is an alternative approach that personality disorders represent maladaptive extensions of the same traits that describe normal personality. Thomas Widiger and his collaborators have contributed to this debate significantly. He discussed the constraints of the categorical approach and argued for the dimensional approach to the personality disorders. Specifically, he proposed the Five Factor Model of personality as an alternative to the classification of personality disorders. For example, this view specifies that Borderline Personality Disorder can be understood as a combination of emotional lability (i.e., high neuroticism), impulsivity (i.e., low conscientiousness), and hostility (i.e., low agreeableness). Many studies across cultures have explored the relationship between personality disorders and the Five Factor Model. This research has demonstrated that personality disorders largely correlate in expected ways with measures of the Five Factor Model and has set the stage for including the Five Factor Model within DSM-5. In clinical practice, individuals are generally diagnosed by an interview with a psychiatrist based on a mental status examination, which may take into account observations by relatives and others. One tool of diagnosing personality disorders is a process involving interviews with scoring systems. The patient is asked to answer questions, and depending on their answers, the trained interviewer tries to code what their responses were. This process is fairly time consuming. Abbreviations used: PPD – Paranoid Personality Disorder, SzPD – Schizoid Personality Disorder, StPD – Schizotypal Personality Disorder, ASPD – Antisocial Personality Disorder, BPD – Borderline Personality Disorder, HPD – Histrionic Personality Disorder, NPD – Narcissistic Personality Disorder, AvPD – Avoidant Personality Disorder, DPD – Dependent Personality Disorder, OCPD – Obsessive-Compulsive Personality Disorder, PAPD – Passive-Aggressive Personality Disorder, DpPD – Depressive Personality Disorder, SDPD – Self-Defeating Personality Disorder, SaPD – Sadistic Personality Disorder, and n/a – not available. As of 2002, there were over fifty published studies relating the five factor model (FFM) to personality disorders. Since that time, quite a number of additional studies have expanded on this research base and provided further empirical support for understanding the DSM personality disorders in terms of the FFM domains. In her seminal review of the personality disorder literature published in 2007, Lee Anna Clark asserted that "the five-factor model of personality is widely accepted as representing the higher-order structure of both normal and abnormal personality traits". The five factor model has been shown to significantly predict all 10 personality disorder symptoms and outperform the Minnesota Multiphasic Personality Inventory (MMPI) in the prediction of borderline, avoidant, and dependent personality disorder symptoms. Research results examining the relationships between the FFM and each of the ten DSM personality disorder diagnostic categories are widely available. For example, in a study published in 2003 titled "The five-factor model and personality disorder empirical literature: A meta-analytic review", the authors analyzed data from 15 other studies to determine how personality disorders are different and similar, respectively, with regard to underlying personality traits. In terms of how personality disorders differ, the results showed that each disorder displays a FFM profile that is meaningful and predictable given its unique diagnostic criteria. With regard to their similarities, the findings revealed that the most prominent and consistent personality dimensions underlying a large number of the personality disorders are positive associations with neuroticism and negative associations with agreeableness. At least three aspects of openness to experience are relevant to understanding personality disorders: cognitive distortions, lack of insight and impulsivity. Problems related to high openness that can cause problems with social or professional functioning are excessive fantasising, peculiar thinking, diffuse identity, unstable goals and nonconformity with the demands of the society. High openness is characteristic to schizotypal personality disorder (odd and fragmented thinking), narcissistic personality disorder (excessive self-valuation) and paranoid personality disorder (sensitivity to external hostility). Lack of insight (shows low openness) is characteristic to all personality disorders and could explain the persistence of maladaptive behavioral patterns. The problems associated with low openness are difficulties adapting to change, low tolerance for different worldviews or lifestyles, emotional flattening, alexithymia and a narrow range of interests. Rigidity is the most obvious aspect of (low) openness among personality disorders and that shows lack of knowledge of one's emotional experiences. It is most characteristic of obsessive-compulsive personality disorder; the opposite of it known as impulsivity (here: an aspect of openness that shows a tendency to behave unusually or autistically) is characteristic of schizotypal and borderline personality disorders. Currently, there are no definitive proven causes for personality disorders. However, there are numerous possible causes and known risk factors supported by scientific research that vary depending on the disorder, the individual, and the circumstance. Overall, findings show that genetic disposition and life experiences, such as trauma and abuse, play a key role in the development of personality disorders. Child abuse and neglect consistently show up as risk factors to the development of personality disorders in adulthood. A study looked at retrospective reports of abuse of participants that had demonstrated psychopathology throughout their life and were later found to have past experience with abuse. In a study of 793 mothers and children, researchers asked mothers if they had screamed at their children, and told them that they did not love them or threatened to send them away. Children who had experienced such verbal abuse were three times as likely as other children (who did not experience such verbal abuse) to have borderline, narcissistic, obsessive-compulsive or paranoid personality disorders in adulthood. The sexually abused group demonstrated the most consistently elevated patterns of psychopathology. Officially verified physical abuse showed an extremely strong correlation with the development of antisocial and impulsive behavior. On the other hand, cases of abuse of the neglectful type that created childhood pathology were found to be subject to partial remission in adulthood. Socioeconomic status has also been looked at as a potential cause for personality disorders. There is a strong association with low parental/neighborhood socioeconomic status and personality disorder symptoms. In a recent study comparing parental socioeconomic status and a child's personality, it was seen that children who were from higher socioeconomic backgrounds were more altuistic, less risk seeking, and had overall higher IQs. These traits correlate with a low risk of developing personality disorders later on in life. In a study looking at female children who were detained for disciplinary actions found that psychological problems were most negatively associated with socioeconomic problems. Furthermore, social disorganization was found to be inversely correlated with personality disorder symptoms. Evidence shows that personality disorders may begin with parental personality issues. These cause the parent to have their own difficulties in adulthood, such as difficulties reaching higher education, obtaining jobs, and securing dependable relationships. By either genetic or modeling mechanisms, children can pick up these traits. Additionally, poor parenting has been shown to have symptom elevating effects on personality disorders. More specifically, lack of maternal bonding has also been correlated with personality disorders. In a study comparing 100 healthy individuals to 100 borderline personality disorder patients, analysis showed that BPD patients were significantly more likely not to have been breastfed as a baby (42.4% in BPD vs. 9.2% in healthy controls). These researchers suggested that this act may be essential in fostering maternal relationships. Additionally, it has been found that personality disorders show a negative correlation with two attachment variables: maternal availability and dependability. When left unfostered, other attachment and interpersonal problems occur later in life ultimately leading to development of personality disorders. Currently, genetic research for the understanding of the development of personality disorders is severely lacking. However, there are a few possible risk factors currently in discovery. Researchers are currently looking into genetic mechanisms for traits such as aggression, fear and anxiety, which are associated with diagnosed individuals. More research is being conducted into disorder specific mechanisms. The prevalence of personality disorder in the general community was largely unknown until surveys starting from the 1990s. In 2008 the median rate of diagnosable PD was estimated at 10.6%, based on six major studies across three nations. This rate of around one in ten, especially as associated with high use of services, is described as a major public health concern requiring attention by researchers and clinicians. The prevalence of individual personality disorders ranges from about 2% to 3% for the more common varieties, such as schizotypal, antisocial, borderline, and histrionic, to 0.5–1% for the least common, such as narcissistic and avoidant. A screening survey across 13 countries by the World Health Organization using DSM-IV criteria, reported in 2009 a prevalence estimate of around 6% for personality disorders. The rate sometimes varied with demographic and socioeconomic factors, and functional impairment was partly explained by co-occurring mental disorders. In the US, screening data from the National Comorbidity Survey Replication between 2001 and 2003, combined with interviews of a subset of respondents, indicated a population prevalence of around 9% for personality disorders in total. Functional disability associated with the diagnoses appeared to be largely due to co-occurring mental disorders (Axis I in the DSM). A UK national epidemiological study (based on DSM-IV screening criteria), reclassified into levels of severity rather than just diagnosis, reported in 2010 that the majority of people show some personality difficulties in one way or another (short of threshold for diagnosis), while the prevalence of the most complex and severe cases (including meeting criteria for multiple diagnoses in different clusters) was estimated at 1.3%. Even low levels of personality symptoms were associated with functional problems, but the most severely in need of services was a much smaller group. Personality disorders (especially Cluster A) are also very common among homeless people. There are some sex differences in the frequency of personality disorders which are shown in the table below. There is a considerable personality disorder diagnostic co-occurrence. Patients who meet the DSM-IV-TR diagnostic criteria for one personality disorder are likely to meet the diagnostic criteria for another. Diagnostic categories provide clear, vivid descriptions of discrete personality types but the personality structure of actual patients might be more accurately described by a constellation of maladaptive personality traits. Sites used DSM-III-R criterion sets. Data obtained for purposes of informing the development of the DSM-IV-TR personality disorder diagnostic criteria. Abbreviations used: PPD – Paranoid Personality Disorder, SzPD – Schizoid Personality Disorder, StPD – Schizotypal Personality Disorder, ASPD – Antisocial Personality Disorder, BPD – Borderline Personality Disorder, HPD – Histrionic Personality Disorder, NPD – Narcissistic Personality Disorder, AvPD – Avoidant Personality Disorder, DPD – Dependent Personality Disorder, OCPD – Obsessive-Compulsive Personality Disorder, PAPD – Passive-Aggressive Personality Disorder. There are many different forms (modalities) of treatment used for personality disorders: - Individual psychotherapy has been a mainstay of treatment. There are long-term and short-term (brief) forms. - Family therapy, including couples therapy. - Group therapy for personality dysfunction is probably the second most used. - Psychological-education may be used as an addition. - Self-help groups may provide resources for personality disorders. - Psychiatric medications for treating symptoms of personality dysfunction or co-occurring conditions. - Milieu therapy, a kind of group-based residential approach, has a history of use in treating personality disorders, including therapeutic communities. - The practice of mindfulness that includes developing the ability to be nonjudgmentally aware of unpleasant emotions appears to be a promising clinical tool for managing different types of personality disorders. There are different specific theories or schools of therapy within many of these modalities. They may, for example, emphasize psychodynamic techniques, or cognitive or behavioral techniques. In clinical practice, many therapists use an 'eclectic' approach, taking elements of different schools as and when they seem to fit to an individual client. There is also often a focus on common themes that seem to be beneficial regardless of techniques, including attributes of the therapist (e.g. trustworthiness, competence, caring), processes afforded to the client (e.g. ability to express and confide difficulties and emotions), and the match between the two (e.g. aiming for mutual respect, trust and boundaries). The management and treatment of personality disorders can be a challenging and controversial area, for by definition the difficulties have been enduring and affect multiple areas of functioning. This often involves interpersonal issues, and there can be difficulties in seeking and obtaining help from organizations in the first place, as well as with establishing and maintaining a specific therapeutic relationship. On the one hand, an individual may not consider themselves to have a mental health problem, while on the other, community mental health services may view individuals with personality disorders as too complex or difficult, and may directly or indirectly exclude individuals with such diagnoses or associated behaviors. The disruptiveness that people with personality disorders can create in an organisation makes these, arguably, the most challenging conditions to manage. Apart from all these issues, an individual may not consider their personality to be disordered or the cause of problems. This perspective may be caused by the patient's ignorance or lack of insight into their own condition, an ego-syntonic perception of the problems with their personality that prevents them from experiencing it as being in conflict with their goals and self-image, or by the simple fact that there is no distinct or objective boundary between 'normal' and 'abnormal' personalities. Unfortunately, there is substantial social stigma and discrimination related to the diagnosis. The term 'personality disorder' encompasses a wide range of issues, each with a different level of severity or disability; thus, personality disorders can require fundamentally different approaches and understandings. To illustrate the scope of the matter, consider that while some disorders or individuals are characterized by continual social withdrawal and the shunning of relationships, others may cause fluctuations in forwardness. The extremes are worse still: at one extreme lie self-harm and self-neglect, while at another extreme some individuals may commit violence and crime. There can be other factors such as problematic substance use or dependency or behavioral addictions. A person may meet the criteria for multiple personality disorder diagnoses and/or other mental disorders, either at particular times or continually, thus making coordinated input from multiple services a potential requirement. Therapists in this area can become disheartened by lack of initial progress, or by apparent progress that then leads to setbacks. Clients may be perceived as negative, rejecting, demanding, aggressive or manipulative. This has been looked at in terms of both therapist and client; in terms of social skills, coping efforts, defense mechanisms, or deliberate strategies; and in terms of moral judgments or the need to consider underlying motivations for specific behaviors or conflicts. The vulnerabilities of a client, and indeed a therapist, may become lost behind actual or apparent strength and resilience. It is commonly stated that there is always a need to maintain appropriate professional personal boundaries, while allowing for emotional expression and therapeutic relationships. However, there can be difficulty acknowledging the different worlds and views that both the client and therapist may live with. A therapist may assume that the kinds of relationships and ways of interacting that make them feel safe and comfortable have the same effect on clients. As an example of one extreme, people who may have been exposed to hostility, deceptiveness, rejection, aggression or abuse in their lives, may in some cases be made confused, intimidated or suspicious by presentations of warmth, intimacy or positivity. On the other hand, reassurance, openness and clear communication are usually helpful and needed. It can take several months of sessions, and perhaps several stops and starts, to begin to develop a trusting relationship that can meaningfully address a client's issues. Before the 20th century Personality disorder is a term with a distinctly modern meaning, owing in part to its clinical usage and the institutional character of modern psychiatry. The currently accepted meaning must be understood in the context of historical changing classification systems such as DSM-IV and its predecessors. Although highly anachronistic, and ignoring radical differences in the character of subjectivity and social relations, some have suggested similarities to other concepts going back to at least the ancient Greeks. For example, the Greek philosopher Theophrastus described 29 'character' types that he saw as deviations from the norm, and similar views have been found in Asian, Arabic and Celtic cultures. A long-standing influence in the Western world was Galen's concept of personality types, which he linked to the four humours proposed by Hippocrates. Such views lasted into the 18th century, when experiments began to question the supposed biologically based humours and 'temperaments'. Psychological concepts of character and 'self' became widespread. In the 19th century, 'personality' referred to a person's conscious awareness of their behavior, a disorder of which could be linked to altered states such as dissociation. This sense of the term has been compared to the use of the term 'multiple personality disorder' in the first versions of the DSM. Physicians in the early 19th century started to diagnose forms of insanity that involved disturbed emotions and behaviors but seemingly without significant intellectual impairment or delusions or hallucinations. Philippe Pinel referred to this as 'manie sans délire' – mania without delusions – and described a number of cases mainly involving excessive or inexplicable anger or rage. James Cowles Prichard advanced a similar concept he called moral insanity, which would be used to diagnose patients for some decades. 'Moral' in this sense referred to affect (emotion or mood) rather than ethics, but it was arguably based in part on religious, social and moral beliefs, with a pessimism about medical intervention so that social control should take precedence. These categories were much different and broader than later definitions of personality disorder, while also being developed by some into a more specific meaning of moral degeneracy akin to later ideas about 'psychopaths'. Separately, Richard von Krafft-Ebing popularized the terms sadism and masochism, as well as homosexuality, as psychiatric issues. The German psychiatrist Koch sought to make the moral insanity concept more scientific, and in 1891 suggested the phrase 'psychopathic inferiority', theorized to be a congenital disorder. This referred to continual and rigid patterns of misconduct or dysfunction in the absence of apparent mental retardation or illness, supposedly without a moral judgment. Described as deeply rooted in his Christian faith, his work has been described as a fundamental text on personality disorders that is still of use today. 20th century In the early 20th century, another German psychiatrist, Emil Kraepelin, included a chapter on psychopathic inferiority in his influential work on clinical psychiatry for students and physicians. He suggested six types – excitable, unstable, eccentric, liar, swindler and quarrelsome. The categories were essentially defined by the most disordered criminal offenders observed, distinguished between criminals by impulse, professional criminals, and morbid vagabonds who wandered through life. Kraepelin also described three paranoid (meaning then delusional) disorders, resembling later concepts of schizophrenia, delusional disorder and paranoid personality disorder. A diagnostic term for the latter concept would be included in the DSM from 1952, and from 1980 the DSM would also include schizoid and schizotypal personality disorders; interpretations of earlier (1921) theories of Ernst Kretschmer led to a distinction between these and another type later included in the DSM, avoidant personality disorder. In 1933 Russian psychiatrist Pyotr Borisovich Gannushkin published his book Manifestations of psychopathies: statics, dynamics, systematic aspects, which was one of the first attempts to develop a detailed typology of psychopathies. Regarding maladaptation, ubiquity, and stability as the three main symptoms of behavioral pathology, he distinguished 9 clusters of psychopaths: cycloids (including constitutionally depressive, constitutionally excitable, cyclothymics, and emotionally labile), asthenics (including psychasthenics), schizoids (including dreamers), paranoiacs (including fanatics), epileptoids, hysterical personalities (including pathological liars), unstable psychopaths, antisocial psychopaths, and constitutionally stupid. Some elements of Gannushkin's typology were later incorporated into the theory developed by a Russian adolescent psychiatrist, Andrey Yevgenyevich Lichko, who was also interested in psychopathies along with their milder forms, the so-called accentuations of character. In 1939, psychiatrist David Henderson published a theory of 'psychopathic states' that contributed to popularly linking the term to anti-social behavior. Hervey M. Cleckley’s 1941 text, The Mask of Sanity, based on his personal categorization of similarities he noted in some prisoners, marked the start of the modern clinical conception of psychopathy and its popularist usage. Towards the mid 20th century, psychoanalytic theories were coming to the fore based on work from the turn of the century being popularized by Sigmund Freud and others. This included the concept of character disorders, which were seen as enduring problems linked not to specific symptoms but to pervasive internal conflicts or derailments of normal childhood development. These were typically understood as weaknesses of character or willful deviance, and were distinguished from neurosis or psychosis. The term 'borderline' stems from a belief that some individuals were functioning on the edge of those two categories, and a number of the other personality disorder categories were also heavily influenced by this approach, including dependent, obsessive-compulsive and histrionic, the latter starting off as a conversion symptom of hysteria particularly associated with women, then a hysterical personality, then renamed histrionic personality disorder in later versions of the DSM. A passive aggressive style was defined clinically by Colonel William Menninger during World War II in the context of men's reactions to military compliance, which would later be referenced as a personality disorder in the DSM. Otto Kernberg was influential with regard to the concepts of borderline and narcissistic personalities later incorporated in 1980 as disorders into the DSM. Meanwhile, a more general personality psychology had been developing in academia and to some extent clinically. Gordon Allport published theories of personality traits from the 1920s—and Henry Murray advanced a theory called personology, which influenced a later key advocate of personality disorders, Theodore Millon. Tests were developing or being applied for personality evaluation, including projective tests such as the Rorshach, as well as questionnaires such as the Minnesota Multiphasic Personality Inventory. Around mid-century, Hans Eysenck was analysing traits and personality types, and psychiatrist Kurt Schneider was popularising a clinical use in place of the previously more usual terms 'character', 'temperament' or 'constitution'. American psychiatrists officially recognised concepts of enduring personality disturbances in the first Diagnostic and Statistical Manual of Mental Disorders in the 1950s, which relied heavily on psychoanalytic concepts. Somewhat more neutral language was employed in the DSM-II in 1968, though the terms and descriptions had only a slight resemblance to current definitions. The DSM-III published in 1980 made some major changes, notably putting all personality disorders onto a second separate 'axis' along with mental retardation, intended to signify more enduring patterns, distinct from what were considered axis one mental disorders. 'Inadequate' and 'asthenic' personality disorder' categories were deleted, and others were expanded into more types, or changed from being personality disorders to regular disorders. Sociopathic personality disorder, which had been the term for psychopathy, was renamed Antisocial Personality Disorder. Most categories were given more specific 'operationalized' definitions, with standard criteria that psychiatrists could agree on in order to conduct research and diagnose patients. In the DSM-III revision, self-defeating personality disorder and sadistic personality disorder were included as provisional diagnoses requiring further study. They were dropped in the DSM-IV, though a proposed 'depressive personality disorder' was added; in addition, the official diagnosis of passive-aggressive personality disorder was dropped, tentatively renamed 'negativistic personality disorder.' International differences have been noted in how attitudes have developed towards the diagnosis of personality disorder. Kurt Schneider had argued that they were simply 'abnormal varieties of psychic life' and therefore not necessarily the domain of psychiatry, a view said to still have influence in Germany today. British psychiatrists have also been reluctant to address such disorders or consider them on par with other mental disorders, which has been attributed partly to resource pressures within the National Health Service, as well as to negative medical attitudes towards behaviors associated with personality disorders. In the US, the prevailing healthcare system and psychanalytic tradition has been said to provide a rationale for private therapists to diagnose some personality disorders more broadly and provide ongoing treatment for them.	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https://en.wikipedia.org/wiki/Neophobia	disease	Neophobia	Neophobia is the fear of anything new, especially a persistent and abnormal fear. In its milder form, it can manifest as the unwillingness to try new things or break from routine. In the context of children the term is generally used to indicate a tendency to reject unknown or novel foods. Food neophobia, as it may be referred to, is an important concern in pediatric psychology. In biomedical research, neophobia is often associated with the study of taste.	The word neophobia comes from the Greek νέος, neos, meaning "new, young", and φόβος, phobos, for "fear". Cainophobia comes from the Greek καινός, kainos, meaning "new, fresh". Alternative terms for neophobia include metathesiophobia, prosophobia, cainotophobia (or cainophobia), and kainophobia (or kainolophobia). Norway rats and house mice are thought to have evolved increased levels of neophobia as they became commensal with humans because humans were routinely devising new methods (e.g., mousetraps) to eradicate them. Neophobia is also a common finding in aging animals, although apathy could also explain, or contribute to explain, the lack of exploratory drive systematically observed in aging. Researchers argued that the lack of exploratory drive was likely due neurophysiologically to the dysfunction of neural pathways connected to the prefrontal cortex observed during aging. Robert Anton Wilson theorized in his book Prometheus Rising that neophobia is instinctual in people after they begin to raise children. Wilson's views on neophobia are mostly negative, believing that it is the reason human culture and ideas do not advance as quickly as our technology. His model includes an idea from Thomas Kuhn's The Structure of Scientific Revolutions, which is that new ideas, however well proven and evident, are implemented only when the generations who consider them "new" die and are replaced by generations who consider the ideas accepted and old. Food neophobia is the fear of eating new or unfamiliar foods. It differs from selective eating disorder. Food neophobia is particularly common in toddlers and young children. It is often related to an individual’s level of sensation-seeking, meaning a person's willingness to try new things and take risks. Not only do people with high food neophobia resist trying new food, they also rate new foods that they do try as lower than neophilics. It is very typical for people to generally have a fear of new things and to prefer things that are familiar and common. Most people experience food neophobia to a certain extent, though some people are more neophobic than others. A measure of individual differences in food neophobia is the Food Neophobia Scale (FNS), which consists of a 10-item survey that requires self-reported responses on a seven-point Likert scale. There is also a separate scale geared towards children called the Food Neophobia Scale for Children (FNSC), in which the parents actually do the reporting for the survey. Food neophobia relates to the omnivore's dilemma, a phenomenon that explains the choice that omnivores, and humans in particular, have between eating a new food and risking danger or avoiding it and potentially missing out on a valuable food source. Having at least some degree of food neophobia has been noted to be evolutionarily advantageous as it can help people to avoid eating potentially poisonous foods. Genetics seem to play a role in both food neophobia and general neophobia. Research shows that about two-thirds of the variation in food neophobia is due to genetics. A study done on twin pairs showed an even higher correlation, indicating that genetics does play a factor in food neophobia. Psychosocial factors can also increase a child's chances of developing food neophobia. Young children carefully watch parental food preferences, and this may produce neophobic tendencies with regard to eating if parents tend to avoid some foods. Another cause includes being more sensitive than average to bitter tastes, which may be associated with a significant history of middle ear infection or an increased perception of bitter foods, known as a supertaster. Sometimes food neophobia is more directly caused by an environmental occurrence. For example, with poison-induced neophobia, a food-poisoning experience can lead to people not only avoiding the flavor(s) they associate with creating their illness but also avoiding all novel flavors during the period directly following the poisoning experience. This can be seen as the body’s attempt to prevent any new and risky food items from entering the body. Besides food poisoning, food neophobia also arises from the person associating a negative experience with new foods, for example suffering from gastroenteritis or other gastrointestinal illnesses after eating undercooked food. Another environmental factor influencing levels of food neophobia is the current arousal level of the individual. Trying a new food is an arousing experience, and if the person prefers to maintain a lower arousal level in general, then he or she might avoid new foods as a method of managing his or her current arousal level. Also, if people are currently experiencing situations with a lot of novelty and are therefore more aroused, they might be reluctant to try new foods as doing so would increase their arousal level to an uncomfortable level. This example can help explain why Americans visiting a foreign country might be less likely to try a new food item and instead gravitate towards the familiar McDonald’s food. Some efforts to address this situation, such as pressuring the child to eat a disliked food or threatening punishment for not eating it, tend to exacerbate the problem. Effective solutions include offering non-food rewards, such as a small sticker, for tasting a new or disliked food, and for parents to model the behavior they want to see by cheerfully eating the new or disliked foods in front of the children. Exposing someone to a new food increases the chances of liking that food item. However, it is not enough to merely look at a new food. Novel food must be repeatedly tasted in order to increase preference for eating it. It can take as many as 15 tries of a novel food item before a child accepts it. There also appears to be a critical period for lowering later food neophobia in children during the weaning process. The variety of solid foods first exposed to children can lower later food refusal. Some researchers believe that even the food variety of a nursing mother and the consequent variety of flavors in her breastmilk can lead to greater acceptance of novel food items later on in life. Food neophobia does tend to naturally decrease as people age.	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