<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Torus palatinus and can you explain it in depth? [/INST] A torus palatinus (pl. tori palatini), or palatal torus (pl. palatal tori), is a bony protrusion on the palate. Palatal tori are usually present on the midline of the hard palate. Most palatal tori are less than 2 cm in diameter, but their size can change throughout life.

Types
Sometimes, the tori are categorized by their appearance. Arising as a broad base and a smooth surface, flat tori are located on the midline of the palate and extend symmetrically to either side. Spindle tori have a ridge located at their midline. Nodular tori have multiple bony growths that each have their own base. Lobular tori have multiple bony growths with a common base.

Cause
Although some research suggest palatal tori to be an autosomal dominant trait, it is generally believed that palatal tori are caused by several factors </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Gastrinoma and can you explain it in depth? [/INST] Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger–Ellison syndrome (ZES). A large number of gastrinomas develop in the pancreas or duodenum, with near-equal frequency, and approximately 10% arise as primary neoplasms in lymph nodes of the pancreaticoduodenal region (gastrinoma triangle).Most gastrinomas are sporadic (75–80%), whereas approximately 20–25% are associated with multiple endocrine neoplasia type 1 (MEN-1). Over 50% of gastrinomas are malignant and can metastasize to regional lymph nodes and liver. One fourth of gastrinomas are related to multiple endocrine neoplasia type 1, Zollinger–Ellison syndrome, peptic ulcer disease.

Signs and symptoms
Gastrinoma in the early stages will have signs and symptoms of indigestion or similar to irritable bowel disease (IBD) such as:

Hypergastrinemia
Refractory or recurrent peptic ulcers involving duodenum
Chronic diarrhea
Generalized cancer symptoms
Abdominal pain
Gastrointestinal bleeding
Obstruction of intestine
Weight loss/poor appetite
Anemia (Due to vitamin B12 malabsorption, and bleeding)
Hematemesis
Gastroesophageal reflux disease
Esophageal complications (Barretts esophagus, esophagitis, stricture formation)
Vomiting
Steatorrhea

Pathophysiology
Gastrin is secreted by the G cells. G cells are primarily found in the pyloric antrum but can also be found in the duodenum and the pancreas. The primary function of gastrin is to induce the release of hydrochloric acid (HCl) from the parietal cells located in the fundus of the stomach. Parietal cells are responsible for hydrochloric (HCl) secretion along with intrinsic factor that binds to vitamin B12 and helps with its uptake in the terminal ileum. Other functions of gastrin include stimulating the growth of gastric mucosa and gastric motility and promoting gastric emptying. These mechanisms of the gastrointestinal tract (GIT) are up-regulated by the vagus nerve of the parasympathetic nervous system (PNS), which carries out the majority of its functions by the release of neurotransmitter Acetylcholine (Ach), and to a lesser extent gastrin releasing peptide (GRP) protein. On the contrary, the functions of GIT are down-regulated by the activation sympathetic nervous system (SNS), which carries out its functions mostly via neurotransmitter epinephrine.Meal consumption causes distention of the stomach, leading to stimulation of the parasympathetic vagus nerve in the gastric mucosa, which causes the release of GRP protein. In gastrinoma, GRP protein causes larger than normal amounts of gastrin secretion, which leads to hyperplasia of the parietal cells. Hyperplasia of parietal cells causes an abnormal release of HCl into the duodenum, which causes the ulcers of the duodenum. Excessive HCl production also causes hyperperistalsis, a condition marked by excessive rapidity of the passage of food through the stomach and intestine and inhibits the activity of lipase, causing severe fatty diarrhea known as steatorrhea. Evenly the long-standing hyper-secretion of gastrin stimulate proliferation of the enterochromaffin like cells (ECL). These cells are found along the side the gastric lumen of the digestive tract. They play a main role in regulation of gastric secretion and motility when stimulated by nervous system. These cells in return will undergo progressive dysplastic changes starting with hyperplasia to neoplasia throughout the gastrointestinal tract.

Diagnosis
In many cases, gastrinoma is diagnosed based on the patients history which is typically characterized by recurrent episodes of peptic ulcer disease or by severe reflux esophagitis and/or diarrhea or by acid-related symptoms which fail to respond to standard treatment regimens. To confirm the diagnosis of gastrinoma a series of blood tests must be made. One of those tests is the serum gastrin level, which is the most reliable test for patients with gastrinoma. The normal levels of gastrin are 150 pg/mL ( > 72.15 pmol/L); therefore elevated levels of > 1000 pg/mL (> 480 pmol/L) would establish the diagnosis of gastrinoma.  Another test that can be conducted is the secretin stimulated test, which is useful in patients who have the sign and symptoms of gastrinoma but the gastrin levels are below < 1000 pg/mL. Usually, an Intravenous bolus consisting of secretin 2mcg/kg and is measured in 10 minute intervals up to 30 minutes total. Secretin, which is a hormone released from the duodenal S cells that induce the release of pancreatic bicarbonate (HCO3) that would neutralize the acidic environment due to high gastrin levels. Therefore, if the patients level of gastrin remains consistently high indicating gastrin release due to tumor such as gastrinoma.Other commonly used tests to further confirm the diagnosis are

CT scan of the abdominal area
Somatostatin receptor scintigraphy which is used to identify the location of the tumor
PET scan
Endoscopic ultrasound if there are no signs of tumor metastases.

Treatment
Surgery is first line treatment in gastrinomas; however it often fails to be curative.
Proton-pump inhibitors such as omeprazole. This group of medications suppress the acid secretion.
H2-receptor antagonist similarly decrease acid secretion.
Octreotide injections directly release somatostatin hormone that inhibits gastrin release.
Chemotherapy.

Prognosis
Patients with gastrinomas that are also known to be part of neuroendocrine neoplasms must have to deal with two factors related to this tumor. First, controlling the high amounts by using medications that inhibit gastrin levels. The second part is stabilizing the tumor progression. Gastrinomas have a rate of 60–90% that will become malignant. Patients who do not seek medical treatment such anti-ulcer medication have high rate of recurrence and death secondary to ulcer disease. The prognosis of gastrinoma depends on the level of metastases of the tumor. If patients present with hepatic metastases they might have remaining life span of one year with a five-year survival rate of 20–30%. In patients with localized tumor or localized lymph spread the survival rate of five years is 90% </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Centronuclear myopathy and can you explain it in depth? [/INST] Centronuclear myopathies (CNM) are a group of congenital myopathies where cell nuclei are abnormally located in the center of muscle cells instead of their normal location at the periphery.
Symptoms of CNM include severe hypotonia, hypoxia-requiring breathing assistance, and scaphocephaly. Among centronuclear myopathies, the X-linked myotubular myopathy form typically presents at birth, and is thus considered a congenital myopathy. However, some centronuclear myopathies may present later in life.

Presentation
As with other myopathies, the clinical manifestations of MTM/CNM are most notably muscle weakness and associated disabilities. Congenital forms often present with neonatal low muscle tone, severe weakness, delayed developmental milestones (particularly gross motor milestones such as head control, crawling, and walking) and pulmonary complications (presumably due to weakness of the muscles responsible for respiration). Involvement of the facial muscles may cause ophthalmoplegia or ptosis.  A mutation in the RYR1 gene causing CNM may also cause susceptibility to malignant hyperthermia, a potentially life-threatening reaction to anesthesia.  While some patients with centronuclear myopathies remain ambulatory throughout their adult life, others may never crawl or walk and may require wheelchair use for mobility. There is substantial variability in the degree of functional impairment among the various centronuclear myopathies. Although this condition only affects the voluntary muscles, several children have had cardiac arrest, possibly due to the additional stress placed on the heart.Other observed features have been high arched palate, long digits, bell shaped chest and long face. Myotubular myopathy only affects muscles and does not impact intelligence in any shape or form.X-linked myotubular myopathy was traditionally a fatal condition of infancy, with life expectancy of usually less than two years. There appears to be substantial variability in the clinical severity for different genetic abnormalities at that same MTM1 gene. Further, published cases show significant differences in clinical severity among relatives with the same genetic abnormality at the MTM1 gene. Most truncating mutations of MTM1 cause a severe and early lethal phenotype, while some missense mutations are associated with milder forms and prolonged survival (up to 54 years).Centronuclear myopathies typically have a milder presentation and a better prognosis. Autosomal dominant CNM tends to have a less severe phenotype than the autosomal recessive version.  Recently, researchers discovered mutations at the gene dynamin 2 (DNM2 on chromosome 19, at site 19p13.2), responsible for the autosomal dominant form of centronuclear myopathy. This condition is now known as dynamin 2 centronuclear myopathy (abbreviated DNM2-CNM). Research has indicated that patients with DNM2-CNM have a slowly progressive muscular weakness usually beginning in adolescence or early adulthood, with an age range of 12 to 74 years.

Genetic
The genetic abnormality associated with the X-linked form of myotubular myopathy (XLMTM) was first localized in 1990 to the X chromosome at site Xq28. MTM1 codes for the myotubularin protein, a highly conserved lipid phosphatase involved in cellular transport, trafficking and signalling. Approximately 80% of males with myotubular myopathy diagnosed by muscle biopsy have mutations in MTM1, and about 7% of these mutations are genetic deletions.Centronuclear myopathies where the genetic abnormality is NOT sex-linked (e.g., not located on the X chromosome) are considered autosomal. Autosomal abnormalities can either be dominant or recessive, and are often referred to as AD for "autosomal dominant" or AR for "autosomal recessive").Many researchers use the term "myotubular myopathy" (MTM) only for cases when the genetic test has come back positive for abnormalities (genetic mutations) at the MTM1 gene on the X chromosome. Cases with a centronuclear (nucleus in the center) appearance on muscle biopsy but a normal genetic test for MTM1 would be referred to as centronuclear myopathy until such time as a specific genetic site is identified to give a more detailed sub-classification.The possible combinations of inheritance of myotubular myopathy are as follows:

Sporadic cases have also been reported where there is no previous family history (these cases are presumably due to a new mutation that was not present in either parent).

Pathology
On examination of muscle biopsy material, the nuclear material is located predominantly in the center of the muscle cells, and is described as having any "myotubular" or "centronuclear" appearance. In terms of describing the muscle biopsy itself, "myotubular" or "centronuclear" are almost synonymous, and both terms point to the similar cellular-appearance among MTM and CNM. Thus, pathologists and treating physicians use those terms almost interchangeably, although researchers and clinicians are increasingly distinguishing between those phrases.In general, a clinical myopathy and a muscle biopsy showing a centronuclear (nucleus in the center of the muscle cell) appearance would indicate a centronuclear myopathy (CNM). The most commonly diagnosed CNM is myotubular myopathy (MTM). However, muscle biopsy analysis alone cannot reliably distinguish myotubular myopathy from other forms of centronuclear myopathies, and thus genetic testing is required.Diagnostic workup is often coordinated by a treating neurologist. In the United States, care is often coordinated through clinics affiliated with the Muscular Dystrophy Association.

Diagnosis
Electrodiagnostic testing
Electrodiagnostic testing (also called electrophysiologic) includes nerve conduction studies which involves stimulating a peripheral motor or sensory nerve and recording the response, and needle electromyography, where a thin needle or pin-like electrode is inserted into the muscle tissue to look for abnormal electrical activity.
Electrodiagnostic testing can help distinguish myopathies from neuropathies, which can help determine the course of further work-up. Most of the electrodiagnostic abnormalities seen in myopathies are also seen in neuropathies (nerve disorders). Electrodiagnostic abnormalities common to myopathies and neuropathies include; abnormal spontaneous activity (e.g., fibrillations, positive sharp waves, etc.) on needle EMG and, small amplitudes of the motor responses compound muscle action potential, or CMAP during nerve conduction studies. Many neuropathies, however, cause abnormalities of sensory nerve studies, whereas myopathies involve only the muscle, with normal sensory nerves. The most important factor distinguishing a myopathy from a neuropathy on needle EMG is the careful analysis of the motor unit action potential (MUAP) size, shape, and recruitment pattern.
There is substantial overlap between the electrodiagnostic findings the various types of myopathy. Thus, electrodiagnostic testing can help distinguish neuropathy from myopathy, but is not effective at distinguishing which specific myopathy is present, here muscle biopsy and perhaps subsequent genetic testing are required.

Treatment
Currently there is no cure for myotubular or centronuclear myopathies. Treatment often focuses on trying to maximize functional abilities and minimize medical complications, and involvement by physicians specializing in Physical Medicine and Rehabilitation, and by physical therapists and occupational therapists.Medical management generally involves efforts to prevent pulmonary complications, since lung infections can be fatal in patients lacking the muscle strength necessary to clear secretions via coughing. Medical devices to assist with coughing help patients maintain clear airways, avoiding mucous plugs and avoiding the need for tracheostomy tubes.Monitoring for scoliosis is also important, since weakness of the trunk muscles can lead to deviations in spinal alignment, with resultant compromise of respiratory function. Many patients with congenital myopathies may eventually require surgical treatment of scoliosis.

Epidemiology
The overall incidence of myotubular myopathy is 1 in 50,000 male live births. The incidence of other centronuclear myopathies is extremely rare, with there only being nineteen families identified with CNM throughout the world. The symptoms currently range from the majority who only need to walk with aids, from a stick to a walking frame, to total dependence on physical mobility aids such as wheelchairs and stand aids, but this latter variety is so rare that only two cases are known to the CNM "community".
Approximately 80% of males with a diagnosis of myotubular myopathy by muscle biopsy will have a mutation in MTM1 identifiable by genetic sequence analysis.Many patients with myotubular myopathy die in infancy prior to receiving a formal diagnosis. When possible, muscle biopsy and genetic testing may still be helpful even after a neonatal death, since the diagnostic information can assist with family planning and genetic counseling as well as aiding in the accurate diagnosis of any relatives who might also have the same genetic abnormality.

History
In 1966, Dr. Spiro (a New York City neurologist) published a medical report of a boy with myopathy, which upon muscle biopsy, showed that the nuclei of the muscle cells were located in the center of the muscle cells, instead of their normal location of the periphery.
The nuclear appearance reminded him of the nucleus-in-the-center appearance during the "myotubular" stage of embryonic development. Thus, he coined the term "myotubular myopathy". Spiro speculated that the embryonic muscle development he had seen in the boy was due to growth arrest during the myotubular phase, causing the myopathy.More than three decades later, it is not fully understood whether this theory regarding halted (or delayed) embryonic muscle development is correct. Some research suggests that this theory may be acceptable for infant-onset myotubular myopathy (mutations at the MTM1 gene on the X chromosome) but may not be acceptable for the autosomal forms of centronuclear myopathy, while other research suggests that the growth arrest mechanism may be responsible for all forms of MTM and CNM.
Regardless of whether the myopathy is caused by arrest at the "myotubular" stage, for historical reasons the name myotubular myopathy persists and is widely accepted.As a reference to the term myotubular myopathy (MTM), when a genetic abnormality on the X chromosome was determined to be involved in a substantial percentage of individuals with the myotubular/centronuclear appearance on muscle biopsy, researchers named the gene segment MTM1. Similarly, the protein typically produced by that gene is called "myotubularin".

Advocacy
There are several global advocacy groups working closely to educate newly affected families on care guidelines </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Granular corneal dystrophy and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Urachal fistula and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Primary familial brain calcification and can you explain it in depth? [/INST] Primary Indiana familial brain calcification (PFBC), also known as familial idiopathic basal ganglia calcification (FIBGC) and Fahrs disease, is a rare, genetically dominant, inherited neurological disorder characterized by abnormal deposits of calcium in areas of the brain that control movement. Through the use of CT scans, calcifications are seen primarily in the basal ganglia and in other areas such as the cerebral cortex.

Signs and symptoms
Symptoms of this disease include deterioration of motor functions and speech, seizures, and other involuntary movement. Other symptoms are headaches, dementia, and vision impairment.
Characteristics of Parkinsons Disease are also similar to PFBC.The disease usually manifests itself in the third to fifth decade of life but may appear in childhood or later in life. It usually presents with clumsiness, fatigability, unsteady gait, slow or slurred speech, difficulty swallowing, involuntary movements or muscle cramping. Seizures of various types are common. Neuropsychiatric symptoms, which may be the first or the most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia.

Causes
This condition can be inherited in an autosomal dominant or recessive fashion. Several genes has been associated with this condition

Mutation
A locus at 14q has been suggested, but no gene has been identified. A second locus has been identified on chromosome 8 and a third has been reported on chromosome 2. This suggests there may be some genetic heterogeneity in this disease.A mutation in the gene encoding the type III sodium dependent phosphate transporter 2 (SLC20A2) located on chromosome 8 has been reported. Biochemical evidence suggests that phosphate transport may be involved in this disease.Two other genes have been associated with this condition: PDGFB on chromosome 22 and PDGFRB on chromosome 5. These genes are biochemically linked: PDGFRB encodes the platelet-derived growth factor receptor β and PDGFB encodes the ligand of PDGF-Rβ. These genes are active during angiogenesis to recruit pericytes which suggests that alterations in the blood brain barrier may be involved in the pathogenesis of this condition.A fourth gene associated with this condition is XPR1. This gene is the long arm of located on chromosome 1 (1q25.3).Another gene that has been associated with this condition is MYORG. This gene is located on the long arm of chromosome 9 (9p13.3). This gene is associated with an autosomal recessive inheritance pattern in this condition.Another gene junctional adhesion molecule 2 (JAM2) has been associated with an autosomal recessive form of this condition. Other genes that have been associated with this condition are Junctional adhesion molecule C (JAM3) and Occludin (OCLN).

Pathology
The most commonly affected region of the brain is the lenticular nucleus and in particular the internal globus pallidus. Calcifications in the caudate, dentate nuclei, putamen and thalami are also common. Occasionally calcifications begin or predominate in regions outside the basal ganglia.Calcification seems to be progressive, since calcifications are generally more extensive in older individuals and an increase in calcification can sometimes be documented on follow up of affected subjects.As well as the usual sites the cerebellar gyri, brain stem, centrum semiovale and subcortical white matter may also be affected. Diffuse atrophic changes with dilatation of the subarachnoid space and/or ventricular system may coexist with the calcifications. Histologically concentric calcium deposits within the walls of small and medium-sized arteries are present. Less frequently the veins may also be affected. Droplet calcifications can be observed along capillaries. These deposits may eventually lead to closure of the lumina of vessels.The pallidal deposits stain positively for iron. Diffuse gliosis may surround the large deposits but significant loss of nerve cells is rare. On electron microscopy the mineral deposits appear as amorphous or crystalline material surrounded by a basal membrane. Calcium granules are seen within the cytoplasm of neuronal and glial cells. The calcifications seen in this condition are indistinguishable from those secondary to hypoparathyroidism or other causes.

Diagnosis
In addition to the usual routine haematologic and biochemical investigations, the serum calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin and parathyroid hormone should also be measured. The cerebrospinal fluid (CSF) should be examined to exclude bacteria, viruses and parasites </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Supernumerary kidney and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Polyonychia and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hyperprolinemia and can you explain it in depth? [/INST] Hyperprolinemia is a condition which occurs when the amino acid proline is not broken down properly by the enzymes proline oxidase or pyrroline-5-carboxylate dehydrogenase, causing a buildup of proline in the body.

Genetics
Mutations in the ALDH4A1 and PRODH genes cause hyperprolinemia.Hyperprolinemia type I is caused by a mutation in the PRODH gene, which codes for the enzyme proline oxidase </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Koro and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ectopic pancreas and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Posner–Schlossman syndrome and can you explain it in depth? [/INST] Posner–Schlossman syndrome (PSS) also known as glaucomatocyclitic crisis (GCC) is a rare acute ocular condition with unilateral attacks of mild granulomatous anterior uveitis and elevated intraocular pressure. It is sometimes considered as a secondary inflammatory glaucoma.

Signs and symptoms
Ocular hypertension (IOP 30 - 70 mmHg) with open angle of anterior chamber and unilateral mild granulomatous anterior uveitis are hallmark signs of Posner–Schlossman syndrome. On slit-lamp examination, conjunctival injections, epithelial corneal edema, small to medium-sized fine keratitic precipitates, aqueous cells and flare may also be noted. Blurring of vision, eye pain and discomfort are the main symptoms. Colored halos may occur due to elevated IOP. Symptoms last from several hours to weeks and may be recurrent. IOP and aqueous humor outflow return to normal in the remission periods.

Etiology
Exact etiology of PSS is unknown </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Couvelaire uterus and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Valve stenosis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Small-cell carcinoma and can you explain it in depth? [/INST] Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell carcinoma, small cell carcinoma has a shorter doubling time, higher growth fraction, and earlier development of metastases.
Extensive stage small cell lung cancer is classified as a rare disorder. Ten-year relative survival rate is 3.5%; however, women have a higher survival rate, 4.3%, and men lower, 2.8%. Survival can be higher or lower based on a combination of factors including stage, age, gender and race.

Types of SCLC
Small-cell lung carcinoma has long been divided into two clinicopathological stages, termed limited stage (LS) and extensive stage (ES). The stage is generally determined by the presence or absence of metastases, whether or not the tumor appears limited to the thorax, and whether or not the entire tumor burden within the chest can feasibly be encompassed within a single radiotherapy portal. In general, if the tumor is confined to one lung and the lymph nodes close to that lung, the cancer is said to be LS. If cancer has spread beyond that, it is said to be ES.

LS-SCLC
In cases of LS-SCLC, combination chemotherapy (usually cisplatin or carboplatin plus etoposide) is administered together with concurrent chest radiotherapy (RT).Chest RT has been shown to improve survival in LS-SCLC.Exceptionally high objective initial response rates (RR) of between 60% and 90% are seen in LS-SCLC using chemotherapy alone, with between 45% and 75% of individuals showing a "complete response" (CR), which is defined as the disappearance of all radiological and clinical signs of tumor. However, relapse rate remains high, and median survival is only 18 to 24 months.Because SCLC usually metastasizes widely very early on in the natural history of the tumor, and because nearly all cases respond dramatically to chemotherapy and/or radiotherapy, there has been little role for surgery in this disease since the 1970s. However, recent work suggests that in cases of small, asymptomatic, node-negative SCLCs ("very limited stage"), surgical excision may improve survival when used prior to chemotherapy ("adjuvant chemotherapy").

ES-SCLC
In ES-SCLC, platinum-based combination chemotherapy is the standard of care, with radiotherapy added only to palliate symptoms such as dyspnea, pain from liver or bone metastases, or for treatment of brain metastases, which, in small-cell lung carcinoma, typically have a rapid, if temporary, response to whole brain radiotherapy.Combination chemotherapy consists of a wide variety of agents, including cisplatin, cyclophosphamide, vincristine and carboplatin. Response rates are high even in extensive disease, with between 15% and 30% of subjects having a complete response to combination chemotherapy, and the vast majority having at least some objective response. Responses in ES-SCLC are often of short duration, and the evidence surrounding the risk of treatment compared to the potential benefit of chemotherapy for people who have extensive SCLC is not clear.If complete response to chemotherapy occurs in a subject with SCLC, then prophylactic cranial irradiation (PCI) is often used in an attempt to prevent the emergence of brain metastases. Although this treatment is often effective, it can cause hair loss and fatigue. Prospective randomized trials with almost two years of follow-up have not shown neurocognitive ill-effects. Meta-analyses of randomized trials confirm that PCI provides significant survival benefits.In August 2018, the FDA approved nivolumab to treat patients with metastatic small cell lung cancer (SCLC) who failed to respond to platinum-based chemotherapy and at least one other line of treatment. Nivolumab is approved in more than 60 countries. According to LUNGevity Foundation, “This approval marks a major milestone for the patients touched by this unrelenting disease and may motivate them to pursue further treatment where there previously were no other approved options.”In September 2018, the results from the global, randomized phase I/III IMpower 133 trial were announced at the World Congress on Lung Cancer in Toronto, ON. In this study, patients with ES-SCLC were treated with standard carboplatin plus etoposide and were randomized to receive atezolizumab or placebo. Atezolizumab was associated with a significant improvement in overall survival (HR for death = 0.70)

Signs and symptoms
Small-cell carcinoma of the lung usually presents in the central airways and infiltrates the submucosa leading to narrowing of bronchial airways. Common symptoms include cough, dyspnea, weight loss, and debility.  Over 70% of patients with small-cell carcinoma present with metastatic disease; common sites include liver, adrenals, bone, and brain.Due to its high grade neuroendocrine nature, small-cell carcinomas can produce ectopic hormones, including adrenocorticotropic hormone (ACTH) and anti-diuretic hormone (ADH). Ectopic production of large amounts of ADH leads to syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).Lambert–Eaton myasthenic syndrome (LEMS) is a well-known paraneoplastic condition linked to small-cell carcinoma.

Small-cell lung cancer
When associated with the lung, it is sometimes called "oat cell carcinoma" due to the flat cell shape and scanty cytoplasm. Caution is required when diagnosing SCLC because small cell mesothelioma – an extremely rare subtype of lung cancer – can be mistaken for small cell lung cancer.It is thought to originate from neuroendocrine cells (APUD cells) in the bronchus called Feyrter cells (named for Friedrich Feyrter).
Hence, they express a variety of neuroendocrine markers, and may lead to ectopic production of hormones like ADH and ACTH that may result in paraneoplastic syndromes and Cushings syndrome. Approximately half of all individuals diagnosed with Lambert–Eaton myasthenic syndrome (LEMS) will eventually be found to have a small-cell carcinoma of the lung.Small-cell carcinoma is most often more rapidly and widely metastatic than non-small-cell lung carcinoma (and hence staged differently).  There is usually early involvement of the hilar and mediastinal lymph nodes.
 The mechanisms of its metastatic progression are not well-understood.

Combined small-cell lung carcinoma (c-SCLC)
Small-cell lung carcinoma can occur in combination with a wide variety of other histological variants of lung cancer, including extremely complex malignant tissue admixtures.
When it is found with one or more differentiated forms of lung cancer, such as squamous cell carcinoma or adenocarcinoma, the malignant tumor is then diagnosed and classified as a combined small cell lung carcinoma (c-SCLC). C-SCLC is the only currently recognized subtype of SCLC.Although combined small-cell lung carcinoma is currently staged and treated similarly to "pure" small-cell carcinoma of the lung, recent research suggests surgery might improve outcomes in very early stages of this tumor type.Smoking is a significant risk factor. Symptoms and signs are as for other lung cancers. In addition, because of their neuroendocrine cell origin, small-cell carcinomas will often secrete substances that result in paraneoplastic syndromes such as Lambert–Eaton myasthenic syndrome.

Extrapulmonary small-cell carcinoma
Very rarely, the primary site for small-cell carcinoma is outside of the lungs and pleural space; in these cases, it is referred to as extrapulmonary small-cell carcinoma (EPSCC). Outside of the respiratory tract, small-cell carcinoma can appear in the cervix, prostate, liver, pancreas, gastrointestinal tract, or bladder. It is estimated to account for 1,000 new cases a year in the U.S. Histologically similar to small-cell lung cancer, therapies for small-cell lung cancer are usually used to treat EPSCC.  First-line treatment is usually with cisplatin and etoposide. In Japan, first-line treatment is shifting to irinotecan and cisplatin. When the primary site is in the skin, it is referred to as a Merkel-cell carcinoma.

Extrapulmonary small-cell carcinoma localized in the lymph nodes
This is an extremely rare type of small cell, and there has been little information in the scientific community. It appears to occur in only one or more lymph nodes, and nowhere else in the body. Treatment is similar to small cell lung cancer, but survival rates are much higher than other small-cell carcinomas.

Small-cell carcinoma of the prostate
Small-cell carcinoma of the prostate (SCCP) is a rare form of prostate cancer (approx. 1% of PC). Due to the fact that there is little variation in prostate specific antigen levels, SCCP is normally diagnosed at an advanced stage, after metastasis.
Symptomatic metastasis of SCCP to the brain is rare, and carries a poor prognosis.

Genetics
TP53 is mutated in 70 to 90% of SCLCs. RB1 and the retinoblastoma pathway are inactivated in most SCLCs. PTEN is mutated in 2 to 10%. MYC amplifications and amplification of MYC family members are found in 30% of SCLCs. Loss of heterozygocity on chromosome arm 3p is found in more than 80% of SCLCs, including the loss of FHIT. One hundred translocations have so far been reported in SCLCs (see the "Mitelman Database" and the Atlas of Genetics and Cytogenetics in Oncology and Haematology,).

Diagnosis
When

Localized: the cancer is confined to the lung (aka: limited stage SCLC).
Regional: the cancer has spread to lymph nodes (or glands) within the chest (between limited and extensive stage SCLC). Lymph nodes act as a filtering system outside the lung, collecting cancer cells that are beginning to migrate out of the lung.
Distant: the cancer has spread (or metastasized) to other parts of the body (aka: extensive stage SCLC).At the time of diagnosis, 60–70% of people already have metastases.Small-cell carcinoma is an undifferentiated neoplasm composed of primitive-appearing cells. As the name implies, the cells in small-cell carcinomas are smaller than normal cells, and barely have room for any cytoplasm. Some researchers identify this as a failure in the mechanism that controls the size of the cells.

Treatment
Small-cell lung cancer is most commonly treated with a combination of two drugs, which is more effective than one drug alone.

Chemotherapy
Cisplatin and etoposide,
Carboplatin and etoposide.

Cisplatin-resistance
The drug paclitaxel may be useful in the treatment of cisplatin-resistant cancer. About 68.1% of cisplatin-resistant cells
appear to be sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells to
cisplatin. The mechanism for this activity is unknown. Paclitaxel-based chemotherapy showed modest activity in SCLC patients refractory to both etoposide- and camptothecin-based chemotherapy. The newer agent lurbinectedin is active in relapsed SCLC and was approved for medical use in the United States in June 2020.

Immunotherapy
In 2018, the FDA approved two immunotherapies for small cell lung cancer:
1. Nivolumab (Opdivo), and
2. Atezolizumab (Tecentriq)

Funding controversy
Tecentriq treatment costs on average $13,200 per month, depending on the dosage schedule.
Despite updated data showing 30% more people with extensive stage small cell lung cancer are alive at 24 months compared to those who received chemotherapy alone, Canadian regulator had rejected to fund Tecentriq for extensive stage small-cell lung cancer "as too costly" followed by United Kingdom also citing "drug’s cost-effectiveness."

Radiation therapy
Chest radiation helps SCLC patients live longer by killing cancer cells and helping prevention of cancer recurrence. Another type of radiation, prophylactic cranial radiation, prevents central nervous system recurrence and can improve survival in patients with good performance status who have had a complete response or a very good partial response to chemoradiation in LD or chemotherapy in ED.

In case of relapse
If small cell lung cancer comes back after treatment, the following combination of drugs may be used as a salvage therapy:
Cyclophosphamide (Cytoxan, Procytox),
Doxorubicin (Adriamycin) and
Vincristine (Oncovin)
Paclitaxel (Taxol)
Irinotecan (Camptosar) Current guidelines recommend that patients who relapse > 6 months from initial therapy should be retreated with the original chemotherapy regimen. For patients who relapse in < 6 months, single-agent chemotherapy either topotecan second-line therapy, or paclitaxel can be used.

Novel agents
Several newer agents, including temozolomide and bendamustine, have activity in relapsed SCLC. Of note, temozolomide yielded a response rate of 38% for brain metastases due to SCLC.In a clinical trial of 50 patients, combination of olaparib and temozolomide in relapsed small-cell lung cancer yielded an overall response rate of 41.7%, median progression-free survival 4.2 months, and overall survival was 8.5 months.Lurbinectedin is the most promising new agent that substantially increased overall survival rate in relapsed small cell lung cancer among sensitive disease patients. As a single agent, lurbinectedin demonstrated following clinical results in refractory small cell lung cancer trial:

Overall survival rate of 15.2 months for sensitive disease (chemotherapy-free interval of ≥ 90 days) with a disease control rate of 79.3% and overall response rate of 46.6%, and
Overall survival rate of 5.1 months for resistant (chemotherapy-free interval of < 90 days) with a disease control rate of 46.8% and overall response rate 21.3%.Lurbinectedin is also being investigated in combination with doxorubicin as second-line therapy in a randomized phase 3 trial. While overall survival in this trial is not yet known, response rates at second line were

91.7% in sensitive disease with median progression-free survival of 5.8 months , and
33.3% in resistant disease with median progression-free of 3.5 months.Lurbinectedin is currently available in the U.S. under an expanded access program (EAP).Trilaciclib, a CKD4/6 inhibitor, reduces chemotheraphy-induced toxicity in patients being treated for small-cell lung cancer.  Trilaciclib’s developer, G1 Therapeutics, makes the drug available in the U.S. under expanded access while the FDA considers its New Drug Application (NDA) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ant venom and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Bone cyst and can you explain it in depth? [/INST] A bone cyst or geode is a cyst that forms in bone.
Types include:

Unicameral bone cyst
Aneurysmal bone cyst
Traumatic bone cyst

Diagnosis
On CT scans, bone cysts that have a radiodensity of 20 Hounsfield units (HU) or less, and are osteolytic, tend to be aneurysmal bone cysts.In contrast, intraosseous lipomas have a lower radiodensity of -40 to -60 HU.

Treatment and Prevention
Simple (Unicameral) Bone Cyst
Some unicameral bone cysts may spontaneously resolve without medical intervention. Specific treatments are determined based on the size of the cyst, the strength of the bone, medical history, extent of the disease, activity level, symptoms an  individual is experiencing, and  tolerance for specific medications, procedures, or therapies. The types of methods used to treat this type of cyst are curettage and bone grafting, aspiration, steroid injections, and bone marrow injections. Watchful waiting and activity modifications are the most common nonsurgical treatments that will help resolve and help prevent unicameral bone cysts from occurring and reoccurring.

Aneurysmal Bone Cyst
Aneurysmal bone cysts can be treated with a variety of different methods. These methods include open curettage and bone grafting with or without adjuvant therapy, cryotherapy, sclerotherapy, ethibloc injections, radionuclide ablation, and selective arterial embolization. En-block resection and reconstruction with strut grafting are the most common treatments and procedures that prevent recurrences of this type of cyst.

Traumatic Bone Cyst
The traumatic bone cyst treatment consists of surgical exploration, curettage of the osseous socket and bony walls, subsequent filling with blood, and intralesional steroid injections. Young athletes can reduce their risk of traumatic bone cyst by wearing protective mouth wear or protective headgear.

History
Aneurysmal bone cysts are benign neoformations which can affect any bone. More than half occur in the metaphysis of long bones (especially femur and tibia) and between 12 and 30% in the spine. They were described in 1893 by Van Arsdale, who called these lesions "homerus ossifying haematoma". In 1940 Ewing used the term "aneurismal" to describe these lesions. Jaffé and Lichtenstein first coined the term "aneurismal cyst" in 1942 In 1950 they modified this term to "aneurismal bone cyst". They may be associated with bone tumors.
The simple bone cyst is a common, benign, fluid-containing lesion, most commonly found in the metaphysis of long bones, typically the proximal humerus or femur. Pathologic fractures are common, often with minor trauma </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ectopic kidney and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Acral persistent papular mucinosis and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Zieves syndrome and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Thyrotoxic periodic paralysis and can you explain it in depth? [/INST] Thyrotoxic periodic paralysis (TPP) is a condition featuring attacks of muscle weakness in the presence of hyperthyroidism (overactivity of the thyroid gland). Hypokalemia (a decreased potassium level in the blood) is usually present during attacks. The condition may be life-threatening if weakness of the breathing muscles leads to respiratory failure, or if the low potassium levels lead to cardiac arrhythmias (irregularities in the heart rate). If untreated, it is typically recurrent in nature.The condition has been linked with genetic mutations in genes that code for certain ion channels that transport electrolytes (sodium and potassium) across cell membranes. The main ones are the L-type calcium channel α1-subunit and potassium inward rectifier 2.6; it is therefore classified as a channelopathy. The abnormality in the channel is thought to lead to shifts of potassium into cells, under conditions of high thyroxine (thyroid hormone) levels, usually with an additional precipitant.
Treatment of the hypokalemia, followed by correction of the hyperthyroidism, leads to complete resolution of the attacks. It occurs predominantly in males of Chinese, Japanese, Vietnamese, Filipino, and Korean descent. TPP is one of several conditions that can cause periodic paralysis.

Signs and symptoms
An attack often begins with muscle pain, cramping, and stiffness. This is followed by weakness or paralysis that tends to develop rapidly, usually in late evening or the early hours of the morning. The weakness is usually symmetrical; the limb muscles closer to the trunk (proximal) are predominantly affected, and weakness tends to start in the legs and spread to the arms. Muscles of the mouth and throat, eyes, and breathing are usually not affected, but occasionally weakness of the respiratory muscles can cause life-threatening respiratory failure. Attacks typically resolve within several hours to several days, even in the absence of treatment. On neurological examination during an attack, flaccid weakness of the limbs is noted; reflexes are usually diminished, but the sensory system is unaffected. Mental status is not affected.Attacks may be brought on by physical exertion, drinking alcohol, or eating food high in carbohydrates or salt. This may explain why attacks are more common in summer when more people drink sugary drinks and engage in exercise. Exercise-related attacks tend to occur during a period of rest immediately after exercise; exercise may, therefore, be recommended to abort an attack.There may be symptoms of thyroid overactivity, such as weight loss, a fast heart rate, tremor, and perspiration; but such symptoms occur in only half of all cases. The most common type of hyperthyroidism, Graves disease, may additionally cause eye problems (Graves ophthalmopathy) and skin changes of the legs (pretibial myxedema). Thyroid disease may also cause muscle weakness in the form of thyrotoxic myopathy, but this is constant rather than episodic.

Causes
Genetics
Genetic mutations in the L-type calcium channel α1-subunit (Cav1.1) have been described in Southern Chinese with TPP. The mutations are located in a different part of the gene from those described in the related condition familial periodic paralysis. In TPP, the mutations described are single-nucleotide polymorphisms located in the hormone response element responsive to thyroid hormone, implying that transcription of the gene and production of ion channels may be altered by increased thyroid hormone levels. Furthermore, mutations have been reported in the genes coding for potassium voltage-gated channel, Shaw-related subfamily, member 4 (Kv3.4) and sodium channel protein type 4 subunit alpha (Na41.4).Of people with TPP, 33% from various populations were demonstrated to have mutations in KCNJ18, the gene coding for Kir2.6, an inward-rectifier potassium ion channel. This gene, too, harbors a thyroid response element.Certain forms of human leukocyte antigen (HLA)—especially B46, DR9, DQB1*0303, A2, Bw22, AW19, B17, and DRW8—are more common in TPP. Linkage to particular forms of HLA, which plays a central role in the immune response, might imply an immune system cause, but it is uncertain whether this directly causes TPP or whether it increases the susceptibility to Graves disease, a known autoimmune disease.

Thyroid disease
The most common underlying form of thyroid disease associated with TPP is Graves disease, a syndrome due to an autoimmune reaction that leads to overproduction of thyroid hormone. TPP has also been described in people with other thyroid problems such as thyroiditis, toxic nodular goiter, toxic adenoma, TSH-producing pituitary adenoma, excessive ingestion of thyroxine or iodine, and amiodarone-induced hyperthyroidism.

Mechanism
The muscle weakness and increased risk of irregular heart beat in TPP result from markedly reduced levels of potassium in the bloodstream. Potassium is not in fact lost from the body, but increased Na+/K+-ATPase activity (the enzyme that moves potassium into cells and keeps sodium in the blood) leads to shift of potassium into tissues, and depletes the circulation. In other types of potassium derangement, the acid-base balance is usually disturbed, with metabolic alkalosis and metabolic acidosis often being present. In TPP, these disturbances are generally absent. Hypokalemia leads to hyperpolarization of muscle cells, making the neuromuscular junction less responsive to normal nerve impulses and leading to decreased contractility of the muscles.It is not clear how the described genetic defects increase the Na+/K+-ATPase activity, but it is suspected that the enzyme becomes more active due to increased thyroid hormone levels. Hyperthyroidism increases the levels of catecholamines (such as adrenaline) in the blood, increasing Na+/K+-ATPase activity. The enzyme activity is then increased further by the precipitating causes. For instance, increased carbohydrate intake leads to increased insulin levels; this is known to activate Na+/K+-ATPase. Once the precipitant is removed, the enzyme activity returns to normal levels. It has been postulated that male hormones increase Na+/K+-ATPase activity, and that this explains why males are at a higher risk of TPP despite thyroid disease being more common in females.TPP is regarded as a model for related conditions, known as "channelopathies", which have been linked with mutations in ion channels; the majority of these conditions occurs episodically.

Diagnosis
Hypokalemia (low blood potassium levels) commonly occurs during attacks; levels below 3.0 mmol/L are typically encountered. Magnesium and phosphate levels are often found to be decreased. Creatine kinase levels are elevated in two thirds of cases, usually due to a degree of muscle injury; severe elevations suggestive of rhabdomyolysis (muscle tissue destruction) are rare. Electrocardiography (ECG/EKG) may show tachycardia (a fast heart rate) due to the thyroid disease, abnormalities due to cardiac arrhythmia (atrial fibrillation, ventricular tachycardia), and conduction changes associated with hypokalemia (U waves, QRS widening, QT prolongation, and T wave flattening). Electromyography shows changes similar to those encountered in myopathies (muscle diseases), with a reduced amplitude of the compound muscle action potentials (CMAPs); they resolve when treatment has commenced.TPP is distinguished from other forms of periodic paralysis (especially hypokalemic periodic paralysis) with thyroid function tests on the blood. These are normal in the other forms, and in thyrotoxicosis the levels of thyroxine and triiodothyronine are elevated, with resultant suppression of TSH production by the pituitary gland. Various other investigations are usually performed to separate the different causes of hyperthyroidism.

Treatment
In the acute phase of an attack, administration of potassium will quickly restore muscle strength and prevent complications. However, caution is advised as the total amount of potassium in the body is not decreased, and it is possible for potassium levels to overshoot ("rebound hyperkalemia"); slow infusions of potassium chloride are therefore recommended while other treatment is commenced.The effects of excess thyroid hormone typically respond to the administration of a non-selective beta blocker, such as propranolol (as most of the symptoms are driven by increased levels of adrenaline and its effect on the β-adrenergic receptors). Subsequent attacks may be prevented by avoiding known precipitants, such as high salt or carbohydrate intake, until the thyroid disease has been adequately treated.Treatment of the thyroid disease usually leads to resolution of the paralytic attacks </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Herpes simplex and can you explain it in depth? [/INST] Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected. Oral herpes involves the face or mouth. It may result in small blisters in groups often called cold sores or fever blisters or may just cause a sore throat. Genital herpes, often simply known as herpes, may have minimal symptoms or form blisters that break open and result in small ulcers. These typically heal over two to four weeks. Tingling or shooting pains may occur before the blisters appear. Herpes cycles between periods of active disease followed by periods without symptoms. The first episode is often more severe and may be associated with fever, muscle pains, swollen lymph nodes and headaches. Over time, episodes of active disease decrease in frequency and severity. Other disorders caused by herpes simplex include: herpetic whitlow when it involves the fingers, herpes of the eye, herpes infection of the brain, and neonatal herpes when it affects a newborn, among others.There are two types of herpes simplex virus, type 1 (HSV-1) and type 2 (HSV-2). HSV-1 more commonly causes infections around the mouth while HSV-2 more commonly causes genital infections. They are transmitted by direct contact with body fluids or lesions of an infected individual. Transmission may still occur when symptoms are not present. Genital herpes is classified as a sexually transmitted infection. It may be spread to an infant during childbirth. After infection, the viruses are transported along sensory nerves to the nerve cell bodies, where they reside lifelong. Causes of recurrence may include: decreased immune function, stress, and sunlight exposure. Oral and genital herpes is usually diagnosed based on the presenting symptoms. The diagnosis may be confirmed by viral culture or detecting herpes DNA in fluid from blisters. Testing the blood for antibodies against the virus can confirm a previous infection but will be negative in new infections.The most effective method of avoiding genital infections is by avoiding vaginal, oral, and anal sex. Condom use decreases the risk. Daily antiviral medication taken by someone who has the infection can also reduce spread. There is no available vaccine and once infected, there is no cure. Paracetamol (acetaminophen) and topical lidocaine may be used to help with the symptoms. Treatments with antiviral medication such as aciclovir or valaciclovir can lessen the severity of symptomatic episodes.Worldwide rates of either HSV-1 or HSV-2 are between 60% and 95% in adults. HSV-1 is usually acquired during childhood. Since there is no cure for either HSV-1 or HSV-2, rates of both inherently increase as people age. Rates of HSV-1 are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. An estimated 536 million people worldwide (16% of the population) were infected with HSV-2 as of 2003 with greater rates among women and those in the developing world. Most people with HSV-2 do not realize that they are infected.

Etymology
The name is from Greek: ἕρπης herpēs, which is related to the meaning "to creep", referring to spreading blisters. The name does not refer to latency.

Signs and symptoms
HSV infection causes several distinct medical disorders.  Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpetic whitlow).  More serious disorders occur when the virus infects and damages the eye (herpes keratitis), or invades the central nervous system, damaging the brain (herpes encephalitis).  People with immature or suppressed immune systems, such as newborns, transplant recipients, or people with AIDS,  are prone to severe complications from HSV infections. HSV infection has also been associated with cognitive deficits of bipolar disorder, and Alzheimers disease, although this is often dependent on the genetics of the infected person.
In all cases, HSV is never removed from the body by the immune system.  Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion. As a result of primary infection, the body produces antibodies to the particular type of HSV involved, which can help reduce the odds of a subsequent infection of that type at a different site. In HSV-1-infected individuals, seroconversion after an oral infection helps prevent additional HSV-1 infections such as whitlow, genital herpes, and herpes of the eye. Prior HSV-1 seroconversion seems to reduce the symptoms of a later HSV-2 infection, although HSV-2 can still be contracted.
Many people infected with HSV-2 display no physical symptoms—individuals with no symptoms are described as asymptomatic or as having subclinical herpes. However, infection with herpes can be fatal.

Other
Neonatal herpes simplex is a HSV infection in an infant. It is a rare but serious condition, usually caused by vertical transmission of HSV-1 or -2 from mother to newborn. During immunodeficiency, herpes simplex can cause unusual lesions in the skin.  One of the most striking is the appearance of clean linear erosions in skin creases, with the appearance of a knife cut. Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicles.: 369  Eczema herpeticum is an infection with herpesvirus in patients with chronic atopic dermatitis may result in spread of herpes simplex throughout the eczematous areas.: 373 Herpetic keratoconjunctivitis, a primary infection, typically presents as swelling of the conjunctiva and eyelids (blepharoconjunctivitis), accompanied by small white itchy lesions on the surface of the cornea.
Herpetic sycosis is a recurrent or initial herpes simplex infection affecting primarily the hair follicle.: 369

Bells palsy
Although the exact cause of Bells palsy—a type of facial paralysis—is unknown, it may be related to reactivation of HSV-1. This theory has been contested, however, since HSV is detected in large numbers of individuals having never experienced facial paralysis, and higher levels of antibodies for HSV are not found in HSV-infected individuals with Bells palsy compared to those without. Antivirals may improve the condition slightly when used together with corticosteroids in those with severe disease.

Alzheimers disease
HSV-1 has been proposed as a possible cause of Alzheimers disease. In the presence of a certain gene variation (APOE-epsilon4 allele carriers), HSV-1 appears to be particularly damaging to the nervous system and increases ones risk of developing Alzheimers disease.  The virus interacts with the components and receptors of lipoproteins, which may lead to its development.

Pathophysiology
Herpes is contracted through direct contact with an active lesion or body fluid of an infected person. Herpes transmission occurs between discordant partners; a person with a history of infection (HSV seropositive) can pass the virus to an HSV seronegative person. Herpes simplex virus 2 is  typically contracted through direct skin-to-skin contact with an infected individual, but can also be contracted by exposure to infected saliva, semen, vaginal fluid, or the fluid from herpetic blisters. To infect a new individual, HSV travels through tiny breaks in the skin or mucous membranes in the mouth or genital areas. Even microscopic abrasions on mucous membranes are sufficient to allow viral entry.
HSV asymptomatic shedding occurs at some time in most individuals infected with herpes.  It can occur more than a week before or after a symptomatic recurrence in 50% of cases.  Virus enters into susceptible cells by entry receptors
such as nectin-1, HVEM and 3-O sulfated heparan sulfate. Infected people who show no visible symptoms may still shed and transmit viruses through their skin; asymptomatic shedding may represent the most common form of HSV-2 transmission. Asymptomatic shedding is more frequent within the first 12 months of acquiring HSV. Concurrent infection with HIV increases the frequency and duration of asymptomatic shedding.  Some individuals may have much lower patterns of shedding, but evidence supporting this is not fully verified; no significant differences are seen in the frequency of asymptomatic shedding when comparing persons with one to 12 annual recurrences to those with no recurrences.Antibodies that develop following an initial infection with a type of HSV can reduce the odds of reinfection with the same virus type. In a monogamous couple, a seronegative female runs a greater than 30% per year risk of contracting an HSV infection from a seropositive male partner. If an oral HSV-1 infection is contracted first, seroconversion will have occurred after 6 weeks to provide protective antibodies against a future genital HSV-1 infection. Herpes simplex is a double-stranded DNA virus.

Diagnosis
Classification
Herpes simplex virus is divided into two types. However, each may cause infections in all areas.
HSV-1 causes primarily mouth, throat, face, eye, and central nervous system infections.
HSV-2 causes primarily anogenital infections.

Examination
Primary orofacial herpes is readily identified by examination of persons with no previous history of lesions and contact with an individual with known HSV infection. The appearance and distribution of sores is typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis. Adults with atypical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.Genital herpes can be more difficult to diagnose than oral herpes, since most people have none of the classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection, lichen planus, atopic dermatitis, and urethritis.

Laboratory testing
Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.Until the 1980s serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection.  However, a glycoprotein G-specific (IgG) HSV test introduced in the 1980s is more than 98% specific at discriminating HSV-1 from HSV-2.

Differential diagnosis
It should not be confused with conditions caused by other viruses in the herpesviridae family such as herpes zoster, which is caused by varicella zoster virus. The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin. Lymphangioma circumscriptum and dermatitis herpetiformis may also have a similar appearance.

Prevention
As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men. On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is about 8–11%.
This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is around 4–5% annually. Suppressive antiviral therapy reduces these risks by 50%. Antivirals also help prevent the development of symptomatic HSV in infection scenarios, meaning the infected partner will be seropositive but symptom-free by about 50%. Condom use also reduces the transmission risk significantly. Condom use is much more effective at preventing male-to-female transmission than vice versa. Previous HSV-1 infection may reduce the risk for acquisition of HSV-2 infection among women by a factor of three, although the one study that states this has a small sample size of 14 transmissions out of 214 couples.However, asymptomatic carriers of the HSV-2 virus are still contagious.  In many infections, the first symptom people will have of their own infections is the horizontal transmission to a sexual partner or the vertical transmission of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV.In October 2011,  the anti-HIV drug tenofovir, when used topically in a microbicidal vaginal gel, was reported to reduce herpes virus sexual transmission by 51%.

Barrier methods
Condoms offer moderate protection against HSV-2 in both men and women, with consistent condom users having a 30%-lower risk of HSV-2 acquisition compared with those who never use condoms. A female condom can provide greater protection than the male condom, as it covers the labia. The virus cannot pass through a synthetic condom, but a male condoms effectiveness is limited  because herpes ulcers may appear on areas not covered by it. Neither type of condom prevents contact with the scrotum, anus, buttocks, or upper thighs, areas that may come in contact with ulcers or genital secretions during sexual activity. Protection against herpes simplex depends on the site of the ulcer; therefore, if ulcers appear on areas not covered by condoms, abstaining from sexual activity until the ulcers are fully healed is one way to limit risk of transmission. The risk is not eliminated, however, as viral shedding capable of transmitting infection may still occur while the infected partner is asymptomatic. The use of condoms or dental dams also limits the transmission of herpes from the genitals of one partner to the mouth of the other (or vice versa) during oral sex. When one partner has a herpes simplex infection and the other does not, the use of antiviral medication, such as valaciclovir, in conjunction with a condom, further decreases the chances of transmission to the uninfected partner. Topical microbicides that contain chemicals that directly inactivate the virus and block viral entry are being investigated.

Antivirals
Antivirals may reduce asymptomatic shedding; asymptomatic genital HSV-2 viral shedding is believed to occur on 20% of days per year in patients not undergoing antiviral treatment, versus 10% of days while on antiviral therapy.

Pregnancy
The risk of transmission from mother to baby is highest if the mother becomes infected around the time of delivery (30% to 60%), since insufficient time will have occurred for the generation and transfer of protective maternal antibodies before the birth of the child. In contrast, the risk falls to 3% if the  infection is recurrent, and is 1–3% if the woman is seropositive for both HSV-1 and HSV-2, and is less than 1% if no lesions are visible. Women seropositive for only one type of HSV are only half as likely to transmit HSV as infected seronegative mothers. To prevent neonatal infections, seronegative women are recommended to avoid unprotected oral-genital contact with an HSV-1-seropositive partner and conventional sex with a partner having a genital infection during the last trimester of pregnancy. Mothers infected with HSV are advised to avoid procedures that would cause trauma to the infant during birth (e.g. fetal scalp electrodes, forceps, and vacuum extractors) and, should lesions be present, to elect caesarean section to reduce exposure of the child to infected secretions in the birth canal. The use of antiviral treatments, such as aciclovir, given from the 36th week of pregnancy, limits HSV recurrence and shedding during childbirth, thereby reducing the need for caesarean section.Aciclovir is the recommended antiviral for herpes suppressive therapy during the last months of pregnancy.  The use of valaciclovir and famciclovir, while potentially improving compliance, have less-well-determined safety in pregnancy.

Management
No method  eradicates herpes virus from the body, but antiviral medications can reduce the frequency, duration, and severity of outbreaks.  Analgesics such as ibuprofen and paracetamol (acetaminophen) can reduce pain and fever.  Topical anesthetic treatments such as prilocaine, lidocaine, benzocaine, or tetracaine can also relieve itching and pain.

Antiviral
Several antiviral drugs are effective for treating herpes, including aciclovir (acyclovir), valaciclovir, famciclovir, and penciclovir. Aciclovir was the first discovered and is now available in generic. Valaciclovir is also available as a generic and is slightly more effective than aciclovir for reducing lesion healing time.Evidence supports the use of aciclovir and valaciclovir in the treatment of herpes labialis as well as herpes infections in people with cancer. The evidence to support the use of aciclovir in primary herpetic gingivostomatitis is weaker.

Topical
A number of topical antivirals are effective for herpes labialis, including aciclovir, penciclovir, and docosanol.

Alternative medicine
Evidence is insufficient to support use of many of these compounds, including echinacea, eleuthero, L-lysine, zinc, monolaurin bee products, and aloe vera. While a number of small studies show possible benefit from monolaurin, L-lysine, aspirin, lemon balm, topical zinc, or licorice root cream in treatment, these preliminary studies have not been confirmed by higher-quality randomized controlled studies.

Prognosis
Following active infection, herpes viruses establish a latent infection in sensory and autonomic ganglia of the nervous system.  The double-stranded DNA of the virus is incorporated into the cell physiology by infection of the nucleus of a nerves cell body.  HSV latency is static; no virus is produced; and is controlled by a number of viral genes, including latency-associated transcript.Many HSV-infected people experience recurrence within the first year of infection.  Prodrome precedes development of lesions.  Prodromal symptoms include tingling (paresthesia), itching, and pain where lumbosacral nerves innervate the skin. Prodrome may occur as long as several days or as short as a few hours before lesions develop.  Beginning antiviral treatment when prodrome is experienced can reduce the appearance and duration of lesions in some individuals. During recurrence, fewer lesions are likely to develop and  are less painful and heal faster (within 5–10 days without antiviral treatment) than those occurring during the primary infection.  Subsequent outbreaks tend to be periodic or episodic, occurring on average four or five times a year when not using antiviral therapy.
The causes of reactivation are uncertain, but several potential triggers have been documented. A 2009 study showed the protein VP16 plays a key role in reactivation of the dormant virus. Changes in the immune system during menstruation may play a role in HSV-1 reactivation. Concurrent infections, such as viral upper respiratory tract infection or other febrile diseases, can cause outbreaks.  Reactivation due to other infections is the likely source of the historic terms cold sore and fever blister.
Other identified triggers include local injury to the face, lips, eyes, or mouth; trauma; surgery; radiotherapy; and exposure to wind, ultraviolet light, or sunlight.The frequency and severity of recurrent outbreaks vary greatly between people. Some individuals outbreaks can be quite debilitating, with large, painful lesions persisting for several weeks, while others experience only minor itching or burning for a few days. Some evidence indicates genetics play a role in the frequency of cold sore outbreaks.  An area of human chromosome 21 that includes six genes has been linked to frequent oral herpes outbreaks. An immunity to the virus is built over time. Most infected individuals experience fewer outbreaks and outbreak symptoms often become less severe. After several years, some people become perpetually asymptomatic and no longer experience outbreaks, though they may still be contagious to others. Immunocompromised individuals may experience longer, more frequent, and more severe episodes.  Antiviral medication has been proven to shorten the frequency and duration of outbreaks.  Outbreaks may occur at the original site of the infection or in proximity to nerve endings that reach out from the infected ganglia.  In the case of a genital infection, sores can appear at the original site of infection or near the base of the spine, the buttocks, or the back of the thighs.
HSV-2-infected individuals are at higher risk for acquiring HIV when practicing unprotected sex with HIV-positive persons, in particular during an outbreak with active lesions.

Epidemiology
Worldwide rates of either HSV-1 and/or HSV-2 are between 60 and 95% in adults. HSV-1 is more common than HSV-2, with rates of both increasing as people age. HSV-1 rates are between 70% and 80% in populations of low socioeconomic status and 40% to 60% in populations of improved socioeconomic status. An estimated 536 million people or 16% of the population worldwide were infected with HSV-2 as of 2003 with greater rates among women and in those in the developing world. Rates of infection are determined by the presence of antibodies against either viral species.In the US, 58% of the population is infected with HSV-1 and 16% are infected with HSV-2. Among those HSV-2-seropositive, only 19% were aware they were infected. During 2005–2008, the prevalence of HSV-2 was 39% in blacks and 21% in women.The annual incidence in Canada of genital herpes due to HSV-1 and HSV-2 infection is not known (for a review of HSV-1/HSV-2 prevalence and incidence studies worldwide, see Smith and Robinson 2002). As many as one in seven Canadians aged 14 to 59 may be infected with herpes simplex type 2 virus and more than 90 per cent of them may be unaware of their status, a new study suggests. In the United States, it is estimated that about 1,640,000 HSV-2 seroconversions occur yearly (730,000 men and 910,000 women, or 8.4 per 1,000 persons).In British Columbia in 1999, the seroprevalence of HSV-2 antibody in leftover serum submitted for antenatal testing revealed a prevalence of 17%, ranging from 7% in women 15–19 years old to 28% in those 40–44 years.In Norway, a study published in 2000 found that up to 70–90% of genital initial infections were due to HSV-1.In Nova Scotia, 58% of 1,790 HSV isolates from genital lesion cultures in women were HSV-1; in men, 37% of 468 isolates were HSV-1.

History
Herpes has been known for at least 2,000 years. Emperor Tiberius is said to have banned kissing in Rome for a time due to so many people having cold sores. In the 16th-century Romeo and Juliet,  blisters "oer ladies lips" are mentioned. In the 18th century, it was so common among prostitutes that it was called "a vocational disease of women". The term herpes simplex appeared in Richard Boultons A System of Rational and Practical Chirurgery in 1713, where the terms herpes miliaris and herpes exedens also appeared. Herpes was not found to be a virus until the 1940s.Herpes antiviral therapy began in the early 1960s with the experimental use of medications that interfered with viral replication called deoxyribonucleic acid (DNA) inhibitors. The original use was against normally fatal or debilitating illnesses such as adult encephalitis, keratitis, in immunocompromised (transplant) patients, or disseminated herpes zoster. The original compounds used were 5-iodo-2-deoxyuridine, AKA idoxuridine, IUdR, or(IDU) and 1-β-D-arabinofuranosylcytosine or ara-C, later marketed under the name cytosar or cytarabine. The usage expanded to include topical treatment of herpes simplex, zoster, and varicella. Some trials combined different antivirals with differing results. The introduction of 9-β-D-arabinofuranosyladenine, (ara-A or vidarabine), considerably less toxic than ara-C, in the mid-1970s, heralded the way for the beginning of regular neonatal antiviral treatment. Vidarabine was the first systemically administered antiviral medication with activity against HSV for which therapeutic efficacy outweighed toxicity for the management of life-threatening HSV disease. Intravenous vidarabine was licensed for use by the U.S. Food and Drug Administration in 1977. Other experimental antivirals of that period included: heparin, trifluorothymidine (TFT), Ribivarin, interferon, Virazole, and 5-methoxymethyl-2-deoxyuridine (MMUdR). The introduction of 9-(2-hydroxyethoxymethyl)guanine, AKA aciclovir, in the late 1970s raised antiviral treatment another notch and led to vidarabine vs. aciclovir trials in the late 1980s. The lower toxicity and ease of administration over vidarabine has led to aciclovir becoming the drug of choice for herpes treatment after it was licensed by the FDA in 1998. Another advantage in the treatment of neonatal herpes included greater reductions in mortality and morbidity with increased dosages, which did not occur when compared with increased dosages of vidarabine. However, aciclovir seems to inhibit antibody response, and newborns on aciclovir antiviral treatment experienced a slower rise in antibody titer than those on vidarabine.

Society and culture
Some people experience negative feelings related to the condition following diagnosis, in particular if they have acquired the genital form of the disease. Feelings can include depression, fear of rejection, feelings of isolation, fear of being found out, and self-destructive feelings. Herpes support groups have been formed in the United States and the UK, providing information about herpes and running message forums and dating websites for affected people. People with the herpes virus are often hesitant to divulge to other people, including friends and family, that they are infected. This is especially true of new or potential sexual partners whom they consider casual.In a 2007 study, 1,900 people (25% of which had herpes) ranked genital herpes second for social stigma, out of all sexually transmitted diseases (HIV took the top spot for STD stigma).

Support groups
United States
An important source of support is the National Herpes Resource Center which arose from the work of the American Sexual Health Association (ASHA) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Paroxysmal extreme pain disorder and can you explain it in depth? [/INST] Paroxysmal extreme pain disorder 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 NaV1.7 encoded by the gene SCN9A. A different mutation in "SCN9A" causes congenital insensitivity to pain.

Symptoms and signs
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.

Cause
The voltage-gated sodium channel NaV1.7 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 channels 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.

Pathophysiology
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.

Diagnosis
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 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Dissociated vertical deviation and can you explain it in depth? [/INST] Dissociated vertical deviation (DVD) is an eye condition which occurs in association with a squint, typically infantile esotropia. The exact cause is unknown, although it is logical to assume it is from faulty innervation of eye muscles.

Presentation
The eye drifts upward spontaneously or after being covered.  The condition usually affects both eyes, but can occur unilaterally or asymmetrically. It is often associated with latent or manifest-latent nystagmus and, as well as occurring with infantile esotropia, can also be found associated with exotropias and vertical deviations.
DVDs are usually controlled from occurring with both eyes open, but may become manifest with inattention. Usually some level of dissociative occlusion is required - to trigger the brain to suppress vision in that eye and then not control a DVD from occurring. The level of dissociative occlusion required may involve using a red filter, a darker filter or complete occlusion (e.g. with a hand).

Onset
DVD typically becomes apparent between 18 months and three years of age, however, the difficulties of achieving the prolonged occlusion required for accurate detection in the very young make it possible that onset is generally earlier than these figures suggest.

Mechanism
Dissociation refers to the situation where the innervation of one eye causes it to move involuntarily and independently of the other eye </s>