<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 Autoimmune hepatitis and can you explain it in depth? [/INST] Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the bodys immune system attacks liver cells, causing the liver to be inflamed. Common initial symptoms may include fatigue, nausea, muscle aches, or weight loss or signs of acute liver inflammation including fever, jaundice, and right upper quadrant abdominal pain. Individuals with autoimmune hepatitis often have no initial symptoms and the disease may be detected by abnormal liver function tests and increased protein levels during routine bloodwork or the observation of an abnormal-looking liver during abdominal surgery.Anomalous presentation of MHC class II receptors on the surface of liver cells, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated immune response against the bodys own liver, resulting in autoimmune hepatitis. This abnormal immune response results in inflammation of the liver, which can lead to further symptoms and complications such as fatigue and cirrhosis. The disease is most often diagnosed in patients in their late teens or early 20s and between the ages of 40 and 50. It affects women more commonly than men.

Signs and symptoms
Autoimmune hepatitis may present completely asymptomatic (12–35% of the cases), with signs of chronic liver disease, or acute or even fulminant hepatic failure.People usually present with one or more nonspecific, long-lasting symptoms such as fatigue, general ill health, lethargy, weight loss, mild right upper quadrant abdominal pain, malaise, anorexia, itching, nausea, jaundice or joint pain especially affecting the small joints. Rarely, rash or unexplained fever may appear. In women, the absence of menstruation (amenorrhoea) is a frequent feature. Physical examination may be normal, but it may also reveal signs and symptoms of chronic liver disease. Many people have only laboratory abnormalities as their initial presentation, as unexplained increase in transaminases and are diagnosed during an evaluation for other reasons. Others have already developed cirrhosis at diagnosis. Of note, alkaline phosphatase and bilirubin are usually normal.
Autoimmune hepatitis may overlap with other autoimmune conditions, mainly type 1 diabetes mellitus, ulcerative colitis, lupus, celiac disease, vasculitis, and autoimmune thyroiditis.

Cause
The prevailing theory for the development of autoimmune hepatitis is thought to be the interplay of genetic predisposition, an environmental trigger (virus, drugs, herbs, immunizations), and failure of the native immune system resulting in chronic inflammation of hepatocytes and subsequent fibrosis of the liver.There is no specific evidence of the cause. Sixty percent of patients have findings associated with chronic hepatitis but without serologic evidence of a viral infection. The disease is strongly associated with anti-smooth muscle autoantibodies.The exact genes and triggers responsible remain undefined, but studies show association of early-onset, severe disease with the HLA-DR3 serotype and late-onset disease with the HLA-DR4 serotype.

Diagnosis
The diagnosis of autoimmune hepatitis is best achieved with a combination of clinical, laboratory, and histological findings after excluding other etiological factors (e.g. viral, hereditary, metabolic, cholestatic, and drug-induced liver diseases). The requirement for histological examination necessitates a liver biopsy, typically performed with a needle by the percutaneous route, to provide liver tissue.

Autoantibodies
A number of specific antibodies found in the blood (antinuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-liver kidney microsomal antibodies (LKM-1, LKM-2, LKM-3), anti soluble liver antigen (SLA), liver–pancreas antigen (LP), and anti-mitochondrial antibody (AMA)) are of use, as is finding an increased immunoglobulin G level. The presence of anti-mitochondrial antibody is more suggestive of primary biliary cholangitis. Hypergammaglobulinemia is also of diagnostic value.

Histology
Autoimmune hepatitis can be characterized histologically by the following nonspecific findings:
Portal mononuclear cell infiltrate that invades the boundary surrounding the portal triad and infiltrates the surrounding lobule.
Periportal lesions, also known as interface hepatitis, that spare the biliary tree (may include centrizonal necrosis).
Bile duct abnormalities (cholangitis, ductal injury, ductular reaction) can be seen and should prompt evaluation for primary biliary cholangitis or sarcoidosis if granulomas are observed.
Plasma cell infiltrate, rosettes of hepatocytes, and multinucleated giant cells.
Varying degrees of fibrosis (except in the mildest form of autoimmune hepatitis). Bridging fibrosis that connects the portal and central areas can distort the structure of the hepatic lobule and result in cirrhosis.

Diagnostic scoring
The Internal Autoimmune Hepatitis Group developed a standardized scoring system for clinical diagnosis in population studies but lacks value in individualized cases. A simplified scoring system for clinical use incorporates titers of autoantibodies, total IgG levels, liver histology, and the exclusion of viral hepatitis for diagnostic scoring.

Classification
On the basis of detected autoantibodies, autoimmune hepatitis can be classified into three subtypes but have no distinct clinical presentations.

Type 1 autoimmune hepatitis. Positive antibodies include:Antinuclear antibody (ANA)
Anti-smooth muscle antibody (ASMA) - 65% of people
Anti-actin antibodies
Anti-mitochondrial antibodies - rare except for overlap syndromes with primary biliary cholangitis
Anti-soluble liver antigen/liver pancreas antibody antigen - 20% of people
Anti-double stranded DNA - 30% of people
Atypical perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA)
Type 2 autoimmune hepatitis. Positive antibodies include:Liver Kidney Microsomal antibody (LKM-1)
Anti-liver cytosol antibody-1 (SLC-1)
Autoantibody negative autoimmune hepatitis.Lack positive ANA, ASMA, LKM-1, etc. antibody panels but present with clinical features of autoimmune hepatitis that resolve with standard treatment.

Differential diagnosis
Other diagnoses to consider include conditions that may cause acute hepatitis or chronic liver inflammation that may be accompanied by cirrhosis:

Other autoimmune diseases that involve the liver:
Primary biliary cholangitis - the presence of isolated elevated AMA antibodies usually signifies primary biliary cholangitis rather than autoimmune hepatitis and further diagnostic evaluation is needed.
Overlap syndromes - autoimmune hepatitis may present similarly to primary sclerosing cholangitis but people with primary sclerosing cholangitis have stricturing and dilatation of intra/extra-hepatic ducts while people with autoimmune hepatitis generally have a spared biliary tree.
Other causes of hepatitis:
Viral hepatitis - it is necessary to distinguish autoimmune hepatitis from acute hepatitis caused by Hepatitis A/B/C/D/E, herpes simplex, varicella zoster, EBV, CMV virus
Drug-induced liver injury - portal neutrophils are more prevalent in drug-induced liver injury on liver biopsy and can help distinguish the two
Nonalcoholic steatohepatitis - related medical history and liver biopsy showing fatty infiltration and the presence of neutrophils and central fibrosis can distinguish the two
Lupus-associated liver disease - rarely presents with elevated ASMA or AMA antibodies
Acute liver failure - people with acute liver failure may have elevated autoantibodies but the antibodies alone are not enough for the diagnosis of autoimmune hepatitis
Iron overload - elevated iron in the body can cause liver inflammation

Treatment
The choice for medical treatment should be based on the individuals severity of symptoms, quantitative elevation of liver enzymes and antibody levels, findings on liver biopsy, and ability to tolerate side effects of medical therapy.
Generally, treatment is not required in asymptomatic patients with normal liver enzyme and antibody levels and liver biopsies that do not demonstrate inflammation because these patients are at a low risk of disease progression. In symptomatic individuals with evidence of interface hepatitis and necrosis on liver biopsy, it is recommended to offer treatment especially if the patient is young and can tolerate the side effects of medical therapy.The mainstay of treatment involves the use of immunosuppressive glucocorticoids such as prednisone during acute episodes and resolution of symptoms can be achieved in up to 60–80% of cases, although many will eventually experience a relapse. In individuals with moderate to severe disease who may not tolerate glucocorticoids, lower dose prednisone monotherapy or combination with azathioprine is a reasonable alternative. Budesonide has been shown to be more effective in inducing remission than prednisone, but evidence is scarce and more data is needed before it can be routinely recommended </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 Vascular headache 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 Spondylocostal dysostosis and can you explain it in depth? [/INST] Spondylocostal dysostosis, also known as Jarcho-Levin syndrome (JLS), is a rare, heritable axial skeleton growth disorder. It is characterized by widespread and sometimes severe malformations of the vertebral column and ribs, shortened thorax, and moderate to severe scoliosis and kyphosis. Individuals with Jarcho-Levin typically appear to have a short trunk and neck, with arms appearing relatively long in comparison, and a slightly protuberant abdomen. Severely affected individuals may have life-threatening pulmonary complications due to deformities of the thorax. The syndrome was first described by Saul Jarcho and Paul M. Levin at Johns Hopkins University in 1938.

Genetics
Types include:

Diagnosis
Subtypes and characteristics
In 1968, Dr. David Rimoin and colleagues in Baltimore first distinguished between the two major presentations of Jarcho-Levin. Both conditions were characterized as failures of proper vertebral segmentation. However, the condition within the family described in their article appeared to be inherited in an  autosomal dominant fashion and had a less severe course than that reported by other investigators. They specified their condition as spondylocostal dysplasia, which has since become known as spondylocostal dysostosis </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 Idiopathic scrotal calcinosis 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 Monosomy 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 Human back and can you explain it in depth? [/INST] The human back, also called the dorsum, is the large posterior area of the human body, rising from the top of the buttocks to the back of the neck. It is the surface of the body opposite from the chest and the abdomen. The vertebral column runs the length of the back and creates a central area of recession. The breadth of the back is created by the shoulders at the top and the pelvis at the bottom.
Back pain is a common medical condition, generally benign in origin.

Structure
The central feature of the human back is the vertebral column, specifically the length from the top of the thoracic vertebrae to the bottom of the lumbar vertebrae, which houses the spinal cord in its spinal canal, and which generally has some curvature that gives shape to the back. The ribcage extends from the spine at the top of the back (with the top of the ribcage corresponding to the T1 vertebra), more than halfway down the length of the back, leaving an area with less protection between the bottom of the ribcage and the hips. The width of the back at the top is defined by the scapula, the broad, flat bones of the shoulders.

Muscles
The muscles of the back can be divided into three distinct groups; a superficial group, an intermediate group and a deep group.

Superficial group
The superficial group, also known as the appendicular group, is primarily associated with movement of the appendicular skeleton. It is composed of trapezius, latissimus dorsi, rhomboid major, rhomboid minor and levator scapulae. It is innervated by anterior rami of spinal nerves, reflecting its embryological origin outside the back.

Intermediate group
The intermediate group is also known as respiratory group as it may serve a respiratory function. It is composed of serratus posterior superior and serratus posterior inferior. Like the superficial group, it is innervated by anterior rami of spinal nerves.

Deep group
The deep group, also known as the intrinsic group due to its embryological origin in the back, can be further subdivided into four groups:

Spinotransversales - composed of splenius capitis and splenius cervicis.
Erector spinae - composed of iliocostalis, longissismus and spinalis
Transversospinales - composed of semispinalis, multifidus and rotatores
Segmental muscles - composed of levatores costarum, interspinales and intertransversariiThe deep group is innervated by the posterior rami of spinal nerves.

Organs near the back
The lungs are within the ribcage, and extend to the back of the ribcage making it possible for them to be listened into through the back. The kidneys are situated beneath the muscles in the area below the end of the ribcage, loosely connected to the peritoneum. A strike to the lower back can damage the kidneys of the person being hit.

Surface of the back
The skin of the human back is thicker and has fewer nerve endings than the skin on any other part of the torso. With some notable exceptions (see, e.g. George "The Animal" Steele), it tends to have less hair than the chest on men. The upper-middle back is also the one area of the body which a typical human under normal conditions might be unable to physically touch.
The skin of the back is innervated by the dorsal cutaneous branches, as well as the lateral abdominal cutaneous branches of intercostal nerves.

Movement
The intricate anatomy of the back provides support for the head and trunk of the body, strength in the trunk of the body, as well as a great deal of flexibility and movement. The upper back has the most structural support, with the ribs attached firmly to each level of the thoracic spine and very limited movement. The lower back (lumbar vertebrae) allows for flexibility and movement in back bending (extension) and forward bending (flexion). It does not permit twisting.

Clinical significance
Back pain
The back comprises interconnecting nerves, bones, muscles, ligaments, and tendons, all of which can be a source of pain. Back pain is the second most common type of pain in adults (the most common being headaches). By far the most common cause of back pain is muscle strain. The back muscles can usually heal themselves within a couple of weeks, but the pain can be intense and debilitating. Other common sources of back pain include disc problems, such as degenerative disc disease or a lumbar disc herniation, many types of fractures, such as spondylolisthesis or an osteoporotic fracture, or osteoarthritis.

Society and culture

The curvature of the female back is a frequent theme in paintings, because the sensibilities of many cultures permit the back to be shown nude - implying full nudity without actually displaying it. Indeed, the practice of showing explicitness on the lower back has been performed for centuries. Certain articles of clothing, such as the haltertop and the backless dress, are designed to expose the back in this manner. The lower back is typically exposed frequently by many types of shirts in womans fashion, and even the more conservative shirts and blouses will reveal the lower back. This happens for a variety of reasons- the lower waist area is a pivot point for the body and lengthens and arches as a person sits or bends </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 Chest injury 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 Eosinophilic folliculitis and can you explain it in depth? [/INST] Eosinophilic folliculitis  is an itchy rash with an unknown cause that is most common among individuals with HIV, though it can occur in HIV-negative individuals where it is known by the eponym Ofuji disease. EF consists of itchy red bumps (papules) centered on hair follicles and typically found on the upper body, sparing the abdomen and legs. The name eosinophilic folliculitis refers to the predominant immune cells associated with the disease (eosinophils) and the involvement of the hair follicles.

Pathophysiology
The cause of EF is unknown. A variety of microorganisms have been implicated, including the mite Demodex, the yeast Pityrosporum, and bacteria </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 Hymen and can you explain it in depth? [/INST] The hymen is a thin piece of mucosal tissue that surrounds or partially covers the external vaginal opening. It forms part of the vulva, or external genitalia, and is similar in structure to the vagina.In children, a common appearance of the hymen is crescent-shaped, although many shapes are possible. During puberty, estrogen causes the hymen to change in appearance and become very elastic. Normal variations of the post-pubertal hymen range from thin and stretchy to thick and somewhat rigid. Very rarely, it may be completely absent.The hymen can rip or tear during first penetrative intercourse, which usually results in pain and, sometimes, mild temporary bleeding or spotting. Sources differ on how common tearing or bleeding after first intercourse are. The state of the hymen is not a reliable indicator of virginity, though "virginity testing" remains a common practice in some cultures, sometimes accompanied by surgical restoration of hymen to give the appearance of virginity. Minor injuries to the hymen may heal on their own, and not require surgical intervention.

Development and histology
The genital tract develops during embryogenesis, from the third week of gestation to the second trimester, and the hymen is formed following the vagina. At week seven, the urorectal septum forms and separates the rectum from the urogenital sinus. At week nine, the Müllerian ducts move downwards to reach the urogenital sinus, forming the uterovaginal canal and inserting into the urogenital sinus. At week twelve, the Müllerian ducts fuse to create a primitive uterovaginal canal called unaleria. At month five, the vaginal canalization is complete and the fetal hymen is formed from the proliferation of the sinovaginal bulbs (where Müllerian ducts meet the urogenital sinus), and normally becomes perforate before or shortly after birth.The hymen has dense innervation. In newborn babies, still under the influence of the mothers hormones, the hymen is thick, pale pink, and redundant (folds in on itself and may protrude). For the first two to four years of life, the infant produces hormones that continue this effect. Their hymenal opening tends to be annular (circumferential).
Post neonatal stage, the diameter of the hymenal opening (measured within the hymenal ring) widens by approximately 1 mm for each year of age. During puberty, estrogen causes the hymen to become very elastic and fimbriated.

The hymen can stretch or tear as a result of various behaviors, by the use of tampons or menstrual cups, pelvic examinations with a speculum, sexual intercourse, insertion of multiple fingers or items into the vagina, and activities such as gymnastics (doing the splits), horseback riding or trauma caused by a "straddle injury". Remnants of the hymen are called carunculae myrtiformes.A glass or plastic rod of 6 mm diameter having a globe on one end with varying diameter from 10 to 25 mm, called a Glaister Keen rod, is used for close examination of the hymen or the degree of its rupture. In forensic medicine, it is recommended by health authorities that a physician who must swab near this area of a prepubescent girl avoid the hymen and swab the outer vulval vestibule instead. In cases of suspected rape or child sexual abuse, a detailed examination of the hymen may be performed, but the condition of the hymen alone is often inconclusive.

Anatomic variations
Normal variations of the hymen range from thin and stretchy to thick and somewhat rigid.  An imperforate hymen occurs in 1-2 out of 1,000 infants. The only variation that may require medical intervention is the imperforate hymen, which either completely prevents the passage of menstrual fluid or slows it significantly. In either case, surgical intervention may be needed to allow menstrual fluid to pass or intercourse to take place at all.Prepubescent hymenal openings come in many shapes, depending on hormonal and activity level, the most common being crescentic (posterior rim): no tissue at the 12 oclock position; crescent-shaped band of tissue from 1–2 to 10–11 oclock, at its widest around 6 oclock. From puberty onwards, depending on estrogen and activity levels, the hymenal tissue may be thicker, and the opening is often fimbriated or erratically shaped. In younger children, a torn hymen will typically heal very quickly. In adolescents, the hymenal opening can naturally extend and variation in shape and appearance increases.Variations of the female reproductive tract can result from agenesis or hypoplasia, canalization defects, lateral fusion and failure of resorption, resulting in various complications.
Imperforate: hymenal opening nonexistent; will require minor surgery if it has not corrected itself by puberty to allow menstrual fluids to escape.
Cribriform, or microperforate: sometimes confused for imperforate, the hymenal opening appears to be nonexistent, but has, under close examination, small perforations.
Septate: the hymenal opening has one or more bands of tissue extending across the opening.

Trauma
Historically, it was believed that first sexual intercourse was necessarily traumatic to the hymen and always resulted in the hymen being "broken" or torn, causing bleeding. However, research on women in Western populations has found that bleeding during first intercourse does not invariably occur. In one cross-cultural study, slightly more than half of all women self-reported bleeding during first intercourse, with significantly different levels of pain and bleeding reported depending on their region of origin </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 Diamond–Blackfan anemia and can you explain it in depth? [/INST] Diamond–Blackfan anemia (DBA) is a congenital erythroid aplasia that usually presents in infancy. DBA causes low red blood cell counts (anemia), without substantially affecting the other blood components (the platelets and the white blood cells), which are usually normal. This is in contrast to Shwachman–Bodian–Diamond syndrome, in which the bone marrow defect results primarily in neutropenia, and Fanconi anemia, where all cell lines are affected resulting in pancytopenia.
A variety of other congenital abnormalities may also occur in DBA.

Signs and symptoms
Diamond–Blackfan anemia is characterized by normocytic or macrocytic anemia (low red blood cell counts) with decreased erythroid progenitor cells in the bone marrow.  This usually develops during the neonatal period.  About 47% of affected individuals also have a variety of congenital abnormalities, including craniofacial malformations, thumb or upper limb abnormalities, cardiac defects, urogenital malformations, and cleft palate.  Low birth weight and generalized growth delay are sometimes observed. DBA patients have a modest risk of developing leukemia and other malignancies.

Genetics
Most pedigrees suggest an autosomal dominant mode of inheritance with incomplete penetrance.  Approximately 10–25% of DBA occurs with a family history of disease.
About 25-50% of the causes of DBA have been tied to abnormal ribosomal protein genes. The disease is characterized by genetic heterogeneity, affecting different ribosomal gene loci: Exceptions to this paradigm have been demonstrated, such as with rare mutations of transcription factor GATA1 and advanced alternative splicing of a gene involved in iron metabolism, SLC49A1 (FLVCR1).
In 1997, a patient was identified who carried a rare balanced chromosomal translocation involving chromosome 19 and the X chromosome.  This suggested that the affected gene might lie in one of the two regions that were disrupted by this cytogenetic anomaly.  Linkage analysis in affected families also implicated this region in disease, and led to the cloning of the first DBA gene.  About 20–25% of DBA cases are caused by mutations in the ribosome protein S19 (RPS19) gene on chromosome 19 at cytogenetic position 19q13.2.  Some previously undiagnosed relatives of DBA patients were found to carry mutations, and also had increased adenosine deaminase levels in their red blood cells, but had no other overt signs of disease.A subsequent study of families with no evidence of RPS19 mutations determined that 18 of 38 families showed evidence for involvement of an unknown gene on chromosome 8 at 8p23.3-8p22.  The precise genetic defect in these families has not yet been delineated.
Malformations are seen more frequently with DBA6 RPL5 and DBA7 RPL11 mutations.The genetic abnormalities underpinning the combination of DBA with Treacher Collins syndrome (TCS)/mandibulofacial dysostosis (MFD) phenotypes are heterogeneous, including RPS26 (the known DBA10 gene), TSR2 which encodes a direct binding partner of RPS26, and RPS28.

Molecular basis
The phenotype of DBA patients suggests a hematological stem cell defect specifically affecting the erythroid progenitor population.  Loss of ribosomal function might be predicted to affect translation and protein biosynthesis broadly and impact many tissues.  However, DBA is characterized by dominant inheritance, and arises from partial loss of ribosomal function, so it is possible that erythroid progenitors are more sensitive to this decreased function, while most other tissues are less affected.

Diagnosis
Typically, a diagnosis of DBA is made through a blood count and a bone marrow biopsy.
A diagnosis of DBA is made on the basis of anemia, low reticulocyte (immature red blood cells) counts, and diminished erythroid precursors in bone marrow.  Features that support a diagnosis of DBA include the presence of congenital abnormalities, macrocytosis, elevated fetal hemoglobin, and elevated adenosine deaminase levels in red blood cells.Most patients are diagnosed in the first two years of life.  However, some mildly affected individuals only receive attention after a more severely affected family member is identified.About 20–25% of DBA patients may be identified with a genetic test for mutations in the RPS19 gene.

Treatment
Corticosteroids can be used to treat anemia in DBA.  In a large study of 225 patients, 82% initially responded to this therapy, although many side effects were noted.  Some patients remained responsive to steroids, while efficacy waned in others.  Blood transfusions can also be used to treat severe anemia in DBA.  Periods of remission may occur, during which transfusions and steroid treatments are not required.  Bone marrow transplantation (BMT) can cure hematological aspects of DBA.  This option may be considered when patients become transfusion-dependent because frequent transfusions can lead to iron overloading and organ damage.  However, adverse events from BMTs may exceed those from iron overloading </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 Neonatal hemochromatosis and can you explain it in depth? [/INST] Neonatal Hemochromatosis is a rare and severe liver disease of unknown origin, though research suggests that it may be alloimmune condition.  Its characteristics are similar to hereditary hemochromatosis, where iron deposition causes damage to the liver and other organs and tissues.

Causes
The causes of neonatal hemochromatosis are still unknown, but recent research has led to the hypothesis that it is an alloimmune disease.  Evidence supporting this hypothesis includes the high rate among siblings (>80%) </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 Descending perineum 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 Pulmonary vein 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 Keratosis pilaris atrophicans faciei 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 Cornea plana 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 Hammer toe and can you explain it in depth? [/INST] A hammer toe or contracted toe is a deformity of the muscles and ligaments of the proximal interphalangeal joint of the second, third, fourth, or fifth toe causing it to be bent, resembling a hammer.  In the early stage a flexible hammertoe is movable at the joints; a rigid hammertoe joint cannot be moved and usually requires surgery.Mallet toe is a similar condition affecting the distal interphalangeal joint.Claw toe is another similar condition, with dorsiflexion of the proximal phalanx on the lesser metatarsophalangeal joint, combined with flexion of both the proximal and distal interphalangeal joints. Claw toe can affect the second, third, fourth, or fifth toes.

Risk factors
Older people are more likely to develop hammer toes. Women are at higher risk, due to the construction of womens shoes </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 Hemeralopia and can you explain it in depth? [/INST] Hemeralopia (from Greek ημέρα hemera, "day", and αλαός alaos, "blindness") is the inability to see clearly in bright light and is the exact opposite of nyctalopia (night blindness), the inability to see clearly in low light. Hemera was the Greek goddess of day, and Nyx was the goddess of night. However, it has been used in an opposite sense by many non-English-speaking doctors. It can be described as insufficient adaptation to bright light. It is also called "heliophobia" and "day blindness".In hemeralopia, daytime vision gets worse, characterised by photoaversion (dislike/avoidance of light) rather than photophobia (eye discomfort/pain in light), which is typical of inflammations of eye. Nighttime vision largely remains unchanged due to the use of rods as opposed to cones (during the day), which are affected by hemeralopia and in turn degrade the daytime optical response </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 Halogen acne 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 Neurofibromatosis type I and can you explain it in depth? [/INST] Neurofibromatosis type I (NF-1) is a complex multi-system human disorder caused by the mutation of neurofibromin, a gene on chromosome 17 that is responsible for production of a protein which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any persons race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy (or allele) of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1.As of 2015, there are at least 100,000 people in the U.S. and about 10,000 people in the UK who have been diagnosed with NF. Common symptoms of NF-1 include brownish-red spots in the colored part of the eye called Lisch nodules, benign skin tumors called neurofibromas, and larger benign tumors of nerves called plexiform neurofibromas, scoliosis (curvature of the spine), learning disabilities, vision disorders, mental disabilities, multiple café au lait spots and epilepsy. NF-1 affected individuals also have a much higher rate of cancer and cardiovascular disease than the population in general.NF-1 is a developmental syndrome caused by germline mutations in neurofibromin, a gene that is involved in the RAS pathway (RASopathy). Due to its rarity and to the fact that genetic diagnosis has been used only in recent years, in the past NF-1 was in some cases confused with Legius syndrome, another syndrome with vaguely similar symptoms, including cafe-au-lait spots.NF-1 is an age specific disease; most signs of NF-1 are visible after birth (during infancy), but many symptoms of NF-1 occur as the person ages and has hormonal changes. NF-1 was formerly known as von Recklinghausen disease, after the researcher (Friedrich Daniel von Recklinghausen) who first documented the disorder.The severity of NF-1 varies widely, and little is known about what causes a person to have a more severe or less severe case. Even within the same family (as there is a 50% chance that a parent will pass their condition to their offspring), levels of severity can vary enormously. However, 60% of people with NF-1 have mild cases, with few symptoms that have very little effect in their day-to-day lives. 20% of NF-1 patients have moderate cases, with several symptoms that have little more than cosmetic effects. The other 20% have severe cases with several symptoms that affect the persons quality of life. Even in this last group, symptoms are rarely life-threatening.

Signs and symptoms
The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. The progression of the condition is roughly as follows:

Congenital musculoskeletal disorders may or may not be present
Cutaneous conditions may be observed in early infancy
Small tumors may arise in the retina which can eventually lead to blindness. Also, Lisch Nodules may grow on the iris, but these are harmless.
Learning disabilities may arise in preschool children
Neurofibromas may occur and can sometimes cause many dependent neurological conditions and cutaneous and skeletal disfigurement.
Depression and social anxiety may occur as a result of disabilities caused by the condition
Neurofibromas may, in 8-13% of cases, transition into cancer, which can be fatal The NF Clinical Program at St. Louis Childrens Hospital maintains a comprehensive list of current NF research studies Archived 2015-11-26 at the Wayback Machine.

Musculoskeletal disorder
Musculoskeletal abnormalities affecting the skull include sphenoid bone dysplasia, congenital hydrocephalus and associated neurologic impairment.  These abnormalities are non-progressive and may be diagnosed in the fetus or at birth.Disorders affecting the spine include:

In NF-1, there can be a generalized abnormality of the soft tissues in the fetus, which is referred to as mesodermal dysplasia, resulting in maldevelopment of skeletal structures.
Meningoceles and formation of cystic diverticula of the dura of the spine, unrelated to Spina bifida
Radiographically, dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic diverticula of the dura of the spine. This may result in temporary or permanent loss of lower extremity sensorimotor function.
Focal scoliosis and/or kyphosis are the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately 25% of patients will require corrective surgery.Skeletal muscle weakness and motor control deficits
Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with a primary problem in muscle function (myopathy).Clinical findings in people with NF-1 include:

Reduced skeletal muscle size
Reduced exercise capacity
Muscle weakness (The most recent study reports between 30–50% reduced upper and lower limb muscle strength in NF-1 children compare with matched controls).Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness.NF-1 is a disease in the RASopathy family of diseases, which include Costello Syndrome, Noonan Syndrome, and Cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness. It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown.

Facial bones and limbs
Bowing of a long bone with a tendency to fracture and not heal, yielding a pseudarthrosis. The most common bone to be affected is the tibia, causing congenital pseudarthrosis of the tibia or CPT. CPT occurs in 2–4% of individuals with NF-1.  Treatment includes limb amputation or correction by Ilizarov method as a limb-sparing technique.
Malformation of the facial bones or of the eye sockets (lambdoid suture defects, sphenoid dysplasia)
Unilateral overgrowth of a limb.  When a plexiform neurofibroma manifests on a leg or arm, it will cause extra blood circulation, and may thus accelerate the growth of the limb. This may cause considerable difference in length between left and right limbs. To equalize the difference during childhood, there is an orthopedic surgery called epiphysiodesis, where growth at the epiphyseal (growth) plate is halted. It can be performed on one side of the bone to help correct an angular deformity, or on both sides to stop growth of that bone completely.  The surgery must also be carefully planned with regard to timing, as it is non-reversible.  The goal is that the limbs are at near-equal length at end of growth...

Skin
Flat pigmented lesions of the skin called café au lait spots, are hyper pigmented lesions that may vary in color from light brown to dark brown; this is reflected by the name of the condition, which means "coffee with milk". The borders may be smooth or irregular. These spots can grow from birth and can continue to grow throughout the persons lifetime. They can increase in size and numbers during puberty and during pregnancies. They are present in about 99% patient of European origin and in about 93% patient of Indian origin.
Freckling of the axillae or inguinal regions.
Dermal neurofibroma, manifested as single or multiple firm, rubbery bumps of varying sizes on a persons skin.  Age of onset is puberty.  Progressive in number and size.  Not malignant.  Can be treated with CO2 lasers or by removal by a plastic surgeon specialized in NF1.

Eye disease
Lisch nodules in the iris.
Optic nerve gliomas along one or both optic nerves or the optic chiasm can cause bulging of the eyes, involuntary eye movement, squinting, and / or vision loss.  Treatment may include surgery, radiation +/- steroids, or chemotherapy (in children).

Neurobehavioral developmental disorder
The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 90% of children and adults with NF-1 and have significant effects on their schooling and everyday life.  These cognitive problems have been shown to be stable into adulthood mainly in the mid 20s to early 30s and do not get worse unlike some of the other physical symptoms of NF-1.  The most common cognitive problems are with perception, executive functioning and attention.   Disorders include:

Approximately 42% of children with NF-1 have symptoms of autism, with 36.78% of them being severe cases, 33.33% being mild to moderate cases, and 29.89% of them having both symptoms of autism and ADHD.
Attention deficit hyperactivity disorder has been shown to be present in approximately 40% of children with NF-1.
Speech and language delays have also been identified in approximately 68% of preschool children with NF-1.
Motor deficits are common.  Motor deficits due to NF-1 are probably not cerebellar.
Spatial deficit. Lovastatin, normally used to treat hypercholesterolemia, is currently in phase one of clinical trial (NCT00352599).  This drug has been shown to reverse spatial deficits in mice. Simvastatin, a drug similar to lovastatin, did not show benefit on cognitive function or behaviour in two randomized controlled trials in children with NF-1.

Nervous system disease
The primary neurologic involvement in NF-1 is of the peripheral nervous system, and secondarily of the central nervous system. Schwannomatosis is a rare condition defined by the presence of multiple benign tumors of nerves that are frequently very painful. In addition to pain, weakness is a common problem. Symptoms usually begin in young or mid-adult years.

Peripheral neuropathy
Neurofibroma
A neurofibroma is a lesion of the peripheral nervous system.  Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts.  Neurofibromas may arise sporadically, or in association with NF-1.  A neurofibroma may arise at any point along a peripheral nerve.  A number of drugs have been studied to treat this condition.Neurofibroma conditions are progressive and include:

Plexiform neurofibroma: Often congenital.  Lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue.  However, early intervention may be beneficial: a 2004 study in Germany concluded "Early surgical intervention of small superficial PNFs is uncomplicated, without burden for even the youngsters and enables total resection of the tumors. It may be considered as a preventive strategy for later disfigurement and functional deficits."
Solitary neurofibroma, affecting 8–12% of patients with NF-1.  This occurs in a deep nerve trunk.   Diagnosis by cross-sectional imaging (e.g., computed tomography or magnetic resonance) as a fusiform enlargement of a nerve.
Schwannomas, peripheral nerve-sheath tumors which are seen with increased frequency in NF-1.  The major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be resected while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve.
Nerve root neurofibroma.
Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibroma or Schwannoma. Similarly, the neural foramen of the spine can be widened due to the presence of a nerve root neurofibroma or schwannoma. Surgery may be needed when NF-1 related tumors compress organs or other structures.

Nerve sheath tumor
Chronic pain, numbness, and/or paralysis due to peripheral nerve sheath tumor.

Other complications
Renal artery anomalies or pheochromocytoma and associated chronic hypertension
Schwannoma
Plexiform fibromas
Optic nerve glioma
Epilepsy

Central nervous system disease
Epilepsy
Occurrence. Epileptic seizures have been reported in up to 7% of NF-1 patients.
Diagnosis.  Electroencephalograph, magnetic resonance imaging, computed tomographic scan, single-photon emission CT and positron emission tomographic scan.
Etiology.  Due to cerebral tumors, cortical malformation, mesial temporal sclerosis.
Therapy.  Drug therapy (57% amenable) where not resistant (29%).

Glial tumors
Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily:
Optic nerve gliomas and associated blindness.
Astrocytoma

Focally degenerative myelin
Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain.  These UBOs are typically found in the Cerebral peduncle, pons, midbrain, globus pallidus, thalamus, and optic radiations.  Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected.  They may represent a focally degenerative bit of myelin.

Dural ectasia
Within the CNS, NF-1 manifests as a weakness of the dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement due to chronic exposure to the pressures of CSF pulsation, and typically presents as paraesthesia or loss of motor or sensory function. It has been shown that dural ectasia occur near plexiform neurofibromas which may be infiltrative leading to weakening of the dura.Acetazolamide has shown promise as a treatment for this condition, and in very few cases do dural ectasia require surgery.

Mental disorder
Children and adults with NF-1 can experience social problems, attention problems, social anxiety, depression, withdrawal, thought problems, somatic complaints, learning disabilities and aggressive behavior. Treatments include psychotherapy, antidepressants and cognitive behavioral therapy.

Puberty and height
Children diagnosed with NF-1 may experience delayed or precocious puberty. Recent studies have correlated precocious puberty in individuals with NF-1 with the presence of optic pathway tumors. Furthermore, the heights of children affected by NF-1 have been shown to increase normally until puberty, after which increases in height lessen when compared to healthy counterparts. This eventually causes a shorter stature than expected in individuals with NF-1.

Cancer
Cancer can arise in the form of malignant peripheral nerve sheath tumor resulting from malignant degeneration of a plexiform neurofibroma.
Frequency. A plexiform neurofibroma has a lifetime risk of 8–12% of transformation into a malignant tumor.
Diagnosis.  MRI.
Treatment.  Surgery (primary), radiation therapy.
Mortality.  Malignant nerve sheath tumor was the main cause of death (60%) in a study of 1895 patients with NF-1 from France in the time period 1980–2006 indicated excess mortality in NF-1 patients compared to the general population.  The cause of death was available for 58 (86.6%) patients.  The study found excess mortality occurred among patients aged 10 to 40 years. Significant excess mortality was found in both males and females.

Cause
Neurofibromin 1 gene
NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin (not to be confused with the disorder itself) which plays a role in cell signaling. The Neurofibromin 1 gene is a negative regulator of the Ras oncogene signal transduction pathway. It stimulates the GTPase activity of Ras.  It shows greater affinity for RAS p21 protein activator 1, but lower specific activity.  The mRNA for this gene is subject to RNA editing (CGA->UGA->Arg1306Term) resulting in premature translation termination.  Alternatively spliced transcript variants encoding different isoforms have also been described for this gene.In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17. It was localized to the long arm of chromosome 17 by chance when researchers discovered chromosome exchanges between chromosome 17 with chromosome 1 and 22. This exchange of genetic material presumably caused a mutation in the neurofibromin gene, leading to the NF1 phenotype. Two recurrent microdeletion types with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion), are found in most cases.

Structure
The neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length. However, the protein is 2818 amino acids long leading to the concept of splice variants. For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively.Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase activating protein (GAP) family. This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase.Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase, and a second with collapsin response mediator protein. Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development.

Inheritance and spontaneous mutation
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation. The incidence of NF-1 is about 1 in 3500 live births.

Related medical conditions
Mutations in the NF1 gene have been linked to NF-1, juvenile myelomonocytic leukemia and Watson syndrome.  A condition with a separate gene mutation but similar Café au lait spots is Legius syndrome, which has a mutation on the SPRED1 gene.

Diagnosis
Prenatal testing and prenatal expectations
Prenatal testing may be used to identify the existence of NF-1 in the fetus. For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis to screen for NF-1.Chorionic villus sampling or amniocentesis can be used to detect NF-1 in the fetus.While the presence of NF-1 can be identified through prenatal testing the severity with which the condition will be expressed is impossible to determine.People with NF-1 have a 50% percent chance of passing the disorder on to their kids, but people can have a child born with NF-1 when they themselves do not have it. This is caused in a spontaneous change in the genes during pregnancy.

Post-natal testing
The National Institutes of Health (NIH) has created specific criteria for the diagnosis of NF-1.  Two of these seven "Cardinal Clinical Features" are required for positive diagnosis. There is practical flowchart to distinguish between NF1, NF2 and schwannomatosis.
Six or more café-au-lait spots over 5 mm in greatest diameter in pre-pubertal individuals and over 15 mm in greatest diameter in post-pubertal individuals.  Note that multiple café-au-lait spots alone are not a definitive diagnosis of NF-1 as these spots can be caused by a number of other conditions.
Two or more neurofibromas of any type or 1 plexiform neurofibroma
Freckling in the axillary (Crowe sign) or inguinal regions
Optic nerve glioma
Two or more Lisch nodules (pigmented iris hamartomas)
A distinctive osseous lesion such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudarthrosis.
A first degree relative (parent, sibling, or offspring) with NF-1 by the above criteria.

Treatment
Selumetinib, sold under the brand name Koselugo, is a drug approved by FDA in April 2020 for the treatment of NF-1 in pediatric population who are two or more years of age. It is a kinase inhibitor and is indicated for use pediatric patients who are symptomatic and have plexiform neurofibromas which cannot be operated.There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications. In progress and recently concluded medical studies on NF-1 can be found by searching the official website of the National Institutes of Health.

Prognosis
NF-1 is a progressive and diverse condition, making the prognosis difficult to predict. The NF-1 gene mutations manifest the disorder differently even amongst people of the same family.  This phenomenon is called variable expressivity. For example, some individuals have no symptoms, while others may have a manifestation that is rapidly more progressive and severe.
For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities. However, there are many more severe complications caused by NF-1 like increased cancer risk, a plexiform neurofibroma has a 10-15% chance of developing into a MPNST (Malignant Peripheral Nerve Sheath Tumour) . Many NF patients live perfectly normal and uninterrupted lives.

Epidemiology
NF-1 is estimated to affect around 25,000 people in the UK.

See also
Neurofibromatosis type II

References
External links

Friedman, J </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 Nitrogen narcosis and can you explain it in depth? [/INST] Narcosis while diving (also known as nitrogen narcosis, inert gas narcosis, raptures of the deep, Martini effect) is a reversible alteration in consciousness that occurs while diving at depth. It is caused by the anesthetic effect of certain gases at high pressure. The Greek word νάρκωσις (narkōsis), "the act of making numb", is derived from νάρκη (narkē), "numbness, torpor", a term used by Homer and Hippocrates. Narcosis produces a state similar to drunkenness (alcohol intoxication), or nitrous oxide inhalation. It can occur during shallow dives, but does not usually become noticeable at depths less than  30 meters (100 ft).
Except for helium and probably neon, all gases that can be breathed have a narcotic effect, although widely varying in degree.  The effect is consistently greater for gases with a higher lipid solubility, and although the mechanism of this phenomenon is still not fully clear, there is good evidence that the two properties are mechanistically related. As depth increases, the mental impairment may become hazardous. Divers can learn to cope with some of the effects of narcosis, but it is impossible to develop a tolerance. Narcosis can affect all divers, although susceptibility varies widely among individuals and from dive to dive. The main class of diving that deals with its prevention and treatment is scuba diving at substantial depth.
Narcosis may be completely reversed in a few minutes by ascending to a shallower depth, with no long-term effects. Thus narcosis while diving in open water rarely develops into a serious problem as long as the divers are aware of its symptoms, and are able to ascend to manage it. Diving much beyond 40 m (130 ft) is generally considered outside the scope of recreational diving. In order to dive at greater depths, as narcosis and oxygen toxicity become critical risk factors, specialist training is required in the use of various helium-containing gas mixtures such as trimix or heliox. These mixtures prevent narcosis by replacing some or all of the inert fraction of the breathing gas with non-narcotic helium.

Classification
Narcosis results from breathing gases under elevated pressure, and may be classified by the principal gas involved. The noble gases, except helium and probably neon, as well as nitrogen, oxygen and hydrogen cause a decrement in mental function, but their effect on psychomotor function (processes affecting the coordination of sensory or cognitive processes and motor activity) varies widely. The effect of carbon dioxide is a consistent diminution of mental and psychomotor function. The noble gases argon, krypton, and xenon are more narcotic than nitrogen at a given pressure, and xenon has so much anesthetic activity that it is a usable anesthetic at 80% concentration and normal atmospheric pressure. Xenon has historically been too expensive to be used very much in practice, but it has been successfully used for surgical operations, and xenon anesthesia systems are still being proposed and designed.

Signs and symptoms
Due to its perception-altering effects, the onset of narcosis may be hard to recognize. At its most benign, narcosis results in relief of anxiety – a feeling of tranquillity and mastery of the environment. These effects are essentially identical to various concentrations of nitrous oxide. They also resemble (though not as closely) the effects of alcohol and the familiar benzodiazepine drugs such as diazepam and alprazolam. Such effects are not harmful unless they cause some immediate danger to go unrecognized and unaddressed. Once stabilized, the effects generally remain the same at a given depth, only worsening if the diver ventures deeper.The most dangerous aspects of narcosis are the impairment of judgement, multi-tasking and coordination, and the loss of decision-making ability and focus. Other effects include vertigo and visual or auditory disturbances. The syndrome may cause exhilaration, giddiness, extreme anxiety, depression, or paranoia, depending on the individual diver and the divers medical or personal history. When more serious, the diver may feel overconfident, disregarding normal safe diving practices. Slowed mental activity, as indicated by increased reaction time and increased errors in cognitive function, are effects which increase the risk of a diver mismanaging an incident. Narcosis reduces both the perception of cold discomfort and shivering and thereby affects the production of body heat and consequently allows a faster drop in the core temperature in cold water, with reduced awareness of the developing problem.The relation of depth to narcosis is sometimes informally known as "Martinis law", the idea that narcosis results in the feeling of one martini for every 10 m (33 ft) below 20 m (66 ft) depth. Professional divers use such a calculation only as a rough guide to give new divers a metaphor, comparing a situation they may be more familiar with.Reported signs and symptoms are summarized against typical depths in meters and feet of sea water in the following table, closely adapted from Deeper into Diving by Lippman and Mitchell:

Causes
The cause of narcosis is related to the increased solubility of gases in body tissues, as a result of the elevated pressures at depth (Henrys law). Modern theories have suggested that inert gases dissolving in the lipid bilayer of cell membranes cause narcosis. More recently, researchers have been looking at neurotransmitter receptor protein mechanisms as a possible cause of narcosis. The breathing gas mix entering the divers lungs will have the same pressure as the surrounding water, known as the ambient pressure. After any change of depth, the pressure of gases in the blood passing through the brain catches up with ambient pressure within a minute or two, which results in a delayed narcotic effect after descending to a new depth. Rapid compression potentiates narcosis owing to carbon dioxide retention.A divers cognition may be affected on dives as shallow as 10 m (33 ft), but the changes are not usually noticeable. There is no reliable method to predict the depth at which narcosis becomes noticeable, or the severity of the effect on an individual diver, as it may vary from dive to dive even on the same day.Significant impairment due to narcosis is an increasing risk below depths of about 30 m (100 ft), corresponding to an ambient pressure of about 4 bar (400 kPa). Most sport scuba training organizations recommend depths of no more than 40 m (130 ft) because of the risk of narcosis. When breathing air at depths of 90 m (300 ft) – an ambient pressure of about 10 bar (1,000 kPa) – narcosis in most divers leads to hallucinations, loss of memory, and unconsciousness. A number of divers have died in attempts to set air depth records below 120 m (400 ft). Because of these incidents, Guinness World Records no longer reports on this figure.Narcosis has been compared with altitude sickness regarding its variability of onset (though not its symptoms); its effects depend on many factors, with variations between individuals. Thermal cold, stress, heavy work, fatigue, and carbon dioxide retention all increase the risk and severity of narcosis. Carbon dioxide has a high narcotic potential and also causes increased blood flow to the brain, increasing the effects of other gases. Increased risk of narcosis results from increasing the amount of carbon dioxide retained through heavy exercise, shallow or skip breathing, or because of poor gas exchange in the lungs.Narcosis is known to be additive to even minimal alcohol intoxication. Other sedative and analgesic drugs, such as opiate narcotics and benzodiazepines, add to narcosis.

Mechanism
The precise mechanism is not well understood, but it appears to be the direct effect of gas dissolving into nerve membranes and causing temporary disruption in nerve transmissions. While the effect was first observed with air, other gases including argon, krypton and hydrogen cause very similar effects at higher than atmospheric pressure. Some of these effects may be due to antagonism at NMDA receptors and potentiation of GABAA receptors, similar to the mechanism of nonpolar anesthetics such diethyl ether or ethylene. However, their reproduction by the very chemically inactive gas argon makes them unlikely to be a strictly chemical bonding to receptors in the usual sense of a chemical bond. An indirect physical effect – such as a change in membrane volume – would therefore be needed to affect the ligand-gated ion channels of nerve cells. Trudell et al. have suggested non-chemical binding due to the attractive van der Waals force between proteins and inert gases.Similar to the mechanism of ethanols effect, the increase of gas dissolved in nerve cell membranes may cause altered ion permeability properties of the neural cells lipid bilayers. The partial pressure of a gas required to cause a measured degree of impairment correlates well with the lipid solubility of the gas: the greater the solubility, the less partial pressure is needed.An early theory, the Meyer-Overton hypothesis, suggested that narcosis happens when the gas penetrates the lipids of the brains nerve cells, causing direct mechanical interference with the transmission of signals from one nerve cell to another. More recently, specific types of chemically gated receptors in nerve cells have been identified as being involved with anesthesia and narcosis. However, the basic and most general underlying idea, that nerve transmission is altered in many diffuse areas of the brain as a result of gas molecules dissolved in the nerve cells fatty membranes, remains largely unchallenged.

Management and diagnosis
The management of narcosis is simply to ascend to shallower depths; the effects then disappear within minutes. In the event of complications or other conditions being present, ascending is always the correct initial response. Should problems remain, then it is necessary to abort the dive. The decompression schedule can still be followed unless other conditions require emergency assistance.The symptoms of narcosis may be caused by other factors during a dive: ear problems causing disorientation or nausea; early signs of oxygen toxicity causing visual disturbances; or hypothermia causing rapid breathing and shivering. Nevertheless, the presence of any of these symptoms should imply narcosis. Alleviation of the effects upon ascending to a shallower depth will confirm the diagnosis. Given the setting, other likely conditions do not produce reversible effects. In the rare event of misdiagnosis when another condition is causing the symptoms, the initial management – ascending closer to the surface – is still essential.

Prevention
The most straightforward way to avoid nitrogen narcosis is for a diver to limit the depth of dives. The other main preventive measure is properly informed selection/choice of which gas to use for the particular dive under consideration.
Since narcosis becomes more severe as depth increases, a diver keeping to shallower depths can avoid serious narcosis. Most recreational dive schools will only certify entry level divers to depths of 18 to 20 m (60 to 70 ft), and at these depths narcosis does not present a significant risk. Further training is normally required for certification up to 30 m (100 ft) on air, and this training should include a discussion of narcosis, its effects, and management. Some diver training agencies offer specialized training to prepare recreational divers to go to depths of 40 m (130 ft), often consisting of further theory and some practice in deep dives under close supervision. Scuba organizations that train for diving beyond recreational depths, may forbid diving with gases that cause too much narcosis at depth in the average diver (such as the typical widely used nitrox mixtures suitable for most recreational diving), and strongly encourage the use of other breathing gas mixes containing helium in place of some or all of the nitrogen in air – such as trimix and heliox – because helium has no narcotic effect. The use of these gases forms part of technical diving and requires further training and certification.While the individual diver cannot predict exactly at what depth the onset of narcosis will occur on a given day, the first symptoms of narcosis for any given diver are often more predictable and personal. For example, one diver may have trouble with eye focus (close accommodation for middle-aged divers), another may experience feelings of euphoria, and another feelings of claustrophobia. Some divers report that they have hearing changes, and that the sound their exhaled bubbles make becomes different. Specialist training may help divers to identify these personal onset signs, which may then be used as a signal to ascend to avoid the narcosis, although severe narcosis may interfere with the judgement necessary to take preventive action.Deep dives should be made only after a gradual training to test the individual divers sensitivity to increasing depths, with careful supervision and logging of reactions. Scientific evidence does not show that a diver can train to overcome any measure of narcosis at a given depth or become tolerant of it.Equivalent narcotic depth (END) is a commonly used way of expressing the narcotic effect of different breathing gases. The National Oceanic and Atmospheric Administration (NOAA) Diving Manual now states that oxygen and nitrogen should be considered equally narcotic. Standard tables, based on relative lipid solubilities, list conversion factors for narcotic effect of other gases. For example, hydrogen at a given pressure has a narcotic effect equivalent to nitrogen at 0.55 times that pressure, so in principle it should be usable at more than twice the depth. Argon, however, has 2.33 times the narcotic effect of nitrogen, and is a poor choice as a breathing gas for diving (it is used as a drysuit inflation gas, owing to its low thermal conductivity). Some gases have other dangerous effects when breathed at pressure; for example, high-pressure oxygen can lead to oxygen toxicity. Although helium is the least intoxicating of the breathing gases, at greater depths it can cause high pressure nervous syndrome, a still mysterious but apparently unrelated phenomenon. Inert gas narcosis is only one factor influencing the choice of gas mixture; the risks of decompression sickness and oxygen toxicity, cost, and other factors are also important.Because of similar and additive effects, divers should avoid sedating medications and drugs, such as cannabis and alcohol before any dive. A hangover, combined with the reduced physical capacity that goes with it, makes nitrogen narcosis more likely. Experts recommend total abstinence from alcohol for at least 12 hours before diving, and longer for other drugs.

Prognosis and epidemiology
Narcosis is potentially one of the most dangerous conditions to affect the scuba diver below about 30 m (100 ft). Except for occasional amnesia of events at depth, the effects of narcosis are entirely removed on ascent and therefore pose no problem in themselves, even for repeated, chronic or acute exposure. Nevertheless, the severity of narcosis is unpredictable and it can be fatal while diving, as the result of illogical behavior in a dangerous environment.Tests have shown that all divers are affected by nitrogen narcosis, though some experience lesser effects than others. Even though it is possible that some divers can manage better than others because of learning to cope with the subjective impairment, the underlying behavioral effects remain. These effects are particularly dangerous because a diver may feel they are not experiencing narcosis, yet still be affected by it.

History
French researcher Victor T. Junod was the first to describe symptoms of narcosis in 1834, noting "the functions of the brain are activated, imagination is lively, thoughts have a peculiar charm and, in some persons, symptoms of intoxication are present." Junod suggested that narcosis resulted from pressure causing increased blood flow and hence stimulating nerve centers. Walter Moxon (1836–1886), a prominent Victorian physician, hypothesized in 1881 that pressure forced blood to inaccessible parts of the body and the stagnant blood then resulted in emotional changes. The first report of anesthetic potency being related to lipid solubility was published by Hans H. Meyer in 1899, entitled Zur Theorie der Alkoholnarkose. Two years later a similar theory was published independently by Charles Ernest Overton. What became known as the Meyer-Overton hypothesis may be illustrated by a graph comparing narcotic potency with solubility in oil.
In 1939, Albert R. Behnke and O. D. Yarborough demonstrated that gases other than nitrogen also could cause narcosis. For an inert gas the narcotic potency was found to be proportional to its lipid solubility. As hydrogen has only 0.55 the solubility of nitrogen, deep diving experiments using hydrox were conducted by Arne Zetterström between 1943 and 1945. Jacques-Yves Cousteau in 1953 famously described it as "livresse des grandes profondeurs" or the "rapture of the deep".Further research into the possible mechanisms of narcosis by anesthetic action led to the "minimum alveolar concentration" concept in 1965. This measures the relative concentration of different gases required to prevent motor response in 50% of subjects in response to stimulus, and shows similar results for anesthetic potency as the measurements of lipid solubility. The (NOAA) Diving Manual was revised to recommend treating oxygen as if it were as narcotic as nitrogen, following research by Christian J. Lambertsen et al. in 1977 and 1978.

See also
Hydrogen narcosis – Psychotropic state induced by breathing hydrogen at high partial pressures
Oxygen toxicity – Toxic effects of breathing oxygen at high concentrations

Footnotes
References
Notes
Sources
Bennett, Peter; Rostain, Jean Claude (2003). "Inert Gas Narcosis".  In Brubakk, Alf O; Neuman, Tom S (eds.). Bennett and Elliotts physiology and medicine of diving (5th ed.). United States: Saunders. ISBN 0-7020-2571-2. OCLC 51607923.
Lippmann, John; Mitchell, Simon J. (2005). "Nitrogen narcosis". Deeper into Diving (2nd ed.). Victoria, Australia: J. L. Publications. pp. 103–8. ISBN 0-9752290-1-X. OCLC 66524750.
U.S. Navy Supervisor of Diving (2008). U.S. Navy Diving Manual (PDF). SS521-AG-PRO-010, revision 6. U.S. Naval Sea Systems Command. Archived from the original (PDF) on 2014-12-10. Retrieved 2014-01-21.

External links
Undersea and Hyperbaric Medical Society Scientific body, publications about nitrogen narcosis.
Rubicon Research Repository Searchable repository of Diving and Environmental Physiology Research.
Diving Diseases Research Centre (DDRC) UK charity dedicated to treatment of diving diseases.
Campbell, Ernest S. (2009-06-25). "Diving While Using Marijuana". Retrieved 2009-08-25 </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 B-cell prolymphocytic leukemia and can you explain it in depth? [/INST] B-cell prolymphocytic leukemia, referred to as B-PLL, is a rare blood cancer. It is a more aggressive, but still treatable, form of leukemia.
Specifically, B-PLL is a prolymphocytic leukemia (PLL) that affects prolymphocytes – immature forms of B-lymphocytes and T-lymphocytes – in the peripheral blood, bone marrow, and spleen. It is an aggressive cancer that presents poor response to treatment.Mature lymphocytes are infection-fighting immune system cells. B-lymphocytes have two responsibilities:
Production of antibodies – In response to antigens, B-lymphocytes produce and release antibodies specific to foreign substances in order to aid in their identification and elimination phagocytes
Generation of memory cells – Interactions between antibodies and antigens allow B-lymphocytes to establish cellular memories, otherwise known as immunities that allow the body to respond more rapidly and efficiently to previously encountered species

Classification
It is categorized as a lymphoproliferative disorder due to the excessive production of lymphocytes, in B-PLL there is excess production of B-prolymphocytes by the bone marrow. These immature lymphocytes are not normally found in the blood; part of their maturation process is being programmed to produce antibodies against foreign material prior to their departure from the bone marrow. In B-PLL, malignant B-prolymphocytes disrupt the adaptive capabilities of the immune system due to the lack of mature B-lymphocytes.It has been suggested that some cases may represent a variant of mantle cell lymphoma.

Signs and symptoms
This type of leukemia is characterized by:
More than 55% of circulating cells in peripheral blood (red blood cells, white blood cells and platelets collectively) are prolymphocytes. Generally, prolymphocyte proportion exceeds 90%
Minimal or absence of lymphadenopathy – abnormalities in size, number or consistency of lymph nodes
Splenomegaly - Abnormal enlargement of the spleen
High white blood cell count
B-symptoms – Fever, night sweats and/or weight lossSimilar to other leukemias, B-cell prolymphocytic leukemia is often asymptomatic. The most common signs and symptoms are the result of the inability of the bone marrow to produce normal levels of blood cells:
Anaemia – due to lack of red blood cells
More frequent, severe and prolonged infections – due to lack of normal white blood cells
Bleeding and bruising – due to lack of platelets

Diagnosis
Diagnosis of B-PLL is difficult due to its considerable overlap with other mature B-cell leukemias and lymphomas. It requires integration of morphology with diagnostic tests including immunophenotyping and chromosome analysis (cytogenetics).

Morphology
The malignant B cells are larger than average.
In order to diagnose a patient with B-PLL, b-prolymphocyte composition of a patients blood cells must exceed 55%. High white blood cell counts – greater than 100 x 109/L  – are also indicative of B-PLL. B-prolymphocytes are characterized by:
Large size – approximately twice the size of a normal small lymphocyte
Round or oval-shaped nuclei
Single prominent nucleolus
Moderately condensed nuclear chromatin
High nuclear-cytoplasmic ratio – indicates more abundant cytoplasm

Immunophenotype
This technique is used to study proteins expressed in cells using immunologic markers. In B-PLL patients there is strong expression of surface immunoglobulin – a membrane-bound form of an antibody, b-lymphocyte surface antigens CD19, CD20, CD22, CD79a and FMC7, and weak expression of CD5 and CD23. Due to the similarities among lymphoproliferative disorders, it is often difficult to diagnose patients. Immunophenotyping helps distinguish B-PLL from similar diseases, one of its key identifiers is the absence in expression of the surface antigens CD10, CD11c, CD25, CD103 and cyclin D1 – an important regulator of cell-cycle progression.A case has been described as CD20+, CD22+, and CD5-.It can also be CD5+.Another case was described as CD45+, CD19+, CD20+, CD5+, HLA-DR+, CD10-, CD23+/-, CD38+ and FMC7-.

Cytogenetics
B-PLL is rare, consequently few genetic studies have focused on this disease. As a result, the associated genetic lesions underlying B-PLL are largely unknown.

Chromosomal Mutations
The most commonly reported abnormalities have occurred at chromosome 14, specifically in a region of the chromosome called band q23 (14q23). Translocations to this location lead to overexpression of the cyclin D1 gene which has been linked to both the development and progression of a number of cancers. Other chromosomal abnormalities have been reported on 6q21, 11q23, 12p12, 13q14 and 17p.It can involve deletions from chromosome 11 and chromosome 13.

TP53 Gene
Among the documented studies, mutations to the TP53 gene have occurred in 75% of all cases of B-PLL. This is the highest incidence among all sub-types of B-cell malignancies. Mutations to this gene have also been documented in other hematologic malignancies.TP53 is an important transcriptional activator of genes involved in the regulation of the G1 checkpoint of the cell cycle as well as certain genes responsible for programmed-cell death (apoptosis). It is believed that mutations to TP53 are responsible for the frequent therapy resistance and aggressive course of this disease.

c-MYC Gene
In a small number of B-PLL cases, abnormalities in the c-MYC gene have been observed. It is considered a global amplifier and influences nearly all aspects of cellular activity. Among the number of genes it regulates, most are involved in cell growth, cell cycle progression, protein biosynthesis and apoptosis. Amplification of c-MYC has been reported in B-PLL patients and while the consequences are unclear, it is generally associated with poor clinical outcome.

Biopsy
After physicians have identified an abnormality in the composition of the peripheral blood, biopsies (tissue samples) from a patients bone marrow and/or spleen are often recommended for confirmation. A bone marrow biopsy involves the removal of a small amount of tissue that is further analyzed for abnormalities, for B-PLL pathologists look for prolymphocytic infiltration where the hematopoietic stem cells of the bone marrow are replaced with prolymphocytes due to excess production. In 50% of reported cases, it was common for patients to be both anemic (lack healthy red blood cells in blood) and thrombocytopenic (deficiency of platelets in blood).

Treatment
The rarity of B-PLL paired with its considerably fast progression compared to other leukemias has resulted in difficult production of effective treatments. This disease is currently incurable, treatments and therapy are guided to reduce prolymphocyte abundance in the blood and production by the bone marrow, treating symptoms and controlling progression.

Watchful Waiting
Some patients do not require immediate treatment after diagnosis; these patients include those that do not show overt symptoms or whose cancer has not been observed to be progressing. Regular check-ups with physicians are required to actively monitor the patients condition; once there is evidence of disease progression or patient distress from symptoms, treatment will be implemented.

Chemotherapy
B-PLL has a very aggressive clinical course and refractoriness to chemotherapy; it is believed this resistance is the result of mutations to the TP53 gene. Its resistant nature has led to the use of combinations of chemotherapy drugs </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 Ochronosis and can you explain it in depth? [/INST] Ochronosis is a syndrome caused by the accumulation of homogentisic acid in connective tissues. The condition was named after the yellowish (ocher-like) discoloration of the tissue seen on microscopic examination. Macroscopically, though, the affected tissues appear bluish-grey because of a light-scattering phenomenon known as the Tyndall effect. The condition is most often associated with alkaptonuria, but can occur from exogenous administration of phenol complexes such as hydroquinone. It was first described by Rudolf Virchow in 1865.

Types
The two types of ochronosis are endogenous and exogenous. The endogenous variety is an autosomal-recessive disease, known as alkaptonuria, that is caused by a lack of homogentisate oxidase enzyme.
Exogenous ochronosis is an avoidable dermatitis that can be caused by the topical application of compounds such as hydroquinone or phenols.
It was first seen in 1912, when a patient who used phenol on a leg ulcer was found by Beddard and Plumtre to have this condition.
Hydroquinone-induced exogenous ochronosis was found in 1975 by Findlay, who observed the condition in patients who used skin lightening creams containing the compound.The three clinical stages of exogenous ochronosis are:
Erythema and mild hyperpigmentation
Hyperpigmentation and "caviar-like" lesions
Papulonodular lesions

Signs and symptoms
Skin: The pigment is deposited throughout the skin, but only becomes apparent in certain locations, where the concentration is great enough to be seen clinically.  This usually occurs in areas where connective tissue is thick (joints, tympanic membrane) or close to the surface of the skin (thenar and hypothenar eminences and the sides of the fingers).  In exogenous ochronosis, the hyperpigmentation is localized to the area where the inciting agent is applied.  Intradermal nevi can appear like blue nevi.
Eye: Ocular manifestations are frequent in patients with ochronosis; most commonly hyperpigmentation of the sclera, primarily observed symmetrically to both sides of the cornea within the palpebral fissure. Furthermore, brown pigment spots in the limbus are generally considered pathognomonic. These ocular signs generally occur early in the development of the disease and can serve as a valuable diagnostic feature of the disease.
Cartilage: Darkening and hardening of ear cartilage is a prominent feature of ochronosis.  Nasal cartilage is also frequently involved.  The voice can be affected by hardening of the laryngeal cartilage.  Stiffening of the ribs with decreased lung function has also been reported.  The intervertebral cartilage is also more prone to herniation.
Connective tissue: Hardening of tendons and ligaments can predispose them to rupture.  Color changes in the joints can be observed clinically. Arthropathy is common due to chronic inflammation and microruptures.
Heart valves: Stenosis can results from the increased rigidity of the connective tissue as well as chronic inflammation.Symptoms of exogenous ochronosis  include:
Yellow-brown, banana-shaped fibers
Caviar-like papules
Brown-grey or blue-black hyperpigmentationMost of the lesions are seen on areas of the body that get the most sun.

Causes
Exogenous ochronosis can be caused from long-term use of certain "skin-lightening" products, even if the hydroquinone is in amounts as small as 2%.
Skin-lightening products are still prevalent in many parts of the world. This may be due to aesthetic or social-standing reasons, in areas where a lighter skin tone is considered to be a sign of wealth or beauty.
Also, skin-lightening creams containing compounds such as hydroquinone are commonly used to help with hyperpigmentation disorders such as melasma.Hydroquinone is the compound most frequently used in skin-whitening products. Due to concerns about its side effects, it was almost banned by the FDA in 2006, as  medical issues of carcinogenicity and reports of disfiguring ochronosis existed.  In the European Union hydroquinone has been banned in cosmetic creams since 2000.Long-term use of creams containing this compound may lead to exogenous ochronotic lesions. The duration of use is directly proportional to the risk of developing the condition, with most cases occurring after years of use.
Around 10–15 million skin lightening products are sold annually, with Japan being the major buyer.

Pathophysiology
Ochronosis occurs because of deposition of phenols (such as homogentisic acid and hydroquinone) as plaques in the matrix of cartilage.  The pigments can also be incorporated into collagen and elastin fibers </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 Phlebitis and can you explain it in depth? [/INST] Phlebitis (or Venitis) is inflammation of a vein, usually in the legs. It most commonly occurs in superficial veins. Phlebitis often occurs in conjunction with thrombosis and is then called thrombophlebitis or superficial thrombophlebitis. Unlike deep vein thrombosis, the probability that superficial thrombophlebitis will cause a clot to break up and be transported in pieces to the lung is very low.

Signs and symptoms
Localized redness and swelling
Pain or burning along the length of the vein
Vein being hard and cord-likeThere is usually a slow onset of a tender red area along the superficial veins on the skin. A long, thin red area may be seen as the inflammation follows a superficial vein. This area may feel hard, warm, and tender. The skin around the vein may be itchy and swollen. The area may begin to throb or burn </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 Paramyotonia congenita and can you explain it in depth? [/INST] Paramyotonia congenita (PC) is a rare congenital autosomal dominant neuromuscular disorder characterized by "paradoxical" myotonia. This type of myotonia has been termed paradoxical because it becomes worse with exercise whereas classical myotonia, as seen in myotonia congenita, is alleviated by exercise. PC is also distinguished as it can be induced by cold temperatures. Although more typical of the periodic paralytic disorders, patients with PC may also have potassium-provoked paralysis. PC typically presents within the first decade of life and has 100% penetrance. Patients with this disorder commonly present with myotonia in the face or upper extremities. The lower extremities are generally less affected. While some other related disorders result in muscle atrophy, this is not normally the case with PC. This disease can also present as hyperkalemic periodic paralysis and there is debate as to whether the two disorders are actually distinct.

Symptoms and signs
Patients typically complain of muscle stiffness that can continue to focal weakness. This muscle stiffness cannot be walked off, in contrast to myotonia congenita. These symptoms are increased (and sometimes induced) in cold environments. For example, some patients have reported that eating ice cream leads to a stiffening of the throat. For other patients, exercise consistently induces symptoms of myotonia or weakness. Typical presentations of this are during squatting or repetitive fist clenching. Some patients also indicate that specific foods are able to induce symptoms of paramyotonia congenita. Isolated cases have reported that carrots and watermelon are able to induce these symptoms. The canonical definition of this disorder precludes permanent weakness in the definition of this disorder. In practice, however, this has not been strictly adhered to in the literature.

Pathophysiology
Paramyotonia congenita (as well as hyperkalemic periodic paralysis and the potassium-aggravated myotonias) is caused by mutations in a sodium channel, SCN4A. The phenotype of patients with these mutations is indicated in Table 1. These mutations affect fast inactivation of the encoded sodium channel. There are also indications that some mutations lead to altered activation and deactivation. The result of these alterations in channel kinetics is that there is prolonged inward (depolarizing) current following muscle excitation. There is also the introduction of a "window current" due to changes in the voltage sensitivity of the channel’s kinetics. These lead to a general increase in cellular excitability, as shown in figure 1.
There has been one study of a large number of patients with paramyotonia congenita. Of 26 kindreds, it found that 17 (71%) had a mutation in SCN4A while 6 (29%) had no known mutation. There is no large difference between these two groups except that patients with no known mutation have attacks precipitated less by cold but more by hunger, are much more likely to have normal muscle biopsies, and show less decreased compound muscle action potentials when compared to patients with known mutations.

Diagnosis
Diagnosis of paramyotonia congenita is made upon evaluation of patient symptoms and case history. Myotonia must increase with exercise or movement and usually must worsen in cold temperatures. Patients that present with permanent weakness are normally not characterized as having PC. Electromyography may be used to distinguish between paramyotonia congenita and myotonia congenita., Clinicians may also attempt to provoke episodes or myotonia and weakness/paralysis in patients in order to determine whether the patient has PC, hyperkalemic periodic paralysis, or one of the potassium-aggravated myotonias. Genomic sequencing of the SCN4A gene is the definitive diagnostic determinant.

Treatment
Some patients do not require treatment to manage the symptoms of paramyotonia congenita. Others require treatment for their muscle stiffness and often find mexiletine to be helpful. Others have found acetazolamide to be helpful as well. Avoidance of myotonia triggering events is also an effective method of myotonia prevention.

Epidemiology
Paramyotonia congenita is considered an extremely rare disorder, though little epidemiological work has been done. Prevalence is generally higher in European-derived populations and lower among Asians. Epidemiological estimates have been provided for the German population. There, it was estimated that the prevalence of PC is between 1:350,000 (0.00028%) and 1:180,000 (0.00056%). However, the German population of patients with PC is not uniformly distributed across the country. Many individuals with PC herald from the Ravensberg area in North-West Germany, where a founder effect seems to be responsible for most cases. The prevalence here is estimated at 1:6000 or 0.017%.

History
Originally thought to be separate from hyperkalemic periodic paralysis and the sodium channel myotonias, there is now considerable disagreement as to whether these disorders represent separate entities or overlapping phenotypes of a complex disorder spectrum. It was once thought that paramyotonia congenita was more common in males. Observation of the most recent generation has shown this to be untrue. On average, half of children in a family inherit the disorder regardless of gender.

References
Notes
Lehmann-Horn F, Rüdel R, Ricker K (1993). "Non-dystrophic myotonias and periodic paralyses. A European Neuromuscular Center Workshop held 4–6 October 1992, Ulm, Germany". Neuromuscul Disord </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 Crenated tongue 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 Chorea gravidarum and can you explain it in depth? [/INST] Chorea gravidarum is a rare type of chorea which presents with involuntary abnormal movement, characterized by abrupt, brief, nonrhythmic, nonrepetitive movement of any limb, often associated with nonpatterned facial grimaces. It is a complication of pregnancy which can be associated with eclampsia and its effects upon the basal ganglia. It is not a causal or pathologically distinct entity but a generic term for chorea of any cause starting during pregnancy. It is associated with history of Sydenhams chorea. It mostly occurs in young patients; the average age is 22 years.Recently there has been a decline in incidence which is probably the result of a decline in rheumatic fever (RF), which was a major cause of chorea gravidarum before the use of antibiotics for streptococcal pharyngitis.

Pathophysiology
Several pathogenetic mechanisms for chorea gravidarum have been offered, but none have been proven.
History of either rheumatic fever or chorea is suspected: the suggestion is that estrogens and progesterone may sensitize dopamine receptors (presumably at a striatal level) and induce chorea in individuals who are vulnerable to this complication by virtue of preexisting pathology in the basal ganglia.
The relation to rheumatic fever was strengthened by many studies that showed that women with normal pregnancies before rheumatic fever developed chorea in subsequent pregnancies. At least 35% of patients have a definite history of acute rheumatic fever and Sydenham chorea; 4% of those with chorea gravidarum had acute rheumatic fever.It has been suggested that use of oral contraceptives is an infrequent cause of chorea. A patient developed this chorea with no definite evidence of previous Sydenhams chorea or recent streptococcal infections, but had anti-basal ganglia antibodies, suggesting immunological basis for the pathophysiology of this chorea.

Diagnosis
Differential diagnoses
Chorea can also be a manifestation of drug toxicity (for example, anticonvulsants, antiparkinson agents, neuroleptics, steroids, and estrogen), or a result of an infectious disease such as meningovascular syphilis, Lyme disease, viral encephalitis, and many others.

Treatment
Drug treatment is indicated for patients with severe disabling chorea </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 Spondyloepimetaphyseal dysplasia 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 Epiphora and can you explain it in depth? [/INST]  </s>