<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Atypical lichen myxedematosus and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Excoriated acne and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Central pain syndrome and explain in detail? [/INST] Central pain syndrome is a neurological condition consisting of constant, moderate to severe pain due to damage to the central nervous system (CNS) which causes a sensitization of the pain system. The extent of pain and the areas affected are related to the cause of the injury.

Signs and symptoms
Pain can either be relegated to a specific part of the body or spread to the entire body. It is typically constant, and may be moderate to severe in intensity.  Those who are afflicted describe it as being stuck in a loop of pain. It is often made worse by touch, movement, emotions, barometric pressure and temperature changes, usually cold temperatures along with many other similar triggers. Cold temperatures regularly make the burning pain worse in certain body parts. Burning pain is the most common sensation, but patients also report pins and needles, pressing, lacerating, aching, and extreme bursts or constant sharp or unremitting excruciating pain. Individuals may have reduced sensitivity to touch in the areas affected by the pain, as if the part is falling asleep. The burning and loss of sense of touch are usually, but not always, most severe on the distant parts of the body, such as the feet or hands, spreading until it is in some cases felt from head to toe. Usually the burning pain in body parts is a result of old injuries that seem like they should have healed long ago, yet the pain lingers on and even years afterwards </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Alveolar rhabdomyosarcoma and explain in detail? [/INST] Alveolar rhabdomyosarcoma (ARMS) is a subtype of the rhabdomyosarcoma soft tissue cancer family whose lineage is from mesenchymal cells and are related to skeletal muscle cells. ARMS tumors resemble the alveolar tissue in the lungs. Tumor location varies from patient to patient, but is commonly found in the head and neck region, male and female urogenital tracts, the torso, and extremities. Two fusion proteins can be associated with ARMS, but are not necessary, PAX3-FKHR (now known as FOXO1). and PAX7-FKHR. In children and adolescents ARMS accounts for about 1 percent of all malignancies, has an incidence rate of 1 per million, and most cases occur sporadically with no genetic predisposition. PAX3-FOXO1 is now known to drive cancer-promoting gene expression programs through creation of distant genetic elements called super enhancers.

Genetics
There is no genetic predisposition for developing ARMS, but there are a few genetic recombination events that occurs to cause the fusion protein to be synthesized. In order to have the PAX3-FOXO1 fusion there needs to be a recombination event that translocates part of chromosome 13 to chromosome 2, and for PAX7-FOXO1 fusion there must be a translocation of part of chromosome 13 to chromosome 1. The 2;13 translocation reciprocal is often balanced and not amplified, while the 1;13 translocation reciprocal is sometimes viewed as balanced and sometimes not, so it is often amplified. The PAX7-FOXO1 fusion is often amplified in tumors (about 70 percent of all PAX7-FOXO1 fusion positive tumors) and the PAX3-FOXO1 fusion is rarely amplified (only in 5 percent of all PAX3-FOXO1 fusion positive tumors). About 60 percent of all ARMS cases are positive for PAX3-FOXO1 fusion gene, 20 percent are positive for PAX7-FOXO1 fusion gene, and the remaining 20 percent are fusion negative ARMS cases. Both fusion genes are composed of either the PAX3 or PAX7 DNA binding domains and the FOXO1 transactivation domain. This fusion causes a dysregulation of transcription and acts as an oncogene promoting cancer formation.

Pathology
ARMS cells are often small with little cytoplasm. The nuclei of the cells are round with normal, dull, chromatin structures. The ARMS cells often clump together and have fibrovascular septae that interrupts the aggregates. The fibrovascular septae that disrupts the aggregates often give the tumor the physiology of the alveoli found in the lungs. In a few cases, there may not be any fibrovascular septae and this gives the tumor a more solid phenotype and no alveoli physiology. Immunostaining for myogenin and for MyoD can be used to determine ARMS from other rhabdomyosarcoma tumors and immunostaining for AP2β and p-cadherin can distinguish fusion positive ARMS from fusion negative.

Embryonic origin and epidemiology
ARMS usually occurs in the skeletal muscles and is postulated to be derived from precursor cells within the muscle tissue. During embryonic development ARMS occurs in the mesoderm which is the precursor for the skeletal muscle tissue. ARMS accounts for roughly 20 to 30 percent of all rhabdomyosarcoma tumors and therefore accounts for roughly 1 percent of malignancies found in children and adolescents. There is an age determination on which PAX proteins fuse together with the FOXO1 transcription factor. PAX3-FOXO1 positive subset of ARMS occurs mostly in older children and young adults, while PAX7-FOXO1 positive subset of ARMS and fusion negative subsets occur most often in younger children.

Clinical
ARMS usually occurs in the skeletal muscle tissue of the extremities, but it is still very common in the torso, head, and neck regions </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Corneal opacity and explain in detail? [/INST] The human cornea is a transparent membrane which allows light to pass through it. The word corneal opacification literally means loss of normal transparency of cornea. The term corneal opacity is used particularly for the loss of transparency of cornea due to scarring. Transparency of the cornea is dependent on the uniform diameter and the regular spacing and arrangement of the collagen fibrils within the stroma. Alterations in the spacing of collagen fibrils in a variety of conditions including corneal edema, scars, and macular corneal dystrophy is clinically manifested as corneal opacity. The term corneal blindness is commonly used to describe blindness due to corneal opacity.

Types
Depending on the density, corneal opacity is graded as nebular, macular and leucomatous.

Nebular corneal opacity
Nebular corneal opacity is a faint opacity which results due to superficial scars involving Bowmans layer and superficial stroma. A nebular corneal opacity allows the details of the iris to be seen through the opacity. A thin, diffuse nebula covering the pupillary area interferes more with vision than a strictly localized dense leucoma, so long as the latter does not block the whole pupillary area. This is because the leucoma stops all the light which falls upon it, whereas the nebula refracts it irregularly, allowing many of the rays to fall upon the retina where they blur the image formed by the regularly refracted rays.

Macular corneal opacity
Macular corneal opacity is a semidense opacity produced when scarring involves about half the corneal stroma.

Leucomatous corneal opacity (leucoma simplex)
Leucomatous corneal opacity is a dense white opacity which results due to scarring of more than half of the stroma. A number of different presentations of leucomatous corneal opacity exist:

Adherent leucoma: results when healing occurs after perforation of cornea with incarceration of iris. The iris is adherent to the back of a leucomatous cornea. One of the major complication of adherent leucoma is Secondary glaucoma
Corneoiridic scar: if iris tissue is incarcerated and incorporated within the scar tissue, as occurs in healing of a large sloughed corneal ulcer, it is called a corneoiridic scar.
Corneal facet: corneal surface depressed at the site of healing (due to less fibrous tissue); such a scar is called facet.
Kerectasia: In this condition, corneal curvature is increased at the site of opacity (bulge due to weak scar).

Presentation
Signs and symptoms include the following:

Loss of vision or blindness (when dense opacity covers the pupillary area)
Blurred vision (due to astigmatic effect and light scattering)
Glare

Complications
Congenital corneal opacity that affecting vision will cause amblyopia. That type of amblyopia is known as form-deprivation amblyopia (or amblyopia ex anopsia).

Secondary changes in corneal opacity
Secondary changes may be seen in long-standing cases include: hyaline degeneration, calcareous degeneration, pigmentation and atheromatous ulceration.

Causes
Congenital opacities may occur as developmental anomalies or following birth trauma. Causes of congenital corneal opacities include sclerocornea, trauma, ulcer, mucopolysaccharidosis, Peter’s anomaly, congenital hereditary endothelial dystrophy.
Ocular trauma
Corneal ulceration
Xerophthalmia, caused by Vitamin A deficiency
Trachoma
Onchocerciasis
Mucous membrane pemphigoid: Ocular form of mucous membrane pemphigoid may cause corneal opacity and loss of vision.

Genetics
Pediatric corneal opacities may be congenital or acquired.

Congenital corneal opacities
Congenital reasons for this condition include:

Congenital hereditary endothelial dystrophy (CHED):  There are 2 forms of congenital hereditary endothelial dystrophy (CHED). Commonest is an autosomal recessive form, which is present at birth, but nonprogressive. Nystagmus is seen in association with this form. Another is an autosomal dominant form that occurs within the first few years of life. This form is progressive, but nystagmus is not seen.  Deafness and CHED are seen in Harboyan syndrome. The histologic findings are very similar to those seen in pseudophakic/ aphakic bullous keratopathy. The appearance of the cornea is similar to that in congenital glaucoma but without increased corneal diameter and elevated intraocular pressure.
Posterior polymorphous corneal dystrophy (PPMD, PPCD): PPCD, also known as Schlichting dystrophy, is an autosomal dominant disorder of the corneal endothelium and Descemet’s membrane.  It is usually present in the second or third decade of life. It has the same entity as the first form of CHED. Most cases of PPMD are asymptomatic, and these cases generally do not require treatment. PPMD patients with bilateral, corneal opacities that can affect vision, descemet’s membrane endothelial keratoplasty or penetrating keratoplasty are the treatments of choice to improve vision and to avoid amblyopia.
Congenital hereditary stromal dystrophy (CHSD): CHSD is also known as Congenital stromal corneal dystrophy or Congenital stromal dystrophy of the cornea. It is a rare autosomal dominant disease caused by mutations in the DCN gene. In this bilateral Snowflake, whitish opacities appear throughout the cornea. The stromal lamellae are abnormal and may be separated by amorphous deposits. Moderate to severe vision loss may occur due to corneal opacity. In case of severe vision loss, treatment of choice is penetrating keratoplasty.
Peters anomaly: Peters anomaly, also known as iridocorneal adhesions or keratolenticular adhesions, is a posterior corneal defect with an overlying stromal opacity, often accompanied by adherent iris strands (Peters anomaly type 1). The size and density of the opacity can range from a mild to dense central leukoma.
Congenital anterior staphyloma: Congenital anterior staphyloma is a rare form of anterior segment dysgenesis that shares similarities with Peters anomaly. It is characterized by an ectatic protrusion of a central opacified cornea lined by uveal tissue. The protrusion extends beyond the plane of the eyelid margins and it can be unilateral or bilateral.
Lattice corneal dystrophy: Lattice corneal dystrophy is an autosomal-dominant characterized by amyloid deposition in the corneal stroma. Due to deposits, lattice-like corneal opacities may occur in stroma. Three types of dystrophies are there, type 1, type 2 and type 3. Type 1 is also known as  Biber-Haab-Dimmer corneal dystrophy, TGFBI type Lattice Dystrophy, or Classic Lattice Dystrophy. LCD type II is not included in corneal dystrophies.
Granular corneal dystrophy: Two types, Type 1 and Type 2 are there.  Both have autosomal dominant inheritance. In Type 1, Discrete crumb-like opacities are seen in the central anterior stroma. Visual symptoms such as glare and photophobia may occur early in life. In Type 2, deposits begin to appear in early childhood or adolescence as tiny whitish dots in the anterior stroma. Larger stellate, ring, or snowflake opacities may occur in later stages. Decrease in vision starts earlier in type2 than type1.
Sclerocornea: Sclerocornea is a congenital disorder in which the cornea is opaque and resembles the sclera, making the limbus indistinct. The central cornea is clearer than the periphery.
Cystinosis: Cystinosis is a rare autosomal recessive metabolic disease characterized by elevated levels of cystine within the cell.  Early deposition of cystine crystals in the cornea cause tinsel-like corneal opacities.
Ichthyosis: X-linked ichthyosis is a genetic skin disorder caused by the hereditary deficiency of the steroid sulfatase enzyme. Ocular manifestations of XLI include superficial or deep corneal opacities.
Trisomy 8 mosaicism (T8M): It is a rare chromosome disorder caused by the presence of an extra chromosome 8 in some cells of the body. Dense corneal opacities may occur in trisomy 8 mosaicism.
Farbers disease: Nodular corneal opacity may be seen in association with this rare autosomal recessive disease.

Acquired pediatric corneal opacities
Acquired reasons for this condition include:

Traumatic: Traumatic breaks in Descemet membrane may cause corneal opacity. Injuries to Descemet membrane occur during delivery. Opacity is commonly unilateral.
Congenital or infantile glaucoma: In Congenital glaucoma, the cornea becomes edematous, cloudy, and enlarged. Treatment should be done to reduce Intraocular pressure.
Congenital corneal ulcers: Unilateral corneal opacity may occur in association with conjunctival injection and other signs of inflammation.
Mucopolysaccharidoses: The mucopolysaccharidoses are a group of inherited metabolic diseases caused by the absence or malfunctioning of certain enzymes the body needs to break down molecules called glycosaminoglycans. It is an autosomal recessive disorder. Sometimes, Corneal haze may be present in early life. Treatment options for significant opacities include penetrating keratoplasty and DALK.

Treatment
Keratoplasty
Keratoplasty also known as corneal transplantation is the main treatment option for visual improvement in corneal opacity. In this, the opaque cornea is replaced with donor tissue. Depending on type and density of corneal opacity different types of keratoplasty may be used such as:
Penetrating keratoplasty: It is the traditional full thickness corneal transplant procedure, in which trephine (a circular cutting device) is used to cut opaque cornea, a similar-sized portion of the donor cornea is removed with a second trephine. The removed part of donor cornea is known as corneal button. The donor tissue is then sutured to the patient eye. Dense corneal opacity which occupies all the corneal layers may be treated with penetrating keratoplasty.
Superficial lamellar keratoplasty: Superficial lamellar keratoplasty is used to treat superficial corneal opacities, which occupies superficial one third part of stroma. In this technique, the opaque part of the cornea is removed and replaced with donor tissue, leaving healthy part of the cornea including deeper parts of stroma and endothelium.
Deep anterior lamellar keratoplasty: DALK may be considered in deep opacities with normal endothelium and descemets membrane. In this procedure, the anterior layers of cornea are removed and replaced with donor tissue, leaving the endothelial layer and the descemets membrane in place.

Optical iridectomy
Optical iridectomy creates a clear entrance pupil, improving vision in patients with segmental corneal opacities. An area of clear peripheral cornea can produce retinal images compatible with good visual acuity.

Phototherapeutic keratectomy (PTK)
Excimer laser phototherapeutic keratectomy (PTK) is useful in superficial (nebular) corneal opacities.

Tattooing of scar
Keratopigmentation or corneal tattooing is a procedure used for centuries to improve the cosmetic appearance of corneal scars. Tattooing will not improve vision </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Microvillous inclusion disease and explain in detail? [/INST] Microvillus inclusion disease, previously known as Davidsons disease, congenital microvillus atrophy and, less specifically, microvillus atrophy (note: microvillus is often misspelled as microvillous), is a rare genetic disorder of the small intestine that is inherited in an autosomal recessive pattern.

Presentation
It is characterized by chronic, intractable diarrhea in new-born infants, starting in the first few days of life.
This results in metabolic acidosis and severe dehydration </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Diabetic embryopathy and explain in detail? [/INST] Diabetic embryopathy refers to congenital maldevelopments that are linked to maternal diabetes. Prenatal exposure to hyperglycemia can result in spontaneous abortions, perinatal mortality, and malformations. Type 1 and Type 2 diabetic pregnancies both increase the risk of diabetes induced teratogenicity. The rate of congenital malformations is similar in Type 1 and 2 mothers because of increased adiposity and the age of women with type 2 diabetes. Genetic predisposition and different environmental factors both play a significant role in the development of diabetic embryopathy. Metabolic dysfunction in pregnant mothers also increases the risk of fetal malformations.

Risk factors
Women with pregestational diabetes are at the highest risk for fetal malformations. The risk of congenital malformations in pregestational type 1 diabetes is directly correlated with glucose and glycohemoglobin levels in the blood. It is also inversely related to the gestational age at first exposure. The comorbidities associated with pregestational type 2 diabetes include advanced maternal age, lipid preroxidation and obesity. Overweight women (BMI ≥ 25) who develop gestational diabetes have an intermediate risk for malformations. Pregnant women who have gestational diabetes but dont have prediabetic markers experience perinatal outcomes that are similar to women without diabetes.

Gestational consequences
Malformations
Type 1 diabetes in pregnant women can result in malformations that affect the musculoskeletal , urogenital, and central nervous systems. Most of these malformations occur within the first 4 weeks of gestation. Caudal dysgenesis is one of the most strongly associated diseases to diabetes. This malformation has the highest risk for diabetic embryopathy. Infants from diabetic mothers usually have several blastogenic malformations. Diabetic embryopathy is therefore an etiological subgroup of defects of blastogenesis that present different monotopic and polytopic developmental defects.

Abortion and perinatal deaths
Diabetic embryopathy may result in early or late spontaneous abortion and stillbirth. In maternal diabetes, 90% of pregnancy losses happen in the first trimester due to oxidative stress. Diabetic embryopathy abortions in the second-trimester are most likely due to severe birth defect, maternal metabolic derangement, placental insufficiency and fetal hypoxia due to membrane rupture.

Pathogenesis
The development of birth defects associated with maternal hyperglycemia is multi-factorial </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Metachromatic leukodystrophy and explain in detail? [/INST] Metachromatic leukodystrophy (MLD) is a lysosomal storage disease which is commonly listed in the family of leukodystrophies as well as among the sphingolipidoses as it affects the metabolism of sphingolipids. Leukodystrophies affect the growth and/or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. MLD involves cerebroside sulfate accumulation. Metachromatic leukodystrophy, like most enzyme deficiencies, has an autosomal recessive inheritance pattern.

Signs and symptoms
Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult.
In the late infantile form, which is the most common form of MLD (50–60%), affected children begin having difficulty walking after the first year of life, usually at 15–24 months. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner.
Children with the juvenile form of MLD (onset between 3 and 10 years of age) usually begin with impaired school performance, mental deterioration, and dementia, then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. Some patients can live for several decades after onset. A recent trend is to try to distinguish early-juvenile (ages 3–7) and late-juvenile forms of the disease.  Generally early-juveniles have motor skill declines as their first symptoms while late-juveniles show cognitive declines first.
The adult form commonly begins after age 16 often with an onset in the 4th or 5th decade of life and presents as a psychiatric disorder or progressive dementia. Adult-onset MLD usually progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more.Palliative care can help with many of the symptoms and usually improves quality of life and longevity.Carriers have low enzyme levels compared to their family population ("normal" levels vary from family to family) but even low enzyme levels are adequate to process the bodys sulfatide.

Causes
MLD is directly caused by a deficiency of the enzyme arylsulfatase A (ARSA) and is characterized by enzyme activity in leukocytes that is less than 10% of normal controls.  However, assay of the ARSA enzyme activity alone is not sufficient for diagnosis; ARSA pseudodeficiency, which is characterized by enzyme activity that is 5~20% of normal controls does not cause MLD.  Without this enzyme, sulfatides build up in many tissues of the body, eventually destroying the myelin sheath of the nervous system. The myelin sheath is a fatty covering that protects nerve fibers. Without it, the nerves in the brain (central nervous system – CNS) and the peripheral nerves (peripheral nervous system – PNS) which control, among other things the muscles related to mobility, cease to function properly.Arylsulfatase A is activated by saposin B (Sap B), a non-enzymatic proteinaceous cofactor.  When the arylsulfatase A enzyme level is normal but the sulfatides are still high – meaning that they are not being broken down because the enzyme is not activated – the resulting disease is saposin B deficiency, which presents similar to MLD. Saposin B Deficiency is very rare, much more rare than traditional MLD. The enzyme that is present is not "enabled" to a normal level of efficiency and cant break down the sulfatides which results in all of the same MLD symptoms and progression.A 2011 study contended sulfatide is not completely responsible for MLD because it is nontoxic. It has been suggested lysosulfatide, sulfatide which has had its acyl group removed, plays a role because of its cytotoxic properties in vitro.

Genetics
MLD has an autosomal recessive inheritance pattern. The inheritance probabilities per birth are as follows:
If both parents are carriers:
25% (1 in 4) children will have the disease
50% (2 in 4) children will be carriers, but unaffected
25% (1 in 4) children will be free of MLD – unaffected child that is not a carrier
If one parent is affected and one is free of MLD:
0% (0) children will have the disorder – only one parent is affected, other parent always gives normal gene
100% (4 in 4) children will be carriers (but unaffected)
If one parent is a carrier and the other is free of MLD:
50% (2 in 4) children will be carriers (but unaffected)
50% (2 in 4) children will be free of MLD – unaffected child that is not a carrierIn addition to these frequencies there is a pseudo-deficiency that affects 7–15% of the population. People with the pseudo deficiency do not have any MLD problems unless they also have affected status. With the current diagnostic tests, Pseudo-deficiency reports as low enzyme levels but sulfatide is processed normally so MLD symptoms do not exist.  This phenomenon wreaks havoc with traditional approaches to Newborn Screening so new screening methods are being developed.

Diagnosis
Clinical examination and MRI are often the first steps in an MLD diagnosis.  MRI can be indicative of MLD but is not adequate as a confirming test. An ARSA-A enzyme level blood test with a confirming urinary sulfatide test is the best biochemical test for MLD.  The confirming urinary sulfatide is important to distinguish between MLD and pseudo-MLD blood results. Genomic sequencing may also confirm MLD, however, there are likely more mutations than the over 200 already known to cause MLD that are not yet ascribed to MLD that cause MLD so in those cases a biochemical test is still warranted.

Newborn screening
MLD Foundation formally launched a newborn screening initiative in late 2017. The screen development started in the early 2010s at the University of Washington Gelb Biochemistry lab.  A deidentified pilot study launched in April 2016 in Washington state. Positive results led to MLD being included in the ScreenPlus identified baby research project in New York state, which is currently scheduled to launch in Q12021.

Treatment
There is currently no approved treatment for MLD in symptomatic late infantile patients or for juvenile and adult-onset with advanced symptoms. These patients typically receive clinical treatment focused on pain and symptom management.Pre-symptomatic late infantile MLD patients, as well as those with juvenile or adult MLD that are either presymptomatic or displaying mild symptoms, can consider bone marrow transplantation (including stem cell transplantation), which may slow down the progression of the disease in the central nervous system. However, results in the peripheral nervous system have been less dramatic, and the long-term results of these therapies have been mixed.In 2020 the European Medical Agency, approved the Cell Therapy Drug Libmeldy for treatment of infantile and juvenile forms of metachromatic leukodystrophy in Europe. Libmeldy is a type of advanced therapy medicine called a ‘gene therapy’. This type of medicine works by delivering genes into the body. The active substance in Libmeldy is stem cells, (CD34+ cells), derived from the patient’s own bone marrow or blood, that have been modified to contain a copy of the gene to make ARSA and can divide to produce other sorts of blood cells.

Atidarsagene autotemcel
A gene therapy called atidarsagene autotemcel was approved for medical use in the European Union in December 2020 and is sold under the trade name Libmeldy. The indication is for use in children with the late infantile or early juvenile forms of MLD who have been identified as carriers of the defective gene but have not yet developed symptoms. It is also indicated in children who have been diagnosed with the early juvenile form who have started developing symptoms but still have the ability to walk independently and before the onset of cognitive decline.In the United States, an Investigational New Drug application for atidarsagene autotemcel was accepted by the Food and Drug Administration in late 2020.

Research directions
Several therapy options are currently being investigated using clinical trials primarily in late infantile patients. These therapies include gene therapy, enzyme replacement therapy (ERT), substrate reduction therapy (SRT), and potentially enzyme enhancement therapy (EET). In addition to the clinical trials, there are several other pre-clinical gene therapy research projects underway.

Epidemiology
The incidence of metachromatic leukodystrophy is estimated to occur in 1 in 40,000 to 1 in 160,000 individuals worldwide. There is a much higher incidence in certain genetically isolated populations, such as 1 in 75 in Habbanites (a small group of Jews who immigrated to Israel from southern Arabia), 1 in 2,500 in the western portion of the Navajo Nation, and 1 in 8,000 among Arab groups in Israel.As an autosomal recessive disease, 1 in 40,000 equates to a 1 in 100 carrier frequency in the general population.There are an estimated 3,600 MLD births per year, with 1,900 alive in the US, 3,100 in Europe, and 49,000 alive worldwide with MLD.MLD is considered a rare disease in the US and other countries.

Research
Bone marrow and stem cell transplant therapies
Several trials are underway to continue to improve the effectiveness and reduce the risks of bone marrow and stem cell transplants.

Gene therapy
(current as of April 2021)
Two different approaches to gene therapy are currently being researched for MLD.

Gene therapy with an autologous stem cell transplant – Italian researchers at the San Raffaele Telethon Institute tested a novel approach combining gene therapy with an autologous stem cell transplant.Gene therapy for late infantile and early juvenile patients was approved by the European Commission in December 2020 after receiving a favorable European Medicines Agency CHMP review in October 2020. The product is being marketed in the EU as Libmeldy. Libmeldy is a gene therapy medicinal product, for which CD34+ haematopoietic stem and progenitor cells are collected either from the patients own bone marrow or mobilised peripheral blood. These cells are transduced ex vivo using a lentiviral vector encoding the human arylsulfatase A gene to insert a functional gene to produce the ARSA enzyme. When the modified cells are transplanted back into the patient as a one-time infusion, the cells have been shown to produce the missing ARSA enzyme. The children by the age of five were all in good condition and going to kindergarten when normally by this age, children with the disease can not even speak. Additional information can be found on the MLD Foundations Gene Therapy page and at the Clinical Trials.gov site.
In November, 2020, Orchard Therapeutics acknowledged IND discussions with the FDA as the part of their effort to seek FDA approval in the USA.
A trial for late juveniles was launched in February 2020.
Orchard Therapeutics acquired the gene therapy IP from GSK in April 2018.
Recruiting for the Phase I/II Clinical Trial formally started on March 24, 2010, after approval from the Italian Authorities. Recruiting the initial cohort of 8 patients was completed in mid-March 2013. The trial was to test the efficacy and safety of autologous (using the patients own cells) hematopoietic stem cell transplantation (HSCT) after genetic modification to deliver a super-therapeutic (over-expressing) ARSA enzyme to the nervous system by the route of the blood cells. Using the patients own stem cells with genetic correction should reduce or eliminate the complications of graft vs. host disease and provide a long-term solution to proper ARSA expression in MLD patients. Bench and animal tests showed positive results. The researchers published 2-year outcomes for the first three patients in July 2013. Results were described as promising.
The Phase I/II clinical trial is complete.  No additional patients are being recruited while the data is analyzed and work progresses to improve the manufacturability and repeatability of the technology while expansion to other geographies to increase access is being considered.
Recruiting was completed for the 20 patient cohort in April 2015, which includes an expansion in December 2014 to add 6 additional patients.
Inclusion criteria are pre-symptomatic late infantiles and both pre- and early-symptomatic juveniles. See details on inclusion criteria and the trial protocol here.
The trial was at a single center at the San Raffaele Institute in Milan, Italy.  All costs were to be paid by the researchers. This was a 3-year study. In March 2013, the last of the 8 primary trial patients started therapy. The trial had several compassionate access patients and ultimately was expanded to 20 patients
In late 2013 GSK exercised its option for the San Rafaelle gene therapy technology and is working with the Milan Investigators to prepare for the next phase of study.
Intracerebral Gene therapy – A Phase I/II Clinical Trial started recruiting in Paris in late March, 2013 for an Intracerebral Gene Therapy clinical trial where special "vectors" carrying genetically modified material are directly injected into a dozen sites in the brain. The hope is that the corrected cells and the enzyme they produce will then diffuse into surrounding areas of the brain </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Lung infarction and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Encephalitis and explain in detail? [/INST] Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, trouble speaking, memory problems, and problems with hearing.Causes of encephalitis include viruses such as herpes simplex virus and rabies virus as well as bacteria, fungi, or parasites. Other causes include autoimmune diseases and certain medications. In many cases the cause remains unknown. Risk factors include a weak immune system. Diagnosis is typically based on symptoms and supported by blood tests, medical imaging, and analysis of cerebrospinal fluid.Certain types are preventable with vaccines. Treatment may include antiviral medications (such as acyclovir), anticonvulsants, and corticosteroids. Treatment generally takes place in hospital. Some people require artificial respiration. Once the immediate problem is under control, rehabilitation may be required. In 2015, encephalitis was estimated to have affected 4.3 million people and resulted in 150,000 deaths worldwide.

Signs and symptoms
Adults with encephalitis present with acute onset of fever, headache, confusion, and sometimes seizures. Younger children or infants may present with irritability, poor appetite and fever. Neurological examinations usually reveal a drowsy or confused person. Stiff neck, due to the irritation of the meninges covering the brain, indicates that the patient has either meningitis or meningoencephalitis.

Cause
Viral
Viral encephalitis can occur either as a direct effect of an acute infection, or as one of the sequelae of a latent infection. The majority of viral cases of encephalitis have an unknown cause, however the most common identifiable cause of viral encephalitis is from herpes simplex infection. Other causes of acute viral encephalitis are rabies virus, poliovirus, and measles virus.Additional possible viral causes are arboviral flavivirus (St. Louis encephalitis, West Nile virus), bunyavirus (La Crosse strain), arenavirus (lymphocytic choriomeningitis virus), reovirus (Colorado tick virus), and henipavirus infections. The Powassan virus is a rare cause of encephalitis.

Bacterial and other
It can be caused by a bacterial infection, such as bacterial meningitis, or may be a complication of a current infectious disease syphilis (secondary encephalitis).Certain parasitic or protozoal infestations, such as toxoplasmosis, malaria, or primary amoebic meningoencephalitis, can also cause encephalitis in people with compromised immune systems. Lyme disease or Bartonella henselae may also cause encephalitis.Other bacterial pathogens, like Mycoplasma and those causing rickettsial disease, cause inflammation of the meninges and consequently encephalitis. A non-infectious cause includes acute disseminated encephalitis which is demyelinated.

Limbic encephalitis
Limbic encephalitis refers to inflammatory disease confined to the limbic system of the brain.  The clinical presentation often includes disorientation, disinhibition, memory loss, seizures, and behavioral anomalies. MRI imaging reveals T2 hyperintensity in the structures of the medial temporal lobes, and in some cases, other limbic structures.  Some cases of limbic encephalitis are of autoimmune origin.

Autoimmune encephalitis
Autoimmune encephalitis signs can include catatonia, psychosis, abnormal movements, and autonomic dysregulation. Antibody-mediated anti-N-methyl-D-aspartate-receptor encephalitis and Rasmussen encephalitis are examples of autoimmune encephalitis. Anti-NMDA receptor encephalitis is the most common autoimmune form, and is accompanied by ovarian teratoma in 58 percent of affected women 18–45 years of age.

Encephalitis lethargica
Encephalitis lethargica is identified by high fever, headache, delayed physical response, and lethargy. Individuals can exhibit upper body weakness, muscular pains, and tremors, though the cause of encephalitis lethargica is not currently known. From 1917 to 1928, an epidemic of encephalitis lethargica occurred worldwide.

Diagnosis
People should only be diagnosed with encephalitis if they have a decreased or altered level of consciousness, lethargy, or personality change for at least twenty-four hours without any other explainable cause. Diagnosing encephalitis is done via a variety of tests:
Brain scan, done by MRI, can determine inflammation and differentiate from other possible causes.
EEG, in monitoring brain activity, encephalitis will produce abnormal signal.
Lumbar puncture (spinal tap), this helps determine via a test using the cerebral-spinal fluid, obtained from the lumbar region.
Blood test
Urine analysis
Polymerase chain reaction (PCR) testing of the cerebrospinal fluid, to detect the presence of viral DNA which is a sign of viral encephalitis.

Prevention
Vaccination is available against tick-borne  and Japanese encephalitis  and should be considered for at-risk individuals. Post-infectious encephalomyelitis complicating smallpox vaccination is avoidable, for all intents and purposes, as smallpox is nearly eradicated. Contraindication to Pertussis immunization should be observed in patients with encephalitis.

Treatment
An ideal drug to treat brain infection should be small, moderately lipophilic at pH of 7.4, low level of plasma protein binding, volume of distribution of litre per kg, does not have strong affinity towards binding with P-glycoprotein, or other efflux pumps on the surface of blood–brain barrier. Some drugs such as isoniazid, pyrazinamide, linezolid, metronidazole, fluconazole, and some fluoroquinolones have good penetration to blood brain barrier.Treatment (which is based on supportive care) is as follows:

Pyrimethamine-based maintenance therapy is often used to treat Toxoplasmic Encephalitis (TE), which is caused by Toxoplasma gondii and can be life-threatening for people with weak immune systems. The use of highly active antiretroviral therapy (HAART), in conjunction with the established pyrimethamine-based maintenance therapy, decreases the chance of relapse in patients with HIV and TE from approximately 18% to 11% </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Barbiturate dependence and explain in detail? [/INST] Barbiturate dependence develops with regular use of barbiturates. This in turn may lead to a need for increasing doses of the drug to get the original desired pharmacological or therapeutic effect. Barbiturate use can lead to both addiction and physical dependence, and as such they have a high potential for excess or non-medical use, however, it does not affect all users. Management of barbiturate dependence involves considering the affected persons age, comorbidity and the pharmacological pathways of barbiturates.Psychological addiction to barbiturates can develop quickly. The patients will then have a strong desire to take any barbiturate-like drug </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pancreatic abscess and explain in detail? [/INST] Pancreatic abscess is a late complication of acute necrotizing pancreatitis, occurring more than 4 weeks after the initial attack. A pancreatic abscess is a collection of pus resulting from tissue necrosis, liquefaction, and infection. It is estimated that approximately 3% of the patients with acute pancreatitis will develop an abscess.According to the Balthazar and Ransons radiographic staging criteria, patients with a normal pancreas, an enlargement that is focal or diffuse, mild peripancreatic inflammations or a single collection of fluid (pseudocyst) have less than 2% chances of developing an abscess. However, the probability of developing an abscess increases to nearly 60% in patients with more than two pseudocysts and gas within the pancreas.

Signs and symptoms
Patients with pancreatic abscesses may experience abdominal pain, chills and fever or the inability to eat. Whereas some patients present an abdominal mass, others do not. Nausea and vomiting may also occur.

Complications
An unremoved infected abscess may lead to sepsis. Also, multiple abscesses may occur. Other complications may include fistula formation and recurrent pancreatitis.

Causes
Pancreatic abscesses usually develop in patients with pancreatic pseudocysts that become infected. They may also form as a result of fibrous wall formation around fluid collections or penetrating peptic ulcers. Other causes include gall stones or alcohol consumption and, in rare cases, drugs, blunt trauma and following extension abscess from nearby structures.

Diagnosis
Most patients who develop pancreatic abscesses have had pancreatitis, so a complete medical history is required as a first step in diagnosing abscesses. On the other hand, a white blood cell count is the only laboratory test that may indicate the presence of an abscess.
Some of the imaging tests are more commonly used to diagnose this condition. Abdominal CT scans, MRIs and ultrasounds are helpful in providing clear images of the inside of the abdomen and successfully used in the diagnosing process. These tests may reveal the presence of infected necrosis which has not yet developed into an abscess and as a result, doctors usually order repeated imaging tests in patients with acute pancreatitis whose abdominal pain worsens and who develop signs of abdominal obstruction. Also, it is recommended that patients who have a prolonged clinical response are tested repeatedly as a prevention method to avoid the development of an abscess that may rupture.

Prevention
In some cases, abscesses may be prevented by draining an existing pseudocyst which is likely to become inflamed. However, in most cases the developing of abscesses cannot be prevented.

Treatment
Antibiotics are commonly used as a curing method for pancreatic abscesses although their role remains controversial. Prophylactic antibiotics are normally chosen based on the type of flora and the degree of antibiotic penetration into the abscess. Pancreatic abscesses are more likely to host enteric organisms and pathogens such as E </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Mongolian spot and explain in detail? [/INST] A Mongolian spot, also known as slate grey nevus or congenital dermal melanocytosis, is a benign, flat, congenital birthmark with wavy borders and an irregular shape. In 1883, it was described and named after Mongolians by Erwin Bälz, a German anthropologist based in Japan, who erroneously believed it to be most prevalent among his Mongolian patients. It normally disappears three to five years after birth and almost always by puberty. The most common color is blue, although they can be blue-gray, blue-black or deep brown.

Cause
Mongolian spot is a congenital developmental condition—that is, one existing from birth—exclusively involving the skin. The blue colour is caused by melanocytes, melanin-containing cells, that are usually located in the surface of the skin (the epidermis), but are in the deeper region (the dermis) in the location of the spot. Usually, as multiple spots or one large patch, it covers one or more of the lumbosacral area (lower back), the buttocks, sides, and shoulders. It results from the entrapment of melanocytes in the lower half to two-thirds of the dermis during their migration from the neural crest to the epidermis during embryonic development.Male and female infants are equally predisposed to slate grey nevus. People who are not aware of the background of the slate grey nevus may mistake them for bruises, possibly resulting in mistaken concerns about abuse.

Anthropological description
The French anthropologist Robert Gessain interested himself in what he called the tache pigmentaire congenitale or coloured birthmark, publishing multiple papers in the Journal de la Société des Américanistes, an academic journal covering the cultural anthropology of the Americas. Gessain spent time with the Huehuetla Tepehua people in Hidalgo, Mexico, and wrote in 1947 about the spots "location, shape, colour, histology, chemistry, genetic transmission, and racial distribution". He had previously spent several winters in Greenland, and wrote an overview in 1953 of what was known about the spot. He hypothesised that the age at which it faded in various populations might prove to be a distinguishing characteristic of those groups. Gessain claimed that the spot was first observed amongst the Inuit.Hans Egede Saabye, a Danish priest and botanist, spent 1770–1778 in Greenland. His diaries, published in 1816 and translated into several European languages, contained much ethnographic information. He described the spot on newborns, saying he had seen it often when the infants were presented naked for baptism. A second Danish observer was doctor and zoologist Daniel Frederik Eschricht, mainly based in Copenhagen. In 1849 he wrote of the "mixed" babies he had delivered at the lying-in hospital. He also says that "the observation made for the first time by Saabye about Inuit children has been completely confirmed by Captain Holbøll", who sent him a fetus pickled in alcohol.Gessain goes on to state that it was only in 1883 that an anthropologist mentions the spot. It was Erwin Bälz, a German working in Tokyo, who described a dark blue mark on Japanese infants. He presented his findings in 1901 in Berlin, and from that point on, Bälzs name was associated with certain skin cells containing pigment. Captain Gustav Frederik Holm wrote in 1887 that his Greenlandic interpreter Johannes Hansen (known as Hanserak) attested to the existence of the birthmark over the kidney region of newborns, which grows larger as they grow older. That year, the Danish anthropologist Soren Hansen drew the connection between the observations of Bälz in Japan and Saabye in Greenland. "This cannot be a coincidence. It is not the first time that the resemblance between the Japanese and the Eskimo has been pointed out." Fridtjof Nansen, the Norwegian polar explorer, said that the spot was widespread in the mixed Danish-Inuit population of West Greenland. Soren Hansen confirmed this. A missionary in Bethel, Alaska, a traditional gathering place of Yupik people, reported that the spots were common on children. Rudolf Trebitsch, an Austrian linguist and ethnologist, spent the summer of 1906 on the West Coast of Greenland, and listed all the examples he came across. Gessain went to north Labrador in 1926, looking for children with these spots. In 1953 Dr Saxtorph, medical advisor to the Greenland department (part of the Danish government), wrote that the Greenlanders do not like outsiders to see or discuss these birthmarks; "they doubtless feel as a reminiscence of the time when they lived on a low cultural level".The presence or absence of the slate grey nevus was used by racial theorists such as Joseph Deniker (1852-1918), the French anthropologist.The Journal of Cutaneous Diseases Including Syphilis, Volume 23 contained several accounts of the slate grey nevus on children in the Americas:

Holm ("Ethnological Sketch. Communications on Greenland," X., Copenhagen, 1887) announced the presence of the spot in the east part of Greenland. Bartels ("The So-Called Mongolian Spots on Infants of Esquimaux," Ethnologic Review, 1903) received letters regarding it from East Greenland and also from Esquimaux of Alaska. In half-breed European-Esquimaux, Hansen says he has encountered it. Among Indians of North Vancouver, British Columbia, there are observations made by Baelz as well as by Tenkate (secondhand). In the Mayas of Central America, Starrs (Data on the Ethnography of Western Mexico, Part H., 1902) facts are corroborated by Herman (Aparecimiento de la Mancha Mongolica. Revista de Ethnologia, 1904). He cites A. F. Chamberlain (Pigmentary Spots, American Anthropologist, 1902,) and Starr (Sacral Spots of Mayan Indians, Science, New Series, xvii., 1903).
In Central America, according to these authorities, the spot is called Uits, "pan," and it is an insult to speak of it. It disappears in the tenth month. It is bluish-reddish (in these Native people), and is remarkable by its small size. The mulberry colored spot is very well known in Afro-Brazilians. In Brazil, among individuals of mixed Indigenous American and West African descent (pardo) it is called "genipapo", from its resemblance in color (bluish-gray) to an indigenous fruit of Brazil, named genipapo (a Native word adopted into Portuguese).

Prevalence
Infants may be born with one or more slate grey nevus ranging from small area on the buttocks to a larger area on the back. The birthmark is prevalent among East, South, Southeast, North and Central Asian peoples, Indigenous Oceanians (chiefly Micronesians and Polynesians), certain populations in Africa, Amerindians, non-European Latin Americans and Caribbeans of mixed-race descent.They occur in around 80% of Asians, and 80% to 85% of Native American infants. Approximately 90% of Polynesians and Micronesians are born with slate grey nevus, as are about 46% of children in Latin America, where they are associated with non-European descent. These spots also appear on 5–10% of babies of full Caucasian descent; Coria del Río in Spain has a high incidence due to the presence of descendants of members of the delegation led by Hasekura Tsunenaga, the first Japanese official envoy to Spain in the early 17th century. African American babies have slate grey nevus at a frequencies of 90% to 96%.According to a 2006 study examining the Mongolian spot among newborns in the Turkish city of İzmir, it was found out that 26% of the examined babies had the condition. It was noted the prevalence rate was 20% and 31% in boys and girls, respectively </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hairball and explain in detail? [/INST] A hairball is a small collection of hair or fur formed in the stomach of animals, and uncommonly in humans, that is occasionally vomited up when it becomes too big. Hairballs are primarily a tight elongated cylinder of packed fur, but may include bits of other elements such as swallowed food. Animals with hairballs are sometimes mistaken as having other conditions of the stomach such as lymphosarcoma, tuberculosis, and tumor of the spleen.  Cats are especially prone to hairball formation since they groom themselves by licking their fur, and thereby ingest it. Rabbits are also prone to hairballs because they groom themselves in the same fashion as cats, but hairballs are especially dangerous for rabbits because they cannot regurgitate them </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Advanced sleep phase disorder and explain in detail? [/INST] Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening (e.g. 7-9 PM) sleepiness and very early morning awakening (e.g. 2-4 AM). This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the bodys central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.

Symptoms
Individuals with ASPD report being unable to stay awake until conventional bedtime, falling asleep early in the evening, and being unable to stay asleep until their desired waking time, experiencing early morning insomnia. When someone has advanced sleep phase disorder their melatonin levels and core body temperature cycle hours earlier than an average person. These symptoms must be present and stable for a substantial period of time to be correctly diagnosed.

Diagnosis
Individuals expressing the above symptoms may be diagnosed with ASPD using a variety of methods and tests. Sleep specialists measure the patients sleep onset and offset, dim light melatonin onset, and evaluate Horne-Ostberg morningness-eveningness questionnaire results. Sleep specialists may also conduct a polysomnography test to rule out other sleep disorders like narcolepsy. Age and family history of the patient is also taken into consideration.

Treatment
Once diagnosed, ASPD may be treated with bright light therapy in the evenings, or behaviorally with chronotherapy, in order to delay sleep onset and offset. The use of pharmacological approaches to treatment are less successful due to the risks of administering sleep-promoting agents early in the morning. Additional methods of treatment, like timed melatonin administration or hypnotics have been proposed, but determining their safety and efficacy will require further research. Unlike other sleep disorders, ASPD does not necessarily disrupt normal functioning at work during the day and some patients may not complain of excessive daytime sleepiness. Social obligations may cause an individual to stay up later than their circadian rhythm requires, however, they will still wake up very early. If this cycle continues, it can lead to chronic sleep deprivation and other sleep disorders.

Epidemiology
ASPD is more common among middle and older adults. The estimated prevalence of ASPD is about 1% in middle-age adults, and is believed to affect men and women equally.  The disorder has a strong familial tendency, with 40-50% of affected individuals having relatives with ASPD. A genetic basis has been demonstrated in one form of ASPD, familial advanced sleep phase disorder (FASPS), which implicates missense mutations in genes hPER2 and CKIdelta in producing the advanced sleep phase phenotype. The identification of two different genetic mutations suggests that there is heterogeneity of this disorder.

Familial advanced sleep phase syndrome
FASPS symptoms
While advanced sleep and wake times are relatively common, especially among older adults, the extreme phase advance characteristic of familial advanced sleep phase syndrome (also known as familial advanced sleep phase disorder) is rare. Individuals with FASPS fall asleep and wake up 4–6 hours earlier than the average population, generally sleeping from 7:30pm to 4:30am. They also have a free running circadian period of 22 hours, which is significantly shorter than the average human period of slightly over 24 hours. The shortened period associated with FASPS results in a shortened period of activity, causing earlier sleep onset and offset. This means that individuals with FASPS must delay their sleep onset and offset each day in order to entrain to the 24-hour day. On holidays and weekends, when the average persons sleep phase is delayed relative to their workday sleep phase, individuals with FASPS experience further advance in their sleep phase.Aside from the unusual timing of sleep, FASPS patients experience normal quality and quantity of sleep. Like general ASPD, this syndrome does not inherently cause negative impacts, however, sleep deprivation may be imposed by social norms causing individuals to delay sleep until a more socially acceptable time, causing them to losing sleep due to earlier-than-usual wakeup time.Another factor that distinguishes FASPS from other advanced sleep phase disorders is its strong familial tendency and life-long expression. Studies of affected lineages have found that approximately 50% of directly related family members experience the symptoms of FASPS, which is an autosomal dominant trait. Diagnosis of FASPS can be confirmed through genetic sequencing analysis by locating genetic mutations known to cause the disorder. Treatment with sleep and wake scheduling and bright light therapy can be used to try to delay sleep phase to a more conventional time frame, however treatment of FASPS has proven largely unsuccessful. Bright light exposure in the evening (between 7:00 and 9:00), during the delay zone as indicated by the phase response curve to light, has been shown to delay circadian rhythms, resulting in later sleep onset and offset in patients with FASPS or other advanced sleep phase disorders.

Discovery
In 1999, Louis Ptáček conducted a study at the University of Utah in which he coined the term familial advanced sleep phase disorder after identifying individuals with a genetic basis for an advanced sleep phase. The first patient evaluated during the study reported "disabling early evening sleepiness" and "early morning awakening"; similar symptoms were also reported in her family members. Consenting relatives of the initial patient were evaluated, as well as those from two additional families. The clinical histories, sleep logs and actigraphy patterns of subject families were used to define a hereditary circadian rhythm variant associated with a short endogenous (i.e. internally-derived) period. The subjects demonstrated a phase advance of sleep-wake rhythms that was distinct not only from control subjects, but also to sleep-wake schedules widely considered to be conventional. The subjects were also evaluated using the Horne-Östberg questionnaire, a structured self-assessment questionnaire used to determine morningness-eveningness in human circadian rhythms. The Horne-Östberg scores of first-degree relatives of affected individuals were higher than those of marry-in spouses and unrelated control subjects. While much of morning and evening preference is heritable, the allele causing FASPS was hypothesized to have a quantitatively larger effect on clock function than the more common genetic variations that influence these preferences. Additionally, the circadian phase of subjects was determined using plasma melatonin and body core temperature measurements; these rhythms were both phase-advanced by 3–4 hours in FASPS subjects compared with control subjects. The Ptáček group also constructed a pedigree of the three FASPS kindreds which indicated a clear autosomal dominant transmission of the sleep phase advance.In 2001, the research group of Phyllis C. Zee phenotypically characterized an additional family affected with ASPS. This study involved an analysis of sleep/wake patterns, diurnal preferences (using a Horne-Östberg questionnaire), and the construction of a pedigree for the affected family. Consistent with established ASPS criteria, the evaluation of subject sleep architecture indicated that the advanced sleep phase was due to an alteration of circadian timing rather than an exogenous (i.e. externally-derived) disruption of sleep homeostasis, a mechanism of sleep regulation. Furthermore, the identified family was one in which an ASPS-affected member was present in every generation; consistent with earlier work done by the Ptáček group, this pattern suggests that the phenotype segregates as a single gene with an autosomal dominant mode of inheritance.In 2001, the research groups of Ptáček and Ying-Hui Fu published a genetic analysis of subjects experiencing the advanced sleep phase, implicating a mutation in the CK1-binding region of PER2 in producing the FASPS behavioral phenotype. FASPS is the first disorder to link known core clock genes directly with human circadian sleep disorders. As the PER2 mutation is not exclusively responsible for causing FASPS, current research has continued to evaluate cases in order to identify new mutations that contribute to the disorder.

Mechanisms (Per2 and CK1)
Two years after reporting the finding of FASPS, Ptáčeks and Fus groups published results of genetic sequencing analysis on a family with FASPS. They genetically mapped the FASPS locus to chromosome 2q where very little human genome sequencing was then available. Thus, they identified and sequenced all the genes in the critical interval. One of these was Period2 (Per2) which is a mammalian gene sufficient for the maintenance of circadian rhythms. Sequencing of the hPer2 gene (h denoting a human strain, as opposed to Drosophila or mouse strains) revealed a serine-to-glycine point mutation in the Casein Kinase I (CK1) binding domain of the hPER2 protein that resulted in hypophosphorylation of hPER2 in vitro. The hypophosphorylation of hPER2 disrupts the transcription-translation (negative) feedback loop (TTFL) required for regulating the stable production of hPER2 protein. In a wildtype individual, Per2 mRNA is transcribed and translated to form a PER2 protein. Large concentrations of PER2 protein inhibits further transcription of Per2 mRNA. CK1 regulates PER2 levels by binding to a CK1 binding site on the protein, allowing for phosphorylation which marks the protein for degradation, reducing protein levels. Once proteins become phosphorylated, PER2 levels decrease again, and Per2 mRNA transcription can resume. This negative feedback regulates the levels and expression of these circadian clock components.Without proper phosphorylation of hPER2 in the instance of a mutation in the CK1 binding site, less Per2 mRNA is transcribed and the period is shortened to less than 24 hours. Individuals with a shortened period due to this phosphorylation disruption entrain to a 24h light-dark cycle, which may lead to a phase advance, causing earlier sleep and wake patterns. However, a 22h period does not necessitate a phase shift, but a shift can be predicted depending on the time the subject is exposed to the stimulus, visualized on a Phase Response Curve (PRC) </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tonsillitis and explain in detail? [/INST] Tonsillitis is inflammation of the tonsils in the upper part of the throat. Tonsillitis is a type of pharyngitis that typically comes on fast (rapid onset). Symptoms may include sore throat, fever, enlargement of the tonsils, trouble swallowing, and large lymph nodes around the neck. Complications include peritonsillar abscess.Tonsillitis is most commonly caused by a viral infection and about 5% to 40% of cases are caused by a bacterial infection. When caused by the bacterium group A streptococcus, it is referred to as strep throat. Rarely bacteria such as Neisseria gonorrhoeae, Corynebacterium diphtheriae, or Haemophilus influenzae may be the cause. Typically the infection is spread between people through the air. A scoring system, such as the Centor score, may help separate possible causes. Confirmation may be by a throat swab or rapid strep test.Treatment efforts involve improving symptoms and decreasing complications. Paracetamol (acetaminophen) and ibuprofen may be used to help with pain. If strep throat is present the antibiotic penicillin by mouth is generally recommended. In those who are allergic to penicillin, cephalosporins or macrolides may be used. In children with frequent episodes of tonsillitis, tonsillectomy modestly decreases the risk of future episodes.About 7.5% of people have a sore throat in any three-month period and 2% of people visit a doctor for tonsillitis each year.   It is most common in school-aged children and typically occurs in the colder months of autumn and winter. The majority of people recover with or without medication. In 82% of people, symptoms resolve within one week, regardless if bacteria or viruses were present. Antibiotics probably reduce the number of people experiencing sore throat or headache, but the balance between modest symptom reduction and the potential hazards of antimicrobial resistance must be recognised.

Signs and symptoms
Those with tonsillitis usually experience sore throat, painful swallowing, malaise, and fever. Their tonsils – and often the back of the throat – appear red and swollen, and sometimes give off a white discharge. Some also have tender swelling of the cervical lymph nodes.Many viral infections that cause tonsillitis will also cause cough, runny nose, hoarse voice, or blistering in the mouth or throat. Infectious mononucleosis can cause the tonsils to swell with red spots or white discharge that may extend to the tongue. This can be accompanied by fever, sore throat, cervical lymph node swelling, and enlargement of the liver and spleen. Bacterial infections that cause tonsillitis can also cause a distinct "scarletiniform" rash, vomiting, and tonsillar spots or discharge.Tonsilloliths occur in up to 10% of the population frequently due to episodes of tonsillitis.

Causes
Viral infections cause 40 to 60% of cases of tonsillitis. Many viruses can cause inflammation of the tonsils (and the rest of throat) including adenovirus, rhinovirus, coronavirus, influenza virus, parainfluenza virus, coxsackievirus, measles virus, Epstein-Barr virus, cytomegalovirus, respiratory syncytial virus, and herpes simplex virus. Tonsillitis can also be part of the initial reaction to HIV infection. An estimated 1 to 10% of the cases are caused by Epstein-Barr virus.Tonsillitis can also stem from infection with bacteria, predominantly Group A β-hemolytic streptococci (GABHS), which causes strep throat. Bacterial infection of the tonsils usually follows the initial viral infection. When tonsillitis recurs after antibiotic treatment for streptococcus bacteria, it is usually due to the same bacteria as the first time, which suggests that the antibiotic treatment was not fully effective.  Less common bacterial causes include:  Streptococcus pneumoniae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis, Fusobacterium sp., Corynebacterium diphtheriae, Treponema pallidum, and Neisseria gonorrhoeae.Anaerobic bacteria have been implicated in tonsillitis, and a possible role in the acute inflammatory process is supported by several clinical and scientific observations.Sometimes tonsillitis is caused by an infection of spirochaeta and treponema, which is called Vincents angina or Plaut-Vincent angina.Within the tonsils, white blood cells of the immune system destroy the viruses or bacteria by producing inflammatory cytokines like phospholipase A2, which also lead to fever.  The infection may also be present in the throat and surrounding areas, causing inflammation of the pharynx.

Diagnosis
There is no firm distinction between a sore throat that is specifically tonsillitis and a sore throat caused by inflammation in both the tonsils and also nearby tissues.  An acute sore throat may be diagnosed as tonsillitis, pharyngitis, or tonsillopharyngitis (also called pharyngotonsillitis), depending upon the clinical findings.

In primary care settings, the Centor criteria are used to determine the likelihood of group A beta-hemolytic streptococcus (GABHS) infection in an acute tonsillitis and the need of antibiotics for tonsillitis treatment. However, the Centor criteria have their weaknesses in making precise diagnosis for adults. The Centor criteria are also ineffective in diagnosis for tonsillitis in children and in secondary care settings (hospitals). A modified version of the Centor criteria, which modified the original Centor criteria in 1998, is often used to aid in diagnosis. The original Centor criteria had four major criteria but the modified Centor criteria have five. The five major criteria of the modified Centor score are:

Presence of tonsillar exudate
Painful neck lymph nodes
History of fever
Age between five and fifteen years
Absence of coughThe possibility of GABHS infection increases with increasing score. The probability for getting GABHS is 2 to 23% for the score of 1, and 25 to 85% for the score of 4.
The diagnosis of GABHS tonsillitis can be confirmed by culture of samples obtained by swabbing the throat and plating them on blood agar medium.  This small percentage of false-negative results are part of the characteristics of the tests used but are also possible if the person has received antibiotics prior to testing. Identification requires 24 to 48 hours by culture but rapid screening tests (10–60 minutes), which have a sensitivity of 85–90%, are available. In 40% of the people without any symptoms, the throat culture can be positive. Therefore, throat culture is not routinely used in clinical practice for the detection of GABHS.Bacterial culture may need to be performed in cases of a negative rapid streptococcal test. An increase in antistreptolysin O (ASO) streptococcal antibody titer  following the acute infection can provide retrospective evidence of GABHS infection and is considered definitive proof of GABHS infection, but not necessarily of the tonsils.
Epstein Barr virus serology can be tested for those who may have infectious mononucleosis with a typical lymphocyte count in full blood count result. Blood investigations are only required for those with hospital admission requiring intravenous antibiotics. Increased values of secreted phospholipase A2 and altered fatty acid metabolism  observed in people with tonsillitis may have diagnostic utility.Nasoendoscopy can be used for those with severe neck pain and inability to swallow any fluids to rule out masked epiglotitis and supraglotitis. Routine nasoendscopy is not recommended for children.

Treatment
Treatments to reduce the discomfort from tonsillitis include:
pain and fever reducing medications such as paracetamol (acetaminophen) and ibuprofen
warm salt water gargle, lozenges, honey, or warm liquidsThere are no antiviral medical treatments for virally caused tonsillitis.

Antibiotics
If the tonsillitis is caused by group A streptococcus, then antibiotics are useful, with penicillin or amoxicillin being primary choices. Cephalosporins and macrolides are considered good alternatives to penicillin in the acute care setting. A macrolide, such as azithromycin or erythromycin, is used for people allergic to penicillin. If penicillin therapy fails, bacterial tonsillitis may respond to treatment effective against beta-lactamase producing bacteria such as clindamycin or amoxicillin-clavulanate. Aerobic and anaerobic beta lactamase producing bacteria that reside in the tonsillar tissues can "shield" group A streptococcus from penicillins. There is no significant difference in efficacy of various groups of antibiotics for treating tonsillitis. Intravenous antibiotics can be for those who are hospitalized with inability to swallow and presented with complications. Oral antibiotics can be resumed immediately if the person is clinically improved and able to swallow orally. Antibiotic treatment is usually taken for seven to ten days.

Pain medication
Paracetamol and  nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to treat throat pain in children and adults. Codeine is avoided in children under 12 years of age to treat throat pain or following tonsilectomy. NSAIDs (such as ibuprofen) and opioids (such as codeine and tramadol) are equally effective at relieving pain, however, precautions should be taken with these pain medications. NSAIDs can cause peptic ulcer disease and kidney damage. Opioids can cause respiratory depression in those who are vulnerable. Anaesthetic mouthwash can also be used for symptomatic relief.

Corticosteroids
Corticosteroids reduce tonsillitis pain and improve symptoms in 24 to 48 hours. Oral corticosteroids are recommended unless the person is unable to swallow medications.

Surgery
When tonsillitis recurs frequently, often arbitrarily defined as at least five episodes of tonsillitis in a year, or when the palatine tonsils become so swollen that swallowing is difficult as well as painful, a tonsillectomy can be performed to surgically remove the tonsils.
Children have had only a modest benefit from tonsillectomy for repeated cases of tonsillitis.

Prognosis
Since the advent of penicillin in the 1940s, a major preoccupation in the treatment of streptococcal tonsillitis has been the prevention of rheumatic fever, and its major effects on the nervous system and heart.
Complications may rarely include dehydration and kidney failure due to difficulty swallowing, blocked airways due to inflammation, and pharyngitis due to the spread of infection.An abscess may develop lateral to the tonsil during an infection, typically several days after the onset of tonsillitis. This is termed a peritonsillar abscess (or quinsy).
Rarely, the infection may spread beyond the tonsil resulting in inflammation and infection of the internal jugular vein giving rise to a spreading infectious thrombophlebitis (Lemierres syndrome).In strep throat, diseases like post-streptococcal glomerulonephritis can occur. These complications are extremely rare in developed nations but remain a significant problem in poorer nations.

Epidemiology
Tonsillitis occurs throughout the world, without racial or ethnic differences. Most children have tonsillitis at least once during their childhood, although it rarely occurs before the age of two. It most typically occurs between the ages of four and five; bacterial infections most typically occur at a later age.

Society and culture
Tonsillitis is described in the ancient Greek Hippocratic Corpus.Recurrent tonsillitis can interfere with vocal function and the ability to perform among people who use their voices professionally.

References
Books cited

Dean-Jones L (2013). "The Child Patient of the Hippocratics: Early Pediatrics?".  In Grubbs JE, Parkin T (eds.). The Oxford Handbook of Childhood and Education in the Classical World. Oxford University Press. doi:10.1093/oxfordhb/9780199781546.013.005. ISBN 9780199781546.
Ferri FF (2015). Ferris Clinical Advisor 2016: 5 Books in 1 (first ed.). Elsevier Health Sciences. ISBN 978-0323280471.
Jones R (2005). Oxford Textbook of Primary Medical Care. Oxford University Press. ISBN 9780198567820.
Lang F (2009). Encyclopedia of Molecular Mechanisms of Disease. Springer Science & Business Media. ISBN 9783540671367.
Nour SG, Mafee MR, Valvassori GE, Valbasson GE, Becker M (2005). Imaging of the head and neck. Stuttgart: Thieme. p. 716]. ISBN 978-1-58890-009-8.
Sataloff RT, Hawkshaw MJ (2019). "Medical Care of Voice Disorders".  In Eidsheim NS, Meisel K (eds.). The Oxford Handbook of Voice Studies. New York, NY: Oxford University Press. pp. 54–75. doi:10.1093/oxfordhb/9780199982295.013.11. ISBN 978-0-19-998229-5. OCLC 1076410526.
Simon HB (2005). "Bacterial infections of the upper respiratory tract".  In Dale DC, Federman DD (eds.). ACP Medicine, 2006 Edition (Two Volume Set) (Second ed.). WebMD Professional Publishing. ISBN 978-0-9748327-6-0.
Sommers M, Fannin E (2015). Diseases & Disorders: A Nursing Therapeutics Manual (5th ed.). F.A. Davis Company. ISBN 978-0803638556.
Stadelman-Cohen TK, Hillman RE (2019). "Voice Dysfunction and Recovery".  In Welch GF, Howard DM, Nix J (eds.). The Oxford Handbook of Singing. Oxford University Press. pp. 30–52. doi:10.1093/oxfordhb/9780199660773.013.018. ISBN 978-0-19-966077-3.
Thuma P (2001). "Pharyngitis and tonsillitis" </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dravet syndrome and explain in detail? [/INST] Dravet syndrome, previously known as severe myoclonic epilepsy of infancy (SMEI), is an autosomal dominant genetic disorder which causes a catastrophic form of epilepsy, with prolonged seizures that are often triggered by hot temperatures or fever. It is very difficult to treat with anticonvulsant medications. It often begins before 1 year of age, with 6 months being the age that seizures, characterized by prolonged convulsions and triggered by fever, usually begin.

Signs and symptoms
Dravet syndrome has been characterized by prolonged febrile and non-febrile seizures within the first year of a childs life. This disease progresses to other seizure types like myoclonic and partial seizures, psychomotor delay, and ataxia. It is characterized by cognitive impairment, behavioural disorders, and motor deficits. Behavioural deficits often include hyperactivity and impulsiveness, and in more rare cases, autistic-like behaviours. Dravet syndrome is also associated with sleep disorders including somnolence and insomnia.  The seizures experienced by people with Dravet syndrome become worse as the patient ages, as the disease is not very observable when symptoms first appear. This coupled with the range of severity differing between each individual diagnosed and the resistance of these seizures to drugs has made it challenging to develop treatments.Dravet syndrome appears during the first year of life, often beginning around six months of age with frequent febrile seizures (fever-related seizures). Children with Dravet syndrome typically experience a lagged development of language and motor skills, hyperactivity and sleep difficulties, chronic infection, growth and balance issues, and difficulty relating to others. The effects of this disorder do not diminish over time, and children diagnosed with Dravet syndrome require fully committed caretakers with tremendous patience and the ability to closely monitor them.Febrile seizures are divided into two categories known as simple and complex. A febrile seizure would be categorized as complex if it has occurred within 24 hours of another seizure or if it lasts longer than 15 minutes. A febrile seizure lasting less than 15 minutes would be considered simple. Sometimes modest hyperthermic stressors like physical exertion or a hot bath can provoke seizures in affected individuals. However, any seizure uninterrupted after 5 minutes, without a resumption of postictal (more normal; recovery-type; after-seizure) consciousness can lead to potentially fatal status epilepticus.

Causes
In most cases the mutations in Dravet syndrome are not hereditary and the mutated gene is found for the first time in a single family member. In 70–90% of patients, Dravet syndrome is caused by nonsense mutations in the SCN1A gene resulting in a premature stop codon and thus a non-functional protein.  This gene normally codes for neuronal voltage-gated sodium channel Nav1.1. In mouse models, these loss-of-function mutations have been observed to result in a decrease in sodium currents and impaired excitability of GABAergic interneurons of the hippocampus. The researchers found that loss of Nav1.1 channels was sufficient to cause the epilepsy and premature death seen in Dravet syndrome.The timing of the first signs and symptoms in Dravet syndrome occur about the same time as normal childhood vaccinations, leading some to believe the vaccine was the cause. However, this is likely a non-specific response to fever, as vaccination often induces fever, and fever is known to be associated with seizures in persons with Dravet syndrome.  Some of the patients who put forth vaccine injury claims from encephalopathy were later found, upon testing, to actually have Dravet syndrome.

Genetics
The genotypic explanation of the disorder has been located on the specific voltage-gated sodium channel genes known as SCN1A and SCN2A. These genes are located on the long (q) arm of chromosome 2 at position 24.3 and code for the alpha subunit of the transmembrane sodium channel protein. A mutation in either of these two genes will cause an individual to develop dysfunctional sodium channels, which are crucial in the pathway for sending chemical signals in the brain, causing the phenotypic display of myoclonic epilepsy from the individual. A properly functioning channel would respond to a voltage difference across the membrane and form a pore through which only sodium ions can pass. The influx of sodium induces the generation of action potential by temporarily changing the charge of the cell. When the gene is mutated, the eventually translated protein improperly folds its pore segment within the cell membrane because it has different amino acid chemistry, which renders the channel inactive. It is also possible for a mutation to reduce the number of channels produced by an individual, which leads to the development of Dravet syndrome.Currently, the SCN1A gene is the most clinically relevant; the largest number of epilepsy related mutations characterized thus far occur in this gene. Typically, a missense mutation in either the S5 or S6 segment of the sodium channel pore results in a loss of channel function and the development of Dravet syndrome. A heterozygous inheritance of an SCN1A mutation is all that is necessary to develop a defective sodium channel; patients with Dravet syndrome will still have one normal copy of the gene.

Diagnosis
According to the Dravet Syndrome Foundation, the diagnostic criteria for DS requires the patient to present with several of the following symptoms:
Onset of seizures in the first year of life in an otherwise healthy infant
Initial seizures are typically prolonged and are generalized or unilateral
Presence of other seizure types (i.e. myoclonic seizures)
Seizures associated with fever due to illness or vaccinations
Seizures induced by prolonged exposure to warm temperatures
Seizures in response to strong lighting or certain visual patterns
Initially normal EEGs and later EEGs with slowing and severe generalized polyspikes
Normal initial development followed by slow development during the first few years of life
Some degree of hypotonia
Unstable gait and balance issues
Ankle pronation and flat feet and/or development of a crouched gait with age

Treatment
Seizures in Dravet syndrome can be difficult to manage but may be reduced by anticonvulsant medications such as clobazam, stiripentol, topiramate and valproate. Because the course of the disorder varies from individual to individual,  treatment protocols may vary. A diet high in fats and low in carbohydrates may also be beneficial, known as a ketogenic diet. Although diet adjustment can help, it does not eliminate the symptoms </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tauopathy and explain in detail? [/INST] Tauopathy belongs to a class of neurodegenerative diseases involving the aggregation of tau protein into neurofibrillary or gliofibrillary tangles (Neurofibrillary tangle) in the human brain. Tangles are formed by hyperphosphorylation of the microtubule protein known as tau, causing the protein to dissociate from microtubules and form insoluble aggregates </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Tailors bunion and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Pelizaeus–Merzbacher disease and explain in detail? [/INST] Pelizaeus–Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in proteolipid protein 1 (PLP1), a major myelin protein. It is characterized by a decrease in the amount of insulating myelin surrounding the nerves (hypomyelination) and belongs to a group of genetic diseases referred to as leukodystrophies.

Signs and symptoms
The hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, and characteristic horizontal movements of the eyes left to right.The onset of Pelizaeus–Merzbacher disease is usually in early infancy. The most characteristic early signs are nystagmus (rapid, involuntary, rhythmic motion of the eyes) and low muscle tone.  Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with Pelizaeus–Merzbacher disease learn to understand language, and usually have some speech. Other signs may include tremor, lack of coordination,  involuntary movements, weakness, unsteady gait, and over time, spasticity in legs and arms.  Muscle contractures often occur over time. Mental functions may deteriorate. Some patients may have convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.

Cause
Pelizaeus–Merzbacher disease is caused by X-linked recessive mutations in the major myelin protein proteolipid protein 1 (PLP1). This causes hypomyelination in the central nervous system and severe neurological disease. The majority of mutations result in duplications of the entire PLP1 gene. Deletions of PLP1 locus (which are rare) cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function.

Diagnosis
The diagnosis of Pelizaeus–Merzbacher disease is often first suggested after identification by magnetic resonance imaging of abnormal white matter (high T2 signal intensity, i.e. T2 lengthening) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless a family history consistent with sex-linked inheritance exists, the condition is often misdiagnosed as cerebral palsy. Once a PLP1 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible.

Classification
The disease is one in a group of genetic disorders collectively known as leukodystrophies that affect the growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the central nervous system. The several forms of Pelizaeus–Merzbacher disease include classic, congenital, transitional, and adult variants.Milder mutations of the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2).

Treatment
No cure for Pelizaeus–Merzbacher disease has been developed </s>