<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 Lassa fever and explain in detail? [/INST] Lassa fever, also known as Lassa hemorrhagic fever (LHF), is a type of viral hemorrhagic fever caused by the Lassa virus. Many of those infected by the virus do not develop symptoms. When symptoms occur they typically include fever, weakness, headaches, vomiting, and muscle pains. Less commonly there may be bleeding from the mouth or gastrointestinal tract. The risk of death once infected is about one percent and frequently occurs within two weeks of the onset of symptoms. Of those who survive, about a quarter have hearing loss, which improves within three months in about half of these cases.The disease is usually initially spread to people via contact with the urine or feces of an infected multimammate mouse. Spread can then occur via direct contact between people. Diagnosis based on symptoms is difficult. Confirmation is by laboratory testing to detect the viruss RNA, antibodies for the virus, or the virus itself in cell culture. Other conditions that may present similarly include Ebola, malaria, typhoid fever, and yellow fever. The Lassa virus is a member of the Arenaviridae family of viruses.There is no vaccine. Prevention requires isolating those who are infected and decreasing contact with the mice. Other efforts to control the spread of disease include having a cat to hunt vermin, and storing food in sealed containers. Treatment is directed at addressing dehydration and improving symptoms. The antiviral medication ribavirin has been recommended, but evidence to support its use is weak.Descriptions of the disease date from the 1950s. The virus was first described in 1969 from a case in the town of Lassa, in Borno State, Nigeria. Lassa fever is relatively common in West Africa including the countries of Nigeria, Liberia, Sierra Leone, Guinea, and Ghana. There are about 300,000 to 500,000 cases which result in 5,000 deaths a year.

Signs and symptoms
Onset of symptoms is typically 7 to 21 days after exposure. In 80% of those who are infected few or no symptoms occur. These mild symptoms may include fever, tiredness, weakness, and headache. In 20% of people more severe symptoms such as bleeding gums, breathing problems, vomiting, chest pain, or dangerously low blood pressure may occur. Long term complications may include hearing loss. In those who are pregnant, miscarriage may occur in 95% of child-bearing women. Lassa fever can be difficult to distinguish clinically from other viral hemorrhagic fevers, such as Ebola virus disease. A combination of pharyngitis, pain behind the sternum, presence of excess protein in the urine and fever can indicate Lassa fever with higher specificity.In cases in which death occurs, this typically occurs within 14 days of onset. About 1% of all Lassa virus infections result in death. Approximately 15%-20% of those who have required hospitalization for Lassa fever die. The risk of death is greater in those who are pregnant. A "Swollen baby syndrome" may occur in newborns, infants and toddlers with pitting edema, abdominal distension and bleeding.

Cause
Virology
Lassa virus is a member of the Arenaviridae, a family of negative-sense, single-stranded RNA viruses. Specifically it is an old world arenavirus, which is enveloped, single-stranded, and bi-segmented RNA. This virus has both a large and a small genome section, with four lineages identified to date: Josiah (Sierra Leone), GA391 (Nigeria), LP (Nigeria) and strain AV.

Spread
Lassa virus commonly spreads to humans from other animals, specifically the Natal multimammate mouse or African rat, also called the Natal multimammate rat (Mastomys natalensis). This is probably the most common mouse in equatorial Africa, common in human households and eaten as a delicacy in some areas.The multimammate mouse can quickly produce a large number of offspring, tends to colonize human settlements, increasing the risk of rodent-human contact, and is found throughout the west, central and eastern parts of the African continent.Once the mouse has become a carrier, it will excrete the virus throughout the rest of its lifetime through feces and urine creating ample opportunity for exposure. The virus is probably transmitted by contact with the feces or urine of animals accessing grain stores in residences. No study has proven presence in breast milk, but the high level of viremia suggests it may be possible.Individuals who are at a higher risk of contracting the infection are those who live in rural areas where Mastomys are discovered, and where sanitation is not prevalent. Infection typically occurs by direct or indirect exposure to animal excrement through the respiratory or gastrointestinal tracts. Inhalation of tiny particles of infectious material (aerosol) is believed to be the most significant means of exposure. It is possible to acquire the infection through broken skin or mucous membranes that are directly exposed to infectious material. Transmission from person to person has been established, presenting a disease risk for healthcare workers. The virus is present in urine for between three and nine weeks after infection, and it can be transmitted in semen for up to three months after becoming infected.

Diagnosis
A range of laboratory investigations are performed, where possible, to diagnose the disease and assess its course and complications. The confidence of a diagnosis can be compromised if laboratory tests are not available. One comprising factor is the number of febrile illnesses present in Africa, such as malaria or typhoid fever that could potentially exhibit similar symptoms, particularly for non-specific manifestations of Lassa fever. In cases with abdominal pain, in countries where Lassa is common, Lassa fever is often misdiagnosed as appendicitis and intussusception which delays treatment with the antiviral ribavirin. In West Africa, where Lassa is most common, it is difficult to diagnose due to the absence of proper equipment to perform testing.The FDA has yet to approve a widely validated laboratory test for Lassa, but there are tests that have been able to provide definitive proof of the presence of the LASV virus. These tests include cell cultures, PCR, ELISA antigen assays, plaque neutralization assays, and immunofluorescence essays. However, immunofluorescence essays provide less definitive proof of Lassa infection. An ELISA test for antigen and Immunoglobulin M antibodies give 88% sensitivity and 90% specificity for the presence of the infection. Other laboratory findings in Lassa fever include lymphocytopenia (low white blood cell count), thrombocytopenia (low platelets), and elevated aspartate transaminase  levels in the blood. Lassa fever virus can also be found in cerebrospinal fluid.

Prevention
Control of the Mastomys rodent population is impractical, so measures focus on keeping rodents out of homes and food supplies, encouraging effective personal hygiene, storing grain and other foodstuffs in rodent-proof containers, and disposing of garbage far from the home to help sustain clean households. Gloves, masks, laboratory coats, and goggles are advised while in contact with an infected person, to avoid contact with blood and body fluids. These issues in many countries are monitored by a department of public health. In less developed countries, these types of organizations may not have the necessary means to effectively control outbreaks.

Vaccine
There is no vaccine for humans as of 2019. Researchers at the United States Army Medical Research Institute of Infectious Diseases facility had a promising vaccine candidate in 2002. They have developed a replication-competent vaccine against Lassa virus based on recombinant vesicular stomatitis virus vectors expressing the Lassa virus glycoprotein. After a single intramuscular injection, test primates have survived lethal challenge, while showing no clinical symptoms.

Treatment
Treatment is directed at addressing dehydration and improving symptoms. All persons suspected of Lassa fever infection should be admitted to isolation facilities and their body fluids and excreta properly disposed of.

Medications
The antiviral medication ribavirin has been recommended, but evidence to support its use is weak. Some evidence has found that it may worsen outcomes in certain cases. Fluid replacement, blood transfusions, and medication for low blood pressure may be required. Intravenous interferon therapy has also been used.

Pregnancy
When Lassa fever infects pregnant women late in their third trimester, inducing delivery is necessary for the mother to have a good chance of survival. This is because the virus has an affinity for the placenta and other highly vascular tissues. The fetus has only a one in ten chance of survival no matter what course of action is taken; hence, the focus is always on saving the life of the mother. Following delivery, women should receive the same treatment as other people with Lassa fever.

Prognosis
About 15–20% of hospitalized people with Lassa fever will die from the illness. The overall case fatality rate is estimated to be 1%, but during epidemics, mortality can climb as high as 50%. The mortality rate is greater than 80% when it occurs in pregnant women during their third trimester; fetal death also occurs in nearly all those cases. Abortion decreases the risk of death to the mother. Some survivors experience lasting effects of the disease, and can include partial or complete deafness.Because of treatment with ribavirin, fatality rates have declined.

Epidemiology
There are about 300,000 to 500,000 cases which result in 5,000 deaths a year. One estimate places  the number as high as 3 million cases per year.Estimates of Lassa fever are complicated by the lack of easy-available diagnosis, limited public health surveillance infrastructure, and high clustering of incidence near high intensity sampling.The infection affects females 1.2 times more than males. The age group predominantly infected is 21–30 years.

Geography
Lassa high risk areas are near the western and eastern extremes of West Africa. As of 2018, the Lassa belt includes Guinea, Nigeria, Sierra Leone and Liberia. As of 2003, 10-16% of people in Sierra Leone and Liberia admitted to hospital had the virus. The case fatality rate for those who are hospitalized for the disease is about 15-20%. Research showed a twofold increase risk of infection for those living in close proximity to someone with infection symptoms within the last year.
The high risk areas cannot be well defined by any known biogeographical or environmental breaks except for the multimammate rat, particularly Guinea (Kindia, Faranah and Nzérékoré regions), Liberia (mostly in Lofa, Bong, and Nimba counties), Nigeria (in about 10 of 36 states) and Sierra Leone (typically from Kenema and Kailahun districts).  It is less common in the Central African Republic, Mali, Senegal and other nearby countries, and less common yet in Ghana and the Democratic Republic of the Congo. Benin had its first confirmed cases in 2014, and Togo had its first confirmed cases in 2016.As of 2013, the spread of Lassa outside of West Africa had been very limited. Twenty to thirty cases had been described in Europe, as being caused by importation through infected individuals. These cases found outside of West Africa were found to have a high fatality risk because of the delay of diagnosis and treatment due to being unaware of the risk associated with the symptoms. Imported cases have not manifested in larger epidemics outside of Africa due to a lack of human to human transmission in hospital settings. An exception had occurred in 2003 when a healthcare worker became infected before the person showed clear symptoms.

Nigeria
2018 outbreak
An outbreak of Lassa fever occurred in Nigeria during 2018 and spread to 18 of the countrys states; it was the largest outbreak of Lassa recorded. On 25 February 2018, there were 1081 suspected cases and 90 reported deaths; 317 of the cases and 72 deaths were confirmed as Lassa which increased to a total of 431 reported cases in 2018.

2019 outbreak
The total cases in Nigeria in 2019 was 810 with 167 deaths, the largest case fatality rate(23.3%) until then.

2020 outbreak
The epidemic started from the second week of the January. By the tenth week the total number of cases has risen to 855 and deaths to 144, the case fatality rate of 16.8%.2021 Outbreak
On the 8th of December 2021, the Nigeria Centre for Disease Control (NCDC) was notified of the death of two persons from Lassa fever.2022 Outbreak
The epidemic took a new form, from 3 to 30 January 2022, 211 laboratory confirmed Lassa fever cases including 40 deaths (case fatality ratio: 19%) have been cumulatively reported in 14 of the 36 Nigerian states and the Federal Capital Territory across the country. In total from January until March, 132 deaths have been reported with a case fatality rate (CFR) of 19.1% which is lower than the CFR for the same period in 2021 (21.0%).

Liberia
Lassa fever is endemic in Liberia. From 1 January 2017 through 23 January 2018, 91 suspected cases were reported from six counties: Bong, Grand Bassa, Grand Kru, Lofa, Margibi, and Nimba. Thirty-three of these cases were laboratory confirmed, including 15 deaths (case fatality rate for confirmed cases = 45.4%).In February 2020, a total of 24 confirmed cases with nine associated deaths has been reported from nine health districts in six counties. Grand Bossa and Bong counties account for 20 of the confirmed cases.

History
The disease was identified in Nigeria in 1969. It is named after the town of Lassa, where it was discovered.A prominent expert in the disease, Aniru Conteh, died from the disease.

Research
The Lassa virus is one of several viruses identified by WHO as a likely cause of a future epidemic. They therefore list it for urgent research and development to develop new diagnostic tests, vaccines, and medicines.In 2007, SIGA Technologies, studied a medication in guinea pig with Lassa fever. Work on a vaccine is continuing, with multiple approaches showing positive results in animal trials.

References
Further reading

Echioya, Deborah U.; Hass, Meike; Olshlager, Stephan; Becker-Ziaja, Beate; Chukwu, Christian O. Onyebuchi; Coker, Jide; Nasidi, Abdulsalam; Ogugua, Osi-Ogdu; Gunther, Stephan; Omilabu, Sunday A. (2010). "Lassa Fever, Nigeria, 2005-2008". Emerging Infectious Diseases. 6. 16 (6): 1040–41 </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 Hereditary spastic paraplegia and explain in detail? [/INST] Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity)  and contraction in the lower limbs. HSP is also known as hereditary spastic paraparesis, familial spastic paraplegia, French settlement disease, Strumpell disease, or Strumpell-Lorrain disease.  The symptoms are a result of dysfunction of  long axons in the spinal cord. The affected cells are the primary motor neurons; therefore, the disease is an upper motor neuron disease. HSP is not a form of cerebral palsy even though it physically may appear and behave much the same as spastic diplegia. The origin of HSP  is different from cerebral palsy. Despite this, some of the same anti-spasticity medications used in spastic cerebral palsy are sometimes used to  treat HSP symptoms.
HSP is caused by defects in  transport of  proteins, structural proteins, cell-maintaining proteins, lipids, and other substances through the cell. Long nerve fibers (axons) are affected because  long distances make nerve cells particularly sensitive to defects in these mentioned mechanisms.The disease was first described in 1880 by the German neurologist Adolph Strümpell. It was described more extensively in 1888 by Maurice Lorrain, a French physician.  Due to their contribution in describing the disease, it is still called Strümpell-Lorrain disease in French-speaking countries. The term hereditary spastic paraplegia was coined by Anita Harding in 1983.

Signs and symptoms
Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.
Individuals with HSP can experience extreme fatigue associated with central nervous system and neuromuscular disorders, which can be disabling. Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices. Disability has been described as progressing more rapidly in adult onset forms.More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles.
In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, intellectual disability, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.Anita Harding classified the HSP in a pure and complicated form. Pure HSP presents with spasticity in the lower limbs, associated with neurogenic bladder disturbance as well as lack of vibration sensitivity (pallhypesthesia). On the other hand, HSP is classified as complex when lower limb spasticity is combined with any additional neurological symptom.This classification is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia with spasticity, intellectual disability (with spasticity), or  leukodystrophy. Some of the genes listed below have been described in other diseases than HSP before. Therefore, some key genes overlap with other disease groups.

Age of onset
In the past, HSP has been classified as early onset beginning in early childhood or later onset in adulthood. The age of onsets has two points of maximum at age 2 and around age 40. New findings propose that an earlier onset leads to a longer disease duration without loss of ambulation or the need for the use of a wheelchair. This was also described earlier, that later onset forms evolve more rapidly.

Cause
HSP is a group of genetic disorders. It follows general inheritance rules and can be inherited in an autosomal dominant, autosomal recessive or X-linked recessive manner. The mode of inheritance involved has a direct impact on the chances of inheriting the disorder. Over 70 genotypes had been described, and over 50 genetic loci have been linked to this condition. Ten genes have been identified with autosomal dominant inheritance. One of these, SPG4, accounts for ~50% of all genetically solved cases, or approximately 25% of all HSP cases. Twelve genes are known to be inherited in an autosomal recessive fashion. Collectively this latter group account for ~1/3 cases.Most altered genes have known function, but for some the function havent been identified yet. All of them are listed in the gene list below, including their mode of inheritance.  Some examples are spastin (SPG4) and paraplegin (SPG7) are both AAA ATPases.

Genotypes
The genes are designated SPG (Spastic gait gene). The gene locations are in the format: chromosome - arm (short or p: long or q) - band number. These designations are for the human genes only. The locations may (and probably will) vary in other organisms.
Despite the number of genes known to be involved in this condition ~40% of cases have yet to have their cause identified. In the table below SPG? is used to indicate a gene that has been associated with HSP but has not yet received an official HSP gene designation.

Pathophysiology
The major feature of HSP is a length-dependent axonal degeneration. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating axons are preserved and there is no evidence of primary demyelination. Loss of anterior horn cells of the spinal cord are observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are not directly affected.HSP affects several pathways in motor neurons. Many genes were identified and linked to HSP. It remains a challenge to accurately define the key players in each of the affected pathways, mainly because many genes have multiple functions and are involved in more than one pathway.

Axon pathfinding
Pathfinding is important for axon growth to the right destination (e.g. another nerve cell or a muscle). Significant for this mechanism is the L1CAM gene, a cell surface glycoprotein of the immunoglobulin superfamily. Mutations leading to a loss-of-function in L1CAM are also found in other X-linked syndromes. All of these disorders display corticospinal tract impairment (a hallmark feature of HSP). L1CAM participates in a set of interactions, binding other L1CAM molecules as well as extracellular cell adhesion molecules, integrins, and proteoglycans or intracellular proteins like ankyrins.The pathfinding defect occurs via the association of L1CAM with neuropilin-1. Neuropilin-1 interacts with Plexin-A proteins to form the Semaphorin-3A receptor complex. Semaphorin-a3A is then released in the ventral spinal cord to steer corticospinal neurons away from the midline spinal cord / medullary junction. If L1CAM does not work correctly due to a mutation, the cortiocospinal neurons are not directed to the correct position and the impairment occurs.

Lipid metabolism
Axons in the central and peripheral nervous system are coated with an insulation, the myelin layer, to increase the speed of action potential propagation. Abnormal myelination in the CNS is detected in some forms of hsp HSP. Several genes were linked to myelin malformation, namely PLP1, GFC2 and FA2H. The mutations alter myelin composition, thickness and integrity.Endoplasmic reticulum (ER) is the main organelle for lipid synthesis. Mutations in genes encoding proteins that have a role in shaping ER morphology and lipid metabolism were linked to HSP. Mutations in ATL1, BSCL2 and ERLIN2 alter ER structure, specifically the tubular network and the formation of three-way junctions in ER tubules. Many mutated genes are linked to abnormal lipid metabolism. The most prevalent effect is on arachidonic acid (CYP2U1) and cholesterol (CYP7B1) metabolism, phospholipase activity (DDHD1 and DDHD2), ganglioside formation (B4GALNT-1) and the balance between carbohydrate and fat metabolism (SLV33A1).

Endosomal trafficking
Neurons take in substances from their surrounding by endocytosis. Endocytic vesicles fuse to endosomes in order to release their content. There are three main compartments that have endosome trafficking: Golgi to/from endosomes; plasma membrane to/from early endosomes (via recycling endosomes) and late endosomes to lysosomes. Dysfunction of endosomal trafficking can have severe consequences in motor neurons with long axons, as reported in HSP. Mutations in AP4B1 and KIAA0415 are linked to disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles. Both genes encode proteins that interact with several other proteins and disrupt the secretory and endocytic pathways.

Mitochondrial function
Mitochondrial dysfunctions have been connected with developmental and degenerative neurological disorders. Only a few HSP genes encode mitochondrial proteins. Two mitochondrial resident proteins are mutated in HSP: paraplegin and chaperonin 60. Paraplegin is a m-AAA metalloprotease of the inner mitochondrial membrane. It functions in ribosomal assembly and protein quality control. The impaired chaperonin 60 activity leads to impaired mitochondrial quality control. Two genes DDHD1 and CYP2U1 have shown alteration of mitochondrial architecture in patient fibroblasts. These genes encode enzymes involved in fatty-acid metabolism.

Diagnosis
Initial diagnosis of HSPs relies upon family history, the presence or absence of additional signs and the exclusion of other nongenetic causes of spasticity, the latter being particular important in sporadic cases.Cerebral and spinal MRI is an important procedure performed in order to rule out other frequent neurological conditions, such as multiple sclerosis, but also to detect associated abnormalities such as cerebellar or corpus callosum atrophy as well as white matter abnormalities. Differential diagnosis of HSP should also exclude spastic diplegia which presents with nearly identical day-to-day effects and even is treatable with similar medicines such as baclofen and orthopedic surgery; at times, these two conditions may look and feel so similar that the only perceived difference may be HSPs hereditary nature versus the explicitly non-hereditary nature of spastic diplegia (however, unlike spastic diplegia and other forms of spastic cerebral palsy, HSP cannot be reliably treated with selective dorsal rhizotomy).Ultimate confirmation of HSP diagnosis can only be provided by carrying out genetic tests targeted towards known genetic mutations.

Classification
Hereditary spastic paraplegias can be classified based on the symptoms; mode of inheritance; the patients age at onset; the affected genes; and biochemical pathways involved.

Treatment
No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being. Therapeutics offered to HSP patients include:

Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone. This can be administered orally or intrathecally </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 overdose and explain in detail? [/INST] Barbiturate overdose is poisoning due to excessive doses of barbiturates. Symptoms typically include difficulty thinking, poor coordination, decreased level of consciousness, and a decreased effort to breathe (respiratory depression). Complications of overdose can include noncardiogenic pulmonary edema. If death occurs this is typically due to a lack of breathing.Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines. The lethal dose varies with a persons tolerance and how the drug is taken. The effects of barbiturates occur via the GABA neurotransmitter. Exposure may be verified by testing the urine or blood.Treatment involves supporting a persons breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Hemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful. While once a common cause of overdose, barbiturates are now a rare cause.

Mechanism
Barbiturates increase the time that the chloride pore of the GABAA receptor is opened, thereby increasing the efficacy of GABA. In contrast, benzodiazepines increase the frequency with which the chloride pore is opened, thereby increasing GABAs potency.

Treatment
Treatment involves supporting a persons breathing and blood pressure. While there is no antidote, activated charcoal may be useful. Multiple doses of charcoal may be required. Hemodialysis may occasionally be considered. Urine alkalinisation has not been found to be useful.If a person is drowsy but awake and can swallow and breathe without difficulty, the treatment can be as simple as monitoring the person closely. If the person is not breathing, it may involve mechanical ventilation until the drug has worn off. Psychiatric consult is generally recommended.

Notable cases
People who are known to have died by suicide from barbiturate overdose include, Gillian Bennett, Charles Boyer, Ruan Lingyu, Victor Folke Nelson, Dalida, Jeannine "The Singing Nun" Deckers, Felix Hausdorff, Abbie Hoffman, Phyllis Hyman, Marilyn Monroe, C </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 Conversion disorder and explain in detail? [/INST] Conversion disorder (CD), or functional neurologic symptom disorder, is a diagnostic category used in some psychiatric classification systems. It is sometimes applied to patients who present with neurological symptoms, such as numbness, blindness, paralysis, or fits, which are not consistent with a well-established organic cause, which cause significant distress, and can be traced back to a psychological trigger. It is thought that these symptoms arise in response to stressful situations affecting a patients mental health or an ongoing mental health condition such as depression. Conversion disorder was retained in DSM-5, but given the subtitle functional neurological symptom disorder. The new criteria cover the same range of symptoms, but remove the requirements for a psychological stressor to be present and for feigning to be disproved. ICD-10 classifies conversion disorder as a dissociative disorder while DSM-IV classifies it as a somatoform disorder.

Signs and symptoms
Conversion disorder begins with some stressor, trauma, or psychological distress. Usually the physical symptoms of the syndrome affect the senses or movement. Common symptoms include blindness, partial or total paralysis, inability to speak, deafness, numbness, difficulty swallowing, incontinence, balance problems, seizures, tremors, and difficulty walking. The symptom of feeling unable to breathe, but where the lips are not turning blue, can indicate conversion disorder or sleep paralysis. Sleep paralysis and narcolepsy can be ruled out with sleep tests. These symptoms are attributed to conversion disorder when a medical explanation for the conditions cannot be found. Symptoms of conversion disorder usually occur suddenly. Conversion disorder is typically seen in people aged 10 to 35, and affects between 0.011% and 0.5% of the general population.Conversion disorder can present with motor or sensory symptoms including any of the following:
Motor symptoms or deficits:

Impaired coordination or balance
Weakness/paralysis of a limb or the entire body (hysterical paralysis or motor conversion disorders)
Impairment or loss of speech (hysterical aphonia)
Difficulty swallowing (dysphagia) or a sensation of a lump in the throat
Urinary retention
Psychogenic non-epileptic seizures or convulsions
Persistent dystonia
Tremor, myoclonus or other movement disorders
Gait problems (astasia-abasia)
Loss of consciousness (fainting)Sensory symptoms or deficits:

Impaired vision (hysterical blindness), double vision
Impaired hearing (deafness)
Loss or disturbance of touch or pain sensationConversion symptoms typically do not conform to known anatomical pathways and physiological mechanisms. It has sometimes been stated that the presenting symptoms tend to reflect the patients own understanding of anatomy and that the less medical knowledge a person has, the more implausible are the presenting symptoms. However, no systematic studies have yet been performed to substantiate this statement.

Diagnosis
Definition
Conversion disorder is now contained under the umbrella term functional neurological symptom disorder. In cases of conversion disorder, there is a psychological stressor.
The diagnostic criteria for functional neurological symptom disorder, as set out in DSM-5, are:

Specify type of symptom or deficit as:

With weakness or paralysis
With abnormal movement (e.g. tremor, dystonic movement, myoclonus, gait disorder)
With swallowing symptoms
With speech symptoms (e.g. dysphonia, slurred speech)
With attacks or seizures
With amnesia or memory loss
With special sensory loss symptoms (e.g. visual blindness, olfactory loss, or hearing disturbance)
With mixed symptoms.Specify if:

Acute episode: symptoms present for less than six months
Persistent: symptoms present for six months or more.Specify if:

Psychological stressor (conversion disorder)
No psychological stressor (functional neurological symptom disorder)

Exclusion of neurological disease
Conversion disorder presents with symptoms that typically resemble a neurological disorder such as stroke, multiple sclerosis, epilepsy, hypokalemic periodic paralysis or narcolepsy. The neurologist must carefully exclude neurological disease, through examination and appropriate investigations. However, it is not uncommon for patients with neurological disease to also have conversion disorder.In excluding neurological disease, the neurologist has traditionally relied partly on the presence of positive signs of conversion disorder, i.e. certain aspects of the presentation that were thought to be rare in neurological disease but common in conversion. The validity of many of these signs has been questioned, however, by a study showing they also occur in neurological disease. One such symptom, for example, is la belle indifférence, described in DSM-IV as "a relative lack of concern about the nature or implications of the symptoms". In a later study, no evidence was found that patients with functional symptoms are any more likely to exhibit this than patients with a confirmed organic disease. In DSM-V, la belle indifférence was removed as a diagnostic criterion.
Another feature thought to be important was that symptoms tended to be more severe on the non-dominant (usually left) side of the body. There have been a number of theories about this, such as the relative involvement of cerebral hemispheres in emotional processing, or more simply, that it was "easier" to live with a functional deficit on the non-dominant side. However, a literature review of 121 studies established that this was not true, with publication bias the most likely explanation for this commonly held view. Although agitation is often assumed to be a positive sign of conversion disorder, release of epinephrine is a well-demonstrated cause of paralysis from hypokalemic periodic paralysis.Misdiagnosis does sometimes occur. In a highly influential study from the 1960s, Eliot Slater demonstrated that misdiagnoses had occurred in one third of his 112 patients with conversion disorder. Later authors have argued that the paper was flawed, however, and a meta-analysis has shown that misdiagnosis rates since that paper was published are around four percent, the same as for other neurological diseases.

Deliberate feigning
Conversion disorder, by its nature, is more prone to deliberate feigning. One neuroimaging study suggested that feigning may be distinguished from conversion by the pattern of frontal lobe activation.

Psychological mechanism
The psychological mechanism of conversion can be the most difficult aspect of a conversion diagnosis. Even if there is a clear antecedent trauma or other possible psychological trigger, it is still not clear exactly how this gives rise to the symptoms observed. Patients with medically unexplained neurological symptoms may not have any psychological stressor, hence the use of the term "functional neurological symptom disorder" in DSM-5 as opposed to "conversion disorder", and DSM-5s removal of the need for a psychological trigger.

Treatment
There are a number of different treatments available to treat and manage conversion syndrome. Treatments for conversion syndrome include hypnosis, psychotherapy, physical therapy, stress management, and transcranial magnetic stimulation. Treatment plans will consider duration and presentation of symptoms and may include one or multiple of the above treatments. This may include the following:
Occupational therapy to maintain autonomy in activities of daily living;
Physiotherapy where appropriate.
Treatment of comorbid depression or anxiety if present.
Educating patients on the causes of their symptoms might help them learn to manage both the psychiatric and physical aspects of their condition. Psychological counseling is often warranted given the known relationship between conversion disorder and emotional trauma. This approach ideally takes place alongside other types of treatment.There is little evidence-based treatment of conversion disorder. Other treatments such as cognitive behavioral therapy, hypnosis, EMDR, and psychodynamic psychotherapy, EEG brain biofeedback need further trials. Psychoanalytic treatment may possibly be helpful. However, most studies assessing the efficacy of these treatments are of poor quality and larger, better controlled studies are urgently needed. Cognitive Behavioural Therapy is the most common treatment, however boasts a mere 13% improvement rate.

Prognosis
Empirical studies have found that the prognosis for conversion disorder varies widely, with some cases resolving in weeks, and others enduring for years or decades. There is also evidence that there is no cure for conversion disorder, and that although patients may go into remission they can relapse at any point. Furthermore, many patients can get rid of their symptoms with time, treatments and reassurance.

Epidemiology
Frequency
Information on the frequency of conversion disorder in the West is limited, in part due to the complexities of the diagnostic process. In neurology clinics, the reported prevalence of unexplained symptoms among new patients is very high (between 30 and 60%). However, diagnosis of conversion typically requires an additional psychiatric evaluation, and since few patients will see a psychiatrist it is unclear what proportion of the unexplained symptoms are actually due to conversion. Large scale psychiatric registers in the US and Iceland found incidence rates of 22 and 11 newly diagnosed cases per 100,000 person-years, respectively. Some estimates claim that in the general population, between 0.011% and 0.5% of the population have conversion disorder.

Culture
Although it is often thought that the frequency of conversion may be higher outside of the West, perhaps in relation to cultural and medical attitudes, evidence of this is limited. A community survey of urban Turkey found a prevalence of 5.6%. Many authors have found occurrence of conversion to be more frequent in rural, lower socio-economic groups, where technological investigation of patients is limited and people may know less about medical and psychological concepts.

Gender
Historically, the concept of hysteria was originally understood to be a condition exclusively affecting women, though the concept was eventually extended to men. In recent surveys of conversion disorder (formerly classified as "hysterical neurosis, conversion type"), females predominate, with between two and six female patients for every male but some research suggests this gender disparity may be confounded by higher rates of violence against women.

Age
Conversion disorder may present at any age but is rare in children younger than ten or in the elderly. Studies suggest a peak onset in the mid-to-late 30s.

History
The first evidence of functional neurological symptom disorder dates back to 1900 BC, when the symptoms were blamed on the uterus moving within the female body. The treatment varied "depending on the position of the uterus, which must be forced to return to its natural position. If the uterus had moved upwards, this could be done by placing malodorous and acrid substances near the womans mouth and nostrils, while scented ones were placed near her vagina; on the contrary, if the uterus had lowered, the document recommends placing the acrid substances near her vagina and the perfumed ones near her mouth and nostrils."In Greek mythology, hysteria, the original name for functional neurological symptom disorder, was thought to be caused by a lack of orgasms, uterine melancholy and not procreating. Plato, Aristotle and Hippocrates believed a lack of sex upsets the uterus. The Greeks believed it could be prevented and cured with wine and orgies. Hippocrates argued that a lack of regular sexual intercourse led to the uterus producing toxic fumes and caused it to move in the body, and that this meant all women should be married and enjoy a satisfactory sexual life.From the 13th century, women with hysteria were exorcised, as it was believed that they were possessed by the devil. It was believed that if doctors could not find the cause of a disease or illness, it must be caused by the devil.At the beginning of the 16th century, women were sexually stimulated by midwives in order to relieve their symptoms. Gerolamo Cardano and Giambattista della Porta believed polluted water and fumes caused the symptoms of hysteria. Towards the end of the century, however, the role of the uterus was no longer thought central to the disorder, with Thomas Willis discovering that the brain and central nervous system were the cause of the symptoms. Thomas Sydenham argued that the symptoms of hysteria may have an organic cause. He also proved the uterus is not the cause of symptom.In 1692, in the US town of Salem, Massachusetts, there was an outbreak of hysteria. This led to the Salem witch trials, where the women accused of being witches had symptoms such as sudden movements, staring eyes and uncontrollable jumping.During the 18th century, there was a move from the idea of hysteria being caused by the uterus to it being caused by the brain. This led to an understanding that it could affect both sexes. Jean-Martin Charcot argued that hysteria was caused by "a hereditary degeneration of the nervous system, namely a neurological disorder".In the 19th century, hysteria moved from being considered a neurological disorder to being considered a psychological disorder, when Pierre Janet argued that "dissociation appears autonomously for neurotic reasons, and in such a way as to adversely disturb the individuals everyday life". However, as early as 1874, doctors including W. B. Carpenter and J. A. Omerod began to speak out against the hysteria phenomenon as there was no evidence to prove its existence.Sigmund Freud referred to the condition as both hysteria and conversion disorder throughout his career. He believed those with the condition could not live in a mature relationship, and that those with the condition were unwell in order to achieve a "secondary gain", in that they are able to manipulate their situation to fit their needs or desires. He also found that both men and women could have the disorder.Freuds model suggested the emotional charge deriving from painful experiences would be consciously repressed as a way of managing the pain, but that the emotional charge would be somehow "converted" into neurological symptoms. Freud later argued that the repressed experiences were of a sexual nature. As Peter Halligan comments, conversion has "the doubtful distinction among psychiatric diagnoses of still invoking Freudian mechanisms".Pierre Janet, the other great theoretician of hysteria, argued that symptoms arose through the power of suggestion, acting on a personality vulnerable to dissociation. In this hypothetical process, the subjects experience of their leg, for example, is split off from the rest of their consciousness, resulting in paralysis or numbness in that leg.
Later authors have attempted to combine elements of these various models, but none of them has a firm empirical basis. In 1908, Steyerthal predicted that: "Within a few years the concept of hysteria will belong to history ... there is no such disease and there never has been. What Charcot called hysteria is a tissue woven of a thousand threads, a cohort of the most varied diseases, with nothing in common but the so-called stigmata, which in fact may accompany any disease." However, the term "hysteria" was still being used well into the 20th century.
Some support for the Freudian model comes from findings of high rates of childhood sexual abuse in conversion patients. Support for the dissociation model comes from studies showing heightened suggestibility in conversion patients. However, critics argue that it can be challenging to find organic pathologies for all symptoms, and so the practice of diagnosing patients with such symptoms as having hysteria led to the disorder being meaningless, vague and a sham diagnosis, as it does not refer to any definable disease. Furthermore, throughout its history, many patients have been misdiagnosed with hysteria or conversion disorder when they had organic disorders such as tumours or epilepsy or vascular diseases. This has led to patient deaths, a lack of appropriate care and suffering for the patients. Eliot Slater, after studying the condition in the 1950s, stated: "The diagnosis of hysteria is all too often a way of avoiding a confrontation with our own ignorance. This is especially dangerous when there is an underlying organic pathology, not yet recognised. In this penumbra we find patients who know themselves to be ill but, coming up against the blank faces of doctors who refuse to believe in the reality of their illness, proceed by way of emotional lability, overstatement and demands for attention ... Here is an area where catastrophic errors can be made. In fact it is often possible to recognise the presence though not the nature of the unrecognisable, to know that a man must be ill or in pain when all the tests are negative. But it is only possible to those who come to their task in a spirit of humility. In the main the diagnosis of hysteria applies to a disorder of the doctor–patient relationship. It is evidence of non-communication, of a mutual misunderstanding ... We are, often, unwilling to tell the full truth or to admit to ignorance ... Evasions, even untruths, on the doctors side are among the most powerful and frequently used methods he has for bringing about an efflorescence of hysteria".Much recent work has been done to identify the underlying causes of conversion and related disorders and to better understand why conversion disorder and hysteria appear more commonly in women. Current theoreticians tend to believe there is no single cause for these disorders </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 Kabuki syndrome and explain in detail? [/INST] Kabuki syndrome (also previously known as Kabuki-makeup syndrome (KMS) or Niikawa–Kuroki syndrome) is a congenital disorder of genetic origin. It affects multiple parts of the body, with varying symptoms and severity, although the most common is the characteristic facial appearance.It is quite rare, affecting roughly one in 32,000 births. It was first identified and described in 1981 by two Japanese groups, led by scientists Norio Niikawa and Yoshikazu Kuroki. It is named Kabuki syndrome because of the facial resemblance of affected individuals to stage makeup used in kabuki, a Japanese traditional theatrical form.

Signs and symptoms
Specific symptoms for Kabuki syndrome vary, with large differences between affected individuals. Most people with Kabuki syndrome have distinctive facial features that include arched eyebrows, long eyelashes, elongated eyelids with lower lids that turn out, prominent ears, a flat tip of the nose and a downward slant to the mouth.Overlapping phenotypic features for patients between KDM6A and KDM6B variations include prominent ears, abnormal dentition, congenital heart disease, feeding difficulties, cryptorchidism, joint hypermobility, developmental delay, hypotonia, and behavioral difficulties.
Other common symptoms are skeletal abnormalities, short stature, heart defects, feeding difficulties and a failure to thrive, vision and hearing difficulties, weak muscle tone (hypotonia), small head size (microcephaly), and frequent infections.Mild to moderate intellectual disability and mild to severe developmental delay are often associated with Kabuki syndrome. Infants and young children often experience difficulties relating to hypotonia, feeding issues/failure to thrive, infections, surgical repair of heart and palate defects and developmental delays.Young children with Kabuki syndrome benefit from early intervention services. School age children tend to have fewer medical issues requiring hospitalization, though frequent infections, hearing loss and feeding issues occur. In addition, intellectual impairment, difficulty with visuospatial tasks and maintaining attention usually require an IEP (individualized education plan) if the child attends public school. Older children and adults report difficulties with anxiety. Endocrine abnormalities and immune system abnormalities such as ITP (idiopathic thrombocytopenia) and CVID (common variable immune deficiency) are medical issues that tend to present in older children, adolescents and adults.

Causes
Type 1 Kabuki syndrome is caused by germline heterozygous loss of function variants in KMT2D (formerly known as the MLL2), located on human chromosome 12. It is estimated that between 55 and 80% of cases of Kabuki syndrome are of Type 1.  Type 1 Kabuki syndrome demonstrates an autosomal dominant pattern of inheritance.
Type 2 Kabuki syndrome is caused by germline hemizygous (in males) or heterozygous (in females) chromosome deletions or loss of function point variants involving KDM6A, located on the X chromosome. Approximately 5% of cases of Kabuki syndrome are of Type 2. Type 2 Kabuki syndrome demonstrates an X-linked dominant pattern of inheritance.Most cases of Kabuki syndrome occur de novo, that is, the parents are unaffected and the gene was mutated early in embryological development. However, several cases of inherited mutations causing Type 1 or Type 2 Kabuki syndrome are now known.About 30% of cases have no identifiable causative mutation. These may represent individuals with types of mutations that are challenging to detect via current routine investigations or patients who have disorders that share some features with Kabuki syndrome.

Pathophysiology
The KMT2D and KDM6A genes belong to a family of genes called chromatin-modifying enzymes. Specifically, these genes code for a histone methyltransferase (KMT2D) and a histone demethylase (KDM6A), and play a part in the regulation of gene expression. Under normal circumstances, these enzymes transfer methyl groups on and off histones to regulate genes via epigenetic pathways. When the genes that encode these enzymes are mutated, epigenetic activation of certain developmental genes is impaired and developmental abnormalities occur, leading to the characteristics of Kabuki syndrome patients. The specific developmental genes that are affected by the impaired epigenetic mechanisms in Kabuki syndrome are not yet fully known.There are hundreds of different mutations that have been identified in Kabuki syndrome patients. Most of these mutations are in the KMT2D gene and involve a change in amino acid sequence that creates a shortened and nonfunctional chromatin-modifying enzyme.

Diagnosis
A consensus on clinical diagnostic criteria for Kabuki syndrome (KS) was defined in December 2018 by an international group of experts. The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, were included in the publication.The original description of Kabuki syndrome by Niikawa et al. defined five cardinal manifestations, although some of these “cardinal manifestations” may or may not be present in a patient with Kabuki syndrome.

Typical facial features: Elongated palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows with the lateral third displaying sparseness or notching; short columella with depressed nasal tip; large, prominent, or cupped ears
Skeletal anomalies: Spinal column abnormalities, including sagittal cleft vertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis, Brachydactyly V Brachymesophalangy Clinodactyly of fifth digits
Dermatoglyphic abnormalities: persistence of fetal fingertip pads
Mild to moderate intellectual disability
Postnatal growth deficiencyKabuki syndrome is diagnosed clinically (through identifying symptoms, physical exams, and lab results), most commonly by a geneticist. Alternatively, it may be discovered using genetic testing (whole exome or whole genome sequencing).Diagnosis can be difficult given the large spectrum of disease. The fact that some patients do not carry one of the two known mutations or can carry multiple mutations complicates the diagnosis further.

Screening
Due to its rarity, Kabuki syndrome is not screened for in routine prenatal testing including blood tests, chorionic villus sampling (CVS), or amniocentesis. Although not routine for the general population, if Kabuki syndrome is a specific concern (i.e. expectant mother who has been diagnosed with Kabuki syndrome or sibling with KS), it is possible to test for one of the specific mutations. This prenatal testing does require a CVS or amniocentesis. However Kabuki syndrome is usually not inherited and therefore most cases do not have a positive family history. Kabuki syndrome can have positive screening tests, such as cystic hygroma seen on nuchal translucency ultrasound screening, although these findings are non-specific and have a wide differential diagnosis.

Management
Newly diagnosed patients with Kabuki syndrome will often undergo tests that are aimed at detecting common abnormalities associated with the syndrome. They include an echocardiogram (ultrasound of the heart) for detection of structural heart defects, kidney ultrasound for detection of structural renal abnormalities, immunoglobulin levels, pneumococcal titers and a hearing screening test. Further evaluation and testing by specialists may be indicated in addition to cardiology, nephrology, allergy/immunology, audiology-mentioned above. This may include orthopedics (such as hip dysplasia), pulmonary (sleep study to rule out obstructive sleep apnea due to hypotonia), ophthalmology evaluation (vision screen), ENT evaluation (hearing evaluation), Neurology evaluation (i.e. if seizures present), Hematology evaluation (if bleeding disorder), GI evaluation (if gi abnormalities), or others as needed.
There is no specific treatment for Kabuki syndrome. Treatment plans are customized to address the symptoms the individual is experiencing. For example, someone experiencing seizures will be treated with the standard anti-epilepsy therapies. Additionally, patients with Kabuki syndrome are routinely evaluated and monitored to address problems that may develop, such as vision or hearing problems, or cognitive difficulties. If congenital heart disease is present, prophylactic antibiotics may be recommended before any procedures such as dental work that might cause infection.

Prognosis
Life expectancy is not shortened in most cases of Kabuki syndrome. Some patients have coexisting conditions which may shorten life expectancy, such as hypoplastic left heart syndrome or kidney dysfunction. It is important that patients with cardiac, renal, or immunologic issues are identified and well-managed.

Epidemiology
Kabuki syndrome occurs about once in every 32,000 births. The disease appears to affect all population groups equally, with no differences based on sex, race, or environment.

Research
Research on Kabuki syndrome is extremely limited due to its low incidence. Despite this, several groups around the world are studying Kabuki syndrome. In the United States, these include the Epigenetics and Chromatin Clinic at Johns Hopkins University (led by Dr. Hans Bjornsson), The Roya Kabuki Program at Boston Childrens Hospital, Dr. Mark Hannibal at the University of Michigan, groups at University of Colorado, University of Utah, University of South Florida and others. In the UK, Prof Siddharth Bankas group at the University of Manchester and Manchester University Hospitals has a research program for Kabuki syndrome </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 Bethlem myopathy and explain in detail? [/INST] Bethlem myopathy is an autosomal dominant myopathy, classified as a congenital form of muscular dystrophy, that is caused by a mutation in one of the three genes coding for type VI collagen. These include COL6A1, COL6A2, and COL6A3.  Gowers sign, tiptoe-walking and contractures of the joints (especially the fingers) are typical signs and symptoms of the disease. Bethlem myopathy could be diagnosed based on clinical examinations and laboratory tests may be recommended. Currently there is no cure for the disease and symptomatic treatment is used to relieve symptoms and improve quality of life. Bethlem myopathy affects about 1 in 200,000 people.

Signs and symptoms
The onset of this disease can begin even before birth but is more commonly in childhood or later into adult life. The progression is slow, with symptoms of weakness and walking difficulties sometimes not presenting until middle age. Early symptoms include Gowers sign ("climbing" up the thighs with the hands when rising from the floor) and tiptoe-walking caused by the beginning of contractures.Contractures of the fingers are a typical symptom of Bethlem myopathy but not of the related Ullrichs myopathy (which does include contractures of arms and legs, as does Bethlem myopathy). Serum creatine kinase is elevated in Bethlem myopathy, as there is ongoing muscle cell death. Patients with Bethlem myopathy may expect a normal life span and continued mobility into adulthood.

Diagnosis
The disease could be diagnosed based on a clinical examination, which identifies signs and symptoms generally associated with the people who have the condition. Additional laboratory tests may be recommended. Creatine kinase (CK) blood test results will generally be normal or only slightly elevated </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 Minimally conscious state and explain in detail? [/INST] A minimally conscious state (MCS) is a disorder of consciousness distinct from persistent vegetative state and locked-in syndrome. Unlike persistent vegetative state, patients with MCS have partial preservation of conscious awareness. MCS is a relatively new category of disorders of consciousness. The natural history and longer term outcome of MCS have not yet been thoroughly studied. The prevalence of MCS was estimated to be 112,000 to 280,000 adult and pediatric cases.

Pathophysiology
Neuroimaging
Because minimally conscious state is a relatively new criterion for diagnosis, there are very few functional imaging studies of patients with this condition. Preliminary data has shown that overall cerebral metabolism is less than in those with conscious awareness (20–40% of normal) and is slightly higher but comparable to those in vegetative states. Activation in the medial parietal cortex and adjacent posterior cingulate cortex are brain regions that seem to differ between patients in MCS and those from vegetative states. These areas are most active during periods of conscious waking and are least active when in altered states of consciousness, such as general anesthesia, propofol, hypnotic state, dementia, and Wernicke–Korsakoff syndrome. Auditory stimulation induced more widespread activation in the primary and pre-frontal associative areas of MCS patients than vegetative state patients. There were also more cortiocortical functional connectivity between the auditory cortex and a large network of temporal and prefrontal cortices in MCS than vegetative states. These findings encourage treatments based on neuromodulatory and cognitive revalidation therapeutic strategies for patients with MCS.
One study used diffusion tensor imaging (DTI) in two case studies. They found that there were widespread cerebral atrophy in both patients. The lateral ventricles were increased in size, and the corpus callosum and the periventricular white matter were diminished. The DTI maps showed that there was significant reduction of volume in the medial corpus callosum and other parts of the brain compared to normal subjects. They also found markedly lower diffusion values in white matter and increased cerebral spinal fluid compartments. Cortical injuries at this level provides a particular favorable environment for sprouting of new axons to occur in the intact areas of the cortex, which may explain some of the greater recovery rates in minimally conscious state patients. The axonal regrowth has been correlated with functional motor recovery. The regrowth and rerouting of the axons may explain some of the changes to brain structure. These findings support the efforts to prospectively and longitudinally characterize neuroplasticity in both brain structure and function following severe injuries. Utilizing DTI and other neuroimaging techniques may further shed light on the debates on long-distance cortical rewiring and may lead to better rehabilitation strategies.Some areas of the brain that are correlated with the subjective experience of pain were activated in MCS patients when noxious stimulation was present. Positron emission tomography (PET) scans found increased blood flow to the secondary sensory cortex, posterior parietal cortex, premotor cortex, and the superior temporal cortex. The pattern of activation, however, was with less spatial extent. Some parts of the brain were less activated than normal patients during noxious stimulus processing. These were the posterior cingulate, medial prefrontal cortex, and the occipital cortex. Even though functional brain imaging can objectively measure changes in brain function during noxious stimulation, the role of different areas of the brain in pain processing is only partially understood. Furthermore, there is still the problem of the subjective experience. MCS patients by definition cannot consistently and reliably communicate their experiences. Even if they were able to answer the question "are you in pain?", there would not be a reliable response. Further clinical trials are needed to access the appropriateness of the use of analgesia in patients with MCS.

Residual language function
A functional magnetic resonance imaging (fMRI) study found that minimally conscious state patients showed activation in auditory networks when they heard narratives that had personally meaningful content that were read forwards by a familiar voice. These activations were not seen when the narratives were read backwards.Another study compared patients in vegetative state and minimally conscious state in their ability to recognize language. They found that some patients in minimally conscious state demonstrated some evidence of preserved speech processing. There was more activation in response to sentences compared to white noise.

Diagnostic
Medical definition
Minimally conscious state (MCS) is defined as a condition of severely altered consciousness in which minimal but definite behavioral evidence of self or environmental awareness is demonstrated.

Diagnosis
Although MCS patients are able to demonstrate cognitively mediated behaviors, they occur inconsistently. They are, however, reproducible or can be sustained long enough to be differentiated from reflexive behavior. Because of this inconsistency, extended assessment may be required to determine if a simple response (e.g. a finger movement or a blink) occurred because of a specific environmental event (e.g. a command to move the finger or to blink) or was merely a coincidental behavior. Distinguishing between VS and MCS is often difficult because the diagnosis is dependent on observation of behavior that show self or environmental awareness and because those behavioral responses are markedly reduced. One of the more common diagnostic errors involving disorders of consciousness is mistaking MCS for VS which may lead to serious repercussions related to clinical management.Giacino et al. have suggested demonstration of the following behaviors in order to make the diagnosis of MCS.

Following simple commands.
Gestural or verbal yes/no responses (regardless of accuracy).
Intelligible verbalization.
Purposeful behavior such as those that are contingent due to appropriate environmental stimuli and are not reflexive. Some examples of purposeful behavior include:
appropriate smiling or crying in response to the linguistic or visual content of emotional but not to neutral topics or stimuli.
vocalizations or gestures that occur in direct response to the linguistic content of questions.
reaching for objects that demonstrates a clear relationship between object location and direction of reach.
touching or holding objects in a manner that accommodates the size and shape of the object.
pursuit eye movement or sustained fixation that occurs in direct response to moving or salient stimuli.

Treatment
There is currently no definitive evidence that support altering the course of the recovery of minimally conscious state. There are currently multiple clinical trials underway investigating potential treatments.
In one case study, stimulation of thalamus using deep brain stimulation (DBS) led to some behavioral improvements. The patient was a 38-year-old male who had remained in minimally conscious state following a severe traumatic brain injury. He had been unresponsive to consistent command following or communication ability and had remained non-verbal over two years in inpatient rehabilitation. fMRI scans showed preservation of a large-scale, bi-hemispheric cerebral language network, which indicates that possibility for further recovery may exist. Positron emission tomography showed that the patients global cerebral metabolism levels were markedly reduced. He had DBS electrodes implanted bilaterally within his central thalamus. More specifically, the DBS electrodes targeted the anterior intralaminar nuclei of thalamus and adjacent paralaminar regions of thalamic association nuclei. Both electrodes were positioned within the central lateral nucleus, the paralaminar regions of the median dorsalis, and the posterior-medial aspect of the centromedian/parafasicularis nucleus complex. This allowed maximum coverage of the thalamic bodies. A DBS stimulation was conducted such that the patient was exposed to various patterns of stimulation to help identify optimal behavioral responses. Approximately 140 days after the stimulation began, qualitative changes in behavior emerged. There were longer periods of eye opening and increased responses to command stimuli as well as higher scores on the JFK coma recovery scale (CRS). Functional object use and intelligible verbalization was also observed. The observed improvements in arousal level, motor control, and consistency of behavior could be a result of direct activation of frontal cortical and basal ganglia systems that were innervated by neurons within the thalamic association nuclei. These neurons act as a key communication relay and form a pathway between the brainstem arousal systems and frontal lobe regions. This pathway is crucial for many executive functions such as working memory, effort regulation, selective attention, and focus.In another case study of a 50-year-old woman who had symptoms consistent with MCS, administration of zolpidem, a sedative hypnotic drug improved the patients condition significantly. Without treatment, the patient showed signs of mutism, athetoid movements of the extremities, and complete dependence for all personal care. 45 minutes after 5 to 10 mg of zolpidem was administered, the patient ceased the athetoid movements, regained speaking ability, and was able to self-feed. The effect lasted 3–4 hours from which she returned to the former state. The effects were repeated on a daily basis. PET scans showed that after zolpidem was administered, there was a marked increase in blood flow to areas of the brain adjacent to or distant from damaged tissues. In this case, these areas were the ipsilateral cerebral hemispheres and the cerebellum. These areas are thought to have been inhibited by the site of injury through a GABA-mediated mechanism and the inhibition was modified by zolpidem which is a GABA agonist. The fact that zolpidem is a sedative drug that induces sleep in normal people but causes arousal in a MCS patient is paradoxical. The mechanisms to why this effect occurs is not entirely clear.There is recent evidence that transcranial direct current stimulation (tDCS), a technique that supplies a small electric current in the brain with non-invasive electrodes, may improve the clinical state of patients with MCS. In one study with 10 patients with disorders of consciousness (7 in VS, 3 in MCS), tDCS was applied for 20 minutes every day for 10 days, and showed clinical improvement in all 3 patients who were in MCS, but not in those with VS. These results remained at 12-month follow-up. Two of the patients in MCS that had their brain insult less that 12 months recovered consciousness in the following months. One of these patients received a second round of tDCS treatment 4 months after his initial treatment, and showed further recovery and emerged into consciousness, with no change of clinical status between the two treatments.

Prognosis
One of the defining characteristics of minimally conscious state is the more continuous improvement and significantly more favorable outcomes post injury when compared with vegetative state. One study looked at 100 patients with severe brain injury. At the beginning of the study, all the patients were unable to follow commands consistently or communicate reliably. These patients were diagnosed with either MCS or vegetative state based on performance on the JFK Coma Recovery Scale and the diagnostic criteria for MCS as recommended by the Aspen Consensus Conference Work-group. Both patient groups were further separated into those that had traumatic brain injury and those that had non-traumatic brain injures (anoxia, tumor, hydrocephalus, infection). The patients were assessed multiple times over a period of 12 months post injury using the Disability Rating Scale (DRS) which ranges from a score of 30=dead to 0=no disabilities. The results show that the DRS scores for the MCS subgroups showed the most improvement and predicted the most favorable outcomes 12 months post injury. Amongst those diagnosed with MCS, DRS scores were significantly lower for those with non-traumatic brain injuries in comparison to the vegetative state patients with traumatic brain injury. DRS scores were also significantly lower for the MCS non-traumatic brain injury group compared to the MCS traumatic brain injury group. Pairwise comparisons showed that DRS scores were significantly higher for those that suffered from non-traumatic brain injuries than those with traumatic brain injuries. For the patients in vegetative states there were no significant differences between patients with non-traumatic brain injury and those with traumatic brain injuries. Out of the 100 patients studied, 3 patients fully recovered (had a DRS score of 0). These 3 patients were diagnosed with MCS and had suffered from traumatic brain injuries.In summary, those with minimally conscious state and non-traumatic brain injuries will not progress as well as those with traumatic brain injuries while those in vegetative states have an all around lower to minimal chance of recovery.
Because of the major differences in prognosis described in this study, this makes it crucial that MCS be diagnosed correctly. Incorrectly diagnosing MCS as vegetative state may lead to serious repercussions related to clinical management.

History
Prior to the mid-1990s, there was a lack of operational definitions available to clinicians and researchers to guide the differential diagnosis among disorders of consciousness. As a result, patients were lumped together into broad categories often based on the severity of the disability (e.g. moderate, severe, extremely severe). These diagnoses were performed without regard to salient differences in behavioral and pathological characteristics. In a three-year period spanning from 1994 to 1996, three position statements regarding the diagnostic criteria of disorder of consciousness were published. The "Medical Aspects of the Persistent Vegetative State" was published by
the American Academy of Neurology (AAN) in 1994. In 1995, "Recommendations for Use of Uniform Nomenclature Pertinent to Patients With Severe Alterations in Consciousness" was published by the American Congress of Rehabilitation Medicine (ACRM). In 1996 the "International Working Party on the Management of the Vegetative State: Summary Report" was published by a group of international delegates from neurology, rehabilitation, neurosurgery, and neuropsychology. However, because the diagnostic criteria were published independently from one another, the final recommendations differed greatly from one another. The Aspen Neurobehavioral Work-group was convened to explore the underlying causes of these disparities. In the end, the Aspen Work-group provided a consensus statement regarding definitions and diagnostic criteria disorder of consciousness which include the vegetative state (VS) and the minimally conscious state (MCS).

Ethical issues
One of the major ethical concerns involving patients with severe brain damage is their inability to communicate. By definition, patients who are unconscious or are minimally conscious are incapable of giving informed consent which is required for participation in clinical research. Typically, written approval is obtained from family members or legal representatives. The inability to receive informed consent has led to much research being refused grants, ethics committee approval, or research publication. This puts patients in these conditions at risk of being denied therapy that may be life-saving.

The right to die
The right to die in patients with severe cognitive impairment has developed over time because of their grave neurological state and the perceived futility of continued treatment. Such cases have been debated vigorously in the past, as in the case with Terri Schiavo who was diagnosed with persistent vegetative state </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 Retiform parapsoriasis 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 Perforating granuloma annulare 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 Erdheim–Chester disease and explain in detail? [/INST] Erdheim–Chester disease (ECD)  is an extremely rare disease characterized by the abnormal multiplication of a specific type of white blood cells called histiocytes, or tissue macrophages (technically, this disease is termed a non-Langerhans-cell histiocytosis). It was declared a histiocytic neoplasm by the World Health Organization in 2016. Onset typically is in middle age. The disease involves an infiltration of lipid-laden macrophages, multinucleated giant cells, an inflammatory infiltrate of lymphocytes and histiocytes in the bone marrow, and a generalized sclerosis of the long bones.

Signs and symptoms
Long bone involvement is almost universal in ECD patients and is bilateral and symmetrical in nature. More than 50% of cases have some sort of extraskeletal involvement. This can include kidney, skin, brain and lung involvement, and less frequently retroorbital tissue, pituitary gland and heart involvement is observed.Bone pain is the most frequent of all symptoms associated with ECD and mainly affects the lower limbs, knees and ankles. The pain is often described as mild but permanent, and juxtaarticular in nature. Exophthalmos occurs in some patients and is usually bilateral, symmetric and painless, and in most cases it occurs several years before the final diagnosis. Recurrent pericardial effusion can be a manifestation, as can morphological changes in adrenal size and infiltration.A review of 59 case studies by Veyssier-Belot et al. in 1996 reported the following symptoms in order of frequency of occurrence:
Bone pain
Retroperitoneal fibrosis
Diabetes insipidus
Exophthalmos
Xanthomas
Neurological signs (including ataxia)
Dyspnea caused by interlobular septal and pleural thickening.
Kidney failure
Hypopituitarism
Liver failure

Diagnosis
Radiologic osteosclerosis and histology are the main diagnostic features. Diagnosis can often be difficult because of the rareness of ECD as well as the need to differentiate it from LCH. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical cerebellar and pontine signal changes on T2-weighted images seem to be typical of ECD, however, multiple sclerosis and metabolic diseases must also be considered in the differential diagnosis. ECD is not a common cause of exophthalmos but can be diagnosed by biopsy.  However, like all biopsies, this may be inconclusive. Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.

Histology
Histologically, ECD differs from Langerhans cell histiocytosis (LCH) in a number of ways. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a glycoproteins, and electron microscopy of cell cytoplasm does not disclose Birbeck granules.  Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden or foamy histiocytes, and are usually surrounded by fibrosis. Bone biopsy is said to offer the greatest likelihood of reaching a diagnosis </s>