<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is High-altitude cerebral edema and can you explain it in depth? [/INST] High-altitude cerebral edema (HACE) is a medical condition in which the brain swells with fluid because of the physiological effects of traveling to a high altitude. It generally appears in patients who have acute mountain sickness and involves disorientation, lethargy, and nausea among other symptoms. It occurs when the body fails to acclimatize while ascending to a high altitude.
It appears to be a vasogenic edema (fluid penetration of the blood–brain barrier), although cytotoxic edema (cellular retention of fluids) may play a role as well. Individuals with the condition must immediately descend to a lower altitude or coma and death can occur. Patients are usually given supplemental oxygen and dexamethasone as well.
HACE can be prevented by ascending to heights slowly to allow the body more time to acclimatize. Acetazolamide also helps prevent the condition. Untreated patients usually die within 48 hours. Those who receive treatment may take weeks to fully recover. It is a rare condition, occurring in less than one percent of people who ascend to 4,000 metres (13,000 ft). Although it was first described in 1913, little was known about the cause of the condition until MRI studies were performed in the 1990s.

Signs and symptoms
Early symptoms of HACE generally correspond with those of moderate to severe acute mountain sickness (AMS). Initial symptoms of HACE commonly include confusion, loss of consciousness, fever, ataxia, photophobia, rapid heart beat, lassitude, and an altered mental state. Those affected generally attempt to cease physical activities, regardless of their necessity for survival. Severe headaches develop and people lose the ability to sit up. Retinal venous dilation occurs in 59% of people with HACE. Rarer symptoms include brisk deep tendon reflexes, retinal hemorrhages, blurred vision, extension plantar reflexes, and ocular paralysis. Cranial nerve palsies occur in some unusual cases.In the bestselling 1996 non-fiction book Into Thin Air: A Personal Account of the Mt. Everest Disaster, Jon Krakauer describes the effects of HACE upon Dale Kruse, a forty-four-year-old dentist and one of the members of Scott Fischers team:
Kruse was having an incredibly difficult time simply trying to dress himself.  He put his climbing harness on inside out, threaded it through the fly of his wind suit, and failed to fasten the buckle; fortunately, Fischer and Neal Beidleman noticed the screwup before Kruse started to descend.  "If hed tried to rappel down the ropes like that," says Beidleman, "he would have immediately popped out of his harness and fallen to the bottom of the Lhotse Face."
"It was like I was very drunk," Kruse recollects.  "I couldnt walk without stumbling, and completely lost the ability to think or speak.  It was a really strange feeling.  Id have some word in my mind, but I couldnt figure out how to bring it to my lips.  So Scott and Neal had to get me dressed and make sure my harness was on correctly, then Scott lowered me down the fixed ropes."  By the time Kruse arrived in Base Camp, he says, "it was still another three or four days before I could walk from my tent to the mess tent without stumbling all over the place."
Patients with HACE have an elevated white blood cell count, but otherwise their blood count and biochemistry are normal. If a lumbar puncture is performed, it will show normal cerebral spinal fluid and cell counts but an increase in pressure. In one study, CT scans of patients with HACE exhibited ventricle compression and low density in the cerebellum. Only a few autopsies have been performed on fatal cases of HACE; they showed swollen gyri, spongiosis of white matter, and compressed sulci. There was some variation between individuals, and the results may not be typical of HACE deaths.

Mechanism
Most people who travel to high altitudes acclimatize. Acclimatization precludes the development of HACE by maintaining adequate levels of cerebral oxygen. The primary cause of HACE is hypoxia (oxygen deprivation). This occurs after the body is exposed to a low-oxygen environment and before it acclimatizes. The rate of change from a normal oxygen environment and how little oxygen is in the new environment can be used to predict the chance of developing HACE. Prolonged exertion in low oxygen also causes serious hypocapnia, lower carbon dioxide in the bloodstream, which may play a role in HACE. These factors cause the brain to swell with fluid, resulting in severe impairment. If the swelling is untreated, it causes death by brain herniation.The brain swelling is likely a result of vasogenic edema, the penetration of the blood–brain barrier by fluids. This process has been observed in MRI studies. Hypoxia increases extracellular fluid, which passes through the vasogenic endothelium in the brain. The leaking may be caused by increased pressure, or it may be caused by inflammation that makes the endothelium vulnerable to leaking. An MRI study found microhemorrhages in the corpus callosum of HACE patients, and hypoxia may also cause microvascular permeability. It has been hypothesized that vascular endothelial growth factor may cause the vascular permeability at the root of HACE. MRI scans of patients with HACE showed increased T2 in the corpus callosum, although grey matter was unchanged. This demonstrated that the blood-brain barrier was broken by cerebral blood vessels, thus interfering with white matter metabolism. Another study looked at the brains of people with HACE several months after their recovery; it showed hemosiderin deposits in the corpus callosum, evidence of vascular permeability.While there is strong evidence that vasogenic edema plays a major role in HACE, cytotoxic edema, cellular retention of fluids, may contribute as well. Cytotoxic edema may be caused by the failure of cellular ion pumps, which results from hypoxia. Then intracellular sodium and osmolarity increase, and there is an influx of water that causes cellular swelling. After the failure of the ATPase pumps, free radicals form and cause damage that complicates the edema. Evidence against cytotoxic edema includes the high levels of hypoxemia (low bloodstream oxygen) needed to cause it.It is not known why some are more vulnerable to HACE than others. One theory is that variations in brain size play a role, but the increase in brain volume from edema does not likely cause cranial vault impingement. The presence of large sulci indicate the condition may be influenced by the brain tightly fitting. Elevated intracranial pressure is generally accepted to be a late effect of HACE. High central venous pressure may also occur late in the conditions progression.One study demonstrated that normal autorelation of cerebral blood flow does not cause HACE. What role the sympathetic nervous system plays in determining who gets HACE is unclear, but it may have an effect.Another theory about the cause of HACE is that hypoxia may induce nitrous oxide synthase. Vasodilation is caused by the release of nitric oxide and adenosine. This in turn can increase vascular permeability and causes edema. This may combine with low levels of cytokines to cause HACE.

Diagnosis
Generally, high-altitude pulmonary edema (HAPE) or AMS precede HACE. In patients with AMS, the onset of HACE is usually indicated by vomiting, headache that does not respond to non-steroidal anti-inflammatory drugs, hallucinations, and stupor. In some situations, however, AMS progresses to HACE without these symptoms. HACE must be distinguished from conditions with similar symptoms, including stroke, intoxication, psychosis, diabetic symptoms, meningitis, or ingestion of toxic substances. It should be the first diagnosis ruled out when sickness occurs while ascending to a high altitude.

Prevention
HACE is generally preventable by ascending gradually with frequent rest days while climbing or trekking. Not ascending more than 1,000 metres (3,300 ft) daily and not sleeping at a greater height than 300 metres (980 ft) more than the previous night is recommended. The risk of developing HACE is diminished if acetazolamide or dexamethasone are administered. Generally, the use of acetazolamide is preferred, but dexamethasone can be used for prevention if there are side effects or contraindications. Some individuals are more susceptible to HACE than others, and physical fitness is not preventive. Age and sex do not by themselves affect vulnerability to HACE.

Treatment
Patients with HACE should be brought to lower altitudes and provided supplemental oxygen, and rapid descent is sometimes needed to prevent mortality. Early recognition is important because as the condition progresses patients are unable to descend without assistance. Dexamethasone should also be administered, although it fails to ameliorate some symptoms that can be cured by descending to a lower altitude. It can also mask symptoms, and they sometimes resume upon discontinuation. Dexamethasones prevention of angiogenesis may explain why it treats HACE well. Three studies that examined how mice and rat brains react to hypoxia gave some credence to this idea.If available, supplemental oxygen can be used as an adjunctive therapy, or when descent is not possible. FiO2 should be titrated to maintain arterial oxygen saturation of greater than 90%, bearing in mind that oxygen supply is often limited in high altitude clinics/environments.In addition to oxygen therapy, a portable hyperbaric chamber (Gamow bag) can by used as a temporary measure in the treatment of HACE. These devices simulate a decrease in altitude of up to 7000 ft, but they are resource intensive and symptoms will often return after discontinuation of the device. Portable hyperbaric chambers should not be used in place of descent or evacuation to definitive care.Diuretics may be helpful, but pose risks outside of a hospital environment. Sildenafil and tadalafil may help HACE, but there is little evidence of their efficacy. Theophylline is also theorized to help the condition.Although AMS is not life-threatening, HACE is usually fatal within 24 hours if untreated. Without treatment, the patient will enter a coma and then die. In some cases, patients have died within a few hours, and a few have survived for two days. Descriptions of fatal cases often involve climbers who continue ascending while experiencing the conditions symptoms.

Prognosis
Recovery varies between days and weeks, but most recover in a few days. After the condition is successfully treated, it is possible for climbers to reascend. Dexamethesone should be discontinued, but continual acetazolamide is recommended. In one study, it took patients between one week and one month to display a normal CT scan following HACE.

Epidemiology
HACE occurs in 0.5% to 1% of people who climb or trek between 4,000 metres (13,000 ft) and 5,000 metres (16,000 ft). In some unusual cases, up to 30% of members of expeditions have had the condition. The condition is seldom seen below 3,000 metres (9,800 ft), but in some rare cases it has developed as low as 2,500 metres (8,200 ft). The condition generally does not occur until an individual has spent 48 hours at an altitude of 4,000 metres (13,000 ft).

History
HACE was first described by a medical officer stationed in Chile in 1913, but few took note of it. Later, access to air travel made the condition more common because it allowed more people access to high mountains, such as those in the Himalayas. One early description of HACE may have been published in 1969 after a group of Indian soldiers made a rapid ascent to almost 6,000 metres (20,000 ft). It is not definitely established whether they had HACE or acute decompression sickness. MRI has been used to study the effects of high altitude on the brain, providing the best evidence about the condition. A 1998 MRI study of nine climbers with HACE clearly demonstrated vasogenic edema.Data about HACE are lacking because it generally occurs in remote areas, far from hospitals and is generally rare. It is uncommon for doctors to be able to study victims within six days of the conditions development. Animal models of HACE have not been developed. Several genes are being examined for the role they may play in the development of the condition.Increased education and helicopter capabilities have combined to cut the number of deaths from the condition. Symptoms of HACE have been reported in many cases of deaths while descending Mount Everest, although HACE may not be the only problem they experienced. HACE also posed a threat to workers on the Qinghai–Tibet Railway.

References
Bibliography
Bärtsch, Peter; Swenson, Erik (2013). "Acute High-Altitude Illnesses". The New England Journal of Medicine. 368 (24): 2294–302. doi:10.1056/NEJMcp1214870. PMID 23758234.
Imray, Chris; Wright, Alex; Subudhi, Andrew; Roach, Robert (2010). "Acute Mountain Sickness: Pathophysiology, Prevention, and Treatment". Progress in Cardiovascular Diseases. 52 (6): 467–484. doi:10.1016/j.pcad.2010.02.003. PMID 20417340.
Rosenberg, Gary (2012). Molecular Physiology and Metabolism of the Nervous System (5 ed.). Oxford University Press. ISBN 978-0-19-539427-6.
Schoene, Robert (2008). "Illnesses at High Altitude". Chest. 134 (2): 402–16. doi:10.1378/chest.07-0561 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Compensatory hyperhidrosis and can you explain it in depth? [/INST] Compensatory hyperhidrosis is a form of neuropathy. It is encountered in patients with myelopathy, thoracic disease, cerebrovascular disease, nerve trauma or after surgeries. The exact mechanism of the phenomenon is poorly understood. It is attributed to the perception in the hypothalamus (brain) that the body temperature is too high. The sweating is induced to reduce body heat.
Excessive sweating due to nervousness, anger, previous trauma or fear is called hyperhidrosis.
Compensatory hyperhidrosis is the most common side effect of endoscopic thoracic sympathectomy, a surgery to treat severe focal hyperhidrosis, often affecting just one part of the body.  It may also be called rebound or  reflex hyperhidrosis.  In a small number of individuals, compensatory hyperhidrosis following sympathectomy is disruptive, because affected individuals may have to change sweat-soaked clothing two or three times a day.
According to Dr. Hooshmand, sympathectomy permanently damages the temperature regulatory system. The permanent destruction of thermoregulatory function of the sympathetic nervous system causes latent complications, e.g., RSD in contralateral extremity.Following surgery for axillary (armpit), palmar (palm) hyperhidrosis (see focal hyperhidrosis) and blushing, the body may sweat excessively at untreated areas, most commonly the lower back and trunk, but can be spread over the total body surface below the level of the cut. The upper part of the body, above the sympathetic chain transection, the body becomes anhidriotic, where the patient is unable to sweat or cool down, which further compromises the bodys thermoregulation and can lead to elevated core temperature, overheating and hyperthermia. Below the level of the sympathetic chain interruption, body temperature is significantly lower, creating a stark contrast that can be observed on thermal images. The difference in temperatures between the sympathetically under- and overactive regions can be as high as 10 Celsius.

Variations
Gustatory sweating or Freys syndrome is another presentation of autonomic neuropathy.  Gustatory sweating is brought on while eating, thinking or talking about food that produces a strong salivary stimulus. It is thought that ANS fibres to salivary glands have become connected in error with the sweat glands after nerve regeneration. Apart from sweating in the anhidriotic area of the body, it can produce flushing, goosebumps, drop of body temperature - vasoconstriction and paresthesia </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Goldenhar syndrome and can you explain it in depth? [/INST] Goldenhar syndrome is a rare congenital defect characterized by incomplete development of the ear, nose, soft palate, lip and mandible on usually one side of the body. Common clinical manifestations include limbal dermoids, preauricular skin tags and strabismus. It is associated with anomalous development of the first branchial arch and second branchial arch.The term is sometimes used interchangeably with hemifacial microsomia, although this definition is usually reserved for cases without internal organ and vertebrae disruption.
It affects between 1 in 3,500 and 1 in 5,600 live births, with a male-to-female ratio of 3:2.

Signs and symptoms
Chief markers of Goldenhar syndrome are incomplete development of the ear, nose, soft palate, lip, and mandible on usually one side of the body. Additionally, some patients will have growing issues with internal organs, especially heart, kidneys and lungs. Typically, the organ will either not be present on one side or will be underdeveloped. While it is more usual for there to be problems on only one side, it has been known for defects to occur bilaterally (approximate incidence 10% of confirmed GS cases).Other problems can include severe scoliosis (twisting of the vertebrae), limbal dermoids and hearing loss (see hearing loss with craniofacial syndromes), and deafness or blindness in one or both ears/eyes. Granulosa cell tumors may be associated as well.

Causes
The cause of Goldenhar syndrome is largely unknown. However, it is thought to be multifactorial, although there may be a genetic component, which would account for certain familial patterns. It has been suggested that there is a branchial arch development issue late in the first trimester.An increase in Goldenhar syndrome in the children of Gulf War veterans has been suggested, but the difference was shown to be statistically insignificant.

Diagnosis
Diagnosis is based on clinical features </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Oculopharyngodistal myopathy and can you explain it in depth? [/INST] Oculopharyngodistal myopathy is a rare genetic disorder characterized by progressive muscle weakness affecting various parts of the body.

Signs and symptoms
People with this condition exhibit symptoms susch as progressive muscle weakness affecting the eyes, face, and pharynx which consequently results in blepharoptosis, ophthalmoparesis, atrophy of the facial muscles, dysphagia, dysarthria, and muscle weakness and atrophy of the upper and lower distal limbs. These symptoms usually start during adulthood.On rare cases, hearing loss, severe proximal weakness and/or unilateral muscle weakness.

Complications
Complications vary depending on the symptoms and their severity, for example, muscle weakness might leave people unable to work on manual labor jobs.

Diagnosis
This condition can be diagnosed through physical examination and sequencing of the genes associated with the condition.

Genetics
There are four known genetic causes of this disorder:
1. Trinucleotide repeat expansion located in the 5-prime untranslated region of the LRP12 gene. (CGG)2. Trinucleotide repeat expansion located in the 5-prime untranslated region of the G1PC gene. (GGC)3 </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Optic papillitis and can you explain it in depth? [/INST] Optic papillitis is a specific type of optic neuritis.  Inflammation of the optic nerve head is called "papillitis" or "intraocular optic neuritis"; inflammation of the orbital portion of the nerve is called "retrobulbar optic neuritis" or "orbital optic neuritis". It is often associated with substantial losses in visual fields, pain on moving the globe, and sensitivity to light pressure on the globe. It is often an early sign of multiple sclerosis.Papillitis may have the same appearance as papilledema. However, papillitis may be unilateral, whereas papilledema is almost always bilateral </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Progressive supranuclear palsy and can you explain it in depth? [/INST] Progressive supranuclear palsy (PSP) is a late-onset degenerative disease involving the gradual deterioration and death of specific volumes of the brain. The condition leads to symptoms including loss of balance, slowing of movement, difficulty moving the eyes, and cognitive impairment.  PSP may be mistaken for other neurodegenerative diseases such as Parkinsons, frontotemporal dementia and Alzheimers. The cause of the condition is uncertain, but involves accumulation of tau protein within the brain.  Medications such as levodopa and amantadine may be useful in some cases.PSP affects about six people per 100,000. The first symptoms typically occur at 60–70 years of age. Males are slightly more likely to be affected than females.  No association has been found between PSP and any particular race, location, or occupation.

Signs and symptoms
The initial symptoms in two-thirds of cases are loss of balance, lunging forward when mobilizing, fast walking, bumping into objects or people, and falls. Dementia symptoms are also initially seen in about one in five cases of frontotemporal dementia.Other common early symptoms are changes in personality, general slowing of movement, and visual symptoms. The most common behavioural  symptoms in patients with PSP include  apathy, disinhibition, anxiety, and dysphoria.Later symptoms and signs can include, but do not necessarily include dementia (typically including loss of inhibition and ability to organize information), slurring of speech, difficulty swallowing, and difficulty moving the eyes, particularly in the vertical direction.  The latter accounts for some of the falls experienced by these patients, as they find it difficult to look up or down.Some of the other signs are poor eyelid function, contracture of the facial muscles, a backward tilt of the head with stiffening of the neck muscles, sleep disruption, urinary incontinence, and constipation.  Some patients retain full cognitive function up to the end.The visual symptoms are of particular importance in the diagnosis of this disorder.  Patients typically complain of difficulty reading due to the inability to look down well. The ophthalmoparesis experienced by these patients mainly concerns voluntary eye movement and the inability to make vertical saccades, which is often worse with downward saccades.  Patients tend to have difficulty looking down (a downgaze palsy) followed by the addition of an upgaze palsy. This vertical gaze paresis will correct when the examiner passively rolls the patients head up and down as part of a test for the oculocephalic reflex.  Involuntary eye movement, as elicited by Bells phenomenon, for instance, may be closer to normal. On close inspection, eye movements called "square-wave jerks" may be visible when the patient fixes at distance. These are fine movements, that can be mistaken for nystagmus, except that they are saccadic in nature, with no smooth phase. Although healthy individuals also make square-wave jerk movements, PSP patients make slower square-wave jerk movements, with smaller vertical components. Assessment of these square-wave jerks and diminished vertical saccades is especially useful for diagnosing progressive supranuclear palsy, because these movements set PSP patients apart from other parkinsonian patients. Difficulties with convergence (convergence insufficiency), where the eyes come closer together while focusing on something near, like the pages of a book, is typical.  Because the eyes have trouble coming together to focus at short distances, the patient may complain of diplopia (double vision) when reading.A characteristic facial appearance known as “procerus sign”, with a wide-eye stare, furrowing of forehead with a frowning expression and deepening of other facial creases is diagnostic of PSP.

Cause
The cause of PSP is unknown. Fewer than 1% of those with PSP have a family member with the same disorder.  A variant in the gene for tau protein called the H1 haplotype, located on chromosome 17 (rs1800547), has been linked to PSP. Nearly all people with PSP received a copy of that variant from each parent, but this is true of about two-thirds of the general population.  Therefore, the H1 haplotype appears to be necessary but not sufficient to cause PSP.  Other genes, as well as environmental toxins, are being investigated as other possible contributors to the cause of PSP.Additionally, the H2 haplotype, combined with vascular dysfunction, seems to be a factor of vascular progressive supranuclear palsy.Besides tauopathy, mitochondrial dysfunction seems to be a factor involved in PSP. Especially, mitochondrial complex I inhibitors (such as acetogenins and quinolines contained in Annonaceae, as well as rotenoids) are implicated in PSP-like brain injuries.

Pathophysiology
The affected brain cells are both neurons and glial cells. The neurons display neurofibrillary tangles (NFTs), which are clumps of tau protein, a normal part of a brain cells internal structural skeleton. These tangles are often different from those seen in Alzheimers disease, but may be structurally similar when they occur in the cerebral cortex. Their chemical composition is usually different, however, and is similar to that of tangles seen in corticobasal degeneration. Tufts of tau protein in astrocytes, or tufted astrocytes, are also considered diagnostic. Unlike globose NFTs, they may be more widespread in the cortex. Lewy bodies are seen in some cases, but whether this is a variant or an independent co-existing process is not clear, and in some cases, PSP can coexist with corticobasal degeneration, Parkinsons, and/or Alzheimers disease, particularly with older patients.The principal areas of the brain affected are the:
basal ganglia, particularly the subthalamic nucleus, substantia nigra, and globus pallidus
brainstem, particularly the tectum (the portion of the midbrain where "supranuclear" eye movement resides), as well as dopaminergic nuclei.
cerebral cortex, particularly that of the frontal lobes and the limbic system (similarly to frontotemporal degeneration)
dentate nucleus of the cerebellum
spinal cord, particularly the area where some control of the bladder and bowel residesSome consider PSP, corticobasal degeneration, and frontotemporal dementia to be variations of the same disease. Others consider them separate diseases. PSP has been shown occasionally to co-exist with Picks disease.

Diagnosis
Magnetic resonance imaging (MRI) is often used to diagnose PSP. MRI may show atrophy in the midbrain with preservation of the pons giving a "hummingbird" sign appearance and Mickey Mouse sign.

Types
Based on the pathological findings in confirmed cases of PSP, it is divided into the following categories:

classical Richardson syndrome (PSP-RS)
PSP-parkinsonism (PSP-P) and PSP-pure akinesia with gait freezing (PSP-PAGF)
frontal PSP, PSP-corticobasal syndrome (PSP-CBS), PSP-behavioural variant of frontotemporal dementia (PSP-bvFTD) and PSP-progressive non-fluent aphasia (PSP-PNFA)
PSP-C
PSP induced by AnnonaceaeRichardson syndrome is characterized by the typical features of PSP. In PSP-P features of Parkinson’s Disease overlap with the clinical presentation of PSP and follows a more benign course. In both PSP-P and PSP- PAGF distribution of abnormal tau is relatively restricted to the brain stem. Frontal PSP initially presents with behavioral and cognitive symptoms, with or without ophthalmoparesis and then evolve into typical PSP. The phenotypes of PSP-P and PSP-PAGF are sometimes referred as the ‘brain stem’ variants of PSP, as opposed to the ‘cortical’ variants which present with predominant cortical features including PSP-CBS, PSP-bvFTD, and PSP-PNFA. Cerebellar ataxia as the predominant early presenting feature is increasingly recognized as a very rare subtype of PSP (PSP-C) which is associated with severe neuronal loss with gliosis and higher densities of coiled bodies in the cerebellar dentate nucleus.

Differential diagnosis
PSP is frequently misdiagnosed as Parkinsons disease because they both involve slowed movements and gait difficulty, with PSP being one of a collection of diseases referred to as Parkinson plus syndromes. Both Parkinsons and PSP have an onset in late middle age and involve slowing and rigidity of movement. However, several distinguishing features exist. Tremor is very common with Parkinsons, but rare with PSP. Speech and swallowing difficulties are more common and severe with PSP and the abnormal eye movements of PSP are essentially absent with PD. A poor response to levodopa along with symmetrical onset can also help differentiate PSP from PD. Patients with the Richardson variant of PSP tend to have an upright posture or arched back, as opposed to the stooped-forward posture of other Parkinsonian disorders, although PSP-Parkinsonism (see below) can demonstrate a stooped posture. Early falls are also more common with PSP, especially with Richardson syndrome.PSP can also be misdiagnosed as Alzheimers disease because of the behavioral changes.Chronic traumatic encephalopathy shows many similarities with PSP.

Management
Treatment
No cure for PSP is known, and management is primarily supportive. PSP cases are often split into two subgroups, PSP-Richardson, the classic type, and PSP-Parkinsonism, where a short-term response to levodopa can be obtained. Dyskinesia is an occasional but rare complication of treatment. Amantadine is also sometimes helpful. After a few years the Parkinsonian variant tends to take on Richardson features. Other variants have been described.  Botox can be used to treat neck dystonia and blepharospasm, but this can aggravate dysphagia.Two studies have suggested that rivastigmine may help with cognitive aspects, but the authors of both studies have suggested a larger sampling be used. There is some evidence that the hypnotic zolpidem may improve motor function and eye movements, but only from small-scale studies.

Rehabilitation
Patients with PSP usually seek or are referred to occupational therapy, speech-language pathology for motor speech changes typically a spastic-ataxic dysarthria,  and physical therapy for balance and gait problems with reports of frequent falls. Evidence-based approaches to rehabilitation in PSP are lacking and, currently, the majority of research on the subject consists of case reports involving only a small number of patients.Case reports of rehabilitation programs for patients with PSP generally include limb-coordination activities, tilt-board balancing, gait training, strength training with progressive resistive exercises, and isokinetic exercises and stretching of the neck muscles. While some case reports suggest that physiotherapy can offer improvements in balance and gait of patients with PSP, the results cannot be generalized across all PSP patients, as each case report followed only one or two patients. The observations made from these case studies can be useful, however, in helping to guide future research concerning the effectiveness of balance and gait training programs in the management of PSP.Individuals with PSP are often referred to occupational therapists to help manage their condition and to help enhance their independence. This may include being taught to use mobility aids.  Due to their tendency to fall backwards, the use of a walker, particularly one that can be weighted in the front, is recommended over a cane </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is 8p23.1 duplication syndrome and can you explain it in depth? [/INST] 8p23.1 duplication syndrome is a rare genetic disorder caused by a duplication of a region from human chromosome 8. This duplication syndrome has an estimated prevalence of 1 in 64,000 births  and is the reciprocal of the 8p23.1 deletion syndrome. The 8p23.1 duplication is associated with a variable phenotype including one or more of speech delay, developmental delay, mild dysmorphism, with prominent forehead and arched eyebrows, and congenital heart disease (CHD).

Presentation
The phenotypic data on 11 patients indicated that cases are not always ascertained for CHD but that CHD was the most common single feature found in 6 out of 11 individuals. Developmental delay and/or learning difficulties were found in 5 out of 11 cases, but one prenatal case was developing normally at 15 months of age (Case 1,). Three other prenatal cases could not yet be reliably assessed </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Mixed affective state and can you explain it in depth? [/INST] A mixed affective state, formerly known as a mixed-manic or mixed episode, has been defined as a state wherein features unique to both depression and  mania—such as episodes of despair, doubt, anguish, rage or homicidal ideation, suicidal ideation, splitting, racing thoughts, sensory overload, pressure of activity, and heightened irritability—occur either simultaneously or in very short succession.
Previously, the diagnostic criteria for both a manic and depressive episode had to be met in a consistent and sustained fashion, with symptoms enduring for at least a week (or any duration if psychiatric hospitalization was required), thereby restricting the official acknowledgement of mixed affective states to only a minority of patients with bipolar I disorder. In current DSM-5 nomenclature, however, a "mixed episode" no longer stands as an episode of illness unto itself; rather, the symptomology specifier "with mixed features" can be applied to any major affective episode (manic, hypomanic, or depressive), meaning that they are now officially recognized in patients with, in addition to bipolar I disorder, bipolar II disorder and, by convention, major depressive disorder. A depressive mixed state in a patient, however, even in the absence of discrete periods of mania or hypomania, effectively rules out unipolar depression.

Diagnostic criteria
As affirmed by the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), the symptomology specifier "with mixed features" can be applied to manic episodes of bipolar I disorder, hypomanic episodes of either bipolar I disorder or bipolar II disorder and depressive episodes of either bipolar disorder or major depressive disorder, with at least three concurrent features of the opposite polarity being present </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Schistosoma mansoni and can you explain it in depth? [/INST] Schistosoma mansoni is a water-borne parasite of humans, and belongs to the group of blood flukes (Schistosoma). The adult lives in the blood vessels (mesenteric veins) near the human intestine. It causes intestinal schistosomiasis (similar to S. japonicum, S. mekongi, S. guineensis, and S. intercalatum). Clinical symptoms are caused by the eggs. As the leading cause of  schistosomiasis in the world, it is the most prevalent parasite in humans. It is classified as a neglected tropical disease. As of 2021, the World Health Organization reports that 236.6 million people have schistosomiasis and most of it is due to S. mansoni. It is found in Africa, the Middle East, the Caribbean, Brazil, Venezuela and Suriname.Unlike other flukes (trematodes) in which sexes are not separate (monoecious), schistosomes are unique in that adults are divided into males and females, thus, gonochoric. However, a permanent male-female pair, a condition called in copula, is required to become adults; for this, they are considered as hermaphrodites.
The life cycle of schistosomes includes two hosts: humans as definitive hosts, where the parasite undergoes sexual reproduction, and snails as intermediate hosts, where a series of asexual reproduction takes place. S. mansoni is transmitted through water, where freshwater snails of the genus Biomphalaria act as intermediate hosts. The larvae are able to live in water and infect the hosts by directly penetrating the skin. Prevention of infection is done by improved sanitation and killing the snails. Infection is treated with praziquantel.
S. mansoni was first noted by Theodor Maximillian Bilharz in Egypt in 1851, while discovering S. haematobium. Sir Patrick Manson identified it as unique species in 1902. Louis Westenra Sambon gave the name Schistosomum mansoni in 1907 in honour of Manson.

Structure
Adult
Schistosomes, unlike other trematodes, are long and cylindrical worms and are sexually dimorphic. The male S. mansoni is approximately 1 cm long (0.6–1.1 cm) and is 0.1 cm wide. It is white, and it has a funnel-shaped oral sucker at its anterior end followed by a second pediculated ventral sucker. The external part of the worm is composed of a double bilayer, which is continuously renewed as the outer layer, known as the membranocalyx, and is shed continuously. The tegument bears a large number of small tubercules. The suckers have small thorns in their inner part as well as in the buttons around them. The male genital apparatus is composed of 6 to 9 testicular masses, situated dorsally. There is one deferent canal beginning at each testicle, which is connected to a single deferent that dilates into a reservatory, the seminal vesicle, located at the beginning of the gynaecophoric canal. The copula happens through the coaptation of the male and female genital orifices.The female has a cylindrical body, longer and thinner than the males (1.2 to 1.6 cm long by 0.016 cm wide). It has the general appearance of a roundworm. The female parasite is darker, and it looks gray. The darker color is due to the presence of a pigment (hemozoin) in its digestive tube. This pigment is derived from the digestion of blood.  The ovary is elongated and slightly lobulated and is located on the anterior half of the body. A short oviduct conducts to the ootype, which continues with the uterine tube. In this tube it is possible to find 1 to 2 eggs (rarely 3 to 4) but only 1 egg is observed in the ootype at any one time. The genital pore opens ventrally. The posterior two-thirds of the body contain the viteline glands and their winding canal, which unites with the oviduct a little before it reaches the ootype.The digestive tube begins at the anterior extremity of the worm, at the bottom of the oral sucker. The digestive tube is composed of an esophagus, which divides in two branches (right and left) and that reunite in a single cecum. The intestines end blindly, meaning that there is no anus.

Sex
S. mansoni and other schistosomes are the only flukes or flatworms that exhibit sex separation as they exist as male and female individuals as in dioecious animals. However, they are not truly dioecious since the adults live in permanent male-female pairs, a condition called in copula. Although they can be physically separated,  isolated females cannot grow into sexually-mature adults. In copula starts in the liver only after which they can move to their final habitation, the inferior mesenteric veins. Individual females cannot enter the mesenteric veins. Sex organs, the gonads, are also incompletely separated and are interdependent between sexes. Egg-making organ, the vitelline gland in female does not develop in the absence of male. Male gametes, spermatozoa, are present in the oviduct. In males, there are rudimentary ovaries, oviduct, and oocytes (developing female gametes), as well as vitelline cells. Males also possess the genes for hermaphroditism in flukes. Thus, they are technically hermaphrodites.

Egg
The eggs are oval-shaped, measuring 115–175 µm long and 45–47 µm wide, and ~150 µm diameter on average. They have pointed spines towards the broader base on one side, i.e. lateral spines. This is an important diagnostic tool because co-infection with S. haematobium (having a terminal-spined eggs) is common, and they are hard to distinguish. When the eggs are released into the water, a lot of them are immature and unfertilised so that they do not hatch. When the eggs are larger than 160 µm in diameter, they also fail to hatch.

Larva
The miracidium (from the Greek word μειράκιον, meirakion, meaning youth) is pear-shaped, and gradually elongates as it ages. It measures about 136 μm long and 55 μm wide. The body is covered by anucleate epidermal plates separated by epidermal ridges. The epidermal cells give off numerous hair-like cilia on the body surface. There are 17–22 epidermal cells. Epidermal plate is absent only at the extreme anterior called apical papilla, or terebratorium, which contains numerous sensory organelles. Its internal body is almost fully filled with glycogen particles and vesicles.The cercaria has a characteristic bifurcated tail, classically called furcae (Latin for fork); hence, the name (derived from a Greek word κέρκος, kerkos, meaning tail). The tail is highly flexible and its beating propels the cercaria in water. It is about 0.2 mm long and 47 μm wide, somewhat loosely attached to the main body. The body is pear-shaped and measures 0.24 mm in length and 0.1 mm in width. Its tegument is fully covered with spine. A conspicuous oral sucker is at the apex. As a non-feeding larva, there are no elaborate digestive organs, only oesophagus is distinct. There are three pairs of mucin glands connected to laterally to the oral sucker at the region of the ventral sucker.

Physiology
Feeding and nutrition
Developing Schistosoma mansoni worms that have infected their definitive hosts, prior to the sexual pairing of males and females, require a nutrient source in order to properly develop from cercariae to adults. The developing parasites lyse host red blood cells to gain access to nutrients and also makes its own fungi from its waste it is hard to detect; the hemoglobin and amino acids the blood cells contain can be used by the worm to form proteins. While hemoglobin is digested intracellularly, initiated by salivary gland enzymes, iron waste products cannot be used by the worms, and are typically discarded via regurgitation.Kasschau et al. (1995) tested the effect of temperature and pH on the ability of developing S. mansoni to lyse red blood cells.  The researchers found that the parasites were best able to destroy red blood cells for their nutrients at a pH of 5.1 and a temperature of 37 °C.

Locomotion
Schistosoma mansoni is locomotive in primarily two stages of its life cycle: as cercariae swimming freely through a body of freshwater to locate the epidermis of their human hosts, and as developing and fully-fledged adults, migrating throughout their primary host upon infection. Cercariae are attracted to the presence of fatty acids on the skin of their definitive host, and the parasite responds to changes in light and temperature in their freshwater medium to navigate towards the skin. Ressurreicao et al. (2015) tested the roles of various protein kinases in the ability of the parasite to navigate its medium and locate a penetrable host surface. Extracellular signal-regulated kinase and protein kinase C both respond to changes in medium temperature and light levels, and the stimulation of p38 mitogen-activated protein kinase, associated with recognition of parasite host surface, results in a glandular secretion that deteriorates the host epidermis, and allows the parasite to burrow into its host.
The parasites nervous system contains bilobed ganglia and several nerve cords which splay out to every surface of the body; serotonin is a transmitter distributed widely throughout the nervous system and plays an important role in nervous reception, and stimulating mobility.

Life cycle
Intermediate host
After the eggs of the human-dwelling parasite are emitted in the faeces and into the water, the ripe miracidium hatches out of the egg. The hatching happens in response to temperature, light and dilution of faeces with water. The miracidium searches for a suitable freshwater snail belonging to the genus Biomphalaria. In South America, the principal intermediate host is Biomphalaria glabrata, while B. straminea and B. tenagophila are less common. A land snail Achatina fulica was reported in 2010 to act as a host in Venezuela. In Africa, B. glabratra, B. pfeifferi, B. choanomphala and B. sudanica act as the hosts; but in Egypt, the main snail host is B. alexandrina.Miracidia directly penetrate the soft tissue of snail. Inside the snail, they lose their cilia and develop into mother sporocysts. The sporocysts rapidly multiply by asexual reproduction, each forming numerous daughter sporocysts. The daughter sporocysts move to the liver and gonads of the snail, where they undergo further growth. Within 2–4 weeks, they undergo metamorphosis and give rise to fork-tailed cercariae. Stimulated by light, hundreds of cercariae penetrate out of the snail into water.

Definitive host
The cercaria emerge from the snail during daylight and they propel themselves in water with the aid of their bifurcated tail, actively seeking out their final host. In water, they can live for up to 12 hours, and their maximum infectivity is between 1 and 9 hours after emergence. When they recognise human skin, they penetrate it within a very short time. This occurs in three stages, an initial attachment to the skin, followed by the creeping over the skin searching for a suitable penetration site, often a hair follicle, and finally penetration of the skin into the epidermis using cytolytic secretions from the cercarial post-acetabular, then pre-acetabular glands. On penetration, the head of the cercaria transforms into an endoparasitic larva, the schistosomule. Each schistosomule spends a few days in the skin and then enters the circulation starting at the dermal lymphatics and venules. Here, they feed on blood, regurgitating the haem as hemozoin. The schistosomule migrates to the lungs (5–7 days post-penetration) and then moves via circulation through the left side of the heart to the hepatoportal circulation (>15 days) where, if it meets a partner of the opposite sex, it develops into a sexually mature adult and the pair migrate to the mesenteric veins. Such pairings are monogamous.Male schistosomes undergo normal maturation and morphological development in the presence or absence of a female, although behavioural, physiological and antigenic differences between males from single-sex, as opposed to bisex, infections have been reported. On the other hand, female schistosomes do not mature without a male. Female schistosomes from single-sex infections are underdeveloped and exhibit an immature reproductive system. Although the maturation of the female worm seems to be dependent on the presence of the mature male, the stimuli for female growth and for reproductive development seem to be independent from each other.
The adult female worm resides within the adult male worms gynaecophoric canal, which is a modification of the ventral surface of the male, forming a groove. The paired worms move against the flow of blood to their final niche in the mesenteric circulation, where they begin egg production (>32 days). The S. mansoni parasites are found predominantly in the small inferior mesenteric blood vessels surrounding the large intestine and caecal region of the host. Each female lays approximately 300 eggs a day (one egg every 4.8 minutes), which are deposited on the endothelial lining of the venous capillary walls. Most of the body mass of female schistosomes is devoted to the reproductive system. The female converts the equivalent of almost her own body dry weight into eggs each day. The eggs move into the lumen of the hosts intestines and are released into the environment with the faeces.

Genome
Schistosoma mansoni has 8 pairs of chromosomes (2n = 16)—7 autosomal pairs and 1 sex pair. The female schistosome is heterogametic, or ZW, and the male is homogametic, or ZZ. Sex is determined in the zygote by a chromosomal mechanism. The genome is approximately 270 MB with a GC content of 34%, 4–8% highly repetitive sequence, 32–36% middle repetitive sequence and 60% single copy sequence. Numerous highly or moderately repetitive elements are identified, with at least 30% repetitive DNA. Chromosomes range in size from 18 to 73 MB and can be distinguished by size, shape, and C banding.In 2000, the first BAC library of Schistosome was constructed. In June 2003, a ~5x whole genome shotgun sequencing project was initiated at the Sanger Institute. Also in 2003, 163,000 ESTs (expressed sequence tags) were generated (by a consortium headed by the University of São Paulo) from six selected developmental stages of this parasite, resulting in 31,000 assembled sequences and an estimated 92% of the 14,000-gene complement.In 2009 the genomes of both S. mansoni and S. japonicum were published, with each describing 11,809 and 13,469 genes, respectively. S. mansoni genome has increased protease families and deficiencies in lipid anabolism; which are attributed its parasitic adaptation. Portease included the invadolysin (host penetration) and cathepsin (blood-feeding) gene families.In 2012, an improved version of the S. mansoni genome was published, which consisted of only 885 scaffolds and more than 81% of the bases organised into chromosomes.In 2019, Ittiprasert, Brindley and colleagues employed programmed CRISPR/Cas9 knockout of the gene encoding the T2 ribonuclease of the egg of Schistosoma mansoni, advancing functional genomics and reverse genetics in the study of schistosomes, and platyhelminths generally <https://doi.org/10.7554/eLife.41337>.

Pathology
Schistosome eggs, which may become lodged within the hosts tissues, are the major cause of pathology in schistosomiasis. Some of the deposited eggs reach the outside environment by passing through the wall of the intestine; the rest are swept into the circulation and are filtered out in the periportal tracts of the liver, resulting in periportal fibrosis. Onset of egg laying in humans is sometimes associated with an onset of fever (Katayama fever). This "acute schistosomiasis" is not, however, as important as the chronic forms of the disease. For S. mansoni and S. japonicum, these are "intestinal" and "hepatic schistosomiasis", associated with formation of granulomas around trapped eggs lodged in the intestinal wall or in the liver, respectively. The hepatic form of the disease is the most important, granulomas here giving rise to fibrosis of the liver and hepatosplenomegaly in severe cases. Symptoms and signs depend on the number and location of eggs trapped in the tissues. Initially, the inflammatory reaction is readily reversible. In the latter stages of the disease, the pathology is associated with collagen deposition and fibrosis, resulting in organ damage that may be only partially reversible.Granuloma formation is initiated by antigens secreted by the miracidium through microscopic pores within the rigid egg shell, and the immune response to granuloma, rather than the direct action of egg antigens, causes the symptoms. The granulomas formed around the eggs impair blood flow in the liver and, as a consequence, induce portal hypertension. With time, collateral circulation is formed and the eggs disseminate into the lungs, where they cause more granulomas, pulmonary arteritis and, later, cor pulmonale. A contributory factor to portal hypertension is Symmers fibrosis, which develops around branches of the portal veins. This fibrosis occurs only many years after the infection and is presumed to be caused in part by soluble egg antigens and various immune cells that react to them.Recent research has shown that granuloma size is consistent with levels of IL-13, which plays a prominent role in granuloma formation and granuloma size. IL-13 receptor α 2 (IL-13Rα2) binds IL-13 with high affinity and blocks the effects of IL-13. Thus, this receptor is essential in preventing the progression of schistosomiasis from the acute to the chronic (and deadly) stage of disease. Synthetic IL-13Rα2 given to mice has resulted in significant decreases in granuloma size, implicating IL-13Rα2 as an important target in schistosomiasis.S. mansoni infection often occurs alongside those of viral hepatitis, either hepatitis B virus (HBV) or hepatitis C virus (HCV). This is due to high prevalence of schistosomiasis in areas where chronic viral hepatitis is prevalent. One important factor was the development of large reservoir of infection due to extensive schistosomiasis control programs that used intravenously administered tartar emetic since the 1960s. Co-infection is known to cause earlier liver deterioration and more severe illness.

Evasion of host immunity
Adult and larval worms migrate through the hosts blood circulation avoiding the hosts immune system. The worms have many tools that help in this evasion, including the tegument, antioxidant proteins, and defenses against host membrane attack complex (MAC). The tegument coats the worm and acts as a physical barrier to host antibodies and complement. Host immune defenses are capable of producing superoxide, but these are counterattacked by antioxidant proteins produced by the parasite. Schistosomes have four superoxide dismutases, and levels of these proteins increase as the schistosome grows. Antioxidant pathways were first recognised as a chokepoints for schistosomes, and later extended to other trematodes and cestodes. Targeting of this pathway with different inhibitors of the central antioxidant enzyme thioredoxin glutathione reductase (TGR) results in reduced viability of worms. Decay accelerating factor (DAF) protein is present on the parasite tegument and protects host cells by blocking formation of MAC. In addition, schistosomes have six homologues of human CD59 which are strong inhibitors of MAC.

Diagnosis
The presence of S. mansoni is detected by microscopic examination of parasite eggs in stool. A staining method called Kato-Katz technique is used for stool examination. It involves methylene blue-stained cellophane soaked in glycerine or glass slides. A bit costlier technique called formalin-ether concentration technique (FECT) is often used in combination with the direct faecal smear for higher accuracy. Serological and immunological tests are also available. Antibodies and antigens can be detected in the blood using ELISA to identify infection. Adult worm antigens can be detected by indirect haemagglutination assays (IHAs). Polymerase chain reaction (PCR) is also used for detecting the parasite DNA. Circulating cathodic antigen (CCA) in urine can be tested with lateral flow immune-chromatographic reagent strip and point-of-care (POC) tests.Egg detection and immunologic tests are not that sensitive. Polymerase chain reaction (PCR) based testing is accurate and rapid. They, however, are not frequency used in countries were the disease is common due to the cost of the equipment and the technical experience required to run them. Using a microscope to detect eggs costs about US$0.40 per test well PCR is about $US7 per test as of 2019. Loop-mediated isothermal amplification (LAMP) are being studied as they are lower cost. LAMP testing is not commercially available as of 2019.

Treatment
The standard drug for S. mansoni infection is praziquantel at a dose of 40 mg/kg. Oxamniquine is also used.

Epidemiology
As of WHO report in 2016, 206.5 million people worldwide are having schistosomiasis due to different species of Schistosoma. More than 105 million people were given medical treatment. S. mansoni is the major species causing an annual death of about 130,000. It is endemic in 55 countries and most prevalent in Africa, the Middle East, the Caribbean, Brazil, Venezuela and Suriname. About 80-85% of schistosomiasis is found in sub-Saharan Africa, where S. haematobium, S. intercalatum and S. mansoni are endemic. Approximately 393 million Africans are at risk of infection from S. mansoni, of which about 55 million are infected at any moment. Annual death due to S. mansoni is about 130,000. The prevalence rate in different countries of Africa are: 73.9% in northern Ethiopia, 37.9% in western Ethiopia, 56% in Nigeria, 60.5% in Kenya, 64.3% in Tanzania, 19.8% in Ghana, and 53.8% in Côte dIvoire. In Egypt, 60% of the population in the Northern and Eastern parts of the Nile Delta and only 6% in the Southern part are infected.S. mansoni is commonly found in places with poor sanitation. Because of the parasites fecal-oral transmission, bodies of water that contain human waste can be infectious. Water that contains large populations of the intermediate host snail species is more likely to cause infection. Young children living in these areas are at greatest risk because of their tendency to swim and bathe in cercaria-infected waters longer than adults
.  Anyone travelling to the areas described above, and who is exposed to contaminated water, is at risk of schistosomiasis.

History
The intermediate hosts Biomphalaria snails are estimated to originate in South America 95–110 million years ago. But the parasites Schistosoma originated in Asia. In Africa, the progenitor species evolved into modern S. mansoni and S. haematobium around 2–5 million years ago.A German physician Theodor Maximillian Bilharz was the first to discover the parasite in 1851, while working at Kasr el-Aini Hospital, a medical school in Cairo. Bilharz recovered them from autopsies of dead soldiers, and noticed two distinct parasites. He described one of them as Distomum haematobium (now S. haematobium) in 1852, but failed to identify the other. In one of his letters to his mentor Karl Theordor von Siebold, he mentioned some of the eggs were different in having terminal spines while some had lateral spines. Terminal-spined eggs are unique to S. haematobium, while lateral spines are found only in S. mansoni. Bilharz also noted that the adult flukes were different in anatomy and number eggs they produced </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Kimuras disease and can you explain it in depth? [/INST] Kimuras disease is a benign rare chronic inflammatory disorder. Its primary symptoms are subdermal lesions in the head or neck or painless unilateral inflammation of cervical lymph nodes.

Cause
Its cause remains unknown. Reasons such as an allergic reaction, tetanus toxoid vaccination, or an alteration of immune regulation are suspected. Other theories like persistent antigenic stimulation following arthropod bites and parasitic or candidal infection have also been proposed. To date, none of these theories has been substantiated.

Pathophysiology
The pathophysiology of Kimuras disease remains unknown, although an allergic reaction, trauma, and an autoimmune process have all been implicated as possible causes. The disease is manifested by an abnormal proliferation of lymphoid follicles and vascular endothelium. Peripheral eosinophilia and the presence of eosinophils in the inflammatory infiltrate suggest it may be a hypersensitivity reaction. Some evidence has indicated TH2 lymphocytes may also play a role, but further investigation is needed.Kimuras disease is generally limited to the skin, lymph nodes, and salivary glands, but patients with Kimuras disease and nephrotic syndrome have been reported. The basis of this possible association is unclear.

Diagnosis
An open biopsy is the chief means by which this disease is diagnosed."Lymphoid nodules with discrete germinal centers can occupy an area extending from the reticular dermis to the fascia and muscle. Follicular hyperplasia, marked eosinophilic infiltrate and eosinophilic abscesses, and the proliferation of postcapillary venules are characteristic histological findings. [18] Centrally, thick-walled vessels are present with hobnail endothelial cells. Immunohistochemical evaluation of the lymphoid nodules demonstrates a polymorphous infiltrate without clonality. [12, 27] Reports have also demonstrated the presence of plasmacytoid dendritic cells in a lesion of Kimura disease. [40] Histopathological examination is an effective way to establish the diagnosis."

Treatment
Observation is acceptable if the lesions are neither symptomatic nor disfiguring. Intralesional or oral steroids can shrink the nodules, but seldom result in cure. Cyclosporine has been reported to induce remission in patients with Kimuras disease, but recurrence of the lesions has been observed once this therapy is stopped.Cetirizine is an effective agent in treating its symptoms. Cetirizines properties of being effective both in the treatment of pruritus (itching) and as an anti-inflammatory agent make it suitable for the treatment of the pruritus associated with these lesions.  In a 2005 study, the American College of Rheumatology conducted treatments initially using prednisone, followed by steroid dosages and azathioprine,  omeprazole, and calcium and vitamin D supplements over the course of two years. The skin condition of the patient began to improve and the skin lesions lessened. However, symptoms of cushingoid and hirsutism were observed before the patient was removed from the courses of steroids and placed on 10 mg/day of cetirizine to prevent skin lesions; an agent suitable for the treatment of pruritus associated with such lesions. Asymptomatically, the patients skin lesions disappeared after treatment with cetirizine, blood eosinophil counts became normal,  corticosteroid effects were resolved, and a remission began within a period of two months.  The inhibition of eosinophils may be the key to treatment of Kimuras disease due to the role of eosinophils, rather than other cells with regards to the lesions of the skin.Radiotherapy has been used to treat recurrent or persistent lesions. However, considering the benign nature of this disease, radiation should be considered only in cases of recurrent, disfiguring lesions.Surgery has been considered the mainstay of therapy. However, recurrence after surgery is common.In 2011, an eight-year-old boy had presented with a firm, nontender, nonfluctuating 15- to 12-cm mass on the left side of the neck involving the lateral region of the neck and jaw and a 5- to 7-cm mass on the right side of his neck. He had an eosinophil concentration of 36% (absolute count: 8172/mL), his IgE level was 9187 IU/mL. He was diagnosed with Kimuras disease. Initially treated with corticosteroids, he was given a single dose of intravenous immunoglobulin (IVIG) as a steroid-sparing agent after the disease flared while tapering prednisone. After IVIG administration, improvement was rapid, both left and right cervical masses diminished to less than 1 cm and his eosinophil and IgE levels returned to normal range. He has been free of disease during a six-year follow-up. IVIG may have value in the treatment of Kimuras disease.A study is going on to assess the efficacy of tacrolimus on Kimuras disease. One case has so far been described </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Monilethrix and can you explain it in depth? [/INST] Monilethrix (also referred to as beaded hair) is a rare autosomal dominant hair disease that results in short, fragile, broken hair that appears beaded.  It comes from the Latin word for necklace (monile) and the Greek word for hair (thrix). Hair becomes brittle, and breaks off at the thinner parts between the beads. It appears as a thinning or baldness of hair and was first described in 1897 by Walter Smith

Signs and symptoms
Some indicators of monilethrix are small bumps on the skin, mainly on the scalp, neck and arms. In most cases, firm, dark papules, covered with dark scales and crusts appears on the skin, especially the scalp. The affected individual would have beaded hair strands. The possible areas for the hair loss are the eyebrows, eyelashes, limbs, and pubic region. Hair strands are usually dull, dry, and brittle. The strands are prone to mild to severe breakage, causing onset alopecia, especially during pregnancy. Fingernail and toenails tend to appear abnormal. The onset for this disease varies from person to person. The frequency of monilethrix is currently unknown.

Presentation
Newborns are not born with Monilethrix; it usually develops within the first few months of life. The presentation may be of alopecia (baldness).  Individuals vary in severity of symptoms.  Nail deformities may also be present as well as hair follicle keratosis and follicular hyperkeratosis. Depending on severity it can effect hair on all areas of the body including head hair, arm and leg hair, pubic hair, underarm hair, eyebrows, and eyelashes. The hair is seen under a microscope with bumps in the hair strand. These cause the hair to be brittle and break in the thinner sections. Severe cases of monilethrix can also effect finger and toe nails causing abnormal growth. Monilethrix can also cause keratosis pilaris (small bumps on the skin). Less severe cases of Monilethrix may only affect certain parts of the scalp, usually the back of the head and neck.

Diagnosis
Monilethrix may be diagnosed with trichoscopy and other forms of dermoscopy. Light microscopic examination is diagnostic and reveals elliptical nodes of normal thickness and intermittent constrictions, internodes at which the hair easily breaks. Under examination, the hair is beaded. The beading is the result of a periodic narrowing of the shaft with nodes separated by about 0.7 mm. In general, there is a tendency for spontaneous improvement with time, especially during puberty and pregnancy, but the condition never disappears completely.

Genetics
Monilethrix is caused by mutations affecting the genes KRTHB1 (KRT81), KRTHB3 (KRT83), or KRTHB6 (KRT86) which code for type II hair cortex keratins </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Sepiapterin reductase deficiency and can you explain it in depth? [/INST] Sepiapterin reductase deficiency is an inherited pediatric disorder characterized by movement problems, and most commonly displayed as a pattern of involuntary sustained muscle contractions known as dystonia. Symptoms are usually present within the first year of age, but diagnosis is delayed due to physicians lack of awareness and the specialized diagnostic procedures. Individuals with this disorder also have delayed motor skills development including sitting, crawling, and need assistance when walking. Additional symptoms of this disorder include intellectual disability, excessive sleeping, mood swings, and an abnormally small head size. SR deficiency is a very rare condition. The first case was diagnosed in 2001, and since then there have been approximately 30 reported cases. At this time, the condition seems to be treatable, but the lack of overall awareness and the need for a series of atypical procedures used to diagnose this condition pose a dilemma.

Signs and symptoms
Cognitive problems
Intellectual disability: Delay in cognitive development
Extreme mood swings
Language delay

Motor problems
Dystonia: involuntary muscle contractions
Axial hypotonia: low muscle tone and strength
Dysarthria: impairment in muscles used for speech
Muscle stiffness and tremors
Seizures
Coordination and balance impairment
Oculogyric crises: abnormal rotation of the eyesThe oculogyric crises usually occur in the later half of the day and during these episodes patients undergo extreme agitation and irritability along with uncontrolled head and neck movements. Apart from the aforementioned symptoms, patients can also display parkinsonism, sleep disturbances, small head size (microcephaly), behavioral abnormalities, weakness, drooling, and gastrointestinal symptoms.

Causes
This disorder occurs through a mutation in the SPR gene, which is responsible for encoding the sepiapterin reductase enzyme. The enzyme is involved in the last step of producing tetrahydrobiopterin, better known as BH4. BH4 is involved in the processing of amino acids and the production of neurotransmitters, specifically that of dopamine and serotonin which are primarily used in transmission of signals between nerve cells in the brain. The mutation in the SPR gene interferes with the production of the enzyme by producing enzymes with little or no function at all. This interference results in a lack of BH4 specifically in the brain. The lack of BH4 only occurs in the brain because other parts of the body adapt and utilize alternate pathways for the production of BH4. The mutation in the SPR gene leads to nonfunctional sepiapterin reductase enzymes, which results in a lack of BH4 and ultimately disrupts the production of dopamine and serotonin in the brain. The disruption of dopamine and serotonin production leads to the visible symptoms present in patients suffering from sepiapterin reductase deficiency. SR deficiency is considered an inherited autosomal recessive condition disorder because each parent carries one copy of the mutated gene, but typically do not show any signs or symptoms of the condition.

Diagnosis
CSF neurotransmitter screening
The diagnosis of SR deficiency is based on the analysis of the pterins and biogenic amines found in the cerebrospinal fluid (CSF) of the brain. The pterin compound functions as a cofactor in enzyme catalysis and biogenic amines which include adrenaline, dopamine, and serotonin have functions that vary from the control of homeostasis to the management of cognitive tasks. This analysis reveals decreased concentrations of homovanillic acid (HVA), 5-hydroxyindolacetic acid (HIAA), and elevated levels of 7,8-dihydrobiopterin, a compound produced in the synthesis of neurotransmitters. Sepiapterin is not detected by the regularly used methods applied in the investigation of biogenic monoamine metabolites in the cerebrospinal fluid. It must be determined by specialized methods that work by indicating a marked and abnormal increase of sepiapterin in cerebrospinal fluid. Confirmation of the diagnosis occurs by demonstrating high levels of CSF sepiapterin and a marked decrease of SR activity of the fibroblasts along with SPR gene molecular analysis.

Treatment
Levodopa and Carbidopa
SR deficiency is currently being treated using a combination therapy of levodopa and carbidopa. These treatments are also used for individuals suffering from Parkinsons. The treatment is noninvasive and only requires the patient to take oral tablets 3 or 4 times a day, where the dosage of levodopa and carbidopa is determined by the severity of the symptoms. Levodopa is in a class of medications called central nervous system agents where its main function is to become dopamine in the brain. Carbidopa is in a class of medications called decarboxylase inhibitors and it works by preventing levodopa from being broken down before it reaches the brain. This treatment is effective in mitigating motor symptoms, but it does not totally eradicate them and it is not as effective on cognitive problems. Patients who have been diagnosed with SR deficiency and have undergone this treatment have shown improvements with most motor impairments including oculogyric crises, dystonia, balance, and coordination.

Case Studies
Autosomal Recessive DOPA-responsive Dystonia
The diagnosis of sepiapterin reductase deficiency in a patient at the age of 14 years was delayed by an earlier diagnosis of an initially unclassified form of methylmalonic aciduria at the age of 2. At that time the hypotonia and delayed development were not considered to be suggestive of a neurotransmitter defect. The clinically relevant diagnosis was only made following the onset of dystonia with diurnal variation, when the patient was a teenager. Variability in occurrence and severity of other symptoms of the condition, such as hypotonia, ataxia, tremors, spasticity, bulbar involvement, oculogyric crises, and cognitive impairment, is comparable with autosomal dominant GTPCH and tyrosine hydroxylase deficiency, which are both classified as forms of DOPA-responsive dystonia.

Homozygous Mutation causing Parkinsonism
Hypotonia and Parkinsonism were present in two Turkish siblings, brother and sister. By using exome sequencing, which sequences a selective coding region of the genome, researchers have found a homozygous five-nucleotide deletion in the SPR gene which confirmed both siblings were homozygous. It is predicted that this mutation leads to premature translational termination </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Stretch marks and can you explain it in depth? [/INST] Stretch marks, also known as striae () or striae distensae, are a form of scarring on the skin with an off-color hue. Over time they may diminish, but will not disappear completely. Striae are caused by tearing of the dermis during periods of rapid growth of the body, such as during puberty or pregnancy, in which they usually form during the last trimester. Usually on the stomach, these striae also commonly occur on the breasts, thighs, hips, lower back, and buttocks. Pregnancy-related striae are known as striae gravidarum. Striae may also be influenced by the hormonal changes associated with puberty, pregnancy, bodybuilding, or hormone replacement therapy.
There is no evidence that creams used during pregnancy prevent stretch marks. Once they have formed there is no clearly effective treatment, though various methods have been attempted and studied.

Signs and symptoms
Striae, or "stretch marks", begin as reddish or purple lesions, which can appear anywhere on the body, but are most likely to appear in places where larger amounts of fat are stored; the most common places are the abdomen (especially near the navel), breasts, upper arms, underarms, back, thighs (both inner and outer), hips, and buttocks.  Over time, they tend to atrophy and lose pigmentation. The affected areas appear empty, and are soft to the touch.Stretch marks occur in the dermis, the resilient middle tissue layer that helps the skin retain its shape. No stretch marks will form as long as there is support within the dermis; stretching plays a role in where the marks occur and in what direction they run, however, there are a number of contributing factors (see: "Causes", below) to their formation.They can (but do not always) cause a burning and itching sensation, as well as emotional distress.  They pose no health risk in and of themselves, and do not compromise the bodys ability to function normally and repair itself, however, they are often considered a cosmetic nuisance. Young women are generally affected the most and often seek treatment for them from a dermatologist and following pregnancy.

Causes
Stretch marks appear to be caused by stretching of the skin. This is especially true when there is an increase in cortisone –  an increase in cortisone levels can increase the probability or severity of stretch marks by reducing the skins pliability. More specifically, it affects the dermis by preventing the fibroblasts from forming collagen and elastin fibers necessary to keep rapidly growing skin taut; this can create a lack of supportive material as the skin is stretched, and lead to dermal and epidermal tearing, which in turn can produce scarring in the form of stretch marks. This is particularly the case when there is new tissue growth (which can interfere with the underlying physical support of the dermis or epidermis, by displacing the supportive tissue).Examples of cases where stretch marks are common, also given by the Mayo Clinic, include weight gain (in the form of fat and/or muscle), pregnancy, and adolescent growth spurts, though it is also noted that some medications, as well as other medical conditions and diseases, may increase the likelihood of stretch marks appearing. In the case of medication, the Clinic points to "corticosteroid creams, lotions and pills and chronic use of oral or systemic steroids" as a common contributing factor. Medical conditions that can contribute to stretch marks include Ehlers-Danlos syndrome, Cushings syndrome, Marfan syndrome, and "adrenal gland diseases".

Pregnancy
Pregnancy stretch marks, also known as striae gravidarum, are a specific form of scarring of the skin of the abdominal area due to rapid expansion of the uterus as well as sudden weight gain during pregnancy. About 90% of pregnant women are affected.A number of additional factors appear to promote the appearance of stretchmarks: one study of 324 women, done just after they had given birth, demonstrated that low maternal age, high body mass index, weight gain over 15 kg (33 pounds) and higher neonatal birth weight were independently correlated with the occurrence of striae. Teenagers were found to be at the highest risk of developing severe striae.These skin marks are symptoms of pregnancy caused by the tearing of the dermis, resulting in atrophy and loss of rete ridges. These scars often appear as reddish or bluish streaks on the abdomen, and can also appear on the breasts and thighs. Some of these striae disappear with time, while others remain as permanent discolorations of the body.Mechanical distension and rapidly developing areas of the body during pregnancy (such as the abdomen, breasts, and thighs) are most commonly associated with striae formation. Some have suggested that relaxin and estrogen combined with higher levels of cortisol during pregnancy can cause an accumulation of mucopolysaccharides, which increases water absorption of connective tissue, making it prime for tearing under mechanical stress.  There also seems to be an association between higher body mass indices and in women with bigger babies and the incidence and severity of striae. Also, younger women seem to be at higher risk of developing striae during pregnancy.The prevalence and severity of striae gravidarum varies among populations. The current literature suggest that in the general population of the US, there is a 50%-90% prevalence of striae associated with pregnancy, partly as a result of the normal hormonal changes of pregnancy and partly due to stretching of skin fibers. Many women experience striae gravidarum during their first pregnancy. Nearly 45% percent of women develop striae gravidarum before 24 weeks of gestation. Many women who develop lesions during the first pregnancy do not develop them during later pregnancies. Genetic factors such as genealogy and race also seem to be predictive in the appearance of striae.

Prevention
Collagen and elastin are proteins in the skin that contribute to the skins strength, resilience, flexibility, and help skin that has been stretched to recover its original state. Boosting the production of collagen and elastin helps prevent stretch marks from occurring </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Caudal regression syndrome and can you explain it in depth? [/INST] Caudal regression syndrome, or sacral agenesis (or hypoplasia of the sacrum), is a rare birth defect.  It is a congenital disorder in which the fetal development of the lower spine—the caudal partition of the spine—is abnormal. It occurs at a rate of approximately one per 60,000 live births.Some babies are born with very small differences compared to typical development, and others have significant changes.  Most grow up to be otherwise typical adults who have difficulty with walking and incontinence.

Signs and symptoms
This condition exists in a variety of forms, ranging from partial absence of the tail bone regions of the spine to absence of the lower vertebrae, pelvis and parts of the thoracic and/or lumbar areas of the spine. In some cases where only a small part of the spine is absent, there may be no outward sign of the condition. In cases where more substantial areas of the spine are absent, there may be fused, webbed or smaller lower extremities and paralysis. Bowel and bladder control is usually affected.

Cause
The condition arises from some factor or set of factors present during approximately the 3rd week to 7th week of fetal development. Formation of the sacrum/lower back and corresponding nervous system is usually nearing completion by the 4th week of development. Due to abnormal gastrulation, the mesoderm migration is disturbed. This disturbance results in symptoms varying from minor lesions of the lower vertebrae to more severe symptoms such as complete fusion of the lower limbs. While the exact cause is unknown, it has been speculated that the condition has a combination of environmental and genetic causes, and that various types of the condition may have differing causes.Sacral agenesis syndrome (a type of caudal regression syndrome involving agenesis of the lumbar spine, sacrum, and coccyx, and hypoplasia of the lower extremities) is a well-established congenital anomaly associated with maternal diabetes mellitus. Other causes are presumably involved, as demonstrated by the rare overall incidence of caudal regression syndrome (1:60,000) compared to diabetes; however, the condition does have a greatly increased incidence among infants born to mothers with diabetes, estimated at 1 in 350 newborns of mothers with diabetes.The dominant inherited sacral agenesis (also referred to as Currarino syndrome) is very often correlated with a mutation in the Hb9 (also called HlxB9) gene (shown by Sally Ann Lynch, 1995, Nature Genetics).It was previously thought to be related to sirenomelia ("Mermaid syndrome") but has now been determined not to be related to this condition.

Prognosis
There are four levels (or types) of malformation. The least severe indicates partial deformation (unilateral) of the sacrum. The second level indicates a bilateral (uniform) deformation. The most severe types involve a total absence of the sacrum.Depending on the type of sacral agenesis, bowel or urinary bladder deficiencies may be present. A permanent colostomy may be necessary in the case of imperforate anus. Incontinence may also require some type of continence control system (e.g., self-catheterization) be utilized. The condition often impacts the formation of the knees, legs or feet that is sometimes addressed through surgery </s>