<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 Stomatitis and can you explain it in depth? [/INST] Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration.In its widest meaning, stomatitis can have a multitude of different causes and appearances. Common causes include infections, nutritional deficiencies, allergic reactions, radiotherapy, and many others.
When inflammation of the gums and the mouth generally presents itself, sometimes the term gingivostomatitis is used, though this is also sometimes used as a synonym for herpetic gingivostomatitis.
The term is derived from the Greek stoma (στόμα), meaning "mouth", and the suffix -itis (-ῖτις), meaning "inflammation".

Causes
Nutritional deficiency
Malnutrition (improper dietary intake) or malabsorption (poor absorption of nutrients into the body) can lead to nutritional deficiency states, several of which can lead to stomatitis. For example, deficiencies of iron, vitamin B2 (riboflavin),: 490  vitamin B3 (niacin), vitamin B6 (pyridoxine), vitamin B9 (folic acid) or vitamin B12 (cobalamine) may all manifest as stomatitis. Iron is necessary for the upregulation of transcriptional elements for cell replication and repair. Lack of iron can cause genetic downregulation of these elements, leading to ineffective repair and regeneration of epithelial cells, especially in the mouth and lips. Many disorders which cause malabsorption can cause deficiencies, which in turn causes stomatitis. Examples include tropical sprue.: 49

Aphthous stomatitis
Aphthous stomatitis (canker sores) is the recurrent appearance of mouth ulcers in otherwise healthy individuals. The cause is not completely understood, but it is thought that the condition represents a T cell mediated immune response which is triggered by a variety of factors. The individual ulcers (aphthae) recur periodically and heal completely, although in the more severe forms, new ulcers may appear in other parts of the mouth before the old ones have finished healing. Aphthous stomatitis is one of the most common diseases of the oral mucosa, and is thought to affect about 20% of the general population to some degree. The symptoms range from a minor nuisance to being disabling in their impact on eating, swallowing, and talking, and the severe forms can cause people to lose weight. There is no cure for aphthous stomatitis, and therapies are aimed at alleviating the pain, reducing the inflammation and promoting healing of the ulcers, but there is little evidence of efficacy for any treatment that has been used.

Angular stomatitis
Inflammation of the corners (angles) of the lips is termed angular stomatitis or angular cheilitis. In children a frequent cause is repeated lip-licking, and in adults it may be a sign of underlying iron deficiency anemia, or vitamin B deficiencies (e.g., B2-riboflavin, B9-folate, or B12-cobalamin, which in turn may be evidence of poor diets or malnutrition such as celiac disease).
Also, angular cheilitis can be caused by a patients jaws at rest being overclosed due to edentulousness or tooth wear, causing the jaws to come to rest closer together than if the complete/unaffected dentition were present. This causes skin folds around the angle of the mouth which are kept moist by saliva, which in turn favours infection; mostly by Candida albicans or similar species. Treatment usually involves the administration of topical nystatin or similar antifungal agents. Another treatment can be to correct the jaw relationship with dental treatment (e.g., dentures or occlusal adjustment).

Denture-related stomatitis
This is a common condition present in denture wearers. It appears as reddened but painless mucosa beneath the denture. 90% of cases are associated with Candida species, and it is the most common form of oral candidiasis. Treatment is by antifungal medication and improved dental hygiene, such as not wearing the denture during sleep.

Allergic contact stomatitis
Allergic contact stomatitis (also termed "allergic gingivostomatitis" or "allergic contact gingivostomatitis") is a type IV (delayed) hypersensitivity reaction that occurs in susceptible atopic individuals when allergens penetrate the skin or mucosa.Allergens, which may be different for different individuals, combine with epithelial-derived proteins, forming haptens which bind with Langerhans cells in the mucosa, which in turn present the antigen on their surface to T lymphocytes, sensitizing them to that antigen and causing them to produce many specific clones. The second time that specific antigen is encountered, an inflammatory reaction is triggered at the site of exposure. Allergic contact stomatitis is less common than allergic contact dermatitis because the mouth is coated in saliva, which washes away antigens and acts as a barrier. The oral mucosa is also more vascular (has a better blood supply) than skin, meaning that any antigens are more quickly removed from the area by the circulation. Finally, there is substantially less keratin in oral mucosa, meaning that there is less likelihood that haptens will form.Allergic contact stomatitis appears as non-specific inflammation, so it may be mistaken for chronic physical irritation. There may be burning or soreness of the mouth and ulceration. Chronic exposure to the allergen may result in a lichenoid lesion. Plasma cell gingivitis may also occur, which may be accompanied by glossitis and cheilitis.

Allergens that may cause allergic contact stomatitis in some individuals include cinnamaldehyde, Balsam of Peru, peppermint, mercury, gold, pyrophosphates, zinc citrate, free acrylic monomer, nickel, fluoride, and sodium lauryl sulfate. These allergens may originate from many sources, including various foods and drink, chewing gum, toothpaste, mouthwash, dental floss, dental fillings, dentures, orthodontic bands or wires, and many other sources. If the substance containing the allergen comes into contact with the lips, allergic contact cheilitis can occur, together with allergic contact stomatitis.
The diagnosis is confirmed by patch test, and management is by avoidance of exposure to the allergen.

Migratory stomatitis
Migratory stomatitis (or geographic stomatitis) is an atypical presentation of a condition which normally presents on the tongue, termed geographic tongue. Geographic tongue is so named because there are atrophic, erythematous areas of depapillation that migrate over time, giving a map-like appearance.
In migratory stomatitis, other mucosal sites in the mouth, such as the ventral surface (undersurface) of the tongue, buccal mucosa, labial mucosa, soft palate, or floor of mouth may be afflicted with identical lesions, usually in addition to the tongue. Apart from not being restricted to the tongue, migratory stomatitis is an identical condition in every regard to geographic tongue </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 Paratyphoid fever and can you explain it in depth? [/INST] Paratyphoid fever, also known simply as paratyphoid, is a bacterial infection caused by one of the three types of Salmonella enterica. Symptoms usually begin 6–30 days after exposure and are the same as those of typhoid fever. Often, a gradual onset of a high fever occurs over several days. Weakness, loss of appetite, and headaches also commonly occur. Some people develop a skin rash with rose-colored spots. Without treatment, symptoms may last weeks or months. Other people may carry the bacteria without being affected; however, they are still able to spread the disease to others. Typhoid and paratyphoid are of similar severity. Paratyphoid and typhoid fever are types of enteric fever.Paratyphoid is caused by the bacterium Salmonella enterica of the serotypes Paratyphi A, Paratyphi B, or Paratyphi C growing in the intestines and blood. They are usually spread by eating or drinking food or water contaminated with the feces of an infected person. They may occur when a person who prepares food is infected. Risk factors include poor sanitation as is found among poor crowded populations. Occasionally, they may be transmitted by sex. Humans are the only animals infected. Diagnosis may be based on symptoms and confirmed by either culturing the bacteria or detecting the bacterial DNA in the blood, stool, or bone marrow. Culturing the bacteria can be difficult. Bone-marrow testing is the most accurate. Symptoms are similar to that of many other infectious diseases. Typhus is a different disease.While no vaccine is available specifically for paratyphoid, the typhoid vaccine may provide some benefit. Prevention includes drinking clean water, better sanitation, and better handwashing. Treatment of the disease is with antibiotics such as azithromycin. Resistance to a number of other previously effective antibiotics is common.Paratyphoid affects about six million people a year. It is most common in parts of Asia and rare in the developed world. Most cases are due to Paratyphi A rather than Paratyphi B or C. In 2015, paratyphoid fever resulted in about 29,200 deaths, down from 63,000 deaths in 1990. The risk of death is between 10 and 15% without treatment, while with treatment, it may be less than 1%.

Signs and symptoms
Paratyphoid fever resembles typhoid fever. Infection is characterized by a sustained fever, headache, abdominal pain, malaise, anorexia, a nonproductive cough (in early stage of illness), a relative bradycardia (slow heart rate), and hepatosplenomegaly (an enlargement of the liver and spleen). About 30% of Caucasians develop rosy spots on the central body. In adults, constipation is more common than diarrhea.Only 20 to 40% of people initially have abdominal pain. Nonspecific symptoms such as chills, sweating, headache, loss of appetite, cough, weakness, sore throat, dizziness, and muscle pains are frequently present before the onset of fever. Some very rare symptoms are psychosis (mental disorder), confusion, and seizures.

Cause
Paratyphoid fever is caused by any of three serovars of Salmonella enterica subsp. enterica: S. Paratyphi A, S. Paratyphi B (invalid alias S. schottmuelleri), S. Paratyphi C (invalid alias S. hirschfeldii).

Transmission
They are usually spread by eating or drinking food or water contaminated with the feces of an infected person. They may occur when a person who prepares food is infected. Risk factors include poor sanitation as is found among poor crowded populations. Occasionally, they may be transmitted by sex. Humans are the only animals infected.

Paratyphoid B
Paratyphoid B is more frequent in Europe. It can present as a typhoid-like illness, as a severe gastroenteritis or with features of both. Herpes labialis, rare in true typhoid fever, is frequently seen in paratyphoid B. Rarely a subdural empyema can occur. Diagnosis is with isolation of the agent in blood or stool and demonstration of antibodies antiBH in the Widal test. The disease responds well to chloramphenicol or co-trimoxazole.

Paratyphoid C
Paratyphoid C is a rare infection, generally seen in the Far East. It presents as a septicaemia with metastatic abscesses. Cholecystitis is possible in the course of the disease. Antibodies to paratyphoid C are not usually tested and the diagnosis is made with blood cultures. Chloramphenicol therapy is generally effective.

Carriers
Humans and, occasionally, domestic animals are the carriers of paratyphoid fever. Members of the same family can be transient or permanent carriers. In most parts of the world, short-term fecal carriers are more common than urinary carriers. The chronic urinary carrier state occurs in those who have schistosomiasis (parasitic blood fluke).Continuing to shed Salmonella Paratyphi is possible for up to one year, and during this phase, a person is considered to be a carrier. The chronic carrier state may follow acute illness, or mild or even subclinical infections. Chronic carriers are most often women who were infected in their middle age.

Pathophysiology
After ingestion, if the immune system is unable to stop the infection, the bacteria multiply and then spread to the bloodstream, after which the first signs of disease are observed in the form of fever. They penetrate further to the bone marrow, liver, and bile ducts, from which bacteria are excreted into the bowel contents. In the second phase of the disease, the bacteria penetrate the immune tissue of the small intestine, and the initial symptoms of small-bowel movements begin.

Diagnosis
Prevention
Providing basic sanitation and safe drinking water and food are the keys for controlling the disease. In developed countries, enteric fever rates decreased in the past when treatment of municipal water was introduced, human feces were excluded from food production, and pasteurization of dairy products began. In addition, children and adults should be carefully educated about personal hygiene. This would include careful handwashing after defecation and sexual contact, before preparing or eating food, and especially the sanitary disposal of feces. Food handlers should be educated in personal hygiene prior to handling food or utensils and equipment. Infected individuals should be advised to avoid food preparation. Sexually active people should be educated about the risks of sexual practices that permit fecal-oral contact.Those who travel to countries with poor sanitation should receive a live attenuated typhoid vaccine—Ty21a (Vivotif), which, in addition to the protection against typhoid fever,  may provide some protection against paratyphoid fever caused by the S. enterica serotypes A and B. In particular, a reanalysis of data from a trial conducted in Chile showed the Ty21a vaccine was 49% effective (95% CI: 8–73%) in preventing paratyphoid fever caused by the serotype B. Evidence from a study of international travelers in Israel also indicates the vaccine may prevent a fraction of infections by the serotype A, although no trial confirms this. This cross-protection by a typhoid vaccine is most likely due to O antigens shared between different S. enterica serotypes.Exclusion from work and social activities should be considered for symptomatic, and asymptomatic people who are food handlers, healthcare/daycare staff who are involved in patient care and/or child care, children attending unsanitary daycare centers, and older children who are unable to implement good standards of personal hygiene </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 Ulnar nerve entrapment and can you explain it in depth? [/INST] Ulnar nerve entrapment is a condition where the ulnar nerve becomes physically trapped or pinched, resulting in pain, numbness, or weakness, primarily affecting the little finger and ring finger of the hand. Entrapment may occur at any point from the spine at cervical vertebra C7 to the wrist; the most common point of entrapment is in the elbow (Cubital tunnel syndrome). Prevention is mostly through correct posture and avoiding repetitive or constant strain (e.g. "cell phone elbow"). Treatment is usually conservative, including medication, activity modification, and exercise, but may sometimes include surgery. Prognosis is generally good, with mild to moderate symptoms often resolving spontaneously.

Signs and symptoms
In general, ulnar neuropathy will result in symptoms in a specific anatomic distribution, affecting the little finger, the ulnar half of the ring finger, and the intrinsic muscles of the hand.
The specific symptoms experienced in the characteristic distribution depend on the specific location of ulnar nerve impingement. Symptoms of ulnar neuropathy may be motor, sensory, or both depending on the location of injury. Motor symptoms consistent of muscle weakness; sensory symptoms or paresthesias consist of numbness or tingling in the areas innervated by the ulnar nerve.Proximal impingement is associated with mixed symptoms, as the proximal nerve consists of mixed sensory and motor innervation.
Distal impingement is associated with variable symptoms, as the ulnar nerve separates near the hand into distinct motor and sensory branches.
In cubital tunnel syndrome (a proximal impingement), sensory and motor symptoms tend to occur in a certain sequence. Initially, there may be numbness of the small and ulnar fourth finger which may be transient. If the impingement is not corrected, the numbness may become constant and progress to hand weakness. A characteristic resting hand position of "ulnar claw," where the small and ring fingers curl up, occurs late in the disease and is a sign of severe neuropathy.
By contrast, in Guyons canal syndrome (distal impingement) motor symptoms and claw hand may be more pronounced, a phenomenon known as the ulnar paradox. Also, the back of the hand will have normal sensation.

Diagnosis
The distinct innervation of the hand usually enables diagnosis of an ulnar nerve impingement by symptoms alone.  Ulnar nerve damage that causes paralysis to these muscles will result in a characteristic ulnar claw position of the hand at rest. Clinical tests such as the card test for Froments sign, can be easily performed for assessment of ulnar nerve. However, a complete diagnosis should identify the source of the impingement, and radiographic imaging may be necessary to determine or rule-out an underlying cause.Imaging studies, such as ultrasound or MRI, may reveal anatomic abnormalities or masses responsible for the impingement.  Additionally, imaging may show secondary signs of nerve damage that further confirm the diagnosis of impingement. Signs of nerve damage include flattening of the nerve, swelling of the nerve proximal to site of injury, abnormal appearance of nerve, or characteristic changes to the muscles innervated by the nerve.

Differential diagnoses
Symptoms of ulnar neuropathy or neuritis do not necessarily indicate an actual physical impingement of the nerve; any injury to the ulnar nerve may result in identical symptoms.  In addition, other functional disturbances may result in irritation to the nerve and are not true "impingement". For example, anterior dislocation and "snapping" of ulnar nerve across the medial epicondyle of the elbow joint can result in ulnar neuropathy.Entrapment of other major sensory nerves of the upper extremities result in deficits in other patterns of distribution.  Entrapment of the median nerve causes carpal tunnel syndrome, which is characterized by numbness in the thumb, index, middle, and half of the ring finger.  Compression of the radial nerve causes numbness of the back of the hand and thumb, and is much rarer.A simple way of differentiating between significant median and ulnar nerve injury is by testing for weakness in flexing and extending certain fingers of the hand. Median nerve injuries are associated with difficulty flexing the index and middle finger when attempting to make a fist. However, with an ulnar nerve lesion, the pinky and ring finger cannot be unflexed when attempting to extend the fingers.Some people are affected by multiple nerve compressions, which can complicate diagnosis.

Classification
Ulnar nerve entrapment is classified by location of entrapment.  The ulnar nerve passes through several small spaces as it courses through the medial side of the upper extremity, and at these points the nerve is vulnerable to compression or entrapment—a so-called "pinched nerve". The nerve is particularly vulnerable to injury when there has been a disruption in the normal anatomy. The most common site of ulnar nerve entrapment is at the elbow, followed by the wrist.Causes or structures which have been reported to cause ulnar nerve entrapment include:
Problems originating at the neck: thoracic outlet syndrome, cervical spine pathology, compression by anterior scalene muscles
Problems originating in the chest: compression by pectoralis minor muscles
Brachial plexus abnormalities
Elbow: fractures, growth plate injuries, cubital tunnel syndrome, flexorpronator aponeurosis, arcade of Struthers
Forearm: tight flexor carpi ulnaris muscles
Wrist: fractures, ulnar tunnel syndrome, hypothenar hammer syndrome
Artery aneurysms or thrombosis
Other: Infections, tumors, diabetes, hypothyroidism, rheumatism, and alcoholism

Cubital tunnel syndrome
The most common location of ulnar nerve impingement at the elbow is within the cubital tunnel, and is known as cubital tunnel syndrome. The tunnel is formed by the medial epicondyle of the humerus, the olecranon process of the ulna and the tendinous arch joining the humeral and ulnar heads of the flexor carpi ulnaris muscle. While most cases of injury are minor and resolve spontaneously with time, chronic compression or repetitive trauma may cause more persistent problems.  Commonly cited scenarios include:

Sleeping with the arm folded behind neck, elbows bent.
Pressing the elbows upon the arms of a chair while typing.
Resting or bracing the elbow on the arm rest of a vehicle.
Bench pressing.
Intense exercising and strain involving the elbow.Compression of the ulnar nerve at the medial elbow may occasionally be caused by an epitrocheloanconeus muscle, an anatomical variant.

Ulnar tunnel syndrome
Ulnar nerve impingement along an anatomical space in the wrist called the ulnar canal is known as ulnar tunnel syndrome. Recognized causes of ulnar nerve impingement at this location include local trauma, fractures, ganglion cysts, and classically avid cyclists who experience repetitive trauma against bicycle handlebars. This form of ulnar neuropathy comprises two work-related syndromes: so-called "hypothenar hammer syndrome," seen in workers who repetitively use a hammer, and "occupational neuritis" due to hard, repetitive compression against a desk surface.

Prevention
Cubital tunnel syndrome may be prevented or reduced by maintaining good posture and proper use of the elbow and arms, such as wearing an arm splint while sleeping to maintain the arm is in a straight position instead of keeping the elbow tightly bent. A recent example of this is popularization of the concept of cell phone elbow and game hand.

Treatment
The most effective treatment for cubital tunnel syndrome is surgical decompression. The most safe and effective operation is in-situ decompression +/- medial epicondylectomy.For pain symptoms, medications such as NSAID, amitriptyline, or vitamin B6 supplementation may help although there is no evidence to support this claim.Mild symptoms may first be treated non-operatively, with the following:
Elbow joint immobilization in extension at night +/- during the day
Neural flossing/gliding exercises
Strengthening/stretching exercises
Activity modification (e.g. avoidance of pressure on the elbows)It is important to identify positions and activities that aggravate symptoms and to find ways to avoid them </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 Epidermolysis bullosa acquisita and can you explain it in depth? [/INST] Epidermolysis bullosa acquisita, also known as acquired epidermolysis bullosa, is a longterm autoimmune blistering skin disease. It generally presents with fragile skin that blisters and becomes red with or without trauma </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Vascular myelopathy and can you explain it in depth? [/INST] Vascular myelopathy (vascular disease of the spinal cord) refers to an abnormality of the spinal cord in regard to its blood supply. The blood supply is complicated and supplied by two major vessel groups: the posterior spinal arteries and the anterior spinal arteries—of which the Artery of Adamkiewicz is the largest. Both the posterior and anterior spinal arteries run the entire length of the spinal cord and receive anastomotic (conjoined) vessels in many places. The anterior spinal artery has a less efficient supply of blood and is therefore more susceptible to vascular disease. Whilst atherosclerosis of spinal arteries is rare, necrosis (death of tissue) in the anterior artery can be caused by disease in vessels originating from the segmental arteries such as atheroma (arterial wall swelling) or aortic dissection (a tear in the aorta).

Spinal cord infarction
Anterior spinal artery syndrome
Anterior spinal artery syndrome is necrosis of tissue in the anterior spinal artery or its branches. It is characterised by pain which radiates at onset and sudden quadraplegia (paralysis of all four limbs) or paraplegia (paralysis of the lower body). Within days, flaccid limbs become spastic and hyporeflexia (underactive nerve responses) turns into hyperreflexia (overactive nerve responses) and extensor plantar nerve responses. Sensory loss to pain and temperature also occurs up to the level of damage on the spinal cord, as damage to different areas will affect different parts of the body.In diagnosis, other causes of abrupt paralysis should be excluded such as cord compression, transverse myelitis (inflammation of the spinal cord) and Guillain–Barré syndrome. A specific cause of the infarction should be looked for, such as diabetes, polyarteritis nodosa (inflammatory damage of vessels) or systemic lupus erythematosus. Neurosyphilis is also a known cause. Other causes include:
Treatment is supportive and aims to relieve symptoms. The prognosis is dependent upon individual circumstances and factors.

Posterior spinal artery syndrome
Posterior spinal artery syndrome is much rarer than its anterior counterpart as the white matter structures that are present are much less vulnerable to ischemia since they have a better blood supply. When posterior spinal artery syndrome does occur, dorsal columns are damaged and ischemia may spread into the posterior horns. Clinically the syndrome presents as a loss of tendon reflexes and loss of joint position sense

Transient ischemic attack
Transient ischemic attacks (TIAs) rarely affect the spinal cord and usually affect the brain; however, cases have been documented in these areas. Spinal arteriovenous malformations are the main cause and are represented later in this article. However, TIAs can result from emboli in calcific aortic disease and aortic coarctation.

Spinal arteriovenous malformations
Spinal arteriovenous malformations (AVMs, or angiomatous malformations) are congenital (from birth) abnormalities of blood vessels. Arteries that directly communicate with veins bypass the capillary network (which has not yet developed) and thus creates a shunt. AVMs appear as a mass of convoluted, dilated vessels. In regards to the spinal cord, they are usually located in the thoracolumbar region (between the thoracic and lumbar regions, 60% of the time), as opposed to the upper thoracic (20%) and cervical regions (approximately 15%). Cervical malformations arise from the anterior spinal artery and lie within the cord, whereas thoracolumbar malformations can be internal, external or encompass both areas of the cord.Malformations can be recognised as part of an acute illness or gradual onset disease </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 Morvans syndrome and can you explain it in depth? [/INST] Morvans syndrome is a rare, life-threatening autoimmune disease named after the nineteenth century French physician Augustin Marie Morvan.  "La chorée fibrillaire" was first coined by Morvan in 1890 when describing patients with multiple, irregular contractions of the long muscles, cramping, weakness, pruritus, hyperhidrosis, insomnia, and delirium.
It normally presents with a slow insidious onset over months to years.
Approximately 90% of cases spontaneously go into remission, while the other 10% of cases lead to death.In 1890, Morvan described a patient with myokymia (muscle twitching) associated with muscle pain, excessive sweating, and disordered sleep.
This rare disorder is characterized by severe insomnia, amounting to no less than complete lack of sleep (agrypnia) for weeks or months in a row, and associated with autonomic alterations consisting of profuse perspiration with characteristic skin miliaria (also known as sweat rash), tachycardia, increased body temperature, and hypertension.  Patients display a remarkable hallucinatory behavior, and peculiar motor disturbances, which Morvan reported under the term “fibrillary chorea” but which are best described in modern terms as neuromyotonic discharges.The association of the disease with thymoma, tumour, autoimmune diseases, and autoantibodies suggests an autoimmune or paraneoplastic aetiology.  Besides an immune-mediated etiology, it is also believed to occur in gold, mercury, or manganese poisoning.

Signs and symptoms
In one of the few reported cases, the subject presented with muscle weakness and fatigue, muscle twitching, excessive sweating and salivation, small joint pain, itching and weight loss.  The subject also developed confusional episodes with spatial and temporal disorientation, visual and auditory hallucinations, complex behavior during sleep and progressive nocturnal insomnia associated with diurnal drowsiness.  There was also severe constipation, urinary incontinence, and excessive lacrimation.  When left alone, the subject would slowly lapse into a stuporous state with dreamlike episodes characterized by complex and quasi-purposeful gestures and movements (enacted dreams).  Marked hyperhidrosis and excessive salivation were evident.  Neurological examination disclosed diffuse muscle twitching and spontaneous and reflex myoclonus, slight muscle atrophy in the limbs, absence of tendon reflexes in the lower limbs and diffuse erythema especially on the trunk with scratching lesions of the skin.
Compulsive behaviours, stereotypies and reduplicative paramnesias can be part of the CNS spectrum.

Insomnia
In all of the reported cases, the need for sleep was severely reduced and in some cases not necessary.  The duration of sleep in one case decreased to about 2–4 hours per 24-hour period.  Clinical features pertaining to insomnia include daytime drowsiness associated with a loss of ability to sleep, intermingled with confusional oneiric status, and the emergence of atypical REM sleep from wakefulness.  The polysomnogram (PSG) picture of this disease is characterized by an inability to generate physiological sleep (key features are the suppression of the hallmarks of stage 2 non-REM sleep: spindles and K complexes) and by the emergence of REM sleep without atonia.  The involvement of the thalamus and connected limbic structures in the pathology indicate the prominent role that the limbic thalamus plays in the pathophysiology of sleep.  In a case documented in 1974, PSG findings documented the sustained absence of all sleep rhythms for up to a period of 4 months.Electroencephalography (EEG) in one case was dominated by "wakefulness" and “subwakefulness” states alternating or intermingled with short (< 1 min) atypical REM sleep phases, characterized by a loss of muscle atonia.  The “subwakefulness” state was characterized by 4–6 Hz theta activity intermingled with fast activity and desynchronized lower voltage theta activity, behaviourally associated with sleep-like somatic and autonomic behavior.  The subject was said to have “agrypnia excitata”, which consists of severe total insomnia of long duration associated with decreased vigilance, mental confusion, hallucinations, motor agitation, and complex motor behavior mimicking dreams, and autonomic activation.  CNS and autonomic symptoms were caused by impaired corticolimbic control of the subcortical structures regulating the sleep-wake and autonomic functions.

Neuromyotonia
Neuromyotonia refers to muscle twitching and cramping at rest that is exacerbated with exercise.  It is caused by sustained or repetitive spontaneous muscle activity of peripheral nerve origin.  Myokymia, or spontaneous rippling and twitching movements of muscles, is a visible component of neuromyotonia.  Electromyography (EMG) discloses spontaneous, repetitive motor unit or single fiber discharges firing in irregular rhythmic bursts at high intraburst frequencies. Some of the muscles exhibiting twitching include the bilateral gastrocnemii, quadriceps femoris, biceps brachii, and right masseter.  In vivo electrophysiological studies suggest at least some dysfunction of the muscle cell membrane.  In the examined muscles, no abnormal insertional activity or fibrillation potentials were noted.  Nerve conduction studies were normal.

Other symptoms
Breathing difficulties can occur, resulting from neuromyotonic activity of the laryngeal muscles.  Laryngeal spasm possibly resulting from neuromyotonia has been described previously, and this highlights that, in patients with unexplained laryngospasm, neuromytonia should be added to the list of differential diagnoses.Studies have shown subtly decreased metabolism on positron emission tomography (PET) and single photon emission computed tomography (SPECT) in the left inferior frontal and left temporal lobes. and or basal ganglia hypermetabolism. Ancillary laboratory tests including MRI and brain biopsy have confirmed temporal lobe involvement.  Cranial MRI shows increased signal in the hippocampus.Cerebral spinal fluid (CSF) shows normal protein, glucose, white blood cell, and immunoglobulin G (IgG) levels, but there are weak oligoclonal bands, which are absent in the blood serum.  Marked changes in circadian serum levels of neurohormones and increased levels of peripheral neurotransmitters were also observed.  The absence of morphological alterations of the brain pathology, the suggestion of diffusion of IgG into the thalamus and striatum, more marked than in the cortex (consistent with effects on the thalamolimbic system) the oligoclonal bands in the CSF and the amelioration after PE all strongly support an antibody-mediated basis for the condition. Raised CSF IgG concentrations and oligoclonal bands have been reported in patients with psychosis.  Anti-acetylcholine receptors (anti-AChR) antibodies have also been detected in patients with thymoma, but without clinical manifestations of myasthenia gravis.  There have also been reports of non-paraneoplastic limbic encephalitis associated with raised serum VGKC suggesting that these antibodies may give rise to a spectrum of neurological disease presenting with symptoms arising peripherally, centrally, or both.  Yet, in two cases, oligoclonal bands were absent in the CSF and serum, and CSF immunoglobulin profiles were unremarkable.

Comorbid conditions
In one case, a patient was diagnosed with both Morvans syndrome and pulmonary hyalinizing granulomas (PHG). PHG are rare fibrosing lesions of the lung, which have central whorled deposits of lamellar collagen.  How these two diseases relate to one another is still unclear.Thymoma, prostate adenoma, and in situ carcinoma of the sigmoid colon have also been found in patients with Morvans Syndrome.

Mechanism
Antibodies against voltage-gated potassium channels (VGKC), which are detectable in about 40% of patients with acquired neuromytonia, have been implicated in Morvans pathophysiology.  Raised serum levels of antibodies to VGKCs have been reported in three patients with Morvans Syndrome.  Binding of serum from a patient with Morvans Syndrome to the hippocampus in a similar pattern of antibodies to known VGKC suggest that these antibodies can also cause CNS dysfunction.  Additional antibodies against neuromuscular junction channels and receptors have also been described.  Experimental evidence exists that these anti-VGKC antibodies cause nerve hyperexcitability by suppression of voltage gated K+ outward currents, whereas other, yet undefined humoral factors have been implicated in anti-VGKC antibody negative neuromyotonia. It is believed that antibodies to the Shaker-type K+ channels (the Kv1 family) are the type of potassium channel most strongly associated with acquired neuromyotonia and Morvans Syndrome.Whether VGKC antibodies play a pathogenic role in the encephalopathy as they do in the peripheral nervous system is as yet unclear.  It has been suggested that the VGKC antibodies may cross the blood–brain barrier and act centrally, binding predominantly to thalamic and striatal neurons causing encephalopathic and autonomic features.

Diagnosis
Differential diagnosis
The symptoms of Morvans Syndrome have been noted to bear a striking similarity to limbic encephalitis (LE). These include the CNS symptoms consisting of insomnia, hallucinations, and disorientation, as well as dementia and psychosis.  Both entities can be paraneoplastic and associated with thymoma.  Recently, VGKC antibodies were found in patients with LE, strengthening the hypothesis that LE and Morvans Syndrome may be closely connected.  Varying symptoms may be used to determine which of the two diseases the subject has.  Amnesia, seizures, and mesial temporal lobe structural abnormalities are features of LE, whereas myokymia, hyperhydrosis, and insomnia favor Morvans Syndrome.

Treatment
In most of the reported cases, the treatment options were very similar.  Plasmapheresis alone or in combination with steroids, sometimes also with thymectomy and azathioprine, have been the most frequently used therapeutic approach in treating Morvans Syndrome. However, this does not always work, as failed response to steroids and to subsequently added plasmapheresis have been reported </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 Calcific tendinitis and can you explain it in depth? [/INST] Calcific tendinitis is a common condition where calcium deposits form in a tendon, sometimes causing pain at the affected site. Deposits can occur in several places in the body, but are by far most common in the rotator cuff of the shoulder. Around 80% of those with deposits experience symptoms, typically chronic pain during certain shoulder movements, or sharp acute pain that worsens at night. Calcific tendinitis is typically diagnosed by physical exam and X-ray imaging. The disease often resolves completely on its own, but is typically treated with non-steroidal anti-inflammatory drugs to relieve pain, rest and physical therapy to promote healing, and in some cases various procedures to breakdown and/or remove the calcium deposits.
Adults aged 30–50 are most commonly affected by calcific tendinitis. It is twice as common in women as men, and is not associated with exercise. Calcifications in the rotator cuff were first described by Ernest Codman in 1934. The name, "calcifying tendinitis" was coined by Henry Plenk in 1952.

Signs and symptoms
Up to 20% of those with calcific tendinitis have no symptoms. For those with symptoms, the symptoms vary based on the phase of the disease. In the initial "formative phase" when the calcium deposits are being formed, people rarely experience any symptoms. Those that do have symptoms tend to have intermittent shoulder pain, particularly during forward should flexion (i.e. lifting the arm in front of the body). In the "resorptive phase" when the calcium deposit is breaking down, many experience severe acute pain that worsens at night. Those affected tend to hold the shoulder rotated inwards to alleviate pain, and have difficulty lying on the affected shoulder. Some people experience heat and redness at the affected shoulder, as well as a limited range of motion.

Cause
Calcific tendinitis is caused by deposits of calcium phosphate crystals in the tendons of the shoulder. These deposits are most frequently found in the supraspinatus tendon (63% of the time), and less frequently in the infraspinatus tendon (7%), subacromial bursa (7%), subscapularis tendon (3%), or in both the supraspinatus and subscapularis tendons at the same time (20%).The development of calcific tendinitis is often divided into three stages. First, in the "precalcific stage", something causes tendon cells to transform into other cells that can act as sites for calcium deposition. This is followed by the two-part "calcific stage"; first calcium is deposited (the formative phase), then the body begins to break down the calcium deposit (the resporptive phase). Finally, in the "postcalcific stage" the calcium deposits are replaced with new tissue and the tendon completely heals.The cause of the calcium deposits remains unclear, although several theories have been put forward. Some theories involve the differentiation of tendon cells into other cells, namely cartilages or bone cells. Others associate the condition with cell death due to aging, wear, or lack of oxygen in the tissue; however, the disease is uncommon in the very old, not associated with exercise, and tends to resolve completely even if untreated.

Diagnosis
Calcific tendinitis is typically diagnosed by physical examination and X-ray imaging. During the formative phase, X-ray images typically reveal calcium deposits with uniform density and a clear margin. In the more painful resorptive phase, deposits instead appear cloudy and with unclear margins. By arthroscopy, formative stage deposits appear crystalline and chalk-like, while resorptive stage deposits appear smooth resembling toothpaste. Ultrasound is also used to locate and assess calcium deposits. In the formative stage, deposits are hyperechoic and arc-shaped; in the resorptive stage deposits are less echogenic and appear fragmented.

Treatment
The first line of treatment for calcific tendinitis is typically nonsteroidal anti-inflammatory drugs to relieve pain, rest for the affected joint, and sometimes physical therapy to avoid joint stiffness. For those with severe pain direct injections of steroids to the affected site are often effective for pain relief, but may interfere with reabsorption of the calcium deposit. For those whose pain doesnt improve with medication and rest, the deposit can be dissolved and removed with techniques called "ultrasound-guided needling", "barbotage", and "US-PICT" (for "ultrasound percutaneous injection in calcific tenditis"). In each, ultrasound is used to locate the deposit and guide a needle to the affected site. There saline and lidocaine are injected to dissolve the deposit, then removed to wash it away </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 Post-kala-azar dermal leishmaniasis and can you explain it in depth? [/INST] Post-kala-azar dermal leishmaniasis (PKDL) is a complication of visceral leishmaniasis (VL); it is characterised by a macular, maculopapular, and nodular rash in a patient who has recovered from VL and who is otherwise well. The rash usually starts around the mouth from where it spreads to other parts of the body depending on severity.
Post-kala-azar dermal leishmaniasis (also known as "Post-kala-azar dermatosis") found mainly on the face, arms, and upper part of the trunk. It occurs years (in the Indian variation) or a few months(in the African strain) after the successful treatment of visceral leishmaniasis.
It is mainly seen in Sudan and India where it follows treated VL in 50% and 5-10% of cases, respectively. Thus, it is largely restricted to areas where Leishmania donovani is the causative parasite. The interval at which PKDL follows VL is 0–6 months in Sudan and 2–3 years in India. PKDL probably has an important role in interepidemic periods of VL, acting as a reservoir for parasites.
PKDL was first identified by Sir Upendranath Brahmachari, who initially called it dermal leishmanoid. He published his observations in the Indian Medical Gazette in 1922.

Mechanism
The cause of PKDL is uncertain. Possibilities may include use of antimonial drugs, sunburn, reinfection with kala-azar, memory T cell responses failing in certain organs; and genetic susceptibility.There is increasing evidence that the pathogenesis is largely immunologically mediated; high concentrations of interleukin 10 in the peripheral blood of VL patients predict the development of PKDL </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 Fordyce spots and can you explain it in depth? [/INST] Fordyce spots (also termed Fordyce granules) are visible sebaceous glands that are present in most individuals. They appear on the genitals and/or on the face and in the mouth. They appear as small, painless, raised, pale, red or white spots or bumps 1 to 3 mm in diameter that may appear on the scrotum, shaft of the penis or on the labia, as well as the inner surface (retromolar mucosa) and vermilion border of the lips of the face. They are not associated with any disease or illness, nor are they infectious but rather they represent a natural occurrence on the body. No treatment is therefore required. Persons with this condition sometimes consult a dermatologist because they are worried they may have a sexually transmitted disease (especially genital warts) or some form of cancer.Some diseases may appear similar to Fordyce spots such as sexually transmitted diseases.

Description
On the shaft of the penis, Fordyce spots are more visible when the skin is stretched, and may only be noticeable during an erection. The spots can also appear on the skin of the scrotum.Oral Fordyce granules appear as rice-like granules, white or yellow-white in color. They are painless papules (small bumps), about 1–3 mm in greatest dimension. The most common site is along the line between the vermilion border and the oral mucosa of the upper lip, or on the buccal mucosa (inside the cheeks) in the commissural region, often bilaterally. They may also occur on the mandibular retromolar pad and tonsillar areas, but any oral surface may be involved. There is no surrounding mucosal change. Some patients will have hundreds of granules while most have only one or two.Occasionally, several adjacent glands will coalesce into a larger cauliflower-like cluster similar to sebaceous hyperplasia of the skin. In such an instance, it may be difficult to determine whether or not to diagnose the lesion as sebaceous hyperplasia or sebaceous adenoma. The distinction may be moot because both entities have the same treatment, although the adenoma has a greater growth potential. Sebaceous carcinoma of the oral cavity has been reported, presumably arising from Fordyce granules or hyperplastic foci of sebaceous glands.In some persons with Fordyce spots, the glands express a thick, chalky discharge when squeezed.

Causes
Normally, sebaceous glands are only found in association with a hair follicle.They appear to be more obvious in people with oily skin types, with some rheumatic disorders, and in hereditary nonpolyposis colorectal cancer. In the latter, the most common site for Fordyce spots is the lower gingiva (gums) and vestibular mucosa.

Diagnosis
Large numbers of lobules coalescing into a definitely elevated mass may be called benign sebaceous hyperplasia, and occasional small keratin-filled pseudocysts may be seen and must be differentiated from epidermoid cyst or dermoid cyst with sebaceous adnexa </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 Linear focal elastosis 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 Phalanx bone and can you explain it in depth? [/INST] The phalanges  (singular: phalanx ) are digital bones in the hands and feet of most vertebrates. In primates, the thumbs and big toes have two phalanges while the other digits have three phalanges. The phalanges are classed as long bones.

Structure
The phalanges are the bones that make up the fingers of the hand and the toes of the foot. There are 56 phalanges in the human body, with fourteen on each hand and foot. Three phalanges are present on each finger and toe, with the exception of the thumb and large toe, which possess only two. The middle and far phalanges of the fourth and fifth toes are often fused together (symphalangism). The phalanges of the hand are commonly known as the finger bones. The phalanges of the foot differ from the hand in that they are often shorter and more compressed, especially in the proximal phalanges, those closest to the torso.A phalanx is named according to whether it is proximal, middle, or distal and its associated finger or toe. The proximal phalanges are those that are closest to the hand or foot. In the hand, the prominent, knobby ends of the phalanges are known as knuckles. The proximal phalanges join with the metacarpals of the hand or metatarsals of the foot at the metacarpophalangeal joint or metatarsophalangeal joint. The intermediate phalanx is not only intermediate in location, but usually also in size. The thumb and large toe do not possess a middle phalanx. The distal phalanges are the bones at the tips of the fingers or toes. The proximal, intermediate, and distal phalanges articulate with one another through interphalangeal joints of hand and interphalangeal joints of the foot.: 708–711 : 708–711

Bone anatomy
Each phalanx consists of a central part, called the body, and two extremities.
The body is flat on either side, concave on the palmar surface, and convex on the dorsal surface. Its sides are marked with rough areas giving attachment to fibrous sheaths of flexor tendons. It tapers from above downwards.
The proximal extremities of the bones of the first row present oval, concave articular surfaces, broader from side to side than from front to back. The proximal extremity of each of the bones of the second and third rows presents a double concavity separated by a median ridge.
The distal extremities are smaller than the proximal, and each ends in two condyles (knuckles) separated by a shallow groove; the articular surface extends farther on the palmar than on the dorsal surface, a condition best marked in the bones of the first row.In the foot, the proximal phalanges have a body that is compressed from side to side, convex above, and concave below. The base is concave, and the head presents a trochlear surface for articulation with the second phalanx. The middle are remarkably small and short, but rather broader than the proximal. The distal phalanges, as compared with the distal phalanges of the finger, are smaller and are flattened from above downward; each presents a broad base for articulation with the corresponding bone of the second row, and an expanded distal extremity for the support of the nail and end of the toe.

Distal phalanx
In the hand, the distal phalanges are flat on their palmar surface, small, and with a roughened, elevated surface of horseshoe form on the palmar surface, supporting the finger pulp.: 6b. 3. The Phalanges of the Hand  The flat, wide expansions found at the tips of the distal phalanges are called apical tufts. They support the fingertip pads and nails. The phalanx of the thumb has a pronounced insertion for the flexor pollicis longus (asymmetric towards the radial side), an ungual fossa, and a pair of unequal ungual spines (the ulnar being more prominent). This asymmetry is necessary to ensure that the thumb pulp is always facing the pulps of the other digits, an osteological configuration which provides the maximum contact surface with held objects.In the foot, the distal phalanges are flat on their dorsal surface. It is largest proximally and tapers to the distal end. The proximal part of the phalanx presents a broad base for articulation with the middle phalanx, and an expanded distal extremity for the support of the nail and end of the toe.: 6b. 3. The Phalanges of the Foot  The phalanx ends in a crescent-shaped rough cap of bone epiphysis — the apical tuft (or ungual tuberosity/process) which covers a larger portion of the phalanx on the volar side than on the dorsal side. Two lateral ungual spines project proximally from the apical tuft. Near the base of the shaft are two lateral tubercles. Between these a V-shaped ridge extending proximally serves for the insertion of the flexor pollicis longus. Another ridge at the base serves for the insertion of the extensor aponeurosis. The flexor insertion is sided by two fossae — the ungual fossa distally and the proximopalmar fossa proximally.

Development
The number of phalanges in animals is often expressed as a "phalangeal formula" that indicates the numbers of phalanges in digits, beginning from the innermost medial or proximal. For example, humans have a 2-3-3-3-3 formula for the hand, meaning that the thumb has two phalanges, whilst the other fingers each have three.
In the distal phalanges of the hand the centres for the bodies appear at the distal extremities of the phalanges, instead of at the middle of the bodies, as in the other phalanges. Moreover, of all the bones of the hand, the distal phalanges are the first to ossify.: 6b. 3. The Phalanges of the Hand

Function
The distal phalanges of ungulates carry and shape nails and claws and these in primates are referred to as the ungual phalanges.

History of phalanges
Etymology
The term phalanx or phalanges refers to an ancient Greek army formation in which soldiers stand side by side, several rows deep, like an arrangement of fingers or toes.

In animals
Most land mammals including humans have a 2-3-3-3-3 formula in both the hands (or paws) and feet. Primitive reptiles usually had the formula 2-3-4-4-5, and this pattern, with some modification, remained in many later reptiles and in the mammal-like reptiles. The phalangeal formula in the flippers of cetaceans (marine mammals) varies widely due to hyperphalangy (the increase in number of phalanx bones in the digits). In humpback whales, for example, the phalangeal formula is 0/2/7/7/3; in pilot whales the formula is 1/10/7/2/1.In vertebrates, proximal phalanges have a similar placement in the corresponding limbs, be they paw, wing or fin. In many species, they are the longest and thickest phalanx ("finger" bone). The middle phalanx also a corresponding place in their limbs, whether they be paw, wing, hoof or fin.
The distal phalanges are cone-shaped in most mammals, including most primates, but relatively wide and flat in humans.

Primates
The morphology of the distal phalanges of human thumbs closely reflects an adaptation for a refined precision grip with pad-to-pad contact. This has traditionally been associated with the advent of stone tool-making. However, the intrinsic hand proportions of australopiths and the resemblance between human hands and the short hands of Miocene apes, suggest that human hand proportions are largely plesiomorphic (as found in ancestral species) — in contrast to the derived elongated hand pattern and poorly developed thumb musculature of other extant hominoids.In Neanderthals, the apical tufts were expanded and more robust than in modern and early upper Paleolithic humans. A proposal that Neanderthal distal phalanges was an adaptation to colder climate (than in Africa) is not supported by a recent comparison showing that in hominins, cold-adapted populations possessed smaller apical tufts than do warm-adapted populations.
In non-human, living primates the apical tufts vary in size, but they are never larger than in humans. Enlarged apical tufts, to the extent they actually reflect expanded digital pulps, may have played a significant role in enhancing friction between the hand and held objects during Neolithic toolmaking.Among non-human primates phylogenesis and style of locomotion appear to play a role in apical tuft size </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 Irregular sleep–wake rhythm and can you explain it in depth? [/INST] Irregular sleep–wake rhythm (ISWD) is a rare form of circadian rhythm sleep disorder. It is characterized by numerous naps throughout the 24-hour period, no main nighttime sleep episode, and irregularity from day to day. Affected individuals have no pattern of when they are awake or asleep, may have poor quality sleep, and often may be very sleepy while they are awake.
The total time asleep per 24 hours is normal for the persons age. The disorder is serious—an invisible disability. It can create social, familial, and work problems, making it hard for a person to maintain relationships and responsibilities, and may make a person home-bound and isolated.

Causes
ISWD has various causes, including neurological disorders such as dementia (particularly Alzheimers Disease), brain damage, or intellectual disabilities. It is thought that those affected have a weak circadian clock. The risk for the disorder increases with age, but only due to increased prevalence of co-morbid medical disorders.

Diagnosis
A sleep diary should be kept to aid in diagnosis and for chronicling the sleep schedule during treatment. Other ways to monitor the sleep schedule are actigraphy or use of a Continuous Positive Airway Pressure (CPAP) machine that can log sleeping times
The following are possible warning signs:

sleeping off and on in a series of naps during the day and at night, with no regular pattern but with normal total sleep time,
difficulty getting restorative sleep, and
excessive daytime sleepiness.Because of the changes in sleep/wake time, and because this is a rare disorder, initially it can seem like another circadian rhythm sleep disorder such as non-24-hour sleep–wake disorder or like insomnia.

Initial visit with sleep physician
A physician specializing in sleep medicine may ask patients about their medical history; for example: neurological problems, prescription or non-prescription medications taken, alcohol use, family history, and any other sleep problems. A thorough medical and neurological exam is indicated. The patient will be asked to complete a sleep diary, recording natural sleep and wake up times, over several weeks. Sleep rating with the Epworth Sleepiness Scale may be used.

Medical testing
A neurological condition or another medical problem may be suspected, in which case, blood tests, a CT scan or an MRI may be used. An overnight sleep study is usually not needed to detect this disorder, but may be indicated if other sleep disorders, such as sleep apnea and periodic limb movement disorder, seem likely. The overnight sleep study is called polysomnography. It charts brain waves, heart beat, muscle activity, and breathing during sleep. It also records arm and leg movement. It will show if there are other sleep disorders that are causing or increasing the problems with ISWD.

Management
Treatment for irregular sleep–wake rhythm tries to enable the body clock in the brain, such that a normal long sleep period at night can be achieved. Education about sleep hygiene is important, and counseling can be helpful. Melatonin, vitamin B12, sleep aids, wake aids, and other medications may also be used. Exposure to light during the daytime and activities occurring at regular times each day may help to restore a normal rhythm.The management of this disorder may vary for different subgroups of patients </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 Fistula and can you explain it in depth? [/INST] A fistula (plural: fistulas or fistulae ; from Latin fistula, "tube, pipe") in anatomy is an abnormal connection between two hollow spaces (technically, two epithelialized surfaces), such as blood vessels, intestines, or other hollow organs. Types of fistula can be described by their location. Anal fistulas connect between the anal canal and the perianal skin. Anovaginal or rectovaginal fistulas occur when a hole develops between the anus or rectum and the vagina. Colovaginal fistulas occur between the colon and the vagina. Urinary tract fistulas are abnormal openings within the urinary tract or an abnormal connection between the urinary tract and another organ such as between the bladder and the uterus in a vesicouterine fistula, between the bladder and the vagina in a vesicovaginal fistula, and between the urethra and the vagina in urethrovaginal fistula. When occurring between two parts of the intestine, it is known as an enteroenteral fistula, between the small intestine and the skin as an enterocutaneous fistula, and between the colon and the skin as a colocutaneous fistula.Fistulas can result from an infection or inflammation, injury or surgery. Fistulas are sometimes surgically created as part of a treatment, for example arteriovenous fistulas for hemodialysis.Treatment for fistula varies depending on the cause and extent of the fistula, but often involves surgical intervention combined with antibiotic therapy. In some cases the fistula is temporarily covered using a fibrin glue or plug. Catheters may be required to drain a fistula.Globally, every year between 50,000 and 100,000 women are affected by fistula relating to childbirth. In botany, the term is most common in its adjectival forms, where it is used in binomial names to refer to species that are distinguished by hollow or tubular structures. Monarda fistulosa, for example, has tubular flowers. The term was first used in the 14th century.

Definition
A fistula is an abnormal connection between vessels or organs that do not usually connect. It can be due to a disease or trauma, or purposely surgically created.

Classification
Various types of fistulas include:

Blind: Only one open end; may also be called sinus tracts.
Complete: Both internal and external openings.
Incomplete: An external skin opening that does not connect to any internal organ.Although most fistulas are in forms of a tube, some can also have multiple branches.

Location
Types of fistula can be described by their location. Anal fistulas connect between the epithelialized surface of the anal canal and the perianal skin. Anovaginal or rectovaginal fistulas occur when a hole develops between the anus or rectum and the vagina. Colovaginal fistulas occur between the colon and the vagina. Urinary tract fistulas are abnormal openings within the urinary tract or an abnormal connection between the urinary tract and another organ such as between the bladder and the uterus in a vesicouterine fistula, between the bladder and the vagina in a vesicovaginal fistula, and between the urethra and the vagina in urethrovaginal fistula. When occurring between two parts of the intestine, it is known as an enteroenteral fistula, between the small intestine and the skin as an enterocutaneous fistula, and between the small intestine and the colon as a colocutaneous fistula.The following list is sorted by the International Statistical Classification of Diseases and Related Health Problems.

H: Diseases of the eye, adnexa, ear, and mastoid process
(H04.6) Lacrimal fistula
(H05.81) Carotid cavernous fistula
(H70.1) Mastoid fistula
Craniosinus fistula: between the intracranial space and a paranasal sinus
(H83.1) Labyrinthine fistula
Perilymph fistula: tear between the membranes between the middle and inner ears
Preauricular fistula
Preauricular fistula: usually on the top of the cristae helicis of the ears

I: Diseases of the circulatory system
(I25.4) Coronary arteriovenous fistula, acquired
(I28.0) Arteriovenous fistula of pulmonary vessels
Pulmonary arteriovenous fistula: between an artery and vein of the lungs, resulting in shunting of blood. This results in improperly oxygenated blood.
(I67.1) Cerebral arteriovenous fistula, acquired
(I77.0) Arteriovenous fistula, acquired
(I77.2) Fistula of artery

J: Diseases of the respiratory system
(J86.0) Pyothorax with fistula
(J95.0) Tracheoesophageal fistula, between the trachea and the esophagus.  This may be congenital or acquired, for example as a complication of a tracheostomy.

K: Diseases of the digestive system
(K11.4) Salivary gland fistula
(K31.6) Fistula of stomach and duodenum
(K31.6) Gastrocolic fistula
(K31.6) Gastrojejunocolic fistula – after a Billroth II a fistula forms between the transverse colon and the upper jejunum (which, post Billroth II, is attached to the remainder of the stomach).  Fecal matter passes improperly from the colon to the stomach and causes halitosis.
Enterocutaneous fistula: between the intestine and the skin surface, namely from the duodenum or the jejunum or the ileum. This definition excludes the fistulas arising from the colon or the appendix.
Gastric fistula: from the stomach to the skin surface
(K38.3) Fistula of appendix
(K60) Anal and rectal fissures and fistulas
(K60.3) Anal fistula
(K60.5) Anorectal fistula (fecal fistula, fistula-in-ano): connecting the rectum or other anorectal area to the skin surface. This results in abnormal discharge of feces through an opening other than the anus.
(K63.2) Fistula of intestine
Enteroenteral fistula: between two parts of the intestine
(K82.3) Fistula of gallbladder
(K83.3) Fistula of bile duct
Biliary fistula: connecting the bile ducts to the skin surface, often caused by gallbladder surgery
Pancreatic fistula: between the pancreas and the exterior via the abdominal wall

M: Diseases of the musculoskeletal system and connective tissue
(M25.1) Fistula of joint

N: Diseases of the urogenital system
(N32.1) Vesicointestinal fistula
(N36.0) Urethral fistula
Innora:between the prostatic utricle and the outside of the body
(N64.0) Fistula of nipple
(N82) Fistulae involving female genital tract / Obstetric fistula
(N82.0) Vesicovaginal fistula: between the bladder and the vagina
(N82.1) Other female urinary-genital tract fistulae
Cervical fistula: abnormal opening in the cervix
(N82.2) Fistula of vagina to small intestine
Enterovaginal fistula: between the intestine and the vagina
(N82.3) Fistula of vagina to large intestine
Rectovaginal: between the rectum and the vagina
(N82.4) Other female intestinal-genital tract fistulae
(N82.5) Female genital tract-skin fistulae
(N82.8) Other female genital tract fistulae
(N82.9) Female genital tract fistula, unspecified

Q: Congenital malformations, deformations and chromosomal abnormalities
(Q18.0) Sinus, fistula and cyst of branchial cleft
Congenital preauricular fistula: A small pit in front of the ear. Also known as an ear pit or preauricular sinus.
(Q26.6) Portal vein-hepatic artery fistula
(Q38.0) Congenital fistula of lip
(Q38.4) Congenital fistula of salivary gland
(Q42.0) Congenital absence, atresia and stenosis of rectum with fistula
(Q42.2) Congenital absence, atresia and stenosis of anus with fistula
(Q43.6) Congenital fistula of rectum and anus
(Q51.7) Congenital fistulae between uterus and digestive and urinary tracts
(Q52.2) Congenital rectovaginal fistula

T: External causes
(T14.5) Traumatic arteriovenous fistula
(T81.8) Persistent postoperative fistula

Causes
Disease: Infections including an anorectal abscess and inflammatory diseases including Crohns disease and ulcerative colitis can result in fistulas. Fistulas to the anus may occur in hidradenitis suppurativa. In women, fistulas can also occur following pelvic infection and inflammation.
Surgical and medical treatment: Complications from gallbladder surgery can lead to biliary fistulas. As well as being congenital or resulting from trauma, arteriovenous fistulas are created purposefully for hemodialysis. Radiation therapy to the pelvis can lead to vesicovaginal fistulas. Persistent gastrocutenaous fistulas can develop after gastrostomy.
Trauma: Prolonged childbirth can lead to fistulas in women, in whom abnormal connections may occur between the bladder and vagina, or the rectum and vagina. An obstetric fistula develops when blood supply to the tissues of the vagina and the bladder (and/or rectum) is cut off during prolonged obstructed labor. The tissues die and a hole forms through which urine and/or feces pass uncontrollably. Vesicovaginal and rectovaginal fistulas may also be caused by rape, in particular gang rape, and rape with foreign objects, as evidenced by the abnormally high number of women in conflict areas who have developed fistulae. In 2003, thousands of women in eastern Congo presented themselves for treatment of traumatic fistulas caused by systematic, violent gang rape, often also with sharp objects that occurred during the countrys five years of war </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 Papillary thyroid cancer and can you explain it in depth? [/INST] Papillary thyroid cancer or papillary thyroid carcinoma is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases. It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck. It is often well-differentiated, slow-growing, and localized, although it can metastasize.

Diagnosis
Papillary thyroid carcinoma is usually discovered on routine examination as an asymptomatic thyroid nodule that appears as a neck mass. In some instances, the mass may have produced local symptoms. This mass is normally referred to a fine needle aspiration biopsy (FNA) for investigation. FNA accuracy is very high and it is a process widely used in these cases. Other investigation methods include ultrasound imaging and nuclear scan. The ultrasound is a useful test to distinguish solid from cystic lesions and to identify calcifications. The thyroid ultrasound is also very effective to discover microcarcinomas, which refer to very small carcinomas (<1 cm).
Papillary thyroid carcinomas are also discovered when a hard nodule is found in multinodular goiter, when enlarged cervical lymph nodes are detected, or when there are unidentified metastatic lesions elsewhere in the body. Expanding lesions found in the thyroid gland, especially if they are painful, should be examined as they may indicate the presence of papillary thyroid carcinoma. Other clinical signs that could indicate papillary thyroid are fixation to the trachea, a firm neck mass, damage to recurrent laryngeal or cervical sympathetic nerves. Five percent of the population can have thyroid nodules, and the majority will be benign.Appropriate workup includes an ultrasound of the neck, followed by lab studies. Patients will usually meet with both an endocrinologist and a surgeon (head and neck surgeon or endocrine surgeon).

Markers
Thyroglobulin can be used as a tumor marker for well-differentiated papillary thyroid cancer. HBME-1 staining may be useful for differentiating papillary carcinomas from follicular carcinomas; in papillary lesions it tends to be positive.Reduced expression of ATP5E is significantly associated with the diagnosis of papillary thyroid cancer and may serve as an early tumor marker of the disease. Serum microRNAs have shown good diagnostic performance for distinguishing patients with papillary thyroid cancer from patients with benign thyroid nodules and healthy controls, and are suggested as novel and minimally invasive diagnostic approach in clinical practice.

Pathology
Papillary thyroid cancer gets its name from the papillae among its cells, visible on microscopy. Features include:

Characteristic Orphan Annie eye nuclear clearings (nuclei with uniform staining, which appear empty due to powdery chromatin and marginal micronucleoli) and psammoma bodies on light microscopy. The former is useful in identifying the follicular variant of papillary thyroid carcinomas.
Lymphatic spread is more common than hematogenous spread
Multifocality is common
The so-called lateral aberrant thyroid is usually a lymph node metastasis from a papillary thyroid carcinoma.
Papillary microcarcinoma is a subset of papillary thyroid cancer defined as measuring less than or equal to 1 cm. The highest incidence of papillary thyroid microcarcinoma in an autopsy series was reported by Harach et al. in 1985, who found 36 of 101 consecutive autopsies to have an incidental microcarcinoma. Michael Pakdaman et al. report the highest incidence in a retrospective surgical series at 49.9 percent of 860 cases. Management strategies for incidental papillary microcarcinoma on ultrasound (and confirmed on FNAB) range from total thyroidectomy with radioactive iodine ablation to observation alone. Harach et al. suggest using the term "occult papillary tumor" to avoid giving patients distress over having cancer. It was Woolner et al. who first arbitrarily coined the term "occult papillary carcinoma" in 1960, to describe papillary carcinomas ≤ 1.5 cm in diameter.Several variants are recognized, although classic papillary thyroid carcinoma is the most frequent: microscopic-follicular variant, diffuse-sclerosing variant, tall-cell variant, columnar-cell variant, hobnail variant, and others. The encapsulated-follicular variant, specifically when noninvasive, has been newly reclassified as the noninvasive follicular thyroid neoplasm with papillary-like nuclear features.Although papillary carcinoma has a propensity to invade lymphatics, it is less likely to invade blood vessels.
These kinds of tumors are most commonly unencapsulated, and they have a high tendency to metastasize locally to lymph nodes, which may produce cystic structures near the thyroid that are difficult to diagnose because of the paucity of malignant tissue. Furthermore, papillary tumors may metastasize to the lungs and produce a few nodules or the lung fields may exhibit a snowflake appearance throughout.
Other characteristics of the papillary carcinoma is that E.M. shows increased mitochondria, increased RER, as well as increased apical microvilli. Moreover, papillary carcinomas have an indolent growth, and 40 percent of cases spread out of the capsule.

Associated mutations
Mutations associated with papillary thyroid cancer are mainly two forms of chromosomal translocation and one form of point mutation. These alterations lead to activation of a common carcinogenic pathway—the MAPK/ERK pathway.
Chromosomal translocations involving the RET proto-oncogene (encoding a tyrosine kinase receptor that plays essential roles in the development of neuroendocrine cells) located on chromosome 10q11 occur in approximately a fifth of papillary thyroid cancers. The fusion oncoproteins generated are termed RET/PTC proteins (ret/papillary thyroid carcinoma), and constitutively activate RET and the downstream MAPK/ERK pathway. The frequency of ret/PTC translocations is significantly higher in papillary cancers arising in children and after radiation exposure. The gene NTRK1 (encoding the TrkA receptor), located on chromosome 1q, is similarly translocated in approximately 5 percent to 10 percent of papillary thyroid cancers.Approximately a third to a half of papillary thyroid carcinomas harbor point mutations in the BRAF oncogene, also activating the MAPK/ERK pathway. In those cases the BRAF mutations found were V600E mutation. After performing a multivariate analysis, it was found that the absence of tumor capsule was the only parameter associated (P=0.0005) with BRAF V600E mutation. According to recent studies, papillary cancers carrying the common V600E mutation tend to have a more aggressive long-term course. BRAF mutations are frequent in papillary carcinoma and in undifferentiated cancers that have developed from papillary tumors.
Many more changes in gene expression are currently being investigated. Previous studies demonstrated the dysregulation of different microRNAs in thyroid cancer. For example, downregulation of miR-369-3p and consequent upregulation of its target TSPAN13 appear to be involved in the pathophysiology of PTC.Mitochondrial mutations:  MtDNA(mitochondrial) haplogroups, characterized by unique sets of non pathological mtDNA polymorphisms can modulate the pathogenesis of different diseases in specific populations because of its influence on the expression of genes related to ROS production and OXPHOS coupling efficiency and the regulation of apoptosis. In Asian populations, haplogroup D4a is associated with an increased risk of thyroid cancer while in European populations, Haplogroup K is considered to be protective of Thyroid cancer.

Treatment
Surgery remains the mainstay of treatment for papillary thyroid cancer. The Revised 2009 American Thyroid Association guidelines for papillary thyroid cancer state that the initial procedure should be near-total or total thyroidectomy. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastasis.
Minimal disease (diameter up to 1.0 centimeters) - hemithyroidectomy (or unilateral lobectomy) and isthmectomy may be sufficient. There is some discussion whether this is still preferable over total thyroidectomy for this group of patients.
Gross disease (diameter over 1.0 centimeters) - total thyroidectomy, and central compartment lymph node removal is the therapy of choice. Additional lateral neck nodes can be removed at the same time if an ultrasound guided FNA and thyroglobulin TG cancer washing was positive on the pre-operative neck node ultrasound evaluation.Arguments for total thyroidectomy are:
Reduced risk of recurrence, if central compartment nodes are removed at the original surgery.
30-85% of papillary carcinoma is multifocal disease. Hemithyroidectomy may leave disease in the other lobe. However, multifocal disease in the remnant lobe may not necessarily become clinically significant or serve as a detriment to patient survival.
Ease of monitoring with thyroglobulin (sensitivity for picking up recurrence is increased in presence of total thyroidectomy, and ablation of the remnant normal thyroid by low dose radioiodine 131 after following a low iodine diet (LID).
Ease of detection of metastatic disease by thyroid and neck node ultrasound.
Post-operative complications at high-volume thyroid surgery centers with experienced surgeons are comparable to that of hemithyroidectomy.Arguments for hemithyroidectomy:

Most patients have low-risk cancer with an excellent prognosis, with similar survival outcomes in low-risk patients who undergo total thyroidectomy versus hemithyroidectomy.
Less likelihood of patient requiring lifelong thyroid hormone replacement after surgery.Thyroid total body scans are less reliable at finding recurrence than TG and ultrasound.
Papillary tumors tend to be more aggressive in patients over age 45. In such cases, it might be required to perform a more extensive resection including portions of the trachea. Also, the sternocleidomastoid muscle, jugular vein, and accessory nerve are to be removed if such procedure allows apparently complete tumor resection. If a significant amount of residual tumor is left in the neck, external radiotherapy has been indicated and has proven useful especially in those cases when the residual tumor does not take up radioiodine.
After surgical thyroid removal, the patient waits around 4–6 weeks to then have radioiodine therapy. This therapy is intended to both detect and destroy any metastasis and residual tissue in the thyroid. The treatment may be repeated 6–12 months after initial treatment of metastatic disease where disease recurs or has not fully responded.Patients are administered hormone replacement levothyroxine for life after surgery, especially after total thyroidectomy. Chemotherapy with cisplatin or doxorubicin has proven limited efficacy, however, it could be helpful for patients with bone metastases to improve their quality of life. Patients are also prescribed levothyroxine and radioiodine after surgery. Levothyroxine influences growth and maturation of tissues and it is involved in normal growth, metabolism, and development. In case of metastases, patients are prescribed antineoplastic agents which inhibit cell growth and proliferation and help in palliating symptoms in progressive disease.
After successful treatment, 35 percent of the patients may experience a recurrence within a 40-year span. Also, patients may experience a high incidence of nodule metastasis, with 35 percent cases of cervical node metastases. Approximately 20 percent of patients will develop multiple tumors within the thyroid gland.There is ongoing discussion regarding the best management regarding the optimal surgical procedure for papillary thyroid cancer. Prognosis of patients with papillary thyroid cancer is found to be dependent on the patients age, the size of the tumor, presence of metastatic disease, and the presence of tumor invasion into adjacent tissues near the thyroid gland. Recent studies have examined a more conservative approach to surgery and have demonstrated that hemithyroidectomy may be acceptable for patients with low-risk papillary thyroid cancer with tumor size 1 cm to 4 cm with no presence of invasion to tissues surrounding the thyroid or metastasis. Studies examining large databases of patients with papillary thyroid cancer have concluded that there is no survival advantage for patients with stage I papillary thyroid cancer size 1–4 cm receiving total thyroidectomy versus hemithyroidectomy. In light of this data, choosing the optimal course of surgical and medical management of papillary thyroid cancer should involve shared decision making from patient, endocrinologists, and surgeons.

Prognosis
Depending on source, the overall 5-year survival rate for papillary thyroid cancer is 96 percent or 97 percent, with a 10-year survival rate of 93 percent.For a more specific prognosis for individual cases, there are at minimum 13 known scoring systems for prognosis; among the more often used are:

AGES - Age, Grade, Extent of disease, Size
AMES - Age, Metastasis, Extent of disease, Size
MACIS - Metastasis, Age at presentation, Completeness of surgical resection, Invasion (extrathyroidal), Size (this is a modification of the AGES system). It is probably the most reliable staging method available. Also known as the MAICS system.
TNM staging - Tumor, node, metastasis. Remarkable about the TNM staging for (differentiated) thyroid carcinoma is that the scoring is different according to age.

MACIS
The MACIS system of estimating the prognosis of papillary thyroid cancer was developed by Clive S. Grant at the Mayo Clinic, and was based on careful evaluation of a large group of patients. It is probably the most reliable staging method available.It assigns scores to the main factors involved, and uses the sum of this score to calculate the prognosis:

Most patients fall into the low-risk category (MACIS score less than 6.0) and are cured of the cancer at the time of surgery.Children with multiple lung metastases and/or a miliary aspect still have an excellent long-term prognosis if given adequate treatment.

Stage
Based on overall cancer staging into stages I to IV, papillary thyroid cancer has a 5-year survival rate of 100 percent for stages I and II, 93 percent for stage III and 51 percent for stage IV.

Epidemiology
According to Surveillance, Epidemiology, and End Results (SEER), the incidence of papillary cancer has increased from 4.8 to 14.9 per 100,000 from 1975 to 2012. Females are more likely to get papillary cancer when compared to males with incidence ratio of 2.5 to 1 where most of the cancers are diagnosed between 40 and 50 years old in females. However, death rates from papillary cancer remains static from 2003 to 2012 at 0.5 per 100,000 men and women. There was an increased incidence of papillary cancer from 1910 to 1960 due to the use of ionising radiation in treating childhood head and neck cancers </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 WAGR syndrome and can you explain it in depth? [/INST] WAGR syndrome (also known as WAGR complex, Wilms tumour-aniridia syndrome, aniridia-Wilms tumour syndrome) is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), Aniridia (absence of the coloured part of the eye, the iris), Genitourinary anomalies, and mental Retardation.  The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies can include tumours of the gonads (testes or ovaries).Some WAGR syndrome patients show severe childhood obesity and hyperphagia; the acronym WAGRO (O for obesity) has been used to describe this category and may be associated with the coinciding loss of BDNF a gene that is also on chromosome 11.The condition, first described by Miller et al. in 1964 in its association with other congenital malformations, results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes.It is possible for those with WAGR syndrome to develop Wilms tumor, a rare form of kidney cancer.

Signs and symptoms
Newborn children with WAGR syndrome are soon noted to have aniridia. The clinical suspicion for WAGR may be increased with the presence of other genital anomalies, though genitourinary anomalies are not always present, particularly in girls.In older children, clinical diagnosis of the syndrome can be made when aniridia and one of the other features are present. While aniridia is rarely absent in WAGR syndrome, cases have been reported without it </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 Costello syndrome and can you explain it in depth? [/INST] Costello syndrome, also called faciocutaneoskeletal syndrome or FCS syndrome, is a rare genetic disorder that affects many parts of the body. It is characterized by delayed development and intellectual disabilities, distinctive facial features, unusually flexible joints, and loose folds of extra skin, especially on the hands and feet.: 571  Heart abnormalities are common, including a very fast heartbeat (tachycardia), structural heart defects, and overgrowth of the heart muscle (hypertrophic cardiomyopathy). Infants with Costello syndrome may be large at birth, but grow more slowly than other children and have difficulty feeding. Later in life, people with this condition have relatively short stature and many have reduced levels of growth hormones.  It is a RASopathy.Beginning in early childhood, people with specific mutations on the Costello syndrome gene variant have an increased risk of developing certain cancerous and noncancerous tumors. Small growths called papillomas are the most common noncancerous tumors seen with this condition. They usually develop around the nose and mouth. The most frequent cancerous tumor associated with Costello syndrome is a soft tissue tumor called a rhabdomyosarcoma. Other cancers also have been reported in children and adolescents with this disorder, including a tumor that arises in developing nerve cells (neuroblastoma) and a form of bladder cancer (transitional cell carcinoma).
Costello syndrome was discovered by Jack Costello, a New Zealand paediatrician, in 1977.  He is credited with first reporting the syndrome in the Australian Paediatric Journal, Volume 13, No.2 in 1977.

Signs and symptoms
Genetics
Costello syndrome is caused by any of at least five different mutations in the HRAS gene on chromosome 11. This gene provides instructions for making a protein, H-Ras, that helps control cell growth and division. Mutations that cause Costello syndrome lead to the production of an H-Ras protein that is permanently active. Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This unchecked cell division may predispose those affected to the development of benign and malignant tumors. It remains unclear how mutations in HRAS cause other features of Costello syndrome, but many of the signs and symptoms may result from cell overgrowth and abnormal cell division.HRAS is a proto-oncogene in which somatic mutations in healthy people can contribute to cancer.  Whereas children with Costello syndrome typically have a mutation in HRAS in every cell of their bodies, an otherwise healthy person with a tumor caused in part by HRAS mutation will only have mutant HRAS within the tumor. The test for the mutation in cancer tumors can also be used to test children for Costello syndrome.Costello syndrome is inherited in an autosomal dominant manner, which means one copy of the altered gene is sufficient to cause the disorder. Almost all cases have resulted from new mutations, and occur in people with no history of the disorder in their family. This condition is rare; as of 20 April 2007, 200 to 300 cases have been reported worldwide.

Diagnosis
Costello Syndrome can be difficult for doctors to immediately clinically diagnose, as there are similar conditions that resemble this syndrome. A physician will start by assessing the childs height, the size of the head, and birth weight.Full genome and Exome next generation DNA testing is the primary diagnostic tool for Costello Syndrome.

Treatments
At the 2005 American Society of Human Genetics meeting, Francis Collins gave a presentation about a treatment he devised for children affected by Progeria.  He discussed how farnesyltransferase inhibitors (FTIs) affects H-Ras. After his presentation, members of the Costello Syndrome Family Network discussed the possibility of FTIs helping children with Costello syndrome. Mark Kieran, who presented at the 1st International Costello Syndrome Research Symposium in 2007, agreed that FTIs might help children with Costello syndrome.  He discussed with Costello advocates what he had learned in establishing and running the Progeria clinical trial with an FTI, to help them consider next steps.Another medication that affects H-Ras is Lovastatin, which is planned as a treatment for neurofibromatosis type I.  When this was reported in mainstream news, the Costello Syndrome Professional Advisory Board was asked about its use in Costello Syndrome </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 Skew deviation 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 Blistering distal dactylitis and can you explain it in depth? [/INST]  </s>