<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 Constriction ring syndrome and can you explain it in depth? [/INST] Constriction ring syndrome (CRS) is a congenital disorder with unknown cause. Because of the unknown cause there are many different, and sometimes incorrect names. It is a malformation due to intrauterine bands or rings that give deep grooves in, most commonly, distal extremities like fingers and toes. In rare cases the constriction ring can form around other parts of the fetus and cause amputation or even intrauterine death. The anatomy proximal to the site of constriction (or amputation) is developmentally normal.
CRS can be associated with other malformations with club foot being most common.
The precise configuration of the bands, lymphedema, and character of the amputations are not predictable and vary with each individual patient. Also more than one extremity is usually affected, and it is rare for only one ring to present as an isolated malformation with no other manifestation of this syndrome.

Signs and symptoms
The constriction of appendages by amniotic bands may result in:
Constriction rings around the digits, arms, and legs
Swelling of the extremities distal to the point of constriction (congenital lymphedema)
Amputation of digits, arms, and legs (congenital amputation)

Cause
There are three different theories to the cause of the constriction ring syndrome.
The first is the intrinsic theory, which was proposed by Streeter in 1930, implicates an anomaly in germ plasm resulting in the defects. This theory is reinforced by the clinical presentation of the constriction rings with other internal visceral and systematic anomalies. Because of these other anomalies the names "Constriction Ring Syndrome", "Constriction Band Syndrome", and "Streeter Bands" are given to this defect/disease. This is sometimes attributed to vascular disruption shared between cleft palate and other forms of cleft defects occurring together with ABS; this co-occurrence suggests an "intrinsic" defect of the blood circulation.The second theory postulates the involvement of an intrauterine disruption during pregnancy followed by a cascade of events involving amniotic rupture. When spontaneous rupture of the amnion occurs early in the second trimester, the separation of amnion from chorion produces many small, thin strands that can become entangled within digits and toes. Later, as the fetus grows but the bands do not, the bands become constricting. This constriction reduces blood circulation, hence causes congenital abnormalities. In some cases a complete "natural" amputation of a digit(s) or limb may occur before birth or the digit(s) or limbs may be necrotic (dead) and require surgical amputation following birth. The names "Amniotic Band Syndrome" (ABS), "Amniotic Disruption Complex", and "Amniochorionic Mesoblastic Fibrous Strings" are based on this theory.
The third theory postulates the involvement of intrauterine trauma. Intrauterine trauma could be something like amniocentesis, or something like a fetal surgery. An intrauterine trauma could result in hemorrhage leading to acrosyndactyly. One study also showed the presence of bands as confirmed by sonography after fetal surgery.Because of these different theories, there are many names for this syndrome. For a long time people believed the second theory about the amniotic rupture and strands. In the research cases not every child had a real (amniotic) strand. It could be that there has to be another explanation for the development of these anomalies.

Diagnosis
The diagnosis of constriction ring syndrome can be confirmed with an ultrasonography. The clinical manifestations can be extremely variable. It could be a single or multiple manifestation. This can be confirmed at the end of the first trimester or at the beginning of the second trimester. But not every patient will be diagnosed at that moment, most will get this diagnosis at birth.Individual strands are small and hard to see on ultrasound, so bands are detected indirectly because of the constrictions and swelling upon limbs or digits. Misdiagnosis is also common, so if there are any signs of amniotic bands, further detailed ultrasound tests should be done to assess the severity. 3D ultrasound and MRI can be used for more detailed and accurate diagnosis of bands and the resulting damage/danger to the fetus.
Decreased fetal movement could be a sign of a serious problem which may include ABS. It is rare but possible for the membrane to become wrapped around the placenta or the neck of the baby in the womb causing strangulation and death.
There is a strong relationship between ABS and clubfoot (also called "talipes"). 31.5% of clubfoot cases can be correlated with ABS, with 20% occurring bilaterally. Other abnormalities found with ABS include: clubhands, cleft lip, and/or cleft palate, and hemangioma.

Differential diagnosis
The differential diagnosis includes:
Symbrachydactyly
Congenital amputations
Hypoplasias of hand, digit, thumb
Adams–Oliver syndrome
ADAM complexADAM Complex; CRS is sometimes mislabeled as ADAM complex. ADAM is an abbreviation for Amniotic Deformity, Adhesions Mutilations. CRS is the malformation due to a constriction ring around mostly a limb. ADAM-complex is the association of limb defects (caused by constriction rings) and certain craniofacial clefts"Adams–Oliver syndrome is often mislabeled as CRS and consists of cutis aplasia of the scalp in which a longitudinal defect can vary in size and can often be associated with full-thickness skullcap loss. The distal digital or toe hypoplasia-aplasia is often confused with CRS. Constriction rings with or without edema are not present. The digital or toe hypoplasia-aplasia usually contains diminutive nails or nail folds".

Classification
The constriction ring syndrome is a complex collection of asymmetric congenital anomalies, in which no two cases are exactly alike. This is why a classification is difficult to make.
The most widely used classification system was proposed by Patterson. This classification system is based on the severity of the syndrome and is useful because, the different types require different treatments. Other clinicians have amended this scheme by separating the depth of the ring into mild, moderate, severe, and amputation and by further defining the presence or absence of lymphedema or soft tissue loss distal to the ring. Expanding over subdivision in depth of the clefts for every classification is not necessary because the principles of treatment and technique for correction are the same.There are four categories:

simple constriction rings
constriction rings associated with deformity of the distal part with or without lymphedema
constriction rings associated with acrosyndactyly
uterine amputationPatterson divided the constriction ring associated with acrosyndactyly into three types:

Type I: conjoined fingertips with well-formed webs of the proper depth
Type II: the tips of the digits are joined, but web formation is not complete
Type III: joined tips, sinus tracts between digits and absent websPatterson IThere are simple constriction rings which are strands most commonly around the distal extremities as fingers and toes. In general, the thumb is not likely to be affected by a constriction ring because the fetus typically holds the thumb in tight adduction flexion, making entanglement with strands less likely. These malformations need to be surgically removed which must be executed in different stages and can done by different techniques (see also treatment).

Patterson IIThe CRS involves strands which obstruct the lymphatic vessels and thus causing fluid retention, distal of the affected extremity. This utters itself with swollen parts distal of the constriction.

Patterson IIIIn this form there is a complex form of syndactyly named acrosyndactyly, the fingers (or toes) were initially separated but due to the constriction they are formed back together. Sometimes multiple fingers can be involved. The distal fusion between digits or toes never initially involves a skeletal coalition. The digits are usually hypoplastic if multiple digits are involved. When the constriction cuts off the blood supply to the fingers, the fingers can form a peak with the most palmar digit being the index finger. Normal neurovascular bundles are not present in the distal parts. Hands with fused fingers need to be released in phases to preserve the distal blood supply.

Paterson IVOne of the most severe consequence of constriction strains is probably intrauterine amputations, this is where the constriction goes as deep as the bone and cuts off the blood supply of the proximal extremity. The result will be that the developing toe or finger will become ischemic and fall off. Because the result is a transverse amputation that cuts off the vascular supply to the developing extremity, the actual constriction ring is not seen.
This can result in different outcomes:

complete resorption; this is the most common form of amputation. In this form the amputated digit is completely resorbed during intrauterine development and therefore the amputated digit cant be found.
recovery of the digit; the digit is recovered with the placenta during delivery.
engraftment elsewhere; the amputated digit can be, in rare cases, engrafted somewhere on the fetus.Intrauterine deathIn extremely rare cases a strain can form around the umbilical cord and cut off the blood supply to the fetus which will result in intrauterine death.

Malformation associated with constriction ring syndromeThe percentage of associated anomalies varies from 40% to as high as 80%
Constriction ring deformities are as common on the lower extremity as on the upper, almost all of these involve the musculoskeletal system, with clubbed feet being the most common in up to 30% of reported cases.
Large reported series reveal an incidence between 5% and 15% of craniofacial malformations with clefting of the lip or palate.

Prevention
Amniotic band syndrome is considered an accidental event and it does not appear to be genetic or hereditary, so the likelihood of it occurring in another pregnancy is remote. The cause of amnion tearing is unknown and as such there are no known preventative measures.

Treatment
Surgical correction is recommended when a constriction ring results in a limb contour deformity, with or without lymphedema.

Surgical technique
At the beginning of the surgery a tourniquet will be applied to the limb. A tourniquet compresses and controls local arterial and venous circulation for about 2 hours. The constriction band must be dissected very carefully to avoid damaging the underlying neurovasculature. When the constriction band is excised, there will be a direct closure. This allows the fatty tissue to naturally reposition itself under the skin."With complete circumferential constriction bands, it is recommended that a two-stage correction approach be used. At the first operation, one-half of the circumference is excised and the other one-half can be excised after three to six months. This will avoid any problems to the distal circulation in the limb, which may already be compromised. Lymphedema, when present, will significantly improve within a few weeks of the first surgery."For the direct closure of the defect after dissecting a constriction band there are two techniques:

Triangular flaps; For this technique the circumference between the two borders must be measured. Depending on the difference the number of triangular flaps can be decided. With a triangular flap you can create more skin.
Z-plasty or W-plasty; "Z-plasty is a plastic surgery technique that is used to improve the functional and cosmetic appearance of scars. It can elongate a contracted scar or rotate the scar tension line. The middle line of the Z-shaped incision (the central element) is made along the line of greatest tension or contraction, and triangular flaps are raised on opposite sides of the two ends and then transposed."In rare cases, if diagnosed in utero, fetal surgery may be considered to save a limb that is in danger of amputation or other deformity. This operation has been successfully performed on fetuses as young as 22 weeks. The Melbournes Monash Medical Centre in Australia, as well as multiple facilities in the United States of America, have performed successful amniotic band release surgery.

Reconstructions and prosthetics
Treatment usually occurs after birth and where plastic and reconstructive surgery is considered to treat the resulting deformity. Plastic surgery ranges from simple to complex depending on the extent of the deformity. Physical and occupational therapy may be needed long term.Prosthetics may help some people with ABS to live more functional lives. The price and complexity of these prosthetics vary dramatically, but advances in 3-D printing have helped to increase the availability of artificial fingers while reducing their cost of production.

Prognosis
The prognosis depends on the location and severity of the constricting bands. Every case is different and multiple bands may be entangled around the fetus.
Bands which wrap around fingers and toes can result in syndactyly or amputations of the digits. In other instances, bands can wrap around limbs causing restriction of movement resulting in clubbed feet. In more severe cases, the bands can constrict the limb causing decreased blood supply and amputation. Amniotic bands can also sometimes attach to the face or neck causing deformities such as cleft lip and palate. If the bands become wrapped around the head or umbilical cord it can be life-threatening for the fetus.
The number of cases of miscarriage that can be attributed to ABS is unknown, although it has been reported that it may be the cause of 178 in 10,000 miscarriages. Up to 50% of cases have other congenital anomalies including cleft lip, cleft palate, and clubfoot deformity. Hand and finger anomalies occur in up to 80%.

Epidemiology
The reported incidence of constriction ring syndrome varies from 1/1200 and 1/15000 live births. The prevalence is equally in male and female.Fetomaternal factors like prematurity, maternal illness, low birth weight, and maternal drug exposure are predisposing factors for the constriction ring syndrome.No positive relationship between CRS and genetic inheritance has been reported.

Society
Notable people living with ABS include:

Sophie Wells, British member Paralympics dressage team
Gina Casillas, US volleyball player
Ian T. Jamison, US artist
Anna Johannes, US Paralympic swimmer
Jean-Jacques Machado, 7th degree red-and-black belt in Brazilian Jiu-Jitsu
Monica Price, a case study of a young woman born with amniotic band syndrome
Kingsley McGowan, U.S. Mens Rugby Player
Troy Fumagalli, University of Wisconsin Football Player (2017 Cotton Bowl Offensive MVP)
Lyric Mariah Heard U.S. model
Shaquem Griffin, Miami Dolphins Football Player (2016 AAC Defensive Player of the Year)
Jennifer Bricker, acrobat and aerialist
Sarah Herron, The Bachelor Season 17 contestant, Bachelor in Paradise Seasons 1 and 3 contestant, founder of "She Lift" for girls with disabilities.
Victoria Canal, Cuban-American singer and songwriter

See also
List of skin conditions
Ainhum, auto-amputation of the fifth toe in adults

References
Further reading
Walter JH, Goss LR, Lazzara AT (1998). "Amniotic band 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 Pneumatosis and can you explain it in depth? [/INST] Pneumatosis is the abnormal presence of air or other gas within tissues.In the lungs, emphysema involves enlargement of the distal airspaces, and is a major feature of chronic obstructive pulmonary disease (COPD). Other pneumatoses in the lungs are focal (localized) blebs and bullae, pulmonary cysts and cavities.
Pneumoperitoneum (or peritoneal emphysema) is air or gas in the abdominal cavity, and is most commonly caused by gastrointestinal perforation, often the result of surgery.
Pneumarthrosis, the presence of air in a joint, is rarely a serious sign.

Lung cysts
A lung cyst, or pulmonary cyst, encloses a small volume of air,  and has a wall thickness of up to 4 mm. A minimum wall thickness of 1 mm has been suggested, but thin-walled pockets may be included in the definition as well </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Mixed receptive-expressive language disorder and can you explain it in depth? [/INST] Mixed receptive-expressive language disorder (DSM-IV 315.32) is a communication disorder in which both the receptive and expressive areas of communication may be affected in any degree, from mild to severe. Children with this disorder have difficulty understanding words and sentences. This impairment is classified by deficiencies in expressive and receptive language development that is not attributed to sensory deficits, nonverbal intellectual deficits, a neurological condition, environmental deprivation or psychiatric impairments. Research illustrates that 2% to 4% of five year olds have mixed receptive-expressive language disorder. This distinction is made when children have issues in expressive language skills, the production of language, and when children also have issues in receptive language skills, the understanding of language. Those with mixed receptive-language disorder have a normal left-right anatomical asymmetry of the planum temporale and parietale. This is attributed to a reduced left hemisphere functional specialization for language. Taken from a measure of cerebral blood flow (SPECT) in phonemic discrimination tasks, children with mixed receptive-expressive language disorder do not exhibit the expected predominant left hemisphere activation. Mixed receptive-expressive language disorder is also known as receptive-expressive language impairment (RELI) or receptive language disorder.

Classification
If assessed on the Wechsler Adult Intelligence Scale, for instance, symptoms of mixed receptive-expressive language disorder may show as relatively low scores for Information, Vocabulary and Comprehension (perhaps below the 25th percentile). If a person has difficulty with specific types of concepts, for example spatial terms, such as over, under, here and there, they may also have difficulties with arithmetic, understanding word problems and instructions, or difficulties using words at all.
They may also have a more general problem with words or sentences, both comprehension and orally. Some children will have issues with pragmatics – the use of language in social contexts as well; and therefore, will have difficulty with inferring meaning. Furthermore, they have severe impairment of spontaneous language production and for this reason, they have difficulty in formulating questions. Generally, children will have trouble with morphosyntax, which is word inflections. These children have difficulty understanding and applying grammatical rules, such as endings that mark verb tenses (e.g. -ed), third-person singular verbs (e.g. I think, he thinks), plurals (e.g. -s), auxiliary verbs that denote tenses (e.g. was running, is running), and with determiners (the, a). Moreover, children with mixed receptive-expressive language disorders have deficits in completing two cognitive operations at the same time and learning new words or morphemes under time pressure or when processing demands are high. These children also have auditory processing deficits in which they process auditory information at a slower rate and as a result, require more time for processing.

Presentation
Related disorders
Studies show that low receptive and expressive language at young ages was correlated to increased autism symptom severity in children in their early school years. Below is a chart depicting language deficits of children on the autistic spectrum. This table indicates the lower levels of language processing, receptive/expressive disorders, which is more severe in children with autism </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 Dicheirus 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 Communication disorder and can you explain it in depth? [/INST] A communication disorder is any disorder that affects an individuals ability to comprehend, detect, or apply language and speech to engage in dialogue effectively with others.  The delays and disorders can range from simple sound substitution to the inability to understand or use ones native language.

Diagnosis
Disorders and tendencies included and excluded under the category of communication disorders may vary by source.  For example, the definitions offered by the American Speech–Language–Hearing Association differ from those of the Diagnostic Statistical Manual 4th edition (DSM-IV).Gleanson (2001) defines a communication disorder as a speech and language disorder which refers to problems in communication and in related areas such as oral motor function. The delays and disorders can range from simple sound substitution to the inability to understand or use ones native language. In general, communication disorders commonly refer to problems in speech (comprehension and/or expression) that significantly interfere with an individuals achievement and/or quality of life.  Knowing the operational definition of the agency performing an assessment or giving a diagnosis may help.Persons who speak more than one language or are considered to have an accent in their location of residence do not have a speech disorder if they are speaking in a manner consistent with their home environment or that is a blending of their home and foreign environment.

DSM-IV
According to the DSM-IV-TR, communication disorders are usually first diagnosed in childhood or adolescence, though they are not limited as childhood disorders and may persist into adulthood.  They may also occur with other disorders.
Diagnosis involves testing and evaluation during which it is determined if the scores/performance are "substantially below" developmental expectations and if they "significantly" interfere with academic achievement, social interactions, and daily living.  This assessment may also determine if the characteristic is deviant or delayed.  Therefore, it may be possible for an individual to have communication challenges but not meet the criteria of being "substantially below" criteria of the DSM IV-TR.
The DSM diagnoses do not comprise a complete list of all communication disorders, for example, auditory processing disorder is not classified under the DSM or ICD-10.
The following diagnoses are included as communication disorders:

Expressive language disorder – characterized by difficulty expressing oneself beyond simple sentences and a limited vocabulary. Individuals can better understand than use language; they may have a lot to say, but have more difficulty organizing and retrieving the words than expected for their developmental stage.
Mixed receptive-expressive language disorder – problems comprehending the commands of others.
Stuttering – a speech disorder characterized by a break in fluency, where sounds, syllables, or words may be repeated or prolonged.
Phonological disorder – a speech sound disorder characterized by problems in making patterns of sound errors (e.g., "dat" for "that").
Communication disorder NOS (not otherwise specified) – the DSM-IV diagnosis in which disorders that do not meet the specific criteria for the disorder listed above may be classified.

DSM-5
The DSM-5 diagnoses for communication disorders completely rework the ones stated above. The diagnoses are made more general in order to capture the various aspects of communications disorders in a way that emphasizes their childhood onset and differentiate these communications disorders from those associated with other disorders (e.g. autism spectrum disorders).
Language disorder – the important characteristics of a language disorder are difficulties in learning and using language, which is caused by problems with vocabulary, with grammar, and with putting sentences together in a proper manner. Problems can both be receptive (understanding language) and expressive (producing language).
Speech sound disorder – previously called phonological disorder, for those with problems with pronunciation and articulation of their native language.
Childhood-Onset Fluency Disorder (Stuttering) - standard fluency and rhythm of speech is interrupted, often causing the repetition of whole words and syllables. May also include the prolongation of words and syllables; pauses within a word; and/or the avoidance of pronouncing difficult words and replacing them with easier words that the individual is better able to pronounce. This disorder causes many communication problems for the individual and may interfere with social communication and performance in work and/or school settings where communication is essential.
Social (pragmatic) communication disorder – this diagnosis described difficulties in the social uses of verbal and nonverbal communication in naturalistic contexts, which affects the development of social relationships and dialogue comprehension. The difference between this diagnosis and autism spectrum disorder is that in the latter there is also a restricted or repetitive pattern of behavior.
Unspecified communication disorder – for those who have symptoms of a communication disorder but who do not meet all criteria, and whose symptoms cause distress or impairment.

Examples
Examples of disorders that may include or create challenges in language and communication and/or may co-occur with the above disorders:

autism spectrum disorders - autistic disorder, pervasive developmental disorder not otherwise specified (PDDNOS), and Asperger disorder – developmental disorders that affect the brains normal development of social and communication skills.
expressive language disorder – affects speaking and understanding where there is no delay in non-verbal intelligence.
mixed receptive-expressive language disorder – affects speaking, understanding, reading and writing where there is no delay in non-verbal intelligence.
specific language impairment – a language disorder that delays the mastery of language skills in children who have no hearing loss or other developmental delays. SLI is also called developmental language disorder, language delay, or developmental dysphasia.

Sensory impairments
Blindness – A link between communication skills and visual impairment with children who are blind is currently being investigated.
Deafness/frequent ear infections – Trouble with hearing during language acquisition may lead to spoken language problems.  Children with frequent ear infections may temporarily develop problems pronouncing words correctly. Some of the above communication disorders can occur with people who use sign language.  The inability to hear is not in itself a communication disorder.

Aphasia
Aphasia is loss of the ability to produce or comprehend language. There are acute aphasias which result from stroke or brain injury, and primary progressive aphasias caused by progressive illnesses such as dementia.

Acute aphasias
Expressive aphasia also known as Brocas aphasia, expressive aphasia is a non-fluent aphasia that is characterized by damage to the frontal lobe region of the brain. A person with expressive aphasia usually speaks in short sentences that make sense but take great effort to produce. Also, a person with expressive aphasia understands another persons speech but has trouble responding quickly.
Receptive aphasia also known as Wernickes aphasia, receptive aphasia is a fluent aphasia that is categorized by damage to the temporal lobe region of the brain. A person with receptive aphasia usually speaks in long sentences that have no meaning or content. People with this type of aphasia often have trouble understanding others speech and generally do not realize that they are not making any sense.
Conduction aphasia
Anomic aphasia
Global aphasia
Primary progressive aphasias
Progressive nonfluent aphasia
Semantic dementia
Logopenic progressive aphasia

Learning disability
Dyscalculia – an impairment in the systems used in communicating numbers
Dyslexia – an impairment in systems used in reading
Dysgraphia – an impairment in the systems used in writing

Speech disorders
cluttering - a syndrome characterized by a speech delivery rate which is either abnormally fast, irregular, or both.
dysarthria - a condition that occurs when problems with the muscles that helps a person to talk make it difficult to pronounce words.
esophageal voice - involves the patient injecting or swallowing air into the esophagus. Usually learnt and used by patients who cannot use their larynges to speak. Once the patient has forced the air into their esophagus, the air vibrates a muscle and creates esophageal voice. Esophageal voice tends to be difficult to learn and patients are often only able to talk in short phrases with a quiet voice.
lisp - a speech impairment that is also known as sigmatism.
speech sound disorder - Speech-sound disorders (SSD) involve impairments in speech-sound production and range from mild articulation issues involving a limited number of speech sounds to more severe phonologic disorders involving multiple errors in speech-sound production and reduced intelligibility.
stuttering - a speech disorder in which sounds, syllables, or words are repeated or last longer than normal. These problems cause a break in the flow of speech (called disfluency).

See also
References
Further reading
Cherney LR, Gardner P, Logemann JA,  et al. (2010). "The role of speech-language pathology and audiology in the optimal management of the service member returning from Iraq or Afghanistan with a blast-related head injury: position of the Communication Sciences and Disorders Clinical Trials Research Group". J Head Trauma Rehabil </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 access steal syndrome and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Dhat syndrome and can you explain it in depth? [/INST] Dhat syndrome (Sanskrit: धातु दोष, IAST: Dhātu doṣa) is a condition found in the cultures of South Asia (including Pakistan, India, Bangladesh, Nepal, and Sri Lanka) in which male patients report that they suffer from premature ejaculation or impotence, and believe that they are passing semen in their urine. The condition has no known organic cause.In traditional Hindu spirituality, semen is described as a "vital fluid". The discharge of this "vital fluid", either through sex or masturbation, is associated with marked feelings of anxiety and dysphoria. Often the patient describes the loss of a whitish fluid while passing urine. At other times, marked feelings of guilt associated with what the patient assumes is "excessive" masturbation are noted.
Many doctors view dhat as a folk diagnostic term used in South Asia to refer to anxiety and hypochondriacal concerns associated with the discharge of semen, with discoloration of the urine, and feelings of weakness and exhaustion.
Dhat is thought to be a culture-bound syndrome similar to jiryan (South-East Asia), prameha (Sri Lanka), and
shenkui (China). Dhat syndrome might be related to other post-orgasmic diseases, such as post-coital tristesse (PCT), postorgasmic illness syndrome (POIS), and sexual headache.

Signs and symptoms
Young males are most often affected, though similar symptoms have been reported in females with excessive vaginal discharge or leucorrhea, which is also considered a "vital fluid". In addition, there are symptoms of fatigue and weakness. Patients with Dhat condition most normally ascribe their semen misfortune (secretion of semen in urine) to reasons like inordinate masturbation, sensual dreams, and unreasonable sexual longing. Nocturnal emission and secretion of semen in urine are considered to be the most widely recognized symptoms of semen misfortune. Patients with Dhat condition frequently dread the result of semen misfortune and regularly have the conviction that it will lead to decrease in sexual performance. The most widely recognized side effects in patients with Dhat condition are shortcoming of the body, sluggishness, low energy, and low temperament. Premature ejaculation and impotence are commonly seen. Other somatic symptoms like weakness, easy fatiguability, palpitations, insomnia, low mood, guilt and anxiety are often present. Males sometimes report a subjective feeling that their penises have shortened. These symptoms are usually associated with an anxious and dysphoric mood state. Another sign of this syndrome is white discharge. According to Ayurvedic, an Indian medical system, men who have experienced this have shown signs of anxiety issues. This disease is a culture bound syndrome. Semen loss is generally viewed as taboo and harmful. It is also associated with a lower socioeconomic class. Being able to produce semen is viewed as longevity of ones health and certain powers. In Indian culture, it is important for a man to produce semen.

Treatment
Cognitive behavioral therapy is the mainstay of treatment </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 Follicular cyst of ovary 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 Polioencephalitis and can you explain it in depth? [/INST] Polioencephalitis is a viral infection of the brain, causing inflammation within the grey matter of the brain stem.  The virus has an affinity for neuronal cell bodies and has been found to affect mostly the midbrain, pons, medulla and cerebellum of most infected patients.  The infection can reach up through the thalamus and hypothalamus and possibly reach the cerebral hemispheres.  The infection is caused by the poliomyelitis virus which is a single-stranded, positive sense RNA virus surrounded by a non-enveloped capsid.  Humans are the only known natural hosts of this virus.  The disease has been eliminated from the U.S. since the mid-twentieth century, but is still found in certain areas of the world such as Africa.

Signs and symptoms
Signs and symptoms may vary and some individuals may not experience any symptoms at all.  The most common reported symptom of polioencephalitis is fatigue. Fatigue is associated with difficulty in attention, cognition, and maintaining wakefulness Some individuals experience psychiatric symptoms that include anxious mood, pain, insomnia, and depressed mood.  Confusion and disorientation of time and space have also been reported.  Motor symptoms vary more from patient to patient, but can include incoordination and tremors, nystagmus, loss of conjugate eye movements, rigidity and hemiparesis.

Mechanism
The poliomyelitis virus is an enterovirus that enters through the mouth and multiplies in the throat and epithelial cells of the gastrointestinal tract.  It will then move to the bloodstream and is carried to the central nervous system.  Once in the CNS, the virus will attach to a host cell by binding with a cell surface receptor.  The host cell surface receptor is a glycoprotein that has been recently identified as CD155.  Once the virus has bound to the host cell, it will penetrate the host cell membrane and begin the replication of its genome.  Many cells contain the surface receptor CD155; however, manifestation of this disease does not occur in all cells.  The reason for incidence of the disease in only certain areas of the brain such as the brainstem is unknown.  Once areas of the brain have been invaded by the virus, inflammation will occur.  During inflammation, the brain’s tissues become swollen due to the body’s immune system response to the infection.  Fluid, white blood cells, dead cellular debris and inactivated viruses resulting from the actions of the immune response can significantly alter the fluid surrounding healthy neurons.  The function of these healthy neurons can decline due to disruptions in the cell membrane affecting electrical properties of the neuron or by interfering with the blood supply causing anoxic cellular damage.  Depending on which neurons are damaged will result in a variety of different symptoms.

Diagnosis
If someone is suspected of having polioencephalitis a sample of throat secretions, stool or cerebrospinal fluid is checked for the virus.  Blood tests can be done to detect antibodies against viral antigens and foreign proteins.  Virus isolation is the most sensitive method and it is most likely to be isolated from stool samples.  Once isolated, RT-PCR is used to differentiate naturally occurring strains from vaccine-like strains.

Prevention
The virus is most often spread by person to person contact with the stool or saliva of the infected person.  Two types of vaccines have been developed to prevent the occurrence and spread of the poliomyelitis virus.  The first is an inactivated, or killed, form of the virus and the second is an attenuated, or weakened, form of the virus.  The development of vaccines has successfully eliminated the disease from the United States.  There are continued vaccination efforts in the U.S. to maintain this success rate as this disease still occurs in some areas of the world.

Treatment
There is no cure for polioencephalitis so prevention is essential.  Many people that become infected will not develop symptoms and their prognosis is excellent. However, the prognosis is dependent on the amount of cellular damage done by the virus and the area of the brain affected.  Many people that develop more severe symptoms can have lifelong disabilities or it can lead to death </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 Pathological jealousy and can you explain it in depth? [/INST] Pathological jealousy, also known as morbid jealousy, Othello syndrome or delusional jealousy, is a psychological disorder in which a person is preoccupied with the thought that their spouse or sexual partner is being unfaithful without having any real proof, along with socially unacceptable or abnormal behaviour related to these thoughts. The most common cited forms of psychopathology in morbid jealousy are delusions and obsessions. It is considered a subtype of delusional disorder.Overvaluing an idea, which is defined as “an acceptable, comprehensible idea pursued by the patient beyond the bounds of reason. The idea is not resisted and, although it is not a delusion, the patient characteristically attaches utmost importance to investigating and maintaining the partner’s fidelity at great personal disadvantage and to the distress of the partner”. Overvalued ideas are characterized by being existent in the individuals own thoughts, being egosyntonic; meaning that the ideas project the behaviors, values, and feelings that are aligned with the desires and aims of the individuals ego, or consistent with the individuals ideal self-image, the ideas are also amenable to reason but are not resisted.

Definition
This disorder occurs when a person typically makes repeated accusations that their spouse or sexual partner is being unfaithful, based on insignificant, minimal, or no evidence, often citing seemingly normal or everyday events or material to back up their claims.
Unlike other delusional disorders, people who suffer from this disorder have a strong association with stalking, cyberstalking, sabotage, or even violence. It can be found in the context of schizophrenia and delusional disorder, such as bipolar disorder, but is also associated with alcoholism and sexual dysfunction and has been reported after neurological illness (i.e. Parkinsons).
The name "Othello Syndrome" comes from the character in Shakespeares play Othello, who murders his wife as a result of a false belief that she has been unfaithful. Recently, some psychologists and psychiatrists have asserted that Othello was deceived rather than deluded about Desdemonas alleged infidelity and thus did not have ‘the Othello Syndrome’.

Psychiatric history
Presenting difficulties: neurotic or psychotic jealousy
Past psychiatric history: neurotic or psychotic disorders, deliberate self-harm and attempted suicide
Family history: mental illness including pathological jealousy
Relationship history: incorporating both the current and previous relationship and taking account of the quality of the relationships and the difficulties experienced
Forensic history: previous and pending charges and convictions as well as deviant behavior which was not reported or did not result in a charge or conviction (including aggressive behavior and stalking)
Medical history: organic causes which may be responsible for the morbid jealousy (i.e. Parkinsons)

Forms
Obsessions: the individuals own thoughts are egodystonic; they are acknowledged to be senseless, and usually resisted. Jealous thoughts are experienced as intrusive and excessive, and compulsive behavior such as checking up on their partner may follow.  Egodystonicity (the distress caused by thoughts that are unwanted and viewed as contrary to conscious wishes) generally varies a large amount between patients and “a continuum from obsessional to delusional, which morbid jealousy has been suggested” (Insel & Akiskal 1986).
Extreme obsessions: much time is taken up by jealous concerns, and there is a great difficulty in putting the concerns out of the mind. Impairment of the relationship, limitation of the partners freedom and checking on the partners behavior may occur. Although a distinction was occasionally difficult to make, the categories of ‘psychotic’ (delusional) and ‘neurotic’ jealousy contained similar proportions (each between one-third and one-half).
Delusions: the individuals own thoughts are egosyntonic; they are regarded as true, and not resisted. Some authors compare morbid jealousy to a delusional state (e.g. Enoch & Trethowan, 1979). Beliefs may include the morbidly jealous subjects suspicion that: 1. he or she is being poisoned or given some substance(s) to decrease sexual potency by the partner, 2. that the partner has contracted a sexually transmitted disease from a third party 3. is engaging in sexual intercourse with a third party while the subject sleeps.

Causes
Psychological
There are many psychological causes that go along with morbid jealousy. Some people equate morbid jealousy with a delusional state. “Delusions of infidelity exist without any other psychopathology and may be considered to be morbid jealousy in its ‘purest’ form” (Kingham and Gordon). For morbid jealousy to occur ones memories are subconsciously changed and their partners actions are misinterpreted as well to the extent that the person is absolutely convinced of betrayal from the partner. It is thought that even some brain disorders might eventually lead to delusions of betrayal. It has also been recorded by Cobb (1979) “that morbid jealousy may be present with all types of cerebral insult or injury.” "It has been suggested that morbid jealousy may potentially arise in response to reduced sexual function”. Cobb (1979) drew attention to the elderly man whose waning sexual powers were insufficient to satisfy a younger wife.
Mullen (1990) considered morbid jealousy to be associated with four features:
An underlying mental disorder emerges before or with the jealousy
The features of the underlying disorder coexist with the jealousy
The course of morbid jealousy closely relates to that of the underlying disorder
The jealousy has no basis in reality

Personality
People who are very insecure, or even fearful, are more likely to become anxious, or question their partners commitment to them. “Insecure attachment style correlates strongly with borderline personality disorder” (Kingham and Gordon).

Environmental
Some people even believe that someone who is morbidly jealous might suspect that he or she is being drugged or given some kind of substance that might decrease their sexual potency, or they might even be under the impression that their significant other has somehow received a sexually transmitted disease from another person while the subject is unaware.

Epidemiology
There is no known prevalence of morbid jealousy; currently there is no community survey tracking its existence in individuals. As of late, it is considered to be a rare occurrence. Still, many counselors encounter cases of morbid jealousy. Some clinicians may never be able to treat this condition due to other dominating psychopathologies present within the jealous person that call for more attention.
Men and women differ dramatically when it comes to morbid jealousy. Men who suffer from morbid jealousy are more likely than women to use violence and also are more likely to harm or kill with their hands rather than a blunt object. Women on the other hand, when using violence, tend to use a blunt object or knife. Men focus on the rivals status and resources when it comes to the threat of jealousy they fear. Women tend to become more jealous of a potential threat on their rivals youth and physical attractiveness.

Triggers
For men the strongest trigger is sexual infidelity and with women the strongest trigger is emotional infidelity. If partner-related violence does not stop infidelity from happening, the male mate will sometimes resort to suicide instead. The final resort to stopping infidelity inside of morbid jealousy is to commit partner murder. Women are much less likely to kill their partner, unless it is in self-defense. Morbid jealousy can occur in a number of conditions such as chronic alcoholism, addiction to substances other than alcohol (i.e. cocaine, amphetamines, marijuana.), organic brain disorders (i.e. Parkinsons, Huntingtons), schizophrenia, neurosis, affective disturbances or personality disorders.

Associated drug and alcohol use
Alcohol and drug misuse has a well-recognized association with morbid jealousy. “In two studies, morbid jealousy was present in 27% and 34% respectively of men recruited from alcohol treatment services” (Shrestha et al., 1985; Michael et al., 1995). Amphetamine and cocaine increase the possibility of a delusion of infidelity that can continue after intoxication stops. (Shepherd, 1961).

Assessment
In an attempt to counsel or treat the morbid jealousy of an individual, proper and thorough assessment must be employed. This approach is broad in nature, but necessary so as to provide adequate information that will aid in the possible reparation of a dynamic containing a morbidly jealous person. To begin, a careful history should be taken of both partners if possible; separate and together. It is imperative that a full and detailed psychiatric history and mental state examination be recorded for the jealous partner; doing so may enable one to distinguish whether the jealousy is obsessional or delusional in nature. It is also possible that the jealousy may be the result of a thought that has been given too much importance. Considering that jealousy is a very delicate issue, any reference made to it should be approached carefully and with tact. It must be kept in mind that the jealous individual may be displacing blame for their issues onto their partner and their alleged infidelity as opposed to their own behavior. If there is any history of relevant or related mental illness and substance misuse it should be noted as it may possibly be a contributing or aiding factor. In order to get the best grasp on the issues and begin positive progression, multiple interviews should be held to assess the marital relationship.After completing the assessment, it is best to deliver information about risk with both individuals in the relationship. Due to confidentiality, the patient should give consent for this information to be shared unless there is a risk to another individual and it is serious and immediate. This is the only case in which confidentiality is invalid. The professional should ensure that all necessary steps are taken to guarantee the safety of a potential victim, keeping in mind that it is possible that authorities may have to be alerted regarding the matter. If the professional has reason to believe that there is a high risk of harm to themselves or another person, the individual who is morbidly jealous should be admitted to hospital as soon as possible to prevent any negative outcomes for any parties involved.

Management
Morbid jealousy encompasses various psychiatric states and the best way to approach treatment depends on the symptoms that are observed in the individual. Therefore, prognosis and outcomes vary from person to person and depends on the situation and the complexities of the interpersonal relationships being observed. Also, other issues that may exacerbate the negative aspects of the environment created by jealous behavior need to be addressed in order to begin reparations. For example, if alcoholism plays a role in the behavior of the morbidly jealous individual, treatment of their addiction can positively affect their progress in trying to change their jealous nature. While psychotherapy can be an effective method of treating morbidly jealous persons, it is not sufficient when the nature of their illness is more serious. It is not possible to say that there is one form of treatment that is superior over all those that are currently available.  Even though this may be true, cognitive behavioral therapy is the treatment that has proven to be most effective.Medical

Treatment of the primary psychiatric condition
Antipsychotic medication
Antidepressant medicationPsychological

Psycho education for the affected person and the partner
Behavioral therapy
Cognitive therapy
Individual psychotherapy
Insight oriented psychotherapies
Family therapy
Couple therapySocial

Geographical separation of the partners
Social work involvement for child protection issues
Alcohol and substance misuse treatment

Risks associated
Confirmatory behaviors
When suspicions of the partners fidelity arise, they quickly become all that is thought about. Certain behaviors, such as interrogation of the partner, repeated telephone calls to work and surprise visits, stalking behavior, setting up recording devices in the home or work, or hiring a private detective to follow the partner, are all common in trying to determine if there is truly infidelity or if it is just perceived. Individuals that are jealous may take drastic measures, such as searching the partners clothing and belongings, look through diaries and other communication methods (email, text messaging), or examining bed sheets, undergarments and even genitalia for evidence of sexual activity.

Harm to self
Suicidal thoughts are common in morbid jealousy, especially because of its association with depression and substance abuse.

Risk to others
Violence can occur in any relationship tainted with jealousy, either normal or morbid jealousy. In a recent study of jealousy by Mullen & Martin in 1994, 15% of both men and women reported that at some time they had been “subjected to physical violence at the hands of a jealous partner.” Culturally, jealousy may be even used to “justify violence towards partners.” Victims in a homicide case are most likely to be current or ex-partners in both female and male perpetrators.
When a partner repeatedly denies infidelity, this may provoke anger and extreme violence. On the other hand, the partner that is suffering may give up and give a false confession, which in turn most likely will provoke rage in the jealous individual. In the U.S. a sample was taken of 20 participants with delusional jealousy. 19 were male and Silva (1998) found that 13 had threatened to kill their spouse because of their perceived infidelity. Of the 13 males, nine actually attacked their spouse. Out of the 20, a weapon was used by three of them, and 12 had harmed their spouse.
A presence of paranoid delusions and hallucinations of injury to the spouse were most often associated with violence. This suggests that individuals that suffer from delusional jealousy that partake in violence may be solely driven by psychotic phenomena. A higher risk of assault was associated with alcohol consumption.

Risk to children
Children that live in a household with a parent that suffers from morbid jealousy may suffer emotional and/or physical abuse as a direct result of the actions made by the parent. Children may also accidentally overhear arguments or witness physical violence between their parents. They could even be potentially accidentally injured during assaults. The morbidly jealous parent may employ a child or more than one to spy on the other parent. It is not out of the question for a child to witness a homicide or suicide where their parent is the victim.

See also
References
Sources
Enoch, D. & Ball, H. (2001) The Othello Syndrome. In Enoch, D. & Ball, H. Uncommon psychiatric syndromes (fourth edition) pp50–73.  London: Arnold. ISBN 0-340-76388-4

Further reading
Easton, J.A.; Shackelford, T.K.; Schipper, L.D. (2008). "Delusional Disorder--Jealous Type: How Inclusive are the DSM-IV Diagnostic Criteria?" (PDF). Journal of Clinical Psychology. 64 (3): 264–275. doi:10.1002/jclp.20442 </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 Traumatic spondylopathy 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 Spinocerebellar ataxia type 1 and can you explain it in depth? [/INST] Spinocerebellar ataxia type 1 (SCA1) is a rare autosomal dominant disorder, which, like other spinocerebellar ataxias, is characterized by neurological symptoms including dysarthria, hypermetric saccades, and ataxia of gait and stance. This cerebellar dysfunction is progressive and permanent. First onset of symptoms is normally between 30 and 40 years of age, though juvenile onset can occur. Death typically occurs within 10 to 30 years from onset.
SCA1 is typically inherited from the parents in an autosomal dominant regime; the children of a person with the disease have a 50% chance of inheriting it themselves, and new mutations can occur in some cases. It is caused by an expanded number of trinucleotide repeats in the polyglutamine tract of the ATXN1 gene, which encodes the ataxin 1 protein. This expansion results in a larger than normal number of repeats of the nucleotide sequence cytosine, adenine, guanine, or CAG, in the gene which, in turn, results in a larger than normal number of consecutive glutamine amino acid residues in the protein. This mutant protein causes degradation in certain types of neurons, like Purkinje neurons, which are common in the cerebellum, spinal cord, and related parts of the brain. While the mechanism is not fully understood, it is suspected that changes in the interactions between ataxin 1 and other proteins result in a toxic gain of function.
The mutation can be detected before or after the onset of symptoms by genetic testing. Currently, no cure for SCA1 is known, so treatment of the disease focuses primarily on management of symptoms to maintain quality of life, focusing on physical therapy to retrain and replace lost functions. Research to develop treatments is ongoing and in addition to conventional pharmaceutical treatment, SCA1 has been the subject of research into more advanced treatment options such as gene therapy and stem cell therapy. Worldwide, an expected 1 to 2 people in 100,000 have spinocerebellar ataxia type 1, however, the prevalence varies between populations and is often linked to the founders effect.
Ataxia as a symptom has been known since the mid 19th century and the heterogeneous group of diseases now known as spinocerebellar ataxias was the subject of extensive research in the latter part of that century. Advances in molecular genetics in the 20th century allowed distinct causes of these diseases to be identified. In the early 1990s the gene causing SCA1 was localized to the human leukocyte antigen complex on chromosome 6 and by 1993, ataxin 1 was identified as the causative gene. It was the first spinocerebellar ataxia-causing gene to be localized and identified.

Signs and symptoms
Ataxia refers to a lack of coordinated muscle movements that include gait abnormality and is the cerebellar sign that typifies all spinocerebellar ataxia (SCA) types, though individuals with SCA1 also develop pyramidal and bulbar signs as the disease progresses. The average age of onset is between 30 and 40 years of age, though exceptions exist. From the first symptoms, duration is typically between one and three decades, where earlier onset correlates with faster progression.Spinocerebellar ataxia 1, like other SCAs, often causes dysarthria, a motor disorder of speech often manifest as slurring of words; pathological nystagmus, a disorder in which eyes drift involuntarily affecting vision; and gait and balance issues. SCA1 is also commonly present with dysphagia, a swallowing disorder that can cause choking while eating and drinking; and hypermetric saccades, where the eye tends to move faster or further than intended as it tracks an object or moves from one focus to another. As the disease progresses, more severe neurologic symptoms can appear like dysmetria, where limb movements consistently overshoot the desired position; dysdiadochokinesia, where repeated body movements become uncoordinated; or hypotonia, where muscles atrophy. While new symptoms appear as SCA1 progresses,  nystagmus may disappear as eye movements and saccades slow down. Fatality may ultimately be caused by loss of bulbar functions, but complications from symptoms, such as pneumonia from swallowing problems, or trauma from falls, can be fatal as well. The severity and exact phenotype of these symptoms may vary between types of SCA. SCA 1 dysarthria may vary in severity depending on the task and is often associated with more strained, strangled or harsh sounding vocalization than that of other disorders.Because of the significant variance between cases of SCA1, typical signs and symptoms may appear alongside more subtle or rare symptoms. Maculopathy has been reported in rare cases, and may be linked effects from the mutation on the ATXN1 locus on genes in neighboring loci. Task specific dystonias have been reported in individual cases, often in the form of writers cramps or cervical dystonia.SCAs can also be detected before serious atrophy with electrophysiologic techniques, using electrodes on the scalp to detect changes in electric potential within the brain in response to sensations or movements. Individuals with SCA1 often exhibit abnormal brainstem auditory evoked potential, including prolonged latency and absent or poorly defined waveforms, with one study reporting 73.3% of test subjects exhibiting abnormalities. The same study also found abnormalities in visual evoked potential and median somatosensory evoked potential in some SCA1 persons. These results were similar to those exhibited in other SCAs and differences between the SCAs were not statistically significant, so electrophysiologic techniques cannot replace genetic testing for specific diagnoses of SCAs.All SCAs cause atrophy in various neural tissues that are detectable using magnetic resonance imaging, computed tomography, or other imaging techniques. In SCA1 some degradation in the grey matter of the cerebellum and brain stem can sometimes be detected in presymptomatic individuals with the expansion in ATXN1. Typically, grey matter loss can be observed in cerebellar vermis in all lobules of the cerebellum and in the paramedian portions of both hemispheres. White matter loss can also be observed in the middle cerebellar peduncles. The volume loss can be correlated to severity and duration.An estimated 77% of cases of progressive cerebellar disease are reported to have one or more mental health disorders, and 19% exhibit cognitive disorders. These estimates are consistently higher than the portion with mental health disorders in the general population, but still follow other general patterns, like correlations between depression frequency and sex or age. It is unclear if depression can be linked causally to cerebellar degeneration; one study reports data consistent with depression primarily being a response to the disability, not a symptom of it, while another reports evidence that depression may have a causal link; prevalence of depression varies differently between SCA types than does the rate of progression of disability.

Genetics
Spinocerebellar ataxia type 1 is caused by a mutation in the ATXN1 gene. This mutation is passed down through an autosomal dominant inheritance pattern, meaning that the disease does not skip generations, at least one parent must have the disease for the children to inherit it, and that the odds of any given child inheriting SCA 1, regardless of gender or other phenotypes, is 50% if the affected parent is heterozygous.: 26  The ATXN1 gene on chromosome 6 encodes the ataxin 1 protein, which is used in signaling pathways and gene regulation, and is heavily expressed in Purkinje neurons. The coding region for Ataxin 1 (6p22.3) contains a polyglutamine tract of variable length. SCA1 is present in individuals where the region on at least one copy of chromosome 6 contains 39 or more continuous repeats of glutamine in which more repeats are correlated to earlier onset and faster progression. Histidine interruptions in the polygluatamine tract can mitigate or prevent SCA1.SCA1 is known to exhibit genetic anticipation, where one generation with the disease may exhibit earlier onset and faster progression than the previous generation. This is typically caused by expansions in the polyglutamine tract between generations and is more common in cases of patrilineal inheritance. This non-Mendelian inheritance is similar to that observed in Huntingtons disease and is believed to be caused by differences in various mechanisms in gamete production between the sexes that result in increased mosaicism in the male germline. DNA with CAG repeats are prone to forming secondary structures, including hairpin loops and R-loops, which can result in mutations and mosaicism if DNA repair mechanisms fail. These secondary structures cause somatic mosaicism by lagging DNA polymerase in Okazaki fragments and by disrupting DNA mismatch repair, base excision repair, nucleotide excision repair and double strand break repair mechanisms. The mechanism for germline expansions is not well understood, but it is believed that only mismatch repair pathways effect germline instability and the MSH2 repair protein has been linked to expansions in male gametes in mice models.

Pathophysiology
Normal ataxin 1 is intimately involved in a number of signaling pathways, in protein ubiquitination, RNA metabolism, in transcription regulation, protein transformation, and protein stabilization.: 149–165  Among other interactions, it forms a transcription complex with Retinoid-related Orphan nuclear-receptor transcription factor α (RORα) following interactions with an activator, Histone acetyltransferase KAT5, sometimes referred to as TIP60, and it is in the signaling mediated by metabotropic glutamate receptor 1 (mGluR1). Resonant Recognition Modeling of the ataxin 1 protein has shown possible binding sites for growth factor independent transcription repressor 1 (Gfi-1). The predictions of this computational model reveal an interaction that could play a role in SCA1 pathology, because the Gfi-1 protein is known to cause selective degradation of Purkinje cells.: 149–165  It is the extensive involvement of ataxin 1 in many different functions that make understanding the biochemical pathophysiology of its mutant form difficult to identify and understand.: 15 The mechanism by which expanded CAG repeat regions in ataxin 1 cause neuronal degeneration is unclear. It was historically believed to be caused by aggregation and deposition of the affected protein similar to other polyglutamine expansion diseases, however rodent model studies have shown significantly later formation of nuclear inclusions of mutant proteins in cerebellum and spinal cord neurons than in cortical and hippocampal neurons, which typically show only mild degeneration in SCA1 persons, suggesting a more complicated mechanism. Ataxin-null mice are shown to exhibit reduced motor and spatial learning, suggesting ataxin 1 plays a role in synaptic plasticity and interactions between the motor neurons and the hippocampus. However mice lacking both copies of ataxin 1 do not develop progressive neurological symptoms or show signs of atrophy, suggesting that toxicity of the mutated protein, not loss of function, is the main mechanism for SCA1 pathology. A comparison of mRNA  between ataxin null mice and mice with ataxin1154Q/+ shows that there are common changes in gene expression, including upregulation of genes known to be repressed by an ataxin 1/CIC complex. This suggest that, while not the primary mechanism, a loss of ataxin 1 function contributes to the pathogenesis of SCA1.  While the ataxin 1/CIC complex losses some of its regulatory function with expanded ataxin 1, CIC knockout mice do not show degeneration, suggesting interactions between ataxin 1 and CIC mediate most of the toxic effects. Mutant ataxin-1 also known to alter the neural circuitry of the developing cerebellum, which may lead to later vulnerability of Purkinje cells and suggests the existence of non-cell autonomous toxicity.The various interactions of ataxin 1 lead to many possible factors that can exasperate or moderate toxicity of its mutant form. Wild type ataxin 1 is quickly degraded in the cytoplasm, but can be stabilized by phosphorylation and 14-3-3 binding as needed by the cell. SCA1 positive mice haplodeficient in 14-3-3ε+/- were shown not to exhibit cerebellar degeneration but still exhibited lethal bulbar degeneration, suggesting that cerebellar atrophy may be related to increased stability of the expanded ataxin 1 protein and that there may be different pathogenic mechanisms for different regions of the brain. The site of phosphorylation is the serine at the 776th residue in ataxin 1. Similar to those that lack 14-3-3 proteins, mice with this residue replaced with alanine do not exhibit cerebellar syndrome. Similarly, removal of the AXH domain from ataxin 1 prevents aberrant interactions with growth factor independent transcription repressor 1 that leads to GFI1 degradation in the proteasome. The expanded polyglutamine region results in increased affinity of the ataxin 1 AXH domain for certain transcription factors, and this effect is believed to play a significant role in ataxin 1 toxicity. Another protein shown to have significant interactions with ataxin 1 is the leucine-rich acidic nuclear protein or LANP. Its function is unknown, but it is predominately expressed in the same neurons as ataxin 1 and has been shown to localize in the nuclei of these neurons at the same substructures as ataxin 1. LANP only interacts with the polyglutamine region of ataxin 1, and its interactions are stronger as the number of glutamine residues increases, so the two proteins are likely vital to each others functions in neurons and LANP may also facilitate pathology of mutant ataxin 1 proteins. Ataxin 1 like, also called Brother of Ataxin 1 or Boat, has significant interactions with ataxin-1 and many associated proteins, like N-CoR. Ataxin 1 like has reduced expression in transgenic mice models and has been shown to moderate cytotoxicity of ataxin-1.Toxicity from the mutated protein causes degradation in neural tissues. This includes loss of dendritic aborization, or branching, early in disease progression and eventual atrophy of brain tissues in later stages. SCA1 causes moderate degradation of a variety of tissues, including both hemispheres of the cerebellum, the cerebellar vermis, the pons, and the brain stem. It also causes mild atrophy in cerebral cortical tissue. A recent study also found significant atrophy of the spinal cord and flattening of the posterior column and found a correlation between cord area, CAG repeats, and SARA scores in SCA1. Central nervous system tissues, unlike that of bone, muscle, or skin, lacks mechanisms for endogenously generating and differentiating new cells and for restoring long distance patterns and connections as they are lost, so as degeneration progresses the losses are permanent.

Diagnosis and evaluation
Most SCAs and other ataxic disorders are clinically heterogeneous, meaning clinical signs and symptoms are similar between diseases and distinguishing between diseases with a neurologic exam alone is difficult. In symptomatic persons, diagnosis of ataxia related disorders often requires a neurological exam, evaluation of neurological and family history, and molecular genetic testing. Absence of a family history does not exclude hereditary causes like spinocerebellar ataxia type 1 because family history may not have been collected or may be unavailable for certain individuals and new cases may originate from anticipation in an allele with a mutable number of repeats.: 2–4  To establish a diagnosis, molecular genetic testing is currently commercially available for 14 SCA types, including SCA1. In cases where SCAs are not present in family history or where family history is unavailable, testing for the 4 most common SCAs will return positive results for 50% of suspected SCA cases.: 11  Individuals who are at risk of inheriting SCA1 but are currently presymptomatic can also be screened with molecular genetic testing.

Genetic testing
Genetic testing is the only definitive way to differentiate between spinocerebellar ataxia types because of the similarity between clinical characteristics of these diseases and the large  variance between cases. Genetic testing is available for many SCA types, including the relatively common types SCA1, 2, 3, 6, and 7; and the less common SCA8, 10, 12, 14, and 17. However, genetic testing is high in cost and has a low diagnostic yield, with positive diagnoses being found in only 24% of tests ordered by a subspecialist and 10% overall.Genetic testing can be administered at various stages of disease progression. When genetic testing is administered after the onset of symptoms, the test is said to be diagnostic; in adults prior to onset of symptoms it is presymptomatic, and the test can be performed for prenatal or preimplantation diagnoses. The European Molecular Quality Genetics Network (EMQN) recommends criteria for each type, which must be met before testing can begin. The EQMN recommends that labs receive a written clinical evaluation of symptoms by a neurologist and a disclosure of family history, or lack of history, before initiating diagnostic genetic testing. Because no preventative or curative treatments are known for SCAs, genetic testing for at risk individuals is not recommended for all cases, and is typically issued on an individual basis. Presymptomatic, prenatal, and preimplantation testing are typically requested through a genetic counsellor and require existing family history and documentation of informed consent of the consultand. Spinocerebellar ataxia type 1 was one of the first late onset diseases for which presymptomatic testing was demonstrated effective and predictive; prior to the development of testing for SCA1, Huntingtons disease was the only similar disease for which presymptomatic testing was available.Molecular genetic testing of SCAs must be able to differentiate samples with the pathogenic allele from those without and be able to accurately measure the number of repeats in repeat expansion disorders. Capillary electrophoresis (CE) is one method that has met these criteria and is recommended by the EMQN. Another method that is common is polyacrylamide gel electrophoresis (PAGE). Both methods require amplification of all loci of interest for a given test. Amplification is done using polymerase chain reactions or PCR. The choice of primers can allow either for a single gene to be amplified or for many genes to amplified for use in a multiplex assay which can save time in cases where a panel of many tests may be required. PAGE and CE both use timed cycles of electricity to draw pieces of DNA through a porous polymer, separating analytes by a combination of ionic mobility, size and mass. CE is advantageous over PAGE in that molecular weight measurements like mass spectrometry can be used with analytes, whereas PAGE requires the use of Southern blot to allow comparison to a sequencing ladder. For repeat lengths within the range where interruptions are relevant, assays like CE and PAGE will not determine if the strain is pathogenic and additional testing will be required.

Clinical
No formal diagnostic criteria exist for most SCAs, and genetic testing is the only certain diagnostic method, but clinical examination of signs and symptoms may be vital to distinguishing SCAs from non-genetic ataxias, and from other types of genetic ataxias. Clinical examination can also help distinguish between SCA types to some extent, so genetic tests for certain types can be prioritized over others. Diagnosis of SCAs often begins with the detection of symptoms that suggest a cerebellar disorder, like progressive ataxia or dysarthria, or with recognition of similar symptoms to a case identified in the individuals family history, especially in first or second degree relatives. Many laboratory studies can be used to further narrow the potential cause of ataxia; imaging of brain and spinal cord and various electrophysiology exams may be useful for identifying disease phenotypes and blood and urine studies may rule out acquired causes.: 4 When evaluating ataxic disorders and their treatments, there are numerous tests that a neurologist may perform. Tests may be evaluated individually or follow a scale for evaluating the ataxia. A cerebellar exam may include saying phrases with many consonants to detect scanning speech, detecting horizontal gaze nystagmus by following a finger with the eyes, performing rapid alternating movements like rotating a hand from palm to back repeatedly, testing the Holmes rebound phenomenon, and testing patellar reflex for hypotonia or hypertonia. Common scales include the International Cooperative Ataxia Rating Scale (ICARS) and Scale for the Assessment and Rating of Ataxic Disorders (SARA) for evaluating the severity of ataxia as a symptom. ICARS measures on a 100 scale, where 0 is normal function and 100 is the highest possible impairment, assigning different point values for different tests. The tests are divided into categories evaluating posture and gait, kinetic functions, speech, and oculomotor functions. While these categories create useful categorization to assess which areas need to be focused on in therapies, this redundancy results in a longer test time, which can skew results of tests performed at the end of a session; and can result in contradictory scores. SARA is a shorter exam, evaluated on a scale of 0 to 40, where again zero is normal function and 40 is highest possible impairment. It comprises eight tests: gait, stance, finger chase, finger-to-nose test, fast alternating hand movements, heel-shin slide, and three limb kinectic function tests.

Differential diagnosis
Differential diagnosis of SCAs by clinical methods is difficult because these diseases are clinically heterogenous and there is significant variance between the expression of individual cases. Using clinical information for differential diagnosis is used to prioritize genetic testing not as a stand-alone diagnosis. Many potential differentiating symptoms have been found, and methods of assessing many symptoms and their progression to guide genetic testing have been developed. Even if a specific type of spinocerebellar ataxia cannot be immediately determined clinical history, family history, clinical examination can help distinguish between other ataxias and can help reduce the number of genetic tests needed to identify a type of SCA. Examination of relatives of individuals thought to have sporadic ataxia can often reveal enough family history to identify a transmission mode.There are some common trends that may be useful to discriminate SCAs. SCA1 tends to progress faster than SCA2, 3, and 6, with greater annual change in SARA scores and earlier loss of functions after onset. In the diagnostics of clinical ataxia, imaging may not be useful to distinguish SCA1 from other SCAs as there is significant variance between individual cases and significant overlap between diseases. Vestibulo-ocular reflex can be tested using a video recorded head impulse test or vHIT. In this test, SCA1 typically has normal reflex latency, and does not consistently show a deficit in VOR function, distinguishing it from SCA3 and Friedreichs ataxia. Certain patterns in ocular motor disorders, detectable with video-oculography, appear to typify certain SCA types. While SCA1 was not significantly correlated with a unique pattern, other possible SCAs can be linked  and absence of a vertical nystagmus following horizontal head shaking reduces the likelihood of an SCA6 diagnosis, while the absence of a square wave pattern during fixation reduces the likelihood of SCA3.One possible system for the differential diagnosis of SCA types is to record the progression of symptoms and use Bayesian probability to build a predictive model, or a Bayesian classifier, that compares the observed data to trends like those described above to find the likelihood of each diagnosis to be correct. One such Bayesian classifier was shown to accurately predict 78% of SCA cases out of a cohort with known types of SCA. The sensitivity and specificity for SCA1 within this model was 76.9% and 98.2% respectively. Regional variance in prevalence, symptoms and clinical assessment might still limit the use of this system on large scales, though the system may implemented by individual clinics using their own regional data.

Management
There is currently no cure for Spinocerebellar ataxia type 1. However, some of its symptoms may be managed with physical, occupational or speech therapies, lifestyle and dietary changes, or with medications. Managing symptoms will not prevent the disease from progressing but can be important for maintaining quality of life.: 48  It is important to note, however, that many disorders that cause ataxia and related symptoms exist, and that management strategies that work for some, such as vitamin E supplements for certain acquired ataxias, will not work for hereditary ataxias like SCA1 and can be dangerous to a persons health.: 52 Small cohort studies have shown that individuals with cerebellar disorders recover coordination and have lower SARA scores regardless of stage or severity of their ataxia before therapy when they are regularly participating in physiotherapy or exergaming over individuals who are not. These studies suggest that multidomain physical therapy, more focused coordinative training, and exergaming routines all produced improvements in SARA scores equivalent to at least one year of normal progression, 2.2 points or more on average, over the course of several weeks. While these results are promising, larger scale studies may be necessary to validate these results. Overall, physical therapy for individuals with ataxia has modest evidence supporting its efficaciousness, but current practice uses custom treatments without a standard decision making procedure between clinics, which limits the ability to reproducibly assess the quality of routines in literature. Among the earliest developed neurorehabilitation practices is Frenkel exercises, which was developed by Heinrich Frenkel in the mid nineteenth century; these exercises were drawn from contemporary physical medicine and rehabilitation techniques, called medical gymnastics, and from everyday activities, like standing up from a chair, to find exercises which are closely related to the pathology of ataxia and rely on slow practice and on the individuals perseverance to relearn key motor skills, replacing lost proprioception with visual feedback. There are exercises for lower limbs, like extending the legs, and upper limbs, like placing pegs in boards, and depending on the severity of the ataxia can be performed laying down, sitting, or standing up. All exercises often start with simple movements and become progressively more difficult to emulate real world movements affected by the disorder.Common recommendations for persons with dysphagia, or swallowing problems, include pureeing food, replacing difficult to eat foods in the diet, or changing posture during eating. When swallowing problems become severe enough that aspiration pneumonias are frequent or dietary changes fail to prevent weight loss, a feeding tube may be considered.: 82–86  Typically these are percutaneous endoscopic gastrostomy jejunal tubes (PEG-Js), however these do not necessarily lead to a decreased incidence of aspiration, as clogs may result in gastroesphageal reflux which can be aspirated. Direct PEG-Js seem to cause less frequent reflux and have lower incidence of aspiration pneumonia compared to the standard PEG-J procedure. Numerous strategies for treating dysphagia have been investigated including physical exercises like modified Valsalva maneuvers, pharmaceutical treatments focused on treating spasticity, and compensatory practices including adjusting posture and longer chewing. These strategies, like the treatment of many symptoms hereditary ataxias, have small scale evidence for their usefulness but are not yet established by large studies.As with all hereditary diseases, concerns about the impact on family members, especially children, are often very important. Individuals diagnosed with SCA 1 may seek genetic counseling to aid in family planning, developing coping skills, and planning for the future. Persons with SCA 1 may consider in vitro fertilization with preimplantation testing to prevent passing the disease on to their children.

Prognosis
Penetrance for SCA1 is 100% for most alleles, so almost all individuals who have at least one copy of the mutated gene will eventually develop symptoms. At least one case has been reported where penetrance may have been incomplete in a woman with 44 glutamine repeats with histidine interruptions whose father had exhibited symptoms, but herself had not shown symptoms at the age of 66. Individuals with a low number of repeats, around 39 to 55, typically live past reproductive age and can pass on the disease to their children, while high repeats may express juvenile onset and fatality.

Epidemiology
The National Institute of Health reports that SCA1 has a prevalence of approximately 1 or 2 per 100,000 however a review of literature has shown that these estimates vary significantly from study to study and can be less than 1 per 100,000 or as high as 6 per 100,000. Among all types of SCA, SCA1 is among the most common and the portion accounted for by SCA1 varies between geographic regions, with percentages as high as 40% of all SCA diagnoses in populations in Russia and South Africa being SCA1. In the United States SCA1 accounts for 6% of SCA diagnoses. Overall, SCA1 accounts for 6-27% of all cases dominant ataxias.: 6  Because of its late onset, often appearing after reproductive age, SCA1 exerts low selection intensity, ranking about 0.19 on the Crows index, but intensity may vary with time within a population or family, as anticipation increases the number of CAG repeats. One implication of this is that SCA1 is unlikely to disappear from a population by natural selection alone.Prevalence of each type of SCA varies with geographic region and ethnicity, possibly because of founder effects and historic migration patterns. High prevalence regions include central Poland, where 68% of autosomal dominant cerebellar disorders are SCA1; communities in Tamil Nadu, where up to 7.2% of the population has SCA1 in some small villages; the Tohoku region on the northern portion of Honshu Island, with 24.8% of cases being SCA1; and among Yakut populations in eastern Siberia, with a prevalence 46 per 100,000 in rural populations.

History
Ataxia as a symptom was first described by French neurologist Duchenne de Boulogne in a subject with tabes dorsalis. By the late 19th and early 20th centuries, extensive research into the characterization, cause, and diagnostics of hereditary cerebellar ataxias was underway with the work of several prominent neurologists, including Jean-Martin Charcot, Pierre Marie, Nikolaus Friedreich, Adolph Strümpell, and others. Marie described a number of cases of hereditary, adult onset disease he thought to be clinically distinct from Friedreichs ataxia, spastic paraplegia, and other known types of ataxia, calling the syndrome hereditary cerebellar ataxia, though it became known Maries ataxia.While the hereditary patterns were clearly distinct, there was on-going debate well into the 1940s over whether Maries ataxia was really distinct from Freidreichs ataxia and Strümpells paraplegia and if these categorys themselves represented a single disease or many. This was because of the heterogenous nature of hereditary ataxias, the similarity of symptoms, and the lack of understood biochemical mechanisms. Further frustration with the ambiguity of terms introduced by Marie and Friedreich resulted in the creation of other systems to classify ataxias. Gordon Morgan Holmes and Godwin Greenfield each developed systems of categorizing ataxias, giving rise to categories called olivopontocerebellar atrophy and spinocerebellar degradation, though little consensus between the systems was achieved, and many terms are used interchangeably.In the depression era United States, the Schut family in Minnesota was one family known to carry a hereditary ataxia. Several members of the family actively participated in research and the family consented to post mortem examinations of the brains of several deceased relatives. The disease in the Schut family was found to have an autosomal dominant inheritance pattern, and afflicted the spinocerebellar tract. In 1945, John Schut received free medical school education for his service with the United States Army during the second world war and began his own efforts researching hereditary ataxia.: 90–91  Schut developed ataxia like many of his relatives. In 1957, when Schuts ataxia progressed to a point where he was unable to continue work in regular medical practice, he founded the National Ataxia Foundation with lab space donated by Glenwood Hills Hospital in Minneapolis.: 131 John Schuts nephew, Lawerence Schut, also became an ataxia researcher and contributed to localizing a spinocerebellar ataxia gene to the human leukocyte antigen complex in chromosome 6. The success in linking one of these class of diseases to a locus showed that the classification systems in use were unable to distinguish between diseases with many different causes. Many ataxic disorders which were historically identified as Maries ataxia, olivopontocerebellar atrophy or other names were now reclassified as types of spinocerebellar ataxia, each type numbered in order as a new locus was found. In 1993, the gene and a mutation causing spinocerebellar ataxia type 1 was identified. It was the first genetic defect found known to cause an ataxic disorder.

Research directions
Treatment and mitigation of neurodegenerative disorders is of particular interest to researchers, and several potential options for SCA1 are under investigation. As the pathology of SCA1 is complex, there are several possible approaches to treatment, which include clearance of expanded ataxin 1 proteins, reducing the toxicity of expanded ataxin 1 proteins, suppressing production of ataxin 1, multiple gene therapies, and replacing lost brain cells. Because many SCAs, including SCA1, are polyglutamine diseases and operate by similar mechanisms to Huntingtons disease many promising treatments for Huntingtons disease are being investigated for SCAs as well.

Gene downregulation and silencing
Because spinocerebellar ataxias are often linked to a mutation on a single gene, modifying how the gene is expressed can modify the phenotype. There are several approaches to modifying the expression of mutant proteins, including techniques that completely stop expression, known as gene silencing. In SCA1, pathogenesis requires constant expression of the mutant ATXN1 gene, and silencing has been shown to halt further progression of the disease, clear nuclear inclusions and aggregates and lead to partial recovery of motor functions in rodent models with conditional expression of the gene. The conditional expression of ATXN1 in mice models differs from how the gene would be silenced therapeutically but the results indicate that therapeutic methods of gene silencing may be viable for treatment and management of SCA1. The process that turns coded information in DNA into proteins requires two steps: transcription, in which DNA is used to generate a complementary RNA strand by RNA polymerase, and translation, in which RNA is used to produce a protein by ribosomes. Disrupting either step can slow or prevent the expression of a mutant gene.
Ataxin 1 is involved in a number of signaling pathways and its expression is controlled by signaling pathways. The MAPK/ERK pathway has been shown to activate ataxin 1 expression, and MSK1 also phosphorylates ataxin 1, controlling its localization and degradation. Inhibitors of key proteins in this pathway may be used in combination therapy to potentially decrease expression and lower steady state concentrations of ataxin 1.One technique for disrupting translation, antisense oligonucleotide therapy, which uses single strands of RNA complementary to the target to prevent the target from binding to a ribosome and trigger the degradation of the target, has already begun clinical trials in other neurodegenerative disorders with many different delivery mechanisms. A similar technique is RNA interference or RNAi. Instead of complementary antisense strands of RNA, RNAi uses very small double stranded segments of RNA called small interfering RNA which triggers degradation of the target before it can be translated. Studies using RNAi agents delivered by adeno associated viruses (AAV) has been shown to halt progression of disease and lead to some recovery of function with treatment applied to only the deep cerebellar nuclei in mice and rhesus macaques. Both of these techniques are difficult to apply to polyglutamine diseases because targeting the polyglutamine tract may cause normal genes to be downregulated as well. SCA1 has also shown to be difficult to target reliably with single-nucleotide polymorphisms limiting the number of ways RNAi and antisense therapy techniques can be designed to treat SCA1.

Reducing toxicity and increasing cell survival
Because of the numerous interactions ataxin-1 has with other proteins, techniques for reducing toxicity of the mutant ataxin-1 protein often change the expression of related proteins. For example, ataxin-1-like has many common domains with ataxin-1 and overexpression of ataxin-1-like compete with ataxin-1 and prevent its integration into other complexes, reducing toxicity. This effect was replicated in mice models using AAVs, and shown to be about as effective as RNAi techniques at slowing the progression of symptoms. Similarly, the drug baclofen, which is used to help reduce spasticity in persons with multiple sclerosis and related diseases, operates as an agonist of γ-aminobutyric acid type B receptors (GABABR). This pathway crosstalks with the mGluR1 pathway, which interacts with the ataxin 1 protein and proteins responsible for localization and degradation of ataxin 1, suggesting that baclofen may be a viable treatment for SCA 1 treatment.Molecular chaperones are introduced proteins that may have interactions with the mutant protein that reduce toxicity by various mechanisms. Studies in both mice models and Drosophila models have shown that heat shock proteins 40 and 70 may reduce toxicity of expanded ataxin 1 proteins and slow progression of SCA1.While there is currently no known method for exclusively promoting polyglutamine contractions in vivo, techniques using programmable nucleases have shown some promise in causing these changes in vitro. Programmable nucleases are proteins that can break DNA strands near sequences that can be specified by scientists before use. This includes CRISPR/Cas9, which uses a protein found in bacteria and guide strand of RNA, and zinc finger nucleases, which use engineered proteins with special recurring DNA binding domains to guide an attached nuclease. A study reports that both CRISPR and Zinc fingers nucleases that rely on double strand breaks trigger contractions and expansions with nearly equal frequency, while CRISPR using a mutant variation of Cas9, Cas9 D10A or Cas9 nickase, which causes only single strand breaks, produced mainly contractions.In mice, mitochondrial impairments contribute to SCA1 progression.  Prominent alterations in Purkinje cell mitochondrial proteins coincide with the symptomatic phase of the disease.  Purkinje cells in SCA1 mice also undergo age-dependent alterations in mitochondrial morphology </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 Gray platelet syndrome and can you explain it in depth? [/INST] Gray platelet syndrome (GPS), or platelet alpha-granule deficiency, is a rare congenital autosomal recessive bleeding disorder caused by a reduction or absence of alpha-granules in blood platelets, and the release of proteins normally contained in these granules into the marrow, causing myelofibrosis. The name derives from the initial observation of gray appearance of platelets with a paucity of granules on blood films from a patient with a lifelong bleeding disorder.

Signs and symptoms
Signs of GPS typically arise at birth or in childhood, these signs and symptoms include thrombocytopenia, bruising susceptibility, and epistaxis. Typically, the observed low platelet count in individuals is progressive, this can result in fatal hemorrhages later in life. Additionally, females who are affected may experience irregular menstrual cycles and heavy menstrual bleeding. Another common effect of GPS is myelofibrosis, where scar tissue builds up in the bone marrow causing it to be unable to produce a sufficient amount of blood cells. To compensate, other organs such as the spleen start to produce more blood cells which can lead to splenomegaly.

Genetics
GPS is primarily inherited in an autosomal recessive manner. The gene that is mutated in GPS has been mapped to chromosome 3p and identified as NBEAL2. The location is 3p21.31. This is caused by a homozygous or compound heterozygous mutations in the NBEAL2 gene. NBEAL2 encodes a protein containing a BEACH domain that is predicted to be involved in vesicular trafficking.  It is expressed in platelets and megakaryocytes and is required for the development of platelet alpha-granules. NBEAL2 expression is also required for the development of thrombocytes in zebrafish.In Japan, GPS was found in 24 affected patients in a single family. There was at least 1 instance of male-to-male transmission, consistent with autosomal dominant inheritance.A study reported of 14 families with GPS, 11 families had clear autosomal recessive inheritance. This was evidenced by consanguinity or multiple affected siblings with unaffected parents. The families had various backgrounds, including Bedouin, Turkish, Mennonite, French, German, Somali, African American, and mixed Northern and Southern European.GPS is characterized by "thrombocytopenia, and abnormally large agranular platelets in peripheral blood smears." The defect in GPS is the failure of megakaryocytes to package secretory proteins into alpha-granules </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 Juvenile plantar dermatosis and can you explain it in depth? [/INST]  </s>