<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 Caffeine-induced sleep disorder and can you explain it in depth? [/INST] Caffeine-induced sleep disorder is a psychiatric disorder that results from overconsumption of the stimulant caffeine.  Caffeine is one of the most widely consumed psychoactive drugs: almost 90% of Americans in a survey consume some type of caffeine each day. "When caffeine is consumed immediately before bedtime or .... throughout the day, sleep onset may be delayed, total sleep time reduced, normal stages of sleep altered, and the quality of sleep decreased." Caffeine reduces slow-wave sleep in the early part of the sleep cycle and can reduce rapid eye movement sleep later in the cycle. Caffeine increases episodes of wakefulness, and high doses in the late evening can increase sleep onset latency. In elderly people, there is an association between use of medication containing caffeine and difficulty in falling asleep.The specific criteria for this disorder in the fourth version of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) include that there must be a significant inability to sleep which is caused entirely by the physiological effects of caffeine as proven by an examination; if sleeping issues can be accounted for due to a breathing-related sleep disorder, narcolepsy, a circadian rhythm sleep disorder or a mental disorder, then caffeine-induced sleep disorder is not the cause.  This condition causes a notable impairment in functioning. The ICD-10 criteria for the principally same disorder is F15:982.

Caffeine and age
Most studies now, find that there is relatively no association between caffeine and its effects on sleep for infants. There was very little difference between mothers who had high caffeine consumption during pregnancy as opposed to mothers who did not have high consumption of caffeine during their pregnancy.Caffeine in younger children has been found to shorten their sleep duration and increase daytime sleepiness. One study, which looked at children ages six to ten years of age, found that those who consistently consumed caffeine lost about 15 minutes of sleep each night. In most cases where younger children are drinking high amounts of caffeine, parents usually buy their children soft drinks, iced tea, or energy drinks without realizing the amount of caffeine these drinks contain or the implications they have on their children.30% of adolescent adults in a survey were found to consume caffeine daily. Individuals with higher caffeine consumption, tended to feel an increase in wakefulness after sleep onset, shorter sleep durations, and longer daytime sleep. Those who consumed high amounts of caffeine daily, were found to be 1.9 times more likely to have difficulty sleeping and 1.8 times more likely to feel sleepy in the morning compared to those who consume almost no caffeine. Individuals with higher caffeine consumption felt an increase in wakefulness after sleep onset, shorter sleep durations, and longer daytime sleep. The higher consumption time for adolescent adults tends to be on the weekends, while the lowest consumption is midweek. This is assumed to be from greater social opportunities among adolescence.

Mechanism of caffeine
Caffeine is an adenosine receptor antagonist. This means that caffeine mainly works by occupying adenosine receptors in the brain, specifically, receptors that influence sleep, arousal, and cognition.  Once it is in the body, caffeine will persist for several hours, and takes about six hours for one half of the caffeine consumed to be eliminated. When caffeine reaches the brain, it increases the secretion of norepinephrine which is related to the "fight or flight" response. The rise in norepinephrine levels increases activity of neurons in areas of the brain and the symptoms resemble those of a panic attack.The half-life of caffeine is roughly 3–4 hours in healthy adults, however, it is dependent on a variety of variables such as age, liver function, medications, level of enzymes, pregnancy. This short half-life has been found to help out daytime functioning, but increase the side effect of sleep problems. So, while caffeine has the potential to increase performance, it comes at a cost of sleep deprivation which in its own way can counter the main point of caffeine. Sleep deprivation alone can cause a variety of problems associated with cognitive control and functions. This can include reduced alertness, attention, vigilance, speed of motor functions.Though caffeine can be shown to decrease the quality of sleep, there is no evidence that caffeine affects all people the same way. In fact, some people report no sleep problems despite regularly consuming caffeine. Regular intake of caffeine may be normal for a person so it is understandable how they may still get satisfactory sleep. This finding shows that caffeine interferes with a modulatory mechanism in sleep regulation rather than a fundamental sleep regulatory brain circuit. Ultimately, regular sleep habits are important in overall quality and timing of sleep.

Caffeine consumption
Overconsumption
Although the maximum daily consumption of caffeine varies with consideration of couple of aspects such as sex, age, race, physical activity and smoking, excessive ingestion of caffeine can lead to a state of intoxication. This period of intoxication is characterized by restlessness, agitation, excitement, rambling thought or speech, and even insomnia. Even doses of caffeine relating to just one cup of coffee can increase sleep latency and decrease the quality of sleep especially in non-REM deep sleep. A dose of caffeine taken in the morning can have these effects the following night, so one of the main practices of sleep hygiene a person can do is to cease the consumption of caffeine.

Moderation
Keeping in mind that caffeine content in beverages and food varies and that some individuals are more sensitive to caffeine consumption than others are, moderation of caffeine is key. Between 200 and 300 mg of caffeine is considered "moderate" for most adults. While children can consume caffeine, it is advised to refrain children and adolescents from consuming caffeine due to their growing brains and to allow them to develop healthy sleep patterns.

Consequences of sleep disruption
Normal healthy sleep is described as having sufficient duration, quality, timing, regulation, and the absence of sleep disturbances or disorders. Even though the suggested amounts of sleep is relatively well known, there are increasing high numbers in the lack of healthy and good quality sleep.Risk factors of sleep can range across many different arrays such as environmental, lifestyle, psychosocial, sleep disorders, or medical conditions. These are all circumstances which put individuals at risk for sleep disruption. Environmental risk factors for sleep disruption can include living in an area where there is excessive noise such as near an interstate, keeping an individual up later than normal. A lifestyle risk factor would include drinking alcohol, drug abuse, or a late shift at work </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 Patella and can you explain it in depth? [/INST] The patella, also known as the kneecap, is a flat, rounded triangular bone which articulates with the femur (thigh bone) and covers and protects the anterior articular surface of the knee joint. The patella is found in many tetrapods, such as  mice, cats, birds and dogs, but not in whales, or most reptiles.
In humans, the patella is the largest sesamoid bone (i.e., embedded within a tendon or a muscle) in the body. Babies are born with a patella of soft cartilage which begins to ossify into bone at about four years of age.

Structure
The patella is a sesamoid bone roughly triangular in shape, with the apex of the patella facing downwards. The apex is the most inferior (lowest) part of the patella. It is pointed in shape, and gives attachment to the patellar ligament.
The front and back surfaces are joined by a thin margin and towards centre by a thicker margin. The tendon of the quadriceps femoris muscle attaches to the base of the patella., with the vastus intermedius muscle attaching to the base itself, and the vastus lateralis and vastus medialis are attached to outer lateral and medial borders of patella respectively.
The upper third of the front of the patella is coarse, flattened, and rough, and serves for the attachment of the tendon of the quadriceps and often has exostoses. The middle third has numerous vascular canaliculi. The lower third culminates in the apex which serves as the origin of the patellar ligament. The posterior surface is divided into two parts.

The upper three-quarters of the patella articulates with the femur and is subdivided into a medial and a lateral facet by a vertical ledge which varies in shape.
In the adult the articular surface is about 12 cm2 (1.9 sq in) and covered by cartilage, which can reach a maximal thickness of 6 mm (0.24 in) in the centre at about 30 years of age. Owing to the great stress on the patellofemoral joint during resisted knee flexion, the articular cartilage of the patella is among the thickest in the human body.
The lower part of the posterior surface has vascular canaliculi filled and is filled by fatty tissue, the infrapatellar fat pad.

Variation
Emarginations (i.e. patella emarginata, a "missing piece") are common laterally on the proximal edge. Bipartite patellas are the result of an ossification of a second cartilaginous layer at the location of an emargination.  Previously, bipartite patellas were explained as the failure of several ossification centres to fuse, but this idea has been rejected. Partite patellas occur almost exclusively in men.  Tripartite and even multipartite patellas occur.
The upper three-quarters of the patella articulates with the femur and is subdivided into a medial and a lateral facet by a vertical ledge which varies in shape.  Four main types of articular surface can be distinguished:

Most commonly the medial articular surface is smaller than the lateral.
Sometimes both articular surfaces are virtually equal in size.
Occasionally, the medial surface is hypoplastic or
the central ledge is only indicated.

Development
In the patella an ossification centre develops at the age of 3–6 years. The patella originates from two centres of ossification which unite when fully formed.

Function
The primary functional role of the patella is knee extension. The patella increases the leverage that the quadriceps tendon can exert on the femur by increasing the angle at which it acts.
The patella is attached to the tendon of the quadriceps femoris muscle, which contracts to extend/straighten the knee. The patella is stabilized by the insertion of the horizontal fibres of vastus medialis and by the prominence of the lateral femoral condyle, which discourages lateral dislocation during flexion. The retinacular fibres of the patella also stabilize it during exercise.

Clinical significance
Dislocation
Patellar dislocations occur with significant regularity, particularly in young female athletes. It involves the patella sliding out of its position on the knee, most often laterally, and may be associated with extremely intense pain and swelling. The patella can be tracked back into the groove with an extension of the knee, and therefore sometimes returns into the proper position on its own.

Vertical alignment
A patella alta is a high-riding (superiorly aligned) patella </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 Epidermis and can you explain it in depth? [/INST] The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water released from the body into the atmosphere through transepidermal water loss.The epidermis is composed of multiple layers of flattened cells that overlie a base layer (stratum basale) composed of columnar cells arranged perpendicularly. The layers of cells develop from stem cells in the basal layer. The human epidermis is a familiar example of epithelium, particularly a stratified squamous epithelium.
The word epidermis is derived through Latin from Ancient Greek  epidermis, itself from Ancient Greek  epi over, upon and from Ancient Greek  derma skin.  Something related to or part of the epidermis is termed epidermal.

Structure
Cellular components
The epidermis primarily consists of keratinocytes (proliferating basal and differentiated suprabasal), which comprise 90% of its cells, but also contains melanocytes, Langerhans cells, Merkel cells,: 2–3  and inflammatory cells. Epidermal thickenings called Rete ridges (or rete pegs) extend downward between dermal papillae.Blood capillaries are found beneath the epidermis, and are linked to an arteriole and a venule.
The epidermis itself has no blood supply and is nourished almost exclusively by diffused oxygen from the surrounding air. Cellular mechanisms for regulating water and sodium levels (ENaCs) are found in all layers of the epidermis.

Cell junctions
Epidermal cells are tightly interconnected to serve as a tight barrier against the exterior environment. The junctions between the epidermal cells are of the adherens junction type, formed by transmembrane proteins called cadherins. Inside the cell, the cadherins are linked to actin filaments. In immunofluorescence microscopy, the actin filament network appears as a thick border surrounding the cells, although the actin filaments are actually located inside the cell and run parallel to the cell membrane. Because of the proximity of the neighboring cells and tightness of the junctions, the actin immunofluorescence appears as a border between cells.

Layers
The epidermis is composed of 4 or 5 layers, depending on the region of skin being considered.  Those layers in descending order are:
cornified layer (stratum corneum)
Composed of 10 to 30 layers of polyhedral, anucleated corneocytes (final step of keratinocyte differentiation), with the palms and soles having the most layers. Corneocytes contain a protein envelope (cornified envelope proteins) underneath the plasma membrane, are filled with water-retaining keratin proteins, attached together through corneodesmosomes and surrounded in the extracellular space by stacked layers of lipids. Most of the barrier functions of the epidermis localize to this layer.
clear/translucent layer (stratum lucidum, only in palms and soles)
This narrow layer is found only on the palms and soles.  The epidermis of these two areas is known as "thick skin" because with this extra layer, the skin has 5 epidermal layers instead of 4.
granular layer (stratum granulosum)
Keratinocytes lose their nuclei and their cytoplasm appears granular. Lipids, contained into those keratinocytes within lamellar bodies, are released into the extracellular space through exocytosis to form a lipid barrier that prevents water loss from the body as well as entry of foreign substances. Those polar lipids are then converted into non-polar lipids and arranged parallel to the cell surface. For example glycosphingolipids become ceramides and phospholipids become free fatty acids.
spinous layer (stratum spinosum)
Keratinocytes become connected through desmosomes and produce lamellar bodies, from within the Golgi, enriched in polar lipids, glycosphingolipids, free sterols, phospholipids and catabolic enzymes. Langerhans cells, immunologically active cells, are located in the middle of this layer.
basal/germinal layer (stratum basale/germinativum)
Composed mainly of proliferating and non-proliferating keratinocytes, attached to the basement membrane by hemidesmosomes. Melanocytes are present, connected to numerous keratinocytes in this and other strata through dendrites. Merkel cells are also found in the stratum basale with large numbers in touch-sensitive sites such as the fingertips and lips. They are closely associated with cutaneous nerves and seem to be involved in light touch sensation.
Malpighian layer (stratum malpighi)
This is both the stratum basale and stratum spinosum.The epidermis is separated from the dermis, its underlying tissue, by a basement membrane.

Cellular kinetics
Cell division
As a stratified squamous epithelium, the epidermis is maintained by cell division within the stratum basale. Differentiating cells delaminate from the basement membrane and are displaced outward through the epidermal layers, undergoing multiple stages of differentiation until, in the stratum corneum, losing their nucleus and fusing to squamous sheets, which are eventually shed from the surface (desquamation). Differentiated keratinocytes secrete keratin proteins, which contribute to the formation of an extracellular matrix that is an integral part of the skin barrier function. In normal skin, the rate of keratinocyte production equals the rate of loss, taking about two weeks for a cell to journey from the stratum basale to the top of the stratum granulosum, and an additional four weeks to cross the stratum corneum.  The entire epidermis is replaced by new cell growth over a period of about 48 days.

Calcium concentration
Keratinocyte differentiation throughout the epidermis is in part mediated by a calcium gradient, increasing from the stratum basale until the outer stratum granulosum, where it reaches its maximum, and decreasing in the stratum corneum. Calcium concentration in the stratum corneum is very low in part because those relatively dry cells are not able to dissolve the ions. This calcium gradient parallels keratinocyte differentiation and as such is considered a key regulator in the formation of the epidermal layers.Elevation of extracellular calcium concentrations induces an increase in intracellular free calcium concentrations. Part of that intracellular increase comes from calcium released from intracellular stores and another part comes from transmembrane calcium influx, through both calcium-sensitive chloride channels and voltage-independent cation channels permeable to calcium. Moreover, it has been suggested that an extracellular calcium-sensing receptor (CaSR) also contributes to the rise in intracellular calcium concentration.

Development
Epidermal organogenesis, the formation of the epidermis, begins in the cells covering the embryo after neurulation, the formation of the central nervous system.  In most vertebrates, this original one-layered structure quickly transforms into a two-layered tissue; a temporary outer layer, the periderm, which is disposed once the inner basal layer or stratum germinativum has formed.This inner layer is a germinal epithelium that gives rise to all epidermal cells.  It divides to form the outer spinous layer (stratum spinosum).  The cells of these two layers, together called the Malpighian layer(s) after Marcello Malpighi, divide to form the superficial granular layer (Stratum granulosum) of the epidermis.The cells in the stratum granulosum do not divide, but instead form skin cells called keratinocytes from the granules of keratin.  These skin cells finally become the cornified layer (stratum corneum), the outermost epidermal layer, where the cells become flattened sacks with their nuclei located at one end of the cell </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 Onychoatrophy 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 Junctional epidermolysis bullosa 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 Sabinas brittle hair syndrome and can you explain it in depth? [/INST] Sabinas brittle hair syndrome, also called Sabinas syndrome or brittle hair-mental deficit syndrome, is an autosomal recessive congenital disorder affecting the integumentary system.

Signs and symptoms
Symptoms include brittle hair, mild mental retardation and nail dysplasia. The syndrome was first observed in Sabinas, a small community in northern Mexico.
The principal biochemical features of the illness are reduced hair cystine levels, increased copper/zinc ratio, and presence of arginosuccinic acid in the blood and urine.The key finding is brittle hair with low sulfur content, but alternating dark and light bands under polarizing microscopy, trichoschisis, and absent or defective cuticle are additional important clues for the diagnosis of trichothiodystrophy.  Review of literature reveals extensive associated findings in trichothiodystrophy. Amino acid analyses of control hair when compared with those of patients with the Sabinas syndrome showed very striking differences with regard to content of sulphur amino acids. As in previous descriptions of amino acid abnormalities in the trichorrhexis nodosa of arginosuccinicaciduria, there were increases in lysine, aspartic acid, alanine, leucine, isoleucine, and tyrosine.
Trichothiodystrophy represents a central pathologic feature of a specific hair dysplasia associated with several disorders in organs derived from ectoderm and neuroectoderm. Trichothiodystrophy or TTD is a heterogeneous group of autosomal recessive disorders, characterized by abnormally sulfur deficient brittle hair and accompanied by ichthyosis and other manifestations.
Patients with trichothiodystrophy should have a thorough evaluation for other associated manifestations, including investigation of photosensitivity and DNA repair defects. Because the disease appears to be inherited in an autosomal recessive pattern, detection of low-sulfur brittle hair syndrome is also important for genetic counseling.

Genetics
Sabinas brittle hair syndrome is inherited as an autosomal recessive genetic trait.In a study by Howell et al. patients were located and studied by means of complete histories and physical examinations, analyses of serum trace metals, ceruloplasmin concentration, urine and serum amino acids, and routine metabolic urine screens. In addition, serum and urine luteinizing hormone (LH) and follicle-stimulating hormone (FSH) values were determined, and were interpreted in conjunction with total plasma estrogen, estradiol, and testosterone levels. Close examination demonstrated the scalp hairs were very brittle, coarse, wiry in texture, and broke off quite easily with mechanical trauma such as combing and brushing. Some hairs could be visualized in their follicles, which were broken off at the skin line. Most patients had accompanying hyperkeratosis (thickening of the skin) of moderate degree on exposed surfaces </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 Ischemic hepatitis and can you explain it in depth? [/INST] Ischemic hepatitis, also known as  shock liver, is a condition defined as an acute liver injury caused by insufficient blood flow (and consequently insufficient oxygen delivery) to the liver. The decreased blood flow (perfusion) to the liver is usually due to shock or low blood pressure. However, local causes involving the hepatic artery that supplies oxygen to the liver, such as a blood clot in the hepatic artery, can also cause ischemic hepatitis.

Signs and symptoms
People who develop ischemic hepatitis may have weakness, fatigue, mental confusion, and low urine production (oliguria). A small percentage of affected people may develop hepatic coma. Yellow discoloration of the skin (jaundice) can occur, but is rare and temporary, as is actual loss of function of the liver.

Cause
Ischemic hepatitis can be caused by a number of reasons (that lead to low blood pressure) including:
Abnormal heart rhythm
Heart failure
Infection
Hypovolemic shock (e.g., due to profuse bleeding)
Blood clots (hepatic artery after surgery)

Mechanism
The mechanism of ischemic hepatitis depends on the etiopathogenetic origin, be it a cardiomyopathy, cardiac tamponade, trauma, or bleeding. Usually ischemic hepatitis reveals itself after a hypotensive event with increased levels of aminotransferases. Because of this, hypotension is thought to be one of the primary insults leading to ischemic hepatitis.

Diagnosis
Blood testing usually shows high levels of the liver transaminase enzymes, AST and ALT, which may exceed 10,000 U/L. It has been found that those who suffer from ischemic hepatitis had significant cardiac disease as well.As a measure of precaution, paracetamol levels and a toxicology screening should be completed to evaluate for possible toxin-mediated injury; it is also imperative to be able to exclude the possibility of acute viral hepatitis.

Related conditions
Ischemic hepatitis is related to another condition called congestive hepatopathy.  Congestive hepatopathy includes a number of liver disorders that occur in right-sided heart failure </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 Intravascular papillary endothelial hyperplasia 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 Choroideremia and can you explain it in depth? [/INST] Choroideremia (; CHM) is a rare, X-linked recessive form of hereditary retinal degeneration that affects roughly 1 in 50,000 males. The disease causes a gradual loss of vision, starting with childhood night blindness, followed by peripheral vision loss and progressing to loss of central vision later in life. Progression continues throughout the individuals life, but both the rate of change and the degree of visual loss are variable among those affected, even within the same family.Choroideremia is caused by a loss-of-function mutation in the CHM gene which encodes Rab escort protein 1 (REP1), a protein involved in lipid modification of Rab proteins. While the complete mechanism of disease is not fully understood, the lack of a functional protein in the retina results in cell death and the gradual deterioration of the retinal pigment epithelium (RPE), photoreceptors and the choroid.As of 2019, there is no treatment for choroideremia; however, retinal gene therapy clinical trials have demonstrated a possible treatment.

Presentation
Since the CHM gene is located on the X chromosome, symptoms are seen almost exclusively in men. While there are a few exceptions, female carriers have a noticeable lack of pigmentation in the RPE but do not experience any symptoms. Female carriers have a 50% chance of having either an affected son or a carrier daughter, while a male with choroideremia will have all carrier daughters and unaffected sons.
Even though the disease progression can vary significantly, there are general trends. The first symptom many individuals with choroideremia notice is a significant loss of night vision, which begins in youth. Peripheral vision loss occurs gradually, starting as a ring of vision loss, and continuing on to "tunnel vision" in adulthood. Individuals with choroideremia tend to maintain good visual acuity into their 40s, but eventually lose all sight at some point in the 50–70 age range. A study of 115 individuals with choroideremia found that 84% of patients under the age of 60 had a visual acuity of 20/40 or better, while 33% of patients over 60 years old had a visual acuity of 20/200 or worse. The most severe visual acuity impairment (only being able to count fingers or worse) did not occur until the seventh decade of life. The same study found the mean rate of visual acuity loss to be about 0.09 logMAR per 5 years, which is roughly 1 row on a Snellen chart.

Diagnosis
A diagnosis of choroideremia can be made based on family history, symptoms and the characteristic appearance of the fundus. However, choroideremia shares several clinical features with retinitis pigmentosa, a similar but broader group of retinal degenerative diseases, making a specific diagnosis difficult without genetic testing. Because of this choroideremia is often initially misdiagnosed as retinitis pigmentosa. A variety of different genetic testing techniques can be used to make a differential diagnosis.

Management
While nothing currently can be done to stop or reverse the retinal degeneration, there are steps that can be taken to slow the rate of vision loss. UV-blocking sunglasses for outdoors, appropriate dietary intake of fresh fruit and leafy green vegetables, antioxidant vitamin supplements, and regular intake of dietary omega-3 very-long-chain fatty acids are all recommended. One study found that a dietary supplement of lutein increases macular pigment levels in patients with choroideremia. Over a long period of time, these elevated levels of pigmentation "could" slow retinal degeneration. Additional interventions that may be needed include surgical correction of retinal detachment and cataracts, low vision services, and  counseling to help cope with depression, loss of independence, and anxiety over job loss.

Gene therapy
Gene therapy is currently not a treatment option, however human clinical trials for both choroideremia and Lebers congenital amaurosis (LCA) have produced somewhat promising results.Clinical trials of gene therapy for patients with LCA began in 2008 at three different sites. In general, these studies found the therapy to be safe, somewhat effective, and promising as a future treatment for similar retinal diseases.
In 2011, the first gene therapy treatment for choroideremia was administered. The surgery was performed by Robert MacLaren, Professor of Ophthalmology at the University of Oxford and leader of the Clinical Ophthalmology Research Group at the Nuffield Laboratory of Ophthalmology (NLO). In the study, 2 doses of the AAV.REP1 vector were injected subretinally in 12 patients with choroideremia. There study had 2 objectives:

to assess the safety and tolerability of the AAV.REP1 vector
to observe the therapeutic benefit, or slowing of the retinal degeneration, of the gene therapy during the study and at a 24-month post-treatment time pointDespite retinal detachment caused by the injection, the study observed initial improved rod and cone function, warranting further study.
In 2016, researchers were optimistic that the positive results of 32 choroideremia patients treated over four and a half years with gene therapy in four countries could be long-lasting.

Preimplantation genetic diagnosis
For women who carry a mutation in the CHM gene, preimplantation genetic diagnosis can be used during the in-vitro fertilization process to select unaffected embryos to implant.  This process call be applied to any monogenic disease.

Other potential therapies
While choroideremia is an ideal candidate for gene therapy there are other potential therapies that could restore vision after it has been lost later in life. Foremost of these is stem cell therapy. A clinical trial published in 2014 found that a subretinal injection of human embryonic stem cells in patients with age-related macular degeneration and Stargardt disease was safe and improved vision in most patients. Out of 18 patients, vision improved in 10, improved or remained the same in 7, and decreased in 1 patient, while no improvement was seen in the untreated eyes. The study found "no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue."  A 2015 study used CRISPR/Cas9 to repair mutations in patient-derived induced pluripotent stem cells that cause X-linked retinitis pigmentosa. This study suggests that a patients own repaired cells could be used for therapy, reducing the risk of immune rejection and ethical issues that come with the use of embryonic stem cells.

Research
History
Choroideremia was first described in 1872 by an Austrian ophthalmologist, Ludwig Mauthner. Initially, the condition was thought to be a developmental disorder which caused the absence of a majority of the choroid (hence the probable use of the ancient Greek suffix “eremia,” meaning barren land or desert). After several decades, the non-progressive nature of the disease was called into doubt, eventually being rejected by Paymerer et al. in 1960. The CHM gene was identified and cloned in 1990 by Frans P.M. Cremers.

Basic research
In many inherited retinal diseases the protein affected by the mutation is directly involved in the light sensing function of the eye, however this is not the case in choroideremia. REP1 assists the prenylation of Rab G-proteins by binding and presenting them to the Rab geranylgeranyltransferase subunit. REP1 also escorts prenylated Rabs through the cytoplasm by binding the hydrophobic prenyl groups and carrying them to a specific destination membrane.In healthy individuals, REP1 is found throughout all of the cells of the body, however patients with choroideremia only experience vision loss, and not broader, systemic symptoms (with the exception of a study that found crystals and fatty acid abnormalities in leukocytes) </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 Cor bovinum and can you explain it in depth? [/INST] Cor bovinum  or cor bovis refers to a massive hypertrophy of the left ventricle of the heart due to volume overload, usually in earlier times in the context of tertiary syphilis but currently more often due to chronic aortic regurgitation, hypertensive and ischaemic heart disease.

Pathophysiology
Due to Syphilitic aortitis (a complication of tertiary syphilis) the aortic valve ring becomes dilated. The free margins of valve cusps no longer approximate leading to aortic valve insufficiency </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 Recurrent pyogenic cholangitis and can you explain it in depth? [/INST] Recurrent pyogenic cholangitis (RPC), also known as Hong Kong disease, Oriental cholangitis, and Oriental infestational cholangitis, is a chronic infection characterized by recurrent bouts of bacterial cholangitis with primary hepatolithiasis. It is exclusive to people who live or have lived in southeast Asia.

Presentation
Presentation can be atypical and without pain or fever, especially in the elderly.  Positive symptoms include biliary colic, acute pancreatitis, obstructive jaundice and less commonly, liver enlargement and abnormal liver function tests. Additional complications in the acute setting include ascending cholangitis, gallbladder empyema, clotting within the hepatic and portal veins, sepsis and death.Chronic biliary obstruction may cause jaundice, itchiness, liver abscesses, and cirrhosis, particularly at the left lobe segment 3, and can eventually lead to intraductal papillary mucinous neoplasm or cholangiocarcinoma.

Pathogenesis
With RPC, the gallstones found within the biliary system are made of calcium bilirubinate or pigmented calcium. Calcium bilirubinate stones are prevalent in Asia and very rare in Europe and the United States. They tend to be friable concretions of various shapes and sizes within the biliary tree, and their associated bile is often muddy in consistency and contains numerous fine particles of calcium bilirubinate as well. This differs greatly from cholesterol stones, which are common in Europe and the United States. The formation of calcium bilirubinate stones in RPC has been attributed to a high incidence of infection with Escherichia coli in bile. In humans, the majority of bilirubin is excreted in the bile as bilirubin glucuronide.Hepatolithiasis is associated with Clonorchis sinensis and Ascaris lumbricoides infestation of the liver </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 Pulled hamstring and can you explain it in depth? [/INST] Straining of the hamstring, also known as a pulled hamstring, is defined as an excessive stretch or tear of muscle fibers and related tissues.  Hamstring injuries are common in athletes participating in many sports.  Track and field athletes are particularly at risk, as hamstring injuries have been estimated to make up 29% of all injuries in sprinters.
Hamstring injuries can also come with a hip injury from sprinting. Symptoms for a hip injury are pain, aching and discomfort while running or any physical exercise.
The biceps femoris long head is at the most risk for injury, possibly due to its reduced moment of knee and hip flexion as compared to the medial hamstrings.

Causes of hamstring strain
The muscle group is prone to injuries due to the explosive nature of movement in sports and thus causing overload and overstretching of the hamstring musculature.
The other causes may be:

Previous injury
Poor muscle strength
Poor flexibility
Inadequate warm-up
Fatigue
Imbalance
OveruseThis condition is most commonly seen in:

Athletes involved in soccer, baseball, football, rugby
Dancers and water skiers
Sports involving cross-country skiing, downhill skiing, judo, cricket, and bull riding

Diagnosis
Grades
Grade 1
Sensation of cramp or tightness and a slight feeling of pain when the muscles are stretched or contracted.

Grade 2
With a grade two hamstring strain there is immediate pain which is more severe than the pain of a grade one injury. It is confirmed by pain on stretch, swelling and contraction of the muscle.

Grade 3
A grade three hamstring strain is a severe injury. There is an immediate burning or stabbing pain and the individual is unable to walk without pain. The muscle is completely torn and there may be a large lump of muscle tissue above a depression where the tear is.
After a few days with grade two and three injuries, a large bruise may appear below the injury site caused by the bleeding within the tissues.

Treatment
Recommended treatment for this injury consists of the RICE protocol — rest, ice, compression and elevation. The RICE method is primarily used to reduce bleeding and damage within the muscle tissue. Lower grade strains can easily become worse if the hamstring is not rested properly. Complete ruptures require surgical repair and rehabilitation.
Initial treatment of the injury, regardless of the severity of the strain, is the same. Within the first five days, the hamstring is rested in an elevated position with an ice pack applied for twenty minutes every two hours. A compression bandage is applied to limit bleeding and swelling in the tissues. After five days of rest, active rehabilitation begins.

Epidemiology
An academic study found that the most common and prevalent musculoskeletal injury in the world is a hamstring strain. The study further explains that hamstring strains represented 15% of all injuries per club per season also had a 34% chance of recurrence. Another study showed that a previous hamstring injury is one of the most cited risks for future injury, with as many as one-third of active individuals experiencing a re-injury within 2 weeks of returning to activity.
A meta-analysis article showed evidence that a history of hamstring injury and being of older age were associated with increased risk of hamstring strains. One study found that men and master athletes (athletes older than forty) were at an increased risk of hamstring strains compared with women and younger athletes. Women were approximately 3 times more likely to develop hamstring strain than males with the majority of these being non-sporting scenarios. Similarly the average age of non-sporting hamstring strains are from the ages of 40–60. Many of these non-sporting injuries are sustained during road traffic accidents, slipping, and falling. These results also show that hamstring strains account for 50% of muscle injuries received by sprinters and are the most common injury in hurdling. One explanation is that older active individuals may be at greater risk due to lower levels of eccentric knee flexor strength compared with their younger counterparts. However, it is unclear whether flexibility serves as a risk factor; this topic should be researched in the future to further understand the relationship between flexibility and risk of injury. Muscle weakness has also been an implication as a predisposing factor for both primary and recurring hamstring strain injuries. Over a 10-year study more than 51.3% of hamstring strains occurred during the preseason of athletics. In another study, that analyzed 25 NCAA sports over four years, it was clearly shown that hamstring strain rates are higher in the preseason. The factors that are being implicated in this trend are the relative deterioration and muscle weakness that occur during the off-season.The hamstrings undergo a complex dynamic process during gait, making it unsurprising that they are frequently injured </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 Hereditary diffuse leukoencephalopathy with spheroids and can you explain it in depth? [/INST] Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare adult onset autosomal dominant disorder characterized by cerebral white matter degeneration with demyelination and axonal spheroids leading to progressive cognitive and motor dysfunction. Spheroids are axonal swellings with discontinuous or absence of myelin sheaths. It is believed that the disease arises from primary microglial dysfunction that leads to secondary disruption of axonal integrity, neuroaxonal damage, and focal axonal spheroids leading to demyelination. Spheroids in HDLS resemble to some extent those produced by shear stress in a closed head injury with damage to axons, causing them to swell due to blockage of axoplasmic transport. In addition to trauma, axonal spheroids can be found in aged brain, stroke, and in other degenerative diseases. In HDLS, it is uncertain whether demyelination occurs prior to the axonal spheroids or what triggers neurodegeneration after apparently normal brain and white matter development, although genetic deficits suggest that demyelination and axonal pathology may be secondary to microglial dysfunction. The clinical syndrome in patients with HDLS is not specific and it can be mistaken for Alzheimers disease, frontotemporal dementia, atypical Parkinsonism, multiple sclerosis, or corticobasal degeneration.

Symptoms
With symptoms of personality changes, behavioral changes, dementia, depression, and epilepsy, HDLS has been commonly misdiagnosed for a number of other diseases. Dementia or frontotemporal behavioral changes, for example, have commonly steered some clinicians to mistakenly consider diagnoses such as Alzheimers disease, frontotemporal dementia or atypical Parkinsonism. The presence of white matter changes has led to misdiagnosis of multiple sclerosis. HDLS commonly manifests with neuropsychiatric symptoms, progressing to dementia, and after a few years shows motor dysfunction. Eventually patients become reliant on wheelchairs.White matter degeneration is associated with and makes differential diagnoses out of other adult onset leukodystrophies such as metachromatic leukodystrophy (MLD), Krabbe disease (globoid cell leukodystrophy), and X-linked adrenoleukodystrophy (X-ADL).

Neuropsychiatric symptoms
Many neuropsychiatric symptoms have been identified in clinical studies of HDLS patients. These include severe depression and anxiety that have been identified in about 70% of HDLS families, verging on suicidal tendencies and substance abuse such as alcoholism. Additionally, patients may exhibit disorientation, confusion, agitation, irritability, aggressiveness, an altered mental state, the loss of the ability to execute learned movements (apraxia), or the inability to speak (mutism).

Motor impairment
Persons with HDLS can develop tremors, decreased body movement, unsteadiness (Parkinsonism, muscles on one side of the body in constant contraction (spastic hemiparesis), impairment in motor and sensory function in the lower extremities (paraparesis), paralysis resulting in partial or total loss of all extremities and torso (tetraparesis), and the lack of voluntary coordination of muscle movements (ataxia).

Causes
The cause of HDLS in most families is mutation in the colony stimulating factor 1 receptor (CSF1R), a growth factor for microglia and monocyte/macrophages, suggesting that microglial dysfunction may be primary in HDLS.The mutations are concentrated in tyrosine kinase domain (TKD) of the protein. Mutations were mainly found in exons 12-22 of the intracellular TKD, including 10 missense mutations that have a single nucleotide deletion and a single codon deletion that consists of a triplet of nucleotides that have been removed causing a whole amino acid to not be coded. Additionally, three splice site mutations were identified that caused an in-frame deletion of an exon, an expressed nucleotide sequence, leading to the removal of more than 40 amino acids in the TKD.This determination has based upon genetic studies of 14 HDLS families confirming mutations in this gene. The CSF1 receptor protein primarily functions in regulation, survival, proliferation, and differentiation of microglial cells. The mechanism of microglial dysfunction due to mutations in CSF1R to the myelin loss and axonal spheroid formation remains unknown. Further research is needed to better understand disease pathogenesis.

Pathology
In HDLS, there is enlargement of the lateral ventricles and marked thinning or weakening of cerebral white matter. The loss of white matter is caused by myelin loss. These changes are associated with diffuse gliosis, moderate loss of axons and many axonal spheroids.Activated or ameboid microglia and macrophages that contain myelin debris, lipid droplets and brown autofluorescent pigment granules are found in the areas with demyelination and axonal spheroids. In severely degenerated areas there are many large, reactive astrocytes filled with glial fibrils.In autopsy cases, it has been shown that white matter abnormalities are relatively confined to the cerebrum while avoiding the cerebellum and many of the major fiber tracts of the nervous system. The exception is the corticospinal tracts(pyramidal tracts) in the brainstem and sometimes spinal cord.The brain pathology of HDLS resembles that of Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy).

Diagnosis
Research as of 2012 includes investigations of microglial function. This work would further clarify whether the disease is primarily a defect in microglia function. For such a study, microglial cells from HDLS kindred can be cultured from autopsy brain and analyzed in comparison to normal microglial cells on the basis of differences in mutation occurrences and growth factor expression.

Differential diagnosis
Related disorders in the same disease spectrum as HDLS include Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), and a type of leukodystrophy with pigment-filled macrophages called pigmentary orthochromatic leukodystrophy (POLD). In addition to white matter disease, Nasu-Hakola causes bone cysts. It is caused by mutations in the genes involved in the same colony stimulating factor (CSF) signaling pathway cascade as identified in HDLS.Nasu-Hakola disease appears to be caused by mutations in the TYRO protein tyrosine kinase-binding protein (TYROBP - also known as DAP12) or the triggering receptor expressed on myeloid cells 2 (TREM2) protein. While different gene mutations occur within the pathway for Nasu-Hakola and HDLS, both are characterized by white matter degeneration with axonal spheroids. Current researchers in the field believe that more in depth analysis and comparison of the two genetic abnormalities in these disorders could lead to a better understanding of the disease mechanisms in these rare disorders. POLD exhibits noninflammatory demyelination of axons with initial symptoms of euphoria, apathy, headache, and executive dysfunction. While HDLS is autosomal dominant, some families with POLD have features that suggest autosomal recessive inheritance. Nevertheless, POLD has recently been shown to have the same genetic basis as HDLS.

Clinical and genealogic studies
To gain a better understanding of the disease, researchers have retrospectively reviewed medical records of probands and others who were assessed through clinical examinations or questionnaires. Blood samples are collected from the families of the probands for genetic testing. These family members are assessed using their standard medical history, on their progression of Parkinsons like symptoms (Unified Parkinsons Disease Rating Scale), and on their progression of cognitive impairment such as dementia (Folstein Test).

Neuroimaging
Standard MRI scans have been performed on 1.5 Tesla scanners with 5 mm thickness and 5 mm spacing to screen for white matter lesions in identified families. If signal intensities of the MRI scans are higher in white matter regions than in grey matter regions, the patient is considered to be at risk for HDLS, although a number of other disorders can also produce white matter changes and the findings are not diagnostic without genetic testing or pathologic confirmation.

Pathology
Tissue sections from brain biopsies or autopsy brains are commonly embedded in paraffin from which sections are cut an mounted on glass slides for histologic studies. Special stains for myelin and axonal pathology show the abnormal changes that are characteristic of HDLS are identified in white matter of the neocortex, basal ganglia, thalamus, midbrain, pons and spinal cord. In addition to routine histologic methods (H&E staining), samples are evaluated with immunohistochemistry for ubiquitin, amyloid precursor protein, and neurofilament to characterize axonal changes and myelin basic protein for myelin pathology. Immunohistochemical stains for microglia (CD68 or HLA-DR) and astrocytes (GFAP) are also helpful techniques to characterize white matter pathology. With a similar pathology to POLD, HDLS is commonly grouped as adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) so as to give these individually under-recognized conditions heightened attention.

Classification
HDLS falls under the category of brain white matter diseases called leukoencephalopathies that are characterized by some degree of white matter dysfunction. HDLS has white matter lesions with abnormalities in myelin sheath around axons, where the causative influences are being continually explored based upon recent genetic findings. Studies by Sundal and colleagues from Sweden showed that a risk allele in Caucasians may be causative because cases identified have thus far been among large Caucasian families.

Management
Epidemiology
An average clinical profile from published studies shows that the median onset age for HDLS patients is 44.3 years with a mean disease duration of 5.8 years and mean age of death at 53.2 years. As of 2012, there have been around 15 cases identified with at least 11 sporadic cases of HDLS. HDLS cases have been located in Germany, Norway, Sweden, and the United States, showing an international distribution focusing between Northern Europe and the United States.Through the study of numerous kindred, it was found that the disease did not occur among just males or females, but rather was evenly distributed indicative of an autosomal rather than a sex-linked genetic disorder </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 Alopecia universalis and can you explain it in depth? [/INST] Alopecia universalis (AU), also known as alopecia areata universalis, is a medical condition involving the loss of all body hair, including eyebrows, eyelashes, chest hair, armpit hair, and pubic hair. It is the most severe form of alopecia areata. People with the disease are usually healthy and have no other symptoms and a normal life expectancy.

Causes
Alopecia universalis can occur at any age, and is currently believed to be an autoimmune disorder, in which a persons immune system attacks the hair follicles. Genetic factors may contribute to AU, as about 20% of those affected have a family member with alopecia.

Treatment
Many treatments have been explored, including immunomodulatory agents such as imiquimod. Tofacitinib citrate may also have benefits. In June 2014,  a 25-year-old man with almost no hair on his body was reported to have grown full head of hair, as well as eyebrows, eyelashes, and facial, armpit, and other hair, following eight months of treatment.Contact immunotherapy involves the use of contact allergens, such as diphencyprone  and squaric acid dibutylester, to induce an immune response that is thought to oppose the action of cells causing hair loss </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 Fibrolamellar hepatocellular carcinoma and can you explain it in depth? [/INST] Fibrolamellar hepatocellular carcinoma (FHCC) is a rare form of hepatocellular carcinoma (HCC) that typically affects young adults and is characterized, under the microscope, by laminated fibrous layers interspersed between the tumour cells.  Approximately 200 new cases are diagnosed worldwide each year.

Cause
A recent study showed the presence of the DNAJB1-PRKACA chimeric transcript (resulting from a 400kb somatic deletion on chromosome 19) in 100% of the FHCCs examined (15/15) This gene fusion has been confirmed in a second study.

Pathology
The histopathology of FHCC is characterized by laminated fibrous layers, interspersed between the tumor cells.  Cytologically, the tumor cells have a low nuclear to cytoplasmic ratio with abundant eosinophilic cytoplasm.  Tumors are non-encapsulated, but well circumscribed, when compared to conventional HCC (which typically has an invasive border).

Diagnosis
Due to lack of symptoms, until the tumor is sizable, this form of cancer is often advanced when diagnosed. Symptoms include vague abdominal pain, nausea, abdominal fullness, malaise and weight loss. They may also include a palpable liver mass. Other presentations include jaundice, ascites, fulminant liver failure, encephalopathy, gynecomastia (males only), thrombophlebitis of the lower limbs, recurrent deep vein thrombosis, anemia and hypoglycemia.The usual markers for liver disease – aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase – are often normal or only slightly elevated. FHCC often does not produce alpha fetoprotein (AFP), a widely used marker for conventional hepatocellular carcinoma. It is associated with elevated neurotensin levels.Diagnosis is normally made by imaging (ultrasound, CT or MRI) and biopsy

Treatment
In FHCC, plasma neurotensin and serum vitamin B12 binding globulin are commonly increased and are useful in monitoring the disease and detecting recurrence.FHCC can often be surgically removed. Liver resection is the optimal treatment and may need to be performed more than once, since this disease has a very high recurrence rate. Due to such recurrence, periodic follow-up medical imaging (CT or MRI) is necessary.As the tumor is quite rare, there is no standard chemotherapy regimen </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 Urticaria pigmentosa and can you explain it in depth? [/INST] Urticaria pigmentosa (also known as generalized eruption of cutaneous mastocytosis (childhood type): 616
) is the most common form of cutaneous mastocytosis.  It is a rare disease caused by excessive numbers of mast cells in the skin that produce hives or lesions on the skin when irritated.

Signs and symptoms
Urticaria pigmentosa is characterized by excessive amounts of mast cells in the skin.  Red or brown spots are often seen on the skin, typically around the chest, forehead, and back.  These mast cells, when irritated (e.g. by rubbing the skin, heat exposure), produce too much histamine, triggering an allergic reaction that leads to hives localized to the area of irritation, sometimes referred to as Dariers sign.  Severe itching usually follows, and scratching the area only serves to further symptoms.  Symptoms can be mild (flushing and hives that require no treatment), moderate (diarrhea, tachycardia, nausea/vomiting, headache, and fainting), or life-threatening (vascular collapse requiring emergency treatment and hospitalization).

Cause
The majority of urticaria pigmentosa cases are caused by a point mutation at amino acid 816 of the proto-oncogene c-kit.  c-kit is a transmembrane protein which, when bound to Mast Cell Growth Factor (MCGF), signals the cell to divide.  Mutations in position 816 of c-kit can result in a constant division signal being sent to the mast cells, resulting in abnormal proliferation.  Different mutations have been linked to different onset times of the disease.
For example, the Asp816Phe and Asp816Val mutations (the aspartate normally at position 816 in the c-kit protein has been replaced with phenylalanine or valine respectively) have been associated with early manifestation of the disease (mean age of onset: 1.3 and 5.9 months respectively).
The c-kit gene is encoded on the q12 locus of chromosome 4.

Irritants
Several factors can worsen the symptoms of urticaria pigmentosa:
Emotional stress
Physical stimuli such as heat, friction, and excessive exercise
Bacterial toxins
Venom
Eye drops containing dextran
NSAIDs
Alcohol
MorphineThe classification of NSAIDs can be disputed.  Aspirin, for example, causes the mast cells to degranulate, releasing histamines and causing symptoms to flare.  However, daily intake of 81 mg aspirin may keep the mast cells degranulated. Thus, while symptoms may be worsened at first, they can get better as the mast cells are unable to recharge with histamine.

Diagnosis
The disease is most often diagnosed as an infant, when parents take their baby in for what appears to be bug bites.  The bug bites are actually the clumps of mast cells.  Doctors can confirm the presence of mast cells by rubbing the babys skin.  If hives appear, it most likely signifies the presence of urticaria pigmentosa.

Treatments
There are no permanent cures for urticaria pigmentosa </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 Pipecolic acidemia 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 Breast hypertrophy and can you explain it in depth? [/INST] Breast hypertrophy is a rare medical condition of the breast connective tissues in which the breasts become excessively large. The condition is often divided based on the severity into two types, macromastia and gigantomastia. Hypertrophy of the breast tissues may be caused by increased histologic sensitivity to certain hormones such as female sex hormones, prolactin, and growth factors. Breast hypertrophy is a benign progressive enlargement, which can occur in both breasts (bilateral) or only in one breast (unilateral). It was first scientifically described in 1648.

Description and types
The indication is an excess breast weight that exceeds approximately 3% of the total body weight. There are varying definitions of what is considered to be excessive breast tissue, that is the expected breast tissue plus extraordinary breast tissue, ranging from as little as 0.6 kilograms (1.3 lb) up to 2.5 kilograms (5.5 lb) with most physicians defining macromastia as excessive tissue of over 1.5 kilograms (3.3 lb). Some resources distinguish between macromastia (Greek, macro: large, mastos: breast), where excessive tissue is less than 2.5 kg, and gigantomastia (Greek, gigantikos: giant), where excessive tissue is more than 2.5 kg. The enlargement can cause muscular discomfort and over-stretching of the skin envelope, which can lead in some cases to ulceration.Hypertrophy of the breast can affect the breasts equally, but usually affects one breast more than the other, thereby causing asymmetry, when one breast is larger than the other. The condition can also individually affect the nipples and areola instead of or in addition to the entire breast. The effect can produce a minor size variation to an extremely large breast asymmetry. Breast hypertrophy is classified in one of five ways: as either pubertal (virginal hypertrophy), gestational (gravid macromastia), in adult women without any obvious cause, associated with penicillamine therapy, and associated with extreme obesity. Many definitions of macromastia and gigantomastia are based on the term of "excessive breast tissue", and are therefore somewhat arbitrary.
A total of 115 cases of breast hypertrophy had been reported in the literature as of 2008.

Virginal breast hypertrophy
When gigantomastia occurs in young women during puberty, the medical condition is known as juvenile macromastia or  juvenile gigantomastia and sometimes as virginal breast hypertrophy or virginal mammary hypertrophy. Along with the excessive breast size, other symptoms include red, itchy lesions and pain in the breasts. A diagnosis is made when an adolescents breasts grow rapidly and achieve great weight, usually soon after her first menstrual period. Some doctors suggest that the rapid breast development occurs before the onset of menstruation.Some women with virginal breast hypertrophy experience breast growth at a steady rate for several years, after which the breasts rapidly develop exceeding normal growth. Some adolescent females experience minimal or negligible breast growth until their breasts suddenly grow very rapidly in a short period of time. This may cause considerable physical discomfort. Women with VBH often experience an excessive growth of their nipples as well. In severe cases of VBH, hypertrophy of the clitoris occurs.At the onset of puberty, some females with who have experienced little or no breast development can reportedly reach three or more cup sizes within a few days (see below).As of 1992, 70 cases of virginal breast hypertrophy had been reported.

Gestational breast hypertrophy
This same effect can also occur at the onset of pregnancy or between the 16th to 20th week of gestation. When the swelling in the connective tissue occurs after birth, it can negatively impact long term milk supply. The swelling increases with each subsequent pregnancy.
The extremely rapid growth of the breasts can result in intense heat. The womans breasts can generate extraordinary discomfort, turning feverish, red, itchy, and even causing the skin to peel. The swelling can suppress the milk supply, pinching off the milk ducts, and leading to mastitis.Gestational gigantomastia is estimated to in 1 out of every 28,000 to 100,000 pregnancies.Breast size in women with gestational breast hypertrophy typically reverts to approximately pre-pregnancy size or near it after pregnancy and cessation of breastfeeding. This is not always the case however and in some only partial reduction in breast size may occur, necessitating surgical breast reduction.

Other types of breast hypertrophy
Only 15% of cases of breast hypertrophy are unrelated to puberty or pregnancy. Other types and causes of breast hypertrophy include idiopathic, drug-induced (e.g., penicillamine, cyclosporine, bucillamine), autoimmunity-associated, tumors, and syndromes. Two case reports of prepubertal breast hypertrophy, both in infants, have been reported.

Causes
The underlying cause of the rapidly growing breast connective tissue, resulting in gigantic proportions, has not been well elucidated. However, proposed factors have included increased levels/expression of or heightened sensitivity to certain hormones (e.g., estrogen, progesterone, and prolactin) and/or growth factors (e.g., hepatocyte growth factor, insulin-like growth factor 1, and epidermal growth factor) in the breasts. Macromastic breasts are reported to be composed mainly of adipose and fibrous tissue, while glandular tissue remains essentially stable.Macromastia occurs in approximately half of women with aromatase excess syndrome (a condition of hyperestrogenism). Hyperprolactinemia has been reported as a cause of some cases of macromastia. Macromastia has also been associated with hypercalcemia (which is thought to be due to excessive production of parathyroid hormone-related protein) and, rarely, systemic lupus erythematosus and pseudoangiomatous stromal hyperplasia. It is also notable that approximately two-thirds of women with macromastia are obese. Aside from aromatase (as in aromatase excess syndrome), at least two other genetic mutations (one in PTEN) have been implicated in causing macromastia.A handful of drugs have been associated with gigantomastia, including penicillamine, bucillamine, neothetazone, ciclosporin, indinavir, and prednisolone.

Treatment
Medical treatment has not proven consistently effective. Medical regimens have included tamoxifen, progesterone, bromocriptine, the gonadotropin-releasing hormone agonist leuprorelin, and testosterone. Gestational macromastia has been treated with breast reduction drugs alone without surgery. Surgical therapy includes reduction mammaplasty and mastectomy. However, breast reduction is not clinically indicated unless at least 1.8 kg (4 lb) of tissue per breast needs to be removed. In the majority of cases of macromastia, surgery is medically unnecessary, depending on body height. Topical treatment includes regimens of ice to cool the breasts.Treatment of hyperprolactinemia-associated macromastia with D2 receptor agonists such as bromocriptine and cabergoline has been found to be effective in some, but not all cases. Danazol, an antiestrogen and weak androgen, has also been found to be effective in the treatment of macromastia.When hypertrophy occurs in adolescence, noninvasive treatments, including pharmaceutical treatment, hormone therapy,  and steroid use are not usually recommended due to known and unknown side effects. Once breast growth rate has stabilized, breast reduction may be an appropriate choice. In some instances after aggressive or surgical treatment, the breast may continue to grow or re-grow, a complete mastectomy may be recommended as a last resort.
Pregnancy is recognized as the second most common reason for hypertrophy. When secondary to pregnancy, it may resolve itself without treatment after the pregnancy ends.

Society and culture
Difficulties
Extremely large breasts are a source of considerable attention. Some women try to hide or mask their breasts with special clothing, including minimizing bras. Women with this condition may be subject to psychological problems due to unwanted attention or harassment. Depression is common in those affected.
In the case of a 12-year-old Japanese girl reported in 1993, her "massively enlarged" breasts caused her "intense psychological problems, incapacitating her in school activities and social relations". Actress Soleil Moon Frye, who starred as a child in the sitcom Punky Brewster, reported in an interview with People magazine that boys taunted her, calling her "Hey, Punky Boobster!". It affected her professional and social life negatively. "People started to think of me as a bimbo", she said in the interview. "I couldnt sit up straight without people looking at me like I was a prostitute", Frye said.Finding large bra-sizes and styles that fit is challenging. Also, larger bras are more costly, challenging to find, and unflattering to the wearer. Ill-fitting bras with narrow straps can cause chronic irritation, redness, and indentations in the shoulders. Skin rashes under the breasts are common, particularly during warm weather. Heavy breasts may cause headaches, neck pain, upper and lower back pain, and numbness or tingling in the fingers. There is a possible connection between macromastia and carpal-tunnel-syndrome.

Medical insurance coverage
Insurance companies in the United States typically require the physician to provide evidence that a womans large breasts cause headaches or back and neck pain before they will pay for reduction mammoplasty. Insurance companies also mandate a woman who is overweight, which is often the case with gigantomastia, to first lose a certain amount of weight. They also commonly require the patient to try alternative treatments like physical therapy for a year or more.

Reported instances
Gigantomastia
One early and extreme case study of gigantomastia dates to 1670. The patient died four months after the onset of enlargement. One breast removed after the womans death weighed 29 kg (64 lb).

On April 17, 1848, a 42-year-old woman named Lu-shi was treated for hypertrophy in a Chinese hospital. She was treated by a missionary physician. On December 24, 1849, the left breast, measuring 67 cm (26.5 in) in circumference, and weighing 2.7 kg (6 lb), was removed in a procedure lasting three and a half minutes. The right breast was removed one month later. It measured 61 cm (24 in) in circumference and weighed 2.5 kg (5.5 lb).In 2005, a woman reported that her breasts grew at puberty from nothing to a C cup in one month. When she became pregnant for the first time, her breasts increased two cup sizes in a few days. Immediately after her first birth, her breasts grew three cup sizes. After her second child was born, her breasts increased six cup sizes. After her third childbirth, they grew 10 cup sizes, and after her fourth child was born, they grew nine cup sizes. In this instance, the swelling abated about 10 days after childbirth, but her bra cup size remained E to a G for the next year. About one year postpartum, her breasts rapidly atrophied to AA cup size.One of the most severe cases of macromastia was reported from Ilorin in Nigeria. In 2007, Dr Ganiyu Adebisi Rahman and his colleagues reported the case of a 26-year-old woman who presented with massive swelling of her breasts and bilateral axillary swellings of 6 years duration. Dr Rahman led a team of surgeons in Ilorin to perform a total bilateral excision of the hypertrophied axillary breasts, and bilateral breast amputation with composite nipple-areola complex graft of the normally located breasts. The total weight of the breast tissues removed was 44.8 kilograms.Another extreme case was observed in 2008 in Maria Vittoria Hospital in Turin, Italy, where the amount removed from both breasts was 17.2 kg (38 lb). The growth occurred during puberty making it a case of juvenile gigantomastia, but the patient did not seek treatment until the age of 29. Another extreme case was observed on August 28, 2003, when a 24-year-old woman was admitted to the Clinical Center Skopje in Macedonia with gigantomastia of pregnancy and the amount later removed from both breasts was 15 kg (33 lb) in total. A second case in Macedonia was reported when the breasts of a 30-year-old woman from a remote mountain village in eastern Macedonia suddenly grew to more than 30 kilograms (66 lb) total.As the disorder becomes more widely known, media reports have increased. French Canadian Isabelle Lanthier appeared on Montel Williams talk show where she told how her chest grew from 86 cm (34 in) to 133 cm (52.5 in) in five months during her pregnancy. At their largest, one breast weighed 6.8 kg (15 lb) and the other 5.4 kg (12 lb). Her husband custom-made a special bra to support her breasts.In 2007, a Chilean TV station covered the story of 32-year-old Yasna Galleguillos from Antofagasta, who experienced ongoing back pain, making everyday tasks very difficult to perform. She underwent breast reduction surgery to relieve her pain. Surgeons removed 4.25 kilograms (9.4 lb) from one breast and 3.33 kilograms (7.3 lb) from the other breast.On October 29, 2009, the Philippine television network GMA News and Public Affairs, producers of Wish Ko Lang ("Just My Wish") hosted by Vicky Morales, profiled the story of Pilma Cabrijas, a 30-year-old woman affected by gigantomastia. The woman was told by a folk healer that her condition may have been caused by a curse. The measured bust circumference without appropriate bra support was 160 cm (63 in). The weight of her breasts was not reported in detail, but seemed to weigh "as much as two children." She had breast reduction surgery performed, but her breasts regrew. The producers of Wish Ko Lang paid for additional surgery.

Virginal breast hypertrophy
In 1993, the Japanese journal Surgery Today reported on the case of a 12-year-old girl. Only 152 centimetres (60 in) tall and weighing 43 kilograms (95 lb), her breasts began to develop at age 11 before the onset of menstruation. Over the next eight months, both breasts grew abnormally large, and physicians treating her found that her physiological development was normal except for her breasts. The weight produced by their symmetrical and massive enlargement resulted in marked curvature of the spine. Lab tests of her blood for hormones and biochemical substances showed normal values, though tests revealed that it might have been caused by hypersensitivity to estrogen. She underwent a bilateral reduction mammoplasty. Surgeons removed  2 kilograms (4.4 lb) of tissue from her right breast and 1.9 kilograms (4.2 lb) from her left breast. She was administered tamoxifen afterward to suppress breast regrowth.A more severe case of virginal breast hypertrophy of an 11-year-old girl was reported in 2008. The breasts had begun to grow rapidly at puberty and had reached the point of causing physical impairment and respiratory compromise after one year. The skin was intact without any ulcerations. Blood chemistry and endocrine investigation was normal. A bilateral reduction mammaplasty with free nipple grafts was performed. Six kg of the right breast and 6.5 kg of the left breast were removed, resulting in a removal of 12.5 kg of tissue in all (24% of the total body weight).

See also
Mammoplasia
Norma Stitz

References
Further reading
Touraine, P. (2005). "Breast Inflammatory Gigantomastia in a Context of Immune-Mediated Diseases". Journal of Clinical Endocrinology & Metabolism. 90 (9): 5287–5294. doi:10.1210/jc.2005-0642. PMID 15972574.
Oladele, AO; Olabanji, JK; Alabi, GH (2007). "Reduction mammoplasty: The experience in Ile-Ife, Nigeria". Nigerian Journal of Medicine. 16 (3): 261–267. PMID 17937167.
Netscher, David T.; Mosharrafa, ALI M.; Laucirica, Rodolfo (1996). "Massive Asymmetric Virginal Breast Hypertrophy". Southern Medical Journal. 89 (4): 434–7. doi:10.1097/00007611-199604000-00019. PMID 8614890.
U.S.A. Library of Congress - Healthy Breasts: A Primer
John Blair Deaver (1917). The Breast: Its Anomalies, Its Diseases, and Their Treatment. P. Blakistons Son & Co. p. 102.
Joseph, Jacques (1987). Rhinoplasty and facial plastic surgery with a supplement on mammaplasty and other operations in the field of plastic surgery of the body: an atlas and textbook. Phoenix: Columella Press. p. 755. ISBN 0-9605972-1-2.
Plummer, Samuel C.; Bump, Warner S. (1927). "Massive Hypertrophy of the Breasts". Annals of Surgery. 85 (1): 61–6. doi:10.1097/00000658-192701000-00008. PMC 1399262. PMID 17865606.
Warren, John Collins (1900). The International text-book of surgery. Vol. II. Saunders. p. 234.
Erichsen, John Eric (1885). The Science and art of surgery. Vol </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 Currarino syndrome and can you explain it in depth? [/INST] Currarino syndrome  is an inherited congenital disorder where either the sacrum (the fused vertebrae forming the back of the pelvis) is not formed properly, or there is a mass in the presacral space in front of the sacrum, and there are malformations of the anus or rectum. It occurs in approximately 1 in 100,000 people.Anterior sacral meningocele is the most common presacral mass in patients with Currarino syndrome, occurring in 60% of cases </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 Gastrojejunocolic fistula 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 Fixed drug reaction 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 Lymphangioma circumscriptum and can you explain it in depth? [/INST] Superficial lymphatic malformation  is a congenital malformation of the superficial lymphatics, presenting as groups of deep-seated, vesicle-like papules resembling frog spawn, at birth or shortly thereafter. Lymphangioma circumscriptum is the most common congenital lymphatic malformation </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 Oxycephaly 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 Isodicentric 15 and can you explain it in depth? [/INST] Isodicentric 15, also called marker chromosome 15 syndrome, idic(15), partial tetrasomy 15q, or inverted duplication 15 (inv dup 15), is a chromosome abnormality in which a child is born with extra genetic material from chromosome 15. People with idic(15) are typically born with 47 chromosomes in their body cells, instead of the normal 46. The extra chromosome, which is classified as a small supernumerary marker chromosome, is made up of a piece of chromosome 15 that has been duplicated end-to-end like a mirror image. It is the presence of this extra genetic material that is thought to account for the symptoms seen in some people with idic(15). Individuals with idic(15) have a total of four copies of this chromosome 15 region instead of the usual two copies (1 copy each on the maternal and paternal chromosomes).
The syndrome is also often referred to by the term Chromosome 15q11.2-q13.1 Duplication Syndrome, shortened to Dup15q Syndrome, or marker chromosome 15 syndrome (mainly in the United States). Dup15q Syndrome includes both idic(15) and interstitial 15q11.2-q13.1, another type of duplication that causes similar clinical traits.
The extra chromosome is occasionally found in the mosaic state, i.e. some of the cells carry the marker chromosome. However, mostly because of the markers instability and tendency to be lost during cell division (mitosis), some cells are completely normal with 46 chromosomes. Occasionally, cells may have more than one idic(15), resulting in 48 or 49 chromosomes in all or some of their cells. A similar clinical picture albeit to a milder degree could be expected in individuals that have the extra chromosome 15 material as an interstitial duplication (when the extra piece of chromosome 15 is included within the long arm of one of the two copies of chromosome 15, rather than as a small extra marker chromosome) - often abbreviated to int dup(15); the individual thus having 46 chromosomes.

Signs and symptoms
The severity of symptoms of idic(15) vary greatly between individuals. Individuals with idic(15) usually have delays in language development and motor skills such as walking or sitting up. Other traits may include low muscle tone (hypotonia), seizures (>50%), short stature, and intellectual disability. Distinctive facial features associated with idic(15) - where present at all - are usually very subtle but may include epicanthal folds (skin folds at the inner corners of one or both eyes), downward slanting palpebral fissures, broad forehead, a flattened nasal bridge, button nose, and a high arched palate (roof of the mouth). Some individuals show other signs that can often be associated with chromosomal conditions, such as pectus excavatum, or a unilateral or bilateral single transverse palmar crease. Many individuals with idic(15) display features of autism, such as problems with communication and social interactions, obsessional interests (often with interactive mechanisms like wheels, doors or switches), unpredictable sleep cycles (and a reduced need for sleep), and repetitive and stereotyped behaviors (e.g., lining up toys, playing with a toy in the same manner over and over again, hand flapping, rocking back and forth). Sensory processing is often affected, especially the vestibular system.  A high pain threshold is often observed. If speech develops, it is often echolalic but some individuals do grasp some language. With a severely affected person there may be an inability to walk or talk.

Genetics
Generally, idic(15) is not inherited; it is said to appear de novo, in one member of the family, by chance. In most cases, the abnormal chromosome is generated in the mothers germ cells: the oocytes. This finding is due to ascertainment bias; cases with maternally derived idic(15) usually have clinical findings and attract attention, but those with paternally derived idic(15) usually do not. Thus, diagnosed cases are usually patients where the duplicated material is derived from the mothers egg cell rather than the fathers sperm cell.People with idic(15) have extra genetic material that has developed from chromosome 15. The material usually exists as a little extra chromosome 15; sometimes called a marker chromosome or an extra structurally abnormal chromosome (ESAC).  The marker usually exists as an isodicentric chromosome; i.e. 2 copies of a specific part of the long arm of chromosome 15q11.2-q13.1 that is mirrored and doubled, with 2 centromeres and 2 DNA satellites. The smallest markers appear to be harmless and they may go undetected. However, if they are large enough to contain a number of important genes, they may result in "idic(15) syndrome" which is characterized by learning disabilities, autism and other neurological symptoms. One of the regions responsible for the symptoms of idic(15) syndrome is the critical PWS/AS-region named after the Prader-Willi and/or Angelman syndromes.

Isodicentric chromosome 15 and autism
For more than 12 years, scientists have noticed that some individuals with autism also have idic(15). In fact, idic(15) is the most frequently identified chromosome problem in individuals with autism. (A chromosome anomaly involves extra or missing chromosomal material, not changes within the genes such as Fragile X syndrome). It is suggested that the co-occurrence of autism and idic(15) is not by chance. There may be a gene or genes in the 15q11-q13 region that is/are related to the development of autism in some individuals.Genetic research studies of individuals without chromosome anomalies also support this idea that an autism-related gene may be present in 15q11.2-q13.1 Specifically, research studies found that certain DNA markers from the (15q1.2-q13.1) region were found more often in individuals with autism than in individuals without autism. Although these DNA markers are too small to be genes, they suggest that researchers may be getting close to finding an autism gene in this region.A recent study reported the introduction of two extra copies of just a single gene present in the 15q11.2-q13.1 region, Ube3a, into mice to model the gene copy number expressed in the brain in idic(15). These mice displayed autism-related behavioral deficits including impaired social interaction, reduced ultrasonic vocal communication, and increased repetitive behavior (self-grooming).

Diagnosis
The extra chromosome in people with idic(15) can be easily detected through chromosome analysis (karyotyping). Additional tests are usually required. FISH (Fluorescent in situ hybridization) is used to confirm the diagnosis by distinguishing idic(15) from other supernumerary marker chromosomes. Array CGH can be used to determine the gene content and magnitude of copy number variation so that the clinical picture can be foreseen.
Interstitial duplications of chromosome 15 can be more difficult to detect on a routine chromosome analysis but are clearly identifiable using a 15q FISH study. Families should always discuss the results of chromosome and FISH studies with a genetic counselor or other genetics professionals to ensure accurate interpretation.

Screening
In general, idic(15) occurs de novo but the parents must be karyotyped to make sure it is not inherited, mostly because this will affect the course of genetic counseling given to the family. If the abnormality is found prenatally and one of the parents harbour the marker, the child has a chance of not carrying the mutation. Further tests should however be done to prove the marker has not been rearranged while being inherited. This information is also necessary for counseling of future pregnancies. Each family is unique and should therefore be handled individually.

Management
At the present time, there is no specific treatment that can undo any chromosomal abnormality, nor the genetic pattern seen in people with idic(15) </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 Acquired generalized lipodystrophy and can you explain it in depth? [/INST] Acquired generalized lipodystrophy (also known as "Lawrence syndrome," and "Lawrence–Seip syndrome", abbreviation: AGL) is a rare skin condition that appears during childhood or adolescence, characterized by fat loss affecting large areas of the body, particularly the face, arms, and legs.: 496  There are 4 types of lipodystrophy based on its onset and areas affected: acquired or inherited (congenital or familial), and generalized or partial. Both acquired or inherited lipodystrophy present as loss of adipose tissues. The near-total loss of subcutaneous adipose tissue is termed generalized lipodystrophy while the selective loss of adipose tissues is denoted as partial lipodystrophy. Thus, as the name suggests, AGL is a near-total deficiency of adipose tissues in the body that is developed later in life. It is an extremely rare disease that only about 100 cases are reported worldwide. There are three main etiologies of AGL suspected: autoimmune, panniculitis-associated, or idiopathic. After its onset, the disease progresses over a few days, weeks, months, or even in years. Clinical presentations of AGL are similar to other lipodystrophies, including metabolic complications and hypoleptinemia. Treatments are also similar and mainly supportive for symptomatic alleviation. Although HIV- or drug-induced lipodystrophy are a type of acquired lipodystrophy, its origin is very specific and distinct hence is usually not discussed with AGL (see HIV-Associated Lipodystrophy).

Symptoms
The clinical presentation is similar to people with congenital lipodystrophy: the only difference is that AGL patients are born with normal fat distribution and symptoms develop in childhood and adolescence years and rarely begins after 30 years of age. Females are more often affected than males, with ratio being 3:1.The hallmark characteristics are widespread loss of subcutaneous fat, ectopic fat deposition, leptin deficiency, and severe metabolic abnormalities such as insulin resistance. Subcutaneous fat loss in AGL patients are visible in all parts of the body. AGL mostly affects face and the extremities and may look sunken or swollen in the eyes. However, the degree and location of severity may vary by person. Especially, intra-abdominal fat loss is variable. As subcutaneous fat is lost, affected areas show prominent structures of veins and muscle. Those with panniculitis-associated AGL may present erythematous nodules.Metabolic complications include insulin resistance, high metabolic rate, and uncontrolled lipid levels such as hypertriglyceridemia, low HDL, and high LDL. Patients may develop diabetes mellitus secondary to insulin resistance.
Recent case reports revealed that lymphoma is present in some patients but its prevalence is not known at this time.

Cause
There is no known cause for this disease; however, three origins of AGL are generally suspected: panniculitis-associated, autoimmune-associated, and idiopathic AGLs. Triggers may include infections that aggravate the panniculitis, or any disease state that can induce autoimmunity. Overlap between panniculitis and autoimmune types also exists. Another theory suggest that AGL is an autoimmune disease itself, as panniculitis can be described as an autoimmune disease, however its triggering factors remains to be unknown. Underlying genetic factor may be associated; however neither confirmed nor rejected.

Panniculitis-associated AGL
About 25% of previously reported AGL is associated with panniculitis. Panniculitis is an inflammatory nodules of the subcutaneous fat, and in this type of AGL, adipose destruction originates locally at the infection or inflammation site and develops into generalized lipodystrophy.

Autoimmune-associated AGL
AGL with autoimmune origin is responsible for about 25% of all AGL reports. Those with autoimmune origin stems from other autoimmune diseases, most commonly with juvenile dermatomyositis and autoimmune hepatitis, but also occurs with rheumatoid arthritis, systemic lupus erythematosus, and Sjogren syndrome.

Idiopathic AGL
Although idiopathic AGL accounts for about 50% of all AGL, it can vary in its origin and it is unclear how it develops.No known preventive measurement has been reported.

Mechanism
The exact pathophysiologic mechanism is mostly unknown; however, each of three main origins, autoimmune, panniculitis, or idiopathic, may have different mechanisms of pathogenesis.Normally, adipose tissues contain adipocytes to store fat for energy during fasting period and release leptin to regulate homeostasis of energy and sensitize insulin. In AGL patients, adipose tissues are insufficient and leads to fat deposition in non-adipose tissues, such as muscle or liver, resulting in hypertriglyceridemia. Continuous elevation in triglyceride levels further contributes to metabolic problems including insulin resistance. As the level of leptin in the body is proportional to the amount of adipose tissue present, AGL patients also have a deficiency of leptin which contributes to excessive eating and worsens the metabolic syndrome.In a few patients with AGL, the presence of antibodies against adipocyte has been identified.

Diagnosis
Diagnosis is made comprehensively, together with visual observation, body fat assessment, a review of lab panels consisting of A1c, glucose, lipid, and patient history.
Caliper measurements of skinfold thickness is recommended to quantify fat loss as a supportive information. In this measurement, skinfold thickness of less than 10mm for men and 22mm for women at the anterior thigh is suggestive cutoff for the diagnosis of lipodystrophy. Less commonly, biphotonic absorptiometry and magnetic resonance imaging (MRI) can be done for the measurement of body fat.Other forms of insulin resistance may be assessed for differential diagnosis. Resistance to conventional therapy for hyperglycemia and hypertriglyceridemia serves as an indication for lipodystrophy. Specifically, the diagnosis is strongly considered for those requiring ≥200 units/day of insulin and persistent elevation of ≥250 mg/dl of triglyceride levels.The use of leptin levels should be carefully approached. While low leptin levels are helpful for making the diagnosis, they are not specific for the lipodystrophy. High leptin levels can help excluding the possible lipodystrophy, but there is no well-established standardized leptin ranges.

Treatment
Initial and general approach for AGL patients are to treat the metabolic complications such as leptin-replacement therapy and/or to control the abnormal levels of lipids or glucose levels. Anti-diabetic medications such as insulin, metformin, or thiazolidinediones are used for insulin-resistance or high glucose levels, or statins or fibrates are used for hyperlipidemia. If symptoms persist, metreleptin can be prescribed.
Metreleptin (MYALEPT) is a recombinant human leptin analog and was approved by FDA in 2014 for generalized lipodystrophy as an adjunct therapy to diet to treat the complication of leptin deficiency. It is the only drug option approved for generalized lipodystrophy-related symptoms and is not intended to use for patients with HIV-related lipodystrophy or complications of partial lipodystrophy. Although it is a recombinant human leptin analog, it is not completely the same as natural leptin as it is produced in e. coli and has added methionine residues at is amino terminus </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 Hereditary pancreatitis and can you explain it in depth? [/INST] Hereditary pancreatitis (HP) is an inflammation of the pancreas due to genetic causes. It was first described in 1952 by Comfort and Steinberg but it was not until 1996 that Whitcomb et al isolated the first responsible mutation in the trypsinogen gene (PRSS1) on the long arm of chromosome seven (7q35).
The term "hereditary pancreatitis" is used when a genetic biomarker is identified, and "familial pancreatitis" otherwise.

Presentation
HP is characterised by attacks of epigastric pain, which are often associated with nausea and vomiting. Symptoms may start shortly after birth but onset varies periodically, with some patients not exhibiting symptoms until adulthood </s>