<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Ventriculitis and explain in detail? [/INST] Ventriculitis is the inflammation of the ventricles in the brain. The ventricles are responsible for containing and circulating cerebrospinal fluid throughout the brain. Ventriculitis is caused by infection of the ventricles, leading to swelling and inflammation. This is especially prevalent in patients with external ventricular drains and intraventricular stents. Ventriculitis can cause a wide variety of short-term symptoms and long-term side effects ranging from headaches and dizziness to unconsciousness and death if not treated early. It is treated with some appropriate combination of antibiotics in order to rid the patient of the underlying infection. Much of the current research involving ventriculitis focuses specifically around defining the disease and what causes it. This will allow for much more advancement in the subject. There is also a lot of attention being paid to possible treatments and prevention methods to help make this disease even less prevalent and dangerous.

Signs and symptoms
There is great deal of variety in the symptoms associated with ventriculitis. The symptoms vary based on a number of different factors including severity of inflammation, underlying cause, and the individual patient.
Patients often present with headaches, painful cranial pressure, and neck pain early in the progression of the disease. Patients with a more advanced infection have been known to complain of many neurological effects such as dizziness, vertigo, confusion, and slurred speech. Very advanced cases can lead to mental instability, nausea, vomiting, rigors, and temporary loss of consciousness. Many patients with ventriculitis also experience some degree of hydrocephalus, which is the buildup of cerebrospinal fluid due to the inability of the ventricles to reabsorb and correctly circulate the fluid. Brain abscess is another common disorder resulting from the inflammation. If left untreated, ventriculitis can lead to serious inhibition of mental function and even death.
The symptoms vary greatly, in part, because of the underlying or causing infection. While the inflammation can cause a number of effects such as those mentioned previously, the base infection could cause other symptoms that dont necessarily have to do with the ventriculitis, itself. One of the challenges doctors face in diagnosing ventriculitis is distinguishing indicative symptoms, in spite of the wide variety of possible presentations of the disease. A great deal of emphasis is being put on research into better and faster ways to diagnose ventriculitis without the delay inherent with microbiological testing of the cerebrospinal fluid.The progression of the disease is also largely dependent on the nature of the specific case. Depending on the underlying infection, the way it entered the brain, and the type and timing of treatment, the infection may spread or withdraw on the order of months or days. Ventriculitis is a very serious condition and should be treated early to ensure as little lasting damage as possible.

Cause
Ventriculitis is caused by an infection of the ventricles, causing an immune response in the lining, which in turn, leads to inflammation. The ventriculitis, is in truth, a complication of the initial infection or abnormality. The underlying infection can come in the form of a number of different bacteria or viruses. The data seems to point to Staphylococci as the leading bacterial cause of infection leading to ventriculitis being present in about 90% of cases, but generally, what is of more concern is the way the infection entered the ventricles. The brain in its natural state is very protected from infection. The blood–brain barrier serves to keep pathogens from entering the sensitive areas of the brain. However, when those natural defenses are by-passed in the hospital setting, the brain is suddenly exposed to a host of potentially harmful bacteria and viruses.
Patients that have had invasive brain surgery or procedures are considered to be the most at risk for experiencing ventriculitis. Two procedures, in particular have been studied extensively due to their high rate of ventriculitis contractions post operation. The first group consists of patients that have had an external ventricular drain implanted to allow physicians to reduce the intracranial pressure they experience. The duration that the drain is implanted varies by necessity, however, the longer the drain is in, the more likely an infection will occur. The second group consists of patients that have an implanted intracranial stent. Both groups of patients have a much higher rate of ventriculitis than the general populace, though there is very little supporting evidence due to the lack of definition of ventriculitis as frequent misdiagnosis. Nearly 25% of patients with an external ventricular drain experience infection-based meningitis or ventriculitis.

Diagnosis
Ventriculitis is commonly diagnosed using a variety of tests or procedures. When a physician suspects that a patient has ventriculitis, the first step is typically to ascertain the presence of the inflammation using computed tomography (CT) or magnetic resonance imaging (MRI) technology to "take a picture" of the brain. The scans allow physicians to check for "intraventricular debris and pus, abnormal periventricular and subependymal signal intensity, and enhancement of the ventricular lining," all of which indicate the likelihood of ventriculitis. MRIs have been reported as being highly effective and sensitive in detecting such indicators, even from an early stage.
After determining whether a patient shows signs of ventriculitis, the doctor may choose to pursue a more specific and useful diagnosis to find the cause of the ventriculitis. This is done by obtaining a sample of cerebrospinal fluid, most commonly via a procedure called a lumbar puncture or spinal tap. For patients with an implanted external ventricular drain, cerebrospinal fluid can be collected from the drains output. After the sample of fluid is obtained, a battery of tests featuring gram staining will be performed to identify any offending pathogen or infection agent. The test will also determine any resistance the pathogen may have to antibiotics. By identifying the viral or bacterial cause of the ventriculitis, doctors are more able to effectively treat the inflammation and infection. This procedure is fairly effective, but is rarely able to isolate anaerobic organisms that may be causing the inflammation, giving cause for further research and procedural development.Though they present with similar symptoms and often occur in tandem, meningitis and ventriculitis are two different diseases, so physicians must be able to distinguish between the two. Meningitis is the inflammation of the protective lining of the central nervous system, called meninges. Because of the similar pathologies and cause of the two types of inflammation, they are difficult to differentiate using chemical testing, but show very different visual effects in both the MRI and CT scans, hence their use as a validation that the patient does, in fact, have ventriculitis and not another, similar condition such as meningitis.

Treatment
Treatment of ventriculitis is critical. If left untreated, it could lead to severe brain damage and even death in some cases. Currently, the only commonly employed treatments of ventriculitis involve an antibiotic regimen targeting the underlying infection causing the inflammation. Typically, the physician will order the patient be placed on broad-spectrum antibiotics in order to manage the symptoms and control the infection while the cerebrospinal fluid samples are analyzed. When a specific bacterial or viral cause is found, the doctor will change the treatment accordingly. There is some debate as to the most effective antibiotics and the best ways to introduce the drugs (e.g. intravenously, orally, etc.), however it is agreed that drug effectiveness is limited by the difficulty of non-invasively allowing the drugs to enter the cerebrospinal fluid.
Should intracranial pressure reach unsafe levels, the patient may need to have cerebrospinal fluid drained. Implanted external ventricular drains are one of the more common ways to manage and monitor the intracranial pressure, however there are several risks involved with such an invasive procedure, including the risk of further infection.
There is a great deal of research focused around prevention of ventriculitis. It is crucial that any procedure involving exposing the brain is performed with the utmost care, as infections in the brain are very dangerous and potentially deadly. When patients undergo such procedures, they are often monitored closely over the next several days to ensure that there were no infections and any instance of even a small headache is treated very seriously. It is also necessary to monitor the intracranial pressure of the patients often enough to observe significant changes that could indicate the presence of and infection and ensuing ventriculitis. It is important not to measure the pressure too often, however, as it could in fact lead to infection.

Current research
Due to the poor definition of the condition that is ventriculitis, there is still a great deal that is not known about this dangerous condition. While other, similar conditions, such as meningitis or encephalitis, have been thoroughly researched, ventriculitis is a very loose grouping of conditions characterized by the fact that the lining of the ventricles is inflamed </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vitamin D deficiency and explain in detail? [/INST] Vitamin D deficiency or hypovitaminosis D is a vitamin D level that is below normal. It most commonly occurs in people when they have inadequate exposure to sunlight, particularly sunlight with adequate ultraviolet B rays (UVB). Vitamin D deficiency can also be caused by inadequate nutritional intake of vitamin D; disorders that limit vitamin D absorption; and disorders that impair the conversion of vitamin D to active metabolites, including certain liver, kidney, and hereditary disorders. Deficiency impairs bone mineralization, leading to bone-softening diseases, such as rickets in children. It can also worsen osteomalacia and osteoporosis in adults, increasing the risk of bone fractures. Muscle weakness is also a common symptom of vitamin D deficiency, further increasing the risk of fall and bone fractures in adults. Vitamin D deficiency is associated with the development of schizophrenia.Vitamin D can be synthesized in the skin under the exposure of UVB from sunlight. Oily fish, such as salmon, herring, and mackerel, are also sources of vitamin D, as are mushrooms. Milk is often fortified with vitamin D; sometimes bread, juices, and other dairy products are fortified with vitamin D. Many multivitamins contain vitamin D in different amounts.

Classifications
Vitamin D deficiency is typically diagnosed by measuring the concentration of the 25-hydroxyvitamin D in the blood, which is the most accurate measure of stores of vitamin D in the body. One nanogram per millilitre (1 ng/mL) is equivalent to 2.5 nanomoles per litre (2.5 nmol/L).

Severe deficiency: <12 ng/mL = <30 nmol/L
Deficiency: <20 ng/mL = <50 nmol/L
Insufficient: 20–29 ng/mL = 50–75 nmol/L
Normal: 30–50 ng/mL = 75–125 nmol/LVitamin D levels falling within this normal range prevent clinical manifestations of vitamin D insufficiency as well as vitamin D toxicity.

Signs and symptoms
In most cases, vitamin D deficiency is almost asymptomatic. It may only be detected on blood tests but is the cause of some bone diseases and is associated with other conditions:

Complications
Rickets, a childhood disease characterized by impeded growth and deformity of the long bones. The earliest sign of vitamin D deficiency is craniotabes, abnormal softening or thinning of the skull.
Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. Women with vitamin D deficiency who have been through multiple pregnancies are at elevated risk of osteomalacia.
Osteoporosis, a condition characterized by reduced bone mineral density and increased bone fragility
Increased risk of fracture
Muscle aches, weakness, and twitching (fasciculations), due to reduced blood calcium (hypocalcemia)
Periodontitis, local inflammatory bone loss that can result in tooth loss.
Pre-eclampsia:  There has been an association of vitamin D deficiency and women who develop pre-eclampsia in pregnancy. The exact relationship of these conditions is not well understood. Maternal vitamin D deficiency may affect the baby, causing overt bone disease from before birth and impairment of bone quality after birth.
Respiratory infections and COVID-19:  Vitamin D deficiency may increase the risk of severe acute respiratory infections and COPD. Emerging studies have suggested a link between vitamin D deficiency and COVID-19 symptoms. A review has shown that vitamin D deficiency is not associated with a higher chance of having COVID-19 but is associated with a greater severity of the disease, including 80% increases in the rates of hospitalization and mortality.
Schizophrenia: Vitamin D deficiency is associated with the development of schizophrenia. People with schizophrenia generally have lower levels of vitamin D. The environmental risk factors of seasonality of birth, latitude, and migration linked to schizophrenia all implicate vitamin D deficiency, as do other health conditions such as maternal obesity. Vitamin D is essential for the normal development of the nervous system. Maternal vitamin D deficiency can cause prenatal neurodevelopmental defects, which influence neurotransmission, altering brain rhythms and the metabolism of dopamine. Vitamin D receptors, CYP27B1, and CYP24A1 are found in various regions of the brain, showing that vitamin D is a neuroactive, neurosteroid hormone essential for the development of the brain and normal function. Inflammation as a causative factor in schizophrenia is normally suppressed by vitamin D.

Risk factors
Those most likely to be affected by vitamin D deficiency are people with little exposure to sunlight. Certain climates, dress habits, the avoidance of sun exposure and the use of too much sunscreen protection can all limit the production of vitamin D.

Age
Elderly people have a higher risk of having a vitamin D deficiency due to a combination of several risk factors, including decreased sunlight exposure, decreased intake of vitamin D in the diet, and decreased skin thickness, which leads to further decreased absorption of vitamin D from sunlight.

Fat percentage
Since vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) are fat-soluble, humans and other animals with a skeleton need to store some fat. Without fat, the animal will have a hard time absorbing vitamin D2 and vitamin D3, and the lower the fat percentage, the greater the risk of vitamin deficiency, which is true in some athletes who strive to get as lean as possible.

Malnutrition
Although rickets and osteomalacia are now rare in Britain, osteomalacia outbreaks in some immigrant communities included women with seemingly adequate daylight outdoor exposure wearing typical Western clothing. Having darker skin and reduced exposure to sunshine did not produce rickets unless the diet deviated from a Western omnivore pattern characterized by high intakes of meat, fish, and eggs and low intakes of high-extraction cereals. In sunny countries where rickets occurs among older toddlers and children, the rickets has been attributed to low dietary calcium intakes. This is characteristic of cereal-based diets with limited access to dairy products. Rickets was formerly a major public health problem among the US population; in Denver, almost two-thirds of 500 children had mild rickets in the late 1920s. An increase in the proportion of animal protein in the 20th-century American diet coupled with increased consumption of milk fortified with relatively small quantities of vitamin D coincided with a dramatic decline in the number of rickets cases. One study of children in a hospital in Uganda, however, showed no significant difference in vitamin D levels of malnourished children compared to non-malnourished children. Because both groups were at risk due to darker skin pigmentation, both groups had vitamin D deficiency. Nutritional status did not appear to play a role in this study.

Obesity
There is an increased risk of vitamin D deficiency in people who are considered overweight or obese based on their body mass index (BMI) measurement. The relationship between these conditions is not well understood. There are different factors that could contribute to this relationship, particularly diet and sunlight exposure. Alternatively, vitamin D is fat-soluble, so excess amounts can be stored in fat tissue and used during winter, when sun exposure is limited.

Sun exposure
The use of sunscreen with a sun protection factor of 8 can theoretically inhibit more than 95% of vitamin D production in the skin. In practice, however, sunscreen is applied so as to have a negligible effect on vitamin D status. The vitamin D status of those in Australia and New Zealand is unlikely to have been affected by campaigns advocating sunscreen. Instead, wearing clothing is more effective at reducing the amount of skin exposed to UVB and reducing natural vitamin D synthesis. Clothing that covers a large portion of the skin, when worn on a consistent and regular basis, such as the burqa, is correlated with lower vitamin D levels and an increased prevalence of vitamin D deficiency.Regions far from the equator have a high seasonal variation of the amount and intensity of sunlight. In the UK, the prevalence of low vitamin D status in children and adolescents is found to be higher in winter than in summer. Lifestyle factors such as indoor versus outdoor work and time spent in outdoor recreation play an important role.
Additionally, vitamin D deficiency has been associated with urbanisation in terms of both air pollution, which blocks UV light, and an increase in the number of people working indoors. The elderly are generally exposed to less UV light due to hospitalisation, immobility, institutionalisation, and being housebound, leading to decreased levels of vitamin D.

Darker skin color
Because of melanin which enables natural sun protection, dark-skinned people are susceptible to vitamin D deficiency. Three to five times greater sun exposure is necessary for naturally darker skinned people to produce the same amount of vitamin D as those with white skin.

Malabsorption
Rates of vitamin D deficiency are higher among people with untreated celiac disease, inflammatory bowel disease, exocrine pancreatic insufficiency from cystic fibrosis, and short bowel syndrome, which can all produce problems of malabsorption. Vitamin D deficiency is also more common after surgical procedures that reduce absorption from the intestine, including weight loss procedures.

Critical illness
Vitamin D deficiency is associated with increased mortality in critical illness. People who take vitamin D supplements before being admitted for intensive care are less likely to die than those who do not take vitamin D supplements. Additionally, vitamin D levels decline during stays in intensive care.
Vitamin D3 (cholecalciferol) or calcitriol given orally may reduce the mortality rate without significant adverse effects.

Breastfeeding
Infants who exclusively breastfeed need a vitamin D supplement, especially if they have dark skin or have minimal sun exposure. The American Academy of Pediatrics recommends that all breastfed infants receive 400 international units (IU) per day of oral vitamin D.

Pathophysiology
Decreased exposure of the skin to sunlight is a common cause of vitamin D deficiency.  People with a darker skin pigment with increased amounts of melanin may have decreased production of vitamin D. Melanin absorbs ultraviolet B radiation from the sun and reduces vitamin D production. Sunscreen can also reduce vitamin D production. Medications may speed up the metabolism of vitamin D, causing a deficiency.The liver is required to transform vitamin D into 25-hydroxyvitamin D. This is an inactive metabolite of vitamin D but is a necessary precursor (building block) to create the active form of vitamin D.The kidneys are responsible for converting 25-hydroxyvitamin D to 1,25-hydroxyvitamin D. This is the active form of vitamin D in the body. Kidney disease reduces 1,25-hydroxyvitamin D formation, leading to a deficiency of the effects of vitamin D.Intestinal conditions that result in malabsorption of nutrients may also contribute to vitamin D deficiency by decreasing the amount of vitamin D absorbed via diet. In addition, a vitamin D deficiency may lead to decreased absorption of calcium by the intestines, resulting in increased production of osteoclasts that may break down a persons bone matrix. In states of hypocalcemia, calcium will leave the bones and may give rise to secondary hyperparathyroidism, which is a response by the body to increase serum calcium levels. The body does this by increasing uptake of calcium by the kidneys and continuing to take calcium away from the bones. If prolonged, this may lead to osteoporosis in adults and rickets in children.

Diagnosis
The serum concentration of calcifediol, also called 25-hydroxyvitamin D (abbreviated 25(OH)D), is typically used to determine vitamin D status. Most vitamin D is converted to 25(OH)D in the serum, giving an accurate picture of vitamin D status. The level of serum 1,25(OH)D is not usually used to determine vitamin D status because it often is regulated by other hormones in the body such as parathyroid hormone. The levels of 1,25(OH)D can remain normal even when a person may be vitamin D deficient. Serum level of 25(OH)D is the laboratory test ordered to indicate whether or not a person has vitamin D deficiency or insufficiency. It is also considered reasonable to treat at-risk persons with vitamin D supplementation without checking the level of 25(OH)D in the serum, as vitamin D toxicity has only been rarely reported to occur.Levels of 25(OH)D that are consistently above 200 nanograms per milliliter (ng/mL) (or 500 nanomoles per liter, nmol/L) are potentially toxic. Vitamin D toxicity usually results from taking supplements in excess. Hypercalcemia is often the cause of symptoms,  and levels of 25(OH)D above 150 ng/mL (375 nmol/L) are usually found, although in some cases 25(OH)D levels may appear to be normal. Periodic measurement of serum calcium in individuals receiving large doses of vitamin D is recommended.

Screening
The official recommendation from the United States Preventive Services Task Force is that for persons that do not fall within an at-risk population and are asymptomatic, there is not enough evidence to prove that there is any benefit in screening for vitamin D deficiency.

Treatment
UVB exposure
Vitamin-D overdose is impossible from UV exposure: the skin reaches an equilibrium where the vitamin degrades as fast as it is created.

Sun tanning
Light therapy
Exposure to photons (light) at specific wavelengths of narrowband UVB enables the body to produce vitamin D to treat vitamin D deficiency.

Supplement
In the United States and Canada as of 2016, the amount of vitamin D recommended is 400 IU per day for children, 600 IU per day for adults, and 800 IU per day for people over age 70. The Canadian Paediatric Society recommends that pregnant or breastfeeding women consider taking 2000 IU/day, that all babies who are exclusively breastfed receive a supplement of 400 IU/day, and that babies living north of 55°N get 800 IU/day from October to April.Treating vitamin D deficiency depends on the severity of the deficit. Treatment involves an initial high-dosage treatment phase until the required serum levels are reached, followed by the maintenance of the acquired levels. The lower the 25(OH)D serum concentration is before treatment, the higher is the dosage that is needed in order to quickly reach an acceptable serum level.The initial high-dosage treatment can be given on a daily or weekly basis or can be given in form of one or several single doses (also known as stoss therapy, from the German word Stoß, meaning "push").Therapy prescriptions vary, and there is no consensus yet on how best to arrive at an optimum serum level. While there is evidence that  vitamin D3 raises 25(OH)D blood levels more effectively than vitamin D2, other evidence indicates that D2 and D3 are equal for maintaining 25(OH)D status.

Initial phase
Daily or weekly or monthly dose
For treating rickets, the American Academy of Pediatrics (AAP) has recommended that pediatric patients receive an initial two- to three-month treatment of "high-dose" vitamin D therapy. In this regime, the daily dose of cholecalciferol is 1,000 IU for newborns, 1,000 to 5,000 IU for 1- to 12-month-old infants, and 5,000 IU for patients over 1 year of age.For adults, other dosages have been called for. A review of 2008/2009 recommended dosages of 1,000 IU cholecalciferol per 10 ng/mL required serum increase, to be given daily over two to three months. In another proposed cholecalciferol loading dose guideline for vitamin D-deficient adults, a weekly dosage is given, up to a total amount that is proportional to the required serum increase (up to the level of 75 nmL/L) and within certain body weight limits, to body weight.According to new data and practices relevant to vitamin D levels in the general population in France, to establish optimal vitamin D status and frequency of intermittent supplement dosing, patients with or at high risk for osteoporosis and vitamin D deficiency should start supplementation with a loading phase consisting of 50,000 IU weekly of vitamin D for 8 weeks in patients with levels <20 ng/mL and 50,000 IU weekly for 4 weeks in patients with levels between 20 and 30 ng/mL. Subsequently, long-term supplementation should be prescribed as 50,000 IU monthly. Should pharmaceutical forms suitable for daily supplementation become available, patients displaying good treatment adherence could take a daily dose determined based on the 25(OH)D level.
Until now, there are no consistent data suggesting the ideal regimen of supplementation with vitamin D, and the question of the ideal time between doses is still of debate. Ish-Shalom et al. performed a study in elderly women to compare the efficacy and safety of a daily dose of 1,500 IU to a weekly dose of 10,500 IU and to a dose of 45,000 IU given every 28 days for two months. They concluded that supplementation with vitamin D can be equally achieved with daily, weekly, or monthly dosing frequencies.
Another study comparing daily, weekly, and monthly supplementation of vitamin D in deficient patients was published by Takacs et al. They reported an equal efficacy of 1,000 IU taken daily, 7,000 IU taken weekly, and 30,000 IU taken monthly. Nevertheless, these consistent findings differ from the report by Chel et al., in which a daily dose was more effective than a monthly dose. In that study, the compliance calculation could be questionable since only random samples of the returned medications were counted. In a study by De Niet et al., 60 subjects with vitamin D deficiency were randomized to receive 2,000 IU vitamin D3 daily or 50,000 IU monthly. They reported a similar efficacy of the two dosing frequencies, with the monthly dose providing a more rapid normalization of vitamin D levels.

Single-dose therapy
Alternatively, a single-dose therapy is used for instance if there are concerns regarding the patients compliance. The single-dose therapy can be given as an injection but is normally given in form of an oral medication.

Vitamin D doses and meals
The presence of a meal and the fat content of that meal may also be important. Because vitamin D is fat-soluble, it is hypothesized that absorption would be improved if patients are instructed to take their supplement with a meal. Raimundo et al. performed different studies confirming that a high-fat meal increased the absorption of vitamin D3 as measured by serum 25(OH) D. A clinical report indicated that serum 25(OH) D levels increased by an average of 57% over a 2-month to 3-month period in 17 clinic patients after they were instructed to take their usual dose of vitamin D with the largest meal of the day.Another study conducted in 152 healthy men and women concluded that diets rich in monounsaturated fatty acids may improve and those rich in polyunsaturated fatty acids may reduce the effectiveness of vitamin D3 supplements. In another study performed by Cavalier E. et al., 88 subjects received orally a single dose of 50,000 IU of vitamin D3 solubilized in an oily solution as two ampoules each containing 25,000 IU (D‐CURE®, Laboratories SMB SA, Brussels, Belgium) with or without a standardized high‐fat breakfast. No significant difference between fasting vs. fed conditions was observed.

Maintenance phase
Once the desired serum level has been achieved, be it by a high daily or weekly or monthly dose or by a single-dose therapy, the AAP recommendation calls for a maintenance supplementation of 400 IU for all age groups, with this dosage being doubled for premature infants, dark-skinned infants and children, children who reside in areas of limited sun exposure (>37.5° latitude), obese patients, and those on certain medications.

Special cases
To maintain blood levels of calcium, therapeutic vitamin D doses are sometimes administered (up to 100,000 IU or 2.5 mg daily) to patients who have had their parathyroid glands removed (most commonly kidney dialysis patients who have had tertiary hyperparathyroidism, but also to patients with primary hyperparathyroidism) or with hypoparathyroidism. Patients with chronic liver disease or intestinal malabsorption disorders may also require larger doses of vitamin D (up to 40,000 IU or 1 mg (1000 micrograms) daily).

Co-supplementation with vitamin K
The combination of vitamin D and vitamin K supplements has been shown in trials to improve bone quality. As high intake of vitamin D is a cause of raised calcium levels (hypercalcemia), the addition of vitamin K may be beneficial in helping to prevent vascular calcification, particularly in people with chronic kidney disease.

Bioavailability
Not all D3 deficiencies can be effectively supplemented or treated with vitamin D3 on its own. Older people or those who have fatty liver or metabolic syndrome have a reduced ability to absorb vitamin D3. In addition, in overweight or obese persons, excessive adipose tissue can sequester D3 from the circulation and reduce its access to other tissues </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vitamin E deficiency and explain in detail? [/INST] Vitamin E deficiency in humans is a very rare condition, occurring as a consequence of abnormalities in dietary fat absorption or metabolism rather than from a diet low in vitamin E </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Waldenström macroglobulinemia and explain in detail? [/INST] Waldenström macroglobulinemia () is a type of cancer affecting two types of B cells: lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. It is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" (i.e., one that tends to grow and spread slowly) and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas. It is commonly classified as a form of plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody isoforms.Waldenström macroglobulinemia  is a rare disease, with only about 1,500 cases per year in the United States. It occurs more frequently in older adults. While the disease is incurable, it is treatable. Because of its indolent nature, many patients are able to lead active lives, and when treatment is required, may experience years of symptom-free remission.

Signs and symptoms
Signs and symptoms of Waldenström macroglobulinemia include weakness, fatigue, weight loss, and chronic oozing of blood from the nose and gums. Peripheral neuropathy occurs in 10% of patients. Enlargement of the lymph nodes, spleen, and/or liver are present in 30–40% of cases. Other possible signs and symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma.

Causes
Waldenström macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The most commonly associated mutations, based on whole-genome sequencing of 30 patients, are a somatic mutation in MYD88 (90% of patients) and a somatic mutation in CXCR4 (27% of patients). CXCR4 mutations cause symptomatic hyperviscosity syndrome and high bone marrow activity characteristic of the disease. However, CXCR4 mutation is not associated with splenomegaly, high platelet counts, or different response to therapy, questioning the relevance of CXCR4 in treating patients. An association has been demonstrated with the locus 6p21.3 on chromosome 6. There is a two- to threefold increased risk of Waldenström macroglobulinemia in people with a personal history of autoimmune diseases with autoantibodies, and a particularly elevated risk associated with liver inflammation, human immunodeficiency virus, and rickettsiosis.There are genetic factors, with first-degree relatives of Waldenström macroglobulinemia patients shown to have a highly increased risk of also developing the disease. There is also evidence to suggest that environmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of Waldenström macroglobulinemia.

Genetics
Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component. A mutation in gene MYD88 has been found to occur frequently in patients. Waldenström macroglobulinemia cells show only minimal changes in cytogenetic and gene expression studies. Their miRNA signature however differs from their normal counterpart. It is therefore believed that epigenetic modifications play a crucial role in the disease.Comparative genomic hybridization identified the following chromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q. FGFR3 is overexpressed. The following signalling pathways have been implicated:

CD154/CD40
Akt
ubiquitination, p53 activation, cytochrome c release
NF-κB
WNT/beta-catenin
mTOR
ERK
MAPK
Bcl-2The protein Src tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells.  Inhibition of Src arrests the cell cycle at phase G1 and has little effect on the survival of Waldenström macroglobulinemia or normal cells.
MicroRNAs involved in Waldenström:
increased expression of miRNAs-363*, -206, -494, -155, -184, -542–3p.
decreased expression of miRNA-9*.MicroRNA-155 regulates the proliferation and growth of Waldenström macroglobulinemia cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways.In Waldenström macroglobulinemia cells, histone deacetylases and histone-modifying genes are de-regulated. Bone marrow tumour cells express the following antigen targets CD20 (98.3%), CD22 (88.3%), CD40 (83.3%), CD52 (77.4%), IgM (83.3%), MUC1 core protein (57.8%), and 1D10 (50%).

Pathophysiology
Symptoms including blurring or loss of vision, headache, and (rarely) stroke or coma are due to the effects of the IgM paraprotein, which may cause autoimmune phenomenon or cryoglobulinemia.  Other symptoms of Waldenström macroglobulinemia are due to hyperviscosity syndrome, which is present in 6–20% of patients. This is attributed to the IgM monoclonal protein increasing the viscosity of the blood by forming aggregates to each other, binding water through their carbohydrate component and by their interaction with blood cells.

Diagnosis
A diagnosis of Waldenström macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key signs of Waldenström macroglobulinemia. A bone marrow biopsy provides a sample of bone marrow, usually from the lower back of  the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate Waldenström macroglobulinemia. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.Additional tests such as computed tomography (CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between Waldenström macroglobulinemia and multiple myeloma. Anemia occurs in about 80% of patients with Waldenström macroglobulinemia. A low white blood cell count, and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with Waldenström macroglobulinemia.Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein. The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated. Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.Criteria for diagnosis of Waldenström macroglobulinemia include:

IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia and Mantle cell lymphoma
Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.

Treatment
There is no single accepted treatment for Waldenström macroglobulinemia. There is marked variation in clinical outcome due to gaps in knowledge of the diseases molecular basis. Objective response rates are high (> 80%) but complete response rates are low (0–15%). The medication ibrutinib targets the MYD88 L265P mutation induced activation of Brutons tyrosine kinase. In a cohort study of previously treated patients, ibrutinib induced responses in 91% of patients, and at 2 years 69% of patients had no progression of disease and 95% were alive. Based on this study, the Food and Drug Administration approved ibrutinib for use in Waldenström macroglobulinemia in 2015.There are different treatment flowcharts: Treon and mSMART.Patients with Waldenström macroglobulinemia are at higher risk of developing second cancers than the general population, but it is not yet clear whether treatments are contributory.

Watchful waiting
In the absence of symptoms, many clinicians will recommend simply monitoring the patient; Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also had Waldenström macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.

First-line
Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.In 2002, a panel at the International Workshop on Waldenströms Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy or spleen enlargement, and anemia due to bone marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, kidney failure, or symptomatic cryoglobulinemia were also suggested as indications for therapy.Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide. Corticosteroids, such as prednisone, may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease. Ibrutinib is another agent that has been approved for use in this condition. Combination treatment with Ibrutinib and Rituximab showed significantly  higher disease progression free survival than with just Rituximab treatment.Autologous bone marrow transplantation is a treatment option.Zanubrutinib is indicated for the treatment of adults with Waldenström macroglobulinemia.

Salvage therapy
When primary or secondary resistance invariably develops, salvage therapy is considered. Allogeneic stem cell transplantation can induce durable remissions for heavily pre-treated patients.

Drug pipeline
As of October 2010, there have been a total of 44 clinical trials on Waldenström macroglobulinemia, excluding transplantation treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with relapsed or refractory Waldenström. A database of clinical trials investigating Waldenström macroglobulinemia is maintained by the National Institutes of Health in the US.

Patient stratification
Patients with polymorphic variants (alleles) FCGR3A-48 and -158 were associated with improved categorical responses to rituximab-based treatments.

Prognosis
Current medical treatments result in survival of some longer than 10 years; in part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wart and explain in detail? [/INST] Warts are typically small, rough, hard growths that are similar in color to the rest of the skin. They typically do not result in other symptoms, except when on the bottom of the feet, where they may be painful. While they usually occur on the hands and feet, they can also affect other locations. One or many warts may appear. They are not cancerous.Warts are caused by infection with a type of human papillomavirus (HPV). Factors that increase the risk include use of public showers and pools, working with meat, eczema and a weak immune system. The virus is believed to enter the body through skin that has been damaged slightly. A number of types exist, including "common warts", plantar warts, "filiform warts", and genital warts. Genital warts are often sexually transmitted.Without treatment, most types of warts resolve in months to years. A number of treatments may speed resolution, including salicylic acid applied to the skin and cryotherapy. In those who are otherwise healthy, they do not typically result in significant problems. Treatment of genital warts differs from that of other types.Warts are very common, with most people being infected at some point in their lives. The estimated current rate of non-genital warts among the general population is 1–13%. They are more common among young people. Prior to widespread adoption of the HPV vaccine, the estimated rate of genital warts in sexually active women was 12%. Warts have been described at least as far back as 400 BC by Hippocrates.

Types
A range of types of wart have been identified, varying in shape and site affected, as well as the type of human papillomavirus involved. These include:

Common wart (verruca vulgaris), a raised wart with roughened surface, most common on hands, but can grow anywhere on the body. Sometimes known as a Palmer wart or Junior wart.
Flat wart (verruca plana), a small, smooth flattened wart, flesh-coloured, which can occur in large numbers; most common on the face, neck, hands, wrists and knees.
Filiform or digitate wart, a thread- or finger-like wart, most common on the face, especially near the eyelids and lips.
Genital wart (venereal wart, condyloma acuminatum, verruca acuminata), a wart that occurs on the genitalia.
Periungual wart, a cauliflower-like cluster of warts that occurs around the nails.
Plantar wart (verruca, verruca plantaris), a hard, sometimes painful lump, often with multiple black specks in the center; usually only found on pressure points on the soles of the feet.
Mosaic wart, a group of tightly clustered plantar-type warts, commonly on the hands or soles of the feet.

Cause
Warts are caused by the human papilloma virus (HPV). There are about 130 known types of human papilloma viruses. HPV infects the squamous epithelium, usually of the skin or genitals, but each HPV type is typically only able to infect a few specific areas on the body. Many HPV types can produce a benign growth, often called a "wart" or "papilloma", in the area they infect. Many of the more common HPV and wart types are listed below.

Common warts – HPV types 2 and 4 (most common); also types 1, 3, 26, 29, and 57 and others.
Cancers and genital dysplasia – "high-risk" HPV types are associated with cancers, notably cervical cancer, and can also cause some vulvar, vaginal, penile, anal and some oropharyngeal cancers.  "Low-risk" types are associated with warts or other conditions.High-risk: 16, 18 (cause the most cervical cancer); also 31, 33, 35, 39, 45, 52, 58, 59, and others.Plantar warts (verruca) – HPV type 1 (most common); also types 2, 3, 4, 27, 28, and 58 and others.
Anogenital warts (condylomata acuminata or venereal warts) – HPV types 6 and 11 (most common); also types 42, 44 and others.Low-risk: 6, 11 (most common); also 13, 44, 40, 43, 42, 54, 61, 72, 81, 89, and others.Verruca plana (flat warts) – HPV types 3, 10, and 28.
Butchers warts – HPV type 7.
Hecks disease (focal epithelial hyperplasia) – HPV types 13 and 32.

Pathophysiology
Common warts have a characteristic appearance under the microscope.  They have thickening of the stratum corneum (hyperkeratosis), thickening of the stratum spinosum (acanthosis), thickening of the stratum granulosum, rete ridge elongation, and large blood vessels at the dermoepidermal junction.

Diagnosis
On dermatoscopic examination, warts will commonly have fingerlike or knoblike extensions.

Prevention
Gardasil 6 is an HPV vaccine aimed at preventing cervical cancers and genital warts.  Gardasil is designed to prevent infection with HPV types 16, 18, 6, and 11. HPV types 16 and 18 currently cause about 70% of cervical cancer cases, and also cause some vulvar, vaginal, penile and anal cancers. HPV types 6 and 11 are responsible for 90% of documented cases of genital warts.Gardasil 9, approved in 2014 protects against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58.HPV vaccines do not currently protect against the virus strains responsible for plantar warts (verrucae).

Disinfection
The virus is relatively hardy and immune to many common disinfectants. Exposure to 90% ethanol for at least 1 minute, 2% glutaraldehyde, 30% Savlon, and/or 1% sodium hypochlorite can disinfect the pathogen.The virus is resistant to drying and heat, but killed by 100 °C (212 °F) and ultraviolet radiation.

Treatment
There are many treatments and procedures associated with wart removal. A review of various skin wart treatments concluded that topical treatments containing salicylic acid were more effective than placebo. Cryotherapy appears to be as effective as salicylic acid, but there have been fewer trials.

Medication
Salicylic acid can be prescribed by a dermatologist in a higher concentration than that found in over-the-counter products.  Several over-the-counter products are readily available at pharmacies and supermarkets of roughly two types: adhesive pads treated with salicylic acid, and bottled concentrated salicylic acid and lactic acid solution.
Fluorouracil — Fluorouracil cream, a chemotherapy agent sometimes used to treat skin cancer, can be used on particularly resistant warts, by blocking viral DNA and RNA production and repair.
Imiquimod is a topical cream that helps the bodys immune system fight the wart virus by encouraging interferon production.  It has been approved by the U.S. Food and Drug Administration (FDA) for genital warts.
Cantharidin, found naturally in the bodies of many members of the beetle family Meloidae, causes dermal blistering. It is used either by itself or compounded with podophyllin.  Not FDA approved, but available through Canada or select US compounding pharmacies.
Bleomycin — A more potent chemotherapy drug, can be injected into deep warts, destroying the viral DNA or RNA. Bleomycin is notably not US FDA approved for this purpose. Possible side effects include necrosis of the digits, nail loss and Raynaud syndrome. The usual treatment is one or two injections.
Dinitrochlorobenzene (DNCB), like salicylic acid, is applied directly to the wart. Studies show this method is effective with a cure rate of 80%. But DNCB must be used much more cautiously than salicylic acid; the chemical is known to cause genetic mutations, so it must be administered by a physician. This drug induces an allergic immune response, resulting in inflammation that wards off the wart-causing virus.
Cidofovir is an antiviral drug which is injected into HPV lesions within the larynx (laryngeal papillomatosis) as an experimental treatment.
Verrutop verruca treatment is a topical solution made from a combination of organic acids, inorganic acids, and metal ions. This solution causes the production of nitrites, which act to denature viral proteins and mummify the wart tissue. The difference between Verrutop and other acid treatments is that it does not damage the surrounding skin.
Another product available over-the-counter that can aid in wart removal is silver nitrate in the form of a caustic pencil, which is also available at drug stores. In a placebo-controlled study of 70 patients, silver nitrate given over nine days resulted in clearance of all warts in 43% and improvement in warts in 26% one month after treatment compared to 11% and 14%, respectively, in the placebo group. The instructions must be followed to minimize staining of skin and clothing. Occasionally, pigmented scars may develop.

Procedures
Keratolysis, of dead surface skin cells usually using salicylic acid, blistering agents, immune system modifiers ("immunomodulators"), or formaldehyde, often with mechanical paring of the wart with a pumice stone, blade etc.
Electrodesiccation
Cryosurgery or cryotherapy, which involves freezing the wart (generally with liquid nitrogen), creating a blister between the wart and epidermal layer after which the wart and the surrounding dead skin fall off.  An average of 3 to 4 treatments are required for warts on thin skin.  Warts on calloused skin like plantar warts might take dozens or more treatments.
Surgical curettage of the wart
Laser treatment – often with a pulse dye laser or carbon dioxide (CO2) laser.  Pulse dye lasers (wavelength 582 nm) work by selective absorption by blood cells (specifically hemoglobin).  CO2 lasers work by selective absorption by water molecules.  Pulse dye lasers are less destructive and more likely to heal without scarring.  CO2 laser works by vaporizing and destroying tissue and skin.  Laser treatments can be painful, expensive (though covered by many insurance plans), and not extensively scarring when used appropriately.  CO2 lasers will require local anaesthetic. Pulse dye laser treatment does not need conscious sedation or local anesthetic.  It takes 2 to 4 treatments, but can be many more for extreme cases. Typically, 10–14 days are required between treatments. Preventative measures are important.
Infrared coagulator – an intense source of infrared light in a small beam like a laser.  This works essentially on the same principle as laser treatment.  It is less expensive.  Like the laser, it can cause blistering, pain and scarring.
Intralesional immunotherapy with purified candida, MMR, and tuberculin (PPD) protein appears safe and effective.
Duct tape occlusion therapy involves placing a piece of duct tape over the wart. The mechanism of action of this technique still remains unknown.  Despite several trials, evidence for the efficacy of duct tape therapy is inconclusive. Despite the mixed evidence for efficacy, the simplicity of the method and its limited side-effects leads some researchers to be reluctant to dismiss it.
No intervention. Spontaneous resolution within a few years can be recommended.

Alternative medicine
Daily application of the latex of Chelidonium majus is a traditional treatment.The acrid yellow sap of Greater Celandine is used as a traditional wart remedy.According to English folk belief, touching toads causes warts; according to a German belief, touching a toad under a full moon cures warts. The most common Northern Hemisphere toads have glands that protrude from their skin that superficially resemble warts. Warts are caused by a virus, and toads do not harbor it. A variety of traditional folk remedies and rituals claim to be able to remove warts.
In The Adventures of Tom Sawyer, Mark Twain has his characters discuss a variety of such remedies.  Tom Sawyer proposes "spunk-water" (or "stump-water", the water collecting in the hollow of a tree stump) as a remedy for warts on the hand.  You put your hand into the water at midnight and say:

You then "walk away quick, eleven steps, with your eyes shut, and then turn around three times and walk home without speaking to anybody. Because if you speak the charms busted."  This is given as an example to Huckleberry Finns planned remedy, which involves throwing a dead cat into a graveyard as a devil or devils comes to collect a recently buried wicked person.  Another remedy involved splitting a bean, drawing blood from the wart and putting it on one of the halves, and burying that half at a crossroads at midnight.  The theory of operation is that the blood on the buried bean will draw away the wart. Twain is recognized as an early collector and recorder of genuine American folklore.Similar practices are recorded elsewhere.  In Louisiana, one remedy for warts involves rubbing the wart with a potato, which is then buried; when the "buried potato dries up, the wart will be cured". Another remedy similar to Twains is reported from Northern Ireland, where water from a specific well on Rathlin Island is credited with the power to cure warts.

History
Surviving ancient medical texts show that warts were a documented disease since at least the time of Hippocrates, who lived c. 460 – c. 370 BC. In the book De Medecia by the Roman physician Aulus Cornelius Celsus, who lived c. 25 BC – c. 50 AD, different types of warts were described </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wernicke encephalopathy and explain in detail? [/INST] Wernicke encephalopathy (WE), also Wernickes encephalopathy, or wet brain is the presence of neurological symptoms caused by biochemical lesions of the central nervous system after exhaustion of B-vitamin reserves, in particular thiamine (vitamin B1). The condition is part of a larger group of thiamine deficiency disorders that includes beriberi, in all its forms, and alcoholic Korsakoff syndrome. When it occurs simultaneously with alcoholic Korsakoff syndrome it is known as Wernicke–Korsakoff syndrome.Classically, Wernicke encephalopathy is characterised by a triad of symptoms: ophthalmoplegia, ataxia, and confusion. Around 10% of patients exhibit all three features, and other symptoms may also be present. While it is commonly regarded as a condition peculiar to malnourished people with alcohol misuse, it can be caused by a variety of diseases.
It is treated with thiamine supplementation, which can lead to improvement of the symptoms and often complete resolution, particularly in those where alcohol misuse is not the underlying cause. Often other nutrients also need to be replaced, depending on the cause.
Wernicke encephalopathy may be present in the general population with a prevalence of around 2%, and is considered underdiagnosed; probably, many cases are in patients who do not have commonly-associated symptoms.

Signs and symptoms
The classic triad of symptoms found in Wernicke encephalopathy is:
ophthalmoplegia (later expanded to other eye movement disorders, most commonly affecting the lateral rectus muscle. Lateral nystagmus is most commonly seen although lateral rectus palsy, usually bilateral, may be seen).
ataxia (later expanded to imbalance or any cerebellar signs)
confusion (later expanded to other mental changes. Has 82% incidence in diagnosis cases)However, in actuality, only a small percentage of patients experience all three symptoms, and the full triad occurs more frequently among those who have overused alcohol.
Also a much more diverse range of symptoms has been found in patients with this condition, including:

pupillary changes, retinal hemorrhage, papilledema, impaired vision and hearing, vision loss
hearing loss,
fatigability, apathy, irritability, drowsiness, psycho and/or motor slowing
dysphagia, blush, sleep apnea, epilepsy and stupor
lactic acidosis
memory impairment, amnesia, depression, psychosis
hypothermia, polyneuropathy, hyperhidrosis.Although hypothermia is usually diagnosed with a body temperature of 35 °C / 95° Fahrenheit, or less, incipient cooling caused by deregulation in the central nervous system (CNS) needs to be monitored because it can promote the development of an infection. The patient may report feeling cold, followed by mild chills, cold skin, moderate pallor, tachycardia, hypertension, tremor or piloerection. External warming techniques are advised to prevent hypothermia.Among the frequently altered functions are the cardio circulatory. There may be tachycardia, dyspnea, chest pain, orthostatic hypotension, changes in heart rate and blood pressure. The lack of thiamine sometimes affects other major energy consumers, the myocardium, and also patients may have developed cardiomegaly. Heart failure with lactic acidosis syndrome has been observed. Cardiac abnormalities are an aspect of the WE, which was not included in the traditional approach, and are not classified as a separate disease.
Infections have been pointed out as one of the most frequent triggers of death in WE. Furthermore, infections are usually present in pediatric cases.In the last stage other symptoms may occur: hyperthermia, increased muscle tone, spastic paralysis, choreic dyskinesias and coma.Because of the frequent involvement of heart, eyes and peripheral nervous system, several authors prefer to call it Wernicke disease rather than simply encephalopathy.Early symptoms are nonspecific, and it has been stated that WE may present nonspecific findings. In Wernicke Korsakoffs syndrome some single symptoms are present in about one-third.

Location of the lesion
Depending on the location of the brain lesion different symptoms are more frequent:
Brainstem tegmentum. - Ocular: pupillary changes. Extraocular muscle palsy;  gaze palsy: nystagmus.
Hypothalamus.  Medulla: dorsal nuc. of vagus. - Autonomic dysfunction: temperature; cardiocirculatory; respiratory.
Medulla: vestibular region. Cerebellum. - Ataxia.
Dorsomedial nuc. of thalamus. Mammillary bodies. - Amnestic syndrome for recent memory.Mamillary lesion are characteristic-small petechial hemorrhages are found.

Diffuse cerebral dysfunction.- Altered cognition: global confusional state.
Brainstem: periaqueductal gray.- Reduction of consciousness
Hypothalamic lesions may also affect the immune system, which is known in people who consume excessive amounts of alcohol, causing dysplasias and infections.

Korsakoff syndrome
Korsakoff syndrome, characterised by memory impairment, confabulation, confusion and personality changes, has a strong and recognised link with WE. A very high percentage of patients with Wernicke–Korsakoff syndrome also have peripheral neuropathy, and many people who consume excess alcohol have this neuropathy without other neurologic signs or symptoms. Korsakoffs occurs much more frequently in WE due to chronic alcoholism. It is uncommon among those who do not consume excessive amounts of alcohol. Up to 80% of WE patients who misuse alcohol develop Korsakoffs syndrome. In Korsakoffs, is usually observed atrophy of the thalamus and the mammillary bodies, and frontal lobe involvement.  In a study, half of Wernicke-Korsakoff cases had good recovery from the amnesic state, which may take from 2 months to 10 years.

Risk factors
Wernicke encephalopathy has classically been thought of as a disease solely of people who drink excessive amounts of alcohol, but it is also found in the chronically undernourished, and in recent years had been discovered post bariatric surgery. Without being exhaustive, the documented causes of Wernicke encephalopathy have included:

pancreatitis, liver dysfunction, chronic diarrhea, celiac disease, Crohns disease, uremia, thyrotoxicosis
vomiting, hyperemesis gravidarum, malabsorption, gastrointestinal surgery or diseases
incomplete parenteral nutrition, starvation/fasting
chemotherapy, renal dialysis, diuretic therapy, stem cell/marrow transplantation
cancer, AIDS,  Creutzfeldt–Jakob disease, febrile infections
this disease may even occur in some people with normal, or even high blood thiamine levels, are people with deficiencies in intracellular transport of this vitamin. Selected genetic mutations, including presence of the X-linked transketolase-like 1 gene, SLC19A2 thiamine transporter protein mutations, and the aldehyde dehydrogenase-2 gene, which may predispose to alcohol use disorder. The APOE epsilon-4 allele, involved in Alzheimers disease, may increase the chance of developing neurological symptoms.

Pathophysiology
Thiamine deficiency and errors of thiamine metabolism are believed to be the primary cause of Wernicke encephalopathy. Thiamine, also called B1, helps to break down glucose. Specifically, it acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt. Thiamine is first metabolised to its more active form, thiamine diphosphate (TDP), before it is used. The body only has 2–3 weeks of thiamine reserves, which are readily exhausted without intake, or if depletion occurs rapidly, such as in chronic inflammatory states or in diabetes. Thiamine is involved in:
Metabolism of carbohydrates, releasing energy.
Production of neurotransmitters including glutamic acid and GABA.
Lipid metabolism, necessary for myelin production.
Amino acid modification. Probably linked to the production of taurine, of great cardiac importance.

Neuropathology
The primary neurological-related injury caused by thiamine deficiency in WE is three-fold: oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway. Thiamine deficiency affects both neurons and astrocytes, glial cells of the brain. Thiamine deficiency alters the glutamate uptake of astrocytes, through changes in the expression of astrocytic glutamate transporters EAAT1 and EAAT2, leading to excitotoxicity. Other changes include those to the GABA transporter subtype GAT-3, GFAP, glutamine synthetase, and the Aquaporin 4 channel. Focal lactic acidosis also causes secondary oedema, oxidative stress, inflammation and white matter damage.

Pathological anatomy
Despite its name, WE is not related to Wernickes area, a region of the brain associated with speech and language interpretation.In most, early lesions completely reversed with immediate and adequate supplementation.Lesions are usually symmetrical in the periventricular region, diencephalon, the midbrain, hypothalamus, and cerebellar vermis. Brainstem lesions may include cranial nerve III, IV, VI and VIII nuclei, the medial thalamic nuclei, and the dorsal nucleus of the vagus nerve. Oedema may be found in the regions surrounding the third ventricle, and fourth ventricle, also appearing petechiae and small hemorrhages. Chronic cases can present the atrophy of the mammillary bodies.Endothelial proliferation, hyperplasia of capillaries, demyelination and neuronal loss can also occur.An altered blood–brain barrier may cause a perturbed response to certain drugs and foods.

Diagnosis
Diagnosis of Wernicke encephalopathy or disease is made clinically.  Caine et al. in 1997 established criteria that Wernicke encephalopathy can be diagnosed in any patient with just two or more of the main symptoms noted above. The sensitivity of the diagnosis by the classic triad was 23% but increased to 85% taking two or more of the four classic features. These criteria are challenged because all the cases he studied were people who drank excessive amounts of alcohol. Some consider it sufficient to suspect the presence of the disease with only one of the principal symptoms. Some British hospital protocols suspect WE with any one of these symptoms: confusion, decreased consciousness level (or unconsciousness, stupor or coma), memory loss, ataxia or unsteadiness, ophthalmoplegia or nystagmus, and unexplained hypotension with hypothermia. The presence of only one sign should be sufficient for treatment.As a much more diverse range of symptoms has been found frequently in patients it is necessary to search for new diagnostic criteria, however Wernicke encephalopathy remains a clinically-diagnosed condition. Neither the MR, nor serum measurements related to thiamine are sufficient diagnostic markers in all cases. However, as described by Zuccoli et al. in several papers the involvement of the cranial nerve nuclei and central gray matter on MRI, is very specific to WE in the appropriate clinical setting. Non-recovery upon supplementation with thiamine is inconclusive.The sensitivity of MR was 53% and the specificity was 93%. The reversible cytotoxic edema was considered the most characteristic lesion of WE. The location of the lesions were more frequently atypical among people who drank appropriate amounts of alcohol, while typical contrast enhancement in the thalamus and the mammillary bodies was observed frequently associated with alcohol misuse. These abnormalities may include:
Dorsomedial thalami, periaqueductal gray matter, mamillary bodies, tectal plate and brainstem nuclei are commonly affected. Involvement is always bilateral and symmetric. Value of DWI in the diagnosis of WE is minimal. Axial FLAIR MRI images represent the best diagnostic MRI sequence. Contrast material may highlight involvement of the mamillary bodies.There appears to be very little value for CT scans.Thiamine can be measured using an erythrocyte transketolase activity assay, or by activation by measurement of in vitro thiamine diphosphate levels. Normal thiamine levels do not necessarily rule out the presence of WE, as this may be a patient with difficulties in intracellular transport.

Prevention
There are hospital protocols for prevention, supplementing with thiamine in the presence of: history of alcohol misuse or related seizures, requirement for IV glucose, signs of malnutrition, poor diet, recent diarrhea or vomiting, peripheral neuropathy, intercurrent illness, delirium tremens or treatment for DTs, and others. Some experts advise parenteral thiamine should be given to all at-risk patients in the emergency department.In the clinical diagnosis should be remembered that early symptoms are nonspecific, and it has been stated that WE may present nonspecific findings. There is consensus to provide water-soluble vitamins and minerals after gastric operations.In some countries certain foods have been supplemented with thiamine, and have reduced WE cases. Improvement is difficult to quantify because they applied several different actions. Avoiding or moderating alcohol consumption and having adequate nutrition reduces one of the main risk factors in developing Wernicke-Korsakoff syndrome..

Treatment
Most symptoms will improve quickly if deficiencies are treated early. Memory disorder may be permanent.In patients suspected of WE, thiamine treatment should be started immediately. Blood should be immediately taken to test for thiamine, other vitamins and minerals levels. Following this an immediate intravenous or intramuscular dose of thiamine should be administered two or three times daily. Thiamine administration is usually continued until clinical improvement ceases.Considering the diversity of possible causes and several surprising symptomatologic presentations, and because there is low assumed risk of toxicity of thiamine, because the therapeutic response is often dramatic from the first day, some qualified authors indicate parenteral thiamine if WE is suspected, both as a resource for diagnosis and treatment. The diagnosis is highly supported by the response to parenteral thiamine, but is not sufficient to be excluded by the lack of it. Parenteral thiamine administration is associated with a very small risk of anaphylaxis.People who consume excessive amounts of alcohol may have poor dietary intakes of several vitamins, and impaired thiamine absorption, metabolism, and storage; they may thus require higher doses.If glucose is given, such as in people with an alcohol use disorder who are also hypoglycaemic, thiamine must be given concurrently. If this is not done, the glucose will rapidly consume the remaining thiamine reserves, exacerbating this condition.The observation of edema in MR, and also the finding of inflation and macrophages in necropsied tissues, has led to successful administration of antiinflammatories.Other nutritional abnormalities should also be looked for, as they may be exacerbating the disease. In particular, magnesium, a cofactor of transketolase which may induce or aggravate the disease.Other supplements may also be needed, including: cobalamin, ascorbic acid, folic acid, nicotinamide, zinc, phosphorus (dicalcium phosphate) and in some cases taurine, especially suitable when there cardiocirculatory impairment.
Patient-guided nutrition is suggested. In patients with Wernicke-Korsakoff syndrome, even higher doses of parenteral thiamine are recommended. Concurrent toxic effects of alcohol should also be considered.

Epidemiology
There are no conclusive statistical studies, all figures are based on partial studies.
Wernickes lesions were observed in 0.8 to 2.8% of the general population autopsies, and 12.5% of people with an alcohol use disorder </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wilms tumor and explain in detail? [/INST] Wilms tumor or Wilms tumor, also known as nephroblastoma, is a cancer of the kidneys that typically occurs in children, rarely in adults.; and occurs most commonly as a renal tumor in child patients. It is named after Max Wilms, the German surgeon (1867–1918) who first described it.Approximately 650 cases are diagnosed in the U.S. annually. The majority of cases occur in children with no associated genetic syndromes; however, a minority of children with Wilms tumor have a congenital abnormality.  It is highly responsive to treatment, with about 90 percent of children being cured.

Signs and symptoms
Typical signs and symptoms of Wilms tumor include the following:
a painless, palpable abdominal mass
loss of appetite
abdominal pain
fever
nausea and vomiting
blood in the urine (in about 20% of cases)
high blood pressure in some cases (especially if synchronous or metachronous bilateral kidney involvement)
Rarely as varicocele

Pathogenesis
Wilms tumor has many causes, which can broadly be categorized as syndromic and non-syndromic. Syndromic causes of Wilms tumor occur as a result of alterations to genes such as the Wilms Tumor 1 (WT1) or Wilms Tumor 2 (WT2) genes, and the tumor presents with a group of other signs and symptoms. Non-syndromic Wilms tumor is not associated with other symptoms or pathologies. Many, but not all, cases of Wilms tumor develop from nephrogenic rests, which are fragments of tissue in or around the kidney that develop before birth and become cancerous after birth. In particular, cases of bilateral Wilms tumor, as well as cases of Wilms tumor derived from certain genetic syndromes such as Denys-Drash syndrome, are strongly associated with nephrogenic rests. Most nephroblastomas are on one side of the body only and are found on both sides in less than 5% of cases, although people with Denys-Drash syndrome mostly have bilateral or multiple tumors. They tend to be encapsulated and vascularized tumors that do not cross the midline of the abdomen. In cases of metastasis it is usually to the lung. A rupture of Wilms tumor puts the patient at risk of bleeding and peritoneal dissemination of the tumor. In such cases, surgical intervention by a surgeon who is experienced in the removal of such a fragile tumor is imperative.Pathologically, a triphasic nephroblastoma comprises three elements:
blastema
mesenchyme (stroma)
epitheliumWilms tumor is a malignant tumor containing metanephric blastema, stromal and epithelial derivatives. Characteristic is the presence of abortive tubules and glomeruli surrounded by a spindled cell stroma. The stroma may include striated muscle, cartilage, bone, fat tissue, and fibrous tissue. Dysfunction is caused when the tumor compresses the normal kidney parenchyma.The mesenchymal component may include cells showing rhabdomyoid differentiation or malignancy (rhabdomyosarcomatous Wilms).Wilms tumors may be separated into two prognostic groups based on pathologic characteristics:
Favorable – Contains well developed components mentioned above
Anaplastic – Contains diffuse anaplasia (poorly developed cells)

Molecular biology and related conditions
Mutations of the WT1 gene which is located on the short arm of chromosome 11 (11p13) are observed in approximately 20% of Wilms tumors, the majority of them being inherited from the germline, while a minority are acquired somatic mutations. In addition at least half of the Wilms tumors with mutations in WT1 also carry acquired somatic mutations in CTNNB1, the gene encoding the proto-oncogene beta-catenin. This latter gene is found on short arm of chromosome 3 (3p22.1).
Most cases do not have mutations in any of these genes.
An association with H19 has been reported. H19 is a long noncoding RNA located on the short arm of chromosome 11 (11p15.5).

Diagnosis
The majority of people with Wilms tumor present with an asymptomatic abdominal mass which is noticed by a family member or healthcare professional. Renal tumors can also be found during routine screening in children who have known predisposing clinical syndromes. The diagnostic process includes taking a medical history, a physical exam, and a series of tests including blood, urine, and imaging tests.Once Wilms tumor is suspected, an ultrasound scan is usually done first to confirm the presence of an intrarenal mass. A computed tomography scan or MRI scan can also be used for more detailed imaging. Finally, the diagnosis of Wilms tumor is confirmed by a tissue sample. In most cases, a biopsy is not done first because there is a risk of cancer cells spreading during the procedure. Treatment in North America is nephrectomy or in Europe chemotherapy followed by nephrectomy. A definitive diagnosis is obtained by pathological examination of the nephrectomy specimen.

Staging
Staging is a standard way to describe the extent of spread of Wilms tumors and to determine prognosis and treatments. Staging is based on anatomical findings and tumor cells pathology. According to the extent of tumor tissue at the time of initial diagnosis, five stages are considered.In Stage I Wilms tumor (43% of cases), all of the following criteria must be met:
Tumor is limited to the kidney and is completely excised.
The surface of the renal capsule is intact.
The tumor is not ruptured or biopsied (open or needle) prior to removal.
No involvement of extrarenal or renal sinus lymph-vascular spaces
No residual tumor apparent beyond the margins of excision.
Metastasis of tumor to lymph nodes not identified.In Stage II (23% of cases), 1 or more of the following criteria must be met:
Tumor extends beyond the kidney but is completely excised.
No residual tumor apparent at or beyond the margins of excision.
Any of the following conditions may also exist:
Tumor involvement of the blood vessels of the renal sinus and/or outside the renal parenchyma.
Extensive tumor involvement of renal sinus soft tissue.In Stage III (20% of cases), 1 or more of the following criteria must be met:
Inoperable primary tumor.
Lymph node metastasis.
Tumor is present at surgical margins.
Tumor spillage involving peritoneal surfaces either before or during surgery, or transected tumor thrombus.
The tumor has been biopsied prior to removal or there is local spillage of tumor during surgery, confined to the flank.Stage IV (10% of cases) Wilms tumor is defined by the presence of hematogenous metastases (lung, liver, bone, or brain), or lymph node metastases outside the abdominopelvic region.Stage V (5% of cases) Wilms tumor is defined by bilateral renal involvement at the time of initial diagnosis. For patients with bilateral involvement, an attempt should be made to stage each side according to the above criteria (stage I to III) on the basis of extent of disease prior to biopsy.

Treatment and prognosis
The overall 5-year survival is estimated to be approximately 90%, but for individuals the prognosis is highly dependent on individual staging and treatment. Early removal tends to promote positive outcomes.
Tumor-specific loss-of-heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of Wilms tumor patients who have a significantly increased risk of relapse and death. LOH for these chromosomal regions can now be used as an independent prognostic factor together with disease stage to target intensity of treatment to risk of treatment failure. Genome-wide copy number and LOH status can be assessed with virtual karyotyping of tumor cells (fresh or paraffin-embedded).Statistics may sometimes show more favorable outcomes for more aggressive stages than for less aggressive stages, which may be caused by more aggressive treatment and/or random variability in the study groups. Also, a stage V tumor is not necessarily worse than a stage IV tumor.
In case of relapse of Wilms tumor, the 4-year survival rate for children with a standard-risk has been estimated to be 80%.

Epidemiology
Wilms tumor is the most common malignant renal tumor in children </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Wrinkle and explain in detail? [/INST] A wrinkle, also known as a rhytid, is a fold, ridge or crease in an otherwise smooth surface, such as on skin or fabric. Skin wrinkles typically appear as a result of ageing processes such as glycation,  habitual sleeping positions, loss of body mass, sun damage, or temporarily, as the result of prolonged immersion in water. Age wrinkling in the skin is promoted by habitual facial expressions, aging, sun damage, smoking, poor hydration, and various other factors. In humans, it can also be prevented to some degree by avoiding excessive solar exposure and through diet (in particular through consumption of carotenoids, tocopherols and flavonoids, vitamins (A, C, D and E), essential omega-3-fatty acids, certain proteins and lactobacilli).

Skin
Causes for aging wrinkles
Development of facial wrinkles is a kind of fibrosis of the skin. Misrepair-accumulation aging theory suggests that wrinkles develop from incorrect repairs of injured elastic fibers and collagen fibers. Repeated extensions and compressions of the skin cause repeated injuries of extracellular fibers in derma. During the repairing process, some of the broken elastic fibers and collagen fibers are not regenerated and restored but replaced by altered fibers. When an elastic fiber is broken in an extended state, it may be replaced by a "long" collagen fiber. Accumulation of "long" collagen fibers makes part of the skin looser and stiffer, and as a consequence, a big fold of skin appears. When a "long" collagen is broken in a compressed state, it may be replaced by a "short" collagen fiber. The "shorter" collagen fibers will restrict the extension of "longer" fibers, and make the “long" fibers in a folding state permanently. A small fold, namely a permanent wrinkle, then appears.

Sleep wrinkles
Sleep wrinkles are created and reinforced when the face is compressed against a pillow or bed surface in side or stomach sleeping positions during sleep. They appear in predictable locations due to the underlying superficial musculoaponeurotic system (SMAS), and are usually distinct from wrinkles of facial expression. As with wrinkles of facial expression, sleep wrinkles can deepen and become permanent over time, unless the habitual sleeping positions which cause the wrinkles are altered.

Water-immersion wrinkling
The wrinkles that occur in skin over prolonged exposure to water are sometimes referred to as pruney fingers or water aging. This is a temporary skin condition where the skin on the palms of the hand or feet becomes wrinkly. This wrinkling response may have imparted an evolutionary benefit by providing improved traction in wet conditions, and a better grasp of wet objects. These results were called into question by a 2014 study that failed to reproduce any improvement of handling wet objects with wrinkled fingertips. However, a 2020 study of gripping efficiency found that wrinkles decreased the force required to grip wet objects by 20%, supporting the traction hypothesis.Prior to a 1935 study, the common explanation was based on water absorption in the keratin-laden epithelial skin when immersed in water, causing the skin to expand and resulting in a larger surface area, forcing it to wrinkle. Usually the tips of the fingers and toes are the first to wrinkle because of a thicker layer of keratin and an absence of hairs which secrete the protective oil called sebum.
In the 1935 study, however, Lewis and Pickering were studying patients with palsy of the median nerve when they discovered that skin wrinkling did not occur in the areas of the patients skin normally innervated by the damaged nerve.  This suggested that the nervous system plays an essential role in wrinkling, so the phenomenon could not be entirely explained simply by water absorption. Recent research shows that wrinkling is related to vasoconstriction. Water probably initiates the wrinkling process by altering the balance of electrolytes in the skin as it diffuses into the hands and soles via their many sweat ducts. This could alter the stability of the membranes of the many neurons that synapse on the many blood vessels underneath skin, causing them to fire more rapidly.  Increased neuronal firing causes blood vessels to constrict, decreasing the amount of fluid underneath the skin.  This decrease in fluid would cause a decrease in tension, causing the skin to become wrinkly.This insight resulted in bedside tests for nerve damage and vasoconstriction. Wrinkling is often scored with immersion of the hands for 30 minutes in water or EMLA cream with measurements steps of 5 minutes, and counting the number of visible wrinkles in time. Not all healthy persons have finger wrinkling after immersion, so it would be safe to say that sympathetic function is preserved if finger wrinkling after immersion in water is observed, but if the
fingers emerge smooth it cannot be assumed that there is a lesion to the autonomic supply or to the peripheral nerves of the hand.

Animals with wrinkles
Examples of wrinkles can be found in various animal species that grow loose, excess skin, particularly when they are young. Several breeds of dog, such as the Pug and the Shar Pei, have been bred to exaggerate this trait. In dogs bred for fighting, this is the result of selection for loose skin, which confers a protective advantage. Wrinkles are also associated with neoteny, as they are a trait associated with juvenile animals.

Techniques for reducing the appearance of aging wrinkles
Current evidence suggests that tretinoin decreases cohesiveness of follicular epithelial cells, although the exact mode of action is unknown. Additionally, tretinoin stimulates mitotic activity and increased turnover of follicular epithelial cells. Tretinoin is better known by the brand name Retin-A.
Topical glycosaminoglycans supplements can help to provide temporary restoration of enzyme balance to slow or prevent matrix breakdown and consequent onset of wrinkle formation. Glycosaminoglycans (GAGs) are produced by the body to maintain structural integrity in tissues and to maintain fluid balance. Hyaluronic acid is a type of GAG that promotes collagen synthesis, repair, and hydration. GAGs serve as a natural moisturizer and lubricant between epidermal cells to inhibit the production of matrix metalloproteinases (MMPs).
Dermal fillers are injectable products frequently used to correct wrinkles, and other depressions in the skin. They are often a kind of soft tissue designed to enable injection into the skin for purposes of improving the appearance </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is X-linked hypophosphatemia and explain in detail? [/INST] X-linked hypophosphatemia (XLH) is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of dietary deficiency rickets in that vitamin D supplementation does not cure it. It can cause bone deformity including short stature and genu varum (bow-leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. PHEX mutations lead to an elevated circulating (systemic) level of the hormone FGF23 which results in renal phosphate wasting, and locally in the extracellular matrix of bones and teeth an elevated level of the mineralization/calcification-inhibiting protein osteopontin.  An inactivating mutation in the PHEX gene results in an increase in systemic circulating FGF23, and a decrease in the enzymatic activity of the PHEX enzyme which normally removes (degrades) mineralization-inhibiting osteopontin protein; in XLH, the decreased PHEX enzyme activity leads to an accumulation of inhibitory osteopontin locally in bones and teeth to block mineralization which, along with renal phosphate wasting, both cause osteomalacia and odontomalacia. For both XLH and hypophosphatasia, inhibitor-enzyme pair relationships function to regulate mineralization in the extracellular matrix through a double-negative (inhibiting the inhibitors) activation effect in a manner described as the Stenciling Principle. Both these underlying mechanisms (renal phosphate wasting systemically, and mineralization inhibitor accumulation locally) contribute to the pathophysiology of XLH that leads to soft bones and teeth (hypomineralization, osteomalacia/odontomalacia).  The prevalence of the disease is 1 in 20,000.X-linked hypophosphatemia may be lumped in with autosomal dominant hypophosphatemic rickets under general terms such as hypophosphatemic rickets. Hypophosphatemic rickets are associated with at least nine other genetic mutations. Clinical management of hypophosphatemic rickets may differ depending on the specific mutations associated with an individual case, but treatments are aimed at raising phosphate levels to promote normal bone formation.

Symptoms and signs
The most common symptoms of XLH affect the bones and teeth, causing pain, abnormalities, and osteoarthritis. Symptoms and signs can vary between children and adults and can include:
Children

Adults

Osteomalacia
Dental abscesses
Limited range of movement (enthesopathy)
Short stature
Fatigue
Fractures / pseudofracture
Bone pain
Craniostenosis
Osteoarthritis
Spinal stenosis
Hearing loss
Depression

Genetics
XLH is associated with a mutation in the PHEX gene sequence, located on the human X chromosome at location Xp22.2-p22.1. The PHEX protein regulates another protein called fibroblast growth factor 23 (produced from the FGF23 gene). Fibroblast growth factor 23 normally inhibits the kidneys ability to reabsorb phosphate into the bloodstream. Gene mutations in PHEX prevent it from correctly regulating fibroblast growth factor 23. The resulting overactivity of FGF-23 reduces vitamin D 1α-hydroxylation and phosphate reabsorption by the kidneys, leading to hypophosphatemia and the related features of hereditary hypophosphatemic rickets. Also in XLH, where PHEX enzymatic activity is absent or reduced, osteopontin—a mineralization-inhibiting secreted substrate protein found in the extracellular matrix of bone—accumulates in bone (and teeth) to contribute to the osteomalacia (and odontomalacia) as shown in the mouse homolog (Hyp) of XLH and in XLH patients.  Biochemically in blood, XLH is recognized by hypophosphatemia and an inappropriately low level of calcitriol (1,25-(OH)2 vitamin D3). Patients often have bowed legs or knock knees in which they usually cannot touch both knees and ankles together at the same time.The disorder is inherited in an X-linked dominant manner. This means the defective gene responsible for the disorder (PHEX) is located on the X chromosome, and only one copy of the defective gene is sufficient to cause the disorder when inherited from a parent who has the disorder </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Xerophthalmia and explain in detail? [/INST] Xerophthalmia (from Ancient Greek "xērós" (ξηρός) meaning "dry" and "ophthalmos" (οφθαλμός) meaning "eye") is a medical condition in which the eye fails to produce tears. It may be caused by vitamin A deficiency, which is sometimes used to describe that condition, although there may be other causes.
Xerophthalmia caused by a severe vitamin A deficiency is described by pathologic dryness of the conjunctiva and cornea. The conjunctiva becomes dry, thick and wrinkled. The first symptom is poor vision at night. If untreated, xerophthalmia can lead to dry eye syndrome, corneal ulceration, and ultimately to blindness as a result of corneal and retinal damage.
Xerophthalmia usually implies a destructive dryness of the conjunctival epithelium due to dietary vitamin A deficiency—a rare condition in developed countries, but still causing much damage in developing countries. Other forms of dry eye are associated with aging, poor lid closure, scarring from a previous injury, or autoimmune diseases such as rheumatoid arthritis and Sjögrens syndrome, and these can all cause chronic conjunctivitis. Radioiodine therapy can also induce xerophthalmia, often transiently, although in some patients late onset or persistent xerophthalmia has been observed.The damage to the cornea in vitamin A associated xerophthalmia is quite different from damage to the retina at the back of the globe, a type of damage which can also be due to lack of vitamin A, but which is caused by lack of other forms of vitamin A which work in the visual system. Xerophthalmia from hypovitaminosis A is specifically due to lack of the hormone-like vitamin A metabolite retinoic acid, since (along with certain growth-stunting effects) the condition can be reversed in vitamin A deficient rats by retinoic acid supplementation (however the retinal damage continues). Since retinoic acid cannot be reduced to retinal or retinol, these effects on the cornea must be specific to retinoic acid. This is in keeping with retinoic acids known requirement for good health in epithelial cells, such as those in the cornea.

Cause
The condition is not congenital and develops over the course of a few months as the lacrimal glands fail to produce tears </s>