<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Diethylstilbestrol and can you explain it in depth? [/INST] Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for women with a history of recurrent miscarriage, hormone therapy for menopausal symptoms and estrogen deficiency in women, treatment of prostate cancer in men and breast cancer in women, and other uses. By 2007, it was only used in the treatment of prostate cancer and breast cancer. In 2011, Hoover and colleagues reported on adverse health outcomes linked to DES including infertility, miscarriage, ectopic pregnancy, preeclampsia, preterm birth, stillbirth, infant death, menopause prior to age 45, breast cancer, cervical cancer, and vaginal cancer. While most commonly taken by mouth, DES was available for use by other routes as well, for instance, vaginal, topical, and by injection.
DES is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. It is a synthetic and nonsteroidal estrogen of the stilbestrol group, and differs from the natural estrogen estradiol in various ways. Compared to estradiol, DES has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus. These differences result in DES having an increased risk of blood clots, cardiovascular issues, and certain other adverse effects.DES was discovered in 1938 and introduced for medical use in 1939. From about 1940 to 1971, the medication was given to pregnant women in the incorrect belief that it would reduce the risk of pregnancy complications and losses. In 1971, DES was shown to cause clear-cell carcinoma, a rare vaginal tumor, in girls and women who had been exposed to this medication in utero. The United States Food and Drug Administration subsequently withdrew approval of DES as a treatment for pregnant women. Follow-up studies have indicated that DES also has the potential to cause a variety of significant adverse medical complications during the lifetimes of those exposed.The United States National Cancer Institute recommends women born to mothers who took DES to undergo special medical exams on a regular basis to screen for complications as a result of the medication. Individuals who were exposed to DES during their mothers pregnancies are commonly referred to as "DES daughters" and "DES sons". Since the discovery of the toxic effects of DES, it has largely been discontinued and is now mostly no longer marketed.

Medical uses
DES has been used in the past for the following indications:
Recurrent miscarriage in pregnancy
Menopausal hormone therapy for the treatment of menopausal symptoms such as hot flashes and vaginal atrophy
Hormone therapy for hypoestrogenism (e.g., gonadal dysgenesis, premature ovarian failure, and after oophorectomy)
Postpartum lactation suppression to prevent or reverse breast engorgement
Gonorrheal vaginitis (discontinued following the introduction of the antibiotic penicillin)
Prostate cancer and breast cancer
Prevention of tall stature in tall adolescent girls
Treatment of acne in girls and women
As an emergency postcoital contraceptive
As a means of chemical castration for hypersexuality and paraphilias in men and sex offenders
Prevention of the testosterone flare at the start of gonadotropin-releasing hormone agonist (GnRH agonist) therapy
Feminizing hormone therapy for transgender womenDES was used at a dosage of 0.2 to 0.5 mg/day in menopausal hormone therapy.Interest in the use of DES to treat prostate cancer in men continues today. However, use of bioidentical parenteral estrogens like polyestradiol phosphate has been advocated in favor of oral synthetic estrogens like DES due to their much lower risk of cardiovascular toxicity. In addition to prostate cancer, some interest in the use of DES to treat breast cancer in women continues today as well. However, similarly to the case of prostate cancer, arguments have been made for the use of bioidentical estrogens like estradiol instead of DES for breast cancer.Oral DES at 0.25 to 0.5 mg/day is effective in the treatment of hot flashes in men undergoing androgen deprivation therapy for prostate cancer.Although DES was used to support pregnancy, it was later found not to be effective for this use.

Side effects
At more than 1 mg/day, DES is associated with high rates of side effects including nausea, vomiting, abdominal discomfort, headache, and bloating (incidence of 15–50%).

Breast changes and feminization
The pigmentation of the breast areolae are often very dark and almost black with DES therapy. The pigmentation that occurs with synthetic estrogens such as DES is much greater than with natural estrogens such as estradiol. The mechanism of the difference is unknown. Progestogens like hydroxyprogesterone caproate have been reported to reduce the nipple hyperpigmentation induced by high-dose estrogen therapy.In men treated with it for prostate cancer, DES has been found to produce high rates of gynecomastia (breast development) of 41 to 77%.

Blood clots and cardiovascular issues
In studies of DES as a form of high-dose estrogen therapy for men with prostate cancer, it has been associated with considerable cardiovascular morbidity and mortality. The risk is dose-dependent. A dosage of 5 mg/day DES has been associated with a 36% increase in non-cancer-related (mostly cardiovascular) deaths. In addition, there is an up to 15% incidence of venous thromboembolism. A 3 mg/day dosage of DES has been associated with an incidence of thromboembolism of 9.6 to 17%, with an incidence of cardiovascular complications of 33.3%. A lower dosage of 1 mg/day DES has been associated with a rate of death due to cardiovascular events of 14.8% (relative to 8.3% for orchiectomy alone).

Other long-term effects
DES has been linked to a variety of long-term adverse effects, such as increased risk of

vaginal clear-cell adenocarcinoma
vaginal adenosis
T-shaped uterus
uterine fibroids
cervical weakness
breast cancer
infertility
hypogonadism
intersexual gestational defects
depression,
and others,in women who were treated with it during pregnancy, and/or in their offspring.A comprehensive animal study in 1993 found a plethora of adverse effects from DES such as (but not limited to)

genotoxicity (due to quinone metabolite)
teratogenicity
penile and testicular hypoplasia
cryptorchidism (in rats and rhesus monkeys),
liver and renal cancer (in hamsters), ovarian papillary carcinoma (in canines), and
malignant uterine mesothelioma (in squirrel monkeys). Evidence was also found linking ADHD to F2 generations, demonstrating that there is at least some neurological and transgenerational effects in addition to the carcinogenic.Rodent studies reveal female reproductive tract cancers and abnormalities reaching to the F2 generation, and there is evidence of adverse effects such as irregular menstrual cycles intersexual in grandchildren of DES mothers. Additionally, evidence also points to transgenerational effects in F2 sons, such as hypospadias.
At this time however, the extent of DES transgenerational effects in humans is not fully understood.

Overdose
DES has been assessed in the past in clinical studies at extremely high doses of as much as 1,500 to 5,000 mg/day.

Pharmacology
Pharmacodynamics
Estrogenic activity
DES is an estrogen; specifically, it is a highly potent full agonist of both of the estrogen receptors (ERs). It has approximately 468% and 295% of the affinity of estradiol at the ERα and ERβ, respectively. However, EC50 values of 0.18 nM and 0.06 nM of DES for the ERα and ERβ, respectively, have been reported, suggesting, in spite of its binding affinity for the two receptors, several-fold preference for activation of the ERβ over the ERα. In addition to the nuclear ERs, DES is an agonist of the G protein-coupled estrogen receptor (GPER), albeit with relatively low affinity (~1,000 nM). DES produces all of the same biological effects attributed to natural estrogens like estradiol. This includes effects in the uterus, vagina, mammary glands, pituitary gland, and other tissues.A dosage of 1 mg/day DES is approximately equivalent to a dosage of 50 µg/day ethinylestradiol in terms of systemic estrogenic potency. Similarly to ethinylestradiol, DES shows a marked and disproportionately strong effect on liver protein synthesis. Whereas its systemic estrogenic potency was about 3.8-fold of that of estropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, the hepatic estrogenic potency of DES was 28-fold that of estropipate (or about 7.5-fold stronger potency for a dosage with equivalent systemic estrogenic effect).DES has at least three mechanisms of action in the treatment of prostate cancer in men. It suppresses gonadal androgen production and hence circulating androgen levels due to its antigonadotropic effects; it stimulates hepatic sex hormone-binding globulin (SHBG) production, thereby increasing circulating levels of SHBG and decreasing the free fraction of testosterone and dihydrotestosterone (DHT) in the circulation; and it may have direct cytotoxic effects in the testes and prostate gland. DES has also been found to decrease DNA synthesis at high doses.DES is a long-acting estrogen, with a nuclear retention of around 24 hours.

Antigonadotropic effects
Due to its estrogenic activity, DES has antigonadotropic effects. That is, it exerts negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis), suppresses the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses sex hormone production as well as gamete production or maturation in the gonads. A study of ovulation inhibition in women found that 5 mg/day oral DES was 92% effective, with ovulation occurring in only a single cycle. DES consistently suppresses testosterone levels in men into the castrate range (<50 ng/dL) within 1 to 2 weeks at doses of 3 mg/day and above. Conversely, a dosage of 1 mg/day DES is unable to fully suppress testosterone levels into the castrate range in men, which instead often stabilize at just above castrate levels (>50 ng/dL). However, it has also been reported that 1 mg/day DES results in approximately 50% suppression of testosterone levels, albeit with wide interindividual variability. It has been said that doses of DES of less than 1 mg/day have no effect on testosterone levels. However, the addition of an "extremely low" dosage of 0.1 mg/day DES to cyproterone acetate has been found to result in a synergistic antigonadotropic effect and to suppress testosterone levels into the castrate range in men. DES at 3 mg/day has similar testosterone suppression to a dose of 300 mg/day, suggesting that suppression of testosterone levels is maximal by 3 mg/day.

Other activities
In addition to the ERs, an in vitro study found that DES also possesses activity, albeit relatively weak, at a variety of other steroid hormone receptors. Whereas the study found EC50 values of 0.18 nM and 0.06 nM of DES for the ERα and ERβ, respectively, the medication showed significant glucocorticoid activity at a concentration of 1 μM that surpassed that of 0.1 nM dexamethasone, as well as significant antagonism of the androgen, progesterone, and mineralocorticoid receptors (75%, 85%, and 50% inhibition of positive control stimulation, respectively, all at a concentration of 1 μM). It also showed approximately 25% inhibition of the activation of PPARγ and LXRα at a concentration of 10 μM. The researchers stated that, to the best of their knowledge, they were the first to report such actions of DES, and hypothesized that these actions could be involved in the clinical effects of DES, for instance, in prostate cancer (notably in which particularly high dosages of DES are employed). However, they also noted that the importance of the activities requires further study in animal models at pharmacologically relevant doses.DES has been identified as an antagonist of all three isotypes of the estrogen-related receptors (ERRs), the ERRα, ERRβ, and ERRγ. Half-maximal inhibition occurs at a concentration of about 1 μM.

Pharmacokinetics
DES is well-absorbed with oral administration. With an oral dosage of 1 mg/day DES, plasma levels of DES at 20 hours following the last dose ranged between 0.9 and 1.9 ng/mL (3.4 to 7.1 nmol/L). Sublingual administration of DES appears to have about the same estrogenic potency of oral DES in women. Intrauterine DES has been studied for the treatment of uterine hypoplasia. Oral DES is thought to have about 17 to 50% of the clinical estrogenic potency of DES by injection.The distribution half-life of DES is 80 minutes. It has no affinity for SHBG or corticosteroid-binding globulin, and hence is not bound to these proteins in the circulation. The plasma protein binding of DES is greater than 95%.Hydroxylation of the aromatic rings of DES and subsequent conjugation of the ethyl side chains accounts for 80 to 90% of DES metabolism, while oxidation accounts for the remaining 10 to 20% and is dominated by conjugation reactions. Conjugation of DES consists of glucuronidation, while oxidation includes dehydrogenation into (Z,Z)-dienestrol. The medication is also known to produce paroxypropione as a metabolite. DES produces transient quinone-like reactive intermediates that cause cellular and genetic damage, which may help to explain the known carcinogenic effects of DES in humans. However, other research indicates that the toxic effects of DES may simply be due to overactivation of the ERs. In contrast to estradiol, the hydroxyl groups of DES do not undergo oxidation into an estrone-like equivalent.The elimination half-life of DES is 24 hours. The metabolites of DES are excreted in urine and feces.

Chemistry
DES belongs to the stilbestrol (4,4-dihydroxystilbene) group of compounds. It is a nonsteroidal open-ring analogue of the steroidal estrogen estradiol. DES can be prepared from anethole, which also happens to be weakly estrogenic. Anethole was demethylated to form anol and anol then spontaneously dimerized into dianol and hexestrol, with DES subsequently being synthesized via structural modification of hexestrol. As shown by X-ray crystallography, the molecular dimensions of DES are almost identical to those of estradiol, particularly in regards to the distance between the terminal hydroxyl groups.

History
Synthesis
DES was first synthesized in early 1938 by Leon Golberg, then a graduate student of Sir Robert Robinson at the Dyson Perrins Laboratory at the University of Oxford. Golbergs research was based on work by Wilfrid Lawson at the Courtauld Institute of Biochemistry, (led by Sir Edward Charles Dodds at Middlesex Hospital Medical School now part of University College London). A report of its synthesis was published in Nature on 5 February 1938.DES research was funded by the UK Medical Research Council (MRC), which had a policy against patenting drugs discovered using public funds. Because it was not patented, DES was produced by more than 200 pharmaceutical and chemical companies worldwide.

Clinical use
DES was first marketed for medical use in 1939. It was approved by the United States Food and Drug Administration (FDA) on September 19, 1941, in tablets up to 5 mg for four indications: gonorrheal vaginitis, atrophic vaginitis, menopausal symptoms, and postpartum lactation suppression to prevent breast engorgement. The gonorrheal vaginitis indication was dropped when the antibiotic penicillin became available. From its very inception, the drug was highly controversial.In 1941, Charles Huggins and Clarence Hodges at the University of Chicago found estradiol benzoate and DES to be the first effective drugs for the treatment of metastatic prostate cancer. DES was the first cancer drug.Orchiectomy or DES or both were the standard initial treatment for symptomatic advanced prostate cancer for over 40 years, until the GnRH agonist leuprorelin was found to have efficacy similar to DES without estrogenic effects and was approved in 1985.From the 1940s until the late 1980s, DES was FDA-approved as estrogen replacement therapy for estrogen deficiency states such as ovarian dysgenesis, premature ovarian failure, and after oophorectomy.
In the 1940s, DES was used off-label to prevent adverse pregnancy outcomes in women with a history of miscarriage. On July 1, 1947, the FDA approved the use of DES for this indication. The first such approval was granted to Bristol-Myers Squibb, allowing use of 25 mg (and later 100 mg) tablets of DES during pregnancy. Approvals were granted to other pharmaceutical companies later in the same year. The recommended regimen started at 5 mg per day in the seventh and eighth weeks of pregnancy (from first day of last menstrual period), increased every other week by 5 mg per day through the 14th week, and then increased every week by 5 mg per day from 25 mg per day in the 15th week to 125 mg per day in the 35th week of pregnancy.
DES was originally considered effective and safe for both the pregnant woman and the developing baby. It was aggressively marketed and routinely prescribed. Sales peaked in 1953.
In the early 1950s, a double-blind clinical trial at the University of Chicago assessed pregnancy outcomes in women who were assigned to either receive or not receive DES. The study showed no benefit of taking DES during pregnancy; adverse pregnancy outcomes were not reduced in the women who were given DES. By the late 1960s, six of seven leading textbooks of obstetrics said DES was ineffective at preventing miscarriage.Despite an absence of evidence supporting the use of DES to prevent adverse pregnancy outcomes, DES continued to be given to pregnant women through the 1960s. In 1971, a report published in the New England Journal of Medicine showed a probable link between DES and vaginal clear cell adenocarcinoma in girls and young women who had been exposed to this drug in utero. Later in the same year, the FDA sent an FDA Drug Bulletin to all U.S. physicians advising against the use of DES in pregnant women. The FDA also removed prevention of miscarriage as an indication for DES use and added pregnancy as a contraindication for DES use. On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975. The number of persons exposed to DES during pregnancy or in utero during the period of 1940 to 1971 is unknown, but may be as high as 2 million in the United States. DES was also used in other countries, most notably France, the Netherlands, and Great Britain.
From the 1950s through the beginning of the 1970s, DES was prescribed to prepubescent girls to begin puberty and thus stop growth by closing growth plates in the bones. Despite its clear link to cancer, doctors continued to recommend the hormone for "excess height".In 1960, DES was found to be more effective than androgens in the treatment of advanced breast cancer in postmenopausal women. DES was the hormonal treatment of choice for advanced breast cancer in postmenopausal women until 1977, when the FDA approved tamoxifen, a selective estrogen receptor modulator with efficacy similar to DES but fewer side effects.Several sources from medical literature in the 1970s and 1980s indicate that DES was used as a component of hormone therapy for transgender women.In 1973, in an attempt to restrict off-label use of DES as a postcoital contraceptive (which had become prevalent at many university health services following publication of an influential study in 1971 in JAMA) to emergency situations such as rape, an FDA Drug Bulletin was sent to all U.S. physicians and pharmacists that said the FDA had approved, under restricted conditions, postcoital contraceptive use of DES.In 1975, the FDA said it had not actually given (and never did give) approval to any manufacturer to market DES as a postcoital contraceptive, but would approve that indication for emergency situations such as rape or incest if a manufacturer provided patient labeling and special packaging as set out in a FDA final rule published in 1975. To discourage off-label use of DES as a postcoital contraceptive, the FDA in 1975 removed DES 25 mg tablets from the market and ordered the labeling of lower doses (5 mg and lower) of DES still approved for other indications changed to state: "This drug product should not be used as a postcoital contraceptive" in block capital letters on the first line of the physician prescribing information package insert and in a prominent and conspicuous location of the container and carton label. In the 1980s, off-label use of the Yuzpe regimen of certain regular combined oral contraceptive pills superseded off-label use of DES as a postcoital contraceptive.In 1978, the FDA removed postpartum lactation suppression to prevent breast engorgement from their approved indications for DES and other estrogens. In the 1990s, the only approved indications for DES were treatment of advanced prostate cancer and treatment of advanced breast cancer in postmenopausal women. The last remaining U.S. manufacturer of DES, Eli Lilly, stopped making and marketing it in 1997.

Trials
Diethylstilbestrol has been used countless times in studies on rats. Once it was discovered that DES was causing vaginal cancer, experiments began on both male and female rats. Many of these male rats were injected with DES while other male rats were injected with olive oil, and they were considered the control group. Each group received the same dosage on the same days, and the researchers performed light microscopy, electron microscopy, and confocal laser microscopy. With both the electron and confocal laser microscopy, it was prevalent that the Sertoli cells, which is a somatic cell where spermatids develop in the testes, was formed thirty-six years later in the rats who were injected with Diethylstilbestrol compared to the rats in the control group. Proceeding the completion of the trial, it was understood that rats of older age who were injected with DES experienced delay in sertoli cell maturation, underdeveloped epididymides, and drastic decrease in weight compared to its counterparts.The female rats used were inbred and most of them were given DES combined in their food. These rats were divided into three groups, one group who received no diethylstilbestrol, one group who had DES mixed into their diet, and the third group who had DES administered into their diet after day 13 of being pregnant. Some rats who were given DES unfortunately died before delivering their pup. The group that received DES in their food for 13 days while being pregnant resulted in early abortion and delivery failure. These outcomes showed that DES had a detrimental effect on pregnancy when administered as often as it was. Providing the dosing of diethylstilbestrol later in the pregnancy term also made visible the occurrence of abortions among the rats. Overall, any interaction with DES in female rats concluded in the rats experiencing abortions, improper fetal growth, and the increase in sterility.A review of people who had been treated or exposed to DES was done to find out how long-term effects would show. People for a long time had been treated during their pregnancy with DES and there have been known to be toxic and adverse effects to the hormone therapy. "Exposure to DES has been associated with an increased risk for breast cancer in DES mothers (relative risk, <2.0) and with a lifetime risk of clear-cell cervicovaginal cancer in DES daughters of 1/1000 to 1/10 000." Side effects of DES are proving to be long-term as it can cause increased risks to cancer after use. There will be continued work to see how far the adverse effects of DES will go after previous therapy as many women had used this during pregnancy and there is a long line to see how it will effect offspring and the mothers longer-term.

Regulations
In 1938, the ability to test the safety of DES on animals was first obtained by the FDA. The results from the preliminary tests showed that DES harmed the reproductive systems of animals. The application of these results to humans could not be determined, so the FDA could not act in a regulatory manner.New Drug Applications for DES approval were withdrawn in 1940 in a decision made by the FDA based on scientific uncertainty. However, this decision resulted in significant political pressure, so the FDA came to a compromise. The compromise meant that DES would be available only by prescription and would have to have warnings about its effects on the bottle, but the warning was dropped in 1945. In 1947, DES finally gained FDA approval for prescription to pregnant women who had diabetes as a method of preventing miscarriages. This led to the widespread prescription of DES to all pregnant women.In 1971, the FDA recommended against the prescription of DES to pregnant women. As a result, DES then began to see a withdraw from the US market starting in 1972 and in the European market starting in 1978, but the FDA still did not withdraw its approval for the use of DES in humans.DES was classified as a Group 1 carcinogen by the International Agency for Research on Cancer. After classification as a carcinogen, DES had its FDA approval withdrawn in 2000. DES is currently only in use for veterinary practices and in research trials as allowed by the FDA.Medical Ethics
Medical Ethics in regard to the approval and use of Diethylstilbestrol have been dismissed because of the actions of the FDA and pharmaceutical companies that were making DES at the time of its use. The Vice President of the American Drug Manufacturers Association, Carson Frailey, was employed by drug companies creating DES in order to help get it approved by the Food and Drug Administration (FDA). Nancy Langston, the author of The Retreat from Precaution: Regulating Diethylstilbestrol (DES), Endocrine Disruptors, and Environmental Health, states that "Frailey persuaded fifty-four doctors from around the country to write to the FDA, describing their clinical experiences with a total of more than five thousand patients. Only four of these fifty-four doctors felt that DES should not be approved, and the result was that, against the concerns of many of the FDA medical staff, the FDAs drug chief Theodore Klumpp recommended that the FDA approve DES." This excerpt describes how DES was unethically approved and shows that the motivation behind its approval was for the benefit of drug companies rather than the people who were going to use the drug. This approval of DES violates the values of medical ethics, autonomy, non-maleficence, beneficence, and justice as there was little thought put into how DES would affect its users. The decisions made by the FDA leaders to approve DES without further study and convince doctors to dissimulate their opinions on the use of DES is unethical. Once DES was approved for public consumption the "warnings [for DES were] made available only on a separate circular that patients would not see. Doctors could get this warning circular only by writing to the drug companies and requesting it. Letters between companies and FDA regulators reveal that both groups feared that if a woman ever saw how many potential risks DES might present, she might refuse to take the drug—or else she might sue the company and the prescribing doctors if she did get cancer or liver damage after taking the drug." Women were not informed about the possible effects of DES because doctors and FDA regulators were afraid DES would fail and never be approved costing the drug companies millions of dollars. The act of distributing potentially dangerous medicine to patients regardless of the affect and harm it may do solely for monetary gain is unethical.

Lawsuits
In the 1970s, the negative publicity surrounding the discovery of DESs long-term effects resulted in a huge wave of lawsuits in the United States against its manufacturers. These culminated in a landmark 1980 decision of the Supreme Court of California, Sindell v. Abbott Laboratories, in which the court imposed a rebuttable presumption of market share liability upon all DES manufacturers, proportional to their share of the market at the time the drug was consumed by the mother of a particular plaintiff.
Eli Lilly, a pharmaceutical company manufacturing DES, and the University of Chicago, had an action filed against them in regard to clinical trials from the 1950s. Three women filed the claim that their daughters had developments of abnormal cervical cellular formations as well as reproductive abnormalities in themselves and their sons. The plaintiffs had asked the courts to certify their case as a class action but were declined by the courts. However, the courts issued an opinion that their case had merit. The court held that Eli Lilly had a duty to notify about the risks of DES once they became aware of them or should have become aware of them. Under Illinois tort law, for the plaintiffs to recover under theories of breach of duty to warn and strict liability, the plaintiffs must have alleged injury to themselves. Ultimately, under their claims of breach of duty to warn and strict liability due to the plaintiffs citing risk of physical injury to others, not physical injury to themselves, the case was dismissed by the courts. Although the case was not certified as class action and their claims of breach of duty to warn and strict liability was dismissed, the courts did not dismiss the battery allegations. The issue was then to determine whether the University of Chicago had committed battery against these women but the case was settled before trial. Part of the settlement agreement for this case, Mink v. University of Chicago, attorneys for the plaintiffs negotiated for the university to provide free medical exams for all offspring exposed to DES in utero during the 1950 experiments as well as  treat the daughters of any women involved who develop DES-associated vaginal or cervical cancer.As of February 1991, there were over a thousand pending legal actions against DES manufacturers. There are over 300 companies that manufactured DES according to the same formula and the largest barrier to recovery is determining which manufacturer supplied the drug in each particular case. Many of the successful cases have relied on joint or several parties holding liability.
A lawsuit was filed in Boston Federal Court by 53 DES daughters who say their breast cancers were the result of DES being prescribed to their mothers while pregnant with them. Their cases survived a Daubert hearing. In 2013, the Fecho sisters who initiated the breast cancer/DES link litigation agreed to an undisclosed settlement amount on the second day of trial. The remaining litigants have received various settlements.The advocacy group DES Action USA helped provide information and support for DES-exposed persons engaged in lawsuits.

Society and culture
Alan Turing, the ground-breaking cryptographer, founder of computing science and programmable computers, who also proposed the actual theoretical model of biological morphogenesis, was forced onto this medication to induce chemical castration as a punitive and discredited "treatment" for homosexual behaviour, shortly before he died in ambiguous circumstances.James Herriot describes a case regarding treating a small dogs testicular Sertoli cell tumor in his 1974 book All Things Bright and Beautiful </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Exercise-induced bronchoconstriction and can you explain it in depth? [/INST] Exercise-induced asthma, or E.I.A., occurs when the airways narrow as a result of exercise.  The preferred term for this condition is exercise-induced bronchoconstriction (EIB). While exercise does not cause asthma, it is frequently an asthma trigger.It might be expected that people with E.I.B. would present with shortness of breath, and/or an elevated respiratory rate and wheezing, consistent with an asthma attack.  However, many will present with decreased stamina, or difficulty in recovering from exertion compared to team members, or paroxysmal coughing from an irritable airway.  Similarly, examination may reveal wheezing and  prolonged expiratory phase, or may be quite normal.  Consequently, a potential for under-diagnosis exists.  Measurement of airflow, such as peak expiratory flow rates, which can be done inexpensively on the track or sideline, may prove helpful. In athletes, symptoms of bronchospasm such as chest discomfort, breathlessness, and fatigue are often falsely attributed to the individual being “out of shape”, having asthma, or possessing a hyperreactive airway rather than E.I.B.

Cause
While the potential triggering events for E.I.B. are well recognized, the underlying pathogenesis is poorly understood. It usually occurs after at least several minutes of vigorous, aerobic activity, which increases oxygen demand to the point where breathing through the nose (nasal breathing) must be supplemented by mouth breathing.  The resultant inhalation of air that has not been warmed and humidified by the nasal passages seems to generate increased blood flow to the linings of the bronchial tree, resulting in edema.  Constriction of these small airways then follows, worsening the degree of obstruction to airflow.  There is increasing evidence that the smooth muscle that lines the airways becomes progressively more sensitive to changes that occur as a result of injury to the airways from dehydration.  The chemical mediators that provoke the muscle spasm appear to arise from mast cells.

Diagnosis
Exercise-induced bronchoconstriction can be difficult to diagnose clinically given the lack of specific symptoms and frequent misinterpretation as manifestations of vigorous exercise.  There are many mimics that present with similar symptoms, such as vocal cord dysfunction, cardiac arrhythmias, cardiomyopathies, and gastroesophageal reflux disease.  It is also important to distinguish those who have asthma with exercise worsening, and who consequently will have abnormal testing at rest, from true exercise-induced bronchoconstriction, where there will be normal baseline results.  Because of the wide differential diagnosis of exertional respiratory complaints, the diagnosis of exercise-induced bronchoconstriction based on history and self-reported symptoms alone has been shown to be inaccurate  and will result in an incorrect diagnosis more than 50% of the time. An important and often over-looked differential diagnosis is exercise-induced laryngeal obstruction EILO. The latter can co-exist with EIB and is best differentiated using objective testing and continuous laryngoscopy during exercise (CLE) testing.

Spirometry
Objective testing should begin with spirometry at rest. In true exercise-induced bronchoconstriction, the results should be within normal limits. Should resting values be abnormal, then asthma, or some other chronic lung condition, is present. There is, of course, no reason why asthma and exercise-induced bronchoconstriction should not co-exist but the distinction is important because without successful treatment of underlying asthma, treatment of an exercise component will likely be unsuccessful.  If baseline testing is normal, some form of exercise or pharmacologic stress will be required, either on the sideline or practice venue, or in the laboratory.

Exercise testing
Treadmill or ergometer-based testing in lung function laboratories are effective methods for diagnosing exercise-induced bronchoconstriction, but may result in false negatives if the exercise stimulus is not intense enough.

Field-exercise challenge
Field-exercise challenge tests that involve the athlete performing the sport in which they are normally involved and assessing FEV1 after exercise are helpful if abnormal but have been shown to be less sensitive than eucapnic voluntary hyperventilation.

Eucapnic voluntary hyperventilation challenge
The International Olympic Committee recommends the eucapnic voluntary hyperventilation (EVH) challenge as the test to document exercise-induced asthma  in Olympic athletes.  In the EVH challenge, the patient voluntarily, without exercising, rapidly breathes dry air enriched with 5% CO2 for six minutes.  The presence of the enriched CO2 compensates for the CO2 losses in the expired air, not matched by metabolic production, that occurs during hyperventilation, and so maintains CO2 levels at normal.

Medication challenge
Medication challenge tests, such as the methacholine challenge test, have a lower sensitivity for detection of exercise-induced bronchoconstriction in athletes and are also not a recommended first-line approach in the evaluation of exercise-induced asthma.Mannitol inhalation has been recently approved for use in the United States.
A relatively recent review of the literature has concluded that there is currently insufficient available evidence to conclude that either mannitol inhalation or eucapnic voluntary hyperventilation are suitable alternatives to exercise challenge testing to detect exercise-induced bronchoconstriction and that additional research is required.

Treatment
Lifestyle
The best treatment is avoidance of conditions predisposing to attacks, when possible.  In athletes who wish to continue their sport or do so in adverse conditions, preventive measures include altered training techniques and medications.
Some take advantage of the refractory period by precipitating an attack by "warming up," and then timing competition such that it occurs during the refractory period.  Step-wise training works in a similar fashion </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Central pontine myelinolysis and can you explain it in depth? [/INST] Central pontine myelinolysis is a neurological condition involving severe damage to the myelin sheath of nerve cells in the pons (an area of the brainstem). It is predominately iatrogenic (treatment-induced), and is characterized by acute paralysis,  dysphagia (difficulty swallowing), dysarthria (difficulty speaking), and other neurological symptoms.
Central pontine myelinolysis was first described as a disorder in 1959. The original paper described four cases with fatal outcomes, and the findings on autopsy. The disease was described as a disease of alcoholics and malnutrition. Central pontine indicated the site of the lesion and myelinolysis was used to emphasise that myelin was affected. The authors intentionally avoided the term demyelination to describe the condition, in order to differentiate this condition from multiple sclerosis and other neuroinflammatory disorders.Since this original description, demyelination in other areas of the central nervous system associated with osmotic stress has been described outside the pons (extrapontine). Osmotic demyelination syndrome is the term used for both central pontine myelinolysis and extrapontine myelinolysis.Central pontine myelinolysis, and osmotic demyelination syndrome, present most commonly as a complication of treatment of patients with profound hyponatremia (low sodium), which can result from a varied spectrum of conditions, based on different mechanisms. It occurs as a consequence of a rapid rise in serum tonicity following treatment in individuals with chronic, severe hyponatremia who have made intracellular adaptations to the prevailing hypotonicity.

Signs and symptoms
Symptoms depend on the regions of the brain involved. Prior to its onset, patients may present with the neurological signs and symptoms of hyponatraemic encephalopathy such as nausea and vomiting, confusion, headache and seizures. These symptoms may resolve with normalisation of the serum sodium concentration. Three to five days later, a second phase of neurological manifestations occurs correlating with the onset of myelinolysis. Observable immediate precursors may include seizures, disturbed consciousness, gait changes, and decrease or cessation of respiratory function.The classical clinical presentation is the progressive development of spastic quadriparesis, pseudobulbar palsy, and emotional lability (pseudobulbar affect), with other more variable neurological features associated with brainstem damage. These result from a rapid myelinolysis of the corticobulbar and corticospinal tracts in the brainstem.In about ten per cent of people with central pontine myelinolysis, extrapontine myelinolysis is also found. In these cases symptoms of Parkinsons disease may be generated.

Causes
The most common cause is overly-rapid correction of low blood sodium levels (hyponatremia). Apart from rapid correction of hyponatraemia, there are case reports of central pontine myelinolysis in association with hypokalaemia, anorexia nervosa when feeding is started, patients undergoing dialysis and burn victims. There is a case report of central pontine myelinolysis occurring in the context of refeeding syndrome, in the absence of hyponatremia.It has also been known to occur in patients suffering withdrawal symptoms of chronic alcoholism.  In these instances, occurrence may be entirely unrelated to hyponatremia or rapid correction of hyponatremia. It could affect patients who take some prescription medicines that are able to cross the blood-brain barrier and cause abnormal thirst reception - in this scenario the central pontine myelinolysis is caused by polydipsia leading to low blood sodium levels (hyponatremia).In schizophrenic patients with psychogenic polydipsia, inadequate thirst reception leads to excessive water intake, severely diluting serum sodium. With this excessive thirst combined with psychotic symptoms, brain damage such as central pontine myelinolysis may result from hyperosmolarity caused by excess intake of fluids, (primary polydipsia) although this is difficult to determine because such patients are often institutionalised and have a long history of mental health conditions.It has been observed following hematopoietic stem cell transplantation.Central pontine myelinolysis may also occur in patients prone to hyponatremia affected by:

Severe liver disease (e.g., cirrhosis)
Liver transplant
Alcoholism
Hypokalemia
People with serum sodium <105 mEq/L
Severe burns
Malnutrition
Anorexia nervosa
Severe electrolyte disorders
HIV/AIDS
hyperemesis gravidarum
Hyponatremia due to peritoneal dialysis
Wernicke encephalopathy

Pathophysiology
The currently accepted theory states that the brain cells adjust their osmolarities by changing levels of certain osmolytes like inositol, betaine, and glutamine in response to varying serum osmolality. In the context of chronic low plasma sodium (hyponatremia), the brain compensates by decreasing the levels of these osmolytes within the cells, so that they can remain relatively isotonic with their surroundings and not absorb too much fluid. The reverse is true in hypernatremia, in which the cells increase their intracellular osmolytes so as not to lose too much fluid to the extracellular space.With correction of the hyponatremia with intravenous fluids, the extracellular tonicity increases, followed by an increase in intracellular tonicity. When the correction is too rapid, not enough time is allowed for the brains cells to adjust to the new tonicity, namely by increasing the intracellular osmoles mentioned earlier. If the serum sodium levels rise too rapidly, the increased extracellular tonicity will continue to drive water out of the brains cells. This can lead to cellular dysfunction and central pontine myelinolysis.

Diagnosis
It can be diagnosed clinically in the appropriate context, but may be difficult to confirm radiologically using conventional imaging techniques.  Changes are more prominent on MRI than on CT, but often take days or weeks after acute symptom onset to develop </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Chlamydia and can you explain it in depth? [/INST] Chlamydia, or more specifically a chlamydia infection, is a sexually transmitted infection caused by the bacterium Chlamydia trachomatis. Most people who are infected have no symptoms. When symptoms do appear they may occur only several weeks after infection; the incubation period between exposure and being able to infect others is thought to be on the order of two to six weeks.  Symptoms in women may include vaginal discharge or burning with urination. Symptoms in men may include discharge from the penis, burning with urination, or pain and swelling of one or both testicles. The infection can spread to the upper genital tract in women, causing pelvic inflammatory disease, which may result in future infertility or ectopic pregnancy.Chlamydia infections can occur in other areas besides the genitals, including the anus, eyes, throat, and lymph nodes. Repeated chlamydia infections of the eyes that go without treatment can result in trachoma, a common cause of blindness in the developing world.Chlamydia can be spread during vaginal, anal, or oral sex, and can be passed from an infected mother to her baby during childbirth. The eye infections may also be spread by personal contact, flies, and contaminated towels in areas with poor sanitation. Infection by the bacterium Chlamydia trachomatis only occurs in humans. Diagnosis is often by screening which is recommended yearly in sexually active women under the age of twenty-five, others at higher risk, and at the first prenatal visit. Testing can be done on the urine or a swab of the cervix, vagina, or urethra. Rectal or mouth swabs are required to diagnose infections in those areas.Prevention is by not having sex, the use of condoms, or having sex with only one other person, who is not infected. Chlamydia can be cured by antibiotics with typically either azithromycin or doxycycline being used. Erythromycin or azithromycin is recommended in babies and during pregnancy. Sexual partners should also be treated, and infected people should be advised not to have sex for seven days and until symptom free. Gonorrhea, syphilis, and HIV should be tested for in those who have been infected. Following treatment people should be tested again after three months.Chlamydia is one of the most common sexually transmitted infections, affecting about 4.2% of women and 2.7% of men worldwide. In 2015, about 61 million new cases occurred globally. In the United States about 1.4 million cases were reported in 2014. Infections are most common among those between the ages of 15 and 25 and are more common in women than men. In 2015 infections resulted in about 200 deaths. The word chlamydia is from the Greek χλαμύδα, meaning "cloak".

Signs and symptoms
Genital disease
Women
Chlamydial infection of the cervix (neck of the womb) is a sexually transmitted infection which has no symptoms for  around 70% of women infected. The infection can be passed through vaginal, anal, or oral sex. Of those who have an asymptomatic infection that is not detected by their doctor, approximately half will develop pelvic inflammatory disease (PID), a generic term for infection of the uterus, fallopian tubes, and/or ovaries. PID can cause scarring inside the reproductive organs, which can later cause serious complications, including chronic pelvic pain, difficulty becoming pregnant, ectopic (tubal) pregnancy, and other dangerous complications of pregnancy.
Chlamydia is known as the "silent epidemic", as at least 70% of genital C. trachomatis infections in women (and 50% in men) are asymptomatic at the time of diagnosis, and can linger for months or years before being discovered. Signs and symptoms may include abnormal vaginal bleeding or discharge, abdominal pain, painful sexual intercourse, fever, painful urination or the urge to urinate more often than usual (urinary urgency).
For sexually active women who are not pregnant, screening is recommended in those under 25 and others at risk of infection. Risk factors include a history of chlamydial or other sexually transmitted infection, new or multiple sexual partners, and inconsistent condom use. Guidelines recommend all women attending for emergency contraceptive are offered chlamydia testing, with studies showing up to 9% of women aged <25 years had chlamydia.

Men
In men, those with a chlamydial infection show symptoms of infectious inflammation of the urethra in about 50% of cases. Symptoms that may occur include: a painful or burning sensation when urinating, an unusual discharge from the penis, testicular pain or swelling, or fever. If left untreated, chlamydia in men can spread to the testicles causing epididymitis, which in rare cases can lead to sterility if not treated. Chlamydia is also a potential cause of prostatic inflammation in men, although the exact relevance in prostatitis is difficult to ascertain due to possible contamination from urethritis.

Eye disease
Trachoma is a chronic conjunctivitis caused by Chlamydia trachomatis. It was once the leading cause of blindness worldwide, but its role diminished from 15% of blindness cases by trachoma in 1995 to 3.6% in 2002. The infection can be spread from eye to eye by fingers, shared towels or cloths, coughing and sneezing and eye-seeking flies. Symptoms include mucopurulent ocular discharge, irritation, redness, and lid swelling. Newborns can also develop chlamydia eye infection through childbirth (see below). Using the SAFE strategy (acronym for surgery for in-growing or in-turned lashes, antibiotics, facial cleanliness, and environmental improvements), the World Health Organization aims for the global elimination of trachoma by 2020 (GET 2020 initiative).

Joints
Chlamydia may also cause reactive arthritis—the triad of arthritis, conjunctivitis and urethral inflammation—especially in young men. About 15,000 men develop reactive arthritis due to chlamydia infection each year in the U.S., and about 5,000 are permanently affected by it. It can occur in both sexes, though is more common in men.

Infants
As many as half of all infants born to mothers with chlamydia will be born with the disease. Chlamydia can affect infants by causing spontaneous abortion; premature birth; conjunctivitis, which may lead to blindness; and pneumonia. Conjunctivitis due to chlamydia typically occurs one week after birth (compared with chemical causes (within hours) or gonorrhea (2–5 days)).

Other conditions
A different serovar of Chlamydia trachomatis is also the cause of lymphogranuloma venereum, an infection of the lymph nodes and lymphatics. It usually presents with genital ulceration and swollen lymph nodes in the groin, but it may also manifest as rectal inflammation, fever or swollen lymph nodes in other regions of the body.

Transmission
Chlamydia can be transmitted during vaginal, anal, or oral sex, or direct contact with infected tissue such as conjunctiva. Chlamydia can also be passed from an infected mother to her baby during vaginal childbirth. It is assumed that the probability of becoming infected is proportionate to the number of bacteria one is exposed to.

Pathophysiology
Chlamydiae have the ability to establish long-term associations with host cells. When an infected host cell is starved for various nutrients such as amino acids (for example, tryptophan), iron, or vitamins, this has a negative consequence for Chlamydiae since the organism is dependent on the host cell for these nutrients. Long-term cohort studies indicate that approximately 50% of those infected clear within a year, 80% within two years, and 90% within three years.The starved chlamydiae enter a persistent growth state wherein they stop cell division and become morphologically aberrant by increasing in size. Persistent organisms remain viable as they are capable of returning to a normal growth state once conditions in the host cell improve.There is debate as to whether persistence has relevance. Some believe that persistent chlamydiae are the cause of chronic chlamydial diseases. Some antibiotics such as β-lactams have been found to induce a persistent-like growth state.

Diagnosis
The diagnosis of genital chlamydial infections evolved rapidly from the 1990s through 2006. Nucleic acid amplification tests (NAAT), such as polymerase chain reaction (PCR), transcription mediated amplification (TMA), and the DNA strand displacement amplification (SDA) now are the mainstays. NAAT for chlamydia may be performed on swab specimens sampled from the cervix (women) or urethra (men), on self-collected vaginal swabs, or on voided urine. NAAT has been estimated to have a sensitivity of approximately 90% and a specificity of approximately 99%, regardless of sampling from a cervical swab or by urine specimen. In women seeking an sexually transmitted infection (STI) clinic and a urine test is negative, a subsequent cervical swab has been estimated to be positive in approximately 2% of the time.At present, the NAATs have regulatory approval only for testing urogenital specimens, although rapidly evolving research indicates that they may give reliable results on rectal specimens.
Because of improved test accuracy, ease of specimen management, convenience in specimen management, and ease of screening sexually active men and women, the NAATs have largely replaced culture, the historic gold standard for chlamydia diagnosis, and the non-amplified probe tests. The latter test is relatively insensitive, successfully detecting only 60–80% of infections in asymptomatic women, and often giving falsely-positive results. Culture remains useful in selected circumstances and is currently the only assay approved for testing non-genital specimens. Other methods also exist including: ligase chain reaction (LCR), direct fluorescent antibody resting, enzyme immunoassay, and cell culture.Rapid point-of-care tests are, as of 2020, not thought to be effective for diagnosing chlamydia in men of reproductive age and nonpregnant women because of high false-negative rates.

Prevention
Prevention is by not having sex, the use of condoms, or having sex with only one other person, who is not infected.

Screening
For sexually active women who are not pregnant, screening is recommended in those under 25 and others at risk of infection. Risk factors include a history of chlamydial or other sexually transmitted infection, new or multiple sexual partners, and inconsistent condom use. For pregnant women, guidelines vary: screening women with age or other risk factors is recommended by the U.S. Preventive Services Task Force (USPSTF) (which recommends screening women under 25) and the American Academy of Family Physicians (which recommends screening women aged 25 or younger). The American College of Obstetricians and Gynecologists recommends screening all at risk, while the Centers for Disease Control and Prevention recommend universal screening of pregnant women. The USPSTF acknowledges that in some communities there may be other risk factors for infection, such as ethnicity. Evidence-based recommendations for screening initiation, intervals and termination are currently not possible. For men, the USPSTF concludes evidence is currently insufficient to determine if regular screening of men for chlamydia is beneficial. They recommend regular screening of men who are at increased risk for HIV or syphilis infection. A Cochrane review found that the effects of screening are uncertain in terms of chlamydia transmission but that screening probably reduces the risk of pelvic inflammatory disease in women.In the United Kingdom the National Health Service (NHS) aims to:

Prevent and control chlamydia infection through early detection and treatment of asymptomatic infection;
Reduce onward transmission to sexual partners;
Prevent the consequences of untreated infection;
Test at least 25 percent of the sexually active under 25 population annually.
Retest after treatment.

Treatment
C. trachomatis infection can be effectively cured with antibiotics. Guidelines recommend azithromycin, doxycycline, erythromycin, levofloxacin or ofloxacin </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Developmental regression and can you explain it in depth? [/INST] Developmental regression is when a child who has reached a certain developmental stage begins to lose previously acquired milestones. It differs from developmental delay in that a child experiencing developmental delay is either not reaching developmental milestones or not progressing to new developmental milestones, while a child experiencing developmental regression will lose milestones and skills after acquiring them. Developmental regression is associated with diagnoses of autism spectrum disorder, childhood disintegrative disorder, Rett syndrome, Landau-Kleffner syndrome, and neuro-degenerative diseases. The loss of motor, language, and social skills can be treated with occupational therapy, physical therapy, and speech therapy.

Associated Diagnoses
Developmental regression is typically a symptom of neurological disorder.

Autism Spectrum Disorder
Autism spectrum disorder is a developmental disorder in which a childs communication and social skills are affected. Children with autism spectrum disorder can experience a loss of their previously acquired language and social skills. This is often reported by the childs parents. Children can experience loss of vocabulary and language understanding, as well as no longer make eye contact or play social and imitative games when they previously had. They can also experience a loss of motor and basic skills like toileting or feeding themselves. In autism spectrum disorder, this regression occurs in the first few years of development.

Childhood Disintegrative Disorder
Childhood disintegrative disorder (CDD) is a developmental disorder in which children experience a regression of social language, and motor functioning skills. CDD was merged with autism spectrum disorder in the DSM-V in 2013. Children with CDD can experience a loss of expressive and receptive language skills, social and self-care skills, play skills, and/or motor skills. Regression commonly occurs at around 3 or 4 years old, but after at least two years of normal development and before age 10.

Rett Syndrome
Rett syndrome is a neurodevelopmental disorder caused by a genetic mutation. It occurs almost exclusively in girls. A child with Rett syndrome experiences a loss of previously had intentional hand skills, and can experience a loss of language skills. Children can also experience a loss of social skills and autism-like symptoms. The regression typically occurs between 1–4 years of age.

Landau-Kleffner Syndrome
Landau-Kleffner syndrome is a form of epilepsy associated with a loss of language skills. Those with LKS lose their ability to understand spoken language and to verbally express themselves. LKS typically has an onset of between the ages of 2 and 8 years old.

Neuro-degenerative diseases
Neuro-degenerative diseases (disorders like Batten disease) can result in a child losing previously acquired motor, language, and speech skills.

Signs and symptoms
Children with developmental regression lose developmental milestones they have previously gained. These can be motor, social, or language skills. The loss of motor skills could include loss of the ability to purposefully use hands, loss of the ability to feed oneself, loss of the ability to walk, loss of the ability to bathe oneself, and loss of the ability to dress oneself. The loss of social skills could include loss of the ability/desire to play, loss of the ability to make appropriate eye contact, and loss of interest in playing social games </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Fibrous dysplasia of bone and can you explain it in depth? [/INST] Fibrous dysplasia is a disorder where normal bone and marrow is replaced with fibrous tissue, resulting in formation of bone that is weak and prone to expansion. As a result, most complications result from fracture, deformity, functional impairment, and pain. Disease occurs along a broad clinical spectrum ranging from asymptomatic, incidental lesions, to severe disabling disease. Disease can affect one bone (monostotic), multiple (polyostotic), or all bones (panostotic) and may occur in isolation or in combination with café au lait skin macules and hyperfunctioning endocrinopathies, termed McCune–Albright syndrome. More rarely, fibrous dysplasia may be associated with intramuscular myxomas, termed Mazabrauds syndrome. Fibrous dysplasia is very rare, and there is no known cure. Fibrous dysplasia is not a form of cancer.

Presentation
Fibrous dysplasia is a mosaic disease that can involve any part or combination of the craniofacial, axillary, and/or appendicular skeleton. The type and severity of the complications therefore depend on the location and extent of the affected skeleton. The clinical spectrum is very broad, ranging from an isolated, asymptomatic monostotic lesion discovered incidentally, to severe disabling disease involving practically the entire skeleton and leading to loss of vision, hearing, and/or mobility.Individual bone lesions typically manifest during the first few years of life and expand during childhood. The vast majority of clinically significant bone lesions are detectable by age 10 years, with few new and almost no clinically significant bone lesions appearing after age 15 years. Total body scintigraphy is useful to identify and determine the extent of bone lesions, and should be performed in all patients with suspected fibrous dysplasia.Children with fibrous dysplasia in the appendicular skeleton typically present with limp, pain, and/or pathologic fractures. Frequent fractures and progressive deformity may lead to difficulties with ambulation and impaired mobility. In the craniofacial skeleton, fibrous dysplasia may present as a painless “lump” or facial asymmetry. Expansion of craniofacial lesions may lead to progressive facial deformity. In rare cases, patients may develop vision and/or hearing loss due to compromise of the optic nerves and/or auditory canals, which is more common in patients with McCune-Albright syndrome associated growth hormone excess. Fibrous dysplasia commonly involves the spine, and may lead to scoliosis, which in rare instances may be severe. Untreated, progressive scoliosis is one of the few features of fibrous dysplasia that can lead to early fatality.
Bone pain is a common complication of fibrous dysplasia. It may present at any age, but most commonly develops during adolescence and progresses into adulthood.
Bone marrow stromal cells in fibrous dysplasia produce excess amounts of the phosphate-regulating hormone fibroblast growth factor-23 (FGF23), leading to loss of phosphate in the urine. Patients with hypophosphatemia may develop rickets/osteomalacia, increased fractures, and bone pain.

Pathophysiology
Fibrous dysplasia is a mosaic disease resulting from post-zygotic activating mutations of the GNAS locus at 20q13.2-q13.3, which codes for the α subunit of the Gs G protein-coupled receptor. In bone, constitutive Gsα signaling results in impaired differentiation and proliferation of bone marrow stromal cells. Proliferation of these cells causes replacement of normal bone and marrow with fibrous tissue. The bony trabeculae are abnormally thin and irregular, and often likened to Chinese characters (bony spicules on biopsy).Fibrous dysplasia is not hereditary, and there has never been a case of genetic inheritance from parent to child.

Diagnosis
On x-ray, fibrous dysplasia appears as bubbly lytic lesions, or a ground glass appearance. Computerized tomography (CT) or magnetic resonance imaging (MRI) scans may be used to determine how extensively bones are affected. CT can better demonstrate the typical "ground glass" appearance, which is a highly specific radiological finding, while MRI can show cystic areas with fluid contents. A bone scan uses radioactive tracers, which are injected into your bloodstream. The damaged parts of bones take up more of the tracer, which show up more brightly on the scan. A biopsy, which uses a hollow needle to remove a small piece of the affected bone for laboratory analysis, can diagnose fibrous dysplasia definitely.

Treatment
Treatment in fibrous dysplasia is mainly palliative, and is focused on managing fractures and preventing deformity </s>


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


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Septic arthritis and can you explain it in depth? [/INST] Acute septic arthritis, infectious arthritis, suppurative arthritis, osteomyelitis, or joint infection is the invasion of a joint by an infectious agent resulting in joint inflammation. Generally speaking, symptoms typically include redness, heat and pain in a single joint associated with a decreased ability to move the joint. Onset is usually rapid. Other symptoms may include fever, weakness and headache. Occasionally, more than one joint may be involved, especially in neonates and younger children. In neonates, infants during the first year of life, and toddlers, the signs and symptoms of septic arthritis can be deceptive and mimic other infectious and non-infectious disorders.In children, septic arthritis is usually caused by non-specific bacterial infection and commonly hematogenous, i.e., spread through the bloodstream. Septic arthritis and/or acute hematogenous osteomyelitis usually occurs in children with no co-occurring health problems. Other routes of infection include direct trauma and spread from a nearby abscess. Other less common cause include specific bacteria as mycobacterium tuberculosis, viruses, fungi and parasites. In children, however, there are certain groups that are specifically vulnerable to such infections namely preterm infants, neonates in general, children and adolescence with hematologic disorders, renal osteodystrophy and immune-compromised status. In adults vulnerable groups include an artificial joint, prior arthritis, diabetes and poor immune function.  Diagnosis is generally based on accurate correlation between history-taking and clinical examination findings and basic laboratory and imaging findings like joint ultrasound.In children septic arthritis can have serious consequences if not treated appropriately and timely. Initial treatment typically includes antibiotics such as vancomycin, ceftriaxone or ceftazidime. Surgery in the form of joint drainage is the gold standard management in large joints like the hip and shoulder. Without early treatment, long-term joint problems may occur, such as irreversible joint destruction and dislocation.

Signs and symptoms
Children
In children septic arthritis usually affects the larger joints like the hips, knees and shoulders. The early signs and symptoms of septic arthritis in children and adolescence can be confused with limb injury. Among the signs and symptoms of septic arthritis are: acutely swollen, red, painful joint with fever. Kocher criteria have been suggested to predict the diagnosis of septic arthritis in children.Importantly, observation of active limb motion or kicking in the lower limb can provide valuable clues to septic arthritis of hip or knee. In neonates/new born and infants the hip joint is characteristically held in abduction flexion and external rotation. This position helps the infant accommodate maximum amount of septic joint fluid with the least tension possible. The tendency to have multiple joint involvements in septic arthritis of neonates and young children should be closely considered.

Adults
In adults, septic arthritis most commonly causes pain, swelling and warmth at the affected joint. Therefore, those affected by septic arthritis will often refuse to use the extremity and prefer to hold the joint rigidly. Fever is also a symptom; however, it is less likely in older people. In adults the most common joint affected is the knee. Hip, shoulder, wrist and elbow joints are less commonly affected. Spine, sternoclavicular and sacroiliac joints can also be involved. The most common cause of arthritis in these joints is intravenous drug use. Usually, only one joint is affected. More than one joint can be involved if bacteria are spread through the bloodstream.

Prosthetic joint
For those with artificial joint implants, there is a chance of 0.86 to 1.1% of getting infected in a knee joint and 0.3 to 1.7% of getting infected in a hip joint. There are three phases of artificial joint infection: early, delayed and late.
Early – infection occurs in less than 3 months. Usual signs and symptoms are fever and joint pain, with redness and warmth over the joint operation site. The mode of infection is during the joint implant surgery. The usual bacteria involved are Staphylococcus aureus and gram negative bacilli.
Delayed – infection occurs between 3 and 24 months. There would be persistent joint pain, due to loosening of the implant. The mode of infection is during the implant surgery. Common bacteria are coagulase-negative Staphylococcus and Cutibacterium acnes.
Late – more than 24 months. It is usually presented with a sudden onset of joint pain and fever. The mode of infection is through the bloodstream. The bacteria involved are the same as those in septic arthritis of a normal joint.

Cause
Septic arthritis is most commonly caused by a bacterial infection. Bacteria can enter the joint by:

The bloodstream from an infection elsewhere (most common)
Direct penetration into the joint (arthrocentesis, arthroscopy, trauma)
A surrounding infection in the bone or tissue (uncommon, from osteomyelitis, septic bursitis, abscess).Microorganisms in the blood may come from infections elsewhere in the body such as wound infections, urinary tract infections, meningitis or endocarditis. Sometimes, the infection comes from an unknown location. Joints with preexisting arthritis, such as rheumatoid arthritis, are especially prone to bacterial arthritis spread through the blood. In addition, some treatments for rheumatoid arthritis can also increase a persons risk by causing an immunocompromised state. Intravenous drug use can cause endocarditis that spreads bacteria in the bloodstream and subsequently causes septic arthritis. Bacteria can enter the joint directly from prior surgery, intraarticular injection, trauma or joint prosthesis.

Risk factors
In children, although septic arthritis occurs in healthy children and adolescents with no co-occurring health issues, there are certain risk factors that may increase the likelihood of acquiring septic arthritis. For example, children with renal osteodystrophy or renal bone disease, certain hematological disorders and diseases causing immune suppression are risk factors for childhood septic arthritis.The rate of septic arthritis varies from 4 to 29 cases per 100,000 person-years, depending on the underlying medical condition and the joint characteristics. For those with a septic joint, 85% of the cases have an underlying medical condition while 59% of them had a previous joint disorder. Having more than one risk factor greatly increases risk of septic arthritis.
Age over 80 years
Diabetes mellitus
Osteoarthritis
Rheumatoid arthritis. Risk of septic arthritis increases with anti-tumor necrosis factor alpha treatment.
Immunosuppressive medication
Intravenous drug abuse
Recent joint surgery
Hip or knee prosthesis and skin infection
HIV infection
Other causes of sepsis

Organisms
Most cases of septic arthritis involve only one organism; however, polymicrobial infections can occur, especially after large open injuries to the joint. Septic arthritis is usually caused by bacteria, but may be caused by viral, mycobacterial, and fungal pathogens as well. It can be broadly classified into three groups: non-gonococcal arthritis, gonococcal arthritis, and others.
Non-gonococcal arthritis – These bacteria account for over 80% of septic arthritis cases and are usually staphylococci or streptococci. Such infections most commonly come from drug abuse, cellulitis, abscesses, endocarditis, and chronic osteomyelitis. Methicillin-resistant Staphylococcus aureus (MRSA) may affect 5 to 25% of the cases while gram negative bacilli affects 14 to 19% of the septic arthritis cases. Gram negative infections are usually acquired through urinary tract infections, drug abuse, and skin infections. Older people who are immunocompromised are also prone to get gram negative infections. Common gram negative organisms are: Pseudomonas aeruginosa and Escherichia coli. Both gram positive and gram negative infections are commonly spread through the blood from an infective source; but can be introduced directly into the joint or from surrounding tissue. It often affects older people, and often happens suddenly, involving only one joint. Joint aspiration cultures are positive in 90% of cases, while only 50% of blood cultures yield any organisms.
Gonococcal arthritis – Neisseria gonorrhoeae is a common cause of septic arthritis in people who are sexually active and under 40 years old. The bacteria is spread through the blood to the joint following sexual transmission. Other symptoms of disseminated gonococcal infection can include migration of joint pain, tenosynovitis and dermatitis. Synovial fluid cultures are positive in 25 to 70% of the cases while blood cultures are seldom positive. Apart from blood and joint cultures, swabs from urethra, rectum, pharynx, and cervix should also be taken. Polymerase chain reaction (PCR) is another useful way of identifying gonococcal infections if diagnosis is difficult and clinical presentation is similar to reactive arthritis.
Others – Fungal and mycobacterial infections are rare causes of septic arthritis and usually have a slow onset of joint symptoms. Mycobacterial joint infection most commonly affects hip and knee joints, caused by reactivation of past mycobacterial infections, with or without signs and symptoms of tuberculosis in lungs. Synovial fluid cultures will be positive in 80% of the cases. However, acid fast smears are not useful. Histology is not specific to myocobacterial infection as there are other granulomatous diseases that can show similar histology. Borrelia burgdorferi, a bacterium that causes lyme disease, can affect multiple large joints such as the knee. Confirmation of Lyme disease is done through enzyme-linked immunosorbent assay (ELISA) followed by confirmation using Western Blot test. It cannot be cultured from synovial fluid. However, PCR testing yields 85% positive result from synovial fluid. Viruses such as rubella, parvovirus B19, chikungunya, and HIV infection can also cause septic arthritis.
Prosthetic joint infection – Artificial joint infection are usually caused by coagulase negative Staphylococci, Staphylococcus aureus, and gram negative bacilli. Concurrent infections by multiple organisms is also reported in 20% of the cases. The risk factors of prosthetic joint infections are:  previous fracture, seropositive rheumatoid arthritis, obesity, revision arthroplasty, and surgical site infections.

List of organisms
Staphylococci (40%)Staphylococcus aureus – the most common cause in most age groups. Can be caused by skin infection, previously damaged joint, prosthetic joint or intravenous drug use.
coagulase-negative staphylococci – usually due to prosthetic joint
Streptococci – the second-most common cause (28%)Streptococcus pyogenes – a common cause in children under 5
Streptococcus pneumoniae
Group B streptococci – a common cause in infants
Haemophilus influenzae
Neisseria gonorrhoeae – the most common cause of septic arthritis in young, sexually active adults. Multiple macules or vesicles seen over the trunk are a pathognomonic feature.
Neisseria meningitidis
Escherichia coli – in the elderly, IV drug users and the seriously ill
Pseudomonas aeruginosa – IV drug users or penetrating trauma through the shoe
M. tuberculosis, Salmonella spp. and Brucella spp. – cause septic spinal arthritis
Eikenella corrodens – human bites
Pasteurella multocida, bartonella henselae, capnocytophaga – animal bites or scratches
Fungal species – immunocompromised state
Borrelia burgdorferi – ticks, causes lyme disease
Spirillum minus, Streptobacillus moniliformis– rat bites

Diagnosis
Septic arthritis should be considered whenever a person has rapid onset pain in a swollen joint, regardless of fever. One or multiple joints can be affected at the same time.Laboratory studies such as blood cultures, white blood cell count with differential, ESR, and CRP should also be included. However, white cell count, ESR, and CRP are nonspecific and could be elevated due to infection elsewhere in the body. Serologic studies should be done if lyme disease is suspected. Blood cultures can be positive in 25 to 50% of those with septic arthritis due to spread of infection from the blood. CRP more than 20 mg/L and ESR greater than 20 mm/hour together with typical signs and symptoms of septic arthritis should prompt arthrocentesis from the affected joint for synovial fluid examination.The synovial fluid should be collected before the administration of antibiotics and should be sent for gram stain, culture, leukocyte count with differential, and crystal studies. This can include NAAT testing for N. gonorrhoeae if suspected in a sexually active person.In children, the Kocher criteria is used for diagnosis of septic arthritis.

Differential diagnosis
The differential diagnosis of septic arthritis is broad and challenging. First, it has to be differentiated from acute hematogenous osteomyelitis. This is because the treatment lines of both conditions are not identical. Noteworthy, septic arthritis and acute hematogenous osteomyelitis can co-occur. Especially in the hip and shoulder joints their co-occurrence is likely and represents a diagnostic challenge. Therefore, physicians should have a high suspicion index in that regard. This is because in both the hip and shoulder joints the metaphysis is intra-articular which in turn facilitates the spread of hematogenous osteomyelitis into the joint cavity. Conversely, joint sepsis may spread to the metaphysis and induce osteomyelitis.
Acute exacerbation of juvenile idiopathic arthritis and transient synovitis of the hip both of which are non-septic conditions may mimic septic arthritis. More serious and life-threatening disorders as bone malignancies e.g. Ewing sarcoma and osteosarcoma may mimic septic arthritis associated with concurrent acute hematogenous osteomyelitis. In this regard, Magnetic resonance imaging may play an important role in the differential diagnosis.

Joint aspiration
In children, joint synovial fluid aspiration techniques aim at isolating the infectious organism by culture and sensitivity analysis. Cytological analysis of the joint aspirate can point to septic arthritis. However, a negative culture and sensitivity test does not rule out the presence of septic arthritis. Various clinical scenarios and technique-related factors may impact the validity of results of the culture and sensitivity. Additionally, results of cytological analysis, though important, should not be interpreted in isolation of the clinical settings.

In the joint fluid, the typical white blood cell count in septic arthritis is over 50,000-100,000 cells per 10−6/l (50,000-100,000 cell/mm3); where more than 90% are neutrophils is suggestive of septic arthritis. For those with prosthetic joints, white cell count more than 1,100 per mm3 with neutrophil count greater than 64% is suggestive of septic arthritis. However, septic synovial fluid can have white blood cell counts as low as a few thousand in the early stages. Therefore, differentiation of septic arthritis from other causes is not always possible based on cell counts alone. Synovial fluid PCR analysis is useful in finding less common organisms such as Borrelia species. However, measuring protein and glucose levels in joint fluid is not useful for diagnosis.The Gram stain can rule in the diagnosis of septic arthritis, however, cannot exclude it.Synovial fluid cultures are positive in over 90% of nongonoccocal arthritis; however, it is possible for the culture to be negative if the person received antibiotics prior to the joint aspiration. Cultures are usually negative in gonoccocal arthritis or if fastidious organisms are involved.If the culture is negative or if a gonococcal cause is suspected, NAAT testing of the synovial fluid should be done.Positive crystal studies do not rule out septic arthritis. Crystal-induced arthritis such as gout can occur at the same time as septic arthritis.A lactate level in the synovial fluid of greater than 10 mmol/L makes the diagnosis very likely.

Blood tests
Laboratory testing includes white blood cell count, ESR and CRP. These values are usually elevated in those with septic arthritis; however, these can be elevated by other infections or inflammatory conditions and are, therefore, nonspecific. Procalcitonin may be more useful than CRP.Blood cultures can be positive in up to half of people with septic arthritis.

Imaging
Imaging such as x-ray, CT, MRI or ultrasound are nonspecific. They can help determine areas of inflammation but cannot confirm septic arthritis.When septic arthritis is suspected, x-rays should generally be taken. This is used to assess any problems in the surrounding structures such as bone fractures, chondrocalcinosis, and inflammatory arthritis which may predispose to septic arthritis. While x-rays may not be helpful early in the diagnosis/treatment, they may show subtle increase in joint space and tissue swelling. Later findings include joint space narrowing due to destruction of the joint.Ultrasound is effective at detecting joint effusions.CT and MRI are not required for diagnosis; but if the diagnosis is unclear or the joints are hard to examine (ie.sacroiliac or hip joints); they can help to assess for inflammation/infection in or around the joint (i.e. Osteomyelitis), bone erosions, and bone marrow oedema. Both CT and MRI scans are helpful in guiding arthrocentesis of the joints.

Differential diagnosis
Crystal induced arthritis such as gout or pseudogout
Inflammatory arthritisRheumatoid arthritis
Seronegative spondyloarthropathy such as ankylosing spondylitis or reactive arthritis
Traumatic arthritis due to hemarthrosis, fracture or foreign body
Osteoarthritis

Treatment
Treatment is usually with intravenous antibiotics, analgesia and washout and/or aspiration of the joint. Draining the pus from the joint is important and can be done either by needle (arthrocentesis) or opening the joint surgically (arthrotomy).Empiric antibiotics for suspected bacteria should be started. This should be based on Gram stain of the synovial fluid as well as other clinical findings. General guidelines are as follows:

Gram positive cocci – vancomycin
Gram negative cocci – Ceftriaxone
Gram negative bacilli – Ceftriaxone, cefotaxime, or ceftazidime
Gram stain negative and immunocompetent – vancomycin
Gram stain negative and immunocompromised – vancomycin + third generation cephalosphorin
IV drug use (possible pseudomonas aeruginosa) – ceftazidime +/- an aminoglycosideOnce cultures are available, antibiotics can be changed to target the specific organism. After a good response to intravenous antibiotics, people can be switched to oral antibiotics. The duration of oral antibiotics varies, but is generally for 1–4 weeks depending on the offending organism.  Repeated daily joint aspiration is useful in the treatment of septic arthritis. Every aspirate should be sent for culture, gram stain, white cell count to monitor the progress of the disease. Both open surgery and arthroscopy are helpful in the drainage of the infected joint. During surgery, lysis of the adhesions, drainage of pus, and debridement of the necrotic tissues are done. Close follow up with physical exam & labs must be done to make sure the person is no longer feverish, pain has resolved, has improved range of motion, and lab values are normalized.In infection of a prosthetic joint, a biofilm is often created on the surface of the prosthesis which is resistant to antibiotics. Surgical debridement  is usually indicated in these cases. A replacement prosthesis is usually not inserted at the time of removal to allow antibiotics to clear infection of the region. People that cannot have surgery may try long-term antibiotic therapy in order to suppress the infection. The use of prophylactic antibiotics before dental, genitourinary, gastrointestinal procedures to prevent infection of the implant is controversial.Low-quality evidence suggests that the use of corticosteroids may reduce pain and the number of days of antibiotic treatment in children.

Outcomes
Risk of permanent impairment of the joint varies greatly. This usually depends on how quickly treatment is started after symptoms occur as longer lasting infections cause more destruction to the joint </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Spastic quadriplegia and can you explain it in depth? [/INST] Spastic quadriplegia, also known as spastic tetraplegia, is a subset of spastic cerebral palsy that affects all four limbs (both arms and legs).
Compared to quadriplegia, spastic tetraplegia is defined by spasticity of the limbs as opposed to strict paralysis. It is distinguishable from other forms of cerebral palsy in that those afflicted with the condition display stiff, jerky movements stemming from hypertonia of the muscles.Spastic quadriplegia, while affecting all four limbs more or less equally, can still present parts of the body as stiffer than others, such as one arm being tighter than another arm, and so forth. Spastic triplegia, meanwhile, involves three limbs (such as one arm and two legs, or one leg and two arms, etc.); spastic diplegia affects two limbs (commonly just the legs), spastic hemiplegia affects one or another entire side of the body (left or right); and spastic monoplegia involves a single limb.

Symptoms and signs
Spastic quadriplegia can be detected by the abnormal development of motor skills in children. Symptoms can present themselves as early as three months but are generally seen before the child reaches two years of age. Some warning signs include: a child of more than two months who has stiff legs that scissor and is unable to control his or her head, and a child of more than twelve months who has not developed the ability to crawl or stand.Spastic quadriplegia also presents a range of symptoms that affect the musculature. Many experience contractures, which are defined as joints that cannot be stretched or moved.  Clonus is another symptom that is characterized by alternating, rapid muscle contraction and relaxation. This presents itself as tremors and scissoring of the limbs. Distonia, or lasting muscle contractions and tightness, is also often experienced by those affected by spastic quadriplegia. These involuntary muscle contractions may affect the development of structural muscle around the hip and lead to hip dysplasia and dislocation, making it difficult to sit. The combination of these symptoms often makes it difficult for the patients to walk as well. Although the arms and legs of patients are often stiff, the neck is usually limp due to the lack of voluntary muscle control.

Causes
Spastic quadriplegia is generally caused by brain damage or disruptions in normal brain development preceding birth. According to the National Institutes of Health, there are four types of brain damage that can cause spastic quadriplegia. These include, damage to the white matter (periventricular leukomalacia), abnormal brain development (cerebral dysgenesis), bleeding in the brain (intracranial hemorrhage), and brain damage due to lack of oxygen (hypoxic-ischemic encephalopathy or intrapartum asphyxia).The white matter of the brain is especially vulnerable between the 26th and 34th weeks of maturation, and damage to the white matter can interfere with the brain’s ability to transmit signals to the rest of the body. Spastic quadriplegia can be caused by a condition known as periventricular leukomalacia which results in the formation of lesions and holes in the white matter of the brain.Prior to the 26th week of maturation, the fetal brain is particularly susceptible to various toxins whose effects can ultimately hinder normal development. Exposure of the brain to infectious agents is especially dangerous because they can trigger immune responses that activate cytokines and lead to inflammation of the brain. Some infections that have been linked to the development of spastic quadriplegia include meningitis, herpes, rubella, and encephalitis. A difference in blood types between the mother and the fetus can also initiate a problematic immune response and cause brain damage. Severe jaundice, can also lead to brain damage and spastic quadriplegia due to a buildup of bilirubin in the blood.Bleeding in the brain caused by fetal strokes, blood clots, weak and malformed blood vessels, or high maternal blood pressure may also lead to brain damage causing spastic quadriplegia. Maternal infection, most specifically pelvic inflammatory disease, has been shown to increase the risk of fetal stroke.Hypoxia, lack of oxygen to the brain, can also cause damage in the cerebral motor cortex and other brain regions </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Carney complex and can you explain it in depth? [/INST] Carney complex and its subsets LAMB syndrome and NAME syndrome are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity. It is distinct from Carneys triad. Approximately 7% of all cardiac myxomas are associated with Carney complex.

Presentation
The spotty skin pigmentation and lentigines occur most commonly on the face, especially on the lips, eyelids, conjunctiva and oral mucosa. Cardiac myxomas may lead to embolic strokes and heart failure and may present with fever, joint pain, shortness of breath, diastolic rumble and tumor plop. Myxomas may also occur outside the heart, usually in the skin and breast </s>


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