<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hyperandrogenism and explain in detail? [/INST] Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facial hair, and infrequent or absent menstruation. Complications may include high blood cholesterol and diabetes. It occurs in approximately 5% of women of reproductive age.Polycystic ovary syndrome accounts for about 70% of hyperandrogenism cases. Other causes include adrenal hyperplasia, hirsutism, insulin resistance, hyperprolactinemia, Cushings disease, certain types of cancers, and certain medications. Diagnosis often involves blood tests for testosterone, 17-hydroxyprogesterone, and prolactin, as well as a pelvic ultrasound.Treatment depends on the underlying cause. Symptoms of hyperandrogenism can be treated with birth control pills or antiandrogens, such as cyproterone acetate or spironolactone. Other palliative measures may include hair removal techniques.The earliest known description of the condition is attributed to Hippocrates.In 2011, the International Association of Athletics Federations (now World Athletics) and IOC (International Olympic Committee)  released statements restricting the eligibility of female athletes with high testosterone, whether through hyperandrogenism or as a result of a difference in sex development (DSD). These regulations were referred to by both bodies as hyperandrogenism regulations and have led to athletes with DSDs being described as having hyperandrogenism. They were revised in 2019 to focus more specifically on DSDs.

Signs and symptoms
Hyperandrogenism affects 5–10% of women of reproductive age. Hyperandrogenism can affect both men and women but is more noticeable in women since elevated levels of androgens in women may facilitate virilization. Because hyperandrogenism is characterized by elevated male sex hormone levels, symptoms of hyperandrogenism in men are often negligible. Hyperandrogenism in women is typically diagnosed in late adolescence with a medical evaluation. The medical evaluation usually consists of a pelvic exam, observation of external symptoms, and a blood test measuring androgen levels. Symptoms may include the following:

Women
Hyperandrogenism, especially high levels of testosterone, can cause serious adverse effects if left untreated. High testosterone levels are associated with other health conditions such as obesity, hypertension, amenorrhea (cessation of menstrual cycles), and ovulatory dysfunction, which can lead to infertility. Prominent signs of hyperandrogenism are hirsutism (unwanted growth of hair, especially in the abdominal region and on the back), adult acne, deepening of the voice, and alopecia (balding).Hyperandrogenism has also been observed to increase insulin tolerance, which can lead to type two diabetes and dyslipidemia, such as high cholesterol. These effects may have psychological impacts, sometimes leading to social anxiety and depression, especially in adolescent girls and young women. Paired with obesity and hirsutism, it can cause the individual to have low self-esteem.

Men
Administration of high-dose testosterone in men over a course of weeks can cause an increase in aggression and hypomanic symptoms, though these were see in only a minority of subjects. Acute high-dose anabolic-androgenic steroid administration in males attenuates endogenous sex hormone production and affects the thyroid hormone axis. Effects on mood and aggression observed during high-dose anabolic-androgenic steroid administration may occur secondarily to hormonal changes. Many of the same signs and symptoms that are seen in women, such as alopecia and acne, may also be found in men. Enlargement of the prostate may also occur.

Causes
While hyperandrogenism in women can be caused by external factors, it can also appear spontaneously.

Polycystic ovary syndrome
Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by an excess of androgens produced by the ovaries. It is estimated that approximately 90% of women with PCOS demonstrate hypersecretion of these hormones. The cause of this condition is unknown. Speculations include genetic predisposition; however, the gene or genes responsible for this remain unidentified. The condition may have a hereditary basis. Other possible causes include elevated insulin production. Most cases of PCOS involve insulin resistance. It is thought that adipose tissue dysfunction plays a role in the insulin resistance seen in PCOS. Insulin can induce excess testosterone secretion from the ovaries. A complication associated with polycystic ovary syndrome is high cholesterol, which is treated with statins. In a meta-analysis, atorvastatin was shown to decrease androgen concentrations in people with hyperandrogenism.Elevated insulin leads to lower production of sex hormone binding globulin (SHBG), a regulatory glycoprotein that suppresses the function of androgens. High blood levels of insulin also work in conjunction with ovarian sensitivity to insulin to cause hyperandrogenemia, the primary symptom of PCOS. Obese individuals may be more biologically inclined to PCOS due to markedly higher insulin. This hormonal imbalance can lead to chronic anovulation, in which the ovaries fail to release mature eggs. These cases of ovulatory dysfunction are linked to infertility and menstrual disturbances. A post hoc analysis from a randomized, placebo-controlled, multi-centre study carried out at 11 secondary care centres, as well as a longitudinal single-centre study on pregnant women in Norway, also determined that metformin had no effect on maternal androgens in pregnancies occurring in the setting of PCOS.One systemic review suggested that polymorphisms in the vitamin D receptor gene are associated with the prognosis of polycystic ovary syndrome, though this is based on small sample sizes and is debated. Studies have shown benefits for vitamin D supplementation in women with vitamin D deficiency and PCOS.Hyperinsulinemia can increase the production of androgens in the ovaries. One context in which this occurs is HAIR-AN syndrome, a rare subtype of PCOS.

Hyperthecosis and hyperinsulinemia
Hyperthecosis occurs when the cells of the ovarian stroma transition from interstitial cells, located between other cells, into luteinized theca cells. Theca cells are located in the ovarian follicles and become luteinized when the ovarian follicle bursts and a new corpus luteum is formed. The dispersal of luteinized theca cells throughout the ovarian stroma — in contrast to their distribution in PCOS, in which luteinized theca cells occur around cystic follicles only — causes women with hyperthecosis to have higher testosterone levels and virilization) than women with PCOS. Elevated insulin is also characteristic of hyperthecosis. Hyperthecosis most commonly develops in postmenopausal women and is linked to acne, hirsutism, growth of the clitoris, baldness, and voice deepening.Obesity can play a role in insulin resistance. It makes thecal cells more responsive to luteinizing hormone. Therefore, obesity increases ovarian androgen production. Additionally, obesity elevates inflammatory adipokines which leads to not only adipogenesis, but also heightened insulin resistance.

Cushing’s syndrome
Cushings syndrome develops as a result of long-term exposure to the hormone cortisol. Cushings syndrome can either be exogenous or endogenous, depending on whether it is caused by an external or internal source, respectively. The intake of glucocorticoids, a type of corticosteroid, is a common cause for the development of exogenous Cushings syndrome. Endogenous Cushings syndrome can occur when the body produces excess cortisol. This occurs when the hypothalamus of the brain signals to the pituitary gland with excess corticotropin-releasing hormone, which in turn secretes adrenocorticotropin hormone (ACTH). ACTH then causes the adrenal glands to release cortisol into the blood. Signs of Cushings syndrome include muscle weakness, easy bruising, weight gain, male-pattern hair growth (hirsutism), coloured stretch marks, and an excessively reddish complexion in the face. Cushings syndrome can cause androgen excess and hence the signs and symptoms of hyperandrogenism.

Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) describes a group of autosomal recessive disorders that cause a lack of an enzyme necessary for the production of cortisol and/or aldosterone, steroid hormones produced by the adrenal cortex. Most cases of CAH are due to 21-hydroxylase deficiencies. The heightened androgen levels seen in congenital adrenal hyperplasia affect the hypothalamic–pituitary–gonadal axis. Heightened androgen levels can also affect the ovaries, which can lead to infertility as well as chronic anovulation.Since CAH consists of multiple disorders, the signs, symptoms and severity of hyperandrogenism may stem from a variety of specific mutations. Genotyping is therefore critical to verify diagnoses and to establish prognostic factors for individuals. Genotyping is also crucial for people seeking to use genetic counselling as an aid to family planning.In women, CAH causes ambiguous genitals at birth and excessive pubic hair, enlargement of the clitoris, and hirsutism in adolescence. Although CAH causes rapid growth in childhood, adult women with CAH are shorter than average due to early puberty and closure of the growth plates in the long bones. Symptoms in males include early showings of pubic hair, enlargement of the penis, and rapid musculoskeletal growth.

Tumors
Adrenocortical carcinoma and tumors
Adrenocortical carcinoma occurs rarely; the average incidence rate is estimated to be 1–2 cases per million annually.  The disease involves the formation of cancerous cells within the cortex of one or both of the adrenal glands. Although these tumors are identified in fewer than two percent of patients diagnosed with hyperandrogenism, the possibility must be considered within this population. In one study, more than half of tumor-affected patients had elevated levels of the androgens androstenedione, dehydroepiandrosterone sulfate, and testosterone. The elevation of androgens caused by adrenocortical carcinomas often causes patients to develop Cushings syndrome, primary aldosteronism, and hyperandrogenism. The molecular basis of the disease has yet to be elucidated.

Adenoma of the adrenal gland
Adrenal adenomas are benign tumors of the adrenal gland. In most cases, the tumors display no symptoms and require no treatment. In rare cases, however, some adrenal adenomas may become activated. When activated, the adenoma begins to produce hormones in much larger quantities than what the adrenal glands would normally produce, leading to health complications including primary aldosteronism and hyperandrogenism.

Arrhenoblastoma
Arrhenoblastoma is an uncommon tumor of the ovary.  It is composed of sterol cells, Leydig cells, or some combination of the two. The tumor can produce male or female hormones and may cause masculinization. In a prepubescent child, a tumor may cause precocious puberty. Malignant arrhenoblastoma accounts for 30% of cases of arrhenoblastoma, the other 70% being largely benign and curable with surgery.

Hilar cell tumor
A hilar cell tumor is an androgen-producing ovarian tumor that is most commonly found in older women and often leads to the development of male sex characteristics. The tumor tends to occur around the region of the ovary where the blood vessels enter the organ, known as the hilum. This type of tumor tends to be small in size and in most cases can be entirely removed and its symptoms reversed through surgery.

Krukenberg tumor
A Krukenberg tumor is a quickly developing malignant tumor found in one or both ovaries. In most cases, the tumor primarily originates from tissues in the stomach, pancreas, gallbladder, colon, or breast. It colonized the ovary by spreading through the peritoneal cavity. These tumors cause virilization. Increased androgen production due to elevations in human chorionic gonadotropin is hypothesized as the main cause of hyperandrogenism in people with Krukenberg tumors.

Menopause
The end of ovulation and the beginning of menopause can result in hyperandrogenism. During this transition, the body stops releasing estrogen at a faster rate than it stops releasing androgens. In some cases, the difference between the lower estrogen levels and higher androgen levels can produce hyperandrogenism. A decrease in sex hormone levels while the free androgen index increases can also contribute to this process.

Drugs
Many drugs can provoke symptoms of hyperandrogenism. These symptoms include, but are not limited to hirsutism, acne, dermatitis, androgenic alopecia, irregularities in menstruation, clitoral hypertrophy, and the deepening of the voice. Drugs most frequently implicated in hyperandrogenism include anabolic steroids, synthetic progestins, and antiepileptics; however, many other drugs may also cause hyperandrogenism. This can happen through one of five mechanisms: the direct introduction of androgens to the body, the binding of the drug to androgen receptors (as is the case with anabolic-androgenic steroids), a reduction of sex hormone-binding globulin plasma concentration that leads to an increase in free testosterone, interference with the hypothalamic–pituitary–ovarian (HPO) axis, or an increase in the release of adrenal androgens. Certain drugs cause hyperandrogenism through mechanisms that remain unclear. For example, the molecular basis by which valproate induces hyperandrogenism and polycystic ovary syndrome has yet to be determined. However, one study showed that women taking valproic acid had higher testosterone levels and incidences of hyperandrogenism compared to women who were not taking valproic acid.

Heredity
Hyperandrogenism can appear as a symptom of many different genetic and medical conditions. Some of the conditions with hyperandrogenic symptoms, including PCOS, may sometimes be hereditary. Additionally, it is thought that epigenetics may contribute to the pathogenesis of polycystic ovary syndrome.One potential cause of PCOS is maternal hyperandrogenism, whereby hormonal irregularities in the mother can affect the development of the child during gestation, resulting in the passing of polycystic ovary syndrome from mother to child. However, no androgen elevations in were found in the umbilical cord blood of children born to mothers with PCOS.

Diagnosis
Diagnosing hyperandrogenism can be complex due to the wide variety and severity of signs and symptoms that may present. It is most often diagnosed by checking for signs of hirsutism according to a standardized method that scores the range of excess hair growth.Girls may show symptoms of hyperandrogenism early in life, but physicians become more concerned when the patient is in her late teens or older.Checking medical history and a physical examination of symptoms are used for an initial diagnosis. Patient history assessed includes age at thelarche, adrenarche, and menarche; patterns of menstruation; obesity; reproductive history; and the start and advancement of hyperandrogenism symptoms. Patterns of menstruation are examined since irregular patterns may accompany hyperandrogenism. Other conditions that may present alongside hirsutism that can contribute to diagnosis include androgenic alopecia and acne. If hyperandrogenism is severe, virilization may occur.Family history is also assessed for occurrences of hyperandrogenism symptoms or obesity in other family members.Laboratory tests can measure FSH, luteininzing hormone, DHEAS, prolactin, 17α-hydroxyprogesterone, and total and free testosterone in the blood. Abnormally high levels of any of these hormones help in diagnosing hyperandrogenism.

Prevention
Since risk factors are not known and vary among individuals with hyperandrogenism, there is no sure method to prevent the condition. Accordingly, more long-term studies are needed to find a cause of the condition before a sufficient method of prevention can be established.Despite this, there are a few things that can help avoid long-term medical issues related to hyperandrogenism and PCOS. Getting checked by a medical professional for hyperandrogenism — especially if one has a family history of the condition, irregular periods, or diabetes — can be beneficial. A healthy weight and diet may reduce the chances, as continued exercise and a healthy diet lead to an improved menstrual cycle, decreased insulin levels, and lowered androgen concentrations.

Treatment
There is no definitive treatment for hyperandrogenism as it varies with the underlying condition that causes it. As a hormonal symptom of PCOS, menopause, and other endocrine conditions, it is primarily treated as a symptom of these conditions. Drugs may be considered only in women who do not plan on becoming pregnant in the near future. Some effective drugs for facial hirsutism includes eflornithine, which may cause birth defects in pregnant women. Retinoids and antibiotics can be used for acne and minoxidil for alopecia. Systemically, it is treated with antiandrogens such as cyproterone acetate, flutamide and spironolactone to reduce androgenic signaling. For hyperandrogenism caused by late-onset congenital adrenal hyperplasia (LOCAH), treatment is primarily focused on providing the patient with glucocorticoids to combat the low cortisol production and the corresponding increase in androgens caused by the increase in size of the adrenal glands. Estrogen-based oral contraceptives are used to treat both LOCAH- and PCOS-associated hyperandrogenism. These hormonal treatments reduce the androgen excess and suppress adrenal androgen production, bringing about a significant decrease in hirsutism.Hyperandrogenism is often managed symptomatically. Hirsutism and acne both respond well to the hormonal treatments described above, with 60–100% of patients reporting an improvement in hirsutism. Androgenic alopecia however, does not show an improvement with hormonal treatments and requires other treatments, such as hair transplantation.Supplementation can also contribute to the managing the symptomatic effects of hyperandrogenism. In a meta-analysis, high-dose vitamin D supplements given to women with vitamin D deficiency due to PCOS improved glucose levels, insulin sensitivity, and cholesterol levels, as well as lowering testosterone, sex hormone-binding globulin, and the free androgen index, all of which are associated with hyperandrogenism. Vitamin D supplementation in women with vitamin D deficiency but without PCOS did not show the same results.

Targeting insulin resistance and obesity
Lifestyle modifications are the first-line treatment for PCOS. They help improve body composition, insulin resistance, and hyperandrogenism. However, it is unclear whether they help improve mood, quality of life, and reproductive outcomes </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Mucositis and explain in detail? [/INST] Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, usually as an adverse effect of  chemotherapy and radiotherapy treatment for cancer. Mucositis can occur anywhere along the gastrointestinal (GI) tract, but oral mucositis refers to the particular inflammation and ulceration that occurs in the mouth. Oral mucositis is a common and often debilitating complication of cancer treatment.Oral and gastrointestinal (GI) mucositis affects almost all patients undergoing high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT), 80% of patients with malignancies of the head and neck receiving radiotherapy, and a wide range of patients receiving chemotherapy. Alimentary tract mucositis increases mortality and morbidity and contributes to rising health care costs.For most cancer treatment, about 5–15% of patients get mucositis. However, with 5-fluorouracil (5-FU), up to 40% get mucositis, and 10–15% get grade 3–4 oral mucositis. Irinotecan is associated with severe GI mucositis in over 20% of patients. Seventy-five to eighty percent of bone marrow transplantation recipients experience mucositis, of which oral mucositis is the most common and most debilitating, especially when melphalan is used. In grade 3 oral mucositis, the patient is unable to eat solid food, and in grade 4, the patient is unable to consume liquids as well.Radiotherapy to the head and neck or to the pelvis or abdomen is associated with Grade 3 and Grade 4 oral or GI mucositis, respectively, often exceeding 50% of patients. Among patients undergoing head and neck radiotherapy, pain and decreased oral function may persist long after the conclusion of therapy. Fractionated radiation dosage increases the risk of mucositis to > 70% of patients in most trials. Oral mucositis is particularly profound and prolonged among HSCT recipients who receive total-body irradiation.

Signs and symptoms
Cancer patients undergoing chemotherapy usually become symptomatic four to five days after beginning treatment, reaching a peak at around day 10, and then slowly improving over the course of a few weeks. Mucositis associated with radiotherapy usually appears at the end of the second week of treatment and may last for six to eight weeks.As a result of cell death in reaction to chemo- or radio-therapy, the mucosal lining of the mouth becomes thin, may slough off and then become red, inflamed and ulcerated. The ulcers may become covered by a yellowish-white fibrin clot called a pseudomembrane. Peripheral erythema is usually present. Ulcers may range from 0.5 cm to greater than 4 cm. Oral mucositis can be severely painful.  The degree of pain is usually related to the extent of the tissue damage.  Pain is often described as a burning sensation accompanied by reddening. Due to pain, the patient may experience trouble speaking, eating, or even opening the mouth.Dysgeusia, or an alteration in taste perception, is common, especially for those who are receiving concomitant radiation therapy to the neck and mouth area. "Taste blindness", or an altered sense of taste, is a temporary condition that occurs because of effects on taste buds that are mostly located in the tongue. Sometimes, only partial recovery of taste occurs. Common complaints are of food tasting too sweet or too bitter or of a continuous metallic taste.

Complications
Sores or ulcerations can become infected by virus, bacteria or fungus. Pain and loss of taste perception makes it more difficult to eat, which leads to weight loss. Ulcers may act as a site for local infection and a portal of entry for oral flora that, in some instances, may cause septicaemia (especially in immunosuppressed patients). Therefore, oral mucositis can be a dose-limiting condition, disrupting a patient’s optimal cancer treatment plan and consequentially decreasing their chances of survival.

Pathophysiology
The pathophysiology of mucositis is complex and multifactorial. Currently, Sonis five phase model is the accepted explanation for the process. The 5 stages are:

Initiation phase. Free radicals are produced due to DNA damage caused by chemo- or radiotherapy.
Primary damage response. Chemotherapy, radiotherapy and free radicals all contribute to the activation of transcription factors, such as NF-κB. This results in the upregulation of pro-inflammatory cytokines, ceramide, nitric oxide and matrix metalloproteinases. The consequence of this is mucosal destruction, caused by thinning of the epithelium due to tissue injury and cell death.
Signal amplification. Positive or negative feedback loops involving some of the molecules in the previous phase can exacerbate or prolong tissue injury. For example, the pro-inflammatory cytokine TNF-α can positively feedback on NF-κB thus inducing more pro-inflammatory cytokine production.
Ulceration. Bacteria colonise ulcers and their cell wall products infiltrate the submucosa. This leads to activation of tissue macrophages, which causes further production of pro-inflammatory cytokines. In addition, bacteria-mediated immune signalling via Toll-like receptors (TLRs) ambiguously shapes chemotherapy-induced genotoxic damage in the gastrointestinal tract.
Healing. Signalling from the extracellular matrix of the submucosa results in epithelial proliferation and differentiation, and thus a thickening of the epithelium. The local oral flora are reinstated.

Diagnosis
Diagnosis is based on the symptoms the patient is experiencing and the appearance of the tissues of the mouth following chemotherapy, bone marrow transplants or radiotherapy. Red burn-like sores or ulcers throughout the mouth is enough to diagnose mucositis.The severity of oral mucositis can be evaluated using several different assessment tools.
Two of the most commonly used are the World Health Organization (WHO) Oral Toxicity score and the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for Oral Mucositis. While the NCI system has separate scores for appearance (erythema and ulceration) and function (pain and ability to eat solids, liquids, or nothing by mouth), the WHO score combines both elements into a single score that grades the severity of the condition from 0 (no oral mucositis) to 4 (swallowing not possible such that patient needs supplementary nutrition). Another scale developed in 1999, the Oral Mucositis Assessment Scale (OMAS) has been shown to be highly reproducible between observers, responsive over time, and accurate in recording symptoms associated with mucositis.   The OMAS provides an objective assessment of oral mucositis based on assessment of the appearance and extent of redness and ulceration in various areas of the mouth.

Prevention
A 2015 Cochrane systematic review assessing the prevention of chemotherapy-induced oral mucositis concluded that oral cryotherapy leads to large reductions in the incidence of oral mucositis of all severities in adults receiving 5-FU treatment for solid cancers. The evidence also indicates a reduction of oral mucositis in adults receiving high-dose melphalan-based cancer treatment prior to haematopoietic stem cell transplantation, although there is uncertainty regarding the size of the reduction in this instance. No evidence was found for use of this preventive measure in children. Oral cryotherapy involves the placement of rounded ice chips in the mouth, which cools the oral tissues and causes vasoconstriction. This decreases blood flow to the region and, hence, also restricts the amounts of the chemotherapy drugs delivered to the tissues.

Treatment
Treatment of mucositis is mainly supportive. Oral hygiene is the mainstay of treatment; patients are encouraged to clean their mouth every four hours and at bedtime, more often if the mucositis becomes worse.Water-soluble jellies can be used to lubricate the mouth. Salt mouthwash can soothe the pain and keep food particles clear so as to avoid infection. Patients are also encouraged to drink plenty of liquids, at least three liters a day, and avoid alcohol. Citrus fruits, alcohol, and foods that are hot are all known to aggravate mucositis lesions. Medicinal mouthwashes may be used such as Chlorhexidine gluconate and viscous Lidocaine for relief of pain. However, care should be taken as the high doses of viscous lidocaine my cause adverse effects. A study reported that lidocaine has a potential toxicity; when it was tested on patients with oral mucositis who underwent a bone marrow transplant, lidocaine anesthetic mouthwash was found to be systemically absorbed.Palifermin is a human KGF (keratinocyte growth factor) that has shown to enhance epithelial cell proliferation, differentiation, and migration. Experimental therapies have been reported, including the use of cytokines and other modifiers of inflammation (e.g., IL-1, IL-11, TGF-beta3), amino acid supplementation (e.g., glutamine), vitamins, colony-stimulating factors, cryotherapy, and laser therapy.Symptomatic relief of the pain of oral mucositis may be provided by barrier protection agents such as concentrated oral gel products (e.g. Gelclair). Caphosol is a mouth rinse which has been shown to prevent and treat oral mucositis caused by radiation and high-dose chemotherapy. MuGard is a FDA-cleared mucoadhesive oral protectant, developed by Access Pharmaceuticals, Inc., that is designed to form a protective hydrogel coating over the oral mucosa while a patient is undergoing chemotherapy and/or radiotherapy cancer treatments to the head and neck </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hermansky–Pudlak syndrome and explain in detail? [/INST] Heřmanský–Pudlák syndrome (often written Hermansky–Pudlak syndrome or abbreviated HPS) is an extremely rare autosomal recessive disorder which results in oculocutaneous albinism (decreased pigmentation), bleeding problems due to a platelet abnormality (platelet storage pool defect), and storage of an abnormal fat-protein compound (lysosomal accumulation of ceroid lipofuscin). It is considered to affect around 1 in 500,000 people worldwide, with a significantly higher occurrence in Puerto Ricans, with a prevalence of 1 in 1800. Many of the clinical research studies on the disease have been conducted in Puerto Rico.
There are eight classic forms of the disorder, based on the genetic mutation from which the disorder stems.

Signs and symptoms
There are three main disorders caused by Hermansky–Pudlak syndrome, which result in these symptoms:

Albinism and eye problems: Individuals will have varying amounts of skin pigment (melanin).  Because of the albinism there are eye problems such as light sensitivity (photophobia), strabismus (crossed eyes), and nystagmus (involuntary eye movements).  Hermansky–Pudlak syndrome also impairs vision.
Bleeding disorders: Individuals with the syndrome have platelet dysfunction. Since platelets are necessary for blood clotting, individuals will bruise and bleed easily.
Cellular storage disorders: The syndrome causes a wax-like substance (ceroid) to accumulate in the body tissues and cause damage, especially in the lungs and kidneys.It is also associated with granulomatous colitis,, an inflammation of the colon, and with pulmonary fibrosis, a potentially fatal lung disease.

Causes
HPS can be caused by mutations in several genes: HPS1, HPS3, HPS4, HPS5, HPS6 and HPS7.HPS type 2, which includes immunodeficiency in its phenotype, is caused by mutation in the AP3B1 gene.HPS type 7 may result from a mutation in the gene coding for dysbindin protein.Hermansky–Pudlak syndrome is thought to be inherited as an autosomal recessive genetic trait. The defective gene, called HSP, responsible for this disorder is located on the long arm of chromosome 10 (10q2). Some research suggests that an abnormality of lysosomal function may be responsible for the development of the disease.
HPS1, AP3B1, HPS3, HPS4, HPS5, HPS6, DTNBP1 and  Biogenesis of Lysosome-related Organelles Complex (BLOC1, BLOC1S2 and BLOC3) are associated with Hermansky–Pudlak syndrome.In autosomal recessive disorders, the condition does not appear unless a person inherits two copies of the defective gene responsible for the disorder, one copy coming from each parent.  If an individual receives one normal gene and one gene for the disorder, the person will be a carrier for the disease, but usually will not show symptoms.  The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent.  Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait).  The risk is the same for each pregnancy.

Pathophysiology
The mechanism of Hermansky–Pudlak syndrome indicates that platelets in affected individuals accumulate abnormally with thrombin, epinephrine, and adenosine diphosphate, furthermore platelets in these individuals have a lower amount of dense bodies

Diagnosis
The diagnosis of HPS is established by clinical findings of hypopigmentation
of the skin and hair, characteristic eye findings, and demonstration of absent
dense bodies on whole mount electron microscopy of platelets.  Molecular
genetic testing of the HPS1 gene is available on a clinical basis for
individuals from northwestern Puerto Rico.  Molecular testing of the HPS3 gene
is available on a clinical basis for individuals of central Puerto Rican or
Ashkenazi Jewish heritage.  Sequence analysis is available on a clinical basis
for mutations in HPS1 and HPS4.  Diagnosis of individuals with other types of
HPS is available on a research basis only.

Treatment
While there is no cure for HPS, treatment for chronic hemorrhages associated with the disorder includes therapy with vitamin E and the antidiuretic dDAVP.

Considerations for patients
A preoperative pulmonology consultation is needed. The anesthesia team should
be aware that patients may have postoperative pulmonary complications as part
of the syndrome.Preoperative hematology consultation is advisable prior to elective ocular
surgeries. Since patients with the syndrome have bleeding tendencies,
intraoperative, perioperative, and postoperative hemorrhages should be
prevented and treated </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Vehicle and explain in detail? [/INST] A vehicle (from Latin: vehiculum) is a machine that transports people or cargo.  Vehicles include wagons, bicycles, motor vehicles (motorcycles, cars, trucks, buses, mobility scooters for disabled people), railed vehicles (trains, trams), watercraft (ships, boats, underwater vehicles), amphibious vehicles (screw-propelled vehicles, hovercraft),  aircraft (airplanes, helicopters, aerostats) and spacecraft.Land vehicles are classified broadly by what is used to apply steering and drive forces against the ground: wheeled, tracked, railed or skied. ISO 3833-1977 is the standard, also internationally used in legislation, for road vehicles types, terms and definitions.

History
The oldest boats found by archaeological excavation are logboats, with the oldest logboat found, the Pesse canoe found in a bog in the Netherlands, being carbon dated to 8040 - 7510 BC, making it 9,500–10,000 years old,
a 7,000-year-old seagoing boat made from reeds and tar has been found in Kuwait.
Boats were used between 4000 -3000 BC in Sumer, ancient Egypt and in the Indian Ocean.
There is evidence of camel pulled wheeled vehicles about 4000–3000 BC.
The earliest evidence of a wagonway, a predecessor of the railway, found so far was the 6 to 8.5 km (4 to 5 mi) long Diolkos wagonway, which transported boats across the Isthmus of Corinth in Greece since around 600 BC. Wheeled vehicles pulled by men and animals ran in grooves in limestone, which provided the track element, preventing the wagons from leaving the intended route.
In 200 CE, Ma Jun built a south-pointing chariot, a vehicle with an early form of guidance system.
Railways began reappearing in Europe after the Dark Ages. The earliest known record of a railway in Europe from this period is a stained-glass window in the Minster of Freiburg im Breisgau dating from around 1350.
In 1515, Cardinal Matthäus Lang wrote a description of the Reisszug, a funicular railway at the Hohensalzburg Fortress in Austria. The line originally used wooden rails and a hemp haulage rope and was operated by human or animal power, through a treadwheel.
1769 Nicolas-Joseph Cugnot is often credited with building the first self-propelled mechanical vehicle or automobile in 1769.
In Russia, in the 1780s, Ivan Kulibin developed a human-pedalled, three-wheeled carriage with modern features such as a flywheel, brake, gear box and bearings; however, it was not developed further.
1783 Montgolfier brothers first balloon vehicle
1801 Richard Trevithick built and demonstrated his Puffing Devil road locomotive, which many believe was the first demonstration of a steam-powered road vehicle, though it could not maintain sufficient steam pressure for long periods and was of little practical use.
1817 Push bikes, draisines or hobby horses were the first human means of transport to make use of the two-wheeler principle, the draisienne (or Laufmaschine, "running machine"), invented by the German Baron Karl von Drais, is regarded as the forerunner of the modern bicycle (and motorcycle). It was introduced by Drais to the public in Mannheim in summer 1817.
1885 Karl Benz built (and subsequently patented) the first automobile, powered by his own four-stroke cycle gasoline engine in Mannheim, Germany
1885 Otto Lilienthal began experimental gliding and achieved the first sustained, controlled, reproducible flights.
1903 Wright brothers flew the first controlled, powered aircraft
1907 First helicopters Gyroplane no.1 (tethered) and Cornu helicopter (free flight)
1928 Opel RAK.1 rocket car
1929 Opel RAK.1 rocket glider
1961 Vostok vehicle carried the first human, Yuri Gagarin, into space
1969 Apollo Program first crewed vehicle landed on the moon
2010 The number of road motor vehicles in operation worldwide surpassed the 1 billion mark – roughly one for every seven people.

Types of vehicles
There are over 1 billion bicycles in use worldwide. In 2002 there were an estimated 590 million cars and 205 million motorcycles in service in the world. At least 500 million Chinese Flying Pigeon bicycles have been made, more than any other single model of vehicle. The most-produced model of motor vehicle is the Honda Super Cub motorcycle, having passed 60 million units in 2008. The most-produced car model is the Toyota Corolla, with at least 35 million made by 2010. The most common fixed-wing airplane is the Cessna 172, with about 44,000 having been made as of 2017. The Soviet Mil Mi-8, at 17,000, is the most-produced helicopter. The top commercial jet airliner is the Boeing 737, at about 10,000 in 2018. At around 14,000 for both, the most produced trams are the KTM-5 and Tatra T3. The most common trolleybus is ZiU-9.

Locomotion
Locomotion consists of a means that allows displacement with little opposition, a power source to provide the required kinetic energy and a means to control the motion, such as a brake and steering system. By far, most vehicles use wheels which employ the principle of rolling to enable displacement with very little rolling friction.

Energy source
It is essential that a vehicle have a source of energy to drive it. Energy can be extracted from external sources, as in the cases of a sailboat, a solar-powered car, or an electric streetcar that uses overhead lines. Energy can also be stored, provided it can be converted on demand and the storing mediums energy density and power density are sufficient to meet the vehicles needs.
Human power is a simple source of energy that requires nothing more than humans. Despite the fact that humans cannot exceed 500 W (0.67 hp) for meaningful amounts of time, the land speed record for human-powered vehicles (unpaced) is 133 km/h (83 mph), as of 2009 on a recumbent bicycle.The most common type of energy source is fuel. External combustion engines can use almost anything that burns as fuel, whilst internal combustion engines and rocket engines are designed to burn a specific fuel, typically gasoline, diesel or ethanol.
Another common medium for storing energy is batteries, which have the advantages of being responsive, useful in a wide range of power levels, environmentally friendly, efficient, simple to install, and easy to maintain. Batteries also facilitate the use of electric motors, which have their own advantages. On the other hand, batteries have low energy densities, short service life, poor performance at extreme temperatures, long charging times, and difficulties with disposal (although they can usually be recycled). Like fuel, batteries store chemical energy and can cause burns and poisoning in event of an accident. Batteries also lose effectiveness with time. The issue of charge time can be resolved by swapping discharged batteries with charged ones; however, this incurs additional hardware costs and may be impractical for larger batteries. Moreover, there must be standard batteries for battery swapping to work at a gas station. Fuel cells are similar to batteries in that they convert from chemical to electrical energy, but have their own advantages and disadvantages.
Electrified rails and overhead cables are a common source of electrical energy on subways, railways, trams, and trolleybuses.
Solar energy is a more modern development, and several solar vehicles have been successfully built and tested, including Helios, a solar-powered aircraft.
Nuclear power is a more exclusive form of energy storage, currently limited to large ships and submarines, mostly military. Nuclear energy can be released by a nuclear reactor, nuclear battery, or repeatedly detonating nuclear bombs. There have been two experiments with nuclear-powered aircraft, the Tupolev Tu-119 and the Convair X-6.
Mechanical strain is another method of storing energy, whereby an elastic band or metal spring is deformed and releases energy as it is allowed to return to its ground state. Systems employing elastic materials suffer from hysteresis, and metal springs are too dense to be useful in many cases.Flywheels store energy in a spinning mass. Because a light and fast rotor is energetically favorable, flywheels can pose a significant safety hazard. Moreover, flywheels leak energy fairly quickly and affect a vehicles steering through the gyroscopic effect. They have been used experimentally in gyrobuses.
Wind energy is used by sailboats and land yachts as the primary source of energy. It is very cheap and fairly easy to use, the main issues being dependence on weather and upwind performance. Balloons also rely on the wind to move horizontally. Aircraft flying in the jet stream may get a boost from high altitude winds.
Compressed gas is currently an experimental method of storing energy. In this case, compressed gas is simply stored in a tank and released when necessary. Like elastics, they have hysteresis losses when gas heats up during compression.
Gravitational potential energy is a form of energy used in gliders, skis, bobsleds and numerous other vehicles that go down hill. Regenerative braking is an example of capturing kinetic energy where the brakes of a vehicle are augmented with a generator or other means of extracting energy.

Motors and engines
When needed, the energy is taken from the source and consumed by one or more motors or engines. Sometimes there is an intermediate medium, such as the batteries of a diesel submarine.Most motor vehicles have internal combustion engines. They are fairly cheap, easy to maintain, reliable, safe and small. Since these engines burn fuel, they have long ranges but pollute the environment. A related engine is the external combustion engine. An example of this is the steam engine. Aside from fuel, steam engines also need water, making them impractical for some purposes. Steam engines also need time to warm up, whereas IC engines can usually run right after being started, although this may not be recommended in cold conditions. Steam engines burning coal release sulfur into the air, causing harmful acid rain.

While intermittent internal combustion engines were once the primary means of aircraft propulsion, they have been largely superseded by continuous internal combustion engines: gas turbines. Turbine engines are light and, particularly when used on aircraft, efficient. On the other hand, they cost more and require careful maintenance. They can also be damaged by ingesting foreign objects, and they produce a hot exhaust. Trains using turbines are called gas turbine-electric locomotives. Examples of surface vehicles using turbines are M1 Abrams, MTT Turbine SUPERBIKE and the Millennium. Pulse jet engines are similar in many ways to turbojets, but have almost no moving parts. For this reason, they were very appealing to vehicle designers in the past; however their noise, heat and inefficiency has led to their abandonment. A historical example of the use of a pulse jet was the V-1 flying bomb. Pulse jets are still occasionally used in amateur experiments. With the advent of modern technology, the pulse detonation engine has become practical and was successfully tested on a Rutan VariEze. While the pulse detonation engine is much more efficient than the pulse jet and even turbine engines, it still suffers from extreme noise and vibration levels. Ramjets also have few moving parts, but they only work at high speed, so that their use is restricted to tip jet helicopters and high speed aircraft such as the Lockheed SR-71 Blackbird.Rocket engines are primarily used on rockets, rocket sleds and experimental aircraft. Rocket engines are extremely powerful. The heaviest vehicle ever to leave the ground, the Saturn V rocket, was powered by five F-1 rocket engines generating a combined 180 million horsepower (134.2 gigawatt). Rocket engines also have no need to "push off" anything, a fact that the New York Times denied in error. Rocket engines can be particularly simple, sometimes consisting of nothing more than a catalyst, as in the case of a hydrogen peroxide rocket. This makes them an attractive option for vehicles such as jet packs. Despite their simplicity, rocket engines are often dangerous and susceptible to explosions. The fuel they run off may be flammable, poisonous, corrosive or cryogenic. They also suffer from poor efficiency. For these reasons, rocket engines are only used when absolutely necessary.Electric motors are used in electric vehicles such as electric bicycles, electric scooters, small boats, subways, trains, trolleybuses, trams and experimental aircraft. Electric motors can be very efficient: over 90% efficiency is common. Electric motors can also be built to be powerful, reliable, low-maintenance and of any size. Electric motors can deliver a range of speeds and torques without necessarily using a gearbox (although it may be more economical to use one). Electric motors are limited in their use chiefly by the difficulty of supplying electricity.Compressed gas motors have been used on some vehicles experimentally. They are simple, efficient, safe, cheap, reliable and operate in a variety of conditions. One of the difficulties met when using gas motors is the cooling effect of expanding gas. These engines are limited by how quickly they absorb heat from their surroundings. The cooling effect can, however, double as air conditioning. Compressed gas motors also lose effectiveness with falling gas pressure.Ion thrusters are used on some satellites and spacecraft. They are only effective in a vacuum, which limits their use to spaceborne vehicles. Ion thrusters run primarily off electricity, but they also need a propellant such as caesium, or more recently xenon. Ion thrusters can achieve extremely high speeds and use little propellant; however they are power-hungry.

Converting energy to work
The mechanical energy that motors and engines produce must be converted to work by wheels, propellers, nozzles, or similar means.
Aside from converting mechanical energy into motion, wheels allow a vehicle to roll along a surface and, with the exception of railed vehicles, to be steered. Wheels are ancient technology, with specimens being discovered from over 5000 years ago. Wheels are used in a plethora of vehicles, including motor vehicles, armoured personnel carriers, amphibious vehicles, airplanes, trains, skateboards and wheelbarrows.
Nozzles are used in conjunction with almost all reaction engines. Vehicles using nozzles include jet aircraft, rockets and personal watercraft.  While most nozzles take the shape of a cone or bell, some unorthodox designs have been created such as the aerospike. Some nozzles are intangible, such as the electromagnetic field nozzle of a vectored ion thruster.Continuous track is sometimes used instead of wheels to power land vehicles. Continuous track has the advantages of a larger contact area, easy repairs on small damage, and high maneuverability. Examples of vehicles using continuous track are tanks, snowmobiles and excavators. Two continuous tracks used together allow for steering. The largest vehicle in the world, the Bagger 288, is propelled by continuous tracks.
Propellers (as well as screws, fans and rotors) are used to move through a fluid. Propellers have been used as toys since ancient times, however it was Leonardo da Vinci who devised what was one of the earliest propeller driven vehicles, the "aerial-screw". In 1661, Toogood & Hays adopted the screw for use as a ship propeller. Since then, the propeller has been tested on many terrestrial vehicles, including the Schienenzeppelin train and numerous cars. In modern times, propellers are most prevalent on watercraft and aircraft, as well as some amphibious vehicles such as hovercraft and ground-effect vehicles. Intuitively, propellers cannot work in space as there is no working fluid, however some sources have suggested that since space is never empty, a propeller could be made to work in space.Similarly to propeller vehicles, some vehicles use wings for propulsion. Sailboats and sailplanes are propelled by the forward component of lift generated by their sails/wings. Ornithopters also produce thrust aerodynamically. Ornithopters with large rounded leading edges produce lift by leading-edge suction forces. Research at the University of Toronto Institute for Aerospace Studies  lead to a flight with an actual ornithopter on July 31, 2010.
Paddle wheels are used on some older watercraft and their reconstructions. These ships were known as paddle steamers. Because paddle wheels simply push against the water, their design and construction is very simple. The oldest such ship in scheduled service is the Skibladner. Many pedalo boats also use paddle wheels for propulsion.
Screw-propelled vehicles are propelled by auger-like cylinders fitted with helical flanges. Because they can produce thrust on both land and water, they are commonly used on all-terrain vehicles. The ZiL-2906 was a Soviet-designed screw-propelled vehicle designed to retrieve cosmonauts from the Siberian wilderness.

Friction
All or almost all of the useful energy produced by the engine is usually dissipated as friction; so minimising frictional losses is very important in many vehicles. The main sources of friction are rolling friction and fluid drag (air drag or water drag).
Wheels have low bearing friction and pneumatic tyres give low rolling friction. Steel wheels on steel tracks are lower still.Aerodynamic drag can be reduced by streamlined design features.
Friction is desirable and important in supplying traction to facilitate motion on land. Most land vehicles rely on friction for accelerating, decelerating and changing direction. Sudden reductions in traction can cause loss of control and accidents.

Control
Steering
Most vehicles, with the notable exception of railed vehicles, have at least one steering mechanism. Wheeled vehicles steer by angling their front or rear wheels. The B-52 Stratofortress has a special arrangement in which all four main wheels can be angled. Skids can also be used to steer by angling them, as in the case of a snowmobile. Ships, boats, submarines, dirigibles and aeroplanes usually have a rudder for steering. On an airplane, ailerons are used to bank the airplane for directional control, sometimes assisted by the rudder.

Stopping
With no power applied, most vehicles come to a stop due to friction. But it is often required to stop a vehicle faster than by friction alone: so almost all vehicles are equipped with a braking system. Wheeled vehicles are typically equipped with friction brakes, which use the friction between brake pads (stators) and brake rotors to slow the vehicle. Many airplanes have high performance versions of the same system in their landing gear for use on the ground. A Boeing 757 brake, for example, has 3 stators and 4 rotors. The Space Shuttle also uses frictional brakes on its wheels. As well as frictional brakes, hybrid/electric cars, trolleybuses and electric bicycles can also use regenerative brakes to recycle some of the vehicles potential energy. High-speed trains sometimes use frictionless Eddy-current brakes; however widespread application of the technology has been limited by overheating and interference issues.Aside from landing gear brakes, most large aircraft have other ways of decelerating. In aircraft, air brakes are aerodynamic surfaces that provide braking force by increasing the frontal cross section thus aerodynamic drag of the aircraft. These are usually implemented as flaps that oppose air flow when extended and are flush with aircraft when retracted. Reverse thrust is also used in many aeroplane engines. Propeller aircraft achieve reverse thrust by reversing the pitch of the propellers, while jet aircraft do so by redirecting their engine exhaust forwards. On aircraft carriers, arresting gears are used to stop an aircraft. Pilots may even apply full forward throttle on touchdown, in case the arresting gear does not catch and a go around is needed.Parachutes are used to slow down vehicles travelling very fast. Parachutes have been used in land, air and space vehicles such as the ThrustSSC, Eurofighter Typhoon and Apollo Command Module. Some older Soviet passenger jets had braking parachutes for emergency landings. Boats use similar devices called sea anchors to maintain stability in rough seas.
To further increase the rate of deceleration or where the brakes have failed, several mechanisms can be used to stop a vehicle. Cars and rolling stock usually have hand brakes that, while designed to secure an already parked vehicle, can provide limited braking should the primary brakes fail. A secondary procedure called forward-slip is sometimes used to slow airplanes by flying at an angle, causing more drag.

Legislation
Motor vehicle and trailer categories are defined according to the following international classification:
Category M: passenger vehicles.
Category N: motor vehicles for the carriage of goods.
Category O: trailers and semi-trailers.

European Union
In the European Union the classifications for vehicle types are defined by:
Commission Directive 2001/116/EC of 20 December 2001, adapting to technical progress Council Directive 70/156/EEC on the approximation of the laws of the Member States relating to the type-approval of motor vehicles and their trailers
Directive 2002/24/EC of the European Parliament and of the Council of 18 March 2002 relating to the type-approval of two or three wheeled motor vehicles and repealing Council Directive 92/61/EECEuropean Community, is based on the Communitys WVTA (whole vehicle type-approval) system. Under this system, manufacturers can obtain certification for a vehicle type in one Member State if it meets the EC technical requirements and then market it EU-wide with no need for further tests. Total technical harmonization already has been achieved in three vehicle categories (passenger cars, motorcycles, and tractors) and soon will extend to other vehicle categories (coaches and utility vehicles). It is essential that European car manufacturers be ensured access to as large a market as possible.
While the Community type-approval system allows manufacturers to benefit fully from internal market opportunities, worldwide technical harmonization in the context of the United Nations Economic Commission for Europe (UNECE) offers a market beyond European borders.

Licensing
In many cases, it is unlawful to operate a vehicle without a license or certification. The least strict form of regulation usually limits what passengers the driver may carry or prohibits them completely (e.g., a Canadian ultra-light license without endorsements). The next level of licensing may allow passengers, but without any form of compensation or payment. A private drivers license usually has these conditions. Commercial licenses that allow the transport of passengers and cargo are more tightly regulated. The most strict form of licensing is generally reserved for school buses, hazardous materials transports and emergency vehicles.
The driver of a motor vehicle is typically required to hold a valid drivers license while driving on public lands, whereas the pilot of an aircraft must have a license at all times, regardless of where in the jurisdiction the aircraft is flying.

Registration
Vehicles are often required to be registered. Registration may be for purely legal reasons, for insurance reasons or to help law enforcement recover stolen vehicles. Toronto Police Service, for example, offers free and optional bicycle registration online. On motor vehicles, registration often takes the form of a vehicle registration plate, which makes it easy to identify a vehicle. In Russia, trucks and buses have their licence plate numbers repeated in large black letters on the back. On aircraft, a similar system is used where a tail number is painted on various surfaces. Like motor vehicles and aircraft, watercraft also have registration numbers in most jurisdictions, however the vessel name is still the primary means of identification  as has been the case since ancient times. For this reason, duplicate registration names are generally rejected. In Canada, boats with an engine power of 10 hp (7.5 kW) or greater require registration, leading to the ubiquitous "9.9 hp (7.4 kW)" engine.
Registration may be conditional on the vehicle being approved for use on public highways, as in the case of the UK and Ontario. Many US states also have requirements for vehicles operating on public highways. Aircraft have more stringent requirements, as they pose a high risk of damage to people and property in event of an accident. In the US, the FAA requires aircraft to have an airworthiness certificate. Because US aircraft must be flown for some time before they are certified, there is a provision for an experimental airworthiness certificate. FAA experimental aircraft are restricted in operation, including no overflights of populated areas, in busy airspace or with unessential passengers. Materials and parts used in FAA certified aircraft must meet the criteria set forth by the technical standard orders.

Mandatory safety equipment
In many jurisdictions, the operator of a vehicle is legally obligated to carry safety equipment with or on them. Common examples include seat belts in cars, helmets on motorcycles and bicycles, fire extinguishers on boats, buses and airplanes and life jackets on boats and commercial aircraft. Passenger aircraft carry a great deal of safety equipment including inflatable slides are rafts, oxygen masks, oxygen tanks, life jackets, satellite beacons and first aid kits. Some equipment such as life jackets has led to debate regarding their usefulness. In the case of Ethiopian Airlines Flight 961, the life jackets saved many people but also led to many deaths when passengers inflated their vests prematurely.

Right-of-way
There are specific real-estate arrangements made to allow vehicles to travel from one place to another. The most common arrangements are public highways, where appropriately licensed vehicles can navigate without hindrance. These highways are on public land and are maintained by the government. Similarly, toll routes are open to the public after paying a toll. These routes and the land they rest on may be government or privately owned or a combination of both. Some routes are privately owned but grant access to the public. These routes often have a warning sign stating that the government does not maintain the way. An example of this are byways in England and Wales. In Scotland, land is open to un-motorised vehicles if the land meets certain criteria. Public land is sometimes open to use by off-road vehicles. On US public land, the Bureau of Land Management (BLM) decides where vehicles may be used. Railways often pass over land not owned by the railway company </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Hodgkin lymphoma and explain in detail? [/INST] Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patients lymph nodes. The condition was named after the English physician Thomas Hodgkin, who first described it in 1832. Symptoms may include fever, night sweats, and weight loss. Often, nonpainful enlarged lymph nodes occur in the neck, under the arm, or in the groin. Those affected may feel tired or be itchy.The two major types of Hodgkin lymphoma are classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. About half of cases of Hodgkin lymphoma are due to Epstein–Barr virus (EBV) and these are generally the classic form. Other risk factors include a family history of the condition and having HIV/AIDS. Diagnosis is conducted by confirming the presence of cancer and identifying RS cells in lymph node biopsies. The virus-positive cases are classified as a form of the Epstein–Barr virus-associated lymphoproliferative diseases.Hodgkin lymphoma may be treated with chemotherapy, radiation therapy, and stem cell transplantation. The choice of treatment often depends on how advanced the cancer has become and whether or not it has favorable features. If the disease is detected early, a cure is often possible. In the United States, 88% of people diagnosed with Hodgkin Lymphoma survive for five years or longer. For those under the age of 20, rates of survival are 97%. Radiation and some chemotherapy drugs, however, increase the risk of other cancers, heart disease, or lung disease over the subsequent decades.In 2015, about 574,000 people globally had Hodgkin lymphoma, and 23,900 (4.2%) died. In the United States, 0.2% of people are affected at some point in their life. Most people are diagnosed with the disease between the ages of 20 and 40.

Signs and symptoms
People with Hodgkin lymphoma may present with the following symptoms:

Lymphadenopathy: the most common symptom of Hodgkin is the painless enlargement of one or more lymph nodes. The nodes may also feel rubbery and swollen when examined. The nodes of the neck, armpits and groin (cervical and supraclavicular) are most frequently involved (80–90% of the time, on average). The lymph nodes of the chest are often affected, and these may be noticed on a chest radiograph.
Systemic symptoms: about one-third of people with Hodgkin disease may also present with systemic symptoms, including:Itchy skin
Night sweats.
Unexplained weight loss of at least 10% of the persons total body mass in six months or less.
Low-grade fever.
Fatigue (lassitude).
Systemic symptoms such as fever, night sweats, and weight loss are known as B symptoms; thus, presence of these indicate that the persons stage is, for example, 2B instead of 2A.
Splenomegaly: enlargement of the spleen is often present in people with Hodgkin lymphoma. The enlargement is seldom massive, and the size of the spleen may fluctuate during the course of treatment.
Hepatomegaly: enlargement of the liver, due to liver involvement, is infrequent in people with Hodgkin Lymphoma.
Hepatosplenomegaly: the enlargement of both the liver and spleen caused by the same disease.
Pain following alcohol consumption: classically, involved nodes are painful after alcohol consumption, though this phenomenon is very uncommon, occurring in only two to three percent of people with Hodgkin lymphoma, thus having a low sensitivity. On the other hand, its positive predictive value is high enough for it to be regarded as a pathognomonic sign of Hodgkin lymphoma. The pain typically has an onset within minutes after ingesting alcohol, and is usually felt as coming from the vicinity where there is an involved lymph node. The pain has been described as either sharp and stabbing or dull and aching.
Back pain: nonspecific back pain (pain that cannot be localised or its cause determined by examination or scanning techniques) has been reported in some cases of Hodgkin lymphoma. The lower back is most often affected.
Cyclical fever: people may also present with a cyclical high-grade fever known as the Pel–Ebstein fever, or more simply "P-E fever". However, there is debate as to whether the P-E fever truly exists.
Nephrotic syndrome can occur in individuals with Hodgkin lymphoma and is most commonly caused by minimal change disease.
May present with airway obstruction, pleural/pericardial effusion, hepatocellular dysfunction, bone marrow infiltration.

Diagnosis
Hodgkin lymphoma must be distinguished from non-cancerous causes of lymph node swelling (such as various infections) and from other types of cancer. Definitive diagnosis is by lymph node biopsy (usually excisional biopsy with microscopic examination). Blood tests are also performed to assess function of major organs and to assess safety for chemotherapy. Positron emission tomography (PET) is used to detect small deposits that do not show on CT scanning. PET scans are also useful in functional imaging (by using a radiolabeled glucose to image tissues of high metabolism). In some cases, a gallium scan may be used instead of a PET scan.

Types
There are two main types of Hodgkin lymphoma: classic Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. The prevalence of classic Hodgkin lymphoma and nodular lymphocyte Hodgkin lymphoma are approximately 90% and 10%, respectively. The morphology, phenotype, molecular features, and, therefore, the clinical behaviour and presentation of the two types differ.

Classic
Classic Hodgkin lymphoma (excluding nodular lymphocyte predominant Hodgkin lymphoma) can be subclassified into four pathologic subtypes based upon Reed–Sternberg cell morphology and the composition of the reactive cell infiltrate seen in the lymph node biopsy specimen (the cell composition around the Reed–Sternberg cell(s)). Presence of EBV in Reed-Sternberg cells is most commonly found in the subtypes lymphocyte depleted HL (>70%) and mixed cellularity HL (70%), whilst being less prevalent in lymphocyte-rich HL (40%) and relatively uncommon by comparison in nodular sclerosing HL.

For the other forms, although the traditional B-cell markers (such as CD20) are not expressed on all cells, Reed–Sternberg cells are usually of B cell origin. Although Hodgkins is now frequently grouped with other B-cell malignancies, some T-cell markers (such as CD2 and CD4) are occasionally expressed. However, this may be an artifact of the ambiguity inherent in the diagnosis.
Hodgkin cells produce interleukin-21 (IL-21), which was once thought to be exclusive to T-cells. This feature may explain the behavior of classic Hodgkin lymphoma, including clusters of other immune cells gathered around HL cells (infiltrate) in cultures.

Nodular lymphocyte predominant
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is another subtype of Hodgkin lymphoma distinct from classic Hodgkin lymphoma and is characterized by the presence of popcorn cells which express CD20. Due to these differences, among others, NLPHL is often treated differently from classic Hodgkin lymphoma, including using rituximab in combination with AVBD chemotherapy, though individual cases vary and clinical trials are ongoing.

Staging
The staging is the same for both Hodgkin and non-Hodgkin lymphomas.
After Hodgkin lymphoma is diagnosed, a person will be staged: that is, they will undergo a series of tests and procedures that will determine what areas of the body are affected. These procedures may include documentation of their histology, a physical examination, blood tests, chest X-ray radiographs, computed tomography (CT)/positron emission tomography (PET)/magnetic resonance imaging (MRI) scans of the chest, abdomen and pelvis, and usually a bone marrow biopsy. PET scan is now used instead of the gallium scan for staging. On the PET scan, sites involved with lymphoma light up very brightly enabling accurate and reproducible imaging. In the past, a lymphangiogram or surgical laparotomy (which involves opening the abdominal cavity and visually inspecting for tumors) were performed. Lymphangiograms or laparotomies are very rarely performed, having been supplanted by improvements in imaging with the CT scan and PET scan.On the basis of this staging, the person will be classified according to a staging classification (the Ann Arbor staging classification scheme is a common one):
Stage I is involvement of a single lymph node region (I) (mostly the cervical region) or single extralymphatic site (Ie);
Stage II is involvement of two or more lymph node regions on the same side of the diaphragm (II) or of one lymph node region and a contiguous extralymphatic site (IIe);
Stage III is involvement of lymph node regions on both sides of the diaphragm, which may include the spleen (IIIs) or limited contiguous extralymphatic organ or site (IIIe, IIIes);
Stage IV is disseminated involvement of one or more extralymphatic organs.The absence of systemic symptoms is signified by adding "A" to the stage; the presence of systemic symptoms is signified by adding "B" to the stage. For localised extranodal extension from mass of nodes that does not advance the stage, subscript "E" is added. Splenic involvement is signified by adding "S" to the stage. The inclusion of "bulky disease" is signified by "X".

Pathology
MacroscopyAffected lymph nodes (most often, laterocervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform; in some histological subtypes (e.g. nodular sclerosis) a nodular aspect may appear.A fibrin ring granuloma may be seen.

Microscopy

Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (RSC) (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed–Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45-, CD30+, CD15+/- immunophenotype. In approximately 50% of cases, the Reed–Sternberg cells are infected by the Epstein–Barr virus.Characteristics of classic Reed–Sternberg cells include large size (20–50 micrometres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed close to the nuclear membrane). Almost all of these cells have an increased copy number of chromosome 9p/9p24.1.Variants:

Hodgkin cell (atypical mononuclear RSC) is a variant of RS cell, which has the same characteristics but is mononucleated.
Lacunar RSC is large, with a single hyperlobulated nucleus, multiple, small nucleoli and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space ("lacunae").
Pleomorphic RSC has multiple irregular nuclei.
"Popcorn" RSC (lympho-histiocytic variant) is a small cell, with a very lobulated nucleus, small nucleoli.
"Mummy" RSC has a compact nucleus with no nucleolus and basophilic cytoplasm.Hodgkin lymphoma can be sub-classified by histological type. The cell histology in Hodgkin lymphoma is not as important as it is in non-Hodgkin lymphoma: the treatment and prognosis in classic Hodgkin lymphoma usually depends on the stage of disease rather than the histotype.

Management
The current approach for treatment aims to reduce the acute and long-term toxicities associated with Hodgkin lymphoma (e.g. cardiac damage and secondary cancers) and increase overall survival.People with early stage disease (IA or IIA) are effectively treated with radiation therapy or chemotherapy. The choice of treatment depends on the age, sex, bulk and the histological subtype of the disease.
Adding localised radiation therapy after the chemotherapy regimen may provide a longer progression-free survival compared with chemotherapy treatment alone. People with later disease (III, IVA, or IVB) are treated with combination chemotherapy alone. People of any stage with a large mass in the chest are usually treated with combined chemotherapy and radiation therapy.
The common non-Hodgkin treatment, rituximab (which is a monoclonal antibody against CD20) is not routinely used to treat Hodgkin lymphoma due to the lack of CD20 surface antigens in most cases. The use of rituximab in Hodgkin lymphoma, including the lymphocyte predominant subtype has been recently reviewed. The evidence is very uncertain about the effect of Nivolumab for patients with a Hodgkins lymphoma e.g. on the overall survival.Increased age is an adverse risk factor for Hodgkin lymphoma, but in general elderly people (≥ 60 years of age) without major comorbidities are sufficiently fit to tolerate therapy with curative intent. Despite this, treatment outcome in the elderly patient is not comparable to that of younger people and the disease is a different entity in older people where different considerations enter into treatment decisions.Recently, two novel targeted drugs have been developed for relapsing and refractory HL patients; Brentuximab vedotin, a CD30 antibody conjugated with a cytotoxic component MMAE, and the checkpoint inhibitors, Nivolumab and Pembrolizumab. This has been an important step in the treatment  for the few, but still existing refractory patients.
For Hodgkin lymphomas, radiation oncologists typically use external beam radiation therapy (sometimes shortened to EBRT or XRT). Radiation oncologists deliver external beam radiation therapy to the lymphoma from a machine called a linear accelerator which produces high energy X-rays and electrons. People usually describe treatments as painless and similar to getting an X-ray. Treatments last less than 30 minutes each.
For lymphomas, there are a few different ways radiation oncologists target the cancer cells. Involved site radiation is when the radiation oncologists give radiation only to those parts of the persons body known to have the cancer. Very often, this is combined with chemotherapy. Radiation therapy directed above the diaphragm to the neck, chest or underarms is called mantle field radiation. Radiation to below the diaphragm to the abdomen, spleen or pelvis is called inverted-Y field radiation. Total nodal irradiation is when the therapist gives radiation to all the lymph nodes in the body to destroy cells that may have spread.

Adverse effects
The high cure rates and long survival of many people with Hodgkin lymphoma has led to a high concern with late adverse effects of treatment, including cardiovascular disease and second malignancies such as acute leukemias, lymphomas, and solid tumors within the radiation therapy field. Most people with early-stage disease are now treated with abbreviated chemotherapy and involved site radiation therapy rather than with radiation therapy alone. Clinical research strategies are exploring reduction of the duration of chemotherapy and dose and volume of radiation therapy in an attempt to reduce late morbidity and mortality of treatment while maintaining high cure rates. Hospitals are also treating those who respond quickly to chemotherapy with no radiation.In childhood cases of Hodgkin lymphoma, long-term endocrine adverse effects are a major concern, mainly gonadal dysfunction and growth retardation. Gonadal dysfunction seems to be the most severe endocrine long-term effect, especially after treatment with alkylating agents or pelvic radiotherapy.It is possible that patients undergoing a chemotherapy need a platelet transfusion. If a stem cell transplantation is necessary for the treatment of a relapse, graft-versus-host diseases might occur.

Supportive treatment
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like Hodgkin lymphoma may result in little to no difference in the mortality, the quality of life and the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events.

Prognosis
Treatment of Hodgkins disease has been improving over the past few decades. Recent trials that have made use of new types of chemotherapy have indicated higher survival rates than have previously been seen. In one recent European trial, the five-year survival rate for those people with a favorable prognosis (FFP) was 98%, while that for people with worse outlooks was at least 85%.In 1998, an international effort identified seven prognostic factors that accurately predict the success rate of conventional treatment in people with locally extensive or advanced-stage Hodgkin lymphoma. Freedom from progression (FFP) at five years was directly related to the number of factors present in a person. The five-year FFP for people with zero factors is 84%. Each additional factor lowers the five-year FFP rate by 7%, such that the five-year FFP for a person with five or more factors is 42%.The adverse prognostic factors identified in the international study are:

Age ≥ 45 years
Stage IV disease
Hemoglobin < 10.5 g/dl
Lymphocyte count < 600/µl or < 8%
Male
Albumin < 4.0 g/dl
White blood count ≥ 15,000/µlOther studies have reported the following to be the most important adverse prognostic factors: mixed-cellularity or lymphocyte-depleted histologies, male sex, large number of involved nodal sites, advanced stage, age of 40 years or more, the presence of B symptoms, high erythrocyte sedimentation rate, and bulky disease (widening of the mediastinum by more than one third, or the presence of a nodal mass measuring more than 10 cm in any dimension.)More recently, the use of positron emission tomography (PET) early after commencing chemotherapy has demonstrated to have powerful prognostic ability. This enables assessment of an individuals response to chemotherapy as the PET activity switches off rapidly in people who are responding. In this study, after two cycles of ABVD chemotherapy, 83% of people were free of disease at 3 years if they had a negative PET versus only 28% in those with positive PET scans. This prognostic method improves on FFP estimates based on the seven conventional factors. Several trials are underway to see if PET-based risk adapted response can be used to improve a persons outcomes by changing chemotherapy early in people who are not responding.
The evidence is very uncertain about the effect of negative (= good prognosis) or positive (= bad prognosis) interim PET scan results for patients with a Hodgkins lymphoma on the progression-free survival. Negative interim PET scan results may result in an increase in progression-free survival compared if the adjusted result was measured. Negative interim PET scan results probably result in a large increase in the overall survival compared to those with a positive interim PET scan result,

Epidemiology
Unlike some other lymphomas, whose number of new cases per year increases with age, Hodgkin lymphoma has a bimodal curve for the number of cases; that is, it occurs most frequently in two separate age groups, the first being young adulthood (age 15–35) and the second being in those over 55 years old although these peaks may vary slightly with nationality. Overall, it is more common in males, except for the nodular sclerosis variant, which is slightly more common in females. The annual number of cases of Hodgkin lymphoma is 2.7 per 100,000 per persons per year, and the disease accounts for slightly less than 1% of all cancers worldwide.In 2010, globally it resulted in about 18,000 deaths down from 19,000 in 1990. In 2012, there were an estimated 65,950 cases and 25,469 deaths from Hodgkin lymphoma worldwide, with 28,852 and 37,098 cases occurring in developed and developing countries, respectively. However, the age-standardized rates were higher in developed regions, with the greatest rates in the Americas (1.5 per 100,000), East Mediterranean Region (1.5 per 100,000), and Europe (2.0 per 100,000). The East Mediterranean Region also has the highest age-standardized mortality rate of 1.0 per 100,000, which is mainly attributed to lifestyle and environmental risk factors associated with transitional economies such as smoking, obesity, physical inactivity, and reproductive behaviors, as well as availability of diagnostic practices and awareness of the disease.The number of cases of Hodgkin lymphoma is increased in people with HIV infection. In contrast to many other lymphomas associated with HIV infection it occurs most commonly in people with higher CD4 T cell counts.

Canada
Hodgkin lymphoma accounts for 0.6% of all male cancer cases, and 0.4% of all female cancer cases in Canada. In 2017, approximately 990 Canadians will be diagnosed with Hodgkin lymphoma, and 140 will die of the disease.

UK
Hodgkin lymphoma accounts for less than 1% of all cancer cases and deaths in the UK. Around 1,800 people were diagnosed with the disease in 2011, and around 330 people died in 2012.

United States
In 2016, there were 8,389 new cases and 1,000 mortalities attributed to Hodgkin Lymphoma, a decrease from the 8,625 new cases and 1,120 mortalities in 2015. As of January 1, 2016, the 5-year limited duration prevalence of Hodgkin Lymphoma was 37,513 representing 0.71% of all diagnosed cancers in the U.S.

History
Hodgkin lymphoma was first described in an 1832 report by Thomas Hodgkin, although Hodgkin noted that perhaps an earlier reference to the condition was provided by Marcello Malpighi in 1666. While occupied as museum curator at Guys Hospital, London, Hodgkin studied seven people with painless lymph node enlargement. Of the seven cases, two were under the care of Richard Bright, one was of Thomas Addison, and one was of Robert Carswell. Carswells report of the seventh case was accompanied by numerous illustrations that aided early descriptions of the disease.Hodgkins report on the seven cases, entitled "On some morbid appearances of the absorbent glands and spleen", was presented to the Medical and Chirurgical Society of London in January 1832 and was subsequently published in the societys journal, Medical-Chirurgical Society Transactions. Hodgkins paper went largely unnoticed, however, even though Bright highlighted it in an 1838 publication. Indeed, Hodgkin himself did not view his contribution as particularly significant.In 1856, Samuel Wilks independently reported on a series of patients with the same disease that Hodgkin had previously described. Wilks, a successor to Hodgkin at Guys Hospital, was unaware of Hodgkins prior work on the subject. Bright informed Wilks of Hodgkins contribution and in 1865, Wilks published a second paper, entitled "Cases of enlargement of the lymphatic glands and spleen", in which he named the illness "Hodgkins disease" in honor of his predecessor.Theodor Langhans and WS Greenfield first described the microscopic characteristics of Hodgkin lymphoma in 1872 and 1878, respectively. In 1898 and 1902, respectively, Carl Sternberg and Dorothy Reed independently described the cytogenetic features of the malignant cells of Hodgkin lymphoma, now called Reed–Sternberg cells.Tissue specimens from Hodgkins seven cases were preserved at Guys Hospital. Nearly 100 years after Hodgkins initial publication, histopathologic reexamination confirmed Hodgkin lymphoma in only three of seven of these people. The remaining cases included non-Hodgkin lymphoma, tuberculosis, and syphilis.Hodgkin lymphoma was one of the first cancers to be treated successfully with radiation therapy and, later, it was one of the first to be treated by combination chemotherapy.

Notable cases
Paul Allen, co-founder of Microsoft was diagnosed with Hodgkin lymphoma in 1982. He later died from non-Hodgkin lymphoma, on October 15, 2018.
Eric Berry, All-Pro strong safety for the Kansas City Chiefs of the National Football League, diagnosed in 2014.
Howard Carter, Egyptologist and discoverer of the Tomb of Tutankhamun, died in 1939 from Hodgkins disease.
Starchild Abraham Cherrix, a teenager whose refusal to undergo further conventional treatment after relapsing in 2006 resulted in a court battle and a change to Virginia laws about medical neglect.
James Conner, running back and 2014 ACC Player of the Year for the Pittsburgh Steelers.
Michael Cuccione, Canadian child actor, was diagnosed in 1994 at age 9. Treatments that rendered him cancer-free, including chemotherapy, a bone marrow transplant, and radiation, left him with permanent lung and respiratory problems and he died in 2001 just after turning 16.
Victoria Duval, American tennis player, was diagnosed in 2014.
Gerald Finzi, British composer, was diagnosed in 1951 and died in 1956.
Mist Edvardsdóttir, Icelandic football player and member of the Icelandic womens national team. Diagnosed in June 2014 at the age of 23. Continued to play until becoming too ill due to chemotherapy. Made recovery in early 2015.
Delta Goodrem, Australian singer, songwriter, and actress. She was diagnosed in July 2003 at the age of 18.
Jiří Grossmann, Czechoslovak theatre actor, poet, and composer
Michael C. Hall (born February 1, 1971), American actor, best known for his lead role as Dexter Morgan, in Showtimes crime series Dexter. In 2010, aged 38, Hall announced he was undergoing treatment for Hodgkin lymphoma; within two years, the disease was in full remission.
Richard Harris, Irish actor who portrayed Albus Dumbledore in the first two Harry Potter movies, died on October 25, 2002, after being diagnosed earlier that year.
Daniel Hauser, whose mother fled with him in 2009 in order to prevent him from undergoing chemotherapy.
Tessa James, Australian actress, was diagnosed in 2014.
Sean Kent, American stand up comedian and actor. Was diagnosed in 2002 while writing on a TV show </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Outline of counseling and explain in detail? [/INST]  </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Dipylidium caninum and explain in detail? [/INST] Dipylidium caninum, also called the flea tapeworm, double-pored tapeworm, or cucumber tapeworm (in reference to the shape of its cucumber-seed-like proglottids, though these also resemble grains of rice or sesame seeds), is a cyclophyllid cestode that infects organisms afflicted with fleas and canine chewing lice, including dogs, cats, and sometimes human pet-owners, especially children.

Adult morphology
The adult worm is about 18 inches (46 cm) long.  Gravid proglottids containing the worms microscopic eggs are either passed in the definitive hosts feces or may leave their host spontaneously and are then ingested by microscopic flea larvae (the intermediate hosts) in the surrounding environment. As in all members of family Dipylidiidae, proglottids of the adult worm have genital pores on both sides (hence the name double-pore tapeworm).  Each side has a set of male and female reproductive organs.  The uterus is paired with 16 to 20 radial branches each. The scolex has a retractable rostellum with four rows of hooks, along with the four suckers that all cyclophyllid cestodes have.

Life cycle
The definitive host within this life cycle is primarily canines, and occasionally felines, and in rare cases young children. The intermediate hosts include fleas (Ctenocephalides spp.) and chewing lice.  The first stage in the life cycle is when the gravid proglottids are either passed out through faecal matter, or actively crawl out of the anus of the host. The gravid proglottids once out of the definitive host release eggs. Then, an intermediate host (the larval stage of a flea or chewing louse) will ingest an egg, which develops into a cysticercoid larva. The cysticercoid larva remains viable, but is not infective to carnivores until the flea hatches to an adult and begins feeding on a host (e.g. a dog). Approximately 36 hours after the flea has consumed a blood meal, the infective metacestode develops inside the flea. The metacestode larva must be ingested in a flea by the dog or cat during grooming in order to develop. Humans can also become infected by D. caninum by accidentally ingesting an infected flea. In the small intestine of the definitive host, the metacestode develops into an adult tapeworm, which reaches maturity 4-6 weeks after ingestion. This adult tapeworm produces proglottids, and over time, the proglottids mature and become gravid and eventually detach from the tapeworm and the life cycle starts all over again.

Geographic Distribution
This parasite occurs worldwide in animals, such as dogs and cats, as well as in humans, though to a significantly lesser degree. It is the most common tapeworm of dogs and is relatively common in cats. Despite human diplydiasis being rare, instances have been reported from every inhabited continent.Human instances of diplydiasis are reported globally, and unsurprisingly roughly one third of the cases occur in children less than 6 months of age. The most at-risk age group is those that range from 2 months to 4 years old.

Pet infections
Tapeworm infection usually does not cause pathology in the dog or cat, and most pets show no adverse reaction to infection other than increased appetite. The bulk of infections are asymptomatic and the infections that do result in symptoms are generally mildly so. Pets behavior may reflect the presence of anal discomfort and itching, or pruritus. This could result in the ‘butt-scooching” across the floor, grass or carpeting. It may be accompanied by slight gastrointestinal disturbances, as this is the region where the worms inhabit. Though not a pathology of the diplydiasis, the most unnerving sign of the infection is the presence of proglottids in the animals, or child’s, feces.  These proglottids can also be found near the perianal region, in the feces, and in diapers (children). The motile proglottids can actively crawl out of the anus of the infected animal/person and migrate small distances, thus potentially covering this array of neighboring surfaces.  It is from these locations that the larval stage of the flea will come along and ingest them. Then the metacestode stage, a cysticercoid, develops in the coelomic cavity (abdominal cavity; main body cavity) of the flea larvae and remains there as the flea matures into an adult. These freshly passed proglottids are motile, allowing them to also be found on the floor and furniture, from a migration out of a pets anus and could be compared to resembling fly larvae, or maggots.The other tapeworm infecting cats is Taenia taeniaeformis, though this form is much less commonly encountered than D. caninum.
A recent (2018) study using genetical analysis and experimental infections and life-cycles showed that two different distinct genotypes of D. caninum occur respectively in dogs and in cats, and suggested that two different species might be involved.

Human infections
A human infection with D. caninum is rare, but if an infection does occur, it is more likely to occur in young children. As of the early 1960s, the number of cases of D. caninum in the U.S. was a mere 21. Therefore, human infection of Dipylidium caninum, or diplydiasis, is a rare occasion. It is largely agreed across the parasitology community that despite the reports of this disease occurring, there are very likely numerous cases that have gone unnoticed and unreported because of its subtle and minor pathology in humans, in addition to its scarceness in clinical records. The adult tapeworm grows within the host for 3–4 weeks after initial infection.  The number of parasites the host is initially infected with is directly related to the number of cysticercoid juveniles present in the fleas coelom. The load of parasites present in the humans is lower, luckily, as the life cycle is not occurring in the ideal conditions or species as humans are not the definitive host.Many cases have an unexciting course of infection, as can be depicted in two cases occurring in the 1960s. The first case occurred in a 9-month-old female. Mother found motile proglottids the child’s diaper, later identified as D. caninum. The child had no apparent signs or symptoms </s>


<s> [INST] <<SYS>> You are a helpful, respectful, and honest assistant. Always answer as helpfully as possible, while being safe. Your answers should not include any harmful, unethical, racist, sexist, toxic, dangerous, or illegal content. Please ensure that your responses are socially unbiased and positive in nature. If a question does not make any sense or is not factually coherent, explain why instead of answering something not correct. If you don't know the answer to a question, please don't share false information. <</SYS>> What is Periodontosis and explain in detail? [/INST]  </s>