<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 Hyperprolactinaemia and explain in detail? [/INST] Hyperprolactinaemia is the presence of abnormally high levels of prolactin in the blood. Normal levels average to about 13 ng/mL in women, and 5 ng/mL in men, with an upper normal limit of serum prolactin levels being 15-25 ng/mL for both. When the fasting levels of prolactin in blood exceed this upper limit,  hyperprolactinemia is indicated.
Prolactin (PRL) is a peptide hormone produced by lactotroph cells in the anterior pituitary gland. PRL is involved in lactation after pregnancy and plays a vital role in breast development. Hyperprolactinemia may cause galactorrhea (production and spontaneous flow of breast milk), infertility, and disruptions in the normal menstrual period in women; as well as hypogonadism, infertility and erectile dysfunction in men.
Although hyperprolactinemia can result from normal physiological changes during pregnancy and breastfeeding, it can also be caused by other etiologies. For example, high prolactin levels could result from diseases affecting the hypothalamus and pituitary gland. Other organs, such as the liver and kidneys, could affect prolactin clearance and consequently, prolactin levels in the serum. The disruption of prolactin regulation could also be attributed to external sources such as medications.In the general population, the prevalence of hyperprolactinemia is 0.4%. The prevalence increases to as high as 17% in women with reproductive diseases, such as polycystic ovary syndrome. In cases of tumor-related hyperprolactinemia, prolactinoma is the most common culprit of consistently high levels of prolactin as well as the most common type of pituitary tumor. For non-tumor related hyperprolactinemia, the most common cause is medication-induced prolactin secretion. Particularly, antipsychotics have been linked to a majority of non-tumor related hyperprolactinemia cases due to their prolactin-rising and prolactin-sparing mechanisms. Typical antipsychotics have been shown to induce significant, dose-dependent increases in prolactin levels up to 10-fold the normal limit. Atypical antipsychotics vary in their ability to elevate prolactin levels, however, medications in this class such as risperidone and paliperidone carry the highest potential to induce hyperprolactinemia in a dose-dependent manner similar to typical antipsychotics.

Signs and symptoms
In women, high blood levels of prolactin are typically associated with hypoestrogenism, anovulatory infertility, and changes in menstruation. Menstruation disturbances experienced in women commonly manifests as amenorrhea or oligomenorrhea. In the latter case, irregular menstrual flow may result in abnormally heavy and prolonged bleeding (menorrhagia). Women who are not pregnant or nursing may also unexpectedly begin producing breast milk (galactorrhea), a condition that is not always associated with high prolactin levels. For instance, many premenopausal women experiencing hyperprolactinemia do not experience galactorrhea and only some women who experience galactorrhea will be diagnosed with hyperprolactinemia. Thus, galactorrhea may be observed in individuals with normal prolactin levels and does not necessarily indicate hyperprolactinemia. This phenomenon is likely due to galactorrhea requiring adequate levels of progesterone or estrogen to prepare the breast tissue. Additionally, some women may also experience loss of libido and breast pain, particularly when prolactin levels rise initially, as the hormone promotes tissue changes in the breast.In men, the most common symptoms of hyperprolactinemia are decreased libido, sexual dysfunction, erectile dysfunction/impotence, infertility, and gynecomastia. Unlike women, men do not experience reliable indicators of elevated prolactin such as menstruation to prompt immediate medical consultation. As a result, the early signs of hyperprolactinemia are generally more difficult to detect and may go unnoticed until more severe symptoms are present. For instance, symptoms such as loss of libido and sexual dysfunction are subtle, arise gradually, and may falsely indicate a differential cause. Many men with pituitary tumor-associated hyperprolactinemia may forego clinical help until they begin to experience serious endocrine and vision complications, such as major headaches or eye problems.Long-term hyperprolactinaemia can lead to detrimental changes in bone metabolism as a result of hypoestrogenism and hypoandrogenism. Studies have shown that chronically elevated prolactin levels lead to increased bone resorption and suppression of bone formation, leading to reduced bone density, increased risk of fractures, and increased risk of osteoporosis. The chronic presence of hyperprolactinemia can lead to hypogonadism and osteolysis in men.

Causes
Prolactin secretion is regulated by both stimulatory and inhibitory mechanisms. Dopamine acts on pituitary lactotroph D2 receptors to inhibit prolactin secretion while other peptides and hormones, such as thyrotropin releasing hormone (TRH), stimulate prolactin secretion. As a result, hyperprolactinemia may be caused by disinhibition (e.g., compression of the pituitary stalk or reduced dopamine levels) or excess production. The most common cause of hyperprolactinemia is prolactinoma (a type of pituitary adenoma). A blood serum prolactin level of 1000–5000 mIU/L (47-235 ng/mL) may arise from either mechanism, however levels >5000 mIU/L (>235 ng/mL) is likely due to the activity of an adenoma. Prolactin blood levels are typically correlated to the size the tumors. Pituitary tumors smaller than 10 mm in diameter, or microadenomas, tend to have prolactin levels <200 ng/mL. Macroadenomas larger than 10 mm in diameter possess prolactin >1000 ng/mL.Hyperprolactinemia inhibits the secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn inhibits the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland and results in diminished gonadal sex hormone production (termed hypogonadism). This is the cause of many of the symptoms described below.
In many people, elevated prolactin levels remain unexplained and may represent a form of hypothalamic–pituitary–adrenal axis dysregulation.

Physiological causes
Physiological (i.e., non-pathological) causes include: ovulation, pregnancy, breastfeeding, chest wall injury, stress, stress-associated REM sleep, and exercise. During pregnancy, prolactin levels can range up to 600 ng/mL, depending on estrogen concentration. At 6 weeks post-birth (postpartum), estradiol concentrations decrease, and prolactin concentrations return to normal even during breastfeeding. Stress-related factors include physical, exercise, hypoglycemia, myocardial infarction, and surgery. Coitus and sleep can also contribute to an increased prolactin release.

Medications
Prolactin secretion in the pituitary is normally suppressed by the brain chemical dopamine, which binds to dopamine receptors. Drugs that block the effects of dopamine at the pituitary or deplete dopamine stores in the brain may cause the pituitary to secrete prolactin without an inhibitory effect. These drugs include the typical antipsychotics: phenothiazines such as chlorpromazine (Thorazine), and butyrophenones such as haloperidol (Haldol); atypical antipsychotics such as risperidone (Risperdal) and paliperidone (Invega); gastroprokinetic drugs used to treat gastro-esophageal reflux and medication-induced nausea (such as that from chemotherapy): metoclopramide (Reglan) and domperidone; less often, alpha-methyldopa and reserpine, used to control hypertension; and TRH. The use of estrogen-containing oral contraceptives are also known to increase prolactin levels when taken in high doses >35 μg. The sleep drug ramelteon (Rozerem) also increases the risk of hyperprolactinaemia. Particularly, the dopamine antagonists metoclopramide and domperidone are both powerful prolactin stimulators and have been used to stimulate breast milk secretion for decades. However, since prolactin is antagonized by dopamine and the body depends on the two being in balance, the risk of prolactin stimulation is generally present with all drugs that deplete dopamine, either directly or as a rebound effect.

Specific diseases
Prolactinoma or other tumors arising in or near the pituitary — such as those that cause acromegaly may block the flow of dopamine from the brain to the prolactin-secreting cells, likewise, division of the pituitary stalk or hypothalamic disease. Other causes include chronic kidney failure, hypothyroidism, bronchogenic carcinoma and sarcoidosis. Some women with polycystic ovary syndrome may have mildly-elevated prolactin levels.
Nonpuerperal mastitis may induce transient hyperprolactinemia (neurogenic hyperprolactinemia) of about three weeks duration; conversely, hyperprolactinemia may contribute to nonpuerperal mastitis.Apart from diagnosing hyperprolactinemia and hypopituitarism, prolactin levels are often checked by physicians in those who have had a seizure, when there is need to differentiate between epileptic seizure or a non-epileptic seizure. Shortly after epileptic seizures, prolactin levels often rise, whereas they are normal in non-epileptic seizures.

Diagnosis
An appropriate diagnosis of hyperprolactinemia starts with conducting a complete clinical history before performing any treatment. Physiological causes, systemic disorders, and the use of certain drugs must be ruled out before the condition is diagnosed. Screening is indicated for those who are asymptomatic and those with elevated prolactin without an associated cause.
The most common causes of hyperprolactinemia are prolactinomas, drug-induced hyperprolactinemia, and macroprolactinemia. Individuals with hyperprolactinemia may present with symptoms including galactorrhea, hypogonadism effects, and/or infertility. The magnitude that prolactin is elevated can be used as an indicator of the etiology of the hyperprolactinemia diagnosis. Prolactin levels over 250 ng/mL may suggest prolactinoma. Prolactin levels less than 100 ng/mL may suggest drug-induced hyperprolactinemia, macroprolactinemia, nonfunctioning pituitary adenomas, or systemic disorders.Elevated prolactin blood levels are typically assessed in women with unexplained breast milk secretion (galactorrhea) or irregular menses or infertility, and in men with impaired sexual function and milk secretion. If high prolactin levels are present, all known conditions and medications which raises prolactin secretion must be assessed and excluded for diagnosis. After ruling out other causes and prolactin levels remain high, TSH levels are assessed. If TSH levels are elevated, hyperprolactinemia is secondary to hypothyroidism and treated accordingly. If TSH levels are normal, an MRI or CT scan is conducted to assess for any pituitary adenomas. Although hyperprolactinemia is often uncommon in postmenopausal women, prolactinomas detected after menopause are typically macroadenomas. While a plain X-ray of the bones surrounding the pituitary may reveal the presence of a large macroadenoma, small microadenomas will not be apparent. Magnetic resonance imaging (MRI) is the most sensitive test for detecting pituitary tumors and determining their size. MRI scans may be repeated periodically to assess tumor progression and the effects of therapy. Computed Tomography (CT scan) is another indicator of abnormalities in pituitary gland size; it also gives an image of the pituitary, but is less sensitive than the MRI. In addition to assessing the size of the pituitary tumor, physicians also look for damage to surrounding tissues, and perform tests to assess whether production of other pituitary hormones are normal. Depending on the size of the tumor, physicians may request an eye exam that includes the measurement of visual fields.However, a high measurement of prolactin may also result from the presence of macroprolactin, otherwise known as big prolactin or big-big prolactin, in the serum. Macroprolactin occurs when prolactin polymerizes together and can bind with IgG to form complexes. Although this can result in high prolactin levels in some assay tests, macroprolactin is biologically inactive and will not cause symptoms typical of hyperprolactinemia. In those who are asymptomatic or without obvious causes of hyperprolactinemia, macroprolactin should be assessed and ruled out.

Treatment
Treatment for hyperprolactinemia is usually dependent upon its cause, ranging from hypothyroidism, drug-induced hyperprolactinemia, hypothalamic disease, idiopathic hyperprolactinemia, macroprolactin, or prolactinoma. Therefore, in order to provide the proper management of hyperprolactinemia, the pathological form and physiological increase in prolactin levels are differentiated, and the correct cause of hyperprolactinemia must be identified before treatment. For functional asymptomatic hyperprolactinemia, the treatment of choice is removing the associated cause, including antipsychotic therapy. However, prolactin levels should be drawn and monitored both prior to any discontinuation or changes to therapy, and afterwards. With symptomatic hyperprolactinemia, stopping antipsychotic drugs for a short trial period are not recommended due to the risk of exacerbation or relapse of symptoms. Options for treatment include decreasing the dose of antipsychotics, adding aripiprazole as an adjunctive therapy, and switching antipsychotics as a last resort </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 Orf (disease) and explain in detail? [/INST] Orf is a farmyard pox, a type of zoonosis. It causes small pustules in the skin of primarily sheep and goats, but can also occur on the hands of humans. A pale halo forms around a red centre. It may persist for several weeks before crusting and then either resolves or leaves a hard lump. There is usually only one lesion, but there may be many, and they are not painful. Sometimes there are swollen lymph glands.It is caused by a Parapoxvirus. It can occur in humans who handle infected animals or contaminated objects. One third of cases may develop erythema multiforme. Once resolved, a person can still be infected again.Generally, treatment options are limited. Injecting the lesion with cidofovir or applying imiquimod has been tried. It is sometimes necessary to cut them out. The vaccine used in sheep to prevent orf is live and has been known to cause disease in humans.The disease is endemic in livestock herds worldwide. A recent outbreak emerged in southwest Ethiopia between October 2019 and May 2020.

Humans
Orf is a zoonotic disease, meaning humans can contract this disorder through direct contact with infected sheep and goats or with fomites carrying the orf virus. It causes a purulent-appearing papule locally and generally no systemic symptoms. Infected locations can include the finger, hand, arm, face and even the penis (caused by infection either from contact with the hand during urination or from bestiality). Consequently, it is important to observe good personal hygiene and to wear gloves when treating infected animals. It may appear similar to cowpox and pseudocowpox.
While orf is usually a benign self-limiting illness which resolves in 3-6 weeks, in the immunocompromised it can be very progressive and even life-threatening. One percent topical cidofovir has been successfully used in a few patients with progressive disease. Serious damage may be inflicted on the eye if it is infected by orf, even among healthy individuals. The virus can survive in the soil for at least six months.

Other animals
Orf is primarily a disease of sheep and goats although it has been reported as a natural disease in humans, steenbok and alpacas, chamois and tahrs, reindeer, musk oxen, dogs, cats, mountain goats, bighorn sheep, dall sheep, and red squirrels.

Sheep and goats
It has been recorded since the late 19th century and has been reported from most sheep-or goat-raising areas, including those in Europe, the Middle East, the United States, Africa, Asia, South America, Canada, New Zealand and Australia. Orf is spread by fomites and direct contact. In some environments, infection is injected by scratches from thistles of both growing and felled plants. Symptoms include papules and pustules on the lips and muzzle, and less commonly in the mouth of young lambs and on the eyelids, feet, and teats of ewes. The lesions progress to thick crusts which may bleed. Orf in the mouths of lambs may prevent suckling and cause weight loss, and can infect the udder of the mother ewe, thus potentially leading to mastitis. Sheep are prone to reinfection </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 Niemann–Pick disease, type C and explain in detail? [/INST] Niemann–Pick type C (NPC) (colloquially, "Childhood Alzheimers") is a lysosomal storage disease associated with mutations in NPC1 and NPC2 genes. Niemann–Pick type C affects an estimated 1:150,000 people. Approximately 50% of cases present before 10 years of age, but manifestations may first be recognized as late as the sixth decade.

Signs and symptoms
Niemann–Pick type C has a wide clinical spectrum. Affected individuals may have enlargement of the spleen (splenomegaly) and liver (hepatomegaly), or enlarged spleen or liver combined (hepatosplenomegaly), but this finding may be absent in later onset cases. Prolonged jaundice or elevated bilirubin can present at birth. In some cases, however, enlargement of the spleen or liver does not occur for months or years – or not at all. Enlargement of the spleen or liver frequently becomes less apparent with time, in contrast to the progression of other lysosomal storage diseases such as Niemann–Pick disease, Types A and B or Gaucher disease. Organ enlargement does not usually cause major complications.Progressive neurological disease is the hallmark of Niemann–Pick type C disease, and is responsible for disability and premature death in all cases beyond early childhood. Classically, children with NPC may initially present with delays in reaching normal developmental milestones skills before manifesting cognitive decline (dementia).Neurological signs and symptoms include cerebellar ataxia (unsteady walking with uncoordinated limb movements), dysarthria (slurred speech), dysphagia (difficulty in swallowing), tremor, epilepsy (both partial and generalized), vertical supranuclear palsy (upgaze palsy, downgaze palsy, saccadic palsy or paralysis), sleep inversion, gelastic cataplexy (sudden loss of muscle tone or drop attacks), dystonia (abnormal movements or postures caused by contraction of agonist and antagonist muscles across joints), most commonly begins with inturning of one foot when walking (action dystonia) and may spread to become generalized, spasticity (velocity dependent increase in muscle tone), hypotonia, ptosis (drooping of the upper eyelid), microcephaly (abnormally small head), psychosis, progressive dementia, progressive hearing loss, bipolar disorder, major and psychotic depression that can include hallucinations, delusions, mutism, or stupor.In the terminal stages of Niemann–Pick type C disease, the patient is bedridden, with complete ophthalmoplegia, loss of volitional movement and severe dementia.

Genetics
Approximately 95% of Niemann–Pick type C cases are caused by genetic mutations in the NPC1 gene, referred to as type C1; 5% are caused by mutations in the NPC2 gene, referred to as type C2. The clinical manifestations of types Niemann–Pick types C1 and C2 are similar because the respective genes are both involved in egress of lipids, particularly cholesterol, from late endosomes or lysosomes. The NPC1 gene is located on chromosome 18 (18q11-q12) and was described by researchers at the National Institutes of Health in July 1997.
The NPC1 gene encodes a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal buildup of lipids and cholesterol within cell membranes.
The NPC2 gene encodes a protein that binds and transports cholesterol. It has been shown to closely interact with NPC1.

"Type D" variant
Type D Niemann–Pick has only been found in the French Canadian population of Yarmouth County, Nova Scotia, and is now known to be allelic with Niemann–Pick type C.
Genealogical research indicates that Joseph Muise (c. 1679–1729) and Marie Amirault (1684 – c. 1735) are common ancestors to all people with Type D. This couple is the most likely origin for the type D variant.

Pathophysiology
Niemann–Pick type C is biochemically, genetically and clinically distinct from Niemann–Pick Types A or and B. In Types A and B, there is complete or partial deficiency of the lysosomal enzyme called acid sphingomyelinase. In Niemann–Pick type C, the protein product of the major mutated gene NPC1 is not an enzyme but appears to function as a transporter in the endosomal-lysosomal system, which moves large water-insoluble molecules through the cell. The protein coded by the NPC2 gene more closely resembles an enzyme structurally but seems to act in cooperation with the NPC1 protein in transporting molecules in the cell. The disruption of this transport system results in the accumulation of cholesterol and glycolipids in lysosomes.Cholesterol and glycolipids have varied roles in the cell. Cholesterol is a major component of cell plasma membranes, which define the cell as a whole and its organelles. It is also the basic building block of steroid hormones, including neurosteroids. In Niemann–Pick type C, large amounts of free or unesterified cholesterol accumulate in lysosomes, and leads to relative deficiency of this molecule in multiple membranes and for steroid synthesis. The accumulation of glycosphingolipids in the nervous system has been linked to structural changes, namely ectopic dendritogenesis and meganeurite formation, and has been targeted therapeutically.Several theories have attempted to link the accumulation of cholesterol and glycolipids in the lysosomes with the malfunction of the NPC-1 protein.

Neufeld et al. hypothesized that the accumulation of mannose 6-phosphate receptors (MPRs) in the late endosome signals failure of retrograde trafficking of cholesterol via the trans Golgi network.
Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the trans Golgi Network cannot bud and form.
Iouannou, et al. have described similarities between the NPC1 protein and members of the resistance-nodulation-division (RND) family of prokaryotic permeases, suggesting a pumping function for NPC1.
Recent 2008 evidence indicates that NPC-1 may play an important role in calcium regulation.

Diagnosis
Niemann–Pick type C is diagnosed by assaying cultured fibroblasts for cholesterol esterification and staining for unesterified cholesterol with filipin. The fibroblasts are grown from a small skin biopsy taken from a patient with suspected NPC. The diagnosis can be confirmed by identifying mutations in the NPC1 or NPC2 genes in 80–90% of cases. This specialized testing is available at Thomas Jefferson University Lysosomal Disease Testing Lab and the Mayo Clinic.

Treatment
There is no known cure for Niemann–Pick type C, nor is there any FDA-standard approved disease modifying treatment. Supportive care is essential and substantially improves the quality of life of people affected by NPC. The therapeutic team may include specialists in neurology, pulmonology, gastroenterology, psychiatrist, orthopedics, nutrition, physical therapy and occupational therapy. Standard medications used to treat symptoms can be used in NPC patients. As patients develop difficulty with swallowing, food may need to be softened or thickened, and eventually, parents will need to consider placement of a gastrostomy tube (g-tube, feeding tube).

Arimoclomol
In 2014, the European Medicines Agency (EMA) granted orphan drug designation to arimoclomol for the treatment of Niemann–Pick type C. This was followed in 2015 by the U.S. Food and Drug Administration (FDA). Dosing in a placebo-controlled phase II/III clinical trial to investigate treatment for Niemann–Pick type C (for patients with both type C1 and C2) using arimoclomol began in 2016. Arimoclomol, which is orally administered, induces the heat shock response in cells and is well tolerated in humans. In 2018, the Sponsor announced the trial did not meet either its primary or secondary endpoints. On July 17, 2021, the US Food and Drug Administration rejected the New Drug Application for Arimoclomol, and issued a complete response letter to the company Sponsor.

Hydroxypropyl-beta-cyclodextrin (HPbCD)
In April 2009, hydroxypropyl-beta-cyclodextrin (HPbCD) was approved under compassionate use by the U.S. Food and Drug Administration (FDA) to treat Addison and Cassidy Hempel, identical twin girls who had Niemann–Pick type C disease. Medi-ports, similar to ports used to administer chemotherapy drugs, were surgically placed into the twins chest walls and allow doctors to directly infuse HPbCD into their bloodstreams. Treatment with cyclodextrin has been shown to delay clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan in both the Niemann–Pick type C mice and feline models. This is the second time in the United States that cyclodextrin alone has been administered in an attempt treat a fatal pediatric disease. In 1987, HPbCD was used in a medical case involving a boy with severe hypervitaminosis A.On May 17, 2010, the FDA granted Hydroxypropyl-beta-cyclodextrin orphan drug status and designated HPbCD cyclodextrin as a potential treatment for Niemann–Pick type C disease. On July 14, 2010, Dr. Caroline Hastings of UCSF Benioff Childrens Hospital Oakland filed additional applications with the FDA requesting approval to deliver HPbCD directly into the central nervous systems of the twins in an attempt to help HPbCD cross the blood–brain barrier. The request was approved by the FDA on September 23, 2010, and bi-monthly intrathecal injections of HPbCD into the spine were administered starting in October 2010.On December 25, 2010, the FDA granted approval for HPbCD to be delivered via IV to an additional patient, Peyton Hadley, aged 13, under an IND through Rogue Regional Medical Center in Medford, Oregon. Soon after in March 2011, approval was sought for similar treatment of his sibling, Kayla, age 11, and infusions of HPbCD began shortly after. Both have since begun intrathecal treatments beginning in January 2012.In April 2011, the National Institutes of Health (NIH), in collaboration with the Therapeutics for Rare and Neglected Diseases Program (TRND), announced they were developing a clinical trial utilizing cyclodextrin for Niemann–Pick type C patients.On September 20, 2011, the European Medicines Agency (EMA) granted HPbCD orphan drug status and designated the compound as a potential treatment for Niemann–Pick type C disease.On December 31, 2011, the FDA granted approval for IV HPbCD infusions for a fifth child in the United States, Chase DiGiovanni, under a compassionate use protocol. The child was 29 months old at the time of his first intravenous infusion, which was started in January 2012.Due to unprecedented collaboration between individual physicians and parents of children affected by NPC, approximately 15 patients worldwide have received HPbCD cyclodextrin therapy under compassionate use treatment protocols. Treatment involves a combination of intravenous therapy (IV), intrathecal therapy (IT) and intracerebroventricular (ICV) cyclodextrin therapy.
On January 23, 2013, a formal clinical trial to evaluate HPβCD cyclodextrin therapy as a treatment for Niemann–Pick disease, type C was announced by scientists from the NIHs National Center for Advancing Translational Sciences (NCATS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).
In January 2021, the Sponsor (Mallinckrodt Pharmaceuticals) concluded that the benefit / risk balance for HPβCD cyclodextrin (adrabetadex) for the treatment of neurologic symptoms of NPC was negative, and that the risks associated with the treatment outweigh the potential benefit. Effective immediately, Mallinckrodt recommended that treatment with adrabetadex be discontinued as soon as possible, with the appropriate physician oversight.

N-Acetyl-Leucine
N-Acetyl-Leucine is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom).N-Acetyl-Leucine has been granted multiple orphan drug designations from the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of various genetic diseases, including Niemann-Pick Disease Type C. The US FDA has granted IntraBio a Rare Pediatric Disease Designation for N-Acetyl-Leucine for the treatment of NPC.Observational studies in NPC patients have demonstrated the symptomatic, as well as disease-modifying, neuroprotective effect of treatment. These studies further demonstrated that the treatment is well tolerated, with a good safety profile.In September 2020, IntraBio announced the successful results of a multinational clinical trial with N-acetyl-L-leucine (IB1001) for NPC, which demonstrated IB1001 demonstrated a statistically significant change in both primary and secondary endpoints, and clinically meaningful improvement in symptoms, functioning, and quality of life.
IntraBio is also conducting parallel clinical trials with N-Acetyl-L-Leucine for the treatment of GM2 Gangliosidosis (Tay-Sachs and Sandhoff) and Ataxia-Telangiectasia. Future opportunities to develop N-Acetyl-Leucine include Lewy body dementia, amyotrophic lateral sclerosis, restless leg syndrome, multiple sclerosis, and migraine.

Other treatments under investigation
One drug that has been tried is Miglustat. Miglustat is a glucosylceramide synthase inhibitor, which inhibits the synthesis of glycosphingolipids in cells. It has been shown to delay the onset of disease in the NPC mouse, and published data from a multi-center clinical trial of Miglustat in the United States and England and from case reports suggests that it may ameliorate the course of human NPC.Several other treatment strategies are under investigation in cell culture and animal models of NPC. These include, cholesterol mobilization, neurosteroid (a special type of hormone that affects brain and other nerve cells) replacement using allopregnanolone, rab overexpression to bypass the trafficking block (Pagano lab) and Curcumin as an anti-inflammatory and calcium modulatory agent. The pregnane X receptor has been identified as a potential target.Neural stem cells have also been investigated in an animal model, and clear evidence of life extension in the mouse model has been shown.Low cholesterol diets are often used, but there is no evidence of efficacy.Gene therapy is being used clinically to treat genetic diseases including haemophilia and spinal muscular atrophy. It has been used preclinically, in a mouse model of Niemann-Pick type C, using an adeno-associated virus derived viral vector has been shown to extend lifespan following injection into the lateral ventricles of the neonatal brain. In a separate proof-of-concept study a similar vector, but with a modified capsid capable of delivering genes to the central nervous system following intravenous injection, was given to Niemann-Pick type C mice at around four weeks of age; this resulted in extended lifespan and improved weight gain.

Prognosis
The lifespan of patients with NPC is usually related to the age of onset. Children with antenatal or infantile onset usually succumb in the first few months or years of life, whereas adolescent and adult onset forms of Niemann–Pick type C have a more insidious onset and slower progression, and affected individuals may survive to the seventh decade. Adult cases of NPC are being recognized with increasing frequency. It is suspected that many patients affected by NPC are undiagnosed, owing to lack of awareness of the disease and the absence of readily available screening or diagnostic tests. For the same reasons the diagnosis is often delayed by many years.

Research directions
Loss of myelin in the central nervous system is considered to be a main pathogenic factor. Research uses animal models carrying the underlying mutation for Niemann–Pick disease, e.g. a mutation in the NPC1 gene Niemann–Pick type C disease. In this model the expression of Myelin gene Regulatory Factor (MRF) has been shown to be significantly decreased </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 Hepatomegaly and explain in detail? [/INST] Hepatomegaly is the condition of having an enlarged liver.  It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass. Depending on the cause, it may sometimes present along with jaundice.

Signs and symptoms
The individual may experience many symptoms, including weight loss, poor appetite and lethargy (jaundice and bruising may also be present).

Causes
Among the causes of hepatomegaly are the following:

Infective
Mechanism
The mechanism of hepatomegaly consists of vascular swelling, inflammation (due to the various causes that are infectious in origin) and deposition of (1) non-hepatic cells or (2) increased cell contents (such due to iron in hemochromatosis or hemosiderosis and fat in fatty liver disease).

Diagnosis
Suspicion of hepatomegaly indicates a thorough medical history and physical examination, wherein the latter typically includes an increased liver span.On abdominal ultrasonography, the liver can be measured by the maximum dimension on a sagittal plane view through the midclavicular line, which is normally up to 18 cm in adults. It is also possible to measure the cranio-caudal dimension, which is normally up to 15 cm in adults. This can be measured together with the ventro-dorsal dimension (or depth), which is normally up to 13 cm. Also, the caudate lobe is enlarged in many diseases. In the axial plane, the caudate lobe should normally have a cross-section of less than 0.55 of the rest of the liver.Other ultrasound studies have suggested hepatomegaly as being defined as a longitudinal axis > 15.5 cm at the hepatic midline, or > 16.0 cm at the midclavicular line.

Workup
Blood tests should be done, importantly liver-function series, which will give a good impression of the patients broad metabolic picture.A complete blood test can help distinguish intrinsic liver disease from extrahepatic bile-duct obstruction. An ultrasound of the liver can reliably detect a dilated biliary-duct system,
it can also detect the characteristics of a cirrhotic liver.Computerized tomography (CT) can help to obtain accurate anatomical information, in individuals with hepatomegaly for the purpose of a complete diagnosis.

Treatment
Treatment of hepatomegaly will vary depending on the cause of the liver enlargement and hence accurate diagnosis is the primary concern. In the case of auto-immune liver disease, prednisone and azathioprine may be used for treatment.In the case of lymphoma the treatment options include single-agent (or multi-agent) chemotherapy and regional radiotherapy, also surgery may be an option in specific situations. Meningococcal group C conjugate vaccine are also used in some cases.In primary biliary cirrhosis ursodeoxycholic acid helps the bloodstream remove bile which may increase survival in some affected individuals.

See also
Hepatosplenomegaly
Liver function tests

References
Further reading
Hoffmann, Georg F.; Zschocke, Johannes; Nyhan, William L. (2009-11-21) </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 Military operation and explain in detail? [/INST] A military operation is the coordinated military actions of a state, or a non-state actor, in response to a developing situation. These actions are designed as a military plan to resolve the situation in the state or actors favor. Operations may be of a combat or non-combat nature and may be referred to by a code name for the purpose of national security. Military operations are often known for their more generally accepted common usage names than their actual operational objectives.

Types of military operations
Military operations can be classified by the scale and scope of force employment, and their impact on the wider conflict. The scope of military operations can be:

Theater: this describes an operation over a large, often continental, area of operation and represents a strategic national commitment to the conflict, such as Operation Barbarossa, with general goals that encompass areas of consideration outside the military, such as the economic and political impact of military goals on areas concerned.
Campaign: this describes either a subset of the theatre of operation, or a more limited geographic and operational strategic commitment, such as the Battle of Britain, and need not represent total national commitment to a conflict, or have broader goals outside the military impact.The United States just recently got out of some of the longest conflicts in the Military history. Operations Enduring Freedom and Operation Iraqi Freedom are some of the most recognizable campaigns as they have to do with the Iraq and a Afghanistan conflicts.<Owens, John, Charles, 2008)>
Battle: this describes a subset of a campaign that will have specific military goals and geographic objectives, as well as clearly defined use of forces, such as the Battle of Gallipoli, which operationally was a combined arms operation originally known as the "Dardanelles landings" as part of the Dardanelles Campaign, where about 480,000 Allied troops took part.
Engagement: this describes a tactical combat event or contest for a specific area or objective by actions of distinct units. For example, the Battle of Kursk, also known from its German designation as Operation Citadel, included many separate engagements, several of which were combined into the Battle of Prokhorovka. The Battle of Kursk, in addition to describing the initial German offensive operation, also included two Soviet counter-offensive operations: Operation Kutuzov and Operation Polkovodets Rumyantsev.
Strike: this describes a single attack, upon a specified target. This often forms part of a broader engagement. Strikes have an explicit goal, such as rendering facilities such as airports inoperable, assassinating enemy leaders, or limiting the delivery of supplies to enemy troops.

Definition
Parallel to and reflecting this framework for operations are organized elements within the armed forces which prepare for and conduct operations at various levels of war </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 Glycogen storage disease type II and explain in detail? [/INST] Glycogen storage disease type II, also called Pompe disease, is an autosomal recessive metabolic disorder which damages muscle and nerve cells throughout the body. It is caused by an accumulation of glycogen in the lysosome due to deficiency of the lysosomal acid alpha-glucosidase enzyme. It is the only glycogen storage disease with a defect in lysosomal metabolism, and the first glycogen storage disease to be identified, in 1932 by the Dutch pathologist J. C. Pompe.
The build-up of glycogen causes progressive muscle weakness (myopathy) throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and the nervous system.

Signs and symptoms
Newborn
The infantile form usually comes to medical attention within the first few months of life. The usual presenting features are cardiomegaly (92%), hypotonia (88%), cardiomyopathy (88%), respiratory distress (78%), muscle weakness (63%), feeding difficulties (57%) and failure to thrive (50%).The main clinical findings include floppy baby appearance, delayed motor milestones, and feeding difficulties. Moderate hepatomegaly may or may not be present. Facial features include macroglossia, wide open mouth, wide open eyes, nasal flaring (due to respiratory distress), and poor facial muscle tone. Cardiopulmonary involvement is manifested by increased respiratory rate, use of accessory muscles for respiration, recurrent chest infections, decreased air entry in the left lower zone (due to cardiomegaly), arrhythmias, and evidence of heart failure.Before developing a treatment, median age at death in untreated cases was 8.7 months, usually due to cardiorespiratory failure; However, this outcome is drastically changed since treatment has been available, improving with early access to treatment.

Late onset form
This form differs from the infantile principally in the relative lack of cardiac involvement. The onset is more insidious and has a slower progression. Cardiac involvement may occur but is milder than in the infantile form. Skeletal involvement is more prominent with a predilection for the lower limbs.Late onset features include impaired cough, recurrent chest infections, hypotonia, progressive muscle weakness, delayed motor milestones, difficulty swallowing or chewing and reduced vital capacity.
Prognosis depends on the age of onset of symptoms with a better prognosis being associated with later onset disease.

Cause
It has an autosomal recessive inheritance pattern. This means the defective gene is located on an autosome, and two faulty copies of the gene — one from each parent — are required to be born with the disorder. As with all cases of autosomal recessive inheritance, children have a 1 in 4 chance of inheriting the disorder when both parents carry the defective gene, and although both parents carry one copy of the defective gene, they are usually not affected by the disorder.The disease is caused by a mutation in a gene (acid alpha-glucosidase: also known as acid maltase) on long arm of chromosome 17 at  17q25.2-q25.3 (base pair 75,689,876 to 75,708,272). The number of mutations described is currently (in 2010) 289 with 67 being non-pathogenic mutations and 197 pathogenic mutations. The remainder are still being evaluated for their association with disease.The gene spans approximately 20 kb and contains 20 exons with the first exon being noncoding. The coding sequence of the putative catalytic site domain is interrupted in the middle by an intron of 101 bp. The promoter has features characteristic of a housekeeping gene. The GC content is high (80%) and distinct TATA and CCAAT motifs are lacking.
Most cases appear to be due to three mutations. A transversion (T → G) mutation is the most common among adults with this disorder. This mutation interrupts a site of RNA splicing.
The gene encodes a protein—acid alpha-glucosidase (EC 3.2.1.20)—which is a lysosomal hydrolase. The protein is an enzyme that normally degrades the alpha -1,4 and alpha -1,6 linkages in glycogen, maltose and isomaltose and is required for the degradation of 1–3% of cellular glycogen. The deficiency of this enzyme results in the accumulation of structurally normal glycogen in lysosomes and cytoplasm in affected individuals. Excessive glycogen storage within lysosomes may interrupt normal functioning of other organelles and lead to cellular injury.
A putative homologue—acid alpha-glucosidase-related gene 1—has been identified in the nematode Caenorhabditis elegans.

Diagnosis
In the early-onset form, an infant will present with poor feeding causing failure to thrive, or with difficulty breathing. The usual initial investigations include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase, alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.In the late-onset form, an adult will present with gradually progressive arm and leg weakness, with worsening respiratory function. Electromyography may be used initially to distinguish Pompe from other causes of limb weakness. The findings on biochemical tests are similar to those of the infantile form, with the caveat that the creatine kinase may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.On May 17, 2013, the Secretarys Discretionary Advisory Committee on Heritable Diseases in Newborns and Children (DACHDNC) approved a recommendation to the Secretary of Health and Human Services to add Pompe to the Recommended Uniform Screening Panel (RUSP). The HHS secretary must first approve the recommendation before the disease is formally added to the panel.

Classification
There are exceptions, but levels of alpha-glucosidase determines the type of GSD II an individual may have. More alpha glucosidase present in the individuals muscles means symptoms occur later in life and progress more slowly. GSD II is broadly divided into two onset forms based on the age symptoms occur.Infantile-onset form is usually diagnosed at 4–8 months; muscles appear normal but are limp and weak preventing the child from lifting their head or rolling over. As the disease progresses, heart muscles thicken and progressively fail. Without treatment, death usually occurs due to heart failure and respiratory weakness.Late or later onset form occurs later than one to two years and progresses more slowly than Infantile-onset form. One of the first symptoms is a progressive decrease in muscle strength starting with the legs and moving to smaller muscles in the trunk and arms, such as the diaphragm and other muscles required for breathing. Respiratory failure is the most common cause of death. Enlargement of the heart muscles and rhythm disturbances are not significant features but do occur in some cases.

Treatment
Cardiac and respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counseling can provide families with information regarding risk in future pregnancies.On April 28, 2006, the US Food and Drug Administration approved a Biologic License Application (BLA) for alglucosidase alfa, rhGAA (Myozyme), the first treatment for patients with Pompe disease, developed by a team of Duke University researchers. This was based on enzyme replacement therapy using biologically active recombinant human alglucosidase alfa produced in Chinese Hamster Ovary cells. Myozyme falls under the FDA Orphan Drug designation and was approved under a priority review.The FDA has approved Myozyme for administration by intravenous infusion of the solution. The safety and efficacy of Myozyme were assessed in two separate clinical trials in 39 infantile-onset patients with Pompe disease ranging in age from 1 month to 3.5 years at the time of the first infusion. Myozyme treatment clearly prolongs ventilator-free survival and overall survival. Early diagnosis and early treatment leads to much better outcomes. The treatment is not without side effects which include fever, flushing, skin rash, increased heart rate and even shock; these conditions, however, are usually manageable.Myozyme costs an average of US$300,000 a year and must be taken for the patients entire life, so some American insurers have refused to pay for it. On August 14, 2006, Health Canada approved Myozyme for the treatment of Pompe disease. On June 14, 2007, the Canadian Common Drug Review issued their recommendations regarding public funding for Myozyme therapy. Their recommendation was to provide funding to treat a tiny subset of Pompe patients (Infants less one year of age with cardiomyopathy).On May 26, 2010, FDA approved Lumizyme, a similar version of Myozyme, for the treatment of late-onset Pompe disease. Lumizyme and Myozyme have the same generic ingredient (alglucosidase alfa) and manufacturer (Genzyme Corporation). The difference between these two products is in the manufacturing process. Myozyme is made using a 160-L bioreactor, while Lumizyme uses a 4000-L bioreactor. Because of the difference in the manufacturing process, the FDA claims that the two products are biologically different. Moreover, Lumizyme is FDA approved as replacement therapy for late-onset (noninfantile) Pompe disease without evidence of cardiac hypertrophy in people 8 years and older. Myozyme is FDA approved for replacement therapy for infantile-onset Pompe disease.In July 2021, the European Medicines Agency (EMA) recommended the authorization of avalglucosidase alfa. Avalglucosidase alfa (Nexviazyme) was approved for medical use in the United States in August 2021.

Prognosis
The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms, along with lifestyle factors. Without treatment the infantile form (which can typically be predicted by mutation analysis) of the disease is particularly lethal - in these cases time to get on treatment is critical, with evidence that days (not weeks or months) matter.Myozyme (alglucosidase alfa) is a recombinant form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of age, which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this devastating disorder. Taiwan and several states in the United States have started the newborn screening and results of such regimen in early diagnosis and early initiation of the therapy have dramatically improved the outcome of the disease; many of these babies have reached the normal motor developmental milestones.Another factor affecting the treatment response is generation of antibodies against the infused enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid alpha-glucosidase. Immune tolerance therapy to eliminate these antibodies has improved the treatment outcome.A Late Onset Treatment Study (LOTS) was published in 2010. The study was undertaken to evaluate the safety and efficacy of aglucosidase alfa  in juvenile and adult patients with Pompe disease. LOTS was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo every other week for 18 months. The average age of study participants was 44 years. The primary efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on pulmonary function as measured by percent predicted forced vital capacity.
The results showed that, at 78 weeks, patients treated with aglucosidase alfa  increased their distance walked in six minutes by an average of approximately 25 meters as compared with the placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters.
Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the placebo group (P=0.006).
There is an emerging recognition of the role that diet and exercise can play in functionally limiting symptom progression. This is an area for further study, as there is not a clear consensus guideline, but rather a body of case study work that suggests that appropriate physical activity can be an effective tool in managing disease progression. In one such study, side-alternating vibration training was used 3 times per week for 15 weeks. The results showed that, at 15 weeks, the patient had a 116-meter (70%) improvement to their 6MWT, which is significant compared with the results from the aforementioned LOTS study.

Epidemiology
The disease affects approximately 1 in 13,000.

History
The disease is named after Joannes Cassianus Pompe, who characterized it in 1932. Pompe described accumulation of glycogen in muscle tissue in some cases of a previously unknown disorder. This accumulation was difficult to explain as the enzymes involved in the usual metabolism of glucose and glycogen were all present and functioning.
The basis for the disease remained a puzzle until Christian de Duves discovery of lysosomes in 1955 for which he won the Nobel Prize in 1974. His co-worker Henri G. Hers realised  in 1965 that the deficiency of a lysosomal enzyme (alpha glucosidase) for the breakdown of glycogen could explain the symptoms of Pompe disease. This discovery led to establishing the concept of lysosomal storage diseases, of which 49 have been described (to date).
Despite recognizing the basis for the disease, treatment proved difficult. Administration of the enzyme lead to its uptake by the liver and not the muscle cells where it is needed. In the early 1990s Dutch scientists Arnold Reuser and Ans van der Ploeg were able to show that using alpha-glucosidase containing phosphorylated mannose residues purified from bovine testes increased the enzymes activity in normal mouse muscles.Later in 1998, Dr. Yuan-Tsong Chen and colleagues at Duke University, using the enzyme produced in Chinese Hamster Ovary cells  demonstrated for the first time that the enzyme can clear the glycogen and improved the muscle function in Pompe disease quail. The results of the work at Duke were impressive with one treated bird recovering to the point of being able to fly again.This was followed by production of clinical grade alpha-glucosidase in Chinese hamster ovary (CHO) cells and in the milk of transgenic rabbits. This work eventually culminated in the start of clinical trials with the first clinical trial including 4 babies receiving enzyme from rabbit milk at Erasmus MC Sophia Childrens Hospital and 3 babies receiving enzyme grown in CHO cells at Duke University in 1999.
The currently approved Myozyme is manufactured by Genzyme Corp. in Cambridge, Massachusetts. Its development was a complex process. Genzyme first partnered with Pharming Group NV who had managed to produce acid alpha-glucosidase from the milk of transgenic rabbits. They also partnered with a second group based at Duke University using Chinese hamster ovary cells </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 Husband and explain in detail? [/INST] A husband is a male in a marital relationship, who may also be referred to as a spouse. The rights and obligations of a husband regarding his spouse and others, and his status in the community and in law, vary between societies and cultures, and have varied over time.
In monogamous cultures, there are only two parties to a marriage, which is enforced by laws against bigamy and polygamy. Traditionally, the husband was regarded as the head of the household and was expected to be the sole provider or breadwinner, a role that continues in some cultures (sometimes described as paternalistic). Today, a husband is not necessarily considered the breadwinner of the family, especially if his spouse has a more financially rewarding occupation or career. In such cases, it is not uncommon for a husband to be considered a stay-at-home father if the married couple have children.
The term continues to be applied to such a man who has separated from his spouse and ceases to be applied to him only when his marriage has come to an end following a legally recognized divorce or the death of his spouse. On the death of his spouse, a husband is referred to as a widower; after a divorce a man may be referred to as the "ex-husband" of his former spouse.

Origin and etymology
The term husband refers to Middle English huseband, from Old English hūsbōnda, from Old Norse hūsbōndi (hūs, house + bōndi, būandi, present participle of būa, to dwell, so, etymologically, a householder).
See also torp.

Related terms
At the conclusion of a valid wedding, the marrying parties acquire the status of married persons and, while the marriage persists, a man is called a husband. In heterosexual marriages the woman is called a wife; in same-sex marriages between males, each male is called a husband.
Although husband is a close term to groom, the latter is a male participant in a wedding ceremony, while a husband is a married man after the wedding and for the duration of the marriage. The term husband refers to the institutionalized role of the married male, while the term father refers to the male in context of his offspring, a state which may or may not indicate that a marriage ceremony has taken place.
In some cases of heterosexual marriage, before the marriage, the forthcoming husband or his family may have received a dowry, or have had to pay a bride price, or both were exchanged. The dowry not only supported the establishment of a household, but also served as a condition that if the husband committed grave offenses upon his wife, he had to return the dowry to the wife or her family. For the time of the marriage, they were made inalienable by the husband.  He might leave his wife (or wives), then widow (or widows), a dower (often a third or a half of his estate) to support her as dowager.As an external symbol of the fact that they are married, each spouse commonly wears a wedding ring on the ring finger; whether this is on the left or right hand depends on the countrys tradition.
Husband further refers to the institutionalized form in relation to the spouse and offspring, unlike father, a term that puts a man into the context of his children. Also compare the similar husbandry, which in the 14th century referred to the care of the household, but today means the "control or judicious use of resources", conservation, and in agriculture, the cultivation of plants and animals, and the science about its profession.

Western culture
Historical status
In premodern heterosexual unions (ancient Roman, medieval, and early modern history), a husband was obliged to protect and support not only his wife and children, but servants and animals of his domain. The father (as the "patron") was awarded with much authority, differing from that of his wife (in these cultures, no polygamy existed).In the Middle Ages and Early Modern European history, it was unusual to marry out of love, but then doing so became an influential ideal. During this period, a husband in a heterosexual marriage had more opportunities in society than his wife, who was not recognized as legally independent.

Contemporary status
In contemporary secularized Western culture, the rights of the spouses have been made equal. The civil marriage generally forces the wealthier spouse, "breadwinner", to provide alimony to the former spouse, even after separation and also after a divorce (see also Law and divorce around the world).
The legal status of marriage allows each spouse to speak on the others behalf when one is incapacitated (e.g., in a coma); a husband is also responsible for his spouses child(ren) in states where he is automatically assumed to be the biological father.

Religion
Christianity
In Christianity, according to the Bible, a husband in a heterosexual marriage has a number of duties:

To present his bride to God throughout their lives as perfectly holy and virtuous as can be.
To protect his wife with his own life, physically, emotionally and "spiritually".
To "lay down" his life, counting her more important than himself.
To lead his wife and his family into the best things for them.
To be the best that he can be in Gods power.
To not withhold his body from her.

Islam
In Islamic marital jurisprudence, husbands are considered protectors of the household and their wives. As protector, the husband has various rights and obligations that he is expected to fulfill and thus is offered opportunities different from that of his wife or wives, not only in legal and economical affairs of the family but within the family as well. As in most cases in Islam law and culture, everything is being related to the Quran.
Many Muslims may agree on a perfectly equal relationship. Islam is the only major religion that puts a cap on polygamy, limiting the number of a mans wives to four—provided the husband can do justice to all of them. Although some religions, such as Catholicism for instance, puts a cap on polygamy all together, or even serial monogamy, allowing one spouse until death does them apart, not even accepting divorce. According to the teachings of Islam a Muslim man should have a valid reason and have to get permission from his existing wife (without any force) if he requires to marry again. Islam vehemently abhors any intimate relationship outside the bond of marriage.
There is no external sign to show his status as a husband, unless he adopted the tradition of wearing a wedding ring.

Hinduism
A Hindu husband traditionally takes his wife to his home. He is expected to provide for her and to prove his abilities to do so. The marriage in Hinduism is a relationship for Seven births (सात जन्मों का सम्बन्ध) </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 Abrasion 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 Schwannomatosis and explain in detail? [/INST] Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF).  Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. The exact frequency of schwannomatosis cases is unknown, although some populations have noted frequencies as few as 1 case per 1.7 million people.Schwannomas are mostly benign tumors that commonly occur in individuals with NF2 and schwannomatosis (sometimes called neurofibromatosis type III). Schwann cells are glial cells that myelinate the axons of nerve cells. Myelin is a lipid covering that speeds the conduction of action potentials. When Schwann cells proliferate out of control in an encapsulation it is called a schwannoma. Although schwannomas are benign they become detrimental when the growing tumor compresses the nerve. Schwannomas on sensory nerve axons cause chronic severe pain. Treatment options for schwannomas are to surgically remove them, have radiation, cyberknife or Intracapsular Enucleation. Previous designations for schwannomas include neurinoma and neurilemmoma.

Cause
The candidate schwannomatosis gene, named SMARCB1, is a tumor suppressor gene that regulates cell cycle, growth and differentiation. An inactivating  germline mutation in exon 1 of the tumor suppressor gene SMARCB1 has been reported in patients with schwannomatosis. It is located on chromosome 22 a short distance from the NF2 gene. However, molecular analysis of the NF2 gene in schwannomatosis patients has shown the presence of inactivating mutations in the tumor cells, but no evidence of the germline mutations that are found in NF2 patients.A mechanism involving both the SMARCB1 and NF2 genes may be responsible for the development of the disease because tumor analysis of schwannomas indicates the presence of inactivating mutations in both the SMARCB1 and NF2 genes. However, there is speculation about the involvement of an unidentified schwannomatosis gene(s) in most cases. This is because one study found no SMARCB1 germinal mutations in patients with familial schwannomatosis. Some schwannomatosis patients do not have SMARCB1 or NF2 mutations. Furthermore, many patients exhibit somatic mosaicism for mutations in the NF2 or SMARCB1 gene, which means that some somatic cells have the mutation and some do not in the same patient. Ultimately, the tumorigenesis of schwannomas is not solely dependent on one gene locus alone. In regards to the SMARCB1 and NF2 genes, it is important to understand constitutional mutations and somatic mutations. Constitutional mutations are the first inactivation events that are often small mutations, such as point mutations and deletion/insertion of single base pairs. Somatic mutations are the second mutations that occur and may also be another small mutation or the loss of the remaining allele of the gene. Schwannomas from one patient share the same constitutional mutations but have distinct somatic mutations. In addition, the constitutional mutation may be present in non-tumor.SMARCB1 is also known as INI1, hSNF5, or BAF47. SMARCB1 is mutated in additional tumors including malignant brain & kidney tumors in children. It seems that heterozygotes for mutations in the SMARCB1 gene have an increased risk to develop a malignant kidney tumor in early childhood but if they survive to adulthood, they may be predisposed to the development of schwannomas. One schwannomatosis patient had a mutation in exon 2 of the SMARCB1 gene. Another patient exhibited a novel germline deletion of the SMARCB1, because most SMARCB1 mutations are point or frameshift. In this patient genetic analysis from different schwannomas indicated  inactivation of both the SMARCB1 and NF2 genes. Schwannomatosis is known to be a genetic disorder. However, familial occurrence is inexplicably rare.

Diagnosis
Prenatal
Schwannomatosis can be tested prenatally on the NHS.

Postnatal
Ferner et al.  give the following diagnostic criteria for Schwannomatosis:

Definite
Age >30 years and ≥2 nonintradermal schwannomas, at least one with histologic confirmation and no evidence of vestibular tumor on MRI scan and no known NF mutation, or
One nonvestibular schwannoma plus a first-degree relative with schwannomatosis
Possible
Age <30 and ≥2 nonintradermal schwannomas, at least one with histologic confirmation and no evidence of vestibular tumor on MRI scan and no known NF mutation, or
Age >45 and ≥2 nonintradermal schwannomas, at least one with histologic confirmation and no symptoms of 8th nerve dysfunction and no NF2, or
Nonvestibular schwannoma and first-degree relative with schwannomatosis
Segmental.  Diagnosed as definite or possible but limited to one limb or ≤5 contiguous segments of spine.Another set of criteria are:

Two or more nonintradermal (cutaneous) schwannomas
No evidence of vestibular tumor
No known NF-2 mutationor

One pathologically confirmed nonvestibular schwannoma plus a first degree relative who meets the above criteria.

Treatment
Schwannomatosis patients represent 2.4% to 5% of patients undergoing surgical resection of their schwannomas.
In isolated regions of the body schwannomas are small and difficult to locate. Intraoperative sonography offers invaluable assistance in such cases by localizing small schwannomas and decreasing operative time and extent of the surgical incision.
If feasible, the schwannomas can be surgically removed. Any tumor-associated pain usually subsides after tumor removal.  Damaged nerves and scar tissue can be a result of surgery and pain can be an ongoing problem.
Sometimes, a tumor will reappear at the same site after surgery.
If surgery is unfeasible, then pain management will have to be used </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 Hemoptysis and explain in detail? [/INST] Hemoptysis is the coughing up of blood or blood-stained mucus from the bronchi, larynx, trachea, or lungs. In other words, it is the airway bleeding. This can occur with lung cancer, infections such as tuberculosis, bronchitis, or pneumonia, and certain cardiovascular conditions. Hemoptysis is considered massive at 300 mL (11 imp fl oz; 10 US fl oz).  In such cases, there are always severe injuries. The primary danger comes from choking, rather than blood loss.

Diagnosis
Past history, history of present illness, family historyhistory of tuberculosis, bronchiectasis, chronic bronchitis, mitral stenosis, etc.
history of cigarette smoking, occupational diseases by exposure to silica dust, etc.
Blood
duration, frequency, amount
Amounts of blood: large amounts of blood, or is there blood-streaked sputum
Probable source of bleeding: Is the blood coughed up, or vomited?
Bloody sputum
color, characters: blood-streaked, fresh blood, frothy pink, bloody gelatinous.
Accompanying symptoms
fever, chest pain, coughing, purulent sputum, mucocutaneous bleeding, jaundice.
Imaging examination
chest X-ray, CT scan and 3D reconstruction images or CT virtual bronchoscopy, bronchial angiography.
Laboratory tests
blood test: WBC
Sputum: cells and bacterial examinations, sputum culture
Bronchial fiber endoscopy

Differential diagnosis
The most common causes for hemoptysis in adults are chest infections such as bronchitis or pneumonia.  In children, hemoptysis is commonly caused by the presence of a foreign body in the airway. Other common causes include lung cancers and tuberculosis. Less common causes include aspergilloma, bronchiectasis, coccidioidomycosis, pulmonary embolism, pneumonic plague, and cystic fibrosis. Rarer causes include hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome), Goodpastures syndrome, and granulomatosis with polyangiitis. A rare cause of hemoptysis in women is endometriosis, which leads to intermittent hemoptysis coinciding with menstrual periods in 7% of women with thoracic endometriosis syndrome. Hemoptysis may be exacerbated or even caused by overtreatment with anticoagulant drugs such as warfarin.Blood-laced mucus from the sinus or nose area can sometimes be misidentified as symptomatic of hemoptysis (such secretions can be a sign of nasal or sinus cancer, but also a sinus infection). Extensive non-respiratory injury can also cause one to cough up blood.  Cardiac causes like congestive heart failure and mitral stenosis should be ruled out.The origin of blood can be identified by observing its color. Bright-red, foamy blood comes from the respiratory tract, whereas dark-red, coffee-colored blood comes from the gastrointestinal tract. Sometimes hemoptysis may be rust-colored.
Lung cancer, including both non-small cell lung carcinoma and small cell lung carcinoma.
Sarcoidosis
Aspergilloma
Tuberculosis
Histoplasmosis
Pneumonia
Pulmonary edema
Endometriosis and thoracic endometriosis syndrome
Foreign body aspiration and aspiration pneumonia
Goodpastures syndrome
Microscopic polyangiitis
Granulomatosis with polyangiitis
Eosinophilic granulomatosis with polyangiitis
Bronchitis
Bronchiectasis
Pulmonary embolism
Anticoagulant use
Trauma
Lung abscess
Mitral stenosis
Tropical pulmonary eosinophilia
Bleeding disorders
Hughes-Stovin syndrome and other variants of Behçets disease
Pulmonary arteriovenous malformations

Massive hemoptysis and mortality
Although there are reports that the fatality rate is as high as 80%, the in-hospital mortality rate for hospitalized hemoptysis patients is 2669/28539=9.4%, calculated from the data in the article by Kinoshita et al. This is probably the most reasonable figure considering the overwhelming number of cases.The general definition of massive hemoptysis is more than 200 ml within 24 hours, but there is a wide range in the literature (100-600 ml). Considering that the total volume of the tracheal and bronchial lumen is about 150 cc, it may be reasonable to define massive hemoptysis as 200 ml, which is a little more than 150 ml, in terms of setting the threshold for fatal hemoptysis </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 Todds paresis and explain in detail? [/INST] Todds paresis (or postictal paresis/paralysis, "after seizure") is focal weakness in a part or all of the body after a seizure. This weakness typically affects appendages and is localized to either the left or right side of the body. It usually subsides completely within 48 hours. Todds paresis may also affect speech, eye position (gaze), or vision.
The condition is named after Robert Bentley Todd (1809–1860), an Irish-born London physiologist who first described the phenomenon in 1849. It may occur in up to 13% of seizure cases.  It is most common after a focal motor seizure affecting one limb or one side of the body. The generally postulated cause is the exhaustion of the primary motor cortex, although no conclusive evidence is available to support this.

Presentation
The classic presentation of Todds paresis is a transient weakness of a hand, arm, or leg after focal seizure activity within that limb.  The weakness may range in severity from mild to complete paralysis.When seizures affect areas other than the motor cortex, other transient neurological deficits can take place.  These include sensory changes if the sensory cortex is involved by the seizure, visual field defects if the occipital lobe is involved, and aphasia if speech, comprehension or conducting fibers are involved.Postictal paresis (PP), although familiar to neurologists, has not been well-studied. One retrospective observational study evaluated 328 selected patients from ages 16 to 57 years who had prolonged video-electroencephalogram (EEG) monitoring for medically intractable epilepsy and focal seizure onset; those with nonepileptic seizures, status epilepticus, and Lennox-Gastaut syndrome were excluded </s>