title: History of tennis

text: Mary Ewing Outerbridge played the game in Bermuda at Clermont, a house with a spacious lawn in Paget parish. Innumerable histories claim that in 1874, Mary returned from Bermuda onboard the ship S.S. "Canima" and introduced lawn tennis to the United States, setting up supposedly the first tennis court in the United States on the grounds of the Staten Island Cricket and Baseball Club, which was near where the Staten Island Ferry Terminal is today. The club was founded on or about March 22, 1872. She is also mistakenly said to have played the first tennis game in the U.S. against her sister Laura in Staten Island, New York on an hourglass-shaped court. However, all this would have been impossible, as the tennis equipment she is said to have brought back from Bermuda was not available in Bermuda until 1875, and her next trip to Bermuda, when it was available there, was in 1877. In fact, lawn tennis was first introduced in the United States on a grass court on Col. William Appleton's Estate in Nahant, Massachusetts by Dr. James Dwight ("the Father of American Lawn Tennis"), Henry Slocum, Richard Dudley Sears and Sears' half-brother Fred Sears, in 1874.


title: Qi'ra

text: Qi'ra is a fictional character in the "Star Wars" franchise, first appearing in the 2018 film "" and portrayed by English actress Emilia Clarke. The character was introduced in the 2018 prequel novel "Most Wanted" by Rae Carson. A practitioner of Teräs Käsi, she is Han Solo's childhood best friend and first love from the planet Corellia. The pair live on the streets before she is captured and he flees the planet. In order to leave the planet herself, Qi'ra becomes a lieutenant in the Crimson Dawn crime syndicate under Maul, assuming control of the organization after his death, becoming its leader during the Galactic Civil War.


title: Qi'ra

text: In the 2018 "Star Wars Anthology" film "Solo: A Star Wars Story", Qi'ra is introduced as an orphaned street thief living on the shipbuilding world of Corellia. She and her lover, Han, attempt to use the valuable fuel source coaxium to bribe their way through a checkpoint to escape the planet and the criminal gang pursuing them. Qi'ra is apprehended, but urges Han to go on without her. He does, and vows to return for her.


title: Qi'ra

text: Three years later, seeking funding to buy a ship to return to Corellia, Han participates in a coaxium heist that goes awry. He accompanies his new associate Tobias Beckett to explain their failure to Dryden Vos, a high-ranking crime boss in the Crimson Dawn syndicate. Han and Qi'ra are reunited, as she is now Vos's top lieutenant. Han suggests a risky plan to steal unrefined coaxium from the mines on the planet Kessel; Vos approves but insists that Qi'ra accompany the team. She leads them to Lando Calrissian, an accomplished smuggler and pilot who agrees to join the mission with his ship, the "Millennium Falcon", in exchange for a share of the profits. The theft is a success, but Han and Qi'ra become sympathetic to the cause of the rebels who are trying to prevent the syndicates and the Galactic Empire from gaining greater domination over the galaxy. They attempt to trick Vos, but the double-crossing Beckett has already alerted the crime lord to their plan. Caught aiding Han, Qi'ra tells Dryden she will prove her loyalty to him by sacrificing something she loves, and advances on Han. She betrays and kills Vos instead, and sends Han after Beckett. Once alone, Qi'ra contacts Vos's superior, Maul, to inform him of the mission's failure and claim Vos's position within the syndicate; she blames the death of Vos on Beckett. Qi'ra then abandons Han and leaves for Dathomir to meet with Maul as he commands her.


title: Qi'ra

text: In the 2018 episode "Triplecross" of "Star Wars Forces of Destiny", pirate Hondo Ohnaka and bounty hunter droid IG-88 pursue Qi'ra, who pits them against each other to collect the bounty on them.


title: Qi'ra

text: Qi'ra is introduced in the novel "Most Wanted" by Rae Carson. The novel focuses on Han and Qi'ra shortly before the events of "". It was published by Disney-Lucasfilm Press on May 25, 2018, in concert with the film.


title: Qi'ra

text: The crossover comic "War of the Bounty Hunters", published on June 2, 2021, and set between the movies "The Empire Strikes Back" and "Return of the Jedi", shows Qi'ra still alive, in control of the Crimson Dawn and plotting a return to power. The organization was thought to be destroyed after Maul's death on Tatooine by Obi-Wan Kenobi. Now, learning that Han Solo had become important to the Galactic Empire, the Rebel Alliance and the Hutt Clan and that he had also been frozen in carbonite, Qi'ra had her agents capture him from bounty hunter Boba Fett.


title: Qi'ra

text: Qi'ra appears as a playable character in "", the mobile RPG game developed by Capital Games and Published by Electronic Arts.


title: Qi'ra

text: Several toys of Qi'ra have been made available. Among them, a 12-inch Qi'ra (Corellia) figure which features a movie-inspired design, a six-inch action figure by Hasbro as part of the company's "" toy line, a Funko Pop figurine, Lego Star Wars figurines, the Star Wars Nerf Qi'Ra blaster by Hasbro, a star wars Mighty Muggs figure, as well as T-shirts featuring the character.


title: Qi'ra

text: Qi'ra is introduced as an earnest thief in love with Han and dreaming of escape from the slums of the planet Corellia. They are separated by circumstance, and when they reunite years later, they have both been through life-changing experiences. Clarke called Qi'ra a "badass" who "kind of follows a femme fatale arc", and said, "She has a couple of guises, but essentially she is just fighting to stay alive. If you've got a really glamorous lady in a really sordid environment, you kind of know the glamour is hiding a few rough roads." "Solo" director Ron Howard described Qi'ra as secretive, slippery, and morally questionable—"a much different sort of a character" from Daenerys Targaryen, Clarke's character from the HBO series "Game of Thrones". Clarke noted that her "Solo" character "isn't like the women that you've seen in "Star Wars" yet", and said that "Qi'ra is different from the other women I've played, but the similarity is her strength, and her survival instincts. She just has a bit more grit." She said, "We're going to hit you with a character that could very easily well be a dude, because you question her motives. That's really ... exciting in the "Star Wars" universe, because that has never happened." Clarke said, "Qi'ra's journey is definitely one of survival and strength. The way that I felt about her was yeah this girl has got a core of steel." Calling Qi'ra a "galactic femme fatale", "Entertainment Weekly" Anthony Breznican wrote:


title: Qi'ra

text: Clarke said, "Every single part of her as a character reflects on the Han Solo that we know and love." She explained:


title: Qi'ra

text: According to "Solo" co-writer Jonathan Kasdan, Qi'ra is Han's "formative experience with romance, and that experience very directly influences the relationships he has later on with people like Leia." Describing Qi'ra's relationship with Han, Clarke explained that "They grew up as comrades, essentially. They grew up as pals, as partners in crime. There is obviously the romantic side of things. But they grew up together. So they were kids together." She said that later, "within that relationship, the thing that you see with Qi'ra is that she is an enigma." Clarke also noted, "There is this underlying joy in an origin story because you know where they end up. And Qi'ra is nowhere to be seen, so...something has happened!...Something must have happened to affect him as a person, but for us fans not to know about her."


title: Qi'ra

text: In October 2016, Tessa Thompson, Naomi Scott, Zoë Kravitz, Emilia Clarke, Kiersey Clemons, Jessica Henwick, and Adria Arjona were being considered for the female lead in "Solo: A Star Wars Story" (named "Kura" in early drafts). Clarke, known for her role as Daenerys Targaryen in the HBO fantasy television series "Game of Thrones", was cast the following month. Clarke told "Vanity Fair" that she struggled with the character under "Solo" original co-directors, Phil Lord and Chris Miller, and sought advice from the film's father-and-son screenwriters, Lawrence and Jonathan Kasdan. She said of the role, "She'll be the sort of character that will keep you on your toes, and I think that was one of the biggest things that drew me to her as a character, and got me really excited."


title: Qi'ra

text: Qi'ra was featured in the May 25, 2018 episode "Triplecross" of the 2D animated web series "Star Wars Forces of Destiny", voiced by Olivia Hack.


title: Qi'ra

text: Qi'ra has been positively received by both critics and fans, with many referring to her as a standout, and the most fascinating aspect of "Solo: A Star Wars Story". Pete Morrison of the "Rebels Report" called her the best character in the film. Stating that Emilia Clarke jumps from genre franchise in "Game of Thrones" to another in a galaxy far, far away and manages to have the most complex and interesting story arc of any character in the film. "Futurism"'s Marguerita Tan wrote that "Qi'ra is a complex character who is not only intelligent and resourceful, but also someone who can look after herself". Tan concluded that it wasn't hard to understand why many fans were so keen to see the character in more on-screen adventures. Dana Brandt of "The Daily Cardinal" was critical of the character's arc stating that Qi'ra, and by extension her relationship with Han was underdeveloped. "Bustle's" Casey Cipriani suggests that Qi'ra may or may not have been a Sith and states that a female villain who can use the Force has never been portrayed in a "Star Wars" film.


title: Qi'ra

text: Many have expressed interest in a follow-up to Qi'ra's story. Derrick Clements of the "Daily Harold" wrote, "she is introduced as a character with depth and mystery to spare. Most of all, where the film leaves her is tremendously full of possibility". Writing for Comic Book Resources, Rita Dorsch proclaimed Qi'ra's turn in Solo to be the most interesting part of the film and went on to state that any follow-up needs to focus on her. "Bustle's" Angelica Floria stated, "the headstrong combatant played by Clarke seems to only have just begun her role in the Star Wars universe". She notes that Clarke signed on for multiple films and adds that the ending of Solo makes it clear that future Star Wars projects could continue the story of Qi'ra and Darth Maul's future with the Crimson Dawn.


title: Hypopituitarism

text: Hypopituitarism is the decreased ("hypo") secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain. If there is decreased secretion of one specific pituitary hormone, the condition is known as selective hypopituitarism. If there is decreased secretion of most or all pituitary hormones, the term panhypopituitarism ("pan" meaning "all") is used.


title: Hypopituitarism

text: The signs and symptoms of hypopituitarism vary, depending on which hormones are undersecreted and on the underlying cause of the abnormality. The diagnosis of hypopituitarism is made by blood tests, but often specific scans and other investigations are needed to find the underlying cause, such as tumors of the pituitary, and the ideal treatment. Most hormones controlled by the secretions of the pituitary can be replaced by tablets or injections. Hypopituitarism is a rare disease, but may be significantly underdiagnosed in people with previous traumatic brain injury. The first description of the condition was made in 1914 by the German physician Dr Morris Simmonds.


title: Hypopituitarism

text: The hormones of the pituitary have different actions in the body, and the symptoms of hypopituitarism therefore depend on which hormone is deficient. The symptoms may be subtle and are often initially attributed to other causes. In most of the cases, three or more hormones are deficient. The most common problem is insufficiency of follicle-stimulating hormone (FSH) and/or luteinizing hormone (LH) leading to sex hormone abnormalities. Growth hormone deficiency is more common in people with an underlying tumor than those with other causes.


title: Hypopituitarism

text: Sometimes, there are additional symptoms that arise from the underlying cause; for instance, if the hypopituitarism is due to a growth hormone-producing tumor, there may be symptoms of acromegaly (enlargement of the hands and feet, coarse facial features), and if the tumor extends to the optic nerve or optic chiasm, there may be visual field defects. Headaches may also accompany pituitary tumors, as well as pituitary apoplexy (infarction or haemorrhage of a pituitary tumor) and lymphocytic hypophysitis (autoimmune inflammation of the pituitary). Apoplexy, in addition to sudden headaches and rapidly worsening visual loss, may also be associated with double vision that results from compression of the nerves in the adjacent cavernous sinus that control the eye muscles.


title: Hypopituitarism

text: Pituitary failure results in many changes in the skin, hair and nails as a result of the absence of pituitary hormone action on these sites.


title: Hypopituitarism

text: Several hormone deficiencies associated with hypopituitarism may lead to secondary diseases. For instance, growth hormone deficiency is associated with obesity, raised cholesterol and the metabolic syndrome, and estradiol deficiency may lead to osteoporosis. While effective treatment of the underlying hormone deficiencies may improve these risks, it is often necessary to treat them directly.


title: Hypopituitarism

text: Deficiency of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), together referred to as the gonadotropins, leads to different symptoms in men and women. Women experience oligo- or amenorrhea (infrequent/light or absent menstrual periods respectively) and infertility. Men lose facial, scrotal and trunk hair, as well as have decreased muscle mass and anemia. Both sexes may experience a decrease in libido and loss of sexual function, and have an increased risk of osteoporosis (bone fragility). Lack of LH/FSH in children is associated with delayed puberty.


title: Hypopituitarism

text: Growth hormone (GH) deficiency leads to a decrease in muscle mass, central obesity (increase in body fat around the waist) and impaired attention and memory. Children experience growth retardation and short stature.


title: Hypopituitarism

text: Adrenocorticotropic hormone (ACTH) deficiency leads to adrenal insufficiency, a lack of production of glucocorticoids such as cortisol by the adrenal gland. If the problem is chronic, symptoms consist of fatigue, weight loss, failure to thrive (in children), delayed puberty (in adolescents), hypoglycemia (low blood sugar levels), anemia and hyponatremia (low sodium levels). If the onset is abrupt, collapse, shock and vomiting may occur. ACTH deficiency is highly similar to primary Addison's disease, which is cortisol deficiency as the result of direct damage to the adrenal glands; the latter form, however, often leads to hyperpigmentation of the skin, which does not occur in ACTH deficiency.


title: Hypopituitarism

text: Thyroid-stimulating hormone (TSH) deficiency leads to hypothyroidism (lack of production of thyroxine (T4) and triiodothyronine (T3) in the thyroid). Typical symptoms are tiredness, intolerance to cold, constipation, weight gain, hair loss and slowed thinking, as well as a slowed heart rate and low blood pressure. In children, hypothyroidism leads to delayed growth and in extreme inborn forms to a syndrome called "cretinism".


title: Hypopituitarism

text: Prolactin (PRL) plays a role in breastfeeding, and inability to breastfeed may point at abnormally low prolactin levels.


title: Hypopituitarism

text: Antidiuretic hormone (ADH) deficiency leads to the syndrome of "diabetes insipidus" (unrelated to diabetes mellitus): inability to concentrate the urine, leading to polyuria (production of large amounts of clear urine) that is low in solutes, dehydration and—in compensation—extreme thirst and constant need to drink (polydipsia), as well as hypernatremia (high sodium levels in the blood). ADH deficiency may be masked if there is ACTH deficiency, with symptoms only appearing when cortisol has been replaced.


title: Hypopituitarism

text: Oxytocin (OXT) deficiency generally causes few symptoms, however may lead to abnormal social developments due to its complex role as a social neuropeptide.


title: Hypopituitarism

text: The pituitary gland is located at the base of the brain, and intimately connected with the hypothalamus. It consists of two lobes: the posterior pituitary, which consists of nervous tissue branching out of the hypothalamus, and the anterior pituitary, which consists of hormone-producing epithelium. The posterior pituitary secretes antidiuretic hormone, which regulates osmolarity of the blood, and oxytocin, which causes contractions of the uterus in childbirth and participates in breastfeeding.


title: Hypopituitarism

text: The pituitary develops in the third week of embryogenesis from interactions between the diencephalon part of the brain and the nasal cavity. The brain cells secrete FGF-8, Wnt5a and BMP-4, and the oral cavity BMP-2. Together, these cellular signals stimulate a group of cells from the oral cavity to form Rathke's pouch, which becomes independent of the nasal cavity and develops into the anterior pituitary; this process includes the suppression of production of a protein called Sonic hedgehog by the cells of Rathke's pouch. The cells then differentiate further into the various hormone-producing cells of the pituitary. This requires particular transcription factors that induce the expression of particular genes. Some of these transcription factors have been found to be deficient in some forms of rare combined pituitary hormone deficiencies (CPHD) in childhood. These are "HESX1", "PROP1", "POU1F1", "LHX3", "LHX4", "TBX19", "SOX2" and "SOX3". Each transcription factor acts in particular groups of cells. Therefore, various genetic mutations are associated with specific hormone deficiencies. For instance, "POU1F1" (also known as Pit-1) mutations cause specific deficiencies in growth hormone, prolactin and TSH. In addition to the pituitary, some of the transcription factors are also required for the development of other organs; some of these mutations are therefore also associated with specific birth defects.


title: Hypopituitarism

text: Most of the hormones in the anterior pituitary are each part of an "axis" that is regulated by the hypothalamus. The hypothalamus secretes a number of releasing hormones, often according to a circadian rhythm, into blood vessels that supply the anterior pituitary; most of these are stimulatory (thyrotropin-releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone and growth hormone-releasing hormone), apart from dopamine, which suppresses prolactin production. In response to the releasing hormone rate, the anterior pituitary produces its hormones (TSH, ACTH, LH, FSH, GH) which in turn stimulate effector hormone glands in the body, while prolactin (PRL) acts directly on the breast gland. Once the effector glands produce sufficient hormones (thyroxine, cortisol, estradiol or testosterone and IGF-1), both the hypothalamus and the pituitary cells sense their abundance and reduce their secretion of stimulating hormones. The hormones of the posterior pituitary are produced in the hypothalamus and are carried by nerve endings to the posterior lobe; their feedback system is therefore located in the hypothalamus, but damage to the nerve endings would still lead to a deficiency in hormone release.


title: Hypopituitarism

text: Unless the pituitary damage is being caused by a tumor that overproduces a particular hormone, it is the lack of pituitary hormones that leads to the symptoms described above, and an excess of a particular hormone would indicate the presence of a tumor. The exception to this rule is prolactin: if a tumor compresses the pituitary stalk, a decreased blood supply means that the lactotrope cells, which produce prolactin, are not receiving dopamine and therefore produce excess prolactin. Hence, mild elevations in prolactin are attributed to stalk compression. Very high prolactin levels, though, point more strongly towards a prolactinoma (prolactin-secreting tumor).


title: Hypopituitarism

text: The diagnosis of hypopituitarism is made on blood tests. Two types of blood tests are used to confirm the presence of a hormone deficiency: basal levels, where blood samples are taken–usually in the morning–without any form of stimulation, and dynamic tests, where blood tests are taken after the injection of a stimulating substance. Measurement of ACTH and growth hormone usually requires dynamic testing, whereas the other hormones (LH/FSH, prolactin, TSH) can typically be tested with basal levels. There is no adequate direct test for ADH levels, but ADH deficiency can be confirmed indirectly; oxytocin levels are not routinely measured.


title: Hypopituitarism

text: Generally, the finding of a combination of a low pituitary hormone together with a low hormone from the effector gland is indicative of hypopituitarism. Occasionally, the pituitary hormone may be normal but the effector gland hormone decreased; in this case, the pituitary is not responding appropriately to effector hormone changes, and the combination of findings is still suggestive of hypopituitarism.


title: Hypopituitarism

text: Levels of LH/FSH may be suppressed by a raised prolactin level, and are therefore not interpretable unless prolactin is low or normal. In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient. Stimulation tests with GnRH are possible, but their use is not encouraged.


title: Hypopituitarism

text: For TSH, basal measurements are usually sufficient, as well as measurements of thyroxine to ensure that the pituitary is not simply suppressing TSH production in response to hyperthyroidism (an overactive thyroid gland). A stimulation test with thyrotropin-releasing hormone (TRH) is not regarded as useful. Prolactin can be measured by basal level, and is required for the interpretation of LH and FSH results in addition to the confirmation of hypopituitarism or diagnosis of a prolactin-secreting tumor.


title: Hypopituitarism

text: Growth hormone deficiency is almost certain if all other pituitary tests are also abnormal, and insulin-like growth factor 1 (IGF-1) levels are decreased. If this is not the case, IGF-1 levels are poorly predictive of the presence of GH deficiency; stimulation testing with the insulin tolerance test is then required. This is performed by administering insulin to lower the blood sugar to a level below 2.2 mmol/L. Once this occurs, growth hormone levels are measured. If they are low despite the stimulatory effect of the low blood sugars, growth hormone deficiency is confirmed. The test is not without risks, especially in those prone to seizures or are known to have heart disease, and causes the unpleasant symptoms of hypoglycemia. Alternative tests (such as the growth hormone releasing hormone stimulation test) are less useful, although a stimulation test with arginine may be used for diagnosis, especially in situations where an insulin tolerance test is thought to be too dangerous. If GH deficiency is suspected, and all other pituitary hormones are normal, two different stimulation tests are needed for confirmation.


title: Hypopituitarism

text: If morning cortisol levels are over 500 nmol/L, ACTH deficiency is unlikely, whereas a level less than 100 is indicative. Levels between 100 and 500 require a stimulation test. This, too, is done with the insulin tolerance test. A cortisol level above 500 after achieving a low blood sugar rules out ACTH deficiency, while lower levels confirm the diagnosis. A similar stimulation test using corticotropin-releasing hormone (CRH) is not sensitive enough for the purposes of the investigation. If the insulin tolerance test yields an abnormal result, a further test measuring the response of the adrenal glands to synthetic ACTH (the ACTH stimulation test) can be performed to confirm the diagnosis. Stimulation testing with metyrapone is an alternative. Some suggest that an ACTH stimulation test is sufficient as first-line investigation, and that an insulin tolerance test is only needed if the ACTH test is equivocal. The insulin tolerance test is discouraged in children. None of the tests for ACTH deficiency are perfect, and further tests after a period of time may be needed if initial results are not conclusive.


title: Hypopituitarism

text: Symptoms of diabetes insipidus should prompt a formal fluid deprivation test to assess the body's response to dehydration, which normally causes concentration of the urine and increasing osmolarity of the blood. If these parameters are unchanged, desmopressin (an ADH analogue) is administered. If the urine then becomes concentrated and the blood osmolarity falls, there is a lack of ADH due to lack of pituitary function ("cranial diabetes insipidus"). In contrast, there is no change if the kidneys are unresponsive to ADH due to a different problem ("nephrogenic diabetes insipidus").


title: Hypopituitarism

text: If one of these tests shows a deficiency of hormones produced by the pituitary, magnetic resonance imaging (MRI) scan of the pituitary is the first step in identifying an underlying cause. MRI may show various tumors and may assist in delineating other causes. Tumors smaller than 1 cm are referred to as "microadenomas", and larger lesions are called "macroadenomas". Computed tomography with radiocontrast may be used if MRI is not available. Formal visual field testing by perimetry is recommended, as this would show evidence of optic nerve compression by a tumor.


title: Hypopituitarism

text: Other tests that may assist in the diagnosis of hypopituitarism, especially if no tumor is found on the MRI scan, are ferritin (elevated in hemochromatosis), angiotensin converting enzyme (ACE) levels (often elevated in sarcoidosis), and human chorionic gonadotropin (often elevated in tumor of germ cell origin). If a genetic cause is suspected, genetic testing may be performed.


title: Hypopituitarism

text: Treatment of hypopituitarism is threefold: removing the underlying cause, treating the hormone deficiencies, and addressing any other repercussions that arise from the hormone deficiencies.


title: Hypopituitarism

text: Pituitary tumors require treatment when they are causing specific symptoms, such as headaches, visual field defects or excessive hormone secretion. Transsphenoidal surgery (removal of the tumor by an operation through the nose and the sphenoidal sinuses) may, apart from addressing symptoms related to the tumor, also improve pituitary function, although the gland is sometimes damaged further as a result of the surgery. When the tumor is removed by craniotomy (opening the skull), recovery is less likely–but sometimes this is the only suitable way to approach the tumor. After surgery, it may take some time for hormone levels to change significantly. Retesting the pituitary hormone levels is therefore performed 2 to 3 months later.


title: Hypopituitarism

text: Prolactinomas may respond to dopamine agonist treatment–medication that mimics the action of dopamine on the lactrotrope cells, usually bromocriptine or cabergoline. This approach may improve pituitary hormone secretion in more than half the cases, and make supplementary treatment unnecessary.


title: Hypopituitarism

text: Other specific underlying causes are treated as normally. For example, hemochromatosis is treated by venesection, the regular removal of a fixed amount of blood. Eventually, this decreases the iron levels in the body and improves the function of the organs in which iron has accumulated.


title: Hypopituitarism

text: Most pituitary hormones can be replaced indirectly by administering the products of the effector glands: hydrocortisone (cortisol) for adrenal insufficiency, levothyroxine for hypothyroidism, testosterone for male hypogonadism, and estradiol for female hypogonadism (usually with a progestogen to inhibit unwanted effects on the uterus). Growth hormone is available in synthetic form, but needs to be administered parenterally (by injection). Antidiuretic hormone can be replaced by desmopressin (DDAVP) tablets or nose spray. Generally, the lowest dose of the replacement medication is used to restore wellbeing and correct the deranged results, as excessive doses would cause side-effects or complications. Those requiring hydrocortisone are usually instructed to increase their dose in physically stressful events such as injury, hospitalization and dental work as these are times when the normal supplementary dose may be inadequate, putting the patient at risk of adrenal crisis.


title: Hypopituitarism

text: Long-term follow up by specialists in endocrinology is generally needed for people with known hypopituitarism. Apart from ensuring the right treatment is being used and at the right doses, this also provides an opportunity to deal with new symptoms and to address complications of treatment.


title: Hypopituitarism

text: Difficult situations arise in deficiencies of the hypothalamus-pituitary-gonadal axis in people (both men and women) who experience infertility; infertility in hypopituitarism may be treated with subcutaneous infusions of FSH, human chorionic gonadotropin–which mimics the action of LH–and occasionally GnRH.


title: Hypopituitarism

text: Several studies have shown that hypopituitarism is associated with an increased risk of cardiovascular disease and some also an increased risk of death of about 50% to 150% the normal population. It has been difficult to establish which hormone deficiency is responsible for this risk, as almost all patients studied had growth hormone deficiency. The studies also do not answer the question as to whether the hypopituitarism itself causes the increased mortality, or whether some of the risk is to be attributed to the treatments, some of which (such as sex hormone supplementation) have a recognized adverse effect on cardiovascular risk.


title: Hypopituitarism

text: The largest study to date followed over a thousand people for eight years; it showed an 87% increased risk of death compared to the normal population. Predictors of higher risk were: female sex, absence of treatment for sex hormone deficiency, younger age at the time of diagnosis, and a diagnosis of craniopharyngioma. Apart from cardiovascular disease, this study also showed an increased risk of death from lung disease.


title: Hypopituitarism

text: Quality of life may be significantly reduced, even in those people on optimum medical therapy. Many report both physical and psychological problems. It is likely that the commonly used replacement therapies do not completely mimic the natural hormone levels in the body. Health costs remain about double those of the normal population.


title: Hypopituitarism

text: There is only one study that has measured the prevalence (total number of cases in a population) and incidence (annual number of new cases) of hypopituitarism. This study was conducted in Northern Spain and used hospital records in a well-defined population. The study showed that 45.5 people out of 100,000 had been diagnosed with hypopituitarism, with 4.2 new cases per year. 61% were due to tumors of the pituitary gland, 9% due to other types of lesions, and 19% due to other causes; in 11% no cause could be identified.


title: Hypopituitarism

text: Recent studies have shown that people with a previous traumatic brain injury, spontaneous subarachnoid hemorrhage (a type of stroke) or radiation therapy involving the head have a higher risk of hypopituitarism. After traumatic brain injury, as much as a quarter have persistent pituitary hormone deficiencies. Many of these people may have subtle or non-specific symptoms that are not linked to pituitary problems but attributed to their previous condition. It is therefore possible that many cases of hypopituitarism remain undiagnosed, and that the annual incidence would rise to 31 per 100,000 annually if people from these risk groups were to be tested.


title: Hypopituitarism

text: The pituitary was known to the ancients, such as Galen, and various theories were proposed about its role in the body, but major clues as to the actual function of the gland were not advanced until the late 19th century, when acromegaly due to pituitary tumors was described. The first known report of hypopituitarism was made by the German physician and pathologist Dr Morris Simmonds. He described the condition on autopsy in a 46-year-old woman who had had severe puerperal fever eleven years earlier, and subsequently had amenorrhea, weakness, signs of rapid aging, and anemia. The pituitary gland was very small and there were few remnants of both the anterior and the posterior pituitary. The eponym "Simmonds' syndrome" is used infrequently for acquired hypopituitarism, especially when cachexia (general ill health and malnutrition) predominates. Most of the classic causes of hypopituitarism were described in the 20th century; the early 21st century saw the recognition of how common hypopituitarism could be in previous head injury victims.


title: Hypopituitarism

text: Until the 1950s, the diagnosis of pituitary disease remained based on clinical features and visual field examination, sometimes aided by pneumoencephalography and X-ray tomography. Nevertheless, the field of pituitary surgery developed during this time. The major breakthrough in diagnosis came with the discovery of radioimmunoassay by Rosalyn Yalow and Solomon Berson in the late 1950s. This allowed the direct measurement of the hormones of the pituitary, which as a result of their low concentrations in blood had previously been hard to measure. Stimulation tests were developed in the 1960s, and in 1973 the triple bolus test was introduced, a test that combined stimulation testing with insulin, GnRH and TRH.


title: Hypopituitarism

text: The scenario of the movie "Orphan" by Jaume Collet-Serra in 2009, is entirely based on the antagonist, a 33-year-old Estonian serial killer named Leena Klammer; who has a form of hypopituitarism that also causes her to have proportional dwarfism, making her look like a 9-year-old child named Esther.


title: Hypopituitarism

text: In 2014, into the french TV show "Profilage", the storyline of the episode "Poupée russe" (Season 5, Episode 2) is also based on the theme of a similar illness.


title: BSD licenses

text: BSD licenses are a family of permissive free software licenses, imposing minimal restrictions on the use and distribution of covered software. This is in contrast to copyleft licenses, which have share-alike requirements. The original BSD license was used for its namesake, the Berkeley Software Distribution (BSD), a Unix-like operating system. The original version has since been revised, and its descendants are referred to as modified BSD licenses.


title: BSD licenses

text: BSD is both a license and a class of license (generally referred to as BSD-like). The modified BSD license (in wide use today) is very similar to the license originally used for the BSD version of Unix. The BSD license is a simple license that merely requires that all code retain the BSD license notice if redistributed in source code format, or reproduce the notice if redistributed in binary format. The BSD license (unlike some other licenses e.g. GPL) does not require that source code be distributed at all.


title: BSD licenses

text: In addition to the original (4-clause) license used for BSD, several derivative licenses have emerged that are also commonly referred to as a "BSD license". Today, the typical BSD license is the 3-clause version, which is revised from the original 4-clause version.


title: BSD licenses

text: In all BSD licenses as following, codice_1 is the year of the copyright. As published in BSD, codice_2 is "Regents of the University of California".


title: BSD licenses

text: Some releases of BSD prior to the adoption of the 4-clause BSD license used a license that is clearly ancestral to the 4-clause BSD license. These releases include some parts of 4.3BSD-Tahoe (1988), about 1000 files, and Net/1 (1989). Although largely replaced by the 4-clause license, this license can be found in 4.3BSD-Reno, Net/2, and 4.4BSD-Alpha.


title: BSD licenses

text: The original BSD license contained a clause not found in later licenses, known as the "advertising clause". This clause eventually became controversial, as it required authors of all works deriving from a BSD-licensed work to include an acknowledgment of the original source in all advertising material. This was clause number 3 in the original license text:


title: BSD licenses

text: This clause was objected to on the grounds that as people changed the license to reflect their name or organization it led to escalating advertising requirements when programs were combined in a software distribution: every occurrence of the license with a different name required a separate acknowledgment. In arguing against it, Richard Stallman has stated that he counted 75 such acknowledgments in a 1997 version of NetBSD. In addition, the clause presented a legal problem for those wishing to publish BSD-licensed software which relies upon separate programs using the GNU GPL: the advertising clause is incompatible with the GPL, which does not allow the addition of restrictions beyond those it already imposes; because of this, the GPL's publisher, the Free Software Foundation, recommends developers not use the license, though it states there is no reason not to use software already using it.


title: BSD licenses

text: The advertising clause was removed from the license text in the official BSD license on July 22, 1999, by William Hoskins, Director of the Office of Technology Licensing for UC Berkeley. Other BSD distributions removed the clause, but many similar clauses remain in BSD-derived code from other sources, and unrelated code using a derived license.


title: BSD licenses

text: While the original license is sometimes referred to as the "BSD-old", the resulting 3-clause version is sometimes referred to by "BSD-new." Other names include "New BSD", "revised BSD", "BSD-3", or "3-clause BSD". This version has been vetted as an Open source license by the OSI as "The BSD License". The Free Software Foundation, which refers to the license as the "Modified BSD License", states that it is compatible with the GNU GPL. The FSF encourages users to be specific when referring to the license by name (i.e. not simply referring to it as "a BSD license" or "BSD-style") to avoid confusion with the original BSD license.


title: BSD licenses

text: This version allows unlimited redistribution for any purpose as long as its copyright notices and the license's disclaimers of warranty are maintained. The license also contains a clause restricting use of the names of contributors for endorsement of a derived work without specific permission.


title: BSD licenses

text: An even more simplified version has come into use, primarily known for its usage in FreeBSD. It was in use there as early as 29 April 1999 and likely well before. The primary difference between it and the New BSD (3-clause) License is that it omits the non-endorsement clause. The FreeBSD version of the license also adds a further disclaimer about views and opinions expressed in the software, though this is not commonly included by other projects.


title: BSD licenses

text: The Free Software Foundation, which refers to the license as the FreeBSD License, states that it is compatible with the GNU GPL. In addition, the FSF encourages users to be specific when referring to the license by name (i.e. not simply referring to it as "a BSD license" or "BSD-style"), as it does with the modified/new BSD license, to avoid confusion with the original BSD license.


title: BSD licenses

text: Other projects, such as NetBSD, use a similar 2-clause license. This version has been vetted as an Open source license by the OSI as the "Simplified BSD License."


title: BSD licenses

text: The ISC license is functionally equivalent, and endorsed by the OpenBSD project as a license template for new contributions.


title: BSD licenses

text: The BSD 0-clause license goes further than the 2-clause license by dropping the requirements to include the copyright notice, license text, or disclaimer in either source or binary forms. Doing so forms a public-domain-equivalent license, the same way as MIT No Attribution License. It is known as "0BSD", "Zero-Clause BSD", or "Free Public License 1.0.0". It was first used by Rob Landley in Toybox.


title: BSD licenses

text: The FreeBSD project argues on the advantages of BSD-style licenses for companies and commercial use-cases due to their license compatibility with proprietary licenses and general flexibility, stating that the BSD-style licenses place only "minimal restrictions on future behavior" and are not "legal time-bombs", unlike copyleft licenses. The BSD License allows proprietary use and allows the software released under the license to be incorporated into proprietary products. Works based on the material may be released under a proprietary license as closed source software, allowing usual commercial usages under them.


title: BSD licenses

text: The 3-clause BSD license, like most permissive licenses, is compatible with almost all FOSS licenses (and as well proprietary licenses).


title: BSD licenses

text: Two variants of the license, the New BSD License/Modified BSD License (3-clause), and the Simplified BSD License/FreeBSD License (2-clause) have been verified as GPL-compatible free software licenses by the Free Software Foundation, and have been vetted as open source licenses by the Open Source Initiative. The original, 4-clause BSD license has not been accepted as an open source license and, although the original is considered to be a free software license by the FSF, the FSF does not consider it to be compatible with the GPL due to the advertising clause.


title: BSD licenses

text: The BSD license family is one of the oldest and most broadly used license families in the Free and open-source software ecosystem. Also, many new licenses were derived or inspired by the BSD licenses. Many FOSS software projects use a BSD license, for instance the BSD OS family (FreeBSD etc.), Google's Bionic or Toybox. the BSD 3-clause license ranked in popularity number five according to Black Duck Software and sixth according to GitHub data.


title: Jewish nose

text: Jewish nose or Jew's nose is a usually exaggerated ethnic stereotype that refers to a hooked nose with a convex nasal bridge and a downward turn of the tip of the nose. The 'Jewish nose' was singled out as a hostile caricature of Jews in mid-13th century Europe, and has since become a defining and persisting element of the Jewish stereotype. In modern times, on the other hand, it has also been adopted by many Jews as a part of their ethnic identity.


title: Jewish nose

text: Research has found that this nose type is most prevalent in the Mediterranean and Middle Eastern regions, where it is equally prevalent among the Jewish population as it is among the other local populations. Still, among the Jewish communities outside the Mediterranean and Middle Eastern regions, such as that in the United States, the so-called "Jewish nose" has come to be embraced by part of its bearers as a defining characteristic of their Jewish identity, with general attitude toward the trait having changed from mostly negative to mostly positive since the 1950s.


title: Jewish nose

text: Robert Knox, an 18th-century anatomist, described the supposed Jewish nose as "a large, massive, club-shaped, hooked nose." Another anatomist, Jerome Webster, described it in 1914 as having "a very slight hump, somewhat broad near the tip and the tip bends down." A popular 1848 essay "Notes on Noses" written by solicitor George Jabet under pseudonym Eden Warwick offers quite a different description, and specifies that though this nose is popularly identified as Jewish, it should be properly defined as a 'Syrian nose'. He writes that it is "very convex, and preserves its convexity like a bow, throughout the whole length from the eyes to the tip. It is thin and sharp." (Jabet prided himself in his lack of connection to ideas of others and condemned scientific proofs.)


title: Jewish nose

text: In the mid-19th century, Jewish folklorist Joseph Jacobs wrote: "A curious experiment illustrates this importance of the nostril toward making the Jewish expression. Artists tell us that the best way to make a caricature of the Jewish nose is to write a figure 6 with a long tail (Fig. 1); now remove the turn of the twist as in Figure 2, and much of the Jewishness disappears; it vanishes entirely when we draw the continuation horizontally as in Figure 3. We may conclude, then, as regards the Jewish nose, that it is more the Jewish nostril than the nose itself which goes to form the characteristic Jewish expression."


title: Jewish nose

text: The statistics cited in the chapter "Nose" of the "Jewish Encyclopedia" (1901–1905) by Joseph Jacobs and Maurice Fishberg, demonstrate that, contrary to the stereotype, the "Jewish", or hooked, nose is found with the same frequency among people of Jewish descent as it is among non-Jewish people from the Mediterranean region generally. The data collected by Jacobs and Fishberg showed that this type of nose is found in the minority of Jews (20–30%) and that the vast majority have a straight nose. In 1914, Fishberg examined the noses of 4,000 Jews in New York and found that only 14% could be described as either aquiline or hooked. In 1906, Felix von Luschan suggested that the arched nose in Jews is not a "Semitic" trait, but is a consequence of the intermixture with the "Hittites" in Asia Minor, noting that other races with Hittite blood, such as the Armenians, have similar noses. The same theory was held in 1910 by Houston Stewart Chamberlain, a racialist writer whose ideas on the racial inferiority of Jews influenced the development of Fascism.


title: Jewish nose

text: A Roman statue depicting a hawk-nosed figure in the collection of the Ny Carlsberg Glyptotek in Copenhagen, and acquired in 1891 from Princess Piombino, lacked an inscription in Latin identifying the subject but was presented by the museum in 1925 as Josephus, an identification defended by Robert Eisler. The grounds for Eisler's inference were simply that a notice in Eusebius stated that Josephus, the most famous Jew of his time, had a statue erected in his honour, and this bust, he thought, corresponded to a "crooked", "broken" "Jewish nose" as distinct from the classic aquiline Roman nose. The identification is still widely used online despite the fact that modern scholarship definitively rejects the claim. Hebrews in ancient Near Eastern art, like other peoples, Canaanites for example, who lived to the west of the Assyrian empire, have straight protruding noses.


title: Jewish nose

text: Art historian Sarah Lipton traces the association of a hooked nose with Jews to the 13th century. Prior to that time, representations of Jews in art and iconography showed no specific facial features. "By the later thirteenth century, however, a move toward realism in art and an increased interest in physiognomy spurred artists to devise visual signs of ethnicity. The range of features assigned to Jews consolidated into one fairly narrowly construed, simultaneously grotesque and naturalistic face, and the hook-nosed, pointy-bearded Jewish caricature was born."


title: Jewish nose

text: While the hooked nose became associated with Jews in the 13th century, the Jewish nose stereotype only became firmly established in the European imagination some centuries later. One early literary use of it is Francisco de Quevedo's "A un hombre de gran nariz" (To a man with a big nose) written against his rival in poetry, Luis de Góngora. The point of his sonnet was to mock his rival by suggesting his large nose was proof he was, not a 'pure blooded Spaniard', but the descendant of conversos, Jews who had converted to Catholicism to avoid expulsion. In particular, the reference to "" () associates such a nose maliciously with the Pharisees and the Scribes responsible for Christ's death according to the New Testament. In his "History of the Indies," (1653), Francisco López de Gómara argued for the thesis that the native population of the Americas must have descended from the Israelites, whom, a decade earlier, Antonio de Montezinos/Aharon Levi had claimed were the lost tribes of Israel, by citing the size of their noses.


title: Jewish nose

text: "The so-called Jewish nose, bent at the top, jutting hawk-like from the face, existed already as a caricature in the sixteenth century […] It became firmly established as a so-called Jewish trademark only by the mid-eighteenth century, however […]"


title: Jewish nose

text: The hooked nose became a key feature in antisemitic Nazi propaganda. "One can most easily tell a Jew by his nose," wrote Nazi propagandist Julius Streicher in a children's story. "The Jewish nose is bent at its point. It looks like the number six. We call it the 'Jewish six.' Many Gentiles also have bent noses. But their noses bend upwards, not downwards. Such a nose is a hook nose or an eagle nose. It is not at all like a Jewish nose."


title: Jewish nose

text: According to writer Naomi Zeveloff, "in prewar Berlin, where the modern nose job was first developed, Jews sought the procedure to hide their ethnic identity." The inventor of rhinoplasty, Jacques Joseph, had "a large Jewish clientele seeking nose jobs that would allow them to pass as gentiles in Berlin", wrote Zeveloff.


title: Jewish nose

text: But this negative view of the Jewish nose was not shared by all Jews; Jewish Kabbalistic texts consider a large nose as a sign of character. In his book "The Secrets of the Face" (), Kabbalistic Rabbi Aharon Leib Biska wrote in 1888 that Jews have "the eagle's nose". "A nose that is curved down […] with a small hump in the middle attests to a character that seeks to discover the secrets of wisdom, who shall govern fairly, be merciful by nature, joyful, wise and insightful."


title: Jewish nose

text: Among those seeking surgery to make their noses smaller were many American Jewish film actresses of the 1920s to 1950s. "Changing one's name is to Jewish males what fixing one's nose is to Jewish females, a way of passing," writes film historian Patricia Erens. One of the actresses to undergo surgery was Fanny Brice, inspiring commentator Dorothy Parker to comment that she "cut off her nose to spite her race." According to Erens, this fashion ended with Barbra Streisand, whose nose is a signature feature. Streisand told "Playboy" magazine in 1977, "When I was young, everyone would say, 'You gonna have your nose done?' It was like a fad, all the Jewish girls having their noses done every week at Erasmus Hall High School, taking perfectly good noses and whittling them down to nothing. The first thing someone would have done would be to cut my bump off. But I love my bump, I wouldn't cut my bump off."


title: Jewish nose

text: "As Jews assimilated into the American mainstream in the 1950s and ’60s, nose jobs became a rite of passage for Jewish teens who wanted a more Aryan look," wrote Zeveloff. By 2014, the number of rhinoplasty operations had declined by 44 percent, and "in many cases the procedure has little bearing on […] religious identity."


title: Jewish nose

text: In "The American Scene" (1905), Henry James alluded to the stereotype in a description of the Jewish slums in New York City's Lower East Side by comparing Jews to a "sallow aquarium [with] innumerable fish, of over-developed proboscis". The Jewish nose stereotype was a common motif in the work of Thomas Mann, who described it as "too flat, fleshy, down-pressed". In his 1909 novel "Royal Highness", for example, Mann invents a Jewish doctor, Sammet, whose nose is described as giving away his origins, being "too broad at the bottom". In "The Great Gatsby" (1925), F. Scott Fitzgerald's portrayal of the gangster Meyer Wolfsheim (also Wolfshiem) focused on his "expressive nose", a reference Fitzgerald later denied was antisemitic, despite privately expressing "bias toward Jews and ethnic others … into the 1930s". In "The Sun Also Rises" (1926), Ernest Hemingway's character Robert Cohn breaks his nose while boxing at Princeton University, an incident which "certainly improve[s] his nose." The alteration is symbolic of the perceived sacrifices required to fit in with a predominantly Anglo-Saxon peer group at a university with a strongly antisemitic atmosphere.


title: Jewish nose

text: In Paul Thomas Anderson's 2021 film "Licorice Pizza", the prominent Jewish nose of leading role Alana Kane, played by Alana Haim, gets featured in dialogue by a casting director (Harriet Sansom Harris), who also emphasizes her sexiness and asks if she would play topless roles. In another scene, producer Jon Peters (Bradley Cooper) brags about Barbra Streisand being his girlfriend and subsequently demonstrates an interest in Alana - as do most other males in that film, most prominently leading role Gary Valentine (Cooper Hoffman). This has been commented as the film capturing "the moment when pop culture finally started to see Jewish women as beautiful".


title: Jewish nose

text: Heinrich Heine in his 'The Baths of Lucca' creates a satiric portrait of the Jewish upstart figure Gumpel trying, under false aristocratic pretenses, to ingratiate his way into high society, while waiting for God to restore the Jews to their ancestral homeland. The problem is his nose, which is so long it almost pokes out the narrator's eyes when they meet. God must eventually make good on his promise of a return to Israel, the narrator reflects:


title: Jewish nose

text: In American Jewish literature and cinema, the Jewish nose has been a defining characteristic – for better or for worse – of the American Jewish identity. "The nose is […] a physical symbol of otherness, definitely for Jews, as Philip Roth" and other artists note, writes literary critic Roy Goldblatt. Big noses for Jews, small noses for non-Jews, and the frequent appearance of rhinoplasty "as an instrument of (attempted) Americanization" all appear in Jewish literature as showing "the special significance attached to the nose as a factor marking the otherness of Jews – historically, in print, on stage, and on the screen," writes Goldblatt.


title: Jewish nose

text: Goldblatt cites numerous examples of Jewish writers discussing the Jewish nose. "Goyim" (Non-Jews), writes Philip Roth in "Portnoy's Complaint", "are the people for whom Nat 'King' Cole sings every Christmastime, 'Chestnuts roasting on an open fire, Jack Frost nipping at your nose' […] 'No, no, theirs are the noses whereof he speaks. Not his flat black one or my long bumpy one, but those tiny bridgeless wonders whose nostrils point northward automatically at birth."


title: Jewish nose

text: Joshua Louis Moss cites Woody Allen's movie "Sleeper" as another example of the Jewish nose as an element of the American Jewish identity. "The historical and ethnoreligious connections are made palpable in the film's main structuring comedy motif, one of the central tropes of twentieth-century anti-Semitism: the contested landscape of the Jewish nose […] Nose jokes recur throughout the film in both dialogue and sight gags." For example, in one scene two robots with outlandishly large noses speak with heavy Yiddish accents. In another scene, Allen assassinates the dictator in the movie by throwing the tyrant's distinctly non-Jewish-looking nose under a steamroller.


title: Jewish nose

text: While large noses are a sign of Jewishness, Jewish authors take small noses as a sign of the Gentile. "Neither Sarah's way of speaking nor her manner was that of a daughter of Israel. Suddenly they remembered she didn't look Jewish, that she had a snub nose, high cheekbones, teeth that were strangely white […] unlike those found among the Jews," writes Isaac Bashevis Singer in his novel "The Slave". "'Don't you know what that girl is who is asleep beside you? Just look at that nose.' 'What nose?' 'That's the point – it's hardly even there […] Schmuck, this is the real McCoy. A Shikse! (non-Jewish woman)'" writes Philip Roth in "Portnoy's Complaint". "We started out with short beards and straight noses – you can look at the wall paintings – and who knows? With a slightly different genetic break in our wanderings and couplings, we might all be as blond and gorgeous today as Danish Schoolchildren," writes Joseph Heller in "God Knows".


title: Jewish nose

text: Bernice Schrank notes that Jewish attitudes toward the Jewish nose has changed from negative in the 1950s to positive today. "The change from unacceptability to acceptability is based on an increasingly successful challenge to the American myth of melting pot sameness by the politics of ethnic difference."


title: Leptin

text: Leptin (from Greek λεπτός "leptos", "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn diminishes fat storage in adipocytes. Leptin is coded for by the "LEP" gene. Leptin acts on cell receptors in the arcuate and ventromedial nuclei, as well as other parts of the hypothalamus and dopaminergic neurons of the ventral tegmental area, consequently mediating feeding.


title: Leptin

text: Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beyond hypothalamic cells that have leptin receptors. Many of these additional functions are yet to be fully defined.


title: Leptin

text: In obesity, a decreased sensitivity to leptin occurs (similar to insulin resistance in type 2 diabetes), resulting in an inability to detect satiety despite high energy stores and high levels of leptin. A synonym for "LEP" is "OB" (for obese).


title: Leptin

text: Predominantly, the "energy expenditure hormone" leptin is made by adipose cells, and is thus labeled "fat cell-specific". In the context of its effects, the short describing words "direct", "central", and "primary" are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the hypothalamic portion of the brain vs non-hypothalamic "location of action" of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the "mode of action" of leptin; and primary vs secondary is an arbitrary description of a particular "function" of leptin.


title: Leptin

text: In vertebrates, the nervous system consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The primary effect of leptins is in the hypothalamus, a part of the central nervous system. Leptin receptors are expressed not only in the hypothalamus but also in other brain regions, particularly in the hippocampus. Thus some leptin receptors in the brain are classified as "central" (hypothalamic) and some as "peripheral" (non-hypothalamic).


title: Leptin

text: Generally, leptin is thought to enter the brain at the choroid plexus, where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.


title: Leptin

text: Increased levels of melatonin causes a downregulation of leptin, however, melatonin also appears to increase leptin levels in the presence of insulin, therefore causing a decrease in appetite during sleeping. Partial sleep deprivation has also been associated with decreased leptin levels.


title: Leptin

text: Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.


title: Leptin

text: Leptin acts on receptors in the lateral hypothalamus to inhibit hunger and the medial hypothalamus to stimulate satiety.


title: Leptin

text: Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).


title: Leptin

text: This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by cholecystokinin (CCK) and the slower suppression of hunger between meals mediated by PYY3-36. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels.


title: Leptin

text: Leptin levels change more when food intake decreases than when it increases. The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.


title: Leptin

text: Leptin binds to neuropeptide Y (NPY) neurons in the arcuate nucleus in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.


title: Leptin

text: Leptin receptor activation inhibits neuropeptide Y and agouti-related peptide (AgRP), and activates α-melanocyte-stimulating hormone (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.


title: Leptin

text: Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, LEPR. Ob-Rb is the only receptor isoform that can signal intracellularly via the JAK-STAT and MAPK signal transduction pathways, and is present in hypothalamic nuclei.


title: Leptin

text: Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of endocannabinoids, responsible for increasing hunger. In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.


title: Leptin

text: The role of leptin/leptin receptors in modulation of T cell activity and the innate immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor.


title: Leptin

text: Leptin microinjections into the nucleus of the solitary tract (NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.


title: Leptin

text: In fetal lung, leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of PTHrP secreted by formative alveolar epithelium (endoderm) under moderate stretch. The leptin from the mesenchyme, in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.


title: Leptin

text: In mice, and to a lesser extent in humans, leptin is required for male and female fertility. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during "in vitro" fertilization. Leptin is involved in reproduction by stimulating gonadotropin-releasing hormone from the hypothalamus.


title: Leptin

text: The placenta produces leptin. Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin. Leptin plays a role in hyperemesis gravidarum (severe morning sickness of pregnancy), in polycystic ovary syndrome and hypothalamic leptin is implicated in bone growth in mice.


title: Leptin

text: Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.


title: Leptin

text: Leptin along with kisspeptin controls the onset of puberty. High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche. This may eventually lead to shorter stature as oestrogen secretion starts during menarche and causes early closure of epiphyses.


title: Leptin

text: Leptin's role in regulating bone mass was identified in 2000. Leptin can affect bone metabolism via direct signalling from the brain. Leptin decreases cancellous bone, but increases cortical bone. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.


title: Leptin

text: Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue. A number of brain-signalling molecules (neuropeptides and neurotransmitters) have been found in bone, including adrenaline, noradrenaline, serotonin, calcitonin gene-related peptide, vasoactive intestinal peptide and neuropeptide Y. Leptin binds to its receptors in the hypothalamus, where it acts through the sympathetic nervous system to regulate bone metabolism. Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway. There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.


title: Leptin

text: Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the inflammatory response, it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory cytokines.


title: Leptin

text: In terms of both structure and function, leptin resembles IL-6 and is a member of the cytokine superfamily. Circulating leptin seems to affect the HPA axis, suggesting a role for leptin in stress response. Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.


title: Leptin

text: Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including hypertension, metabolic syndrome, and cardiovascular disease. While leptin is associated with body fat mass, the size of individual fat cells, and overeating, it is not affected by exercise (for comparison, IL-6 is released in response to muscular contractions). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation. Leptin is a pro-angiogenic, pro-inflammatory and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer. High leptin levels have been also demonstrated in patients with COVID-19 pneumonia.


title: Leptin

text: Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to grow larger or increase in number in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels. (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from preadipocytes in a time- and dose-dependent manner.) Furthermore, plasma leptin concentrations have been observed to gradually increase when acipimox is administered to prevent lipolysis, concurrent hypocaloric dieting and weight loss notwithstanding. Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.


title: Leptin

text: Leptin increases the production of leukocytes via actions on the hematopoietic niche, a pathway that is more active in sedentary mice and humans when compared to individuals which are physically active.


title: Leptin

text: The "Ob(Lep)" gene (Ob for obese, Lep for leptin) is located on chromosome 7 in humans. Human leptin is a 16-kDa protein of 167 amino acids.


title: Leptin

text: A human mutant leptin was first described in 1997, and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it "is" detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency. These eight mutations all cause extreme obesity in infancy, with hyperphagia.


title: Leptin

text: A nonsense mutation in the leptin gene that results in a stop codon and lack of leptin production was first observed in mice. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.


title: Leptin

text: A recessive frameshift mutation resulting in a reduction of leptin has been observed in two consanguineous children with juvenile obesity. A 2001 study of 13 people with a heterozygous frameshift mutation known as delta-G133 found that they had lower blood leptin levels than controls. There was an increased rate of obesity in these individuals, with 76% having a BMI of over 30 compared to 26% in the control group.


title: Leptin

text: A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the leptin receptor gene (Q223R, K109R and K656N) and two mutations in the "PPARG" gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.


title: Leptin

text: A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in Taiwanese aborigines, but a 2014 meta-analysis did not, however, this polymorphism has been associated with weight gain in patients taking antipsychotics.


title: Leptin

text: The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer, gestational diabetes, and osteoporosis.


title: Leptin

text: A single case of a homozygous transversion mutation of the gene encoding for leptin was reported in January 2015. It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed aspartic acid to tyrosine at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor "in vitro", nor in leptin-deficient mice "in vivo". It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss."


title: Leptin

text: The lack of leptin or leptin receptors leads to uncontrolled hunger, resulting in obesity. Leptin concentrations are increased in those with hypertension, but high endogenous (and exogenous) leptins do not normalize their weight when obese, indicating the possibility of leptin resistance, which has been proposed internationally. Studies have also found a correlation between serum leptin levels, and expression levels of testosterone, estradiol, follicle-stimulating hormone, and aromatase in women with hyperandrogenism, and polycystic ovary syndrome. While in vitro experiments have confirmed a negative correlation between thyroxine and leptin, there is still no conclusion in the human body. The existence of leptin is the basis for the exertion of the growth hormone’s physiological effects, but the growth hormone itself does not appear to have a direct effect on leptin.


title: Leptin

text: Leptin is produced primarily in the adipocytes of white adipose tissue. It also is produced by brown adipose tissue, placenta (syncytiotrophoblasts), ovaries, skeletal muscle, stomach (the lower part of the fundic glands), mammary epithelial cells, bone marrow, gastric chief cells and P/D1 cells.


title: Leptin

text: Leptin levels vary exponentially, not linearly, with fat mass. Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night. The diurnal rhythm of blood leptin levels may be modified by meal-timing.


title: Leptin

text: In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:


title: Leptin

text: All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 which is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese -year-old boy who had high levels of circulating leptin which had no effect on leptin receptors, so he was functionally leptin-deficient.


title: Leptin

text: Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher percentage body fat. These people show resistance to leptin, similar to resistance of insulin in type 2 diabetes, with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the arcuate nucleus, however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. Triglycerides crossing the blood brain barrier (BBB) can induce leptin and insulin resistance in the hypothalamus. Triglycerides can also impair leptin transport across the BBB.


title: Leptin

text: Studies on leptin cerebrospinal fluid (CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people. In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight. The reason for this may be high levels of triglycerides affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated. Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals. These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies), it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.


title: Leptin

text: When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more parts of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization.


title: Leptin

text: Leptin is known to interact with amylin, a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.


title: Leptin

text: It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food. This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage. Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods. This effect is reversed when the animals are put back on a low-energy diet. This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.


title: Leptin

text: A fad diet, the Rosedale diet is based on ideas about how leptin might affect weight. It is based on unsound science and marketed with unevidenced claims of health benefits.


title: Leptin

text: Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.


title: Leptin

text: Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands). Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se. This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.


title: Leptin

text: Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.


title: Leptin

text: Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.


title: Leptin

text: The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals. In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation. For example, leptin can be found in the synovial fluid in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.


title: Leptin

text: As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI. The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus and bone. An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators which contribute to the pathogenesis of osteoarthritis


title: Leptin

text: The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors.


title: Leptin

text: This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients.


title: Leptin

text: Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health.


title: Leptin

text: There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions.


title: Leptin

text: Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized lipodystrophy.


title: Leptin

text: An analog of human leptin metreleptin (trade names Myalept, Myalepta) was first approved in Japan in 2013, and in the United States in February 2014 and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and hypertriglyceridemia associated with congenital or acquired generalized lipodystrophy. In Europe based on EMA, metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in adults and children above the age of 2 years with generalised lipodystrophy (Berardinelli-Seip syndrome and Lawrence syndrome); and in adults and children above the age of 12 years with partial lipodystrophy (including Barraquer-Simons syndrome), when standard treatments have failed.


title: Leptin

text: The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1, 2019.


title: Leptin

text: The leptine was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models


title: Leptin

text: In 1949, a non-obese mouse colony being studied at the Jackson Laboratory produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese. In the 1960s, a second mutation causing obesity and a similar phenotype was identified by Douglas Coleman, also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese. In 1990 Rudolph Leibel and Jeffrey M. Friedman reported mapping of the "db" gene.


title: Leptin

text: Consistent with Coleman's and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.


title: Leptin

text: In 1994, Friedman's laboratory reported the identification of the gene. In 1995, Jose F. Caro's laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility. At the suggestion of Roger Guillemin, Friedman named this new hormone "leptin" from the Greek "lepto" meaning thin. Leptin was the first fat cell-derived hormone (adipokine) to be discovered.


title: Leptin

text: Subsequent studies in 1995 confirmed that the db gene encodes the leptin receptor, and that it is expressed in the hypothalamus, a region of the brain known to regulate the sensation of hunger and body weight.


title: Leptin

text: Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the Gairdner Foundation International Award (2005), the Shaw Prize (2009), the Lasker Award, the BBVA Foundation Frontiers of Knowledge Award and the King Faisal International Prize, Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman's omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including Ellen Ruppel Shell’s 2002 book "The Hungry Gene".


title: Leptin

text: The discovery of leptin also is documented in a series of books including "Fat: Fighting the Obesity Epidemic" by Robert Pool, "The Hungry Gene" by Ellen Ruppel Shell, and "Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting" by Gina Kolata. "Fat: Fighting the Obesity Epidemic" and "Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting" review the work in the Friedman laboratory that led to the cloning of the ob gene, while The "Hungry Gene" draws attention to the contributions of Leibel.


title: David Gulpilil

text: David Dhalatnghu Gulpilil (1 July 1953 – 29 November 2021), known professionally as David Gulpilil and posthumously (at his family's request, to avoid naming the dead) as David Dalaithngu for three days, was an Indigenous Australian actor and dancer, known for the films "Walkabout", "Storm Boy", "Crocodile Dundee", "Rabbit-Proof Fence" and "The Tracker".


title: David Gulpilil

text: He was one of the Yolngu people and was raised in a traditional lifestyle in Arnhem Land, in northern Australia, and was a skilled dancer as a young man when British director Nicolas Roeg recognised his talent. He also made several appearances on stage. He was honoured with numerous awards for individual films and for lifetime achievement, and also published books and artworks.


title: David Gulpilil

text: Gulpilil was probably born in 1953, although he stated in the 2021 documentary about his life, "My Name is Gulpilil", that he did not know how old he was. Local missionaries recorded his birth on 1 July 1953, based on "guesswork". He was a man of the Mandjalpingu (Djilba) clan of the Yolngu people, who are an Aboriginal people of Arnhem Land in the Northern Territory of Australia.


title: David Gulpilil

text: As a young boy, Gulpilil was an accomplished hunter, tracker, and ceremonial dancer. Gulpilil spent his childhood in the bush, outside the range of non-Aboriginal influences and did not set eyes on a white man until he was 8 years old. He received a traditional upbringing in the care of his family, until the death of his parents, after which he attended the school at Maningrida in North East Arnhem Land, where he was assigned the name "David". When he came of age, Gulpilil was initiated into the Mandhalpuyngu tribal group. His skin group totemic animal was the kingfisher (the meaning of the name "Gulpilil") and his homeland was Marwuyu.


title: David Gulpilil

text: After appearing in his first film, "Walkabout" (1971), Gulipilil became fluent in English, adding to his linguistic ability in several Aboriginal languages.


title: David Gulpilil

text: In 1969, Gulpilil's skill as a tribal dancer caught the attention of British filmmaker Nicolas Roeg, who had come to Maningrida scouting locations for a forthcoming film. Roeg promptly cast the 16-year-old unknown to play a principal role in his internationally acclaimed motion picture "Walkabout", released in 1971. Before this, any portrayal of an Aboriginal character in Australia had been played by a white actor in blackface. This was also groundbreaking, as it was the first time that an Aboriginal character had been portrayed as sexually attractive. Gulpilil's on-screen charisma, combined with his acting and dancing skills, was such that he became an instant national and international celebrity. He travelled internationally, mingled with prominent people, and was presented to heads of state. During these travels to promote the film, he met and was impressed with John Lennon, Bob Marley, Bruce Lee, Marlon Brando, and Jimi Hendrix. He taught Bob Marley how to play the didgeridoo, while Marley introduced him to "ganja".


title: David Gulpilil

text: Gulpilil appeared in many more films and television productions. He played a lead role in the commercially successful and critically acclaimed "Storm Boy" (1976). He "dominated" the film "The Last Wave" (1977), with his performance as tribal Aboriginal man Chris Lee.


title: David Gulpilil

text: A documentary about his life, "Gulpilil: One Red Blood", was aired on ABC Television in 2003. The title comes from a quote by Gulpilil: "We are all one blood. No matter where we are from, we are all one blood, the same".


title: David Gulpilil

text: Gulpilil was a major creative influence throughout his life in both dance and film. He initiated and narrated the film "Ten Canoes" which won a Special Jury Prize at the 2006 Cannes Festival. The prize-winning, low-budget film, based on 1,000-year-old traditional story of misplaced love and revenge, features non-professional Aboriginal actors speaking their local language. Gulpilil collaborated with the director, Rolf de Heer, urging him to make the film, and although he ultimately withdrew from a central role in the project for "complex reasons," Gulpilil also provided the voice of the storyteller for the film. De Heer had directed Gulpilil in another film, "The Tracker" (2002).


title: David Gulpilil

text: In 2007, he starred in Richard Friar's hour-long independent documentary, "Think About It!" which was focussed on Indigenous rights and the anti-war movement and included commentary from former Prime Minister Malcolm Fraser, former Greens leader Bob Brown, and David Hicks, then a detainee at Guantanamo Bay detention camp.


title: David Gulpilil

text: In 2014, he again collaborated with De Heer, this time sharing on screenwriting credits for "Charlie's Country". The film won several awards, including Best Actor in Un Certain Regard at the Cannes Film Festival.


title: David Gulpilil

text: In 2015, Gulpilil appeared in the documentary "Another Country" directed by Molly Reynolds. In this film, Gulpilil narrates the story of his life, from when he was a child living on country, the arrival of the first white men ("ghosts"), in the form of missionaries, through The Intervention and the introduction of the BasicsCard, often making serious criticisms hidden beneath his trademark humour.


title: David Gulpilil

text: Gulpilil again worked with Reynolds when she directed a documentary about his life, "My Name Is Gulpilil", which premiered at the 2021 Adelaide Festival.


title: David Gulpilil

text: Gulpilil was renowned for portraying Aboriginal culture before it became threatened by the white civilisations, though the irony is that he became divorced from his own culture by doing so. He felt that he was stretched somewhere between the two, with "one tiptoe in champage and caviar, and the other in the dirt of his Dreamtime".


title: David Gulpilil

text: In March 2004, he performed in the autobiographical stage production, "Gulpilil" at the Adelaide Festival of Arts, to standing ovations. This work, co-written with Reg Cribb, and directed by Neil Armfield, was based on stories of his life assembled into a script. These included tales from the making of "Walkabout", performing at Buckingham Palace, and inadvertently causing a bomb scare at Cannes. The show was later staged in Brisbane and Sydney.


title: David Gulpilil

text: He also performed on stage in "The Cradle of Hercules" at the Sydney Opera House in 1974; the Commonwealth Gala Performance in Brisbane in 1982 (in front of Queen Elizabeth II and the Duke of Edinburgh, Prince Philip); the Message Sticks Film Festival in Sydney in 2002.


title: David Gulpilil

text: Perhaps the most renowned traditional dancer in Australia, Gulpilil organised troupes of dancers and musicians and performed at festivals throughout the country, including the prestigious Darwin Australia Day Eisteddfod dance competition, which he won four times. In November 1997, Gulipilil's dance troupe performed at the second National Aboriginal Dance Conference in Adelaide (hosted by the National Aboriginal Dance Council Australia (NADCA)), at which cultural and intellectual property rights and copyright issues for Australian Indigenous dancers were discussed. A free concert was given in Rymill Park / Murlawirrapurka. The troupe was given a grant from the Northern Territory Government to attend the third conference in Sydney in 1999.


title: David Gulpilil

text: In addition to his career in dance, music, film and television, Gulpilil was also an acclaimed storyteller. He wrote the text for two volumes of children's stories based on Yolngu beliefs. These books also feature photographs and drawings by Australian artists, and convey Gulpilil's reverence for the landscape, people and traditional culture of his homeland.


title: David Gulpilil

text: "King brown snake with blue tongue lizard at Gulparil waterhole", painted by Gulpilil in 2013–14, is in the Art Gallery of South Australia's collection.


title: David Gulpilil

text: Gulpilil was appointed a Member of the Order of Australia (AM) in 1987, and the Centenary Medal in 2001.


title: David Gulpilil

text: He twice received the AACTA/AFI Award for Best Actor in a Leading Role, for "The Tracker" in 2002 and "Charlie's Country" in 2014. He was also nominated for this award in 1977 for "Storm Boy". Gulpilil was nominated for the AFI Award for Best Actor in a Supporting Role for "Rabbit-Proof Fence" in 2002. In 2003, he was awarded the inaugural Don Dunstan Award at the Adelaide Film Festival.


title: David Gulpilil

text: He was nominated for the Helpmann Award for Best Male Actor in a Play in 2004 for the stage production "Gulpilil". A portrait of Gulpilil by Craig Ruddy won the 2004 Archibald Prize, Australia's best-known art prize.