title: Eurostar

text: In March 2010, it was announced that Eurotunnel was in discussions with the Intergovernment Commission, which oversees the tunnel, with the aim of amending elements of the safety code governing the tunnel's usage. Most saliently, the requirement that trains be able to split within the tunnel and each part of the train be driven out to opposite ends has been removed. However, the proposal to allow shorter trains was not passed. Eurotunnel Chairman & Chief Executive Jacques Gounon said that he hoped the liberalisation of rules would allow entry into the market of competitors such as Deutsche Bahn. Sources at Eurotunnel suggested that Deutsche Bahn could have entered the market at the timetable change in December 2012. This, however, did not happen.


title: Eurostar

text: In July 2010 Deutsche Bahn (DB) announced that it intended to make a test run with a high-speed ICE-3MF train through the Channel Tunnel in October 2010 in preparation for possible future operations. The trial ran on 19 October 2010 with a Class 406 ICE train specially liveried with a British "Union flag" decal. The train was then put on display for the press at London St Pancras International. However, this is not the class of train that would be used for the proposed service. At the London St Pancras International ceremony, DB revealed that it planned to operate from London to Frankfurt and Amsterdam (two of the biggest air travel markets in Europe), with trains 'splitting & joining' in Brussels. It hoped to begin these services in 2013 using Class 407 ICE units, with three trains per day each way—morning, midday and afternoon. Initially the only calling points would be Rotterdam on the way to Amsterdam, and Köln on the way to Frankfurt. Amsterdam and Köln would be under four hours from London, Frankfurt around five hours. DB decided to put this on hold mainly due to advance passport check requirements. DB had hoped that immigration checks could be done on board, but British authorities required immigration and security checks to be done at Lille-Europe station, taking at least 30 minutes.


title: Eurostar

text: In August 2010, Trenitalia announced its desire to eventually run high-speed trains from Italy to the United Kingdom, using its newly ordered high-speed trains. The trains will be delivered from 2013.


title: Eurostar

text: Cumulative ridership since 1994 has reached 190 million, 11 million passengers had used its international services during 2018, the highest ever, a 7% increase on the 10.3 million carried in 2017.


title: Histamine

text: Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered in 1910, it has been considered a local hormone (autocoid) because it lacks the classic endocrine glands to secrete it; however, in recent years, histamine has been recognized as a central neurotransmitter. Histamine is involved in the inflammatory response and has a central role as a mediator of itching. As part of an immune response to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby connective tissues. Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues. It consists of an imidazole ring attached to an ethylamine chain; under physiological conditions, the amino group of the side-chain is protonated.


title: Histamine

text: Histamine base, obtained as a mineral oil mull, melts at 83–84 °C. Hydrochloride and phosphorus salts form white hygroscopic crystals and are easily dissolved in water or ethanol, but not in ether. In aqueous solution, the imidazole ring of histamine exists in two tautomeric forms, identified by which of the two nitrogen atoms is protonated. The nitrogen farther away from the side chain is the 'tele' nitrogen and is denoted by a lowercase tau sign and the nitrogen closer to the side chain is the 'pros' nitrogen and is denoted by the pi sign. The tele tautomer, "N-H"-histamine, is preferred in solution as compared to the pros tautomer, "N-H"-histamine.


title: Histamine

text: Histamine has two basic centres, namely the aliphatic amino group and whichever nitrogen atom of the imidazole ring does not already have a proton. Under physiological conditions, the aliphatic amino group (having a p"K" around 9.4) will be protonated, whereas the second nitrogen of the imidazole ring (p"K" ≈ 5.8) will not be protonated.


title: Histamine

text: Thus, histamine is normally protonated to a singly charged cation. Since human blood is slightly basic (with a normal pH range of 7.35 to 7.45) therefore the predominant form of histamine present in human blood is monoprotic at the aliphatic nitrogen. Histamine is a monoamine neurotransmitter.


title: Histamine

text: Histamine is derived from the decarboxylation of the amino acid histidine, a reaction catalyzed by the enzyme -histidine decarboxylase. It is a hydrophilic vasoactive amine.


title: Histamine

text: Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-"N"-methyltransferase or diamine oxidase. In the central nervous system, histamine released into the synapses is primarily broken down by histamine-"N"-methyltransferase, while in other tissues both enzymes may play a role. Several other enzymes, including MAO-B and ALDH2, further process the immediate metabolites of histamine for excretion or recycling.


title: Histamine

text: Bacteria also are capable of producing histamine using histidine decarboxylase enzymes unrelated to those found in animals. A non-infectious form of foodborne disease, scombroid poisoning, is due to histamine production by bacteria in spoiled food, particularly fish. Fermented foods and beverages naturally contain small quantities of histamine due to a similar conversion performed by fermenting bacteria or yeasts. Sake contains histamine in the 20–40 mg/L range; wines contain it in the 2–10 mg/L range.


title: Histamine

text: Most histamine in the body is generated in granules in mast cells and in white blood cells (leukocytes) called basophils. Mast cells are especially numerous at sites of potential injury – the nose, mouth, and feet, internal body surfaces, and blood vessels. Non-mast cell histamine is found in several tissues, including the hypothalamus region of the brain, where it functions as a neurotransmitter. Another important site of histamine storage and release is the enterochromaffin-like (ECL) cell of the stomach.


title: Histamine

text: The most important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their membranes, degranulate when exposed to the appropriate antigen. Certain amines and alkaloids, including such drugs as morphine, and curare alkaloids, can displace histamine in granules and cause its release. Antibiotics like polymyxin are also found to stimulate histamine release.


title: Histamine

text: Histamine release occurs when allergens bind to mast-cell-bound IgE antibodies. Reduction of IgE overproduction may lower the likelihood of allergens finding sufficient free IgE to trigger a mast-cell-release of histamine.


title: Histamine

text: Histamine is released by mast cells as an immune response and is later degraded primarily by two enzymes: diamine oxidase (DAO), coded by AOC1 genes, and histamine-N-methyltransferase (HNMT), coded by the HNMT gene. The presence of single nucleotide polymorphisms (SNPs) at these genes are associated with a wide variety of disorders caused by an overactive immune system, from ulcerative colitis to autism spectrum disorder (ASD). Histamine degradation is crucial to the prevention of allergic reactions to otherwise harmless substances.


title: Histamine

text: DAO is typically expressed in epithelial cells at the tip of the villus of the small intestine mucosa. Reduced DAO activity is associated with gastrointestinal disorders and widespread food intolerances. This is due to an increase in histamine absorption through enterocytes, which increases histamine concentration in the bloodstream. One study found that migraine patients with gluten sensitivity were positively correlated with having lower DAO serum levels. Low DAO activity can have more severe consequences as mutations in the ABP1 alleles of the AOC1 gene have been associated with ulcerative colitis. Heterozygous or homozygous recessive genotypes at the rs2052129, rs2268999, rs10156191 and rs1049742 alleles increased the risk for reduced DAO activity. People with genotypes for reduced DAO activity can avoid foods high in histamine, such as alcohol, fermented foods, and aged foods, to attenuate any allergic reactions. Additionally, they should be aware whether any probiotics they are taking contain any histamine-producing strains and consult with their doctor to receive proper support.


title: Histamine

text: HNMT is expressed in the central nervous system, where deficiencies have been shown to lead to aggressive behavior and abnormal sleep-wake cycles in mice. Since brain histamine as a neurotransmitter regulates a number of neurophysiological functions, emphasis has been placed on the development of drugs to target histamine regulation. Yoshikawa et al. explores how the C314T, A939G, G179A, and T632C polymorphisms all impact HNMT enzymatic activity and the pathogenesis of various neurological disorders. These mutations can have either a positive or negative impact. Some patients with ADHD have been shown to exhibit exacerbated symptoms in response to food additives and preservatives, due in part to histamine release. In a double-blind placebo-controlled crossover trial, children with ADHD who responded with aggravated symptoms after consuming a challenge beverage were more likely to have HNMT polymorphisms at T939C and Thr105Ile. Histamine’s role in neuroinflammation and cognition has made it a target of study for many neurological disorders, including autism spectrum disorder (ASD). De novo deletions in the HNMT gene have also been associated with ASD.


title: Histamine

text: Mast cells serve an important immunological role by defending the body from antigens and maintaining homeostasis in the gut microbiome. They act as an alarm to trigger inflammatory responses by the immune system. Their presence in the digestive system enables them to serve as an early barrier to pathogens entering the body. People who suffer from widespread sensitivities and allergic reactions may have mast cell activation syndrome (MCAS), in which excessive amounts of histamine are released from mast cells, and cannot be properly degraded. The abnormal release of histamine can be caused by either dysfunctional internal signals from defective mast cells or by the development of clonal mast cell populations through mutations occurring in the tyrosine kinase Kit. In such cases, the body may not be able to produce sufficient degradative enzymes to properly eliminate the excess histamine. Since MCAS is symptomatically characterized as such a broad disorder, it is difficult to diagnose and can be mislabeled as a variety of diseases, including irritable bowel syndrome and fibromyalgia.


title: Histamine

text: Histamine is often explored as a potential cause for diseases related to hyper-responsiveness of the immune system. In patients with asthma, abnormal histamine receptor activation in the lungs is associated with bronchospasm, airway obstruction, and production of excess mucus. Mutations in histamine degradation are more common in patients with a combination of asthma and allergen hypersensitivity than in those with just asthma. The HNMT-464 TT and HNMT-1639 TT are significantly more common among children with allergic asthma, the latter of which is overrepresented in African-American children.


title: Histamine

text: In humans, histamine exerts its effects primarily by binding to G protein-coupled histamine receptors, designated H through H. As of 2015, histamine is believed to activate ligand-gated chloride channels in the brain and intestinal epithelium.


title: Histamine

text: Although histamine is small compared to other biological molecules (containing only 17 atoms), it plays an important role in the body. It is known to be involved in 23 different physiological functions. Histamine is known to be involved in many physiological functions because of its chemical properties that allow it to be versatile in binding. It is Coulombic (able to carry a charge), conformational, and flexible. This allows it to interact and bind more easily.


title: Histamine

text: It has been known for more than one hundred years that an intravenous injection of histamine causes a fall in the blood pressure. The underlying mechanism concerns both vascular hyperpermeability and vasodilation. Histamine binding to endothelial cells causes them to contract, thus increasing vascular leak. It also stimulates synthesis and release of various vascular smooth muscle cell relaxants, such as nitric oxide, endothelium-derived hyperpolarizing factors and other compounds, resulting in blood vessel dilation. These two mechanisms play a key role in the pathophysiology of anaphylaxis.


title: Histamine

text: Increased vascular permeability causes fluid to escape from capillaries into the tissues, which leads to the classic symptoms of an allergic reaction: a runny nose and watery eyes. Allergens can bind to IgE-loaded mast cells in the nasal cavity's mucous membranes. This can lead to three clinical responses:


title: Histamine

text: Histamine is a neurotransmitter that is released from histaminergic neurons which project out of the mammalian hypothalamus. The cell bodies of these neurons are located in a portion of the posterior hypothalamus known as the tuberomammillary nucleus (TMN). The histamine neurons in this region comprise the brain's histamine system, which projects widely throughout the brain and includes axonal projections to the cortex, medial forebrain bundle, other hypothalamic nuclei, medial septum, the nucleus of the diagonal band, ventral tegmental area , amygdala, striatum, substantia nigra, hippocampus, thalamus and elsewhere. The histamine neurons in the TMN are involved in regulating the sleep-wake cycle and promote arousal when activated. The neural firing rate of histamine neurons in the TMN is strongly positively correlated with an individual's state of arousal. These neurons fire rapidly during periods of wakefulness, fire more slowly during periods of relaxation/tiredness, and stop firing altogether during REM and NREM (non-REM) sleep.


title: Histamine

text: First-generation H antihistamines (i.e., antagonists of histamine receptor H) are capable of crossing the blood–brain barrier and produce drowsiness by antagonizing histamine H receptors in the tuberomammillary nucleus. The newer class of second-generation H antihistamines do not readily permeate the blood–brain barrier and thus are less likely to cause sedation, although individual reactions, concomitant medications and dosage may increase the likelihood of a sedating effect. In contrast, histamine H receptor antagonists increase wakefulness. Similar to the sedative effect of first-generation H antihistamines, an inability to maintain vigilance can occur from the inhibition of histamine biosynthesis or the loss (i.e., degeneration or destruction) of histamine-releasing neurons in the TMN.


title: Histamine

text: Enterochromaffin-like cells, located within the gastric glands of the stomach, release histamine that stimulates nearby parietal cells by binding to the apical H receptor. Stimulation of the parietal cell induces the uptake of carbon dioxide and water from the blood, which is then converted to carbonic acid by the enzyme carbonic anhydrase. Inside the cytoplasm of the parietal cell, the carbonic acid readily dissociates into hydrogen and bicarbonate ions. The bicarbonate ions diffuse back through the basilar membrane and into the bloodstream, while the hydrogen ions are pumped into the lumen of the stomach via a K/H ATPase pump. Histamine release is halted when the pH of the stomach starts to decrease. Antagonist molecules, like ranitidine, block the H receptor and prevent histamine from binding, causing decreased hydrogen ion secretion.


title: Histamine

text: While histamine has stimulatory effects upon neurons, it also has suppressive ones that protect against the susceptibility to convulsion, drug sensitization, denervation supersensitivity, ischemic lesions and stress. It has also been suggested that histamine controls the mechanisms by which memories and learning are forgotten.


title: Histamine

text: Libido loss and erectile failure can occur during treatment with histamine H receptor antagonists such as cimetidine, ranitidine, and risperidone. The injection of histamine into the corpus cavernosum in men with psychogenic impotence produces full or partial erections in 74% of them. It has been suggested that H antagonists may cause sexual difficulties by reducing the functional binding of testosterone to its endogenous receptors.


title: Histamine

text: Metabolites of histamine are increased in the cerebrospinal fluid of people with schizophrenia, while the efficiency of H receptor binding sites is decreased. Many atypical antipsychotic medications have the effect of increasing histamine production, because histamine levels seem to be imbalanced in people with that disorder.


title: Histamine

text: Histamine therapy for treatment of multiple sclerosis is currently being studied. The different H receptors have been known to have different effects on the treatment of this disease. The H and H receptors, in one study, have been shown to be counterproductive in the treatment of MS. The H and H receptors are thought to increase permeability in the blood-brain barrier, thus increasing infiltration of unwanted cells in the central nervous system. This can cause inflammation, and MS symptom worsening. The H and H receptors are thought to be helpful when treating MS patients. Histamine has been shown to help with T-cell differentiation. This is important because in MS, the body's immune system attacks its own myelin sheaths on nerve cells (which causes loss of signaling function and eventual nerve degeneration). By helping T cells to differentiate, the T cells will be less likely to attack the body's own cells, and instead, attack invaders.


title: Histamine

text: As an integral part of the immune system, histamine may be involved in immune system disorders and allergies. "Mastocytosis" is a rare disease in which there is a proliferation of mast cells that produce excess histamine.


title: Histamine

text: Some people may accumulate excessive dietary histamine in their bodies as a result of histamine intolerance. This may lead to symptoms such as hives, itchy or flushed skin, red eyes, facial swelling, runny nose and congestion, headaches, or asthma attacks.


title: Histamine

text: The properties of histamine, then called β-imidazolylethylamine, were first described in 1910 by the British scientists Henry H. Dale and P.P. Laidlaw. By 1913 the name "histamine" was in use, using combining forms of "histo-" + "amine", yielding "tissue amine".


title: Histamine

text: "H substance" or "substance H" are occasionally used in medical literature for histamine or a hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the responses of tissue to inflammation.


title: Ken Leung

text: Kenneth Leung (; born January 21, 1970) is an American actor. His roles include Sang in "Rush Hour", Miles Straume in "Lost", Admiral Statura in "", and Eric Tao in HBO's "Industry".


title: Ken Leung

text: Leung was born in New York City, to Chinese parents, and was initially raised in the Two Bridges section of the Lower East Side of Manhattan. His family moved to Midwood, Brooklyn, where he grew up before finishing high school in Old Bridge, New Jersey.


title: Ken Leung

text: Leung attended New York University as a University Scholar. He discovered acting in his junior year, studying with Catherine Russell and Nan Smithner, and then briefly with Anne Jackson at HB Studio. During this time he acted mostly in downtown spaces and black box theaters, working with groups such as Ma-Yi Theater Company, New Perspectives, and STAR, a troupe of actors-educators based at Mount Sinai Hospital.


title: Ken Leung

text: In 1998, Leung made his debut as the villainous henchman Sang opposite Jackie Chan and Chris Tucker in Brett Ratner's "Rush Hour". Ratner stated, "[Leung]'s a great actor. In my opinion, he's equivalent to Philip Seymour Hoffman as far as talent is concerned." He would later work with Ratner in the films "Red Dragon", "The Family Man", and "". Edward Norton cast Leung in his directorial debut "Keeping the Faith" in 2000. According to "The Washington Post", Norton said Leung's "showstopping performance...turned a throwaway scene into one of the film's best." Impressed with his acting skills, Norton said that Leung would be appropriate for a role in "Hamlet" or Osborne's "Look Back in Anger": "You sense hidden levels within him and he conveys an intensity of mind. I don't think anybody's tapped his full range yet." Additionally, Leung has appeared in several independent and television films, as well as features, including four films with Brett Ratner and two with Spike Lee. In 1998, he played James the Less and God in Terrence McNally's passion play, "Corpus Christi", and in 2002 made his Broadway debut in the musical "Thoroughly Modern Millie", also appearing on the cast recording.


title: Ken Leung

text: In 2007, he starred in the independent film "Shanghai Kiss" with Hayden Panettiere, and earned a Special Mention at the San Francisco International Asian American Film Festival. That same year he guest-starred in the final season of the HBO drama series "The Sopranos". He followed this with the ABC drama "Lost" as Miles Straume from the series' fourth season through the rest of its run.


title: Muskox

text: The muskox (Ovibos moschatus, in Latin "musky sheep-ox"), also spelled musk ox and musk-ox, plural muskoxen or musk oxen (in ; in Woods Cree: ), is a hoofed mammal of the family Bovidae. Native to the Arctic, it is noted for its thick coat and for the strong odor emitted by males during the seasonal rut, from which its name derives. This musky odor has the effect of attracting females during mating season. Its Inuktitut name "umingmak" translates to "the bearded one".


title: Muskox

text: Its Woods Cree names "mâthi-môs" and "mâthi-mostos" translate to "ugly moose" and "ugly bison", respectively. Muskoxen primarily live in Greenland and the Canadian Arctic of the Northwest Territories and Nunavut, with reintroduced populations in the American state of Alaska, the Canadian territory of Yukon, and Siberia, and an introduced population in Norway, part of which emigrated to Sweden, where a small population now lives.


title: Muskox

text: The muskox is in the subtribe Ovibovina (or tribe Ovibovini) in the tribe Caprini (or subfamily Caprinae) of the subfamily Antilopinae in the family Bovidae. It is more closely related to sheep and goats than to oxen; it is placed in its own genus, "Ovibos" (Latin: "sheep-ox"). It is one of the two largest extant members of the caprines, along with the similarly sized takin. While the takin and muskox were once considered possibly closely related, the takin lacks common ovibovine features, such as the muskox's specialized horn morphology, and genetic analysis shows that their lineages actually separated early in caprine evolution. Instead, the muskox's closest living relatives appear to be the gorals of the genus "Naemorhedus", nowadays common in many countries of central and east Asia. The vague similarity between takin and muskox is therefore an example of convergent evolution.


title: Muskox

text: The modern muskox is the last member of a line of ovibovines that first evolved in temperate regions of Asia and adapted to a cold tundra environment late in its evolutionary history. Muskox ancestors with sheep-like high-positioned horns (horn cores being mostly over the plane of the frontal bones, rather than below them as in modern muskoxen) first left the temperate forests for the developing grasslands of Central Asia during the Pliocene, expanding into Siberia and the rest of northern Eurasia. Later migration waves of Asian ungulates that included high-horned muskoxen reached Europe and North America during the first half of the Pleistocene. The first well known muskox, the "shrub-ox" "Euceratherium", crossed to North America over an early version of the Bering Land Bridge two million years ago and prospered in the American southwest and Mexico. "Euceratherium" was larger yet more lightly built than modern muskoxen, resembling a giant sheep with massive horns, and preferred hilly grasslands.


title: Muskox

text: A genus with intermediate horns, "Soergelia", inhabited Eurasia in the early Pleistocene, from Spain to Siberia, and crossed to North America during the Irvingtonian (1.8 million years to 240,000 years ago), soon after "Euceratherium". Unlike "Euceratherium", which survived in America until the Pleistocene-Holocene extinction event, "Soergelia" was a lowland dweller that disappeared fairly early, displaced by more advanced ungulates, such as the "giant muskox" "Praeovibos" (literally "before "Ovibos""). The low-horned "Praeovibos" was present in Europe and the Mediterranean 1.5 million years ago, colonized Alaska and the Yukon one million years ago and disappeared half a million years ago. "Praeovibos" was a highly adaptable animal that appears associated with cold tundra (reindeer) and temperate woodland (red deer) faunas alike. During the Mindel glaciation 500,000 years ago, "Praeovibos" was present in the Kolyma river area in eastern Siberia in association with many Ice Age megafauna that would later coexist with "Ovibos", in the Kolyma itself and elsewhere, including wild horses, reindeer, woolly mammoth and stag-moose. It is debated, however, if "Praeovibos" was directly ancestral to "Ovibos", or both genera descended from a common ancestor, since the two occurred together during the middle Pleistocene. Defenders of ancestry from "Praeovibos" have proposed that "Praeovibos" evolved into "Ovibos" in one region during a period of isolation and expanded later, replacing the remaining populations of "Praeovibos".


title: Muskox

text: Two more "Praeovibos"-like genera were named in America in the 19th century, "Bootherium" and "Symbos", which are now identified as the male and female forms of a single, sexually dimorphic species, the "woodland muskox", "Bootherium bombifrons". "Bootherium" inhabited open woodland areas of North America during the late Pleistocene, from Alaska to Texas and maybe even Mexico, but was most common in the Southern United States, while "Ovibos" replaced it in the tundra-steppe to the north, immediately south of the Laurentian ice sheet.


title: Muskox

text: Modern "Ovibos" appeared in Germany almost one million years ago and was common in the region through the Pleistocene. By the Mindel, muskoxen had also reached the British Isles. Both Germany and Britain were just south of the Scandinavian ice sheet and covered in tundra during cold periods, but Pleistocene muskoxen are also rarely recorded in more benign and wooded areas to the south like France and Green Spain, where they coexisted with temperate ungulates like red deer and aurochs. Likewise, the muskox is known to have survived in Britain during warm interglacial periods.


title: Muskox

text: Today's muskoxen are descended from others believed to have migrated from Siberia to North America between 200,000 and 90,000 years ago, having previously occupied Alaska (at the time united to Siberia and isolated periodically from the rest of North America by the union of the Laurentide and Cordilleran Ice Sheets during colder periods) between 250,000 and 150,000 years ago. After migrating south during one of the warmer periods of the Illinoian glaciation, non-Alaskan American muskoxen would be isolated from the rest in the colder periods. The muskox was already present in its current stronghold of Banks Island 34,000 years ago, but the existence of other ice-free areas in the Canadian Arctic Archipelago at the time is disputed.


title: Muskox

text: Along with the bison and the pronghorn, the muskox was one of a few species of Pleistocene megafauna in North America to survive the Pleistocene/Holocene extinction event and live to the present day. The muskox is thought to have been able to survive the last glacial period by finding ice-free areas (refugia) away from prehistoric peoples.


title: Muskox

text: Fossil DNA evidence suggests that muskoxen were not only more geographically widespread during the Pleistocene, but also more genetically diverse. During that time, other populations of muskoxen lived across the Arctic, from the Ural Mountains to Greenland. By contrast, the current genetic makeup of the species is more homogenous. Climate fluctuation may have affected this shift in genetic diversity: research indicates colder periods in Earth's history are correlated with more diversity, and warmer periods with more homogeneity.


title: Muskox

text: Both male and female muskoxen have long, curved horns. Muskoxen stand high at the shoulder, with females measuring in length, and the larger males . The small tail, often concealed under a layer of fur, measures only long. Adults, on average, weigh and range from . The thick coat and large head suggest a larger animal than the muskox truly is; the bison, to which the muskox is often compared, can weigh up to twice as much. However, heavy zoo-kept specimens have weighed up to . Their coat, a mix of black, grey, and brown, includes long guard hairs that almost reach the ground. Rare "white muskoxen" have been spotted in the Queen Maud Gulf Bird Sanctuary. Muskoxen are occasionally domesticated for wool, meat, and milk. The wool, qiviut, is highly prized for its softness, length, and insulation value. Prices for yarn range between .


title: Muskox

text: During the Pleistocene period, muskoxen were much more widespread. Fossil evidence shows that they lived across the Siberian and North American Arctic, from the Urals to Greenland. The ancestors of today's muskoxen came across the Bering Land Bridge to North America between 200,000 and 90,000 years ago. During the Wisconsinan, modern muskox thrived in the tundra south of the Laurentide Ice Sheet, in what is now the Midwest, the Appalachians and Virginia, while distant relatives "Bootherium" and "Euceratherium" lived in the forests of the Southern United States and the western shrubland, respectively. Though they were always less common than other Ice Age megafauna, muskox abundance peaked during the Würm II glaciation 20,000 years ago and declined afterwards, especially during the Pleistocene/Holocene extinction event, where its range was greatly reduced and only the populations in North America survived. The last known muskox population in Europe died out in Sweden 9,000 years ago, and the last one in Asia, which lived on Siberia's Taymyr Peninsula, about 2,000 years ago.


title: Muskox

text: After the disappearance of the Laurentide Ice Sheet, the muskox gradually moved north across the Canadian Arctic Archipelago, arriving in Greenland from Ellesmere Island at about 350 AD, during the late Holocene. Their arrival in northwestern Greenland probably occurred within a few hundred years of the arrival of the Dorset and Thule cultures in the present-day Qaanaaq area. Human predation around Qaanaaq may have restricted muskoxen from moving down the west coast, and instead kept them confined to the northeastern fringes of the island.


title: Muskox

text: In modern times, muskoxen were restricted to the Arctic areas of Northern Canada, Greenland, and Alaska. The Alaskan population was wiped out in the late 19th or early 20th century. Their depletion has been attributed to excessive hunting, but an adverse change in climate may have contributed. However, muskoxen have since been reintroduced to Alaska. The United States Fish and Wildlife Service introduced the muskox onto Nunivak Island in 1935 to support subsistence living. Other reintroduced populations are in Arctic National Wildlife Refuge, Bering Land Bridge National Preserve, Yukon's Ivvavik National Park, a wildlife conservation center in Anchorage, Aulavik National Park in Northwest Territories, Kanuti National Wildlife Refuge, Gates of the Arctic National Park, and Whitehorse, Yukon's wildlife preserve.


title: Muskox

text: There have been at least two domestication endeavours. In the 1950s an American researcher and adventurer was able to capture muskox calves in Northern Canada for relocation to a property he prepared in Vermont. One condition imposed by the Canadian government was he was not allowed to kill adults defending their young. When nets and ropes proved useless, he and his crew herded family groups into open water, where calves were successfully separated from the adults. Once airfreighted to Montreal and trucked to Vermont, the young animals habituated to the temperate conditions. Although the calves thrived and grew to adulthood, parasite and disease resistance problems impaired the overall success of the effort. The surviving herd was eventually moved to a farm in Palmer, Alaska, where it has been successful since the mid-1950s.


title: Muskox

text: The species was reintroduced from Banks Island to the Dovre mountain range of Norway in 1932 but were hunted to extinction there during the Second World War. It was reintroduced to Norway in 1947; this population expanded into Härjedalen, Sweden, in 1971.


title: Muskox

text: In 1913, workers building a railway over Dovrefjell found two fossil muskox vertebrae. This led to the idea of introducing muskoxen to Norway from Greenland. The first release in the world was made on Gurskøy outside Ålesund in 1925–26. They were muskoxen caught by Norwegian seal-hunting boats in Greenland. The animals colonized the island, but eventually died out there. An attempt to introduce the muskox to Svalbard also failed. Seventeen animals were released in 1929 by Adventfjorden on West Spitsbergen. In 1940, the herd numbered 50, but in the 1970s, the whole herd disappeared. In September 1932, polar researcher Adolf Hoel conducted another experiment, importing 10 muskoxen to Dovrefjell. This herd survived until World War II, when they were hunted and exterminated. In 1947 and later, new animals were released. A small group of muskoxen from Dovrefjell migrated across the national border to Sweden in 1971 and established themselves in Härjedalen, whereby a Swedish herd was established.


title: Muskox

text: The Norwegian population on Dovrefjell is managed over an area of and in the summer of 2012 consisted of approximately 300 animals. Since 1999, the population has mostly been increasing, but it suffered a measles outbreak in the summer of 2004 that killed 29. Some animals are also occasionally killed as a result of train collisions on the Dovre Railway. The population is divided into flocks in the Nystuguhø area, Kolla area and Hjerkinn. In the summer they move down towards Driva, where there are lush grass pastures.


title: Muskox

text: Although the muskox belongs to the dry Arctic grassland, it seems to do well on Dovrefjell. However, the pastures are marginal, with little grass available in winter (the muskox eats only plants, not lichen as reindeer do), and over time, inbreeding depression is expected in such a small population which originated from only a few introduced animals.


title: Muskox

text: In addition to the population on Dovrefjell, the University of Tromsø had some animals on outside Tromsø until 2018.


title: Muskox

text: Muskoxen were introduced to Svalbard in 1925–26 and 1929, but this population died out in the 1970s. They were also introduced in Iceland around 1930 but did not survive.


title: Muskox

text: In Russia, animals imported from Banks and Nunivak were released in the Taymyr Peninsula in 1974 and 1975, and some from Nunivak were released in Wrangel Island in 1975. Both locations are north of the Arctic Circle. By 2019 the population on Wrangel Island was about 1100, and the Taymyr Peninsula, about 11,000–14,000. A few muskoxen herds migrated from the Taymyr Peninsula far to the south to the Putorana Plateau. Once established, these populations have been, in turn, used as sources for further reintroductions in Siberia between 1996 and 2010. One of the last of these actions was the release of six animals within the Pleistocene Park project area in the Kolyma River in 2010, where a team of Russian scientists led by Sergey Zimov aims to prove that muskoxen, along with other Pleistocene megafauna that survived into the early Holocene in northern Siberia, did not disappear from the region due to climate change, but because of human hunting.


title: Muskox

text: Ancient muskox remains have never been found in eastern Canada, although the ecological conditions in the northern Labrador Peninsula are suitable for them. In 1967, 14 animals were captured near Eureka on Ellesmere Island by the Institute for Northern Agricultural Research (INAR) and brought to a farm in Old Fort Chimo Kuujjuaq, northern Quebec, for domestication to provide a local cottage industry based on "qiviut", a fine natural fiber. The animals thrived and the "qiviut" industry showed early success with the training of Inuit knitters and marketing, but it soon became clear that the Quebec government had never intended that the muskoxen be domestic, but had used INAR to capture muskoxen to provide a wild population for hunting. Government officials demanded that INAR leave Quebec and the farm be closed. Subsequently, 54 animals from the farm were released in three places in northern Quebec between 1973 and 1983, and the remaining were ceded to local zoos. Between 1983 and 1986, the released animals increased from 148 to 290, at a rate of 25% per year, and by 2003, an estimated 1,400 muskoxen were in Quebec. Additionally, 112 adults and 25 calves were counted in the nearby Diana Island in 2005, having arrived there by their own means from the mainland. Vagrant adults are sometimes spotted in Labrador, though no herds have been observed in the region.


title: Muskox

text: During the summer, muskoxen live in wet areas, such as river valleys, moving to higher elevations in the winter to avoid deep snow. Muskoxen will eat grasses, arctic willows, woody plants, lichens, and mosses. When food is abundant, they prefer succulent and nutritious grasses in an area. Willows are the most commonly eaten plants in the winter. Muskoxen require a high threshold of fat reserves in order to conceive, which reflects their conservative breeding strategy. Winter ranges typically have shallow snow to reduce the energy costs of digging through snow to reach forage. The primary predators of muskoxen are arctic wolves, which may account for up to half of all mortality for the species. Other occasional predators, likely mainly predators of calves or infirm adults, can include grizzly bears and polar bears.


title: Muskox

text: Muskox are heterothermic mammals, meaning they have the ability to shut off thermal regulation in some parts of their body, like their lower limbs. Maintaining the lower limbs at a cooler temperature than the rest of their body helps reduce the loss of body heat from their extremities. Muskox display the unique characteristic of having hemoglobin that is three times less temperature sensitive than human hemoglobin. This temperature insensitivity allows the muskox’s hemoglobin to have a heightened oxygen affinity in an extremely cold environment and continue to diffuse high amounts of oxygen into its cold tissues.


title: Muskox

text: Muskoxen live in herds of 12–24 in the winter and 8–20 in the summer. They do not hold territories, but they do mark their trails with preorbital glands. Male and female muskoxen have separate age-based hierarchies, with mature oxen being dominant over juveniles. Dominant oxen tend to get access to the best resources and will displace subordinates from patches of grass during the winter. Muskox bulls assert their dominance in many different ways. One is a "rush and butt", in which a dominant bull rushes a subordinate from the side with its horns, and will warn the subordinate so it can have a chance to get away. Bulls will also roar, swing their heads, and paw the ground. Dominant bulls sometimes treat subordinate bulls like cows. A dominant bull will tap a subordinate with its foreleg, something they do to cows during mating. Dominant bulls will also mock copulate subordinates and sniff their genitals. A subordinate bull can change his status by charging a dominant bull.


title: Muskox

text: The mating (or "rutting") season of the muskoxen begins in late June or early July. During this time, dominant bulls will fight others out of the herds and establish harems of usually six or seven cows and their offspring. Fighting bulls will first rub their preorbital glands against their legs while bellowing loudly, and then display their horns. The bulls then back up about , lower their heads, and charge into each other, and will keep doing so until one bull gives up. Subordinate and elderly bulls will leave the herds to form bachelor groups or become solitary. However, when danger is present, the outside bulls can return to the herd for protection. Dominant bulls will prevent cows from leaving their harems. During mating, a bull will tap an estrous cow with his foreleg to calm her down and make her more receptive to his advances. The herds reassemble when summer ends.


title: Muskox

text: While the bulls are more aggressive during the rutting season and lead their groups, the females take charge during gestation. Pregnant females are aggressive and decide what distance the herd travels in a day and where they will bed for the night. The herds move more often when cows are lactating, to let them get enough food to nurse their offspring. Cows have an eight- to nine-month gestation period, with calving occurring from April to June. Cows do not calve every year. When winters are severe, cows will not go into estrus and thus not calve the next year. When calving, cows stay in the herd for protection. Muskox are precocial, and calves can keep up with the herd within just a few hours after birth. The calves are welcomed into the herd and nursed for the first two months. After that, a calf then begins eating vegetation and nurses only occasionally. Cows communicate with their calves through braying. The calf's bond with its mother weakens after two years.


title: Muskox

text: Muskoxen have a distinctive defensive behavior: when the herd is threatened, the adults will face outward to form a stationary ring or semicircle around the calves. The bulls are usually the front line for defense against predators, with the cows and juveniles gathering close to them. Bulls determine the defensive formation during rutting, while the cows decide the rest of the year.


title: Muskox

text: The preorbital gland secretion of muskoxen has a "light, sweetish, ethereal" odor. Analysis of preorbital gland secretion extract showed the presence of cholesterol (which is nonvolatile), benzaldehyde, a series of straight-chain saturated γ-lactones ranging from CHO to CHO (with CHO being most abundant), and probably the monounsaturated γ-lactone CHO. The saturated γ-lactone series has an odor similar to that of the secretion.


title: Muskox

text: The odor of dominant rutting males is described as "strong" and "rank". It derives from the preputial gland and is distributed over the fur of the abdomen via urine. Analysis of extract of washes of the prepuce revealed the presence of benzoic acid and "p"-cresol, along with a series of straight-chain saturated hydrocarbons from CH to CH (with CH being most abundant).


title: Muskox

text: Muskox are not known to be aggressive but have occasionally attacked humans who came close, although fatal attacks are extremely rare.


title: Muskox

text: On 22 July 1964, a 73-year-old man was killed in a muskox attack in Norway. The animal was later killed by local authorities.


title: Muskox

text: On 13 December 2022, a court services officer with the Alaska State Troopers was killed by a muskox near Nome, Alaska. The officer was trying to scare away a group of muskox near a dog kennel at his home when one of the animals attacked him.


title: Muskox

text: Historically, this species declined because of overhunting, but population recovery has taken place following enforcement of hunting regulations. Management in the late 1900s was mostly conservative hunting quotas to foster recovery and recolonization from the historic declines. The current world population of muskoxen is estimated at between 80,000 and 125,000, with an estimated 47,000 living on Banks Island.


title: Muskox

text: In Greenland there are no major threats, although populations are often small in size and scattered, which makes them vulnerable to local fluctuations in climate. Most populations are within national parks, where they are protected from hunting. Muskoxen occur in four of Greenland's protected areas, with indigenous populations in Northeast Greenland National Park and introduced populations in and Kangerlussuaq and Maniitsoq Caribou Reserves. Within these areas, muskoxen receive full protection.


title: Single sign-on

text: Single sign-on (SSO) is an authentication scheme that allows a user to log in with a single ID to any of several related, yet independent, software systems.


title: Single sign-on

text: True single sign-on allows the user to log in once and access services without re-entering authentication factors.


title: Single sign-on

text: It should not be confused with same-sign on (Directory Server Authentication), often accomplished by using the Lightweight Directory Access Protocol (LDAP) and stored LDAP databases on (directory) servers.


title: Single sign-on

text: A simple version of single sign-on can be achieved over IP networks using cookies but only if the sites share a common DNS parent domain.


title: Single sign-on

text: For clarity, a distinction is made between Directory Server Authentication (same-sign on) and single sign-on: Directory Server Authentication refers to systems requiring authentication for each application but using the same credentials from a directory server, whereas single sign-on refers to systems where a single authentication provides access to multiple applications by passing the authentication token seamlessly to configured applications.


title: Single sign-on

text: Conversely, single sign-off or single log-out (SLO) is the property whereby a single action of signing out terminates access to multiple software systems.


title: Single sign-on

text: As different applications and resources support different authentication mechanisms, single sign-on must internally store the credentials used for initial authentication and translate them to the credentials required for the different mechanisms.


title: Single sign-on

text: Other shared authentication schemes, such as OpenID and OpenID Connect, offer other services that may require users to make choices during a sign-on to a resource, but can be configured for single sign-on if those other services (such as user consent) are disabled. An increasing number of federated social logons, like Facebook Connect, do require the user to enter consent choices upon first registration with a new resource, and so are not always single sign-on in the strictest sense.


title: Single sign-on

text: SSO shares centralized authentication servers that all other applications and systems use for authentication purposes and combines this with techniques to ensure that users do not have to actively enter their credentials more than once.


title: Single sign-on

text: The term "reduced sign-on" (RSO) has been used by some to reflect the fact that "single sign-on" is impractical in addressing the need for different levels of secure access in the enterprise, and as such more than one authentication server may be necessary.


title: Single sign-on

text: As single sign-on provides access to many resources once the user is initially authenticated ("keys to the castle"), it increases the negative impact in case the credentials are available to other people and misused. Therefore, single sign-on requires an increased focus on the protection of the user credentials, and should ideally be combined with strong authentication methods like smart cards and one-time password tokens.


title: Single sign-on

text: Single sign-on also makes the authentication systems highly critical; a loss of their availability can result in denial of access to all systems unified under the SSO. SSO can be configured with session failover capabilities in order to maintain the system operation. Nonetheless, the risk of system failure may make single sign-on undesirable for systems to which access must be guaranteed at all times, such as security or plant-floor systems.


title: Single sign-on

text: Furthermore, the use of single-sign-on techniques utilizing social networking services such as Facebook may render third party websites unusable within libraries, schools, or workplaces that block social media sites for productivity reasons. It can also cause difficulties in countries with active censorship regimes, such as China and its "Golden Shield Project," where the third party website may not be actively censored, but is effectively blocked if a user's social login is blocked.


title: Single sign-on

text: In March, 2012, a research paper reported an extensive study on the security of social login mechanisms. The authors found 8 serious logic flaws in high-profile ID providers and relying party websites, such as OpenID (including Google ID and PayPal Access), Facebook, Janrain, Freelancer, FarmVille, and Sears.com. Because the researchers informed ID providers and relying party websites prior to public announcement of the discovery of the flaws, the vulnerabilities were corrected, and there have been no security breaches reported.


title: Single sign-on

text: In May 2014, a vulnerability named Covert Redirect was disclosed. It was first reported "Covert Redirect Vulnerability Related to OAuth 2.0 and OpenID" by its discoverer Wang Jing, a Mathematical PhD student from Nanyang Technological University, Singapore. In fact, almost all Single sign-on protocols are affected. Covert Redirect takes advantage of third-party clients susceptible to an XSS or Open Redirect.


title: Single sign-on

text: In December 2020, flaws in federated authentication systems were discovered to have been utilized by attackers during the 2020 United States federal government data breach.


title: Single sign-on

text: Due to how single sign-on works, by sending a request to the logged-in website to get a SSO token and sending a request with the token to the logged-out website, the token cannot be protected with the HttpOnly cookie flag and thus can be stolen by an attacker if there is an XSS vulnerability on the logged-out website, in order to do session hijacking. Another security issue is that if the session used for SSO is stolen (which can be protected with the HttpOnly cookie flag unlike the SSO token), the attacker can access all the websites that are using the SSO system.


title: Single sign-on

text: As originally implemented in Kerberos and SAML, single sign-on did not give users any choices about releasing their personal information to each new resource that the user visited. This worked well enough within a single enterprise, like MIT where Kerberos was invented, or major corporations where all of the resources were internal sites. However, as federated services like Active Directory Federation Services proliferated, the user's private information was sent out to affiliated sites not under control of the enterprise that collected the data from the user. Since privacy regulations are now tightening with legislation like the GDPR, the newer methods like OpenID Connect have started to become more attractive; for example MIT, the originator of Kerberos, now supports OpenID Connect.


title: Single sign-on

text: Single sign-on in theory can work without revealing identifying information such as email addresses to the relying party (credential consumer), but many credential providers do not allow users to configure what information is passed on to the credential consumer. As of 2019, Google and Facebook sign-in do not require users to share email addresses with the credential consumer. 'Sign in with Apple' introduced in iOS 13 allows a user to request a unique relay email address each time the user signs up for a new service, thus reducing the likelihood of account linking by the credential consumer.


title: Single sign-on

text: Windows environment - Windows login fetches TGT. Active Directory-aware applications fetch service tickets, so the user is not prompted to re-authenticate.


title: Single sign-on

text: Unix/Linux environment - Login via Kerberos PAM modules fetches TGT. Kerberized client applications such as Evolution, Firefox, and SVN use service tickets, so the user is not prompted to re-authenticate.


title: Single sign-on

text: Initial sign-on prompts the user for the smart card. Additional software applications also use the smart card, without prompting the user to re-enter credentials. Smart-card-based single sign-on can either use certificates or passwords stored on the smart card.


title: Single sign-on

text: "Integrated Windows Authentication" is a term associated with Microsoft products and refers to the SPNEGO, Kerberos, and NTLMSSP authentication protocols with respect to SSPI functionality introduced with Microsoft Windows 2000 and included with later Windows NT-based operating systems. The term is most commonly used to refer to the automatically authenticated connections between Microsoft Internet Information Services and Internet Explorer. Cross-platform Active Directory integration vendors have extended the Integrated Windows Authentication paradigm to Unix (including Mac) and Linux systems.


title: Single sign-on

text: Security Assertion Markup Language (SAML) is an XML-based method for exchanging user security information between an SAML identity provider and a SAML service provider. SAML 2.0 supports W3C XML encryption and service-provider–initiated web browser single sign-on exchanges. A user wielding a user agent (usually a web browser) is called the subject in SAML-based single sign-on. The user requests a web resource protected by a SAML service provider. The service provider, wishing to know the identity of the user, issues an authentication request to a SAML identity provider through the user agent. The identity provider is the one that provides the user credentials. The service provider trusts the user information from the identity provider to provide access to its services or resources.


title: Single sign-on

text: A newer variation of single-sign-on authentication has been developed using mobile devices as access credentials. Users' mobile devices can be used to automatically log them onto multiple systems, such as building-access-control systems and computer systems, through the use of authentication methods which include OpenID Connect and SAML, in conjunction with an X.509 ITU-T cryptography certificate used to identify the mobile device to an access server.


title: Single sign-on

text: A mobile device is "something you have," as opposed to a password which is "something you know," or biometrics (fingerprint, retinal scan, facial recognition, etc.) which is "something you are." Security experts recommend using at least two out of these three factors (multi-factor authentication) for best protection.


title: Osteogenesis imperfecta

text: Osteogenesis imperfecta (; OI), colloquially known as brittle bone disease, is a group of genetic disorders that all result in bones that break easily. The range of symptoms—on the skeleton as well as on the body's other organs—may be mild to severe. Symptoms found in various types of OI include whites of the eye (sclerae) that are blue instead, short stature, loose joints, hearing loss, breathing problems and problems with the teeth (dentinogenesis imperfecta). Potentially life-threatening complications, all of which become more common in more severe OI, include: tearing (dissection) of the major arteries, such as the aorta; pulmonary valve insufficiency secondary to distortion of the ribcage; and basilar invagination.


title: Osteogenesis imperfecta

text: The underlying mechanism is usually a problem with connective tissue due to a lack of, or poorly formed, type I collagen. In more than 90% of cases, OI occurs due to mutations in the "COL1A1" or "COL1A2" genes. These mutations may be inherited from a person's parents in an autosomal dominant manner but may also occur spontaneously ("de novo"). There are four clinically defined types: type I, the least severe; type IV, moderately severe; type III, severe and progressively deforming; and type II, perinatally lethal. , 19 different genes are known to cause the 21 documented genetically defined types of OI, many of which are extremely rare and have only been documented in a few individuals. Diagnosis is often based on symptoms and may be confirmed by collagen biopsy or DNA sequencing.


title: Osteogenesis imperfecta

text: Although there is no cure, most cases of OI do not have a major effect on life expectancy, death during childhood from it is rare, and many adults with OI can achieve a significant degree of autonomy despite disability. Maintaining a healthy lifestyle by exercising, eating a balanced diet sufficient in vitamin D and calcium, and avoiding smoking can help prevent fractures. Genetic counseling may be sought by those with OI to prevent their children from inheriting the disorder from them. Treatment may include acute care of broken bones, pain medication, physical therapy, mobility aids such as leg braces and wheelchairs, vitamin D supplementation, and, especially in childhood, rodding surgery. Rodding is an implantation of metal intramedullary rods along the long bones (such as the femur) in an attempt to strengthen them. Medical research also supports the use of medications of the bisphosphonate class, such as pamidronate, to increase bone density. Bisphosphonates are especially effective in children, however it is unclear if they either increase quality of life or decrease the rate of fracture incidence.


title: Osteogenesis imperfecta

text: OI affects only about one in 15,000 to 20,000 people, making it a rare genetic disease. Outcomes depend on the genetic cause of the disorder (its type). Type I (the least severe) is the most common, with other types comprising a minority of cases. Moderate-to-severe OI primarily affects mobility; if rodding surgery is performed during childhood, some of those with more severe types of OI may gain the ability to walk. The condition has been described since ancient history. The Latinate term "osteogenesis imperfecta" was coined by Dutch anatomist Willem Vrolik in 1849; translated literally, it means "imperfect bone formation".


title: Osteogenesis imperfecta

text: The main symptom of osteogenesis imperfecta is fragile, low mineral density bones; all types of OI have some bone involvement. In moderate and especially severe OI, the long bones may be bowed, sometimes extremely so. The weakness of the bones causes them to fracture easily; a study in Pakistan found an average of 5.8 fractures per year in untreated children. Fractures typically occur much less after puberty, but begin to increase again in women after menopause and in men between the ages of 60 and 80.


title: Osteogenesis imperfecta

text: Joint hypermobility is also a common sign of OI, thought to be because the affected genes are the same as those that cause some types of Ehlers–Danlos syndrome.


title: Osteogenesis imperfecta

text: By the age of 50, about 50% of adults with OI experience significant hearing loss, much earlier as compared to the general population. Hearing loss in OI may or may not be associated with visible deformities of the ossicles and inner ear. Hearing loss frequently begins during the second, third, and fourth decades of life, and may be conductive, sensorineural, or a combination of both ("mixed"). If hearing loss does not occur by age 50, it is significantly less likely to occur in the years afterwards. Mixed hearing loss is most common among those with OI of all age groups, while conductive hearing loss is most likely to affect older people, with sensorineural hearing loss most likely to affect children.


title: Osteogenesis imperfecta

text: Although relatively rare, OI-related hearing loss can also begin in childhood; in a study of forty-five children aged four to sixteen, two were found to be affected, aged 11 and 15. In a different 2008 study, the hearing of 41 people with OI was checked. The results showed that 88% of those over 20 years of age had some form of hearing loss, while only 38% of those under 20 did.


title: Osteogenesis imperfecta

text: Hearing loss is most common in type I OI; it is less common in types III and IV. Other parts of the inner ear may also be affected by OI. causing balance issues; however, only small studies have found links between vertigo and OI. OI may worsen the outcome of medical treatments which correct hearing loss.


title: Osteogenesis imperfecta

text: Besides OI's association with sensorineural hearing loss, OI is associated with a number of neurological abnormalities, usually involving the central nervous system, due to deformities in the skeletal structures surrounding it. Neurological complications, especially basilar invagination, may adversely affect life expectancy. In OI, this is most often due to upwards migration of the dens, a feature of the C2 vertebra. Neurosurgery may be needed to correct severe abnormalities when they risk the patient's life or cause either great suffering or intolerable neurological deficits.


title: Osteogenesis imperfecta

text: As its biological causes have been more precisely determined, it has become more widely recognized that while the primary disease process of OI happens in the bones, the most common types of OI—those caused by type I collagen gene mutations—affect virtually all of the human body's organs in some way.


title: Osteogenesis imperfecta

text: Type I collagen is present throughout the circulatory and respiratory systems: from the ventricles of the heart itself, to the heart valves, to the vasculature, it is an integral part of the connective tissue of the lungs. As such, cardiovascular complications, among them aortic insufficiency, aortic aneurysm, and arterial dissections, are sometimes comorbid with OI, but not as frequently as they are comorbid with Marfan syndrome.


title: Osteogenesis imperfecta

text: Respiratory illnesses are a major cause of death in OI. The most obvious source of respiratory problems in OI is pulmonary insufficiency caused by problems in the architecture of the thoracic wall. However, respiratory tract infections, such as pneumonia, are also more fatal among those with OI than the general population. Those with more severe ribcage deformities were found to have worse lung restriction in a small-scale 2012 study involving 22 Italian patients with OI types III and IV, plus 26 non-affected controls.


title: Osteogenesis imperfecta

text: OI—especially its severe form type III—also has effects on the gastrointestinal system. It was found to be associated with recurrent abdominal pain and chronic constipation in two studies on patients affected by OI. Chronic constipation is especially common, and is thought to be aggravated by an asymmetric pelvis (acetabular protrusion). Especially in childhood, OI-associated constipation may cause a feeling of fullness and associated food refusal, leading to malnutrition.


title: Osteogenesis imperfecta

text: There are two typing systems for OI in modern use. The first, created by David Sillence in 1979, classifies patients into four types, or syndromes, according to their clinical presentation, without taking into account the genetic cause of their disease. The second system expands on the Sillence model, but assigns new numbered types genetically as they are found. Therefore, people with OI can be described as having both a "clinical" type and a "genetic" type, which may or may not be equivalent.


title: Osteogenesis imperfecta

text: Type I is the most common, and 90% of cases result from mutations to either "COL1A1" or "COL1A2". Symptoms vary a lot between types, as well as vary from person to person, even in the same family.


title: Osteogenesis imperfecta

text: Sillence's four types have both a clinical and a genetic meaning; the descriptions below are clinical and can be applied to several genetic types of OI. When used to refer to a genetic as well as a clinical type, it indicates that the clinical symptoms are indeed caused by mutations in the "COL1A1" or "COL1A2" genes which are inherited in an autosomal dominant fashion.


title: Osteogenesis imperfecta

text: Collagen is of normal quality but is produced in insufficient quantities. Bones fracture more easily than in the general public, but not as easily as more severe types of OI; there might be scoliosis, albeit mild compared to OI types III and IV, with a lower Cobb angle; the joints may be loose; blue sclerae may be apparent; hearing loss is likely to occur; and there might be a slight decrease in height. Because cases exist missing one or more of these symptoms, OI type I in some cases goes undetected into adulthood.


title: Osteogenesis imperfecta

text: Some further split type I into types I–A and I–B, defined as being distinguished by the absence (I–A) or presence (I–B) of dentinogenesis imperfecta (opalescent teeth). People with type I generally have a normal lifespan.


title: Osteogenesis imperfecta

text: Collagen is fatally defective at its C-terminus. Most cases result in death shortly after birth, or within the first year of life, due to respiratory failure. Another common cause of death is intracranial bleeds from skull fractures present at, or sustained during or shortly after, birth. In many cases, the newborn already has multiple broken bones at the time of birth. Type II infants also exhibit severe respiratory problems, and have severely deformed bones. Sixty percent of infants die less than 24 hours after being born, and survival after the first year is extremely unlikely and normally requires mechanical ventilation. In the rare cases of infants who survive their first year of life, severe developmental and motor delays are seen; neither of two infants studied in 2019, both aged around two years, had achieved head control, and both required a ventilator to breathe.


title: Osteogenesis imperfecta

text: Type II is also known as the "lethal perinatal" form of OI, and is not compatible with survival into adulthood. Due to similarly severely deformed bones, sometimes infants with severe type III are wrongly initially classified as type II; once long-term survival is shown, they are considered as having type III instead.


title: Osteogenesis imperfecta

text: Collagen quantity is sufficient, but is not of a high enough quality. Clinical differentiation between types III and IV is not always simple, and is further confounded by the fact that an untreated adult with type IV may have worse symptoms than a treated adult with type III; features only found in type III are its progressively deforming nature and the presence of a face with a "triangular" appearance. Another differentiating factor between type III and IV is blue sclerae; in type III, infants commonly have blue sclerae that gradually turn white with age, but blue sclerae are not commonly seen in type IV, although they are seen in 10% of cases.


title: Osteogenesis imperfecta

text: OI type III causes osteopenic bones that fracture very easily, sometimes even "in utero", often leading to hundreds of fractures during a lifetime; early scoliosis that progresses until puberty; dwarfism (a final adult height frequently less than ); loose joints; and possible respiratory problems due to low rib cage volume causing low lung volumes.


title: Osteogenesis imperfecta

text: Due to the severity of the issues with the bones, neurological and seizure disorders are more likely to develop in type III. Basilar invagination, which puts pressure on the brainstem, may cause or contribute to early death; surgical treatment of it is more complex in OI cases.


title: Osteogenesis imperfecta

text: Collagen quantity is sufficient, but is not of a high enough quality. Type IV is for cases of variable severity, which do not fit into either types III or I. While one of Sillence's required characteristics for type IV was having normal sclerae, modern classification allows even those with blue sclerae to fit the criteria for type IV if they meet the other clinical requirements of the type.


title: Osteogenesis imperfecta

text: In type IV, bone deformity can be mild to severe, bones fracture easily (especially before puberty), dwarfism is common, vertebral collapse and scoliosis are evident, and hearing loss is possible, although uncommon. Type IV OI is mostly defined in contrast to type III and type I, being the clinical classification for patients somewhere in the middle ground between the two. As such, type IV OI is often termed "variable" OI, with the severity of even those in the same family (so, with the same genetic mutation) differing.


title: Osteogenesis imperfecta

text: Prepubertal bone fracture rates are another way of clinically assessing type IV OI—those with it tend to have fracture rates of ≈1 per year, compared to ≈3 per year for severe OI (type III).


title: Osteogenesis imperfecta

text: As in type I, some further split type IV into types IV–A and IV–B, defined again by the absence (IV–A) or presence (IV–B) of dentinogenesis imperfecta.


title: Osteogenesis imperfecta

text: Given the rapid rate of type discovery, it is extremely likely that there are other genes associated with OI that have yet to be reported.


title: Osteogenesis imperfecta

text: Osteogenesis imperfecta is a group of genetic disorders, all of which cause bone fragility. OI has high genetic heterogeneity, that is, many different genetic mutations lead to the same or similar sets of observable symptoms (phenotypes).


title: Osteogenesis imperfecta

text: The main causes for developing the disorder are a result of mutations in the "COL1A1" and/or "COL1A2" genes which are jointly responsible for the production of collagen type I. Approximately 90% of people with OI are heterozygous for mutations in either the "COL1A1" or "COL1A2" genes. There are several biological factors that are results of the dominant form of OI. These factors include: intracellular stress; abnormal tissue mineralization; abnormal cell to cell interactions; abnormal cell-matrix interactions; a compromised cell matrix structure; and, abnormal interaction between non-collagenous proteins and collagen.


title: Osteogenesis imperfecta

text: Previous research lead to the belief that OI was an autosomal dominant disorder with few other variations in genomes. However, with the lowering of the cost of DNA sequencing in the wake of 2003's Human Genome Project, autosomal recessive forms of the disorder have been identified. Recessive forms of OI relate heavily to defects in the collagen chaperones responsible for production of procollagen and the assembly of the related proteins. Examples of collagen chaperones that are defective in patients with recessive forms of OI include chaperone HSP47 (Cole-Carpenter syndrome) and FKBP65. Mutations in these chaperones result in an improper folding pattern in the collagen 1 proteins which causes the recessive form of the disorder. There are three significant types of OI that are a result of mutations in the collagen prolyl 3-hydroxylation complex (components CRTAP, P3H1, and CyPB). These components are responsible for the modification of collagen α1(l)Pro986. Mutations in other genes such as "SP7", "SERPINF1", "TMEM38B" and "BMP1" can also lead to irregularly formed proteins and enzymes that result in other recessive types of osteogenesis imperfecta.


title: Osteogenesis imperfecta

text: Defects in the proteins pigment epithelium-derived factor (PEDF) and bone-restricted interferon-induced transmembrane protein (BRIL) are the causes of type V and VI osteogenesis imperfecta. Defects in these proteins lead to defective bone mineralization which causes the characteristic brittle bones of osteogenesis imperfecta. A single point mutation in the 5′ untranslated region (5′ UTR) of the "IFITM5" gene, which encodes BRIL, is linked directly to OI type V.


title: Osteogenesis imperfecta

text: In the rare case of type XIX, first discovered in 2016, OI is inherited as an X-linked genetic disorder, with its detrimental effects resulting ultimately from a mutation in the gene "MBTPS2." Genetic research is ongoing, and it is uncertain when all the genetic causes of OI will be identified, as the number of genes that need to be tested to rule out the disorder continue to increase.


title: Osteogenesis imperfecta

text: In a study of 37 families, a 1.3% chance was found that OI recurs in multiple siblings born to two unaffected parents—this is a much higher rate than would be expected if all such recurrences were "de novo". The cause is genetic mosaicism; that is, some of, or most of, the germ cells of one parent have a dominant form of OI, but not enough of their somatic cells do to cause symptoms or obvious disability in the parent—the parent's different cells have two (or more) sets of slightly different DNA. It has been clinically observed that ≈5–10% of cases of OI types II and III are attributable to genetic mosaicism.


title: Osteogenesis imperfecta

text: People with OI are either born with defective connective tissue, born without the ability to make it in sufficient quantities, or, in the rarest genetic types, born with deficiencies in other aspects of bone formation such as chaperone proteins, the Wnt signaling pathway, the BRIL protein, et cetera. In type I the collagen's structure itself is normal, it is just its quantity that is low. Types II, III and IV are usually, but not always, related to a deficiency of type I collagen. One possible deficiency arises from an amino acid substitution of glycine to a bulkier amino acid, such as alanine, in the collagen protein's triple helix structure. The larger amino acid side-chains lead to steric effects that creates a bulge in the collagen complex, which in turn influences both the molecular nanomechanics and the interaction between molecules, which are both compromised. Depending on both the location of the substitution and the amino acid being used instead, different effects are seen which account for the type diversity in OI despite the same two collagen genes being responsible for most cases. Replacements of glycine with serine or cysteine are seen less often in fatal type II OI, while replacements with valine, aspartic acid, glutamic acid, or arginine are seen more often.


title: Osteogenesis imperfecta

text: At a larger scale, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness. Bone fractures occur because the stress state within collagen fibrils is altered at the locations of mutations, where locally larger shear forces lead to rapid failure of fibrils even at moderate loads because the homogeneous stress state normally found in healthy collagen fibrils is lost. OI is therefore a multi-scale phenomenon, where defects at the smallest levels of tissues (genetic, nano, micro) domino to affect the macro level of tissues.


title: Osteogenesis imperfecta

text: Diagnosis is typically based on medical imaging, including plain X-rays, and symptoms. In severe OI, signs on medical imaging include abnormalities in all extremities and in the spine. As X-rays are often insensitive to the comparatively smaller bone density loss associated with type I OI, DEXA scans may be needed.


title: Osteogenesis imperfecta

text: An OI diagnosis can be confirmed through DNA or collagen protein analysis, but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclerae are sufficient for a diagnosis. A skin biopsy can be performed to determine the structure and quantity of type I collagen. While DNA testing can confirm the diagnosis, it cannot absolutely exclude it because not all mutations causing OI are yet known and/or tested for. OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be visible. Relative to control, OI cortical bone shows increased porosity, canal diameter, and connectivity in micro-computed tomography. OI can also be detected before birth by using an "in vitro" genetic testing technique such as amniocentresis.


title: Osteogenesis imperfecta

text: In order to determine whether osteogenesis imperfecta is present, genetic sequencing of the most common problematic genes, "COL1A1", "COL1A2", and "IFITM5", may be done; if no mutation is found yet OI is still suspected, the other 10+ genes known to cause OI may be tested. Duplication and deletion testing is also suggested to parents who suspect their child has OI. The presence of frameshift mutations caused by duplications and deletions is generally the cause of increased severity of disease.


title: Osteogenesis imperfecta

text: An important differential diagnosis of OI is child abuse, as both may present to a clinician with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. This can become an issue in court; in the United States, several child abuse cases were resolved with a finding that osteogenesis imperfecta was the true cause of a child's fractures, leading to lawsuits seeking redress such as "Alice Velasquez, et al. v. United States".


title: Osteogenesis imperfecta

text: Other differential diagnoses include rickets and osteomalacia, both caused by malnutrition, as well as rare skeletal syndromes such as Bruck syndrome, hypophosphatasia, geroderma osteodysplasticum, and Ehlers–Danlos syndrome. Various forms of osteoporosis, such as iatrogenic osteoporosis, idiopathic juvenile osteoporosis, disuse osteoporosis and exercise-related osteoporosis should also be considered as explanations when OI is suspected.


title: Osteogenesis imperfecta

text: There is no cure for osteogenesis imperfecta. Maintaining a healthy lifestyle by exercising and avoiding smoking can help prevent fractures. Treatment may include care of broken bones, pain medication, physical therapy, mobility aids such as braces or wheelchairs, and surgery.


title: Osteogenesis imperfecta

text: Judging the success or failure of treatment can be difficult in OI patients, as decreased bone fracture rates may just be coincidental. While these rates are often used in medical studies to judge treatment efficacy, a Norwegian study of fifteen people with OI emphasized that they feel doctors should consider the whole patient and not just fracture rates.


title: Osteogenesis imperfecta

text: Bone fractures are treated in individuals with osteogenesis imperfecta in much the same way as they are treated in the general population—OI bone heals at the same rate as non-OI bone. A greater emphasis is placed on using lightweight materials to immobilize the fracture, as in moderate or severe types of OI, using heavy casts, such as hip spica casts, can cause fractures at the bones at the boundaries of the cast, as well as generalized osteopenia. The lightweight cast or splint is then replaced with a removable orthosis after a few weeks and once evidence of union is seen on X-ray. In order to prevent a nonunion or malunion, all fractures should be immobilized, even if the fracture seems trivial (microfracture), as people with OI are at greater risk of nonunion.


title: Osteogenesis imperfecta

text: Bone infections secondary to fractures are treated as and when they occur with the appropriate antibiotics and antiseptics, as in the general population.


title: Osteogenesis imperfecta

text: In 1998, an initial observational trial demonstrated the effectiveness of intravenous pamidronate, a bisphosphonate which had previously been used in adults to treat osteoporosis. In severe OI, this trial showed that pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of long-bone fractures.


title: Osteogenesis imperfecta

text: Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and intravenous bisphosphonates are generally more effective, although this is under study. Some studies have found oral and intravenous bisphosphonates, such as oral alendronate and intravenous pamidronate, equivalent. In a 2013 double-blind trial of children with mild OI, oral risedronate increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures. A "Cochrane" review in 2016 concluded that though bisphosphonates seem to improve bone mineral density, it is uncertain whether this leads either to a reduction in bone fractures or improvement in the quality of life of individuals with osteogenesis imperfecta. Even in trials with as many as 125 children, no causal link has been found between bisphosphonates and decreased fracture rates; placebo controlled trials were also unable to prove that they brought about increased strength, motor control or lower pain levels.


title: Osteogenesis imperfecta

text: OI is a genetic disorder and is not caused by insufficient intake of any vitamin or mineral; supplementation cannot cure OI. With that said, people with OI tend to be severely deficient in vitamin D at much higher rates than the general population, and the cause of this is not well understood. The severity of the deficiency and the likelihood of its occurrence is thought to be related to severity of OI. Vitamin D supplementation may be recommended, at least until levels of 25(OH)D in blood return to normal. Below normal levels of vitamin D are also concerning as they may decrease the benefit of bisphosphanates.


title: Osteogenesis imperfecta

text: A surgery of any type inherently carries more risks when done on a patient who has (especially moderate to severe) OI. Skeletal deformities and dentinogenesis imperfecta may hinder access to the airway. Use of, and weaning off of, mechanical ventilation is also more challenging to carry out on patients with OI. During the procedure itself or the healing process, defective OI collagen may lead to bleeding diatheses.


title: Osteogenesis imperfecta

text: The safety of anesthesia is also of more concern among patients with OI, with anesthetic complications 5.6x more likely to occur when the patient has OI type III. A unique concern of anesthesia in OI is perioperative fracture—fractures sustained due to patient transfer and airway access techniques that, while routine when a patient's bones are strong, may cause injury with brittle OI bones. As an example, due to a 1972 report of a humerus fracture from a sphygmomanometer cuff sustained in an OI patient during surgery, blood pressure monitoring protocols are often modified for patients with OI, with neonatal size cuffs and machine settings being used even in adults; further, the least deformed of the patient's limbs is preferred to receive the cuff.


title: Osteogenesis imperfecta

text: Metal rods can be surgically inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield when he was Chief of Staff at Chicago's Shriners Hospitals for Children, a hospital that offers orthopedic care and surgery to children regardless of their family's ability to pay. Large numbers of children with OI came to Shriners, and Sofield experimented with various methods to strengthen their bones. In 1959, with Edward A. , Sofield wrote a seminal article describing a three-part surgery that seemed radical at the time: precisely breaking the bones ("fragmentation"), putting the resulting bone fragments in a straight line ("realignment"), then placing metal rods into the intramedullary canals of the long bones to stabilize and strengthen them ("rod fixation"). His treatment proved useful for increasing the mobility of people with OI, and it has been adopted throughout the world—it became standard surgical treatment for severe OI by 1979, in which year David Sillence found that ≈ of the patients he surveyed with OI type III had undergone at least one rodding surgery.


title: Osteogenesis imperfecta

text: Rodding surgery is often done with the hope that it will offer a path to ambulation, walking, to patients with moderate or severe OI. A 2020 review in "The Journal of Bone and Joint Surgery" ("JB&JS") found it remains broadly popular: ≈ of people with OI types III and IV (severe OI) have undergone some form of rodding surgery in their lives, at a mean age of and years respectively; one possible explanation for a tendency towards earlier intervention in type III is that one half of affected children could not walk at all without the surgery, as their limbs were more bowed, so surgery was sought sooner.


title: Osteogenesis imperfecta

text: In those with type III OI who had undergone rodding surgery, 79.5% had the femurs and tibias of both legs rodded. The most common form of rods used are intramedullary (IM) rods, some of which, such as the Fassier–Duval IM rod, are telescoping, meaning that they are designed to grow as the child grows, in an attempt to avoid the necessity of revision surgeries. Telescoping IM rods are widely used, and the common Fassier–Duval IM rod is designed to be used to rod the femur, tibia, and humerus. The surgery involves breaking the long bones in between one and three (or more) places, then fixing the rod alongside the bone to keep it straight.


title: Osteogenesis imperfecta

text: While telescoping IM rods are intended to grow along with both the femur and tibia in developing children; surgeons have a preference to use non-telescoping IM rods, such as Rush rods, in the tibia, which grows less comparatively—the "JB&JS" review found that while 69.7% of femurs were treated with telescoping IM rods, only 36.9% of tibiae were.


title: Osteogenesis imperfecta

text: While the review in the "JB&JS" was able to correlate receiving rodding surgery with greater mobility across all types of OI, in patients with type IV, the surgery did not decrease the incidence of broken bones as compared to non-rodded patients—while type IV patients with rodded tibiae experienced 0.93 tibia fractures per year, patients with natural tibiae experienced only 0.81. However, in patients with type III, rodding surgery decreased the average number of tibia fractures per year from 0.84 to 0.57.


title: Osteogenesis imperfecta

text: Spinal fusion can be performed either as a preventative measure or to correct existing scoliosis, although the inherent fragility of OI bone makes this operation more complex in OI patients than it does with patients who have adolescent idiopathic scoliosis, but normal bone density. Despite the risks, however, three Nemours–duPont orthopedic surgeons who specialize in surgical intervention for osteogenesis imperfecta recommend operating if the curve is greater than 50° after a child is past peak height velocity, as the spine's curve can continue to worsen even into adulthood.


title: Osteogenesis imperfecta

text: Due to the risk involved, the same surgeons recommend that surgery for basilar impressions and basilar invaginations should only be carried out if the pressure being exerted on the spinal cord and brain stem is causing actual neurological symptoms. Once basilar invagination has become symptomatic, only surgery can halt or reverse the progression of neurological deficits.


title: Osteogenesis imperfecta

text: Physical therapy is generally recommended, however individualized protocols are required due to the variability of OI. Physical therapy is used to strengthen muscles, improve motility, improve flexibility, and help with weight maintenance, although it must be done in a gentle manner to minimize the risk of bone fracture. In people with OI, exercise often involves water aerobics, light resistance exercises, and walking, if the patient is able. However, even in patients with mild OI, contact sports, as well as activities likely to put unnecessary stress on the joints, such as jumping, are contraindicated due to the risks they pose.


title: Osteogenesis imperfecta

text: Individuals with more limited mobility are encouraged to change positions regularly throughout the day; people who sit in a wheelchair most or all of the day are recommended to get out of it every two hours, as a form of exercise, to decrease stiffness, and to prevent pressure ulcers.


title: Osteogenesis imperfecta

text: Individuals with moderate to severe OI, who require assistive mobility devices and adapted vehicles, face significant barriers to access wheelchair-accessible pools or gyms—they either may not have any in their area, nor the means to get there. Obesity may be more likely to present among those with severe OI, (especially after the age of 20,) and can, in some, cause further declines in mobility.


title: Osteogenesis imperfecta

text: Tilt table whole body vibration may also be done to increase the mobility of long-term immobilized (bedridden) patients with OI; in at least two cases it helped bedridden children to be able to sit upright.


title: Osteogenesis imperfecta

text: More than 1 in 2 people with OI also have dentinogenesis imperfecta (DI)—a congenital abnormality in the formation of dentin, one of the four major components of the human tooth. Dental treatment may pose as a challenge as a result of the various deformities, skeletal and dental, due to OI. Children with OI should go for a dental check-up as soon as their teeth erupt; this may minimize tooth structure loss as a result of abnormal dentine, and they should be monitored regularly to preserve their teeth and oral health.


title: Osteogenesis imperfecta

text: Many people with OI are treated with bisphosphonates, and there are several possible related complications with dental procedures, for example, medication-related osteonecrosis of the jaw (MRONJ). However, no report of bisphosphonate-related MRONJ in either a child or adult with OI was found in a 2016 "Cochrane" review of the safety and efficacy of bisphosphonates for OI.


title: Osteogenesis imperfecta

text: Monoclonal antibodies have long been considered for OI, but as of 2021, such therapy has not been approved for OI, neither in the European Union nor in the United States. Thus, it is unclear whether they are safe or effective. Among the monoclonal antibodies that have been studied are romosozumab (targets sclerostin, by Amgen), fresolimumab (TGF-β, Sanofi), blosozumab (sclerostin, Lilly), and setrusumab (sclerostin, begun by Novartis).


title: Osteogenesis imperfecta

text: Setrusumab, formerly known as BPS-804, is a monoclonal antibody that targets sclerostin, and has been studied in OI specifically more than any of the others. In the body, sclerostin binds to the LRP5 and LRP6 receptors, resulting in inhibition of the Wnt signaling pathway. This decreases bone formation, and is not a problem when a person has healthy bones. It is thought, though, that decreasing the concentration of sclerostin in the body may lead to the formation of more bone, and that is the premise as to why monoclonal antibodies that reduce the concentrations of naturally occurring sclerostin may help strengthen OI bone. While setrusumab was first developed at the pharmaceutical company Novartis, Novartis sold its rights to patent the drug to Mereo Biopharma in 2015, who has continued its development in conjunction with Ultragenyx. In 2019, Mereo announced that it had concluded collecting data for its phase II-B trial of setrusumab; the study was completed on 12 November 2020. Despite the trial data failing to show improvements in bone density on QCT scans, its primary goal, there were improvements on DXA scans. In a September 2020 press release, Mereo said it was seeking to do a phase III trial in 2021, and had received a Rare Pediatric Disease (RPD) designation from the US Food and Drug Administration (FDA).


title: Osteogenesis imperfecta

text: Romosozumab, which also is a monoclonal antibody targeting sclerostin, is an approved drug in the US and EU for the treatment of osteoporosis. The pharmaceutical industry analyst Evercore has remarked that "it could wipe out setrusumab's economics", as romosozumab is priced more cheaply than a drug for a rare disease would be, claiming that it will be "vital" to Ultragenyx's profit margins to prove its setrusumab is more efficacious than romosozumab for OI. A clinical trial evaluating romosozumab's efficacy in OI began in September 2020 and as of September 2021 is ongoing. Ultragenyx predicts that its phase 2/3 trials for setrusumab will be completed in 2026.


title: Osteogenesis imperfecta

text: As a genetic disorder, the mainstay of twenty-first century prevention of osteogenesis imperfecta is based on preventing affected individuals from being born in the first place. Genetic counseling can help patients and their families determine what types of screening, if any, are right for their situation. Patients can consider preimplantation genetic diagnosis after in vitro fertilization to select fertilized embryos which are not affected. Common mutations which cause OI may be caught by exome sequencing and whole genome sequencing. If a pregnancy is already in progress, the procedure of amniocentesis may be undergone to see if the fetus is affected. If affected, it is up to the family to consider whether or not they want to terminate the pregnancy and try again—raising questions of medical ethics and a woman's right to choose.


title: Osteogenesis imperfecta

text: Without intervention, patients with the most common mutations causing osteogenesis imperfecta have a 50% chance per gestation of passing on the disorder, as these mutations are inherited in an autosomal dominant pattern of Mendelian inheritance. Those with the rare autosomal recessive forms of OI have a 25% chance of passing on the disorder. Genetic testing of the affected members of the family can be used to determine which inheritance pattern applies.


title: Osteogenesis imperfecta

text: As OI type I may be difficult to detect in a newborn child, the cord blood of the child can be tested to determine if it has been passed on if the family has already rejected the more invasive genetic screening methods. In more severe cases, the diagnosis may be able to be done via ultrasound, especially if OI is already a possibility. An ethical concern with prenatal screening for OI often arises when parents inquire as to how severely affected their child will be—such questions are as yet difficult to answer conclusively.


title: Osteogenesis imperfecta

text: If a non-affected person has already had a child with OI, there is a greater likelihood (although still quite remote), that their future children will have OI due to genetic mosaicism.


title: Osteogenesis imperfecta

text: The disability rights critique of prenatal screening for OI, held by some bioethicists and some affected individuals, negatively compares it to eugenics, with even those not opposed to abortion opposing selective abortions on the ethical ground that their existence betrays the belief that the lives of those with OI are "less worth living [and] less valuable".


title: Osteogenesis imperfecta

text: In the mild form of the disorder, type I, the life expectancy of patients is near that of the general population. In type II, however, patients only very rarely live past the age of two, and typically die in their first weeks of life. Assessment of the life expectancy of patients with types III and IV is more complicated, as lifestyle choices can cause fatally traumatic injuries that would not have otherwise occurred, or not been fatal in the general population. Life expectancy in type IV OI is thought to be close to normal, but in type III it is lower than in the general population.


title: Osteogenesis imperfecta

text: A 2016 study of data in Denmark's found that across all types of OI, all-cause mortality was three times higher, leading to a loss of around seven years in females and nine years in males. A 1996 study published in the "British Medical Journal" found that mortality in type III OI is significantly higher, with many patients dying in their 20's, 30's, and 40's; patients who survive to the age of 10 were further found to have longer life expectancy than newborns.


title: Osteogenesis imperfecta

text: People with mild (type I) OI as adults need few pieces of adaptive equipment, although in infancy they reach motor milestones at a significant delay compared to the general population.


title: Osteogenesis imperfecta

text: With adaptive equipment such as crutches, motorized wheelchairs, splints, reach extenders, and/or modifications to the home, many individuals with moderate to severe OI can achieve or maintain a significant degree of independence. With treatment and physical therapy, the maximum levels of mobility are expected to be unassisted community walking for type I, household or exercise walking for type III, and household or community walking for type IV; due to the variability of OI between individuals, mobility achieved varies and may be below this expected maximum.


title: Osteogenesis imperfecta

text: In the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 live births. An estimated 20,000 to 50,000 people are affected by OI in the United States.


title: Osteogenesis imperfecta

text: The most common types are I, II, III, and IV, while the rest are very rare. Type I is the most common and has been reported to be around three times more common than type II. The prevalence of types III and IV is less certain. In a 1989 study in Denmark, type I was found to comprise 71% of cases and type II 12% of cases, with other types comprising the other 17%. In a 2015 study in Sweden, type I was nearly six times more common than type III and nearly four times more common than type IV.