title: Uto-Aztecan languages

text: The internal classification of the family often divides it into two branches: a northern branch including all the languages of the US and a southern branch including all the languages of Mexico, although it is still being discussed whether this is best understood as a genetic classification or as a geographical one. Below this level of classification the main branches are well accepted: Numic (including languages such as Comanche and Shoshoni) and the Californian languages (formerly known as the Takic group, including Cahuilla and Luiseño) account for most of the Northern languages. Hopi and Tübatulabal are languages outside those groups. The Southern languages are divided into the Tepiman languages (including O'odham and Tepehuán), the Tarahumaran languages (including Raramuri and Guarijio), the Cahitan languages (including Yaqui and Mayo), the Coracholan languages (including Cora and Huichol), and the Nahuan languages.


title: Uto-Aztecan languages

text: The homeland of the Uto-Aztecan languages is generally considered to have been in the Southwestern United States or possibly Northwestern Mexico. An alternative theory has proposed the possibility that the language family originated in southern Mexico, within the Mesoamerican language area, but this has not been generally considered convincing.


title: Uto-Aztecan languages

text: Uto-Aztecan languages are spoken in the North American mountain ranges and adjacent lowlands of the western United States (in the states of Oregon, Idaho, Montana, Utah, California, Nevada, Arizona) and of Mexico (states of Sonora, Chihuahua, Nayarit, Durango, Zacatecas, Jalisco, Michoacán, Guerrero, San Luis Potosí, Hidalgo, Puebla, Veracruz, Morelos, Estado de México, and Ciudad de México). Classical Nahuatl, the language of the Aztecs, and its modern relatives are part of the Uto-Aztecan family. The Pipil language, an offshoot of Nahuatl, spread to Central America by a wave of migration from Mexico, and formerly had many speakers there. Now it has gone extinct in Guatemala, Honduras, and Nicaragua, and it is nearly extinct in western El Salvador, all areas dominated by use of Spanish.


title: Uto-Aztecan languages

text: Uto-Aztecan has been accepted by linguists as a language family since the early 1900s, and six subgroups are generally accepted as valid: Numic, Takic, Pimic, Taracahitic, Corachol, and Aztecan. That leaves two ungrouped languages: Tübatulabal and Hopi (sometimes termed "isolates within the family"). Some recent studies have begun to question the unity of Taracahitic and Takic and computer-assisted statistical studies have begun to question some of the long-held assumptions and consensuses. As to higher-level groupings, disagreement has persisted since the 19th century. Presently scholars also disagree as to where to draw language boundaries within the dialect continua.


title: Uto-Aztecan languages

text: The similarities among the Uto-Aztecan languages were noted as early as 1859 by J. C. E. Buschmann, but he failed to recognize the genetic affiliation between the Aztecan branch and the rest. He ascribed the similarities between the two groups to diffusion. Daniel Garrison Brinton added the Aztecan languages to the family in 1891 and coined the term Uto-Aztecan. John Wesley Powell, however, rejected the claim in his own classification of North American indigenous languages (also published in 1891). Powell recognized two language families: "Shoshonean" (encompassing Takic, Numic, Hopi, and Tübatulabal) and "Sonoran" (encompassing Pimic, Taracahitan, and Corachol). In the early 1900s Alfred L. Kroeber filled in the picture of the Shoshonean group, while Edward Sapir proved the unity among Aztecan, "Sonoran", and "Shoshonean". Sapir's applications of the comparative method to unwritten Native American languages are regarded as groundbreaking. argued for a three-way division of Shoshonean, Sonoran and Aztecan, following Powell.


title: Uto-Aztecan languages

text: As of about 2011, there is still debate about whether to accept the proposed basic split between "Northern Uto-Aztecan" and "Southern Uto-Aztecan" languages. Northern Uto-Aztecan corresponds to Powell's "Shoshonean", and the latter is all the rest: Powell's "Sonoran" plus Aztecan. Northern Uto-Aztecan was proposed as a genetic grouping by Jeffrey Heath in based on morphological evidence, and Alexis Manaster Ramer in adduced phonological evidence in the form of a sound law. Terrence Kaufman in accepted the basic division into Northern and Southern branches as valid. Other scholars have rejected the genealogical unity of either both nodes or the Northern node alone. Wick R. Miller's argument was statistical, arguing that Northern Uto-Aztecan languages displayed too few cognates to be considered a unit. On the other hands he found the number of cognates among Southern Uto-Aztecan languages to suggest a genetic relation. This position was supported by subsequent lexicostatistic analyses by and . Reviewing the debate, considers the evidence in favor of the genetic unity of Northern Uto-Aztecan to be convincing, but remains agnostic on the validity of Southern Uto-Aztecan as a genetic grouping. also considered the North/South split to be valid based on phonological evidence, confirming both groupings. adduced further evidence for the unity of Southern Uto-Aztecan as a valid grouping.


title: Uto-Aztecan languages

text: Some classifications have posited a genetic relation between Corachol and Nahuan (e.g. ). Kaufman recognizes similarities between Corachol and Aztecan, but explains them by diffusion instead of genetic evolution. Most scholars view the breakup of Proto-Uto-Aztecan as a case of the gradual disintegration of a dialect continuum.


title: Uto-Aztecan languages

text: Below is a representation of the internal classification of the language family based on . The classification reflects the decision to split up the previous Taracahitic and Takic groups, that are no longer considered to be valid genetic units. Whether the division between Northern and Southern languages is best understood as geographical or phylogenetic is under discussion. The table contains demographic information about number of speakers and their locations based on data from The Ethnologue. The table also contains links to a selected bibliography of grammars, dictionaries on many of the individual languages.( = extinct)


title: Uto-Aztecan languages

text: In addition to the above languages for which linguistic evidence exists, it is suspected that among dozens of now extinct, undocumented or poorly known languages of northern Mexico, many were Uto-Aztecan.


title: Uto-Aztecan languages

text: A large number of languages known only from brief mentions are thought to have been Uto-Aztecan languages that became extinct before being documented.


title: Uto-Aztecan languages

text: An "Aztec–Tanoan" macrofamily that unites the Uto-Aztecan languages with the Tanoan languages of the southwestern United States was first proposed by Edward Sapir in the early 20th century, and later supported with potential lexical evidence by other scholars. This proposal has received much criticism about the validity of the proposed cognate sets and has been largely abandoned by the end of the last century as unproven.


title: Spartanburg, South Carolina

text: Spartanburg is a city in and the seat of Spartanburg County, South Carolina, United States. The city of Spartanburg has a municipal population of 38,732 as of the 2020 census, making it the 11th-largest city in the state. For a time, the Office of Management and Budget (OMB) grouped Spartanburg and Union Counties together as the Spartanburg metropolitan statistical area, but as of 2018,the OMB defines only Spartanburg County as the Spartanburg MSA.


title: Spartanburg, South Carolina

text: Spartanburg is the second-largest city in the greater Greenville–Spartanburg–Anderson combined statistical area, which had a population of 1,385,045 as of 2014. It is part of a 10-county region of northwestern South Carolina known as "The Upstate", and is located northwest of Columbia, west of Charlotte, North Carolina, and about northeast of Atlanta, Georgia.


title: Spartanburg, South Carolina

text: Spartanburg is the home of Wofford College, Converse University, and Spartanburg Community College, and the area is home to USC Upstate and Spartanburg Methodist College. It is also the site of headquarters for Denny's. Spartanburg was ranked number 24 on the "150 Best Places to Live in the U.S. in 2021-2022" by "US News & World Report".


title: Spartanburg, South Carolina

text: Spartanburg was formed in 1785, after a deal was made with the Cherokee Nation in 1753, and was named after a local militia called the Spartan Regiment in the American Revolutionary War. The Spartan Regiment, commanded by Andrew Pickens, participated in the nearby Battle of Cowpens. In 1831, Spartanburg was incorporated, later becoming known as the "Hub City"; railroad lines radiated from the city forming the shape of a wheel hub.


title: Spartanburg, South Carolina

text: It became a center of textile manufacturing in the late 19th century, with around 40 textile mills being established through the early 1900s.


title: Spartanburg, South Carolina

text: During World War I, Camp Wadsworth was used to train 100,000 soldiers for the war. Camp Croft trained soldiers during World War II. The facility was transferred to the state and adapted as Croft State Park.


title: Spartanburg, South Carolina

text: By the 1950s, the production in these mills began to decline as wages increased. Most textile manufacturing jobs were moved offshore by the companies.


title: Spartanburg, South Carolina

text: According to the United States Census Bureau, the city has a total area of , of which , or 0.47%, is covered by water. The most common soil series is Cecil. The bedrock is mostly biotite gneiss.


title: Spartanburg, South Carolina

text: The city of Spartanburg has a humid subtropical climate with long, hot, and humid summers, and cool to semimild winters. The average annual temperature is . In the summer from June through September, average highs are in the 80s °F (20s °C) to low 90s °F (30s °C), while in the winter, average highs are in the mid-50s °F (10s °C). Annual rainfall is spread fairly evenly throughout the whole year. Spartanburg receives very little snowfall, with the annual average being only . Average precipitation is and the average growing season is 231 days.


title: Spartanburg, South Carolina

text: As of the census of 2010, 37,013 people, 15,989 households, and 9,721 families were residing in the city. The population density was 2,066.3 people per square mile (799.9/km). The 17,696 housing units had an average density of 923.9 per square mile (356.8/km). The racial makeup was 49.55% African American, 47.15% White, 0.18% Native American, 1.33% Asian, 0.82% from other races, and 0.96% from two or more races. Hispanics or Latinos of any race were 1.78% of the population.


title: Spartanburg, South Carolina

text: Of the 15,989 households, 28.9% had children under 18 living with them, 34.0% were married couples living together, 23.0% had a female householder with no husband present, and 39.2% were not families. About 34.0% of all households were made up of individuals, and 13.2% had someone living alone who was 65 or older. The average household size was 2.33, and the average family size was 3.00.


title: Spartanburg, South Carolina

text: In the city, the age distribution was 25.2% under 18, 12.2% from 18 to 24, 26.6% from 25 to 44, 20.6% from 45 to 64, and 15.4% who were 65 or older. The median age was 35 years. For every 100 females, there were 79.6 males.


title: Spartanburg, South Carolina

text: The median income for a household in the city was $28,735, and for a family was $36,108. Males had a median income of $30,587 versus $23,256 for females. The per capita income for the city was $18,136. About 29.4% of families and 23.3% of the population were below the poverty line, including 34.6% of those under age 18 and 15.4% of those age 65 or over.


title: Spartanburg, South Carolina

text: As of the 2020 United States census, e 38,732 people, 15,154 households, and 8,638 families resided in the city.


title: Spartanburg, South Carolina

text: Within the past decade, developers and community leaders have spearheaded an effort to revitalize Spartanburg's downtown commercial district. This has resulted in a remodeling of Morgan Square, the restoration of a number of historic structures and the relocation of several businesses and company headquarters to the downtown vicinity. These new developments include a nine-floor, 240-room Marriott hotel.


title: Spartanburg, South Carolina

text: Spartanburg is home to many large companies, including Denny's, KYMCO, Smith Drug Company, Advance America Cash Advance, Southern Conference, Spartanburg Herald-Journal, RJ Rockers Brewing Company, American Credit Acceptance, and Upward Sports.


title: Spartanburg, South Carolina

text: The economy of Spartanburg benefits from the BMW manufacturing facility located in the city of Greer, South Carolina, which is in Spartanburg County. As of February 2017, the plant employed around 8,800 people with an average daily output of about 1,400 vehicles.


title: Spartanburg, South Carolina

text: Spartanburg is also home to the world headquarters and research facility for Milliken & Company, a textile and chemical manufacturer.


title: Spartanburg, South Carolina

text: According to Spartanburg's 2015 Comprehensive Annual Financial Report, the principal employers in the city are:


title: Spartanburg, South Carolina

text: Early European settlers to this area included French fur trappers, English woodsmen, and Scots-Irish farmers. Few remnants survive from these early pioneering days, but traces can be found in the more rural areas of the county.


title: Spartanburg, South Carolina

text: First established in the 1780s as a courthouse village, Spartanburg may have been named for the Spartan regiment of the South Carolina militia. The city was incorporated in 1831, at the time of the 50th anniversary of the Battle of Cowpens, a pivotal fight of the American Revolution that took place only a few miles away. The city's streets and architectural record reflect the changes of the 19th and 20th centuries.


title: Spartanburg, South Carolina

text: Cotton mills have abounded in the Spartanburg area since 1816, earning Spartanburg the reputation as the "Lowell of the South." Although there were few mills in the area before the Civil War, technological advances, northern capital, and out-migration from the poor farms that made white labor available, created a wave of postbellum mill development here and in much of the Piedmont South. Additionally, the abundant streams and rivers in the area are just beginning their descent towards the lower-lying Midlands region. In many places, these waterways descend abruptly, providing a source for plentiful waterpower. Cotton mills were built along these rivers to harness this power, and so began the region's servitude to King Cotton. These mills, their owners and their slaves dominated the politics and economy of the region for nearly a century. Although nearly all abandoned, many mills remain along the riverbanks, the Piedmont equivalent of Gothic ruins.


title: Spartanburg, South Carolina

text: When the United States entered World War I in 1917, one of the sixteen divisional cantonments for the training of National Guard troops was Camp Wadsworth, which is located in the vicinity of Westgate Mall. Large numbers of New York National Guardsmen trained there in addition to many southern troops. During World War II, Camp Croft south of the city trained Army recruits. This is now a South Carolina state park with the same name. Some portions of the park contain the original quonset huts.


title: Spartanburg, South Carolina

text: Spartanburg is host to the NFL's Carolina Panthers training camp each year on the campus of Wofford College.


title: Spartanburg, South Carolina

text: Historic Duncan Park Stadium was once home to the Spartanburg Stingers in the Coastal Plain League and the Spartanburg Crickets in the Southern Collegiate Baseball League and is the oldest minor league baseball stadium in the country. It was also once home to the Spartanburg Phillies, a minor league team of the Philadelphia Phillies. It now is the home stadium for the baseball teams of Spartanburg High School and the Spartanburgers.


title: Spartanburg, South Carolina

text: The Shrine Bowl of the Carolinas is held each year at Wofford's Gibbs Stadium. It is a high school football all-star game played between the top players from South Carolina and the top players from North Carolina.


title: Spartanburg, South Carolina

text: The USC Upstate Spartans, Spartanburg Methodist College Pioneers, and the Wofford College Terriers offer a variety of sports for both men and women. Converse College also offers NCAA Division II women's sports teams.


title: Spartanburg, South Carolina

text: The city hosts the Spartanburg Criterium. The criterium is a yearly event and is usually one of the events associated with Speed Week which is part of the USA Crits bicycle racing series. The event is billed as the “fastest night in Spartanburg.”


title: Spartanburg, South Carolina

text: The current mayor, Jerome Rice, was elected in 2021. Spartanburg operates under a city manager form of government in which the mayor and six city council members have equal votes. Council members represent districts within the city and the mayor is elected at large. The council appoints a city manager, who is responsible for the daily administration of city governmental affairs. City Hall is located at 145 West Broad Street.


title: Spartanburg, South Carolina

text: The Spartanburg County Administration Building (this is the old Sears building which was vacated in the mid-1970s when Sears moved to Westgate Mall and renovated in the late 1980s or early 1990s) is located at 366 North Church Street. It is across the street from the Spartanburg Memorial Auditorium.


title: Spartanburg, South Carolina

text: Most of the City of Spartanburg's public schools are run by Spartanburg County School District 7, one of seven loosely affiliated districts located in Spartanburg County. District 7 students are zoned to Spartanburg High School. However, the westernmost part of the city is served by Spartanburg County School District 6, which has two elementary schools within city limits. District 6 students are zoned to Paul M. Dorman High School in Roebuck.


title: Spartanburg, South Carolina

text: The Spartanburg area is home to the main campus of the South Carolina School for the Deaf and the Blind, which is outside of the city limits in an unincorporated area. It has five Regional Outreach Centers throughout the state. The city is also home to Spartanburg Preparatory School, a K-8 public charter school that is the only "brick and mortar" charter school in the Upstate.


title: Spartanburg, South Carolina

text: Spartanburg is also home to Spartanburg Christian Academy, a K-12 private school in North Spartanburg, the Spartanburg Day School, a K-12 private school offering the International Baccalaureate in grades K-4, and to Oakbrook Preparatory and Westgate Christian schools, both K-12 private schools. Located in Hampton Heights, the Montessori Academy of Spartanburg is a PreK-8 private school providing a Montessori educational approach. The Meeting Street Academy in downtown Spartanburg is a branch of a Charleston-based private school and currently offers PreK and Kindergarten.


title: Spartanburg, South Carolina

text: St. Paul the Apostle Catholic School is located in downtown Spartanburg. It is affiliated with the Diocese of Charleston and is K-8.


title: Spartanburg, South Carolina

text: Spartanburg is part of the much greater Greenville-Spartanburg-Anderson-Asheville DMA which is the nation's 38th largest and is served by the following major television affiliates:


title: Spartanburg, South Carolina

text: Spartanburg is served by the Spartanburg Area Regional Transit Agency (SPARTA), covering the city of Spartanburg and the surrounding urbanized area with 8 routes leading to a wide variety of destinations. All SPARTA buses are equipped with bicycle racks. Two hybrid-electric buses were added to the fleet in 2012. The SPARTA Passenger Center is located at 100 North Liberty Street and also serves Greyhound buses.


title: Spartanburg, South Carolina

text: Mass Transit is provided to all citizens of Spartanburg County through Spartanburg County Dial-A-Ride. It is a door to door service that operates six days a week.


title: Spartanburg, South Carolina

text: The Greenville-Spartanburg International Airport (GSP) lies mostly in suburban Greer, and it serves Greenville as well as Spartanburg. It has become one of the busiest airports in South Carolina.


title: Spartanburg, South Carolina

text: The Spartanburg Downtown Memorial Airport (SPA) is a general aviation/small craft airport owned and operated by the City, which lies southwest of town.


title: Spartanburg, South Carolina

text: Amtrak's "Crescent" train connects Spartanburg with the cities of New York, Philadelphia, Baltimore, Washington, Greensboro, Charlotte, Atlanta, Birmingham and New Orleans. The Amtrak station is situated at 290 Magnolia Street.


title: Spartanburg, South Carolina

text: Spartanburg County's healthcare is mainly provided by Spartanburg Regional Healthcare System. Spartanburg Regional is a public, not-for-profit, integrated health care delivery system with several facilities in Spartanburg, including:


title: Pearson Education

text: Pearson Education is a British-owned education publishing and assessment service to schools and corporations, as well for students directly. Pearson owns educational media brands including Addison–Wesley, Peachpit, Prentice Hall, eCollege, Longman, Scott Foresman, and others. Pearson is part of Pearson plc, which formerly owned the "Financial Times". It claims to have been formed in 1840, with the current incarnation of the company created when Pearson plc purchased the education division of Simon & Schuster (including Prentice Hall and Allyn & Bacon) from Viacom and merged it with its own education division, Addison-Wesley Longman, to form Pearson Education. Pearson Education was rebranded to Pearson in 2011 and split into an International and a North American division.


title: Pearson Education

text: Although Pearson generates approximately 60 percent of its sales in North America, it operates in more than 70 countries. Pearson International is headquartered in London, and maintains offices across Europe, Asia and South America. Its online chat support is based in the Philippines. Pearson North America is headquartered at 330 Hudson in New York City, New York. It previously was located in Upper Saddle River, New Jersey. Pearson International is headquartered at 80 Strand, London, UK. Pearson Italia SpA, also known as "Pearson Paravia Bruno Mondadori", was created through the purchase of PBM Editori, which was, in turn, a merge of Paravia (based in Turin) and Bruno Mondadori (based in Milan).


title: Pearson Education

text: Pearson's logo is the unconventional symbol known as the interrobang (‽), a combination of a question mark and an exclamation point, meant to convey "the excitement and fun of learning."


title: Pearson Education

text: Pearson has partnered with five other higher-education publishers to create CourseSmart, a company developed to sell college textbooks in eTextbook format on a common platform. In 2010, Pearson agreed to a 5-year, $32 million, contract with the New York State Department of Education to design tests for students in grades 4–8.


title: Pearson Education

text: GreyCampus partnered with Pearson for higher-education teaching-learning solutions under the Learningware brand.


title: Pearson Education

text: Que Publishing, a publishing imprint of Pearson-based out of Seattle, partnered with AARP to develop and add to a series of technology books for seniors. The series, which includes "My iPad For Seniors," and "My Social Media for Seniors," are large-print and colourful.


title: Pearson Education

text: In the spring of 2012, tests that Pearson designed for the NYSED were found to contain over 30 errors, which caused controversy. One of the most prominent featured a passage about a talking pineapple on the 8th Grade ELA test (revealed to be based on Daniel Pinkwater's "The Story of the Rabbit and the Eggplant", with the eggplant changed into a pineapple). After public outcry, the NYSED announced it would not count the questions in scoring. Other errors included a miscalculated question on the 8th Grade Mathematics test regarding astronomical units, a 4th grade math question with two correct answers, errors in the 6th grade ELA scoring guide, and over twenty errors on foreign-language math tests. In May 2015, British comedian John Oliver analysed problems with Pearson's standardized tests and the company's greater lack of accountability on his HBO series "Last Week Tonight".


title: Pearson Education

text: In 2006, Pearson acquired PowerSchool, a student information system, from Apple. Terms of the deal were not disclosed. PowerSchool was a profitable product for Pearson. In 2014, it generated $97 million in revenue and $20 million in operating income. In 2015, Pearson sold PowerSchool to Vista Equity Partners for $350 million cash.


title: Pearson Education

text: In 2007 the company developed the youth-oriented online quest game "Poptropica", through its Family Education Network. In 2015 Pearson's Family Education Network, along with Poptropica, were sold to the London-based investment group Sandbox Partners.


title: Pearson Education

text: Pearson owns Cogmed, a brain fitness and working memory training program founded in 1999 by Swedish researcher Torkel Klingberg.


title: Pearson Education

text: In 2016 Pearson acquired StatCrunch, a statistical analysis tool created by Webster West in 1997. Pearson had already been the primary distributor of StatCrunch for several years.


title: Pearson Education

text: InformIT, a subsidiary of Pearson Education, is an online book vendor and an electronic publisher of technology and education content.


title: Pearson Education

text: InformIT.com is one of the web sites of the Pearson Technology Group, and one of several sites in the "InformIT Network". The site features free articles, blogs, and podcasts on IT topics and products, as well as a bookstore carrying all titles from these imprints. Publishing imprints represented on InformIT.com include Addison-Wesley Professional, Cisco Press, IBM Press, Prentice Hall Professional Technical Reference, Que Publishing, and Sams Publishing.


title: Pearson Education

text: In 2001, the Pearson Technology Group and O'Reilly Media LLC formed a joint partnership called Safari Books Online, to offer a web-based electronic library of technical and business books from InformIT's imprint partners and O'Reilly Media. The InformIT Network offers access to this service via its web sites. Pearson sold its interest in Safari Books Online to O'Reilly in 2014.


title: Pearson Education

text: Realidades is a standards-based high school curriculum that balances communications and grammar. With books for both middle school and high school students, Realidades features insight on the Spanish language, culture and technology.


title: Pearson Education

text: In July 2019 Pearson announced it would begin the process of phasing out the publishing of printed textbooks, in a plan to move into a more digital first strategy.


title: Pearson Education

text: The company reportedly envisions students relying more on e-textbooks which would be updated frequently, while printed books will be updated less often. Students wanting printed books will need to rent them.


title: Pearson Education

text: As of 2019, the firm gets half of their annual revenues from digital sales. The United States accounts for 20 percent of Pearson's annual revenue coming from courseware.


title: Cholestasis

text: Cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system that can occur from a gallstone or malignancy, and metabolic types of cholestasis which are disturbances in bile formation that can occur because of genetic defects or acquired as a side effect of many medications. Classification is further divided into acute or chronic and extrahepatic or intrahepatic.


title: Cholestasis

text: The signs and symptoms of cholestasis vary according to the cause. In case of sudden onset, the disease is likely to be acute, while the gradual appearance of symptoms suggests chronic pathology. In many cases, patients may experience pain in the abdominal area. Localization of pain to the upper right quadrant can be indicative of cholecystitis or choledocholithiasis, which can progress to cholestasis.


title: Cholestasis

text: Pruritus or itching is often present in many patients with cholestasis. Patients may present with visible scratch marks as a result of scratching. Pruritus is often misdiagnosed as a dermatological condition, especially in patients that do not have jaundice as an accompanying symptom. In a typical day, pruritus worsens as the day progresses, particularly during the evening time. Overnight, pruritus dramatically improves. This cycle can be attributed to an increase in the concentration of biliary elements during the day due to food consumption, and a decline at night. Pruritus is mostly localized to the limbs, but can also be more generalized. The efficacy of naltrexone for cholestatic pruritus suggests involvement of the endogenous opioid system.


title: Cholestasis

text: Many patients may experience jaundice as a result of cholestasis. This is usually evident after physical examination as yellow pigment deposits on the skin, in the oral mucosa, or conjunctiva. Jaundice is an uncommon occurrence in intrahepatic (metabolic) cholestasis, but is common in obstructive cholestasis. The majority of patients with chronic cholestasis also experience fatigue. This is likely a result of defects in the corticotrophin hormone axis or other abnormalities with neurotransmission. Some patients may also have xanthomas, which are fat deposits that accumulate below the skin. These usually appear waxy and yellow, predominantly around the eyes and joints. This condition results from an accumulation of lipids within the blood. If gallstones prevent bile flowing from the pancreas to the small intestine, it can lead to gallstone pancreatitis. Physical symptoms include nausea, vomiting, and abdominal pain.


title: Cholestasis

text: Bile is required for the absorption of fat-soluble vitamins. As such, patients with cholestasis may present with a deficiency in vitamins A, D, E, or K due to a decline in bile flow. Patients with cholestasis may also experience pale stool and dark urine.


title: Cholestasis

text: Drugs such as gold salts, nitrofurantoin, anabolic steroids, sulindac, chlorpromazine, erythromycin, prochlorperazine, cimetidine, estrogen, and statins can cause cholestasis and may result in damage to the liver.


title: Cholestasis

text: Acute and chronic cholestasis can be caused by certain drugs or their metabolites. Drug-induced cholestasis (DIC) falls under drug-induced liver injury (DILI), specifically the cholestatic or mixed type. While some drugs (e.g., acetaminophen) are known to cause DILI in a predictable dose-dependent manner (intrinsic DILI), most cases of DILI are idiosyncratic, i.e., affecting only a minority of individuals taking the medication. Seventy-three percent of DIC cases can be attributed to a single prescription medication, commonly antibiotics & antifungals, anti-diabetics, anti-inflammatory, & cardiovascular drugs, psychotropic drugs. The exact pathomechanism may vary for different drugs and requires further elucidation.


title: Cholestasis

text: Typical symptoms of DIC include pruritus and jaundice, nausea, fatigue, and dark urine, which usually resolve after discontinuation of the offending medication.


title: Cholestasis

text: Clinically, DIC can manifest as acute bland (pure) cholestasis, acute cholestatic hepatitis, secondary sclerosing cholangitis (involving bile duct injury), or vanishing bile duct syndrome (loss of intrahepatic bile ducts). Bland cholestasis occurs when there is obstruction to bile flow in the absence of inflammation or biliary and hepatic injury, whereas these features are present in cholestatic hepatitis.Bland cholestasis is almost always caused by anabolic steroids or estrogen contraceptive use, while many drugs may cause cholestatic hepatitis, including penicillins, sulfonamides, rifampin, cephalosporins, fluoroquinolones, tetracyclines, and methimazole, among others.


title: Cholestasis

text: Antibiotics and antifungals that commonly cause DIC are penicillins, macrolides, trimethoprim/sulfamethoxazole, and tetracyclines. Due to its clavulanic acid component, penicillin amoxicillin-clavulanate is the most common culprit of cholestatic liver injury. Flucloxacillin, which is commonly prescribed in the UK, Sweden, and Australia, is another penicillin frequently implicated in DIC. Cholestasis induced by penicillins usually resolves after withdrawal. Macrolides with cholestatic potential include erythromycin, clarithromycin, and azithromycin, and prognosis is likewise favorable with these drugs. Trimethoprim/sulfamethoxazole (via its sulfonamide component) is the fourth most common antibiotic responsible for DILI in North America. However, DIC is comparatively less common with low-dose tetracyclines like doxycycline. Other cholestatic antimicrobials include the antifungal terbinafine, notable for its potential to cause life-threatening cholestatic injury, and quinolones (ciprofloxacin, levofloxacin), which have been linked to cholestatic hepatitis and vanishing bile duct syndrome.


title: Cholestasis

text: Among psychotropic drugs, chlorpromazine is known to cause cholestatic hepatitis. Tricyclic antidepressants (imipramine, amitriptyline) and SSRIs (duloxetine) causing cholestasis have also been reported. Anti-inflammatory drugs with cholestatic potential include the immunosuppressant azathioprine, which has been reported to cause fatal cholestatic hepatitis, and the NSAID diclofenac.


title: Cholestasis

text: The causes of cholestasis are diverse, and some feature more prominently than others. Some rare causes include primary sclerosing cholangitis, primary biliary cholangitis, familial intrahepatic cholestasis, Alagille syndrome, sepsis, total parenteral nutrition-based cholestasis, benign recurrent intrahepatic cholestasis, biliary atresia, and intrahepatic cholestasis of pregnancy.


title: Cholestasis

text: Chronic cholestasis occurs in primary biliary cholangitis (PBC). PBC is a progressive autoimmune liver disease in which small intrahepatic bile ducts are selectively destroyed, leading to cholestasis, biliary fibrosis, cirrhosis, and eventually liver failure that requires transplantation. Prevalence of PBC ranges from 19 to 402 cases/million depending on geographic location, with a 9:1 female preponderance and median ages of diagnosis of 68.5 years for females and 54.5 years for males.


title: Cholestasis

text: At diagnosis, 50% of PBC patients are asymptomatic, indicative of an early stage of disease, while another 50% report fatigue and daytime sleepiness. Other symptoms include pruritus and skin lesions, and in prolonged cholestasis, malabsorption and steatorrhea leading to fat-soluble vitamin deficiency. Disease progression is accompanied by intensifying portal hypertension and hepatosplenomegaly. Clinically, diagnosis generally requires a 1:40 or greater titer of anti-mitochondrial antibody (AMA) against PDC-E2 and elevated alkaline phosphatase persisting for 6+ months.


title: Cholestasis

text: Ursodeoxycholic acid (UDCA) is an FDA-approved first-line treatment for PBC. At moderate doses, UDCA has been demonstrated to slow disease progression and improve transplant-free survival. A complete response is achieved in 25-30% patients, and similar survival as the general population is expected in 2/3 of patients on UDCA. For the 1/3 non-responders, obeticholic acid (OCA) is approved by the FDA as a second-line treatment.


title: Cholestasis

text: The precise etiology of PBC remains poorly understood, though a clearer picture is starting to emerge. A loss of immune tolerance is indicated by the presence of AMAs and autoreactive CD4+ and CD8+ T cells targeting cholangiocytes that line the bile ducts. Cholangiocytes are normally responsible for 40% of bile flow, mostly through secretion of bicarbonate into bile via anion exchanger 2 (AE2) on their apical membrane. The resulting bicarbonate "umbrella" that forms over cholangiocytes provides protection from toxic bile salts. However, in PBC there is repression of AE2 activity due to upregulation of miR-506. This results in decreased biliary bicarbonate secretion and consequently, cholestasis and injury to cholangiocytes by bile salts. Injury may induce cholangiocytes to undergo apoptosis, and during this process, the unique way in which cholangiocytes handle the degradation of PDC-E2 (the E2 subunit of mitochondrial pyruvate dehydrogenase complex) may be a trigger for PSC. Specifically, PDC-E2 in apoptotic cholangiocytes undergo a covalent modification that may render them recognizable to antibodies and thereby trigger a break in self-tolerance. The problem is compounded by cholangiocytes' peculiarly abundant expression of HLA-II and HLA-I, as well as adhesion and chemoattractant molecules, which recruit aid in recruitment of mononuclear immune cells.


title: Cholestasis

text: Both genetic and environmental factors probably contribute to PBC pathogenesis. Genetic predisposition is suggested by high concordance between identical twins, higher incidence among relatives, and a strong association of disease with certain HLA variants. Disease is likely triggered in the genetically predisposed by some environmental factor, such as pollutants, xenobiotics (e.g., chemicals in makeup), diet, drugs, stress, and infectious agents. Urinary tract infection with E. coli is a particularly strong risk factor for  PBC. A possible explanation is that E. coli possess a similar PDC-E2 as humans which could trigger autoimmunity via molecular mimicry.


title: Cholestasis

text: Chronic cholestasis is a feature in primary sclerosing cholangitis (PSC). PSC is a rare and progressive cholestatic liver disease characterized by narrowing, fibrosis, and inflammation of intrahepatic or extrahepatic bile ducts, leading to reduced bile flow or formation (i.e., cholestasis). The pathogenesis of PSC remains unclear but probably involves a combination of environmental factors and genetic predisposition. Notably, 70-80% of patients with PSC are comorbid with inflammatory bowel disease (e.g., ulcerative colitis or Crohn's colitis), suggesting there exists a link between the two.


title: Cholestasis

text: PSC predominantly affects males (60-70%) of 30–40 years of age. The disease has an incidence is 0.4-2.0 cases/100,000 and a prevalence of 16.2 cases/100,000, making it a rare disease. Nonetheless, PSC accounts for 6% of liver transplants in the US due to its eventual progression to end-stage liver disease, with a mean transplant-free survival of 21.3 year.


title: Cholestasis

text: Though 40-50% of patients are asymptomatic, commonly reported symptoms include abdominal pain in the right upper quadrant, pruritus, jaundice, fatigue, and fever. The most common signs are hepatomegaly and splenomegaly. Prolonged cholestasis in PSC may cause fat-soluble vitamin deficiency leading to osteoporosis


title: Cholestasis

text: Diagnosis requires elevated serum alkaline phosphatase persisting for at least 6 months and the presence of bile duct strictures on cholangiogram. Unlike primary biliary cholangitis, PSC lacks a diagnostic autoantibody or reliable biomarker of disease progression. Although a liver biopsy is not required for diagnosis, the characteristic histological finding is concentric periductal fibrosis resembling onion skin.


title: Cholestasis

text: PSC is associated with increased risk of several cancers, most notably, a 400 times greater risk for cholangiocarcinoma compared to the general population. Patients with PSC also face elevated risk of pancreatic and colorectal cancer. Therefore, regular screening is recommended.


title: Cholestasis

text: No drugs are currently approved for treating PSC specifically. Although commonly given, ursodeoxycholic acid at moderate doses failed to improve transplant-free survival in randomized controlled trials. Due to disease progression, 40% of patients eventually require liver transplantation, which has survival rates (91% at 1 year, 82% at 5 years, and 74% at 10 years). However, the disease recurs in at least 25% of transplant recipients, particularly in those with IBD and an intact colon. Clinical trials are underway for several novel therapies, including obeticholic acid (a bile acid analogue), simtuzumab (a monoclonal antibody), and 24-norursodeoxycholic acid (a synthetic bile acid).


title: Cholestasis

text: Although the pathogenesis of PSC is poorly understood, three dominant theories have been proposed: 1) aberrant immune response, 2) increased intestinal permeability, and 3) dysbiosis of gut microbiota. The first theory involves immune-mediated damage to bile ducts by T cells. In PSC, cholangiocytes and hepatocytes display aberrant expression of adhesion molecules, which facilitate homing of intestinal T cells to the liver. Additionally, intestinal microbiota may produce pathogen-associated molecular patterns that stimulate cholangiocytes and hepatic macrophages to produce proinflammatory cytokines, which promote recruitment of immune cells to the bile ducts, fibrosis, cholangiocyte apoptosis and senescence, and ultimately destruction of the bile ducts. In support of T cell involvement, certain human leukocyte antigen (HLA) variants are strongly associated with PSC risk. Further evidence for genetic predisposition include the identification of 23 non-HLA susceptibility loci and a higher disease risk among siblings, though environmental factors appear to play a much greater role in pathogenesis.


title: Cholestasis

text: Another theory postulates that increased intestinal permeability contributes to PSC. Tight junctions, which normally maintain the integrity of the intestinal epithelium, may become disrupted in inflammation. Leaky tight junctions could allow commensal bacteria and toxins to enter portal circulation and reach the liver, where they can trigger inflammation and fibrosis.


title: Cholestasis

text: The intestinal dysbiosis theory hypothesizes that yet unidentified environmental triggers (e.g., diet, medication, inflammation) reduce microbiota diversity and/or alter the population of specific species. The resulting imbalance between primary and secondary bile acids may lead to PSC via the gut-liver axis. The primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) are synthesized in the liver and undergo conjugation before being released into the small intestine to aid digestion. In the distal ileum, 95% of these conjugated BAs are actively reabsorbed via ASBT but 5% enter the colon and are converted by gut microbes into deconjugated secondary bile acids, predominantly deoxycholic acid (DCA) and lithocholic acid (LCA). DCA and LCA are then reabsorbed into portal circulation and reach the liver, where they serve as signaling molecules that maintain bile acid homeostasis. Specifically, DCA and LCA and potent agonists of farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5), both of which mediate anti-inflammatory and cholangioprotective effects upon activation. On cholangiocytes, TGR5 activation induces CFTR to secrete chloride into bile ducts, which then drives anion exchanger 2 to secrete bicarbonate into bile canaliculi. Bicarbonate serves to protect the apical surface of cholangiocytes from damage by bile acids. On macrophages, activation of FXR and TGR5 inhibits NF-κB, thereby reducing production of proinflammatory cytokines. Therefore, it is hypothesized that a reduction in secondary bile acid production, as a result of dysbiosis, could lead to bile duct damage via decreased activation of FXR and TGR5. Indeed, lower levels of secondary bile acids were found in PSC patients, but a causal relationship is yet to be confirmed.


title: Cholestasis

text: Familial intrahepatic cholestasis (FIH) is a group of disorders that lead to intrahepatic cholestasis in children. Most often, FIH occurs during the first year of life, with an incidence rate of 1/50,000 to 1/100,000. There are three different versions of FIH, with each causing a different severity of jaundice. Typically, children exhibit recurrent jaundice episodes, which eventually become permanent. Diagnosis usually occurs by analyzing laboratory features, liver biopsy results, DNA/RNA sequences, and biliary lipid analysis. The definitive treatment for FIH is liver transplant which usually results in a high recovery rate. Each type of FIH is a result of a different mutation. The three genes thought to be involved include "APT8B1", which encodes for the FIC1 protein. The "ABCB11" gene encodes for the bile salt export pump (BSEP) protein, and the "ABCB4" gene encodes for the multidrug resistance 3 (MDR3) protein. BSEP and MDR3 are respectively responsible for transporting bile salt and phospholipid, two major constituents of bile, across the apical membrane of hepatocytes.


title: Cholestasis

text: Alagille syndrome is an autosomal dominant disorder that impacts five systems, including the liver, heart, skeleton, face, and eyes. In the early part of life (within the first three months), patients with Alagille syndrome exhibit conjugated hyperbilirubinemia, severe pruritus, and jaundice. Bile duct obliteration usually worsens over time, causing cirrhosis of the liver and eventual failure. Diagnosis usually occurs using the classic criteria by looking at changes associated with the five systems discussed earlier. Like FIH, the definitive treatment is a liver transplant. Almost all patients with Alagille syndrome have mutations of the genes involved in the Notch signaling pathway. Most have a mutation of the JAG1 gene, while a small minority have a mutation of the NOTCH2 gene.


title: Cholestasis

text: A variety of factors associated with sepsis may cause cholestasis. Typically, patients have conjugated hyperbilirubinemia and alkaline phosphatase (ALP) elevation but not to extreme levels. Sepsis-induced cholestasis may occur due to increased serum lipopolysaccharide levels. Lipopolysaccharides can inhibit and down-regulate bile salt transporters in hepatocytes, thereby leading to cholestasis. As such, in the case of sepsis, cholestasis occurs not as a result of impaired obstruction but rather the disruption of bile flow. Ischemic liver injury resulting from sepsis can also cause cholestasis. Importantly, jaundice is not indicative of cholestasis in all cases. Widespread hemolysis resulting from sepsis may release bilirubin, thereby overwhelming bilirubin reabsorption and excretion mechanism.


title: Cholestasis

text: Total parenteral nutrition (TPN) is given to patients with intestinal failure or a variety of other gastrointestinal problems. Under normal settings, TPN causes a slight elevation of ALP levels. However, this does not indicate cholestasis alone. In the case of TPN-induced cholestasis, there is an excessive elevation of ALP, gamma-glutamyltransferase (GGT), and conjugated bilirubin. Without appropriate intervention, symptoms can quickly exacerbate, leading to liver cirrhosis and failure. Cholestasis arising from TPN has a diverse range of causes, including toxicity to TPN components, underlying disorders, or a lack of enteral nutrition. Without enteral food consumption, gallbladder function is greatly inhibited, leading to gallstone formation, subsequent blockage, and eventually cholestasis. Cholestasis resulting from TPN may also be a result of reduced bile flow from portal endotoxins. With TPN, there is a reduction in gastrointestinal motility, immunity, with an increase in permeability. These changes facilitate bacteria growth and increase the amount of circulating endotoxin. Moreover, given that patients using TPN often have underlying health problems, drugs being used with known liver toxicity may also cause cholestasis. Lipids in TPN may cause cholestasis and liver damage by overwhelming clearage mechanisms. Intravenous glucose can also cause cholestasis as a result of increased fatty acid synthesis and decreased breakdown, which facilitates the accumulation of fats.


title: Cholestasis

text: Intrahepatic cholestasis of pregnancy (ICP) is an acute cause of cholestasis that manifests most commonly in the third trimester of pregnancy. It affects 0.5-1.5% of pregnancies in Europe and the US and up to 28% in women of Mapuche ethnicity in Chile. ICP is characterized by severe pruritus and elevated serum levels of bile acids as well as transaminases and alkaline phosphatase. These signs and symptoms resolve on their own shortly after delivery, though they may reappar in subsequent pregnancies for 45-70% of women. In the treatment of ICP, current evidence suggests ursodeoxycholic acid (UDCA), a minor secondary bile acid in humans, is the most effective drug for reducing pruritus and improving liver function.


title: Cholestasis

text: The etiology of ICP is multifactorial and likely involves hormonal, genetic, and environmental factors. Several observations suggest estrogen plays a major role: ICP begins in the third trimester, when estrogen levels are highest, resolves after estrogen levels return to normal post-delivery, and occurs with higher incidence in multiple pregnancies, where estrogen levels are more elevated than usual. Although estrogen's exact pathomechanism in ICP remains unclear, several explanations have been offered. Estrogen may induce a decrease in the fluidity of the hepatic sinusoidal membrane, leading to a decrease in the activity of basolateral Na+/K+-ATPase. A weaker Na+ gradient results in diminished sodium-dependent uptake of bile acids from venous blood into hepatocytes by the sodium/bile acid cotransporter. More recent evidence suggests that estrogen promotes cholestasis via its metabolite estradiol-17-β-D-glucuronide (E2). E2 secreted into the canaliculi by MRP2 was found to repress the transcription of bile salt export pump (BSEP), the apical ABC transporter responsible for exporting monoanionic conjugated bile acids from hepatocytes into bile canaliculi. E2 was also found to upregulate miR-148a, which represses expression of the pregnane X receptor (PXR). PXR is a nuclear receptor in hepatocytes that senses intracellular bile acid concentrations and regulates gene expression accordingly to increase bile efflux.


title: Cholestasis

text: Genetic predisposition for ICP is suggested by familial and regional clustering of cases. Several studies have implicated heterozygous mutations of the genes "ABCB11" and "ABCB4" in ICP, which respectively encode the canalicular transport proteins BSEP and multidrug resistance protein 3 (MDR3). MDR3 is responsible for exporting phosphatidylcholine, the major lipid component of bile, into bile canaliculi where it forms micelles with bile salts to prevent the latter from damaging luminal epithelium. Bile flow requires canalicular secretion of both bile salts and phosphatidylcholine. MDR3 mutations are an established predisposing factor, found in 16% of ICP cases. More recently, studies have demonstrated involvement of BSEP mutations in at least 5% of cases. The V444A polymorphism of "ABCB11" in particular may lead to ICP by causing a reduction in hepatic BSEP expression and consequently decreased bile salt export. Other notable mutations identified in ICP patients include ones in the farnesoid X receptor (FXR), a nuclear receptor in hepatocytes which activates transcription of MDR3 and BSEP upon binding intracellular bile acids, thereby increasing canalicular bile efflux.


title: Cholestasis

text: Bile is secreted by the liver to aid in the digestion of fats. Bile formation begins in bile canaliculi that form between two adjacent surfaces of liver cells (hepatocytes) similar to the terminal branches of a tree. The canaliculi join each other to form larger and larger structures, sometimes referred to as the canals of Hering, which themselves join to form small bile ductules that have an epithelial surface. The ductules join to form bile ducts that eventually form either the right main hepatic duct that drains the right lobe of the liver, or the left main hepatic duct draining the left lobe of the liver. The two ducts join to form the common hepatic duct, which in turn joins the cystic duct from the gall bladder, to give the common bile duct. This duct then enters the duodenum at the ampulla of Vater. In cholestasis, bile accumulates in the hepatic parenchyma.


title: Cholestasis

text: One of the most common causes of extrahepatic, or obstructive cholestasis, is biliary obstruction. This is better known as choledocholithiasis where gallstones become stuck in the common bile duct.


title: Cholestasis

text: Drugs may induce cholestasis by interfering with 1) hepatic transporters, 2) bile canaliculi dynamics, and/or 3) cell structure and protein localization. Hepatic transporters are essential for maintaining enterohepatic bile flow and bile acid homeostasis. Therefore, their direct inhibition by certain drugs may lead to cholestasis. Relevant transporters implicated include BSEP, MDR3, MRP2-4, and NTCP.


title: Cholestasis

text: Cholestasis can result from competitive inhibition of BSEP by several drugs, including cyclosporine A, rifampicin, nefazodone, glibenclamide, troglitazone, and bosentan. BSEP is the main transporter in hepatocytes responsible for exporting bile salts across the apical membrane into bile canaliculi. Therefore, inhibiting BSEP should cause cytotoxic bile salts to accumulate in hepatocytes, leading to liver injury and impaired bile flow. Indeed, there is a strong association between BSEP inhibition and cholestasis in humans, and BSEP inhibitors are shown to induce cholestasis "in vitro". However, hepatocytes have safety mechanisms that can compensate for impaired canalicular bile efflux. In response to cholestasis, MRP3 and MRP4 on the basolateral membrane are upregulated to allow efflux of accumulated bile salts into portal blood. Similarly, MRP2 can accommodate additional bile flow across the apical membrane in cholestatic conditions. These compensatory mechanisms explain why some BSEP inhibitors do not cause cholestasis. On the contrary, contrast, drugs that inhibit both MRP3/4 and BSEP (e.g., rifampicin, troglitazone, bosentan) pose greater risk for cholestasis


title: Cholestasis

text: MDR3 is another key canalicular efflux transporter that is the target of inhibition by certain drugs. MDR3 secretes phosphatidylcholine into bile canaliculi, where it form micelles with bile salts to dissolve cholesterol as well as protect hepatocyte and cholangiocytes from damage by bile salts. MDR3 inhibition leads to low phospholipid concentrations in bile that damages cholangiocytes and leads to cholestasis. Antifungal azoles such itraconazole have been shown to inhibit both MDR3 and BSEP,  thus giving them higher cholestatic potential. Other MDR3-inhibiting drugs are chlorpromazine, imipramine, haloperidol, ketoconazole, saquinavir, clotrimazole, ritonavir, and troglitazone.


title: Cholestasis

text: Another target for inhibition, MRP2 is an apical efflux transporter that mainly exports bilirubin glucuronide and glutathione into bile. However, MRP2 is also the preferential route of export for certain sulfated conjugated BAs (taurolithocholic acid and glycolithocholic acid), so its inhibition could contribute to cholestasis.


title: Cholestasis

text: On the hepatocyte basolateral membrane, Na+-taurocholate cotransporting peptide (NTCP) is the major transporter of conjugated bile acids. Enterohepatic bile flow requires the concerted activity of both NTCP and BSEP, which form the major route by which BAs enter and exit hepatocytes respectively. Therefore, NTCP inhibitors, such as cyclosporine A, ketoconazole, propranolol, furosemide, rifamycin, saquinavir, and ritonavir, should theoretically cause cholestasis by decreasing hepatocyte BA uptake. However, no relationship was found between NTCP inhibition and DIC risk, possibly because basolateral sodium-independent OATPs can partially compensate for bile salt uptake. Therefore, NTCP inhibition alone seems to be insufficient for causeing cholestasis. Indeed, the cholestatic effect of cyclosporine A relies on its inhibition of both NTCP and the compensatory OATP1B1.


title: Cholestasis

text: In addition to direct inhibition, drugs can also induce cholestasis by promoting downregulation and internalization of transporters. For example, cyclosporine A in rats was shown to induce BSEP internalization in addition to inhibition. Furthermore, human hepatocytes showed decreased expression of BSEP mRNA and protein following long-term exposure to metformin and tamoxifen, neither of which are direct BSEP inhibitors.


title: Cholestasis

text: Bile canaliculi dynamics refers to the contractile motion of bile canaliculi (ducts) required for bile flow. Cholestasis can result when drugs constrict or dilate bile canaliculi. Constrictors include chlorpromazine, nefazodone, troglitazone, perhexiline, metformin, cyclosporin A. These drugs activate the RhoA/Rho-kinase pathway, which inhibits myosin light chain phosphatase (MLCP), and in turn, increases myosin light chain phosphorylation by MLC kinase leading to constriction of bile canaliculi. Drugs that dilate canaliculi work by inhibiting MLCK or RhoA/Rho-kinase and include diclofenac, bosentan, entacapone, tacrolimus, cimetidine, and flucloxacillin. Constriction is more serious than dilation, as the former causes irreversible cell damage and death.


title: Cholestasis

text: Minor mechanisms that may contribute to DIC include aberrant paracellular permeability, membrane fluidity, and transporter localization. Tight junctions normally seal the gap between hepatocytes to prevent bile from diffusing out of the canaliculi. If a drug causes internalization of hepatocyte tight junctions, like rifampicin does in mice, bile flow may become impaired due to paracellular leakage. Membrane fluidity can affect bile flow by regulating the activity of hepatocyte Na+/K+-ATPase, which maintains the inwardly-directed Na+ gradient that drives BA uptake by apical NTCP. In rats, cyclosporine A was found to increase canalicular membrane fluidity and consequently reduce bile secretion. Bile flow was similarly reduced in rats as a result of alterations to basolateral membrane fluidity by ethinylestradiol and chlorpromazine. Lastly, some agents (rimpaficin and 17β-estradiol) were shown to hinder proper localization of hepatocyte transporters by interfering with the microtubules required for their insertion into plasma membranes.


title: Cholestasis

text: Cholestasis can be suspected when there is an elevation of both 5'-nucleotidase and ALP enzymes. With a few exceptions, the optimal test for cholestasis would be elevations of serum bile acid levels. However, this is not normally available in most clinical settings necessitating the use of other biomarkers. If 5' nucleosidase and ALP enzymes are elevated, imaging studies such as computed tomography (CT) scan, ultrasound, and magnetic resonance imaging (MRI) are used to differentiate intrahepatic cholestasis from extrahepatic cholestasis. Additional imaging, laboratory testing, and biopsies might be conducted to identify the cause and extent of cholestasis.


title: Cholestasis

text: ALP enzymes are found abundantly within the bile canaliculi and bile. If a duct is obstructed, tight junctions permit migration of the ALP enzymes until the polarity is reversed and the enzymes are found on the whole of the cell membrane. Serum ALP levels exceeding 2-3 times the upper baseline value may be due to a variety of liver diseases. However, an elevation that exceeds 10 times the upper baseline limit is strongly indicative of either intrahepatic or extrahepatic cholestasis and requires further investigation. Cholestasis can be differentiated from other liver disorders by measuring the proportion of ALP to serum aminotransferases, where a greater proportion indicates a higher likelihood of cholestasis. Typically, aminotransferase enzymes are localized within hepatocytes and leak across the membrane upon damage. However, measurement of serum aminotransferase levels alone is not a good marker to determine cholestasis. In up to a third of patients, ALP levels may be elevated without the presence of cholestasis. As such, other biomarkers should be measured to corroborate findings.


title: Cholestasis

text: Measurement of 5' nucleosidase levels may be used to identify cholestasis in conjunction with ALP. Levels of ALP may rise within a few hours of cholestasis onset while 5' nucleosidase levels may take a few days. Many labs cannot measure 5' nucleosidase and ALP levels so, GGT may be measured in some cases. Abnormal GGT elevation may be attributable to a variety of factors. As such, GGT elevations lack the necessary specificity to be a useful confirmatory test for cholestasis.


title: Cholestasis

text: Importantly, conjugated hyperbilirubinemia is present in 80% of patients with extrahepatic cholestasis and 50% of patients with intrahepatic cholestasis. Given that many patients with hyperbilirubinemia may not have cholestasis, the measurement of bilirubin levels is not a good diagnostic tool for identifying cholestasis. In a later stage of cholestasis aspartate transaminase (AST), alanine transaminase (ALT) and unconjugated bilirubin may be elevated due to hepatocyte damage as a secondary effect of cholestasis.


title: Cholestasis

text: After determination using biomarkers, a variety of imaging studies may be used to differentiate between intrahepatic or extrahepatic cholestasis. Ultrasound is often used to identify the location of the obstruction but, is often insufficient in determining the level of biliary obstruction or its cause because it can pick up bowel gas that may interfere with readings. CT scans are not impacted by bowel gas and may also be more suitable for overweight patients. Typically, the cause of cholestasis and magnitude of obstruction is better diagnosed with CT compared to ultrasound. MRI scans provide similar information to CT scans but are more prone to interference from breathing or other bodily functions.


title: Cholestasis

text: Although CT, ultrasound, and MRI may help differentiate intrahepatic and extrahepatic cholestasis, the cause and extent of obstruction is best determined by cholangiography. Potential causes of extrahepatic cholestasis include obstructions outside the wall of the lumen, those outside the duct, and obstructions found in the duct lumen. Endoscopic retrograde cholangiography may be useful to visualize the extrahepatic biliary ducts. In case of anatomical anomalies, or if endoscopic retrograde cholangiography is unsuccessful, percutaneous transhepatic cholangiography may be used. CT or MRI-based cholangiography may also be useful, particularly in cases where additional interventions are not anticipated.


title: Cholestasis

text: There is a significant overlap between cholestasis resulting from a hepatocellular origin and cholestasis caused by bile duct obstruction. Due to this, obstructive cholestasis can only be diagnosed after finding additional diagnostic signs that are specific to obstructive changes to the bile ducts or portal tracts. In both non-obstructive and obstructive cholestasis, there is an accumulation of substances that are typically secreted in the bile, as well as degeneration of hepatocytes. The most significant feature from a histopathological perspective includes pigmentation resulting from the retention of bilirubin. Under a microscope, the individual hepatocytes will have a brownish-green stippled appearance within the cytoplasm, representing bile that cannot get out of the cell. Pigmentation can involve regurgitation of bile into the sinusoidal spaces caused by phagocytosis from Kupffer cells, an accumulation of bilirubin within hepatocytes, and inspissated bile in the canaliculi. Most pigmentation and canaliculi dilation occurs in the perivenular region of the hepatic lobule. In chronic cases, this may extend into the periportal area.


title: Cholestasis

text: Hepatocyte necrosis is not a significant feature of cholestasis; however, apoptosis may often occur. Under the microscope, hepatocytes in the perivenular zone appear enlarged and flocculent. In cases of obstructive cholestasis, bile infarcts may be produced during the degeneration and necrosis of hepatocytes. Bile infarcts are marked by a large amount of pigmented tissue surrounded by a ring of necrotic hepatocytes. In some cases, hepatocyte degeneration is uncommon. E.g., with Alagille syndrome limited degeneration occurs, however, there may be a small amount of apoptosis and enlarged hepatocytes.


title: Cholestasis

text: Cholestasis is often marked by cholate statis, which are a set of changes that occur in the periportal hepatocytes. Cholate statis is more common in obstructive cholestasis compared to non-obstructive cholestasis. During the cholate statis process, hepatocytes first undergo swelling and then degeneration. Under the microscope, this is evident as a lucent cell periphery and enlarged cytoplasm around the nucleus. Oftentimes, Mallory bodies may also be found in the periportal areas. Due to the retention of bile, which contains copper, stains made for staining copper-associated protein can be used to visualize bile accumulation in the hepatocytes.


title: Cholestasis

text: Cholestatic liver cell rosettes may occur in children with chronic cholestasis. Histologically, this is evident as two or more hepatocytes in a pseudotubular fashion that encircle a segment of enlarged bile canaliculi. Children may also have giant hepatocytes present, which are characterized by a pigmented spongy appearance. Giant cell formation is likely caused by the detergent properties of bile salts causing a loss of the lateral membrane and joining of hepatocytes. In the case of Alagille syndrome, hepatocyte degeneration is uncommon. However, there may be a small amount of apoptosis and enlarged hepatocytes.


title: Cholestasis

text: In non-obstructive cholestasis, changes to the portal tracts are unlikely. However, it may occur in some unique situations. In the case of neutrophilic pericholangitis, neutrophils surround the portal ducts and obstruct them. Neutrophilic pericholangitis has a variety of causes including endotoxemia, Hodgkin's disease, among others. Cholangitis lenta can also cause changes to the portal tracts. This occurs during chronic cases of sepsis and results in dilation of the bile ductules. Cholangitis lenta is likely a result of a stoppage of bile secretion and bile flow through the ductules.


title: Cholestasis

text: Back pressure created from obstructive cholestasis can cause dilation of the bile duct and biliary epithelial cell proliferation, mainly in the portal tracts. Portal tract edema may also occur as a result of bile retention, as well as periductular infiltration of neutrophils. If the obstruction is left untreated, it can lead to a bacterial infection of the biliary tree. Infection is mostly caused by coliforms and enterococci and is evident from a large migration of neutrophils to the duct lumina. This can result in the formation of a cholangitic abscess. With treatment, many of the histological features of cholestasis can be corrected once the obstruction is removed. If the obstruction is not promptly resolved, portal tract fibrosis can result. Even with treatment, some fibrosis may remain.


title: Cholestasis

text: In cases involving obstructive cholestasis, the primary treatment includes biliary decompression. If bile stones are present in the common bile duct, an endoscopic sphincterotomy can be conducted either with or without placing a stent. To do this, a duodenoscope is placed by the endoscopist in the second portion of the duodenum. A catheter and guidewire is moved up into the common bile duct. A sphincterotome can then enlarge the ampulla of Vater and release the stones. Later, the endoscopist can place a stent in the common bile duct to soften any remaining stones and allow for bile drainage. If needed, a balloon catheter is available to remove any leftover stones. If these stones are too large with these methods, surgical removal may be needed. Patients can also request an elective cholecystectomy to prevent future cases of choledocholithiasis. In case of narrowing of the common bile duct, a stent can be placed after dilating the constriction to resolve the obstruction.


title: Cholestasis

text: The treatment approach for patients with obstructive cholestasis resulting from cancer varies based on whether they are a suitable candidate for surgery. In most cases, surgical intervention is the best option. For patients whom complete removal of the biliary obstruction is not possible, a combination of a gastric bypass and hepaticojejunostomy can be used. This can reestablish bile flow into the small intestine, thereby bypassing the blockage. In cases where a patient is not a suitable candidate for surgery, an endoscopic stent can be placed. If this is not possible or successful, a percutaneous transhepatic cholangiogram and percutaneous biliary drainage can be used to visualize the blockage and re-establish bile flow.


title: Cholestasis

text: A significant portion of patients with cholestasis (80%) will experience pruritus at some point during their disease. This is a condition that can severely decrease a patient's quality of life as it can impact sleep, concentration, work ability, and mood. Many treatments exist, but how effective each option is depends on the patient and their condition. Assessment using a scale, such as a visual analogue scale or a 5-D itch scale will be useful to identify an appropriate treatment. Possible treatment options include antihistamines, ursodeoxycholic acid, and phenobarbital. Nalfurafine hydrochloride can also be used to treat pruritus caused by chronic liver disease and was recently approved in Japan for this purpose.


title: Cholestasis

text: Bile acid binding resins like cholestyramine are the most common treatment. Side effects of this treatment are limited and include constipation and bloating. Other commonly used treatments include rifampin, naloxone, and sertraline.


title: Cholestasis

text: In cholestatic liver disease, when bilirubin concentration starts to build up, a deficiency of fat soluble vitamins may also occur. To manage this, doses of vitamin A, D, E, and K are recommended to retain appropriate vitamin levels.


title: Cholestasis

text: Cholestatic liver disease can impact lipids, and possibly lead to dyslipidemia, which may present a risk for coronary artery disease. Statins and fibrates are generally used as lipid lowering therapy to treat patients with cholestatic liver disease.


title: Cholestasis

text: For intrahepatic cholestasis in pregnant women, S-adenosylmethionine has proven to be an effective treatment. Dexamethasone is a viable treatment in regards to the symptom of intensive itching.


title: Cholestasis

text: Primary sclerosing cholangitis (PSC) is one of the most common cholestatic liver diseases, yet treatment options remain limited. Treatment for primary biliary cholangitis (PBC) is often done with ursodeoxycholic acid (UDCA) and with no other suitable alternative, it poses a problem for those that are not responsive to (UDCA). However, with advancing technology in the molecular biochemistry field and higher understanding of bile acid regulation, novel pharmacological treatments have been considered.


title: Cholestasis

text: For patients with primary biliary cholangitis, current guidelines recommend about 13–15 mg/kg of ursodeoxycholic acid as a first line treatment. This drug stimulates biliary bicarbonate secretion, improves survival without having to resort to a liver transplantation, and is very well tolerated— making it an ideal treatment. However, around 40% of patients with primary biliary cholangitis are not responsive to UDCA.


title: Cholestasis

text: Obeticholic acid has been approved by the US Food and Drug Administration for PBC in 2016 after experiments found beneficial improvements for the liver in half of patients with inadequate response to UDCA.


title: Cholestasis

text: Primary sclerosing cholangitis is a challenging liver disease as treatment options are limited. There is still uncertainty about the efficacy of ursodeoxycholic acid for PSC and researchers offer conflicting recommendations. One study found UDCA had improved biochemical functions but did lower the rate for death or transplant-free survival.


title: Cholestasis

text: An important regulator in bile acid homeostasis is the alpha and delta isoforms of the peroxisome proliferator-activated receptor (PPARα, PPARδ). The function of PPARα is that it promotes bile acid excretion and lowers inflammation by acting on nuclear transcription factors. A well known agonist are fibrates and in the clinical trials, there was a significant biochemical response in most patients. A combination therapy with bezafibrate showed remarkable biochemical improvement, with 67% of patients normalizing their alkaline phosphatase levels. Another study of 48 patients with PBC found a combination of bezafibrate and UDCA showed a decrease of alkaline phosphatase in all patients. Further, the study found those treated had a marked relief in pruritus.


title: Cholestasis

text: However, fibrates are associated with a number of adverse effects including arthritis, leg edema, polydipsia, and myalgias. Elevations of creatinine and creatinine phosphokinase were also found over a long term use.


title: Cholestasis

text: A new novel treatment option is the farnesoid X receptor is responsible for regulating bile acid homeostasis. An agonist of this nuclear hormone receptor is seen as a possible treatment as it can downregulate bile acid synthesis and reabsorption. Further the farnesoid X receptor is partly responsible for lipid and glucose homeostasis, as well as pathogen recognition. An agonist for the farnesoid X receptor can therefore lead to an anti-cholestatic environment to minimize the effect of toxic bile acids on the liver.  A candidate agonist for the farnesoid X receptor is obeticholic acid with experiments showing it has very strong affinity. A worry though is despite benefits in the biochemical pathways, pruritus was more intense and prevalent than the placebo. A titration strategy may help to mitigate pruritus, but FDA approval for obeticholic acid is currently unlikely. In fact, in February 2018, the FDA gave a black box warning for OCA. A recent study did find that if the drug is given with UDCA, the incidence for cirrhosis and liver transplants decreases.


title: Cholestasis

text: Another target that is being looked into is the All-trans retinoic acid (ATRA), an activator for the retinoid X receptor. In vitro and animal studies found ATRA had lowered the amount of bile acid and decreased hepatic inflammation.


title: Cholestasis

text: A recent scientific breakthrough for cholestasis that has allowed us to evaluate a new treatment option is that a hydrophilic environment and bicarbonate production protects hepatocytes from bile acid. The novel agent norUDCA (24-norursodeoxycholic acid) can be passively absorbed by cholangiocytes. This leads to bicarbonate production and an environment that is less toxic. Mouse models have found promising results with norUDCA with the drug showing antiproliferative and anti-inflammatory properties. A recent clinical trial found norUDCA had significant dose-dependent reductions for ALP levels. This makes norUDCA a viable possibility to look into as it clearly plays a significant role in the treatment of cholestasis.


title: Cholestasis

text: In PBC, the liver is filled with T cells and B cells that contribute to a worsening condition. Therefore, some treatments are looking into targeting the antigens of these immune cells. The monoclonal antibody Rituximab targets the CD20 antigen on the B cells, and is already used in a wide array of other rheumatologic diseases. In an open-label study, six patients that were unresponsive to UDCA had improvement in ALP levels after rituximab infusions. However, the efficacy of rituximab is still uncertain, and awaits further studies and trials. PBC can also lead to higher levels of interleukin 12 and interleukin 23.  This was what motivated researches to look at the viability of ustekinumab, a monoclonal antibody targeted against interleukin 12 and 23. An experiment found though it did not significantly improve serum ALP levels. The researchers were further even criticized for placing patients at risk by allowing them to move to advanced disease stages where immunomodulatory therapies may not even be an option.


title: Cholestasis

text: In several chronic liver diseases, the gut microbiome, which regulates both the innate and adaptive immune systems, is implicated. This can result in abnormal immunological development and an accumulation of primary bile acids. Using this information a bile-acid–intestinal-microbiota–cholestasis triangle is thought to be involved in the pathogenesis of PBC and PSC. After all, bile acids do modulate the gut microbiota; a disturbance here can result in development and progression of cholestasis. This information has prompted researchers into manipulating the microbiota via antibiotics and probiotics for new treatment options. Some antibiotics examined for PSC include vancomycin, which has extensively studied and reviewed. The usage of the drug is found along with a significant decrease in ALP levels, although the long term clinical benefit is unknown.


title: Cholestasis

text: As biochemistry technology becomes more advanced, promising targets have appeared, prompting numerous studies and trials to evaluate the feasibility. Fibrates, FXR agonists, and norUDCA are all innovative therapies for cholestasis.


title: 75th British Academy Film Awards

text: The 75th British Academy Film Awards, also known as the BAFAs (or BAFTAs), were held on 13 March 2022 at the Royal Albert Hall in London, honouring the best national and foreign films of 2021. Presented by the British Academy of Film and Television Arts, accolades were handed out for the best feature-length film and documentaries of any nationality that were screened at British cinemas in 2021.


title: 75th British Academy Film Awards

text: The nominations were announced on 3 February 2022. The EE Rising Star Award nominees, which is the only category voted for by the British public, were announced on 1 February 2022; the nomination and eventual win of Lashana Lynch confused commentators, who did not consider her "rising".


title: 75th British Academy Film Awards

text: The epic science fiction film "Dune" received the most nominations with eleven; "The Power of the Dog" and "Belfast" followed with eight and six, respectively. The former ultimately won two—Best Film and Best Director (Jane Campion); "Dune" received the most wins, with five, but did not take home any major category awards.


title: 75th British Academy Film Awards

text: The ceremony was hosted by actress and comedian Rebel Wilson. Many winners were not present to collect their awards, though the ceremony was exclusively in-person. This allowed the speeches of winners who were present to go on at length. While many awards were won by frontrunners in the Oscars race, a surprise win came in the Best Actress category – already populated by no Oscar nominees – for Welsh actress Joanna Scanlan for her performance in "After Love".


title: 75th British Academy Film Awards

text: This year, BAFTA did not hand out two of its honorary awards—BAFTA Fellowship and BAFTA Outstanding British Contribution to Cinema Award—as it plans to implement new vetting processes following the previous year's controversy surrounding Noel Clarke.


title: 75th British Academy Film Awards

text: The ceremony was broadcast on BBC One, BBC One HD and BBC iPlayer at 7:00 p.m on 13 March 2022, the day of the ceremony, and was available to stream exclusively on BritBox in North America and South Africa simultaneously with the UK broadcast. The broadcast was not live with the awards presentation, and some parts were edited out, including host Rebel Wilson ranting about a film production gone awry and cursing the production company. Wilson was selected as host after having presented an award at the previous in-person BAFA ceremony in February 2020; in his live coverage of the 2022 ceremony for "The Guardian", British film journalist Stuart Heritage wrote that Wilson had been the only funny part of the 2020 ceremony.


title: 75th British Academy Film Awards

text: While Heritage enjoyed many parts of Wilson's opening monologue at the 2022 ceremony, including jokes about the demise of the BAF(T)As and her own weight loss, he was unimpressed with her wordplay regarding Tom Hiddleston's "low key" ("Loki") appearance at the ceremony; Heritage went on to note throughout the broadcast that Wilson's various skits (including drawing nipples on a flip chart, inviting Andy Serkis to defile a cake shaped like Benedict Cumberbatch, and throwing her bras into the audience) were bad. "NME" wrote that, while the hosting was troubled, Wilson improved towards the end of the ceremony, particularly her one-liners. Digital Spy, by collecting popular tweets about the ceremony, reported that many viewers were off-put by Wilson's unfunny hosting, though some enjoyed the fact she did not hold back when it came to topical humour. The BBC (which broadcast the ceremony) agreed that Wilson's monologue and one-liners were her strongest points, writing that some of her other jokes fell flat, but they thought "on the whole [she] did a fine job". "The Telegraph" was instead highly negative of Wilson's hosting and the mismatched tone of the ceremony she created, but praised her ability to "plough on" anyway; it also noted that in coming on after a strong opening song, Wilson was already at a disadvantage.


title: 75th British Academy Film Awards

text: The "de facto" theme of the ceremony was "all things Bond". Opening the ceremony, to mark the 60th anniversary of the "James Bond" franchise, Dame Shirley Bassey, who is connected with the franchise after contributing to the soundtrack of multiple Bond films throughout her career, performed a rendition of the title song from "Diamonds Are Forever" (1971), the seventh installment of the franchise, with "NME" praising that her voice was as good as ever, writing: "At 85, her voice remains fully capable of filling the Royal Albert Hall to the rafters". Before the ceremony, it was announced that Bassey would perform an iconic Bond theme, only to be revealed on the night. Also performing live during the ceremony was English actress and singer Emilia Jones, nominated for Best Actress in a Leading Role for her performance in "CODA". She performed a rendition of Joni Mitchell's "Both Sides, Now", which her character sings in the film; she was joined by two translators signing the song in American Sign Language (ASL) and British Sign Language (BSL).


title: 75th British Academy Film Awards

text: Jones' performance was introduced by Wilson, who, while welcoming the interpreters, joked that the sign for "Vladimir Putin" was instead universal, holding up a middle finger to the camera. The same gesture had been made in a different context a week earlier at the 37th Independent Spirit Awards by its hosts, Megan Mullally and Nick Offerman, and presenter Kristen Stewart. Deaf journalist Liam O'Dell wrote that Wilson's version was offensive to sign language users as it reduced their language and accessibility to a punchline. Other political humour included Wilson saying she cut a planned musical number about Prince Andrew called "Pizza Express" and a lengthy but earnest joke Serkis made about the policies of Home Secretary Priti Patel while introducing the award for Best Director. Serious statements regarding the War in Ukraine were also made by Wilson, following the "In Memoriam" montage, and by BAFTA Chair Krishnendu Majumdar in his opening speech, condemning the Russian invasion and reading a message from the Ukrainian Film Academy. For the second year in a row, Prince William, Duke of Cambridge, BAFTA President, did not attend the ceremony, instead delivering a speech via a pre-recorded video that aired during the ceremony.


title: 75th British Academy Film Awards

text: The acceptance speeches during the ceremony were noted for their excessive length; Heritage found some of them overlong but several of them, instead, moving. He also noted that the speeches could afford to run long because the lack of winners present at the ceremony naturally cut down on speech time; Heritage was more critical towards the nominees for not attending, saying that "they [BAFTA] could have held this ceremony in a minivan for all the people who turned up to collect their awards" and, before the "In Memoriam" montage, that people featured in it "actually have a good excuse" for not being there. While hosting, Wilson made a poorly-received joke about the personal life of Best Actor in a Leading Role winner Will Smith and, at the response, commented that it was deserved as Smith had not shown up to the ceremony. The high number of absent nominees may be attributed to the ceremony taking place on the same day as the 27th Critics' Choice Awards, which rescheduled their ceremony shortly beforehand and stated that there were no other possible dates, acknowledging the clash and setting up a parallel venue in London (in addition to usual city Los Angeles) to encourage people to attend both ceremonies.


title: 75th British Academy Film Awards

text: In a series of long speeches, Lady Gaga introduced last year's Rising Star Award winner, Bukky Bakray, so that Bakray could present the award; Lashana Lynch won. Heritage was also critical of this, explaining his outlook by noting that Lynch had "already risen quite high", playing main characters in major movies, including "Captain Marvel" (2019) (plus other Marvel Cinematic Universe entries) and the Bond film "No Time to Die", and so her career did not need the profile boost of the EE Rising Star Award. "NME" was more positive, saying the award "underlines her rise". Lynch's acceptance speech referred to her family migrating as part of the Windrush generation and how they taught her "about failure, about noes and what noes mean and how to celebrate your yeses", preparing her for the film industry.


title: 75th British Academy Film Awards

text: Unusually, none of the Best Actress nominees were also nominated in the same category at the 94th Academy Awards. Additionally, of the actresses nominated for the BAFA, only Lady Gaga had been nominated at the 28th Screen Actors Guild Awards. American film journalist Anne Thompson described Joanna Scanlan's nomination in the category as "bizarre"; Scanlan ultimately won and was surprised herself. In her speech, she thanked BAFTA in Welsh. "NME" and British film critic Peter Bradshaw wrote that she was a deserving winner. In winning the award for Best Actor in a Supporting Role, "CODA" actor Troy Kotsur became the first deaf actor to win a BAFA, as well as the first deaf actor to win a BAFTA in a major category and first deaf male actor to win a BAFTA. Bradshaw had worried that "Belfast" winning Outstanding British Film, and thus being labelled "British", could have been controversial, but was "very pleased" to see it was not significantly so, attributing this to the quality of the film.


title: 75th British Academy Film Awards

text: Overall, Bradshaw felt that the winners were "well-judged and satisfying". Heritage also noted that the BAFA winners at the ceremony gave little fresh insight to the likely Oscar winners, with a mix of frontrunner and left-field wins.


title: 75th British Academy Film Awards

text: The "In Memoriam" montage this year was played to the song "Send In the Clowns" by Stephen Sondheim, who was included in the montage.


title: Feline immunodeficiency virus

text: Feline immunodeficiency virus (FIV) is a "Lentivirus" that affects cats worldwide, with 2.5% to 4.4% of felines being infected.


title: Feline immunodeficiency virus

text: FIV was first isolated in 1986, by Niels C Pedersen and Janet K. Yamamoto at the UC Davis School of Veterinary Medicine in a colony of cats that had a high prevalence of opportunistic infections and degenerative conditions and was originally called Feline T-lymphotropic virus. It has since been identified in domestic cats. It has been suggested FIV originated in Africa and has since spread to feline species worldwide.


title: Feline immunodeficiency virus

text: FIV compromises the immune system of cats by infecting many cell types, including CD4+ and CD8+ T lymphocytes, B lymphocytes, and macrophages. FIV can be tolerated well by cats, but can eventually lead to debilitation of the immune system in its feline hosts by the infection and exhaustion of T-helper (CD4+) cells.


title: Feline immunodeficiency virus

text: FIV and HIV are both lentiviruses. However, humans cannot be infected by FIV, nor can cats be infected by HIV. FIV is transmitted primarily through deep bite wounds, where the virus present in the infected cat's saliva enters the body tissues of another cat. FIV+ cats can share water bowls, food bowls (for both wet and dry cat food), and use the same litter box with low danger of transmitting the disease. A vigilant pet owner who treats secondary infections can allow an infected cat to live a reasonably long life. The chance that an FIV-infected cat will pass the virus to other cats within a household is low, unless there is fighting between cats, or wounds present that could allow entry of the virus from infected to non-infected cat.


title: Feline immunodeficiency virus

text: Newborn kittens may test positive for up to six months and most thereafter will gradually test negative. It is thought that this is due to antibodies transferred to the kittens via the mother's milk. However these antibodies are transient so subsequent testing will be negative. Once they have received vaccinations against FIV, they will, in the future, always test positive, as the various blood tests detect and show the antibodies that have developed in response to the vaccination.


title: Feline immunodeficiency virus

text: FIV is known in other feline species, and in fact is endemic in some large wild cats, such as African lions. Three main clades of FIV are recognized as of 2006, FIV-Ple (lion), FIV-Fca (domestic cat), and FIV-Pco (puma). The host boundaries are usually well-kept due to the limited types of APOBEC3 enzymes viral infectivity factor can neutralize.


title: Feline immunodeficiency virus

text: Consensus in the United States on whether there is a need to euthanize FIV-infected cats has not been established. The American Association of Feline Practitioners (an organization in the United States), as well as many feral cat organizations, recommends against euthanizing FIV-positive cats, or even spending funds to test for the virus, as spaying or neutering cats seems to effectively control transmission (spayed/neutered cats are less likely to engage in territorial fights).


title: Feline immunodeficiency virus

text: The virus gains entry to host cells through the interaction of its own envelope glycoproteins with the target cells' surface receptors. First, the SU glycoprotein binds to CD134, a receptor on the host cell. This initial binding changes the shape of the SU protein to one that facilitates interaction between SU and the chemokine receptor CXCR4. This interaction causes the viral and cellular membranes to fuse, allowing the transfer of the viral RNA into the cytoplasm, where it is reverse transcribed and integrated into the cellular genome through nonhomologous recombination. Once integrated into the host cell's genome, the virus can lay dormant in the asymptomatic stage for extended periods of time without being detected by the immune system or can cause lysis of the cell.


title: Feline immunodeficiency virus

text: CD134 is predominantly found on activated T cells and binds to OX40 ligand, causing T-cell stimulation, proliferation, activation, and apoptosis (3). This leads to a significant drop in cells that have critical roles in the immune system. Low levels of CD4+ and other affected immune system cells cause the cat to be susceptible to opportunistic diseases once the disease progresses to feline acquired immune deficiency syndrome (FAIDS).


title: Feline immunodeficiency virus

text: The primary mode of transmission is via deep bite wounds, in which the infected cat's saliva enters the other cat's tissues. FIV may also be transmitted from pregnant females to their offspring in utero; however, this vertical transmission is considered to be relatively rare, based on the small number of FIV-infected kittens and adolescents. This differs from FeLV, which may be spread by more casual, non-aggressive contact, such as mutual grooming and sharing of food bowls.


title: Feline immunodeficiency virus

text: Risk factors for infection include male sex, adulthood, and outdoor access. One case study conducted in São Paulo found that 75% of FIV-infected cats were males. Higher rates of infection in males than females occurs due to biting being more frequently engaged in by males defending their territory.


title: Feline immunodeficiency virus

text: FIV progresses through similar stages to HIV. The initial stage, or acute phase, is accompanied by mild symptoms such as lethargy, anorexia, fever, and lymphadenopathy (swelling of the lymph nodes). This initial stage is fairly short and is followed by the asymptomatic stage. Here the cat demonstrates no noticeable symptoms for a variable length of time. Some cats stay in this latent stage for only a few months, but for some it can last for years. Factors that influence the length of the asymptomatic stage include the pathogenicity of the infecting virus and FIV subtype (A–E), the age of the cat, and exposure to other pathogens. Finally, the cat progresses into the final stage (known as the feline acquired immune deficiency syndrome (FAIDS) stage), wherein the cat is extremely susceptible to secondary diseases that inevitably are the cause of death.


title: Feline immunodeficiency virus

text: Veterinarians will check a cat's history, look for clinical signs, and possibly administer a blood test for FIV antibodies. FIV affects 2–3% of cats in the US and testing is readily available. This testing identifies those cats that carry the FIV antibody but does not detect the actual virus.


title: Feline immunodeficiency virus

text: "False positives" occur when the cat carries the antibody (which is harmless) but does not carry the virus. The most frequent occurrence of this is when kittens are tested after ingesting the antibodies from mother's milk (passive immunity), and when testing cats that have been previously vaccinated for FIV (active immunity). For this reason, neither kittens under eight weeks nor cats that have been previously vaccinated are tested. Kittens and young cats that test positive for the FIV antibody via passive immunity test negative later in life due to seroreversion, provided they have never been infected with FIV and have never been immunized with the FIV vaccine.


title: Feline immunodeficiency virus

text: Cats that have been vaccinated will test positive for the FIV antibody for the rest of their lives owing to seroconversion, even though they are not infected. Therefore, testing of strays or adopted cats is inconclusive, since it is impossible to know whether or not they have been vaccinated in the past. For these reasons, a positive FIV antibody test by itself should never be used as a criterion for euthanasia.


title: Feline immunodeficiency virus

text: Tests can be performed in a vet's office with results in minutes, allowing for quick consultation. Early detection helps maintain the cat's health and prevents spreading infection to other cats. With proper care, infected cats can live long and healthy lives.


title: Feline immunodeficiency virus

text: In 2006, the United States Department of Agriculture issued a conditional license for a new treatment aid termed Lymphocyte T-Cell Immunomodulator (LTCI). Lymphocyte T-Cell Immunomodulator is manufactured and distributed exclusively by T-Cyte Therapeutics, Inc.


title: Feline immunodeficiency virus

text: Lymphocyte T-Cell Immunomodulator is intended as an aid in the treatment of cats infected with feline leukemia virus (FeLV) and/or feline immunodeficiency virus (FIV), and the associated symptoms of anemia (reduced oxygen-carrying ability in the blood), opportunistic infection, lymphocytopenia, granulocytopenia, or thrombocytopenia (low levels of lymphocytes, granulocytes, and platelets respectively, the first two are types of white blood cell). The absence of any observed adverse events in several animal species suggests that the product has a very low toxicity profile.


title: Feline immunodeficiency virus

text: Lymphocyte T-Cell Immunomodulator is a potent regulator of CD-4 lymphocyte production and function. It has been shown to increase lymphocyte numbers and Interleukin 2 production in animals. It is a single-chain polypeptide and a strongly cationic glycoprotein, and is purified with cation exchange resin. Purification of protein from bovine-derived stromal cell supernatants produces a substantially homogeneous factor, free of extraneous materials. The bovine protein is homologous with other mammalian species and is a homogeneous 50 kDa glycoprotein with an isoelectric point of 6.5. The protein is prepared in a lyophilized (freeze-dried) 1 microgram dose. Reconstitution in sterile diluent produces a solution for subcutaneous injection.