title: Apache OpenOffice

text: Version 4.1 was released in April 2014. Various features lined up for 4.1 include comments on text ranges, IAccessible2, in-place editing of input fields, interactive cropping, importing pictures from files and other improvements. 4.1.1 (released 14 August 2014) fixed critical issues in 4.1. 4.1.2 (released in October 2015) was a bugfix release, with improvements in packaging and removal of the HWP file format support associated with the vulnerability . 4.1.3 (September 2016) had updates to the existing language dictionaries, enhanced build tools for AOO developers, a bug fix for databases on macOS, and a security fix for vulnerability . 4.1.4 contained security fixes. Version 4.1.5 was released in December 2017, containing bug fixes.


title: Apache OpenOffice

text: As a result of harmful downloads being offered by scammers, the project strongly recommends all downloads be made via its official download page, which is managed off-site by SourceForge. SourceForge reported 30 million downloads for the Apache OpenOffice 3.4 series by January 2013, making it one of SourceForge's top downloads; the project claimed 50 million downloads of Apache OpenOffice 3.4.x as of 15 May 2013, slightly over one year after the release of 3.4.0 (8 May 2012), 85,083,221 downloads of all versions by 1 January 2014, 100 million by April 2014, 130 million by the end of 2014 and 200 million by November 2016.


title: Apache OpenOffice

text: As of May 2012 (the first million downloads), 87% of downloads via SourceForge were for Windows, 11% for Mac OS X and 2% for Linux; statistics for the first 50 million downloads remained consistent, at 88% Windows, 10% Mac OS X, and 2% Linux.


title: Apache OpenOffice

text: Derivatives include AndrOpen Office, a port for Android, and Office 700 for iOS, both ported by Akikazu Yoshikawa.


title: Apache OpenOffice

text: LibreOffice also used some changes from Apache OpenOffice. In 2013, 4.5% of new commits in LibreOffice 4.1 came from Apache contributors; in 2016, only 11 commits from Apache OpenOffice were merged into LibreOffice, representing 0.07% of LibreOffice's commits for the period. LibreOffice earlier rebased its LGPL-3.0-or-later codebase on the Apache OpenOffice 3.4 source code (though it used MPL-2.0, not the Apache-2.0) to allow wider (but still copyleft) licensing under MPL-2.0 and LGPL-3.0-or-later.


title: Apache OpenOffice

text: Older versions of NeoOffice included stability fixes from Apache OpenOffice, though NeoOffice 2017 and later versions are based on LibreOffice 4.4.


title: Kim Myung-min

text: Kim Myung-min (, born October 8, 1972) is a South Korean actor. He is best known for his leading roles in the television series "Immortal Admiral Yi Sun-shin" (2004), "White Tower" (2007), "Beethoven Virus" (2008), "Six Flying Dragons" (2015-2016), and "Law School" (2021), as well as the films "Closer to Heaven" (2009) and the "Detective K" film series. His first leading role was in the film, "Sorum" (2001). Praised for his acting skills, he is often called 'The Acting Expert'.


title: Kim Myung-min

text: Kim Myung-min debuted as an actor when he won the 6th SBS public talent audition in 1996. Over the next five years he appeared in a number of television series in various supporting roles.


title: Kim Myung-min

text: Kim' first leading role came with critically appraised 2001 horror film "Sorum", the feature debut of the director Yoon Jong-chan, telling the story of a taxi driver moving into a decrepit building that hides several dark secrets. For this part Kim received Best New Actor award at 2001 Busan Film Critics Awards and Director's Cut Awards


title: Kim Myung-min

text: Building on his new status of a lead actor, Kim started to work on several film projects, many of which however ended unfinished, mostly due to financial problems. At that time he also suffered from injuries incurred while he was shooting action scenes.


title: Kim Myung-min

text: When he starred in the 2004 KBS family drama "More Beautiful than a Flower", he was expected to have a successful career as a lead actor. However, he was badly injured while performing a stunt and his film contracts kept being withdrawn. This series of unfortunate events led him to quit stage acting in 2004. Kim then decided to end his acting career and emigrate to New Zealand with his family following the birth of his son. A turning point came in his career when he was given the opportunity to play the lead role in the 2004-2005 historical drama "Immortal Admiral Yi Sun-shin" after producers viewed his work in "More Beautiful than a Flower". The 104-episode TV series based on the life of Korea's hero of the Imjin War put Kim in the spotlight and brought him a host of awards including Grand Prize at KBS Drama Awards.


title: Kim Myung-min

text: Kim was then cast in leading roles, playing a comical ex-gangster in "Bad Family" and a detective in "Open City". He then played a surgeon in two productions: the television series "White Tower" and film "Wide Awake". "White Tower" was a critical and ratings hit in South Korea, gaining praise for its acting (particularly by Kim), writing, direction, and its intelligent and uncompromising story without concessions to melodrama or romance. Kim won the Best Actor awards at the year-end Baeksang Arts Awards and Grimae Awards, and was chosen as the Best Performer of the year by producers.


title: Kim Myung-min

text: Subsequently, his performance as a maestro in the 2008 TV series "Beethoven Virus" created a sensation in Korea referred to as "Kang Mae Syndrome" and again earned him acclaim from critics and viewers. Kim received the Grand Prize (Daesang) at the MBC Drama Awards and his second Baeksang for Best Actor in television. In late 2008, it was announced that his next project was a film about a character living with Lou Gehrig's disease, titled "Closer to Heaven". To realistically portray the role of the dying patient, Kim painstakingly lost 20 kilos during the course of the filming. Kim was widely commended for this feat, and won Best Actor Awards in Korea's leading film ceremonies, the 46th Grand Bell Awards and the 30th Blue Dragon Film Awards.


title: Kim Myung-min

text: "Closer to Heaven" was followed by another film, "Man of Vendetta", where Kim portrayed the role of a father for the first time.


title: Kim Myung-min

text: In January 2011, Kim took on the role of Joseon's Sherlock Holmes in historical comedy-mystery film "". He then starred in sports movie, "Pacemaker", where he played a marathon runner. Summer of 2012 saw Kim as a pharmaceutical agent in disaster movie "Deranged". The film, directed by Park Jung-woo became the fastest Korean film in 2012 to reach 2 million admissions, eight days after its July 5 release date. and topped the box office for three consecutive weeks.


title: Kim Myung-min

text: Kim then starred in "The Spies", his second collaboration with Woo Min-ho, director of his 2010 film, "Man of Vendetta". The film is centered on a North Korean agent and his three comrades who are working undercover in South Korea.


title: Kim Myung-min

text: Kim made a comeback to the small screen after four years in satire dramedy "The King of Dramas", where he played a drama production company CEO. He next played a brilliant but cynical lawyer who gets into an accident and loses his memory in "A New Leaf" (2014). In 2015, Kim reprised his role as Detective K in "", the second installment in the Detective K series. The historical television series "Six Flying Dragons" followed, in which he played Jeong Do-jeon, who served as the First Prime Minister of the Joseon Dynasty. He next starred in the disaster film "Pandora", portraying the aftermath of an explosion in a nuclear plant. Crime drama "Proof of Innocence" followed, where Kim played a former cop-turned-legal broker.


title: Kim Myung-min

text: In 2017, Kim starred in the noir film "V.I.P", playing a police detective.; followed by mystery thriller "A Day". The same year, he was cast in the period comedy film ""Monstrum"". In 2018, Kim again reprised his role as Detective K in "", the third installment in the Detective K series. The same year, he returned to the small screen in the melodrama "Miracle That We Met". which won him another Grand Prize at the KBS Drama Awards. In 2019, Kim starred in the war film "The Battle of Jangsari". In 2021, he starred in the legal drama series "Law School" playing a prosecutor-turned-professor who teaches criminal law. In 2022, it was reported that the contract with agency C-JeS Entertainment Kim's has expired. Later the same day it was confirmed that the original agency contract had expired.


title: Ray-Ban Wayfarer

text: Ray-Ban Wayfarer sunglasses have been manufactured by Ray-Ban since 1952, which in turn has belonged to the Italian Luxottica Group since 1999. Wayfarers enjoyed early popularity in the 1950s and 1960s, returning to popularity again after a 1982 product placement. A second revival occurred in the mid-2000s.


title: Ray-Ban Wayfarer

text: Wayfarers were designed in 1952 by American optical designer Raymond Stegeman, who worked for Bausch & Lomb, Ray-Ban's parent company at that time. The design was inspired by, "a mid-century classic to rival Eames chairs and Cadillac tail fins." According to design critic Stephen Bayley, the "distinctive trapezoidal frame spoke a non-verbal language that hinted at unstable dangerousness, but one nicely tempered by the sturdy arms which, according to the advertising, gave the frames a 'masculine look'." The sunglasses also featured a new plastic molding technology.


title: Ray-Ban Wayfarer

text: After Wayfarers' heyday in the 1950s and 1960s, sales declined. Though Wayfarers' cultural popularity was aided in 1980 by the film "The Blues Brothers", only 18,000 pairs were sold in 1981, and Wayfarers were on the verge of discontinuation. In 1982 Ray-Ban signed a $50,000-a-year deal with Unique Product Placement of Burbank, California, to place Ray-Bans in movies and television shows. Between 1982 and 1987, Ray-Ban sunglasses appeared in over 60 movies and television shows per year, continuing through 2007. Tom Cruise's wearing of Wayfarers in the 1983 movie "Risky Business" was one of the key placements, and that year 360,000 pairs were sold. Additional appearances in movies like "The Breakfast Club", and series like "Miami Vice" and "Moonlighting", led to sales of 1.5 million annually.


title: Ray-Ban Wayfarer

text: Wayfarers were also worn by various musicians, including Roy Orbison, Michael Jackson, George Michael, Rick Astley, Billy Joel, Johnny Marr, Blondie's Debbie Harry, Madonna, Depeche Mode, Elvis Costello, and members of U2 and Queen, as well as public figures such as Max Headroom, Jack Nicholson, and Anna Wintour.


title: Ray-Ban Wayfarer

text: The novels of Bret Easton Ellis often contain references to Wayfarers. Lyrics that mentioned the style of glasses included Don Henley's 1984 song "The Boys Of Summer", which contained the lyric "You got that hair slicked back and those Wayfarers on, baby". Corey Hart's music video Sunglasses at Night shows the artists wearing Wayfarers in darkness. In response to these placements, Ray-Ban's Wayfarer expanded from two models in 1981 to about 40 models by 1989.


title: Ray-Ban Wayfarer

text: As the 1990s began, the frames again became unpopular. The 1950s revival that fueled the glasses' popularity in the 1980s lost momentum, and Wayfarers were outcompeted by wraparound frames. During the slump of the 1990s, Ray-Ban's parent company, Bausch & Lomb was facing pressure from competitors like Oakley. In 1999, Bausch & Lomb sold Ray-Ban to Luxottica Group S.p.A. of Italy for $640 million. In 2001, the Wayfarer underwent a significant redesign (RB2132), with the frames made smaller and less angular, and changed from acetate to a lighter injected plastic. The changes were intended to update the frames' style during a period of unpopularity and to make them easier to wear (the frames' previous tilt made them impossible to perch on top of one's head, for instance).


title: Ray-Ban Wayfarer

text: Wayfarers were brought back into fashion in the late 2000s when public figures including Chloë Sevigny and Mary-Kate Olsen began wearing vintage frames. When Ray-Ban noticed that vintage Wayfarers were selling for significant prices on eBay, a 2007 re-introduction of the original Wayfarer (RB2140) design was initiated. The RB2140 model is identical to the original B&L5022 model, except the metal "studs" on the temple arms were replaced with the Ray-Ban logo and the right lens now bears the logo as well. (As of 2007, Wayfarers were available in Original Wayfarer, New Wayfarer, and Wayfarer Folding styles.) Ray-Ban's marketing strategy was threefold: a return to the sunglasses' original, rebellious design, an "edgy" advertising campaign and "high-profile PR events", and the use of new media like MySpace to connect with consumers. Sales in 2007 were 231% greater than in 2006 at Selfridge's London; as of October 2007, the Wayfarer was the Luxottica Group's third-best-selling style.


title: Ray-Ban Wayfarer

text: In September 2021, Ray-Ban and Facebook Reality Labs announced a collaboration for smart glasses including Wayfarers with built in cameras called Ray-Ban Stories.


title: Ray-Ban Wayfarer

text: During the 2000s Wayfarer revival, many sunglasses designs inspired by the original Wayfarers were produced by designers unaffiliated with Ray-Ban. Grey Ant's Grant Krajecki designed a larger, cartoonish version of the glasses "so extreme that [they] are best worn by those with a good sense of humor". Other Wayfarer-inspired sunglasses included Oliver Peoples' Hollis, REM Eyewear's Converse, and various designs in Juicy Couture, Hugo Boss, Kate Spade, Marc Jacobs's and Kaenon Polarized 2008 lines. Between July and September 2008, retailers began selling frameless Wayfarers.


title: 2008 NHL Entry Draft

text: The 2008 NHL Entry Draft was the 46th NHL Entry Draft. It was hosted by the Ottawa Senators at Scotiabank Place in the city of Ottawa, Ontario, on June 20–21, 2008. The Senators were originally awarded the 2005 NHL Entry Draft, but because of the lockout, that draft was scaled back significantly from its usual format of being open to the public and having many draft-eligible players in attendance. The actual 2005 drafting was held in Ottawa's Westin Hotel instead of the Corel Centre, as Canadian Tire Centre was then known. As a result of 2005's abridged draft, Ottawa was compensated with the 2008 draft.


title: 2008 NHL Entry Draft

text: The draft was part of a festival of events that Ottawa and the NHL presented at the Scotiabank Place arena. Before the first round and during the later rounds, the patio outside the main doors was the site of the 'Senators Fan Fest', with hockey games and music. Indoors, the NHL presented an exhibit of NHL trophies, including the Stanley Cup. A hockey card and memorabilia sale was also held.


title: 2008 NHL Entry Draft

text: The 2008 draft lottery was held April 7. The Tampa Bay Lightning retained the first overall selection. There were no changes from the reverse order of finish of the 2007–08 NHL season.


title: Ethinylestradiol

text: Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disorders, and certain hormone-sensitive cancers. It is usually taken by mouth but is also used as a patch and vaginal ring.


title: Ethinylestradiol

text: The general side effects of EE include breast tenderness and enlargement, headache, fluid retention, and nausea among others. In men, EE can additionally cause breast development, feminization in general, hypogonadism, and sexual dysfunction. Rare but serious side effects include blood clots, liver damage, and cancer of the uterus.


title: Ethinylestradiol

text: EE is an estrogen, or an agonist of the estrogen receptors, the biological target of estrogens like estradiol. It is a synthetic derivative of estradiol, a natural estrogen, and differs from it in various ways. Compared to estradiol, EE has greatly improved bioavailability when taken by mouth, is more resistant to metabolism, and shows relatively increased effects in certain parts of the body like the liver and uterus. These differences make EE more favorable for use in birth control pills than estradiol, though also result in an increased risk of blood clots and certain other rare adverse effects.


title: Ethinylestradiol

text: EE was developed in the 1930s and was introduced for medical use in 1943. The medication started being used in birth control pills in the 1960s. Today, EE is found in almost all combined forms of birth control pills and is nearly the exclusive estrogen used for this purpose, making it one of if not the most widely used estrogens.


title: Ethinylestradiol

text: There are many uses for EE. It is most commonly used as contraception in combined oral contraceptives (COC), also known as birth control, to prevent pregnancy after sex. EE in its birth control formulation is not only used to prevent pregnancy, but can also be used to treat absence of menstruation, symptoms during menstruation, and acne.


title: Ethinylestradiol

text: EE is also used as menopausal hormone therapy. The main reason for using HRT in menopausal women is to relieve common vasomotor symptoms such as hot flashes, night sweats, and flushing. Studies have found that estrogen replacement helps improve these symptoms when compared to a placebo. Other common menopause symptoms, such as vaginal dryness (which can cause pain during sexual intercourse), vaginal itching, and depressed mood, can benefit from HRT. In addition to treatment of menopausal symptoms, EE has been used as a component of feminizing hormone therapy for transgender women. However, it is no longer commonly used nor recommended for this purpose, with estradiol having largely superseded it.


title: Ethinylestradiol

text: EE can also be used to treat hypogonadism in women, prevent osteoporosis in women, and has been used as palliative care for prostate cancer in men and breast cancer in women. It has also been used to reduce sex drive in sex offenders.


title: Ethinylestradiol

text: EE or any estrogen alone is contraindicated for women who have a uterus due to the increased risk of endometrial cancer; giving a progestogen with an estrogen mitigates the risk.


title: Ethinylestradiol

text: EE is available in combination with a progestin in a vast number of COCs. It is also available in combination with progestins as a transdermal contraceptive patch and as a contraceptive vaginal ring. In addition, there is a single preparation (brand name FemHRT) containing very low doses of EE (2.5 and 5 µg) plus a progestin in an oral tablet that remains in use for menopausal hormone therapy. EE was previously available by itself under the brand name Estinyl in the form of 0.02, 0.05, and 0.5 mg (20, 50, and 500 µg) tablets.


title: Ethinylestradiol

text: The amount of EE in COCs has reduced over the years. Previously, COCs contained high doses of EE of as much as 100 µg/day. Doses of more than 50 µg EE are considered high-dose, doses of 30 and 35 µg EE are considered low-dose, and doses of 10 to 25 µg EE are considered very low dose. Today, COCs generally contain 10 to 50 µg EE. The higher doses of EE were discontinued due to a high risk of VTE and cardiovascular problems.


title: Ethinylestradiol

text: EE should be avoided in individuals with a history of or known susceptibility to arterial or venous thrombosis (blood clots), due to an increased risk of cardiovascular problems such as venous thromboembolism (VTE), myocardial infarction, and ischemic stroke. This includes women with:


title: Ethinylestradiol

text: Except when being used to treat it, EE should be avoided in women with current breast cancer due to a possible worsening of prognosis.


title: Ethinylestradiol

text: EE should also be avoided in breastfeeding women who are less than 21 days postpartum due to an increased risk of VTE. EE use in breastfeeding women who are at least 21 days postpartum should be discussed with a provider and include information on the advantages, disadvantages, and alternatives for using EE.


title: Ethinylestradiol

text: Due to risk of cholestatic hepatotoxicity, it is widely considered that COCs containing EE should be avoided in women with a history of cholestasis of pregnancy, hepatic tumors, active hepatitis, and familial defects in biliary excretion.


title: Ethinylestradiol

text: The severity of side effects can vary based on the dose and administration route of EE. General side effects of EE are the same as for other estrogens and include breast tenderness, headache, fluid retention (bloating), nausea, dizziness, and weight gain. The estrogen component of oral contraceptives, which is almost always EE, can cause breast tenderness and fullness. In males, EE has additional side effects, including gynecomastia (breast development), feminization in general, hypogonadism, infertility, and sexual dysfunction (e.g., reduced libido and erectile dysfunction). In men who received high-dose estrogen therapy with 200 μg/day oral EE for more than three months, gynecomastia occurred in 98% and decreased libido occurred in 42 to 73%.


title: Ethinylestradiol

text: VTE is a blood clot in a vein, and includes deep vein thrombosis (DVT) and pulmonary embolism (PE). Estrogens are known to increase the risk of VTE due to their effects on liver synthesis of coagulation factors. EE carries a greater risk of blood clot formation and VTE than does natural estradiol, which is thought to be due to structural differences between the two compounds and different susceptibilities to liver inactivation.


title: Ethinylestradiol

text: A 2012 meta-analysis estimated that the absolute risk of VTE is 2 per 10,000 women for non-use, 8 per 10,000 women for EE and levonorgestrel-containing birth control pills, and 10 to 15 per 10,000 women for birth control pills containing EE and a third- or fourth-generation progestin such as desogestrel or drospirenone. For comparison, the absolute risk of VTE is generally estimated as 1 to 5 per 10,000 woman–years for non-use, 5 to 20 per 10,000 woman–years for pregnancy, and 40 to 65 per 10,000 woman–years for the postpartum period. Modern COCs are associated with about a 2- to 4-fold higher risk of VTE than non-use. The route of administration of EE does not appear to influence VTE risk, as EE/progestin-containing contraceptive vaginal rings and contraceptive patches have the same or even higher risk of VTE than COCs. Pregnancy is associated with about a 4.3-fold increase in risk of VTE. It has been estimated that at least 300 to 400 healthy young women die each year in the United States due to VTE caused by EE-containing birth control pills.


title: Ethinylestradiol

text: Modern COCs contain 10 to 35 μg EE, but typically 20, 30, or 35 μg. The initial formulations of COCs that were introduced in the 1960s contained 100 to 150 μg EE. However, it was soon found that EE is associated with increased risk of VTE and that the risk is dose-dependent. Following these events, the dose of EE was greatly reduced, and is now always less than 50 μg. These lower doses have a significantly reduced risk of VTE with no loss of contraceptive effectiveness. Gerstman et al. (1991) found that COCs containing more than 50 μg EE had 1.7-fold and COCs containing 50 μg EE 1.5-fold the risk of VTE of COCs containing less than 50 μg. A 2014 Cochrane review found that COCs containing 50 μg EE with levonorgestrel had 2.1- to 2.3-fold the risk of COCs containing 30 μg or 20 μg EE with levonorgestrel, respectively. COCs containing 20 μg EE are likewise associated with a significantly lower risk of cardiovascular events than COCs containing 30 or 40 μg EE. However, discontinuation of COCs is more common with doses of EE from 10 to 20 μg due to problematic changes in bleeding patterns.


title: Ethinylestradiol

text: Women with thrombophilia have a dramatically higher risk of VTE with EE-containing contraception than women without thrombophilia. Depending on the condition, risk of VTE can be increased 5- to 50-fold relative to non-use in such women.


title: Ethinylestradiol

text: Sex hormone-binding globulin (SHBG) levels indicate hepatic estrogenic exposure and may be a surrogate marker for coagulation and VTE risk with estrogen therapy, although this topic has been debated. SHBG levels with birth control pills containing different progestins are increased by 1.5 to 2-fold with levonorgestrel, 2.5- to 4-fold with desogestrel and gestodene, 3.5- to 4-fold with drospirenone and dienogest, and 4- to 5-fold with cyproterone acetate. Contraceptive vaginal rings and contraceptive patches likewise have been found to increase SHBG levels by 2.5-fold and 3.5-fold, respectively. Birth control pills containing high doses of ethinylestradiol (>50 μg) can increase SHBG levels by 5- to 10-fold, which is similar to the increase that occurs during pregnancy. Conversely, increases in SHBG levels are much lower with estradiol, especially when used parenterally. High-dose parenteral polyestradiol phosphate therapy has been found to increase SHBG levels by about 1.5-fold.


title: Ethinylestradiol

text: When used orally at high dosages, for instance as a form of high-dose estrogen therapy in men with prostate cancer and in women with breast cancer, synthetic and non-bioidentical estrogens like EE and diethylstilbestrol are associated with fairly high rates of severe cardiovascular complications such as VTE, myocardial infarction, and stroke. Diethylstilbestrol has been associated with an up to 35% risk of cardiovascular toxicity and death and a 15% incidence of VTE in men treated with it for prostate cancer. EE has a to some degree lower risk of cardiovascular complications than does diethylstilbestrol when used in the treatment of prostate cancer in men. However, both EE and diethylstilbestrol nonetheless have highly disproportionate effects on liver protein synthesis, which is thought to be responsible for their cardiovascular toxicity.


title: Ethinylestradiol

text: In contrast to oral synthetic estrogens like EE and diethylstilbestrol, high-dosage polyestradiol phosphate and transdermal estradiol have not been found to increase the risk of cardiovascular mortality or thromboembolism in men with prostate cancer. However, significantly increased cardiovascular morbidity has been observed with high-dosage polyestradiol phosphate. In any case, these estrogens are considered to be much safer than oral synthetic estrogens like EE and diethylstilbestrol. In addition, ethinylestradiol sulfonate (EES), an oral but parenteral-like long-lasting prodrug of EE, is used in the treatment of prostate cancer, and is said to have a considerably better profile of cardiovascular safety than EE.


title: Ethinylestradiol

text: Because of its disproportionate effects on liver protein synthesis and associated cardiovascular risks, synthetic estrogens like EE and diethylstilbestrol are no longer used in menopausal hormone therapy. They are also being replaced by parenteral forms of estradiol like polyestradiol phosphate and transdermal estradiol in the treatment of prostate cancer.


title: Ethinylestradiol

text: At the lower dosages that are now used in birth control pills, EE has been associated rarely with cholestatic hepatotoxicity similarly to 17α-alkylated androgens/anabolic steroids and 17α-ethynylated 19-nortestosterone progestins. Cholestasis can manifest as pruritus and jaundice. Glucuronide metabolites of EE, via effects on the ABCB11 (BSEP) and MRP2 (ABCC2) proteins and consequent changes in bile flow and bile salt excretion, appear to be responsible for the cholestasis. Very high concentrations of estradiol, via its metabolite estradiol glucuronide, are also implicated in cholestasis, for instance in cholestasis of pregnancy. However, the incidence and severity of cholestatic hepatotoxicity appear to be much greater with EE than with estradiol, which is thought to be due to the reactive C17α ethynyl substitution in EE as well as its greatly reduced susceptibility to hepatic metabolism. Whereas abnormal liver function tests (LFTs) are normally found in about 1% of women not on birth control pills or taking lower-dose EE-containing birth control pills, this increases to more than 10% of women taking birth control pills containing 50 μg/day EE or more. With birth control pills containing 50 μg/day EE, alanine aminotransferase (ALT) levels increase by 50%, hematocrit by 19%, and leukocytes by 50%, while gamma-glutamyltransferase (GGT) decreases by 30%. However, the values usually remain in the normal range. In addition to abnormal LFTs, pathological changes in partial liver functions and liver morphology can be observed in half of women on birth control pills with 50 μg/day EE. EE-containing birth control pills have also been associated with a 25- to 50-fold increase in the risk of rare benign liver tumors and a 3- to 6-fold increase in the risk of hepatocellular carcinoma, as well as greater risk of other liver complications. At one time, EE-containing birth control pills were estimated to be responsible for 84% of all drug-related and histologically verified liver damage. However, these risks now are reduced with modern lower-dose EE-containing birth control pills, with contain 35 μg/day EE or less.


title: Ethinylestradiol

text: The high doses of EE that were used in early COCs were associated with a significantly increased risk of endometrial cancer in certain preparations, for instance those containing the progestogen dimethisterone. Unopposed estrogens like EE have carcinogenic effects in the endometrium and progestogens protect against these effects, but dimethisterone is a relatively weak progestogen and was unable to adequately antagonize the endometrial carcinogenic effects of EE, in turn resulting in the increased risk of endometrial cancer. COCs containing dimethisterone have since been discontinued (with more potent progestogens used instead) and doses of EE in COCs in general have been dramatically reduced, abrogating the risk. In turn, most studies of modern COCs have found a decreased risk of endometrial cancer.


title: Ethinylestradiol

text: Wastewater contains various estrogens, including EE, that are not completely broken down by wastewater treatment procedures. The input of artificial estrogens into freshwater ecosystems affects fish and amphibian populations. Chronic exposure to low levels of EE over seven years led to the collapse of fathead minnow populations in an experimental lake in Ontario, Canada. EE changed oogenesis in female fish and feminized male fish such that they produced a protein associated with egg maturation, vitellogenin, as well as early-stage eggs. In amphibians, exposure to EE can reduce hatching success and alter gonadal development. Exposure to hormones can change frogs' gonadal development even though it is encoded in their genes. A study of mink frogs found more intersex tadpoles in those experimentally exposed to EE than those not exposed to EE, and green frogs showed much lower rates of hatching success.


title: Ethinylestradiol

text: EE is metabolized by certain cytochrome P450 isoforms, including CYP3A4 and CYP2C9. Thus, inducers of enzymes such as CYP3A4 can decrease circulating concentrations of EE. Examples of inducers include anticonvulsants like phenytoin, primidone, ethosuximide, phenobarbital, and carbamazepine; azole antifungals like fluconazole; and rifamycin antibiotics like rifampin (rifampicin). Conversely, inhibitors of CYP3A4 and other cytochrome P450 enzymes may increase circulating levels of EE. An example is troleandomycin, which is a potent and highly selective inhibitor of CYP3A4.


title: Ethinylestradiol

text: Paracetamol (acetaminophen) has been found to competitively inhibit the sulfation of EE, with pretreatment of 1,000 mg of paracetamol significantly increasing the AUC levels of EE (by 22%) and decreasing the AUC levels of ethinylestradiol sulfate (EE sulfate) in women. The same has been found for ascorbic acid (vitamin C) and EE, although the significance of the interaction has been regarded as dubious.


title: Ethinylestradiol

text: In contrast to estradiol, it is unlikely that there is a pharmacokinetic interaction between smoking (which potently induces certain cytochrome P450 enzymes and markedly increases the 2-hydroxylation of estradiol) and EE. This suggests that estradiol and EE are metabolized by different cytochrome P450 enzymes. There is, however, an increased risk of cardiovascular complications with smoking and EE, similarly to the case of smoking and other estrogens.


title: Ethinylestradiol

text: EE is known to inhibit several cytochrome P450 enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, and is possibly an inducer of CYP2A6. As a result, it can affect the metabolism and concentrations of many other drugs. Examples of known interactions include bupropion, caffeine, mephenytoin, midazolam, nicotine, nifedipine, omeprazole, propranolol, proguanil, selegiline, theophylline, and tizanidine. One of the most notable interactions is that EE strongly increases levels of selegiline, a substrate of CYP2B6 and CYP2C19. EE may also induce glucuronidation and possibly alter sulfation. It has been found to increase the clearance of and reduce the concentrations of a variety of drugs known to be glucuronidated. Examples include clofibrate, lamotrigine, lorazepam, oxazepam, and propranolol.


title: Ethinylestradiol

text: Progestins, which are often used in combination with EE, are also known to inhibit cytochrome P450 enzymes, and this may contribute to drug interactions with EE-containing contraceptives as well. Examples include gestodene, desogestrel, and etonogestrel, which are CYP3A4 and CYP2C19 inhibitors. In addition, these progestins are known to progressively inhibit the metabolism of and increase concentrations of EE itself.


title: Ethinylestradiol

text: EE is an estrogen similarly to natural estrogens like estradiol and conjugated estrogens (Premarin) and synthetic estrogens like diethylstilbestrol. It binds to and activates both isoforms of the estrogen receptor, ERα and ERβ. In one study, EE was found to have 233% and 38% of the affinity of estradiol for the ERα and ERβ, respectively. In another study, it was found to possess 194% and 151% of the affinity of estradiol for the ERα and ERβ, respectively. EE also appears to act as a potent agonist of the G protein-coupled estrogen receptor (GPER) (affinity unknown), a membrane estrogen receptor, similarly to estradiol. Estrogens have antigonadotropic effects through activation of the ERα. As a contraceptive, EE acts in concert with a progestin to inhibit the mid-cycle surge in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) via its antigonadotropic effects, thereby inhibiting folliculogenesis and preventing ovulation and hence the possibility of pregnancy.


title: Ethinylestradiol

text: Orally, EE is on the order of 100 times as potent by weight as natural estrogens like micronized estradiol and conjugated estrogens, which is largely due to substantially greater resistance to first-pass metabolism. It is specifically in the range of 80 to 200 times as potent as estropipate (piperazine estrone sulfate), which has similar potency to micronized estradiol, in terms of systemic estrogenic potency. In contrast, the potencies of EE and natural estrogens are similar when they are administered intravenously, due to the bypassing of first-pass metabolism. Relative to its prodrug mestranol, EE is about 1.7 times as potent by weight orally.


title: Ethinylestradiol

text: EE is a potent functional antiandrogen in both women and men. It mediates its antiandrogenic effects by 1) stimulating the production of sex hormone-binding globulin (SHBG) in the liver, which decreases free and thus bioactive concentrations of testosterone in the blood; and by 2) suppressing luteinizing hormone (LH) secretion from the pituitary gland, which decreases production of testosterone by the gonads. Birth control pills that contain EE are useful in the treatment of androgen-dependent conditions like acne and hirsutism by virtue of their antiandrogenic effects.


title: Ethinylestradiol

text: Birth control pills containing EE have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%. Birth control pills containing high doses of EE can increase SHBG levels in women by as much as 5- to 10-fold. This is similar to the 5- to 10-fold increase in SHBG levels that occurs during pregnancy. Due to the marked increase in SHBG levels, free testosterone levels become very low during treatment with EE-containing birth control pills. In men, a study found that treatment with a relatively low dosage of 20 μg/day EE for five weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease in free testosterone levels, increased total circulating levels of testosterone by 50% (via upregulation of gonadal testosterone production due to reduced negative feedback by androgens on the hypothalamic–pituitary–gonadal axis). The stimulation of hepatic SHBG production by EE is far stronger than with other estrogens like estradiol, owing to the high resistance of EE to inactivation in the liver and hence its disproportionate effects in this part of the body.


title: Ethinylestradiol

text: Estrogens are antigonadotropins and are able to suppress the secretion of LH and FSH from the pituitary gland and by extension gonadal testosterone production. High-dose estrogen therapy, including with EE, is able to suppress testosterone levels in men by around 95%, or into the castrate/female range. The dosage of EE required for use as a component of hormone therapy for preoperative transgender women is 50 to 100 µg/day. This high dosage is associated with a high incidence of VTE, particularly in those over the age of 40 years, and it has been said that it should not be used. The dosage of EE used in the treatment of prostate cancer in men is 150 to 1,000 µg/day (0.15–1.0 mg/day). A dosage of EE of 50 μg twice daily (100 μg/day total) has been found to suppress testosterone levels in men to an equivalent extent as 3 mg/day oral diethylstilbestrol, which is the minimum dosage of diethylstilbestrol required to consistently suppress testosterone levels into the castrate range. The ovulation-inhibiting dose of EE by itself and not in combination with a progestin in women is 100 μg/day. However, it has been found to be about 75 to 90% effective at inhibiting ovulation at a dosage of 20 μg/day and about 97 or 98% effective at a dosage of 50 μg/day. In another study, ovulation occurred in 25.2% with an EE dose of 50 μg/day.


title: Ethinylestradiol

text: Lower dosages of EE also have significant antigonadotropic effects. A "very low" dosage of 15 µg/day EE has been described as the "borderline" amount required for suppression of LH and testosterone levels in men, and a study found that LH and testosterone levels were "reliably" suppressed in men by a dosage of 30 µg/day EE. However, other clinical studies have found that 20 µg/day EE increased testosterone levels by 50% in men (as described above) and that dosages of 32 µg/day and 42 µg/day EE suppressed FSH levels in men but did not significantly affect LH levels. A stronger suppression of testosterone levels was observed in men following daily treatment with a combined oral contraceptive containing 50 µg ethinylestradiol and 0.5 mg norgestrel for 9 days. However, investigation revealed that the progestin was the more important component responsible for the suppression in testosterone levels. In accordance, the progestin component of COCs is primarily responsible for inhibition of ovulation in women. A combination of 20 µg/day EE and 10 mg/day methyltestosterone was found to suppress FSH secretion in men to an extent sufficient to stop spermatogenesis. Studies in women have found that 50 µg/day EE suppresses LH and FSH levels both by about 70% in postmenopausal women.


title: Ethinylestradiol

text: In addition to its antigonadotropic effects, EE can significantly suppress androgen production by the adrenal glands at high concentrations. One study found that treatment with a high dosage of 100 µg/day EE suppressed circulating adrenal androgen levels by 27 to 48% in transgender women. This may additionally contribute to suppression of androgen levels by estrogens.


title: Ethinylestradiol

text: EE has marked effects on liver protein synthesis, even at low dosages and regardless of route of administration. These effects are mediated by its estrogenic activity. The medication dose-dependently increases circulating levels of SHBG, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG), and also affects a broad range of other liver proteins. EE affects triglyceride levels at a dose as low as 1 μg/day and LDL and HDL cholesterol levels at a dose as low as 2.5 μg/day. EE affects several hepatic proteins at a dosage as low as 5 µg/day. At doses above 20 µg/day, the incremental effects of EE on liver protein synthesis become continuously smaller.


title: Ethinylestradiol

text: EE at 5 μg/day has been found to increase SHBG levels by 100% in postmenopausal women, while a dosage of 20 µg/day EE increased them by 200%. Androgens decrease hepatic SHBG production, and have been found to oppose the effects of EE on SHBG levels. This is of particular relevance when it is considered that many progestins used in COCs have varying degrees of weak androgenic activity. A combination of 20 µg/day EE and 0.25 mg/day levonorgestrel, a progestin with relatively high androgenicity, decreases SHBG levels by 50%; 30 µg/day EE and 0.25 mg/day levonorgestrel has no effect on SHBG levels; 30 µg/day EE and 0.15 mg/day levonorgestrel increases SHBG levels by 30%; and triphasic COCs containing EE and levonorgestrel increase SHBG levels by 100 to 150%. The combination of 30 µg/day EE and 150 µg/day desogestrel, a progestin with relatively weak androgenicity than levonorgestrel, increases SHBG levels by 200%, while the combination of 35 µg/day EE and 2 mg/day cyproterone acetate, a progestin with potent antiandrogenic activity, increases SHBG levels by 400%. As such, the type and dosage of progestin contained in COCs potently moderates the effects of EE on SHBG levels.


title: Ethinylestradiol

text: A dosage of 10 µg/day EE has been found to increase CBG levels by 50%, while a dosage of 20 µg/day EE increased them by 100%. Progestins that are progesterone derivatives have no effect on CBG levels, while androgenic progestins like the 19-nortestosterone derivatives have only a weak effect on CBG levels. COCs may increase CBG levels by 100 to 150%. A dosage of 5 µg/day EE has been found to increase TBG levels by 40%, while a dosage of 20 µg/day EE increased them by 60%. Progestins that are progesterone derivatives do not affect TBG levels, while progestins with androgenic activity may decrease TBG levels. A combination of 30 µg/day EE and 1 mg/day norethisterone, a moderately androgenic progestin, have been found to increase TBG levels by 50 to 70%, while the combination of 30 µg/day EE and 150 µg/day desogestrel increased them by 100%.


title: Ethinylestradiol

text: EE shows strong and disproportionate effects on liver protein synthesis relative to estradiol. The liver as well as the uterus express 17β-hydroxysteroid dehydrogenase (17β-HSD), and this enzyme serves to inactivate estradiol and effectively suppress its potency in these tissues by reversibly converting it into the far less potent estrogen estrone (which has approximately 4% of the estrogenic activity of estradiol). In contrast to estradiol, the 17α-ethynyl group of EE prevents oxidation of the C17β position of EE by 17β-HSD, and for this reason, EE is not inactivated in these tissues and has much stronger relative estrogenic activity in them. This is the mechanism of the disproportionately strong effects of EE on hepatic protein production, which results in a greatly increased magnitude of effect on VTE and cardiovascular risks relative to estradiol.


title: Ethinylestradiol

text: On the other hand, due to the loss of inactivation of EE by 17β-HSD in the endometrium (uterus), EE is relatively more active than estradiol in the endometrium and, for this reason, is associated with a significantly lower incidence of vaginal bleeding and spotting in comparison. This is particularly so in the case of combined estrogen and progestogen therapy (as in COCs or menopausal HRT), as progestogens induce the expression of 17β-HSD in the endometrium. The reduced vaginal bleeding and spotting with EE is one of the main reasons that it is used in COCs instead of estradiol, in spite of its potentially inferior safety profile (related to its adverse effects on hepatic protein synthesis and VTE incidence).


title: Ethinylestradiol

text: EE has been found to have disproportionate effects on liver protein synthesis and VTE risk regardless of whether the route of administration is oral, transdermal, or vaginal, indicating that the use of parenteral routes over the oral route does not result in EE having proportional hepatic actions relative to non-hepatic actions. However, the potency of EE on liver protein synthesis is in any case reduced with parenteral administration. A dosage of 10 µg/day vaginal EE has been found to be equivalent to 50 µg oral EE in terms of effects on liver protein synthesis, such as stimulation of hepatic SHBG production. As such, parenteral EE, which bypasses the first pass through the liver that occurs with oral EE, has been found to have a 5-fold lower impact on liver protein synthesis by weight than oral EE. In contrast to EE as well as to oral estradiol, transdermal estradiol shows few or no effects on liver protein synthesis at typical menopausal dosages.


title: Ethinylestradiol

text: The oral bioavailability of EE is 45% on average, with a wide range of 20% to 74% (though most commonly between 38 and 48%) that is due to high interindividual variability. Although relatively low, the oral bioavailability of EE is considerably higher than that of micronized estradiol (5%). Following a single 20 μg dose of EE in combination with 2 mg norethisterone acetate in postmenopausal women, EE concentrations have been found to reach a maximum of 50 pg/mL within an average of 1.5 hours. Following the first dose, mean levels of EE in general further increase by about 50% until steady-state concentrations are reached; steady-state is reached after one week of daily administration. For comparison, the mean peak levels of estradiol achieved with 2 mg micronized estradiol or estradiol valerate are 40 pg/mL following the first dose and 80 pg/mL after three weeks of administration. These maximal concentrations of estradiol are in the same range as the concentrations of EE that are produced by an oral dose of EE that is 100 times lower by weight, which is in accordance with the approximately 100-fold increased oral potency of EE relative to estradiol. In accordance with the high interindividual variability in the oral bioavailability of EE, there is a large degree of interindividual variation in EE levels. A dosage of EE of 50 μg/day has been found to achieve a wide range of circulating EE levels of about 100 to 2,000 pg/mL. Taking EE in combination with a high-fat meal has been found to significantly decrease its peak concentrations.


title: Ethinylestradiol

text: EE levels after a single 50 μg dose by intravenous injection are several times higher than levels of EE after a single 50 mg dose given orally. Besides the difference in levels, the course of elimination is similar for the two routes.


title: Ethinylestradiol

text: There may be gender-specific differences in the pharmacokinetics of EE, such that EE may have greater oral potency in women than in men. A study found that a combination of 60 μg/day EE and 0.25 mg/day levonorgestrel in women and men resulted in peak levels of EE of 495 pg/mL and 251 pg/mL, area-under-the-curve levels of EE of 6.216 pg/mL/hour and 2.850 pg/mL/hour, and elimination half-lives of 16.5 hours and 10.2 hours, respectively. It has been suggested that this phenomenon could represent a "protection mechanism" of males against environmental estrogen exposure.


title: Ethinylestradiol

text: The plasma protein binding of EE is 97 to 98%, and it is bound almost exclusively to albumin. Unlike estradiol, which binds with high affinity to SHBG, EE has very low affinity for this protein, about 2% of that of estradiol, and hence does not bind to it importantly.


title: Ethinylestradiol

text: Due to high first-pass metabolism in the intestines and liver, only 1% of an oral dose of an EE appears in the circulation as EE itself. During first-pass metabolism, EE is extensively conjugated via glucuronidation and sulfation into the hormonally inert ethinylestradiol glucuronides and ethinylestradiol sulfate (EE sulfate), and levels of EE sulfate in circulation are between 6- and 22-fold higher than those of EE. For comparison, with oral administration of 2 mg micronized estradiol, levels of estrone and estrone sulfate are 4- to 6-fold and 200-fold higher than those of estradiol, respectively. In contrast to estradiol, EE, due to steric hindrance by its C17α ethynyl group, is not metabolized or inactivated by 17β-HSD, and this is the primary factor responsible for the dramatically increased potency of oral EE relative to oral estradiol. EE is also not metabolized into estradiol.


title: Ethinylestradiol

text: Aside from sulfate conjugation, EE is mainly metabolized by hydroxylation into catechol estrogens. This is mainly by 2-hydroxylation into 2-hydroxy-EE, which is catalyzed primarily by CYP3A4. Hydroxylation of EE at the C4, C6α, and C16β positions into 4-, 6α-, and 16β-hydroxy-EE has also been reported, but appears to contribute to its metabolism to only a small extent. 2- and 4-methoxy-EE are also formed via transformation by catechol O-methyltransferase of 2- and 4-hydroxy-EE. Unlike the case of estradiol, 16α-hydroxylation does not occur with EE, owing to steric hindrance by its ethynyl group at C17α. The ethynylation of EE is largely irreversible, and so EE is not metabolized into estradiol, unlike estradiol esters. A review found that the range of the reported elimination half-life of EE in the literature was 13.1 to 27.0 hours. Another review reported an elimination half-life of EE of 10 to 20 hours. However, the elimination half-life of EE has also been reported by other sources to be as short as 7 hours and as long as 36 hours.


title: Ethinylestradiol

text: Unlike the case of estradiol, in which there is a rapid rise in its levels and which remain elevated in a plateau-like curve for many hours, levels of EE fall rapidly after peaking. This is thought to be because estrone and estrone sulfate can be reversibly converted back into estradiol and serve as a hormonally inert reservoir for estradiol, whereas the EE sulfate reservoir for EE is much smaller in comparison. In any case, due to the formation of EE sulfate, enterohepatic recirculation is involved in the pharmacokinetics of EE similarly to estradiol, although to a lesser extent. The contribution of enterohepatic recirculation to total circulating EE levels appears to be 12 to 20% or less, and is not observed consistently. A secondary peak in EE levels 10 to 14 hours after administration can often be observed with oral EE.


title: Ethinylestradiol

text: EE, following oxidative formation of a very reactive metabolite, irreversibly inhibits cytochrome P450 enzymes involved in its metabolism, and this may also play a role in the increased potency of EE relative to estradiol. Indeed, EE is said to have a marked effect on hepatic metabolism, and this is one of the reasons, among others, that natural estrogens like estradiol may be preferable. A 2-fold accumulation in EE levels with an EE-containing COC has been observed following 1 year of therapy.


title: Ethinylestradiol

text: EE, also known as 17α-ethynylestradiol or as 17α-ethynylestra-1,3,5(10)-triene-3,17β-diol, is a synthetic estrane steroid and a derivative of estradiol with an ethynyl substitution at the C17α position. The 17α-ethynylation of estradiol to create EE is analogous to the 17α-substitution of testosterone to make testosterone derivatives such as 17α-ethynylated progestins like ethisterone (17α-ethynyltestosterone) and norethisterone (17α-ethynyl-19-nortestosterone) as well as 17α-alkylated androgens/anabolic steroids like methyltestosterone (17α-methyltestosterone).


title: Ethinylestradiol

text: A number of derivatives of EE exist. These include mestranol (EE 3-methyl ether), quinestrol (EE 3-cyclopentyl ether), ethinylestradiol sulfonate (EE 3-isopropylsulfonate), and moxestrol (11β-methoxy-EE). The former three are prodrugs of EE, while the latter one is not. A few analogues of EE with other substitutions at the C17α position exist. Examples include the estradiol derivatives methylestradiol (17α-methylestradiol) and ethylestradiol (17α-ethylestradiol), and the estriol derivatives ethinylestriol (17α-ethynylestriol) and nilestriol (17α-ethynylestriol 3-cyclopentyl ether). Androstane analogues of EE with significant although weak estrogenic activity include ethinylandrostenediol (17α-ethynyl-5-androstenediol), 17α-ethynyl-3β-androstanediol, 17α-ethynyl-3α-androstanediol, and methandriol (17α-methyl-5-androstenediol).


title: Ethinylestradiol

text: EE was the first orally active synthetic estrogen and was described in 1938 by Hans Herloff Inhoffen and Walter Hohlweg of Schering AG in Berlin. It was approved by the in the on June 25, 1943, and marketed by Schering under the brand name "Estinyl". The FDA withdrew approval of Estinyl effective June 4, 2004 at the request of Schering, which had discontinued marketing it.


title: Ethinylestradiol

text: EE was first used in COCs, as an alternative to mestranol, in 1964, and shortly thereafter superseded mestranol in COCs.


title: Ethinylestradiol

text: "Ethinylestradiol" is the English generic name of the drug and its , , , and . It has also been spelled as "ethynylestradiol", "ethynyloestradiol", and "ethinyloestradiol" (all having the same pronunciation), and the latter was formerly its but was eventually changed. In addition, a space is often included in the name of EE such that it is written as "ethinyl estradiol" (as well as variations thereof), and this is its name. The generic name of EE in French and its are "éthinylestradiol", in Spanish is "etinilestradiol", in Italian and its are "etinilestradiolo", and in Latin is "ethinylestradiolum".


title: Ethinylestradiol

text: EE has been marketed as a standalone oral drug under the brand names "Esteed", "Estinyl", "Feminone", "Lynoral", "Menolyn", "Novestrol", "Palonyl", "Spanestrin", and "Ylestrol" among others, although most or all of these formulations are now discontinued. It is marketed under a very large number of brand names throughout the world in combination with progestins for use as an oral contraceptive. In addition, EE is marketed in the in combination with norelgestromin under the brand names "Ortho Evra" and "Xulane" as a contraceptive patch, in combination with etonogestrel under the brand name "NuvaRing" as a contraceptive vaginal ring, and in combination with norethisterone acetate under the brand name "FemHRT" in oral hormone replacement therapy for the treatment of menopausal symptoms.


title: Ethinylestradiol

text: EE is marketed widely throughout the world. It is marketed exclusively or almost exclusively in combination with progestins.


title: Karun Nair

text: Karun Kaladharan Nair (born 6 December 1991) is an Indian international cricketer who plays for Karnataka in domestic cricket and Rajasthan Royals in Indian Premier League. He is a right-handed top order batter and occasional off break bowler. He is only the second Indian batter to score a triple century in Test cricket.


title: Karun Nair

text: He made his India debut in the 2016 away ODI against Zimbabwe. He made his Test debut against England in 2016.


title: Karun Nair

text: Karun was born on 6 December 1991 in Jodhpur, Rajasthan. His parents Kaladharan Nair and Prema Nair hails from Chengannur in Alappuzha district of Kerala. Kaladharan, who is a mechanical engineer, was posted in Jodhpur at the time of his son's birth and later moved with his family to Koramangala, Bangalore where he also worked on the sprinkler system at the M. Chinnaswamy Stadium. Nair's mother, Prema is a teacher at Chinmaya Vidyalaya, Bangalore. Karun has an elder sister, Shruthi Nair.


title: Karun Nair

text: Born as a premature baby, Karun's parents were advised by the doctors to introduce their son to sports as part of the treatment for his weak lungs. Nair joined Koramangala Cricket Academy on 28 March 2001, a year after his family moved to Bengaluru and was coached under Shivanand. He studied at Chinmaya Vidyalaya, were his mother taught until fourth grade and switched to the Frank Anthony Public School for better cricketing opportunities. He studied BCom (Hons) at Jain University in Bangalore. He is fluent in several languages : English, Hindi, Malayalam, Kannada and Tamil. His mother-tongue is Malayalam.


title: Karun Nair

text: Nair made his first-class debut in the 2013–14 season in which Karnataka won the Ranji Trophy. He scored three consecutive centuries in their final league game and the first-two knockout matches. He went through a lean patch in the 2014–15 season with a string of low scores but bounced back smashing 328 runs in the final helping Karnataka to win the title again. He also became the second player from Karnataka to score a triple century and the first batter to score a triple century in a Ranji final since 1946–47. It was also the highest total by a batter in the final of Ranji Trophy. He scored 500 runs in the 2015–16 Ranji Trophy including two centuries and two half-centuries. He continued his good run in the next season hitting one century and three half-centuries from his six appearances in the season.


title: Karun Nair

text: In October 2018, he was named in India A's squad for the 2018–19 Deodhar Trophy. The following month, he was named as one of eight players to watch ahead of the 2018–19 Ranji Trophy. In August 2019, he was named in the India Red team's squad for the 2019–20 Duleep Trophy.


title: Karun Nair

text: Nair was named in the Indian ODI and T20I squads for their series against Zimbabwe in May 2016 and made his One Day International (ODI) debut in the series at Harare Sports Club on 11 June 2016.


title: Karun Nair

text: On 26 November 2016, he made his Test debut against England at Mohali. He scored his maiden Test century in the final match of the series at the M. A. Chidambaram Stadium, going on to finish 303 not out. He was only three innings old in international cricket then, thus becoming the quickest batsman to hit a maiden triple-hundred in Test cricket history in term of number of matches played. He was also India's second ever triple-centurion after Virender Sehwag, and only the third man in the game's history to convert a maiden Test ton into a triple. India won the match by an innings and 75 runs, and Nair was named as the player of the match.


title: Karun Nair

text: Karun was a part of Royal Challengers Bangalore in the 2012 and 2013 seasons of Indian Premier League. He got his breakthrough season with Rajasthan Royals in the 2014 IPL scoring 330 runs in the season at a strike rate of 142.24.


title: Karun Nair

text: In 2016, Delhi Daredevils signed Karun after Rajasthan was banned from the competition for two years after being found guilty in illegal betting and match-fixing probe. He captained Delhi in 3 matches after an injury to Zaheer Khan in the 2017 season.


title: Karun Nair

text: He was bought by Kings XI Punjab in the 2018 IPL auction. In February 2021, Nair was bought by the Kolkata Knight Riders in the IPL auction ahead of the 2021 Indian Premier League. In February 2022, he returned to Rajasthan Royals in the auction for the 2022 Indian Premier League tournament.


title: Karun Nair

text: In July 2016, Karun survived a boat accident in river Pampa in Kerala during a thanksgiving temple visit after making his ODI debut.


title: Karun Nair

text: He announced his engagement with longtime girlfriend Sanaya Tankariwala, a media professional on 29 June 2019 through his social media handles. The couple got married in a private ceremony at Udaipur, Rajasthan on 19 January 2020. Their son, Kayaan Nair was born in January 2022.


title: Supraclavicular lymph nodes

text: Supraclavicular lymph nodes are lymph nodes found above the clavicle, that can be felt in the supraclavicular fossa. The supraclavicular lymph nodes on the left side are called Virchow's nodes. It leads to an appreciable mass that can be recognized clinically, called Troisier sign.


title: Supraclavicular lymph nodes

text: Malignancies of the internal organs can reach an advanced stage before giving symptoms. Stomach cancer, for example, can remain asymptomatic while metastasizing. One of the first visible spots where these tumors metastasize is one of the left supraclavicular lymph node.


title: Supraclavicular lymph nodes

text: Virchow's nodes take their supply from lymph vessels in the abdominal cavity, and are therefore sentinel lymph nodes of cancer in the abdomen, particularly gastric cancer, ovarian cancer, testicular cancer and kidney cancer, that has spread through the lymph vessels, and Hodgkin's lymphoma. Such spread typically results in Troisier's sign, which is the finding of an enlarged, hard Virchow's node.


title: Supraclavicular lymph nodes

text: The left supraclavicular nodes are the classical Virchow's node because they receive lymphatic drainage of most of the body (from the thoracic duct) and enters the venous circulation via the left subclavian vein. The metastasis may block the thoracic duct leading to regurgitation into the surrounding Virchow's nodes. Another concept is that one of the supraclavicular nodes corresponds to the end node along the thoracic duct and hence the enlargement.


title: Supraclavicular lymph nodes

text: Differential diagnosis of an enlarged Virchow's node includes lymphoma, various intra-abdominal malignancies, breast cancer, and infection (e.g. of the arm). Similarly, an enlarged right supraclavicular lymph node tends to drain thoracic malignancies such as lung and esophageal cancer, as well as Hodgkin's lymphoma.


title: Supraclavicular lymph nodes

text: Virchow's nodes are named after Rudolf Virchow (1821–1902), the German pathologist who first described the nodes and their association with gastric cancer in 1848. The French pathologist Charles Emile Troisier noted in 1889 that other abdominal cancers, too, could spread to the nodes.


title: Gilbert and Marshall Islands campaign

text: The Gilbert and Marshall Islands campaign were a series of battles fought from August 1942 through February 1944, in the Pacific theatre of World War II between the United States and Japan. They were the first steps of the drive across the central Pacific by the United States Pacific Fleet and Marine Corps. The purpose was to establish airfields and naval bases that would allow air and naval support for upcoming operations across the Central Pacific. Operation "Galvanic" and Operation "Kourbash" were the code names for the Gilberts campaign (in modern Kiribati) that included the seizures of Tarawa and Makin, during the Battle of Tarawa of 20–23 November and the Battle of Makin of 20–24 November 1943. Operation "Flintlock" and Operation "Catchpole" were aimed at capturing Japanese bases at Kwajalein, Eniwetok, and Majuro in the Marshall Islands.


title: Gilbert and Marshall Islands campaign

text: The Imperial Japanese Navy occupied the Gilbert Islands three days after the attack on Pearl Harbor, Hawaii. They built a seaplane base on Makin and dispersed troops along the coastlines of the northern atolls to monitor the Allied forces' movement in the South Pacific.


title: Gilbert and Marshall Islands campaign

text: The Marshall Islands is located approximately 220 miles (350  km) northwest of the Gilbert Islands, and had been occupied by the Japanese since World War I as part of the South Seas Mandate. The Japanese regarded the islands as an important outpost for their navy.


title: Gilbert and Marshall Islands campaign

text: Allied commanders knew that an eventual surrender of Japan would require penetration of these islands. While commander of the United States Army, General Douglas MacArthur, wanted to push towards the Philippines via New Guinea, United States Navy Admiral Chester W. Nimitz favored a drive across the central Pacific, through the Gilberts, the Marshalls, the Carolines, and eventually the Marianas, which would put American B-29 bombers within range of Tokyo. In addition to forcing the Japanese to fight two fronts against the Allies (Nimitz driving from the east and MacArthur from the south), Nimitz's plan would neutralize the outer Japanese defenses, allowing American ground, naval, and air bases to be stationed there for future attacks against other occupied island groups. These outer islands included the atolls of Tarawa and Makin in the Gilberts, and Majuro, Kwajalein, and Eniwetok in the Marshalls.


title: Gilbert and Marshall Islands campaign

text: Japanese forces occupied the Gilbert islands on 9 December 1941, landing troops of the South Seas Detachment on Tarawa (10) and Makin islands (now Butaritari and Makin) (9), a few days after the attack on Pearl Harbor, in order to protect their south-eastern flank from allied counterattacks, and isolate Australia. The islands were to become a staging post for the planned invasion of the Ellice Islands by the Japanese, under the codename Operation FS, but their setback at the Battle of the Coral Sea delayed the plans, and their defeat at the Battle of Midway and later in the Solomon Islands put a definitive end to it.


title: Gilbert and Marshall Islands campaign

text: Following Carlson's Raiders' diversionary Raid on Makin Island and the defeat at Guadalcanal, the Japanese command was growing aware of the vulnerability and strategic significance of the Gilbert Islands, and started adopting a defensive stance. Although Imperial leaders wanted to heavily fortify the Marianas and Palau before the Americans could get there, commanders in the outer islands were told to try and hold the island as long as possible. Fortifications were quickly improved by the Japanese, starting in March 1943. Makin Atoll had a seaplane base built on the main island of Butaritari, while Tarawa housed barely enough room for an airfield on its main harbour island, Betio.


title: Gilbert and Marshall Islands campaign

text: When the Americans landed, in the Battle of Tarawa fought on 20–23 November 1943, nearly 5,000 Imperial Japanese Navy Land Forces, among them 3,000 Special Naval Landing Forces and 1,247 construction laborers were stationed on Tarawa; the Makin Islands, in contrast, were only held by a total of 798 combat troops, including some 100 isolated Japanese aviation personnel. A detachment of soldiers from Tarawa island also occupied the island of Abemama in September 1942, and though initially numbering about 300, by the time the Americans invaded the island in November 1943, most of them had been evacuated back to Tarawa, leaving only 25 Special Naval Landing Forces behind to defend the island.


title: Gilbert and Marshall Islands campaign

text: Lieutenant Junior Grade Seizo Ishikawa, the Japanese commander in charge of defending Makin, ordered his troops to build extensive fortifications on the island. These included coastal defense guns, anti-tank gun positions, machine gun emplacements, rifle pits, deep tank barriers with anti-tank guns and barbed wire. These were designed to hold the island until reinforcements could arrive.


title: Gilbert and Marshall Islands campaign

text: On Tarawa, Keiji Shibazaki had 4,836 troops, including around 2,600 Special Naval Landing Forces, 1,000 Japanese construction workers and 1,200 Korean laborers. He planned to use these units to primarily defend Betio, the largest island in the atoll. Betio was the site of a crucial Japanese airfield. To protect it from capture, Keiji had 14 coastal defense guns, 50 pieces of field artillery, 100 machine gun nests, and 500 pillboxes installed, as well as a large wall built across the northern lagoon.


title: Gilbert and Marshall Islands campaign

text: After the Gilberts fell to the Americans in late November 1943, Admiral Mineichi Koga of the Japanese Combined Fleet was unsure of which islands the Americans would strike. Without any carrier aircraft to inform him, he ordered Admiral Masami Kobayashi to disperse his 28,000 troops primarily to the outer islands of Maloelap, Wotje, Jaliuit, and Mili. However, Allied intelligence intercepted Imperial code, informing the Americans of which islands were more heavily defended. The Americans decided to invade the least protected but strategically important islands of Majuro, Kwajalein, and Eniwetok.


title: Gilbert and Marshall Islands campaign

text: As early as November, Consolidated B-24 Liberator from the Seventh Air Force stationed in the Ellice Islands had flown bombing missions over Mili and Maloelap. On 3 December 1943, Task Force 50, under Rear Admiral Charles Alan Pownall, including fleet carriers , , , and and light carriers and , launched carrier aircraft against Kwajalein. Four transports and fifty Japanese aircraft were lost, but the attack lacked strategic value. Fearing a counterattack from Wotje, Pownall ordered a second strike against the island. The Japanese did counterattack via a night bombing strike, in which "Lexington" sustained a torpedo hit but was not sunk. The task force later returned to Pearl Harbor. The "Yorktown"'s aircraft would continue to fly air cover over the atoll on 29 January, 31 January, and from 1 February to 3 February.


title: Gilbert and Marshall Islands campaign

text: The invasion of the Marshalls was delayed for about a month due to logistical problems. Japanese commander Rear Admiral Monzo Akiyama was aware that he lacked sufficient fortifications. He had 8,000 men, but only about half of them were soldiers; a large fraction of the rest were Korean laborers. To defend Kwajalein, Akiyama planned to use an aerial counterstrike with his 110 aircraft to weaken the American landing forces. However, on 29 January 1944, American carrier aircraft from carriers "Yorktown", "Lexington", and "Cowpens" destroyed 92 Japanese fighters and bombers. Akiyama now lacked the ability to effectively mount a successful counteroffensive.


title: Gilbert and Marshall Islands campaign

text: On 31 January 1944, Rear Admiral Harry W. Hill dispatched the Reconnaissance Company from the V Amphibious Corps of the Marines and the Army's 2nd Battalion, 106th Infantry, 27th Infantry Division to land on Majuro. This marked the beginning of Operation Flintlock, the invasion of Kwajalein. The island was seen as an important base for conducting air operations against the rest of the Marshall Islands and eventually the Marianas. The force took the lightly defended island in one day without any casualties.


title: Gilbert and Marshall Islands campaign

text: The same day as the Majuro invasion, the 4th Marine Division under Major General Harry Schmidt began their assault on Kwajalein. Schmidt's troops first landed on Roi-Namur, a group of islands in the northern part of the atoll. Major confusion and delays were caused by poor weather and American troops inexperienced in amphibious operations, but the pre-invasion naval and air bombardment was extremely effective. Out of roughly 3,000 Japanese soldiers, only about 300 were left to guard the island.


title: Gilbert and Marshall Islands campaign

text: On the southern island of Kwajalein, Major General Charles H. Corlett's 7th Infantry Division landed on southern Kwajalein with relative ease. Although the Japanese pillboxes, bunkers, and intense infantry offensives slowed the Americans, more troops, more experience in amphibious landings, effective pre-landing bombardment, and Japanese defenses on the opposite side of the atoll from where the Americans landed contributed to the capture of Kwajalein and its surrounding islands on 7 February. Of the entire force of about 8,000 Japanese guarding Majuro and Kwajalein, only 51 survived, and 253 were taken prisoner. The Americans suffered 348 men killed, 1,462 wounded, and 183 missing in the eight days it took to take the atoll.


title: Gilbert and Marshall Islands campaign

text: Eniwetok's islands and islets housed enough room for airfields critical for the upcoming invasion of the Marianas. Major General Yoshimi Nishida knew that it would be extremely difficult to hold the main island of Eniwetok against the invasion. He had roughly 4,000 troops, half of them Army soldiers, while the rest were a variety of Navy sailors. Since the Americans would be landing with naval and air support, therefore giving them the upper hand, he decided to stop them at the beaches.


title: Gilbert and Marshall Islands campaign

text: On 17 February 1944, a naval bombardment of Eniwetok Atoll began. This marked the beginning of Operation Catchpole. The same day, the 22nd Marine Regiment under Colonel John T. Walker landed on the northern island of Engebi. The landings were a logistical nightmare, with American troops, gear, and supplies scattered along the beach. Walker and his Marines took the island on 18 February with 85 dead and 166 wounded. On 19 February, the 106th Infantry Regiment, under Lieutenant General Thomas E. Watson, landed on the main island of Eniwetok after a heavy bombardment. However, the Japanese spider holes and bunkers repelled much of the bombardment by battleships. The landing group also faced the same logistical problems as the 22nd Marine Regiment. Japanese forces concentrated in the southwest corner of the island counterattacked the American flank, forcing the Americans to attack mainly at night. Eniwetok Island was captured on 21 February with the loss of 37 Americans and nearly 800 Japanese. On another one of Eniwetok's islands, Parry Island, the Americans used heavy gunfire support from battleships before the 22nd Marine Regiment, under Watson, waded ashore at Parry Island on 22 February. They captured the island and the entire atoll on 23 February. Of those engaged, 313 Americans died, 879 were wounded, and 77 were reported missing on Eniwetok, while the Japanese suffered 3,380 dead and 105 captured. This marked an end to the Marshall Islands campaign.


title: Gilbert and Marshall Islands campaign

text: In the Gilberts, the Americans emerged victorious, but were caught unprepared, suffering 2,459 dead and 2,286 wounded. Japan suffered a total of 5,085 dead and 247 captured. The heavy casualties and gruesome fighting conditions for both sides convinced General Holland Smith, commanding general of the V Amphibious Corps, that Tarawa should have been bypassed, although other American admirals disagreed.


title: Gilbert and Marshall Islands campaign

text: The Marshalls, by contrast, were a much easier landing. The Americans used the lessons learned at Tarawa by outnumbering the enemy defenders nearly 6 to 1 with heavier firepower (including use of armor-piercing shells) after the islands took nearly a month of heavy air and naval bombardment. In the Marshalls, the Americans lost 611 men, suffered 2,341 wounded, and 260 missing, while the Japanese lost over 11,000 men and had 358 captured.


title: Gilbert and Marshall Islands campaign

text: After the Gilberts and Marshalls were taken, the Allies built naval bases, fortifications, and airfields on the islands to prepare for an assault on the Marianas. The Japanese defeat forced military leaders to draw back to a new defensive perimeter, the Absolute National Defense Zone, which included the Marianas and Palau. These islands were heavily fortified for an upcoming assault because if captured, they would put American heavy bombers within range of Tokyo.


title: Natalie Wood filmography

text: Natalie Wood (1938–1981) was an American actress who started her career as a child by appearing in films directed by Irving Pichel. Wood's first credited role was as an Austrian war refugee in the Pichel-directed "Tomorrow Is Forever" (1946) with Claudette Colbert and Orson Welles. The following year, she played a child who does not believe in Santa Claus in the Christmas comedy-drama "Miracle on 34th Street" (1947) opposite Maureen O'Hara, John Payne, and Edmund Gwenn.


title: Natalie Wood filmography

text: Wood appeared as a regular cast member in the television sitcom "The Pride of the Family" (1953). Two years later, she starred as a recalcitrant teenager in "Rebel Without a Cause" with James Dean, for which she was nominated for the Academy Award for Best Supporting Actress, and received the Golden Globe Award for Most Promising Newcomer – Female.


title: Natalie Wood filmography

text: The following year, Wood appeared as a kidnapped girl in the John Ford-directed western "The Searchers" (1956) with John Wayne and Jeffrey Hunter. Two years later, she played a Jewish student in "Marjorie Morningstar" (1958) opposite Gene Kelly, and an American girl living in World War II France who is caught in a love triangle in "Kings Go Forth" (1958) with Frank Sinatra and Tony Curtis.


title: Natalie Wood filmography

text: In 1961, Wood starred as a teenager struggling with sexual repression in the period drama "Splendor in the Grass" with Warren Beatty, and as Maria in the highly successful musical film "West Side Story". For the former, she received a nomination for Best Actress at the Academy Awards, British Academy Film Awards, and Golden Globes. She followed "West Side Story" with another musical film "Gypsy" (1962), in which she played the title role of the burlesque entertainer Gypsy Rose Lee. She was nominated for the Golden Globe Award for Best Actress – Motion Picture Comedy or Musical. The following year, Wood portrayed a woman who becomes pregnant following a one-night stand in "Love with the Proper Stranger" (1963) with Steve McQueen. For her performance she garnered her second nomination for the Academy Award for Best Actress, and Golden Globe Award for Best Actress in a Motion Picture – Drama.


title: Natalie Wood filmography

text: In 1969, she starred in the comedy "Bob & Carol & Ted & Alice" about two couples who decide to pursue an open relationship. Four years later, Wood appeared opposite Robert Wagner in the television film "The Affair". She received the Golden Globe Award for Best Actress – Television Series Drama for her portrayal of an adulterous wife in the miniseries "From Here to Eternity" (1979). Two years later, she died of drowning during the filming of her last film "Brainstorm", which was posthumously released in 1983.


title: Panjshir Province

text: Panjshir (Dari: , literally "Five Lions," also spelled as Panjsher) is one of the thirty-four provinces of Afghanistan, located in the northeastern part of the country containing the Panjshir Valley. The province is divided into seven districts and contains 512 villages. As of 2021, the population of Panjshir province was about 173,000. Bazarak serves as the provincial capital.


title: Panjshir Province

text: Panjshir became an independent province from neighboring Parwan Province in 2004. It is bordered by Baghlan and Takhar in the north, Badakhshan and Nuristan in the east, Laghman and Kapisa in the south, and Parwan in the west.


title: Panjshir Province

text: The territory was ruled by the Khanate of Bukhara between the early 16th century and the mid-18th century. The Parwan region, including the later Panjshir, was conquered by Ahmad Shah Durrani, and officially accepted as a part of the Durrani Empire, by Murad Beg of Bukhara, after a treaty of friendship was signed in or about 1750. The rule of the Durranis was followed by that of the Barakzai dynasty. During the 19th century, the region became part of the Emirate of Afghanistan, but was largely unaffected by British incursions, such as the Anglo-Afghan wars. Like the rest of Afghanistan, Panjshir became part of the newly established Kingdom of Afghanistan in June 1926.


title: Panjshir Province

text: In July 1973, troops under the command of General "Sardar" Mohammed Daoud Khan overthrew the Afghan monarchy and established the Republic of Afghanistan. In this "coup d'état", General Daoud seized power for himself, effectively proclaiming himself as the first President of Afghanistan. He began making claims over large swathes of Pashtun-dominant territory in Pakistan, causing great anxiety to the government of Pakistan. By 1975, the young Ahmad Shah Massoud and his followers initiated an uprising in Panjshir, but were forced to flee to Peshawar in Pakistan where they received support from Pakistani Prime Minister Zulfiqar Ali Bhutto. Bhutto is said to have paved the way for the April 1978 Saur Revolution in Kabul by making General Daoud spread the Afghan Armed Forces to the countryside.


title: Panjshir Province

text: Panjshir was attacked multiple times during the 1980s Soviet–Afghan War, against Ahmad Shah Massoud and his forces. The Panjshir region was in rebel control from August 17, 1979, after a regional uprising. Aided by its mountainous terrain, the region was well defended by mujahedeen commanders during the war against the PDPA government and the Soviet Union.


title: Panjshir Province

text: After the collapse of the Democratic Republic of Afghanistan in 1992, the area became part of the Islamic State of Afghanistan. By the late 1990s, Panjshir and neighboring Badakhshan province served as a staging ground for the Northern Alliance against the Taliban. On September 9, 2001, Defense Minister Massoud was assassinated by two al-Qaeda operatives. Two days later the September 2001 attacks occurred in the United States and this led to the start of a major U.S.-led war in Afghanistan.


title: Panjshir Province

text: Containing the Panjshir Valley, in April 2004 Panjshir District of Parwan Province was turned into a province under the Karzai administration. The Afghan National Security Forces (ANSF) established several bases in the province. In the meantime, the International Security Assistance Force (ISAF) also established bases, a US-led Provincial Reconstruction Team (PRT) began operating in Panjshir in the late 2000s.


title: Panjshir Province

text: Following the Fall of Kabul on 15 August 2021, anti-Taliban forces loyal to the Islamic Republic of Afghanistan fled to the Panjshir Province. They formed the National Resistance Front of Afghanistan and kept fighting the new Islamic Emirate of Afghanistan in an ongoing conflict. The new resistance forces flew the old flag of the Northern Alliance. The resistance have held the Panjshir Valley and captured districts in neighboring provinces. By early September 2021, Taliban forces managed to push into Panjshir and capture several districts from the National Resistance Front of Afghanistan, before gaining control of Bazarak on 6 September, pushing remaining resistance fighters into the mountains. However, clashes still remain ongoing between the Taliban and resistance fighters in Panjshir Province. A subsequent visit by Radio Télévision Suisse and Journeyman Pictures into Bazarak in October 2021 also revealed that despite claims of NRF inactivity by local Taliban officials, an armed confrontation between the NRF Taliban was in fact occurring in an undisclosed location in the mountains surrounding Bazarak, with resistance forces gaining the upper hand, thus confirming that the NRF remains still active near Bazarak and in Panjshir Province.


title: Panjshir Province

text: Four Technical and Vocational Education and Training (TVET) schools service the agriculturally-oriented Panjshir Province, including the Ahmad Shah Massoud TVET. The school was established with the help from the Hilfe Paderborn and German Foreign Office and as of 2014 had about 250 students and 22 staff members.


title: Panjshir Province

text: According to the Institute for the Study of War, Tajiks form the majority of the population. There is a Sunni Hazara minority in the province, who form the majority in Darah district.


title: Panjshir Province

text: Dari (Afghan Persian) is the dominant language in the province. All inhabitants are followers of Islam, and exclusively Sunni.


title: Ho-Chunk

text: The Ho-Chunk, also known as Hoocągra or Winnebago (referred to as "Hotúŋe" in the neighboring indigenous Iowa-Otoe language), are a Siouan-speaking Native American people whose historic territory includes parts of Wisconsin, Minnesota, Iowa, and Illinois. Today, Ho-Chunk people are enrolled in two federally recognized tribes, the Ho-Chunk Nation of Wisconsin and the Winnebago Tribe of Nebraska.


title: Ho-Chunk

text: The Winnebago Tribe of Nebraska have an Indian reservation in Nebraska. While related, the two tribes are distinct federally recognized sovereign nations and peoples, each having its own constitutionally formed government and completely separate governing and business interests. Since the late 20th century, both tribal councils have authorized the development of casinos.


title: Ho-Chunk

text: The Ho-Chunk Nation is working on language restoration and has developed a Hoocąk-language iOS app. Since 1988, it has pursued a claim to the Badger Army Ammunition Plant as traditional territory; the area has since been declared surplus, but the Ho-Chunk have struggled with changes in policy at the Department of the Interior. The department supported the Ho-Chunk claim in 1998, but in 2011 refused to accept the property on their behalf.


title: Ho-Chunk

text: In 1994, to build on its revenues from casinos, the Winnebago created an economic development corporation; it has been successful and received awards as a model of entrepreneurial small business. With a number of subsidiaries, it employs more than 1400 people. It has also contributed to housing construction on the reservation. Like more than 60% of federally recognized tribes, the Winnebago legalized alcohol sales on the reservation to secure revenues that previously went to the state in taxes.


title: Ho-Chunk

text: The Ho-Chunk was the dominant tribe in its territory in the 16th century with a population estimated at several thousand. Ethnologists have speculated that, like some other Siouan peoples, the Ho-Chunk may have originated along the East Coast and migrated west in pre-colonial times. Nicolas Perrot wrote that the names given to them by neighboring Algonquian peoples may have referred to their origin near an ocean.


title: Ho-Chunk

text: The Ho-Chunk suffered severe population loss in the 17th century to a low of perhaps 500 individuals. This has been attributed to casualties of a lake storm, epidemics of infectious disease, and competition for resources from migrating Algonquian tribes. By the early 1800s, their population had increased to 2,900 but they suffered further losses in the smallpox epidemic of 1836. In 1990 they numbered 7,000; current estimates of total population of the two tribes are 12,000.


title: Ho-Chunk

text: The Ho-Chunk speak a Siouan language, which they believe to be given to them by their creator, Mą’ųna (Earthmaker). Their native name is "Ho-Chunk" (or Hoocạk), which has been variously translated as "sacred voice" or "People of the Big Voice", meaning mother tongue, as in they originated the Siouan language family. They usually refer to themselves as meaning "sacred voice people of the Pines".


title: Ho-Chunk

text: Nicolas Perrot was a 17th-century French trader who believed that the Algonquian terms referred to salt-water seas, as these have a distinctive aroma compared with fresh-water lakes. An early Jesuit record says that the name refers to the origin of "Le Puans" near the salt water seas to the north. Algonquins also called the Winnebago, "the people of the sea". (A Native people who lived on the shores of Hudson Bay were called by the same name.)


title: Ho-Chunk

text: When the explorers Jean Nicolet and Samuel de Champlain learned of the "sea" connection to the tribe's name, they were optimistic that it meant "Les Puans" were from or had lived near the Pacific Ocean. They hoped it indicated a passage to China via the great rivers of the Midwest.


title: Ho-Chunk

text: In recent studies, ethnologists have speculated that the Hoocągra, like the other Siouan-speaking peoples, originated on the east coast of North America and gradually migrated west. Recently, several Hoocąk elders have claimed that they originated in the Midwest and that they predated the last ice age. The early 20th-century researcher H.R. Holand claimed they originated in Mexico, where they had contact with the Spanish and gained a knowledge of horses. David Lee contends the Hoocąk were once akin to the Olmec there. His evidence derived from a culture based on corn cultivation, civilization type, and mound building following the receding ice shield. However, Holand cites the records of Jonathan Carver, who lived with the Hoocągra in 1766–1768. Contact with the Spanish could have occurred along the Gulf of Mexico or the south Atlantic coast, where other Hoocąk tribes originated and lived for centuries. Others suggested that the Hoocągra originated near saltwater to explain how mid-western tribes had a knowledge of the Pacific Ocean, which they described as being located where the earth ends and the sun sets into the sea. Oral histories from a past Hoocąk orator, Wakąhaga, or Snake Skin, say that they migrated to Wisconsin from the Pacific southwest, where their endonym originally meant "People of the Big Fish", or more accurately "People of the Whale". Generally, the Hoocągra today claim their people have always lived in what is now the north central United States. Linguistic and ethnographic studies have generated other deep histories of the various Native American peoples.


title: Ho-Chunk

text: Ho-Chunk oral history states they had always lived in their current homelands of Wisconsin, Minnesota, Iowa, Missouri, and Illinois. Their Siouan language indicates common origin with other peoples of this language group. They state their ancestors built the thousands of effigy mounds through Wisconsin and surrounding states during the Late Woodland period.


title: Ho-Chunk

text: The tribe historically adopted corn agriculture at the end of the Late Woodland period as well as hunting, fishing, and gathering wild plants. They cultivated wild rice ("Zizania" spp.) and gathered sugar from sugar maple trees.


title: Ho-Chunk

text: European contact came in 1634 with the arrival of French explorer Jean Nicolet. He wrote that the Winnebago/Ho-Chunk occupied the area around Green Bay of Lake Michigan in Wisconsin, reaching beyond Lake Winnebago to the Wisconsin River and to the Rock River in Illinois.


title: Ho-Chunk

text: The oral history also indicates that in the mid-16th century, the influx of Ojibwe peoples in the northern portion of their lands caused the Ho-Chunk to move to the south of their territory. They had some friction with the tribes of the Illinois Confederacy as well as fellow Chiwere-speaking peoples splitting from the Ho-Chunk. These groups, who became the Iowa, Missouria, and Otoe tribes, moved south and west because the reduced range made it difficult for such a large population to be sustained.


title: Ho-Chunk

text: Nicolet reported a gathering of approximately 5,000 warriors as the Ho-Chunk entertained him. Historians estimate that the population in 1634 may have ranged from 8,000 to more than 20,000. Between that time and the first return of French trappers and traders in the late 1650s, the population was reduced drastically. Later reports were that the Ho-Chunk numbered only about 500 people. When numerous Algonquian tribes migrated west to escape the aggressive Iroquois tribes in the Beaver Wars, they competed with the Ho-Chunk for game and resources, who had to yield to their greater numbers.


title: Ho-Chunk

text: The reasons given by historians for the reduction in population vary, but they agree on three major causes: the loss of several hundred warriors in a storm on a lake, infectious disease epidemics after contact with Europeans, and attacks by the Illinois Confederacy.


title: Ho-Chunk

text: The warriors were said to be lost on Lake Michigan after they had repulsed the first attack by invading the Potawatomi from what is now Door County, Wisconsin. Another says the number was 600. Another claim is that the 500 were lost in a storm on Lake Winnebago during a failed campaign against the Meskwaki, while yet another says it was in a battle against the Sauk.


title: Ho-Chunk

text: Even with such a serious loss of warriors, the historian R. David Edmunds notes that it was not enough to cause the near elimination of an entire people. He suggests two additional causes. The Winnebago apparently suffered from a widespread disease, perhaps an epidemic of one of the European infectious diseases. They had no immunity to the new diseases and suffered high rates of fatalities. Ho-Chunk accounts said the victims turned yellow, which is not a trait of smallpox. Historians have rated disease as the major reason for the losses in all Native American populations.


title: Ho-Chunk

text: Edmunds notes as a third cause of the population decline the following historic account: decimation by the Illinois Confederacy. The Ho-Chunk had been helped at one time by many of their enemies, in particular the Illinois Confederacy, during their time of suffering and famine, aggravated by the loss of their hunters. The Winnebago then attacked the Illinois Confederacy. Enraged, additional Illinois warriors retaliated and killed nearly all the Ho-Chunk.


title: Ho-Chunk

text: After peace was established between the French and Iroquois in 1701, many of the Algonquian peoples returned to their homelands to the east. The Ho-Chunk were then relieved of that pressure on their territory and after 1741, most returned inland. From a low of perhaps less than 500, the population gradually recovered, aided by intermarriage with neighboring tribes and some of the French traders and trappers. A count from 1736 gives a population of 700; in 1806, they numbered more than 2,900. A census in 1846 reported 4,400 people but by 1848, there were reportedly 2,500. Like other Native American tribes, the Ho-Chunk suffered great losses during the smallpox epidemics of 1757–58 and 1836. In the 19th-century epidemic, they lost nearly one quarter of their population. Today the total population of the Ho-Chunk people is about 12,000.


title: Ho-Chunk

text: The Black Hawk War of 1832 was fought largely on Ho Chunk land. In early 1832, White Cloud invited the Sauk band to live in the Rock River band's Illinois villages. About 1,200 Ho-Chunk, Fox, Kickapoo, and others came, from locations such as Saukenuk on the Iowa reservation, where there was little food. The arrivals included Black Sparrow Hawk, who had been a pro-British warrior in his youth.


title: Ho-Chunk

text: Through a series of moves imposed by the U.S. government in the 19th century, the tribe was relocated to reservations increasingly further west: in Wisconsin, Minnesota, South Dakota, and finally Nebraska. Oral history suggests some of the tribe may have been forcibly relocated up to 13 times by the US federal government to steal land through forced treaty cession, losses estimated at 30 million acres in Wisconsin alone.


title: Ho-Chunk

text: The Ho Chunk often resisted removal by staying home, or simply returning home, rather than engaging in uprisings.


title: Ho-Chunk

text: The Winnebago ceded lands in Wisconsin in 1829, 1832 and 1837; further removal attempts occurred in Wisconsin in 1840, 1846, 1850, and 1873-4.


title: Ho-Chunk

text: The 1848 removal from Iowa was documented by a soldier in Morgan's Mounted Volunteers. About 2,500 people were forced to travel by wagon, on foot, and on horseback from Fort Atkinson, Iowa to Winona, Minnesota, and thence by steamboat to the Long Prairie Reservation. The Long Prairie Reservation, which was heavily wooded, was more suitable for logging than for farming. It was dissolved in 1855, and its residents were moved to Blue Earth County, Minnesota. In 1863, the Ho Chunk were forced to leave Blue Earth County when a secret society organized by settlers in Mankato, "The Knights of the Forest", sent armed men to surround the Ho Chunks' prime farmland. About 2,000 Ho Chunk were moved to Camp Porter, in Mankato, and thence to Crow Creek, South Dakota. Poor conditions at Crow Creek led many Ho Chunk to leave for an Omaha reservation in Nebraska. The Winnebago Reservation was founded for the Ho Chunk in Nebraska in 1865.


title: Ho-Chunk

text: Following the forced relocations, many tribe members returned to previous homes, especially in Wisconsin, despite the U.S. Army's repeated roundups and removals. The U.S. government finally allowed the Wisconsin Winnebago to settle land in the state, where they have achieved federal recognition as a tribe. The Ho-Chunk in Nebraska have gained independent federal recognition as a tribe and have a reservation in Thurston County. The Ho-Chunk Nation now has a constitution that reinforces its sovereign abilities to negotiate with the US government.


title: Ho-Chunk

text: Waukon and Decorah, county seats of Allamakee and Winneshiek County, Iowa, respectively, were named after the 19th-century Ho-Chunk chief Waukon Decorah.


title: Ho-Chunk

text: Before Europeans ventured into Ho-Chunk territory, the Ho-Chunk were known to hunt, farm, and gather food from local sources, including nuts, berries, roots, and edible leaves. They knew what the forest and river's edge had to give and both genders had a role in making best use of resources. With the changing seasons, Ho-Chunk families would move from area to area to find food. For example, many families would return to Black River Falls, Wisconsin, to pick berries in the summer.