title: David Headley

text: After being told by his LeT handlers that the plot would be put on hold, Headley became disenchanted with the group. Syed became Headley's new handler and introduced him to Ilyas Kashmiri, a former Pakistani military commando and leader of Harkat-ul-Jihad al-Islami, an Islamist organization active in Pakistan, India, and Bangladesh. Kashmiri took over sponsorship of the Denmark plot and made changes to the plan, using the Mumbai attacks as inspiration; he wanted terrorists to storm the "Jyllands-Posten" offices, have its staff be taken hostage and executed, and then have their severed heads thrown out of the windows of the newsroom in an international media spectacle.


title: David Headley

text: Headley planned to return to Copenhagen during the summer of 2009. Kashmiri put him in contact with two al-Qaeda operatives called Simon and Bash, who were living in Derby, England. However, when Headley visited Derby on July 26, 2009, Simon and Bash informed him that they did not want to participate in the Denmark plot and were unable to supply weapons, instead giving him US$15,000 in financing. Headley then traveled to Stockholm to meet a veteran militant named Farid. Farid, reportedly agitated, was also unable to help Headley as he was under tight surveillance by Swedish police. When Headley arrived in Copenhagen by train on July 31, he shot video of a Royal Danish Army barracks and approached drug dealers about acquiring guns.


title: David Headley

text: Upon flying to Atlanta, Georgia on August 5, 2009, Headley was questioned by airport inspectors. By this point, the FBI had put Headley on a watch list and engaged in a two-month surveillance operation, debriefing Headley's former DEA handler and reviewing records of past inquiries. Eventually, investigators began to suspect Headley of being involved with the Mumbai attacks. On October 9, Headley was arrested at Chicago's O'Hare International Airport while he was attempting to travel to Pakistan to deliver the footage he collected in Denmark.


title: David Headley

text: During his interrogation, Headley gave up information on LeT, al-Qaeda, the ISI, and various terror plots and methods. Supervised by federal agents, he helped set up a trap against a militant in Germany and attempted to lure Sajid Mir out of Pakistan. Despite this, Headley, along with Rana, was charged in his involvement with Kashmiri's plot against "Jyllands-Posten". Headley was accused of traveling to Denmark to scout the "Jyllands-Posten" office and a nearby synagogue. The FBI later additionally charged Headley of conspiring to bomb targets in the Mumbai attacks and providing material support to LeT.


title: David Headley

text: India's National Investigation Agency (NIA) registered a case against Headley and Rana for allegedly plotting the Mumbai attacks. After questioning Headley in Chicago for a week, the NIA requested a Delhi court to issue non-bailable warrants to arrest Headley and other conspirators. Indian Home Minister Palaniappan Chidambaram reported that U.S. authorities shared "significant information" about the case. U.S. Assistant Secretary of State Robert O. Blake, Jr. promised that India would have "full access" to question Headley, although the possibility of extraditing him to appeared to be precluded by Headley's plea agreement with U.S. Attorney Patrick Fitzgerald.


title: David Headley

text: Headley's admissions, e.g., that he made video recordings of terrorism targets for the LeT, had corroborated other evidence in the trial of Ajmal Amir Kasab in Mumbai.


title: David Headley

text: A classified Indian report, based on Headley's interrogation by Indian investigators in Chicago, concludes that some of Headley's scouting trips to Mumbai were financed and planned by the ISI. When this report was leaked to U.S. media in October 2010, its conclusions were denied by Pakistani authorities.


title: David Headley

text: In March 2009, Headley made another trip to India to conduct surveillance of the National Defence College in Delhi, and of Chabad Houses in various cities in India.


title: David Headley

text: Indian investigators were surprised at how easily Headley had obtained a visa to enter India, a process that is extremely difficult for Pakistani nationals and Pakistani-origin individuals. Headley's U.S. passport, his new Western and English-sounding name, and the fact that the passport and his visa application made no mention of his prior name or his father's nationality, made it easy for him to obtain an Indian visa from the Indian consulate in Chicago. He falsely stated on his visa application that his father's name was William Headley and that his own name at birth was "Headley", a claim that was difficult to refute since the U.S. passport, unlike the Indian one, does not provide the father's name, and does not require endorsements on name changes by the passport holder.


title: David Headley

text: Indian government officials said that if the name change had been noted on his passport, Indian immigration officials would have been alerted during his multiple visits to India.


title: David Headley

text: On his visits to India, Headley befriended several people, including Rahul Bhatt, the son of Mahesh Bhatt, a famous movie producer, who said he never suspected Headley of any wrongdoing.


title: David Headley

text: While government officials in India cite full cooperation by U.S. authorities, the opposition parties and others in India have demanded explanations of why Headley was allowed to travel freely for years between India, Pakistan, and the U.S., and why he was working undercover for the DEA. Some Indian analysts have speculated that David Headley was a double agent for the Central Intelligence Agency that had infiltrated LeT, an accusation denied by the CIA. As soon as Headley was arrested in Chicago, the Indian media had a barrage of questions for the government about him, whose answers were slow in coming.


title: David Headley

text: Among other questions, Indian investigators wanted the FBI to share its tapes of Headley's communications with his Pakistani handlers to match with the voices taped on cell phones during the 2008 Mumbai attacks.


title: David Headley

text: Following intense coverage and speculation in the Indian press, U.S. ambassador Timothy J. Roemer in April 2010 told reporters in New Delhi that the United States was working at the "highest level" to provide India access to Headley, even as it was passing along answers to questions in "real time".


title: David Headley

text: News reports in October 2010 revealed that U.S. authorities had much advance knowledge about Headley's terrorist associations and activities. Headley's American and Moroccan wives had contacted American authorities in 2005 and 2007, respectively, complaining about his terrorist activities. The Moroccan wife told reporters that she had even shown the U.S. embassy in Islamabad photographs of their stay at the Taj Mahal hotel in Mumbai, warning them that he was doing something on behalf of Lashkar-e-Taiba.


title: David Headley

text: Since Headley's guilty plea, Home Minister P. Chidambaram was repeatedly asked why the U.S. cannot extradite Headley to India. Analysts in some media outlets have speculated that the United States conspired to have Headley work undercover despite knowledge that he was involved in terrorism.


title: David Headley

text: In June 2010, US National Security Adviser James Jones announced that India's National Investigation Agency (NIA) had been given access to Headley. The investigation has confirmed that Lashkar-e-Taiba terrorists carried out the Mumbai attack under the "guidance" of Pakistan's Inter-Services Intelligence (ISI). Headley stated that the ISI was engaged with the Lashkar commanders responsible for the Mumbai deaths and injuries at each and every stage of the plot. Headley mentioned that Major Sameer Ali, Major Iqbal and Major Haroon Ashique, who are serving officers of the Pakistan Army, collaborated with the LeT.


title: David Headley

text: Headley has also spoken of how after the Mumbai attacks, ISI wanted LeT to disown them in order to prevent global attention to the terror group. Pakistan considers it to be an important strategic asset to be used against India. With Ajmal Kasab as the only terrorist captured, ISI wanted to blame the terrorist act on al-Qaida. It prepared a list of 4-5 al-Qaida figures who were to be projected as the conspirators. The plan, however, did not work due to resistance from Lashkar leaders, particularly Zakiur Rehman Lakhvi.


title: David Headley

text: Headley said that while he had started off as a Lashkar recruit, he started drifting towards al-Qaida under the influence of Major Abdul Rahman Saeed, who retired in 2002. Headley was respected by the retired major because of the data which he provided for the Mumbai attack.


title: David Headley

text: Saeed, with the help of Ilyas Kashmiri, drafted Headley for the plan to attack the Danish newspaper "Jylland Posten," which had published cartoons of Muhammad considered controversial by Muslims. Headley's original handler, Sajid Mir, wanted him to focus on Lashkar's anti-India mission.


title: David Headley

text: Headley has claimed that Ishrat Jahan, thought to be a case of staged police "encounter killing", was a trained LeT suicide bomber. On May 31, 2011, however, Headley contradicted his previous statements, and testified that the Inter-Services Intelligence (ISI) leadership was not involved in planning the 2008 Mumbai attacks.


title: David Headley

text: In relation to the 2010 Pune blast at the German bakery that injured at least 53 people and killed 18, of whom 6 were foreigners, Indian Home Secretary, G. K. Pillai and the "Hindustan Times" referred to Headley. The "Hindustan Times" stated that Headley had visited Pune in July 2008 and March 2009 and referred to him as a Lashkar-e-Taiba member. "The Hindustan Times" also reported that the CCTV footage which was accessed by the Investigating agency, could, per "The Hindustan Times", help solve the mystery. The "Times of India" reported similar reports, along with "The Telegraph", "The Hindu", "The Pioneer" and also "Indian Express".


title: David Headley

text: The United States Director of National Intelligence James R. Clapper conducted a review of slip-ups in handling Headley's involvement in the 26/11 Mumbai terror attacks. His report was shared with India's Union Home Ministry.


title: David Headley

text: On January 24, 2013, Headley, then 52 years old, was sentenced by U.S. District Judge Harry Leinenweber of the United States District Court for the Northern District of Illinois in Chicago to 35 years in prison for his part in the 2008 Mumbai attacks. Leinenweber called Headley a terrorist and said he hoped he would die in prison, telling him he deserved to be executed. "The sentence I impose, I'm hopeful it will keep Mr. Headley under lock and key for the rest of his natural life," Leinenweber said. "That's what you deserve. I don't have any faith in Mr. Headley when he says he's a changed person and believes in the American way of life." Headley could have been sentenced to life imprisonment, but federal prosecutors recommended a 35-year sentence in view of Headley's extensive cooperation with the government. Headley had provided details on the operations of the Pakistani terrorist group Lashkar-e-Taiba, which planned the Mumbai attacks, and information that he provided to the government led to charges against Tahawwur Hussain Rana and six other terrorist figures. Judge Leinenweber stated that the sentence was sufficient to put Headley "under lock and key for the rest of his life" so that he would "never [be] in a position again to commit a terrorist attack."


title: David Headley

text: Others, including survivors of the attacks, have been critical of the sentence, saying that the length of the sentence was an "appalling dishonor" and that Headley has "no right to live."


title: David Headley

text: The day after the sentence was imposed, the Indian government announced it would continue to seek Headley's extradition to India.


title: David Headley

text: In April 2013, it was reported that while imprisoned, Headley had written a memoir detailing his involvement with Lashkar-e-Taiba and the Mumbai attacks.


title: David Headley

text: In July 2015, it was reported that the Mumbai police were seeking to take a deposition of Headley by video conference to provide evidence against Zabiuddin Ansari (Abu Jundal).


title: David Headley

text: On December 10, 2015, a Mumbai court pardoned Headley, making him an approver in the Mumbai case. Deposition started in Bombay High Court via video conference on February 8, 2016. He told the court that LeT made two unsuccessful attempts to carry out terror attacks before finally striking in November 2008, once in September and again in October.


title: David Headley

text: On July 24, 2018, it was reported that Headley was seriously injured after being attacked in prison and admitted to the critical care unit of Evanston Hospital of the NorthShore University HealthSystem. Earlier, on February 9, 2016, it was reported that Headley had confessed to a Mumbai court about LeT and Inter-Services Intelligence having penetrated into the ranks of the Indian Army, to work for them as spies and an attack was also planned on the Indian defence scientists who were to meet at the conference hall in Taj Hotel, in Mumbai, in 2007. For this purpose he had carried out a recce on the Naval air station, INS Kunjali, INS Shikra and the Siddhivinayak Temple, Mumbai.


title: Storm of the Century

text: Storm of the Century, alternatively known as Stephen King's Storm of the Century, is a 1999 American horror television miniseries written by Stephen King and directed by Craig R. Baxley. Unlike many other television adaptations of King's work, "Storm of the Century" was not based on a novel but was an original screenplay written by the author and directly produced for television. King described the screenplay as a "novel for television." The screenplay was published as a mass-market book in February 1999 prior to the TV broadcast of the mini-series.


title: Storm of the Century

text: King has called "Storm of the Century" his personal favorite of all the TV productions related to his works.


title: Storm of the Century

text: A powerful blizzard hits the fictional small island town of Little Tall Island (also the setting of King's novel "Dolores Claiborne") off the coast of Maine. The storm is so powerful that all access to the island is cut off and no one is able to leave. As the town prepares for the storm, tragedy strikes when elderly resident Martha Clarendon is brutally murdered by André Linoge (Colm Feore), a menacing stranger with a black cane decorated by a silver wolf's head. When Robbie Beals, the town manager, investigates, Linoge claims to know the repetitious inner workings of hell and states that Robbie's mother has turned cannibal and is waiting in hell to eat him. Linoge is arrested by supermarket manager and part-time constable Michael "Mike" Anderson (Timothy Daly) and his friend and deputy Alton "Hatch" Hatcher. As he is taken to his cell, Linoge makes passing remarks at nearby townspeople, revealing he knows secrets about all of them. Linoge gives no hint of his origins or motives, only vaguely saying, "Give me what I want, and I'll go away."


title: Storm of the Century

text: While imprisoned, Linoge demonstrates a supernatural ability to peer into and control minds, inflict hallucinations, and drive people to commit suicide and murder. Linoge shows he also has the ability to control the physical world, not just minds, by watching broken televisions, putting messages on computer screens, catching a speeding bullet, levitating objects and people, causing nosebleeds, jamming unlocked doors, and opening locked cell doors to leave at will. Linoge causes three suicides and a murder shortly after being jailed.


title: Storm of the Century

text: Later that evening, as the 200 remaining residents sleep, an escaped Linoge enters the lighthouse and supernaturally causes everyone to have the same dream: a dream of the entire town suicidally walking into the ocean and mystifying authorities in the aftermath as to what happened to everyone. The dream has Linoge, appearing heavier and bald, as a journalist reporting on the mass disappearance and comparing it to the 1587 disappearance event at Roanoke Island, Virginia. This suggests to the islanders that Linoge had the power to make an island community disappear before and that he may do it again. Linoge also appears in the same dream as a televangelist threatening that suffering will result if people sin by refusing to give the wanderer what he wants.


title: Storm of the Century

text: The next day, Linoge causes three residents to vanish while everyone is watching the lighthouse collapse. Two die and the third, lost resident Angie Carver, is discovered alive with her dark hair now turned shock white. Angie reveals Linoge kidnapped her and warned that if he does not get what he wants he will cause mass suicides as he did at Roanoke before. All eight of the town's young children are then enchanted and fall unconscious. Linoge then appears in the town hall and levitates Joanna and threatens to burn her. Linoge says that Mike is good through and through, but the rest of the town is, "full of adulterers, pedophiles, thieves, gluttons, murderers, bullies, scoundrels, and covetous morons."


title: Storm of the Century

text: Throughout Mike resists the calls of others to simply execute Linoge. Mike believes that giving in to evil is wrong. Mike earlier recounted the biblical story of Job and realized that Linoge's surname is an anagram for Legion, a collective group of demons exorcised by Jesus according to the Gospel of Mark and Gospel of Luke. Linoge frequently displays disgust at the immorality of humanity and states he possesses the supernatural power to punish. This raises the question whether Linoge is a force in the ultimate service of good rather than evil or perhaps reinforces the biblical reference that Mike made to the tests of Job, in which God allowed Satan to punish Job to test Job's faith in the face of suffering. The reference to Legion demons and Linoge's intimate knowledge of cannibalism and repetition in hell, murderous tactics, and insight into human sin, makes it seem to Mike that Linoge, "can only see the bad," and Linoge's primary obligation is darkness rather than being an agent of morality on earth to judge and punish.


title: Storm of the Century

text: Linoge demands a town hall meeting and then arrives claiming he will cause total suicide among everyone on the island including dropping all eight children unless one of them is given to him. Linoge reveals he is thousands of years old, but not immortal and is now dying and sick. He desires a protégé to raise and teach who can carry on his "work". He promises the child will become like him, long-lived, powerful, and seeing much. He cannot take a child by force, but he "can" punish the town and make them all to suffer and die if they refuse him. He leaves the townspeople half an hour to make their decision.


title: Storm of the Century

text: Mike begs the town to refuse, arguing the villain is not all-powerful and may soon leave the town just as the storm will if they trust in God and their own power. He appeals to their common decency and points out they may be aiding an evil man in harming a child. The other townspeople, including Mike's wife Molly, are too frightened of Linoge and think they have no choice. They argue this is not human sacrifice but rather an "adoption" and it is better to lose one child rather than all. Mike wishes to abstain from voting and take Ralphie away, but his friends stop him and Molly insists that being part of the town means they must accept Ralphie may be the child taken. Everyone but Mike votes in favor to give Linoge what he desires, and Hatch says he will see this is the right decision. Linoge arrives and has one parent of each child draw one of eight "weirding stones" that predate the sinking of Atlantis. Molly draws the lone black stone, marking Ralphie as the one who will be taken. Linoge transforms into his true form and thanks the town, suggesting they will be better off if they do not reveal his existence or this arrangement to the outside world. Mike is held back by Hatch and other townsfolk who fear reprisal. Now regretting her choice, Molly frantically cries at Mike to help save Ralphie; but the townspeople continue to restrain him and refuse to aid her. In anguish, Molly madly accuses Linoge of tricking them by fixing the result of the stones before she attacks him in a frenzy. Linoge merely knocks Molly aside and remarks that she and the townspeople may have all tricked themselves, adding that Ralphie will eventually call him "father." Carrying the child, Linoge flies off into the night.


title: Storm of the Century

text: The following summer, a thoroughly depressed Molly is in therapy discussing her now failing marriage; lamenting she is now losing the last thing she ever loved. She insists Ralphie was "lost in the storm" along with perhaps another who also was never found that weekend and refuses to discuss him further despite the therapist warning that pain will fester if she can't be honest. Molly says she now understands some wounds can't be cleaned out no matter what. Despite the desperate pleas of his neighbors to stay, Mike is unable to condone or accept the townspeople sacrificing his son along with their morals and principles; he resigns as constable and market manager and leaves Little Tall, divorcing Molly and deciding to never return (though his narration reveals he keeps in contact with some residents). He settles in San Francisco, and continues to represent law and order, eventually becoming a US Marshal. As time passes, he hears of several in Little Tall committing suicide over the years (including Hatch's wife Melinda, Angela Carver's husband Jack, and Robbie Beals' wife Sandy). Hatch, now a widower, marries Molly; Mike wishes the best for them. Nine years after the storm, Mike notices an old man and a teenage boy on the sidewalk, both humming "I'm a little teapot." He recognizes the boy as an older Ralphie and both turn to face him. The old man resembles Linoge while the boy briefly hisses with a fanged mouth. Mike follows them, but they vanish in an alley. Mike considers telling Molly what he saw that day, but ultimately decides against it; it is implied he severs contact with Little Tall Island permanently. He sometimes wonders if this is the wrong decision, then admits in narration "in daylight, I know better."


title: Storm of the Century

text: The screenplay for the miniseries was written by Stephen King expressly for television. The screenplay was published as a mass-market book by Pocket Books just prior to the initial airing of "Storm of the Century" on ABC. The book included photographs of the TV mini-series. The book contains an introduction in which King describes the genesis of the idea as it occurred to him in late 1996. Beginning to write it in December 1996, he initially debated if the story should be either a novel or a screenplay. He described the result as a "novel for television." A hardcover edition, written as a screenplay rather than "prose", was published concurrently by the Book of the Month Club.


title: Storm of the Century

text: "Storm of the Century" aired on ABC on February 14–18, 1999. It was released on DVD on June 22 the same year.


title: Storm of the Century

text: On Rotten Tomatoes, the film holds an approval rating of 82% based on 22 reviews, with an average rating of 7.33/10. The website's critical consensus reads, "Chilling performances and an even darker moral dilemma shelter "Storm of the Century"'s somewhat long-winded tale from ever being anything less than watchable."


title: Antarctic

text: The Antarctic ( or , American English also or ; commonly ) is a polar region around Earth's South Pole, opposite the Arctic region around the North Pole. The Antarctic comprises the continent of Antarctica, the Kerguelen Plateau and other island territories located on the Antarctic Plate or south of the Antarctic Convergence. The Antarctic region includes the ice shelves, waters, and all the island territories in the Southern Ocean situated south of the Antarctic Convergence, a zone approximately wide varying in latitude seasonally. The region covers some 20 percent of the Southern Hemisphere, of which 5.5 percent (14 million km) is the surface area of the Antarctica continent itself. All of the land and ice shelves south of 60°S latitude are administered under the Antarctic Treaty System. Biogeographically, the Antarctic realm is one of eight biogeographic realms of Earth's land surface.


title: Antarctic

text: As defined by the Antarctic Treaty System, the Antarctic region is everything south of the 60°S latitude. The Treaty area covers Antarctica and the archipelagos of the Balleny Islands, Peter I Island, Scott Island, the South Orkney Islands, and the South Shetland Islands. However, this area does not include the Antarctic Convergence, a transition zone where the cold waters of the Southern Ocean collide with the warmer waters of the north, forming a natural border to the region. Because the Convergence changes seasonally, the Convention for the Conservation of Antarctic Marine Living Resources approximates the Convergence line by joining specified points along parallels of latitude and meridians of longitude. The implementation of the convention is managed through an international commission headquartered in Hobart, Australia, by an efficient system of annual fishing quotas, licenses and international inspectors on the fishing vessels, as well as satellite surveillance


title: Antarctic

text: The islands situated between 60°S latitude parallel to the south and the Antarctic Convergence to the north, and their respective exclusive economic zones fall under the national jurisdiction of the countries that possess them: South Georgia and the South Sandwich Islands (United Kingdom), Bouvet Island (Norway), and Heard and McDonald Islands (Australia).


title: Antarctic

text: Kerguelen Islands (France; also an EU Overseas territory) are situated in the Antarctic Convergence area, while the Isla Grande de Tierra del Fuego, Falkland Islands, Isla de los Estados, Hornos Island with Cape Horn, Diego Ramírez Islands, Campbell Island, Macquarie Island, Amsterdam and Saint Paul Islands, Crozet Islands, Prince Edward Islands, and Gough Island and Tristan da Cunha group remain north of the Convergence and thus outside the Antarctic region.


title: Antarctic

text: Most of the Antarctica continent is permanently covered by ice and snow, leaving less than 1 percent of the land exposed. There are only two species of flowering plant, Antarctic hair grass and Antarctic pearlwort, but a range of mosses, liverworts, lichens and macrofungi.


title: Antarctic

text: Biodiversity among terrestrial flora and fauna is low on the islands: studies have theorized that the harsh climate was a major contributor towards species richness, but multiple correlations have been found with area, temperature, remoteness of islands, and food chain stability. For example, herbivorous insects are poor in number due to low plant richness, and likewise, indigenous bird numbers are related to insects, which are a major food source.


title: Antarctic

text: The Antarctic hosts the world's largest protected area comprising 1.07 million km, the South Georgia and the South Sandwich Islands Marine Protection Area created in 2012. The latter exceeds the surface area of another vast protected territory, the Greenland National Park’s . (While the Ross Sea Marine Protection Area established in 2016 is still larger at 1.55 million km, its protection is set to expire in 35 years.) To protect the area, all Antarctic ships over 500 tonnes are subject to mandatory regulations under the Polar Code, adopted by the International Maritime Organization (in force since 1 January 2017).


title: Antarctic

text: The first recorded sighting of Antarctica is credited to the Spaniard Gabriel de Castilla, who reported seeing distant southern snow-capped mountains in 1603. The first Antarctic land discovered was the island of South Georgia, visited by the English merchant Anthony de la Roché in 1675. Although myths and speculation about a "Terra Australis" ("Southern Land") date back to antiquity, the first confirmed sighting of the continent of Antarctica is commonly accepted to have occurred in 1820 by the Russian expedition of Fabian Gottlieb von Bellingshausen and Mikhail Lazarev on "Vostok" and "Mirny".


title: Antarctic

text: The Australian James Kerguelen Robinson (1859–1914) was the first human born in the Antarctic, on board the sealing ship "Offley" in the Gulf of Morbihan (Royal Sound then), Kerguelen Island on 11 March 1859. The first human born on an Antarctic island was Solveig Gunbjørg Jacobsen born on 8 October 1913 in Grytviken, South Georgia.


title: Antarctic

text: Emilio Marcos Palma (born 7 January 1978) is an Argentine man who was the first documented person born on the continent of Antarctica at the Esperanza Base. His father, Captain Jorge Palma, was head of the Argentine Army detachment at the base. While ten people have been born in Antarctica since, Palma's birthplace remains the southernmost. In late 1977, Silvia Morella de Palma, who was then seven months pregnant, was airlifted to Esperanza Base, in order to complete her pregnancy in the base. The airlift was a part of the Argentine solutions to the sovereignty dispute over territory in Antarctica. Emilio was automatically granted Argentine citizenship by the government since his parents were both Argentine citizens, and he was born in the claimed Argentine Antarctica. Palma can be considered to be the first native Antarctican.


title: Antarctic

text: The Antarctic region had no indigenous population when first discovered, and its present inhabitants comprise a few thousand transient scientific and other personnel working on tours of duty at the several dozen research stations maintained by various countries. However, the region is visited by more than 40,000 tourists annually, the most popular destinations being the Antarctic Peninsula area (especially the South Shetland Islands) and South Georgia Island.


title: Antarctic

text: In December 2009, the growth of tourism, with consequences for both the ecology and the safety of the travellers in its great and remote wilderness, was noted at a conference in New Zealand by experts from signatories to the Antarctic Treaty. The definitive results of the conference were presented at the Antarctic Treaty states' meeting in Uruguay in May 2010.


title: Antarctic

text: Because Antarctica surrounds the South Pole, it is theoretically located in all time zones. For practical purposes, time zones are usually based on territorial claims or the time zone of a station's owner country or supply base.


title: Skin Diamond

text: Raylin Joy, formerly known by her stage name Skin Diamond (born February 18, 1987) is a British-American actress, model, singer-songwriter and former pornographic actress.


title: Skin Diamond

text: A very active performer in the adult industry since her late teens, Christensen has recently retired from adult film acting to pursue other interests such as songwriting and mainstream acting.


title: Skin Diamond

text: Christensen was born on February 18, 1987 in Ventura, California, She was raised in Dunfermline, Scotland where her parents took up position as missionaries. Her father is of Eritrean descent and her mother is of Czech, Danish, German and Yugoslavian descent.


title: Skin Diamond

text: Christensen started her career as an alternative model posing for GodsGirls, before branching out into art modeling and fetish modeling for photographers in Europe and the United States. Her unique look attracted the attention of a wide variety of photographers.


title: Skin Diamond

text: In 2009, she posed on the cover of Bizarre winning their first ever "Cover Girl Search" competition, after which she was signed to London-based modeling agency Girl Management. She also entered the adult film industry in 2009, performing her first scenes with Joanna Angel and James Deen for Burning Angel.


title: Skin Diamond

text: In 2011, she posed in an editorial campaign for i-D magazine's "The Exhibitionist Issue No. 312" wearing Louis Vuitton and American Apparel.


title: Skin Diamond

text: In 2012, Christensen posed for comic book artist David Mack, who portrayed her as Echo in the Marvel Comics miniseries "".


title: Skin Diamond

text: Christensen first dabbled in the music industry with her 2013 song/music video, "Sex in a Slaughter House". which she wrote as part of a scene for Brazzers.


title: Skin Diamond

text: In 2014, Christensen was on CNBC's list of "The Dirty Dozen: Porn's Most Popular Stars". Diamond also starred (with Allie Haze) in the music video for American hip hop recording artist B.o.B, for his song "John Doe", which features Priscilla Renea.


title: Skin Diamond

text: Christensen was the "Penthouse" Pet of the Month for July 2014. That same year, she made her directorial debut with the film "Skin Diamond's Dollhouse" for Deviant Entertainment.


title: Skin Diamond

text: In 2016, Christensen performed her last adult film scenes to pursue mainstream acting and singing full-time, after she was cast in the role of Dylan Quinn in "Submission", a series on Showtime exploring BDSM themes. It was also during this time period that she launched her music project with the release of her first official single and music video ("Fire" produced by Ben Cole) under her real name, "Raylin Joy". She briefly posed for Dechristo Studios in 2019 in a shoot for Penthouse magazine


title: Skin Diamond

text: In April 2020, Christensen and eleven other adult/former adult actresses appeared in the music video for the G-Eazy song "Still Be Friends".


title: Skin Diamond

text: Diamond has two piercings in her navel, and one in her right nostril. She is also well known for her distinctive shaved-on-one-side haircut; because of this, she has been featured in the column "Beauty Showdown" in the magazine "Cosmopolitan". When she first entered the adult film industry, her hair was pink. She is bisexual.


title: Ip Man 3

text: Ip Man 3 is a 2015 Hong Kong biographical martial arts film directed by Wilson Yip, produced by Raymond Wong and written by Edmond Wong with action choreography by Yuen Woo-ping. It is the third in the "Ip Man" film series based on the life of the Wing Chun grandmaster Ip Man and features Donnie Yen reprising the title role. Ip Man's pupil Bruce Lee is portrayed by Danny Chan and Ip Man's fellow Wing Chun expert and rival Cheung Tin-chi (張天志), also known as Sum Nung, is portrayed by Zhang Jin. The film also features Mike Tyson. Principal photography commenced in March 2015 and ended in June of that year.


title: Ip Man 3

text: The premiere of the film was released in Hong Kong on 16 December 2015, and officially released in Hong Kong, Singapore, Malaysia on 24 December 2015. It opened in Taiwan on 31 December 2015, New Zealand and United Kingdom on 15 January 2016 and one week later in Australia. It was released in the United States on 22 January 2016, and was released in mainland China on 4 March 2016. The film received positive reviews and eight Hong Kong Film Award nominations, including Best Film and Best Director, and won in the Best Editing category. It also won Best Action Choreography, Best Director and Best Picture at the 2016 Shanghai International Film Festival.


title: Ip Man 3

text: In 1959, Ip Man lives a low-profile life in Hong Kong. His elder son, Ip Chun, has returned to Foshan to study, leaving Ip with his younger son, Ip Ching, and his wife, Cheung Wing-sing, in Hong Kong. Bruce Lee visits Ip and asks to become one of his students. After Lee demonstrates his speed, Ip neither accepts nor rejects him, but insinuates for him to leave by opening the door.


title: Ip Man 3

text: After Ip Ching gets into a fight with his schoolmate Cheung Fong, their teacher, Miss Wong, asks the parents to come to the school, though only the Ips arrive. As an apology, the Ips invite Fong to their home for dinner. At Ip's house, Fong displays rudimentary but impressive Wing Chun skills. When asked who his mentor is, Fong says it is his father, Cheung Tin-chi, who shows up to collect his son shortly after. Although Tin-chi interacts cordially with Ip, he secretly envies and seeks to surpass him.


title: Ip Man 3

text: Tin-chi participates in underground fights organized by Ma King-sang, a local triad leader who works for Frank, an American property developer and highly proficient boxer. Frank orders Ma to acquire the land occupied by the school where Ching and Fong study. When Ip goes to collect his son from school, he witnesses Ma and his men beating the school principal after he refuses to sell. Ip intervenes and restrains Ma, but is forced to release him. Ip seeks help from his close friend Fat Po, a local police sergeant. Po agrees to help, but says that he lacks the manpower and influence to protect the school every day. Ip then decides to guard the school alongside his students.


title: Ip Man 3

text: That night, Ma's men set fire to the school and attempt to kidnap the principal. Tin-chi happens to be passing by, and helps fight off Ma's thugs. Tin Ngo-san, a local martial arts master and Ma's former mentor, is enraged by Ma's unscrupulous acts and confronts Ma at a Hong Kong shipyard, humiliating him in front of his men. Ma retaliates with a hidden knife, but Ip stops him. Po arrives and keeps tensions from escalating further. Ma offers Tin-chi a large sum of money to get revenge against Ngo-san on his behalf. Desperate for money and wanting to open his own martial arts school, Tin-chi accepts the offer and attacks Ngo-san, hospitalizing him.


title: Ip Man 3

text: Ip receives a call from the hospital and visits Ngo-san. Upon learning that Ngo-san did not call him, Ip realizes it was a set-up by Ma to lure him away from the school, where Ma's gang have abducted some of the students, including Ching and Fong. Ip arrives alone at Ma's shipyard, where Ma holds Ching at knife point and threatens to sell the children into slavery if the principal refuses to sell the school. Tin-chi is allowed to leave with Fong due to being an associate, but after his son tells him that they still have his friends, he returns and fights alongside Ip. Ip and Tin-chi hold their own until a troop of policemen led by Po arrives to arrest the gang. Frank dismisses Ma for his failures and sends a Thai boxer after Ip instead.


title: Ip Man 3

text: Returning home, Ip learns that Wing-sing has been diagnosed with cancer. On their way home from a medicine shop, Ip and Wing-sing are attacked in an elevator by the Thai boxer, who Ip defeats before the elevator reaches the ground floor. Po tells Ip about Frank, who wants to eliminate Ip at all costs for obstructing his plans. Ip confronts Frank in his office, where Frank promises to leave the school alone if Ip can last an entire three minute fight. Initially overwhelmed by Frank's muscle and sheer force, Ip turns the tide by attacking Frank's lower half. They fight to a draw after the three minutes pass; seemingly impressed, Frank keeps his promise.


title: Ip Man 3

text: Tin-chi opens his martial arts school with the money he obtained from Ma, and claims that his Wing Chun is genuine while Ip's is not. He publicly challenges Ip to a battle that will decide who is the true Grandmaster of Wing Chun. However, Ip instead spends more time with his ailing wife, ashamedly feeling that he had neglected her. Wanting to dance with his wife, Ip is taught how to dance by Lee, whom Ip finally accepts as a student; because of Ip's failure to attend, Tin-chi is declared the winner. Wing-sing makes arrangements for another match on her husband's behalf, correctly guessing that Ip would have attended if not for her deteriorating health, and accompanies him to the fight. After a long battle involving staffs, butterfly knives and unarmed combat, Ip eventually overpowers Tin-chi. Accepting defeat, Tin-chi destroys the banner proclaiming himself Grandmaster, and Ip tells him that spending time with their loved ones is more important than competing with others.


title: Ip Man 3

text: A closing onscreen text states that Wing-sing died in 1960, and that Ip helped make Wing Chun well known internationally and left a legacy.


title: Ip Man 3

text: Donnie Yen, who played the Wing Chun grandmaster Ip Man in two films, initially expressed no interest in appearing in a third film, feeling that, "Because "Ip Man 2" will incontrovertibly become a classic, bettering the first. I believe it's best to end something when it's at perfection, and leave behind a good memory." Before the release of "Ip Man 2", he stated he would no longer be involved in a film based on Ip Man's life due to the proliferation of Ip Man films produced by different studios following the success of the first "Ip Man" film. While both Yen and Raymond Wong were not initially keen on making a third "Ip Man" film, director Wilson Yip had expressed interest in making one that would focus on the relationship between Ip Man and Bruce Lee. While "Ip Man 2" very briefly shows Lee as a child, Wilson Yip hoped to find a suitable actor to portray Lee as an adult for the third instalment. In March 2014, "Variety" announced that "Ip Man 3" would be shot in early 2015, and would be released in 3D during Chinese New Year that year, with Wilson Yip, Yen, and Wong reprising their duties. In December 2015, regarding the decision to make "Ip Man 3" five years after "Ip Man 2", Wong said there were numerous unrelated Ip Man films being made such as "", "" and "The Grandmaster", so they wanted to wait till all that ended.


title: Ip Man 3

text: In March 2015, "The Hollywood Reporter" announced that Mike Tyson would also be starring as a street fighter and property developer. This marks the first time Tyson appears in film or television as a substantial character other than himself. They also noted that because the team could not find an actor who could portray Bruce Lee's intensity onscreen, they decided to use CGI to portray Lee. In the same month, Kris Storti, the COO of Bruce Lee Enterprises (BLE), said that BLE, which is the sole owner of all worldwide rights relating to Lee, including his name, image and likeness, was "justifiably shocked" over Pegasus Motion Pictures' decision to include Lee in their film, which Storti said was "completely unauthorized" by BLE. "To state it in no uncertain terms, BLE intends to seek all remedies available to it to stop Pegasus from including the computer-generated version of Bruce Lee in "Ip Man 3"," he added. However, Pegasus asserted that Bruce Lee's brother Robert Lee, who worked as a consultant on "Ip Man 3", owns the intellectual property rights of Lee, a claim which was denied by BLE. "The Guardian" noted that plans to use a CGI Bruce Lee were dropped as a result, though Lee did appear in the film, portrayed by Danny Chan, who had previously portrayed Lee in the 2008 TV series, "The Legend of Bruce Lee".


title: Ip Man 3

text: Yen said that, despite initial reluctance, he agreed to return to the role of Ip Man because "no matter where I go, nobody knows me as Donnie Yen. They call me Ip Man. So I decided to play the role one more time to fulfil everyone's wishes", and implied that "Ip Man 3" could be his final martial arts film. Lynn Hung reprised her role as Ip Man's wife from the first two films. In November 2015, it was revealed on the website of music composer Kenji Kawai (who scored the series' first two films) that he had returned to work on the soundtrack of "Ip Man 3".


title: Ip Man 3

text: Principal photography began in Shanghai on 25 March 2015. While filming an action sequence with Yen, Tyson's finger was fractured.


title: Ip Man 3

text: Despite Yuen Woo-ping being credited as the action choreographer of the film, both Yuen and Yen have revealed during interviews that many scenes are actually choreographed by Yen himself as he often improvised on the set and add new actions and sequences while filming. This is especially evident in the fight scene against Tyson where Yen wanted to include some MMA and physics theories, targeting the lower body of Tyson. Principal photography wrapped in June 2015. Yen has gone uncredited in action choreography many times, and his improvisation and contribution includes many Hong Kong Film Award winners such as the previous two "Ip Man" films, "Bodyguards and Assassins" and "".


title: Ip Man 3

text: "Ip Man 3" was released in Hong Kong on 24 December 2015, as well as in Malaysia and Singapore. Earlier, it was scheduled for a 2016 release. The film had a limited release in New Zealand on 25 December 2015, followed by a wide release in Taiwan on 31 December 2015, and a limited release in the United States on 22 January 2016. It was released in mainland China on 4 March. It was released in Sri Lanka in March 2016.


title: Ip Man 3

text: The review aggregator Rotten Tomatoes reported that 76% of critics have given "Ip Man 3" a positive review based on 51 reviews, with an average rating of 6.4/10. The website's critics consensus reads, ""Ip Man 3" isn't the most tightly plotted biopic a kung fu fan could ask for, but the fight scenes are fun to watch — and at times, the drama is even genuinely poignant." Another review aggregator, Metacritic gives the film a weighted average score of 57 out of 100 based on 14 critic reviews, indicating "mixed or average reviews".


title: Ip Man 3

text: Clarence Tsui of "The Hollywood Reporter" wrote, "Bolstered by Yuen Woo-ping's exhilarating action choreography and some stunt casting in the shape of Mike Tyson and Zhang Jin (the breakout star in Wong Kar-wai's rival Ip Man biopic "The Grandmaster"), Yen and Yip have managed to wring a serviceable film out of a pedestrian plot riddled with erroneous period details." Tsui called it "a fitfully effective finale to the franchise." James Marsh of "Screen International" stated, ""Ip Man 3" trades the crowd-pleasing intensity of its predecessors for a more introspective portrait of its central character." However, Marsh added, "Yen has always portrayed Ip Man as a modest beacon of calm and restraint, which has added to the enigmatic nature of the character, but he struggles here when called upon to express grander emotions. As expected, Mike Tyson fails to convince in his role of Frank, whose origins are never revealed in the film, and whose motivation is simply greed."


title: Ip Man 3

text: Edmund Lee of "South China Morning Post" gave the film a 3.5/5 rating and commented, "A respectable action drama that doesn't try to replicate the pleasure of its predecessors, instead admirably turning to contemplate Ip's priorities in life, "Ip Man 3" will reward those who come in with no preconceptions about what an Ip Man biopic headed by Donnie Yen should be like. For the character has irreversibly mellowed and it's left to audiences to respond in kind." Andrew Chan of "Film Critics Circle of Australia" commented "Rarely do a trilogy of films, gets better with age and this one provides us with plenty of the evergreen Yuen Woo Ping inspired fight sequences one after another."


title: Ip Man 3

text: Hans David Tampubolon of "The Jakarta Post" called the film a "messy patchwork of stitched-together plotlines" that was an "action-packed but ultimately disappointing finale of the Wing Chun trilogy" and concluded, "Well, judging by the atrocious script and character development in "Ip Man 3", there is a very large possibility that Donnie is regretting his final decision to portray the legendary grandmaster for the third time."


title: Ip Man 3

text: According to Box Office Mojo, "Ip Man 3" has earned in Hong Kong and $2,679,437 in the United States. In China, it made US$24.1 million on its opening day, debuting at No. 1 and US$28.7 million on its second day for a two-day total of $52.4 million. In its opening weekend, it topped the box office with an estimated US$71.2 million from 191,400 screenings and 10.4 million admissions. Internationally, the film earned $154,165,316, bringing its worldwide total to $156,844,753.


title: Ip Man 3

text: "Ip Man 3" Blu-ray was released on 10 March 2016 in Hong Kong and on 25 April 2016 in United Kingdom. It was 2016's second best-selling foreign language film on home video in the UK, behind French film "Victor Young Perez".


title: Ip Man 3

text: While many sources suggested that "Ip Man 3" could be the final film in the franchise, Patrick Brzeski of "The Hollywood Reporter" stated that due to the film's strong commercial performance, he "wouldn't be surprised" if a sequel was made. Raymond Wong had expressed interest in making a fourth "Ip Man" film, which Donnie Yen stated was possible if there was a good script, and if reaction to "Ip Man 3" warranted it. On 30 September 2016, Yen announced via Facebook that he and Wilson Yip would continue the franchise with "Ip Man 4". Filming began in April 2018, and this final film was released on 20 December 2019.


title: Erfurt latrine disaster

text: The Erfurt latrine disaster occured in July 1184, when Henry VI, King of Germany (later Holy Roman Emperor), held a "Hoftag" (informal assembly) in the Petersberg Citadel in Erfurt. On the morning of 26 July, the combined weight of the assembled nobles caused the wooden second story floor of the building to collapse and most of them fell through into the latrine cesspit below the ground floor, where about 60 of them drowned in liquid excrement. This event is called the "Erfurter Latrinensturz" () in several German sources.


title: Erfurt latrine disaster

text: A feud between Landgrave Louis III of Thuringia and Archbishop Conrad of Mainz, which had existed since the defeat of Henry the Lion, intensified to the point that King Henry VI was forced to intervene while he was traveling through the region during a military campaign against Poland. Henry decided to call a diet in Erfurt, where he was staying, to mediate the situation between the two and invited a number of other figures to the negotiations.


title: Erfurt latrine disaster

text: All of the nobles across the Holy Roman Empire were invited to the meeting, and many arrived on 25 July to attend. Just as the assembly began, the wooden floor of the deanery, in which the nobles were sitting, broke under the stress, and people fell down through the first floor into the latrine in the cellar. About 60 people died, including Count Gozmar III of Ziegenhain, Count Friedrich I of , Burgrave Friedrich I of , Count , Count , Burgmeister Breuer of Wartschitt and Beringer of Meldingen. King Henry was said to have survived only because he sat in an alcove with a stone floor.


title: Java (software platform)

text: Java is a set of computer software and specifications developed by James Gosling at Sun Microsystems, which was later acquired by the Oracle Corporation, that provides a system for developing application software and deploying it in a cross-platform computing environment. Java is used in a wide variety of computing platforms from embedded devices and mobile phones to enterprise servers and supercomputers. Java applets, which are less common than standalone Java applications, were commonly run in secure, sandboxed environments to provide many features of native applications through being embedded in HTML pages.


title: Java (software platform)

text: Writing in the Java programming language is the primary way to produce code that will be deployed as byte code in a Java virtual machine (JVM); byte code compilers are also available for other languages, including Ada, JavaScript, Python, and Ruby. In addition, several languages have been designed to run natively on the JVM, including Clojure, Groovy, and Scala. Java syntax borrows heavily from C and C++, but object-oriented features are modeled after Smalltalk and Objective-C. Java eschews certain low-level constructs such as pointers and has a very simple memory model where objects are allocated on the heap (while some implementations e.g. all currently supported by Oracle, may use escape analysis optimization to allocate on the stack instead) and all variables of object types are references. Memory management is handled through integrated automatic garbage collection performed by the JVM.


title: Java (software platform)

text: On November 13, 2006, Sun Microsystems made the bulk of its implementation of Java available under the GNU General Public License (GPL).


title: Java (software platform)

text: The latest version is Java 19, released in September 2022, while Java 17, the latest long-term support (LTS), was released in September 2021. As an open source platform, Java has many distributors, including Amazon, IBM, Azul Systems, and AdoptOpenJDK. Distributions include Amazon Corretto, Zulu, AdoptOpenJDK, and Liberica. Regarding Oracle, it distributes Java 8, and also makes available e.g. Java 11, both also currently supported LTS versions. Oracle (and others) "highly recommend that you uninstall older versions of Java" than Java 8, because of serious risks due to unresolved security issues. Since Java 9 (as well as versions 10-16, and 18-19) are no longer supported, Oracle advises its users to "immediately transition" to a supported version. Oracle released the last free-for-commercial-use public update for the legacy Java 8 LTS in January 2019, and will continue to support Java 8 with public updates for personal use indefinitely. Oracle extended support for Java 6 ended in December 2018.


title: Java (software platform)

text: The Java platform is a suite of programs that facilitate developing and running programs written in the Java programming language. A Java platform includes an execution engine (called a virtual machine), a compiler and a set of libraries; there may also be additional servers and alternative libraries that depend on the requirements. Java platforms have been implemented for a wide variety of hardware and operating systems with a view to enable Java programs to run identically on all of them. Different platforms target different classes of device and application domains:


title: Java (software platform)

text: The Java platform consists of several programs, each of which provides a portion of its overall capabilities. For example, the Java compiler, which converts Java source code into Java bytecode (an intermediate language for the JVM), is provided as part of the Java Development Kit (JDK). The Java Runtime Environment (JRE), complementing the JVM with a just-in-time (JIT) compiler, converts intermediate bytecode into native machine code on the fly. The Java platform also includes an extensive set of libraries.


title: Java (software platform)

text: The essential components in the platform are the Java language compiler, the libraries, and the runtime environment in which Java intermediate bytecode executes according to the rules laid out in the virtual machine specification.


title: Java (software platform)

text: The heart of the Java platform is the "virtual machine" that executes Java bytecode programs. This bytecode is the same no matter what hardware or operating system the program is running under. However, new versions, such as for Java 10 (and earlier), have made small changes, meaning the bytecode is in general only forward compatible. There is a JIT (Just In Time) compiler within the "Java Virtual Machine", or JVM. The JIT compiler translates the Java bytecode into native processor instructions at run-time and caches the native code in memory during execution.


title: Java (software platform)

text: The use of bytecode as an intermediate language permits Java programs to run on any platform that has a virtual machine available. The use of a JIT compiler means that Java applications, after a short delay during loading and once they have "warmed up" by being all or mostly JIT-compiled, tend to run about as fast as native programs.


title: Java (software platform)

text: Since JRE version 1.2, Sun's JVM implementation has included a just-in-time compiler instead of an interpreter.


title: Java (software platform)

text: Although Java programs are cross-platform or platform independent, the code of the Java Virtual Machines (JVM) that execute these programs is not. Every supported operating platform has its own JVM.


title: Java (software platform)

text: In most modern operating systems (OSs), a large body of reusable code is provided to simplify the programmer's job. This code is typically provided as a set of dynamically loadable libraries that applications can call at runtime. Because the Java platform is not dependent on any specific operating system, applications cannot rely on any of the pre-existing OS libraries. Instead, the Java platform provides a comprehensive set of its own standard class libraries containing many of the same reusable functions commonly found in modern operating systems. Most of the system library is also written in Java. For instance, the Swing library paints the user interface and handles the events itself, eliminating many subtle differences between how different platforms handle components.


title: Java (software platform)

text: The Java class libraries serve three purposes within the Java platform. First, like other standard code libraries, the Java libraries provide the programmer a well-known set of functions to perform common tasks, such as maintaining lists of items or performing complex string parsing. Second, the class libraries provide an abstract interface to tasks that would normally depend heavily on the hardware and operating system. Tasks such as network access and file access are often heavily intertwined with the distinctive implementations of each platform. The codice_1 and codice_2 libraries implement an abstraction layer in native OS code, then provide a standard interface for the Java applications to perform those tasks. Finally, when some underlying platform does not support all of the features a Java application expects, the class libraries work to gracefully handle the absent components, either by emulation to provide a substitute, or at least by providing a consistent way to check for the presence of a specific feature.


title: Java (software platform)

text: The word "Java", alone, usually refers to Java programming language that was designed for use with the Java platform. Programming languages are typically outside of the scope of the phrase "platform", although the Java programming language was listed as a core part of the Java platform before Java 7. The language and runtime were therefore commonly considered a single unit. However, an effort was made with the Java 7 specification to more clearly treat the Java language and the Java Virtual Machine as separate entities, so that they are no longer considered a single unit.


title: Java (software platform)

text: Third parties have produced many compilers or interpreters that target the JVM. Some of these are for existing languages, while others are for extensions to the Java language. These include:


title: Java (software platform)

text: The success of Java and its write once, run anywhere concept has led to other similar efforts, notably the .NET Framework, appearing since 2002, which incorporates many of the successful aspects of Java. .NET was built from the ground-up to support multiple programming languages, while the Java platform was initially built to support only the Java language, although many other languages have been made for JVM since. Like Java, .NET languages compile to byte code and are executed by the Common


title: Java (software platform)

text: Language Runtime (CLR), which is similar in purpose to the JVM. Like the JVM, the CLR provides memory management through automatic garbage collection, and allows .NET byte code to run on multiple operating systems.


title: Java (software platform)

text: .NET included a Java-like language first named J++, then called Visual J# that was incompatible with the Java specification. It was discontinued 2007, and support for it ended in 2015.


title: Java (software platform)

text: The "Java Development Kit" ("JDK") is a Sun product aimed at Java developers. Since the introduction of Java, it has been by far the most widely used Java software development kit (SDK). It contains a Java compiler, a full copy of the Java Runtime Environment (JRE), and many other important development tools.


title: Java (software platform)

text: The Java Runtime Environment (JRE) released by Oracle is a freely available software distribution containing a stand-alone JVM (HotSpot), the Java standard library (Java Class Library), a configuration tool, and—until its discontinuation in JDK 9—a browser plug-in. It is the most common Java environment installed on personal computers in the laptop and desktop form factor. Mobile phones including feature phones and early smartphones that ship with a JVM are most likely to include a JVM meant to run applications targeting Micro Edition of the Java platform. Meanwhile, most modern smartphones, tablet computers, and other handheld PCs that run Java apps are most likely to do so through support of the Android operating system, which includes an open source virtual machine incompatible with the JVM specification. (Instead, Google's Android development tools take Java programs as input and output Dalvik bytecode, which is the native input format for the virtual machine on Android devices.)


title: Java (software platform)

text: The last Critical Path Update version of JRE with an Oracle BCL Agreement was 8u201 and, the last Patch Set Update version with the same license was 8u202. The last Oracle JRE implementation, regardless of its licensing scheme, was 9.0.4.Since Java Platform SE 9, the whole platform also was grouped into modules. The modularization of Java SE implementations allows developers to bundle their applications together with all the modules used by them, instead of solely relying on the presence of a suitable Java SE implementation in the user device.


title: Java (software platform)

text: The JVM specification gives a lot of leeway to implementors regarding the implementation details. Since Java 1.3, JRE from Oracle contains a JVM called HotSpot. It has been designed to be a high-performance JVM.


title: Java (software platform)

text: To speed-up code execution, HotSpot relies on just-in-time compilation. To speed-up object allocation and garbage collection, HotSpot uses generational heap.


title: Java (software platform)

text: The "permanent generation" (or "permgen") was used for class definitions and associated metadata prior to Java 8. Permanent generation was not part of the heap. The "permanent generation" was removed from Java 8.


title: Java (software platform)

text: Originally there was no permanent generation, and objects and classes were stored together in the same area. But as class unloading occurs much more rarely than objects are collected, moving class structures to a specific area allowed significant performance improvements.


title: Java (software platform)

text: Oracle's JRE is installed on a large number of computers. End users with an out-of-date version of JRE therefore are vulnerable to many known attacks. This led to the widely shared belief that Java is inherently insecure. Since Java 1.7, Oracle's JRE for Windows includes automatic update functionality.


title: Java (software platform)

text: Before the discontinuation of the Java browser plug-in, any web page might have potentially run a Java applet, which provided an easily accessible attack surface to malicious web sites. In 2013 Kaspersky Labs reported that the Java plug-in was the method of choice for computer criminals. Java exploits are included in many exploit packs that hackers deploy onto hacked web sites. Java applets were removed in Java 11, released on September 25, 2018.


title: Java (software platform)

text: The Java platform and language began as an internal project at Sun Microsystems in December 1990, providing an alternative to the C++/C programming languages. Engineer Patrick Naughton had become increasingly frustrated with the state of Sun's C++ and C application programming interfaces (APIs) and tools, as well as with the way the NeWS project was handled by the organization. Naughton informed Scott McNealy about his plan of leaving Sun and moving to NeXT; McNealy asked him to pretend he was God and send him an e-mail explaining how to fix the company. Naughton envisioned the creation of a small team that could work autonomously without the bureaucracy that was stalling other Sun projects. McNealy forwarded the message to other important people at Sun, and the "Stealth Project" started.


title: Java (software platform)

text: The Stealth Project was soon renamed to the "Green Project", with James Gosling and Mike Sheridan joining Naughton. Together with other engineers, they began work in a small office on Sand Hill Road in Menlo Park, California. They aimed to develop new technology for programming next-generation smart appliances, which Sun expected to offer major new opportunities.


title: Java (software platform)

text: The team originally considered using C++, but rejected it for several reasons. Because they were developing an embedded system with limited resources, they decided that C++ needed too much memory and that its complexity led to developer errors. The language's lack of garbage collection meant that programmers had to manually manage system memory, a challenging and error-prone task. The team also worried about the C++ language's lack of portable facilities for security, distributed programming, and threading. Finally, they wanted a platform that would port easily to all types of devices.


title: Java (software platform)

text: Bill Joy had envisioned a new language combining Mesa and C. In a paper called "Further", he proposed to Sun that its engineers should produce an object-oriented environment based on C++. Initially, Gosling attempted to modify and extend C++ (a proposed development that he referred to as "C++ ++ --") but soon abandoned that in favor of creating a new language, which he called "Oak", after the tree that stood just outside his office.


title: Java (software platform)

text: By the summer of 1992, the team could demonstrate portions of the new platform, including the Green OS, the Oak language, the libraries, and the hardware. Their first demonstration, on September 3, 1992, focused on building a personal digital assistant (PDA) device named "Star7" that had a graphical interface and a smart agent called "Duke" to assist the user. In November of that year, the Green Project was spun off to become "Firstperson", a wholly owned subsidiary of Sun Microsystems, and the team relocated to Palo Alto, California. The Firstperson team had an interest in building highly interactive devices, and when Time Warner issued a request for proposal (RFP) for a set-top box, Firstperson changed their target and responded with a proposal for a set-top box platform. However, the cable industry felt that their platform gave too much control to the user, so Firstperson lost their bid to SGI. An additional deal with The 3DO Company for a set-top box also failed to materialize. Unable to generate interest within the television industry, the company was rolled back into Sun.


title: Java (software platform)

text: In June and July 1994 after three days of brainstorming with John Gage (the Director of Science for Sun), Gosling, Joy, Naughton, Wayne Rosing, and Eric Schmidt the team re-targeted the platform for the World Wide Web. They felt that with the advent of graphical web browsers like Mosaic the Internet could evolve into the same highly interactive medium that they had envisioned for cable TV. As a prototype, Naughton wrote a small browser, WebRunner (named after the movie "Blade Runner"), renamed HotJava in 1995.


title: Java (software platform)

text: Sun renamed the Oak language to "Java" after a trademark search revealed that Oak Technology used the name "Oak". Sun priced Java licenses below cost to gain market share. Although Java 1.0a became available for download in 1994, the first public release of Java, Java 1.0a2 with the HotJava browser, came on May 23, 1995, announced by Gage at the SunWorld conference. Accompanying Gage's announcement, Marc Andreessen, Executive Vice President of Netscape Communications Corporation, unexpectedly announced that Netscape browsers would include Java support. On January 9, 1996, Sun Microsystems formed the JavaSoft group to develop the technology.


title: Java (software platform)

text: While the so-called Java applets for web browsers no longer are the most popular use of Java (with it e.g. more used server-side) or the most popular way to run code client-side (JavaScript took over as more popular), it still is possible to run Java (or other JVM-languages such as Kotlin) in web browsers, even after JVM-support has been dropped from them, using e.g. TeaVM.


title: Java (software platform)

text: The Java language has undergone several changes since the release of JDK (Java Development Kit) 1.0 on January 23, 1996, as well as numerous additions of classes and packages to the standard library. Since J2SE 1.4 the Java Community Process (JCP) has governed the evolution of the Java Language. The JCP uses "Java Specification Requests" (JSRs) to propose and specify additions and changes to the Java platform. The "Java Language Specification" (JLS) specifies the language; changes to the JLS are managed under JSR 901.


title: Java (software platform)

text: Sun released "JDK 1.1" on February 19, 1997. Major additions included an extensive retooling of the AWT event model, inner classes added to the language, JavaBeans and JDBC.


title: Java (software platform)

text: "J2SE 1.2" (December 8, 1998) – Codename "Playground". This and subsequent releases through J2SE 5.0 were rebranded "Java 2" and the version name "J2SE" (Java 2 Platform, Standard Edition) replaced JDK to distinguish the base platform from J2EE (Java 2 Platform, Enterprise Edition) and J2ME (Java 2 Platform, Micro Edition). Major additions included reflection, a collections framework, Java IDL (an interface description language implementation for CORBA interoperability), and the integration of the Swing graphical API into the core classes. A Java Plug-in was released, and Sun's JVM was equipped with a JIT compiler for the first time.


title: Java (software platform)

text: "J2SE 1.3" (May 8, 2000) – Codename "Kestrel". Notable changes included the bundling of the HotSpot JVM (the HotSpot JVM was first released in April, 1999 for the J2SE 1.2 JVM), JavaSound, Java Naming and Directory Interface (JNDI) and Java Platform Debugger Architecture (JPDA).


title: Java (software platform)

text: "J2SE 1.4" (February 6, 2002) – Codename "Merlin". This became the first release of the Java platform developed under the Java Community Process as JSR 59. Major changes included regular expressions modeled after Perl, exception chaining, an integrated XML parser and XSLT processor (JAXP), and Java Web Start.


title: Java (software platform)

text: "J2SE 5.0" (September 30, 2004) – Codename "Tiger". It was originally numbered 1.5, which is still used as the internal version number. Developed under JSR 176, Tiger added several significant new language features including the for-each loop, generics, autoboxing and var-args.


title: Java (software platform)

text: "Java SE 6" (December 11, 2006) – Codename "Mustang". It was bundled with a database manager and facilitates the use of scripting languages with the JVM (such as JavaScript using Mozilla's Rhino engine). As of this version, Sun replaced the name "J2SE" with "Java SE" and dropped the ".0" from the version number. Other major changes include support for pluggable annotations (JSR 269), many GUI improvements, including native UI enhancements to support the look and feel of Windows Vista, and improvements to the Java Platform Debugger Architecture (JPDA) & JVM Tool Interface for better monitoring and troubleshooting.


title: Java (software platform)

text: "Java SE 7" (July 28, 2011) – Codename "Dolphin". This version developed under JSR 336. It added many small language changes including strings in switch, try-with-resources and type inference for generic instance creation. The JVM was extended with support for dynamic languages, while the class library was extended among others with a join/fork framework, an improved new file I/O library and support for new network protocols such as SCTP. Java 7 Update 76 was released in January 2015, with expiration date April 14, 2015.


title: Java (software platform)

text: In June 2016, after the last public update of Java 7, "remotely exploitable" security bugs in Java 6, 7, and 8 were announced.


title: Java (software platform)

text: "Java SE 8" (March 18, 2014) Codename "Kenai". Notable changes include language-level support for lambda expressions (closures) and default methods, the Project Nashorn JavaScript runtime, a new Date and Time API inspired by Joda Time, and the removal of PermGen. This version is not officially supported on the Windows XP platform. However, due to the end of Java 7's lifecycle it is the recommended version for XP users. Previously, only an unofficial manual installation method had been described for Windows XP SP3. It refers to JDK8, the developing platform for Java that also includes a fully functioning Java Runtime Environment. Java 8 is supported on Windows Server 2008 R2 SP1, Windows Vista SP2 and Windows 7 SP1, Ubuntu 12.04 LTS and higher (and some other OSes).


title: Java (software platform)

text: "Java SE 9" and "10" had higher system requirements, i.e. Windows 7 or Server 2012 (and web browser minimum certified is upped to Internet Explorer 11 or other web browsers), and Oracle dropped 32-bit compatibility for all platforms, i.e. only Oracle's "64-bit Java virtual machines (JVMs) are certified".


title: Java (software platform)

text: "Java SE 11" was released September 2018, the first LTS release since the rapid release model was adopted starting with version 9. For the first time, OpenJDK 11 represents the complete source code for the Java platform under the GNU General Public License, and while Oracle still dual-licenses it with an optional proprietary license, there are no code differences nor modules unique to the proprietary-licensed version. Java 11 features include two new garbage collector implementations, Flight Recorder to debug deep issues, a new HTTP client including WebSocket support.


title: Java (software platform)

text: In addition to language changes, significant changes have been made to the Java class library over the years, which has grown from a few hundred classes in JDK 1.0 to over three thousand in J2SE 5.0. Entire new APIs, such as Swing and Java 2D, have evolved, and many of the original JDK 1.0 classes and methods have been deprecated.


title: Java (software platform)

text: According to Oracle in 2010, the Java Runtime Environment was found on over 850 million PCs. Microsoft has not bundled a Java Runtime Environment (JRE) with its operating systems since Sun Microsystems sued Microsoft for adding Windows-specific classes to the bundled Java runtime environment, and for making the new classes available through Visual J++. Apple no longer includes a Java runtime with OS X as of version 10.7, but the system prompts the user to download and install it the first time an application requiring the JRE is launched. Many Linux distributions include the OpenJDK runtime as the default virtual machine, negating the need to download the proprietary Oracle JRE.


title: Java (software platform)

text: Some Java applications are in fairly widespread desktop use, including the NetBeans and Eclipse integrated development environments, and file sharing clients such as LimeWire and Vuze. Java is also used in the MATLAB mathematics programming environment, both for rendering the user interface and as part of the core system. Java provides cross platform user interface for some high end collaborative applications such as Lotus Notes.


title: Java (software platform)

text: Oracle plans to first deprecate the separately installable Java browser plugin from the Java Runtime Environment in JDK 9 then remove it completely from a future release, forcing web developers to use an alternative technology.


title: Java (software platform)

text: When Sun announced that Java SE and Java ME would be released under a free software license (the GNU General Public License), they released the Duke graphics under the free BSD license at the same time. A new Duke personality is created every year. For example, in July 2011 "Future Tech Duke" included a bigger nose, a jetpack, and blue wings.


title: Java (software platform)

text: The source code for Sun's implementations of Java (i.e. the de facto reference implementation) has been available for some time, but until recently, the license terms severely restricted what could be done with it without signing (and generally paying for) a contract with Sun. As such these terms did not satisfy the requirements of either the Open Source Initiative or the Free Software Foundation to be considered open source or free software, and Sun Java was therefore a proprietary platform.


title: Java (software platform)

text: While several third-party projects (e.g. GNU Classpath and Apache Harmony) created free software partial Java implementations, the large size of the Sun libraries combined with the use of clean room methods meant that their implementations of the Java libraries (the compiler and VM are comparatively small and well defined) were incomplete and not fully compatible. These implementations also tended to be far less optimized than Sun's.


title: Java (software platform)

text: Sun announced in JavaOne 2006 that Java would become free and open source software, and on October 25, 2006, at the Oracle OpenWorld conference, Jonathan I. Schwartz said that the company was set to announce the release of the core Java Platform as free and open source software within 30 to 60 days.


title: Java (software platform)

text: Sun released the Java HotSpot virtual machine and compiler as free software under the GNU General Public License on November 13, 2006, with a promise that the rest of the JDK (that includes the JRE) would be placed under the GPL by March 2007 ("except for a few components that Sun does not have the right to publish in distributable source form under the GPL"). According to Richard Stallman, this would mean an end to the "Java trap". Mark Shuttleworth called the initial press announcement, "A real milestone for the free software community".


title: Java (software platform)

text: Sun released the source code of the Class library under GPL on May 8, 2007, except some limited parts that were licensed by Sun from third parties who did not want their code to be released under a free software and open-source license. Some of the encumbered parts turned out to be fairly key parts of the platform such as font rendering and 2D rasterising, but these were released as open-source later by Sun (see OpenJDK Class library).


title: Java (software platform)

text: Sun's goal was to replace the parts that remain proprietary and closed-source with alternative implementations and make the class library completely free and open source. In the meantime, a third-party project called IcedTea created a completely free and highly usable JDK by replacing encumbered code with either stubs or code from GNU Classpath. However OpenJDK has since become buildable without the encumbered parts (from OpenJDK 6 b10) and has become the default runtime environment for most Linux distributions.


title: Java (software platform)

text: In June 2008, it was announced that IcedTea6 (as the packaged version of OpenJDK on Fedora 9) has passed the Technology Compatibility Kit tests and can claim to be a fully compatible Java 6 implementation.


title: Java (software platform)

text: Because OpenJDK is under the GPL, it is possible to redistribute a custom version of the JRE directly with software applications, rather than requiring the enduser (or their sysadmin) to download and install the correct version of the proprietary Oracle JRE onto each of their systems themselves.


title: Java (software platform)

text: In most cases, Java support is unnecessary in Web browsers, and security experts recommend that it not be run in a browser unless absolutely necessary. It was suggested that, if Java is required by a few Web sites, users should have a separate browser installation specifically for those sites.


title: Java (software platform)

text: When generics were added to Java 5.0, there was already a large framework of classes (many of which were already deprecated), so generics were chosen to be implemented using erasure to allow for "migration compatibility" and re-use of these existing classes. This limited the features that could be provided by this addition as compared to some other languages. The addition of type wildcards made Java unsound.


title: Java (software platform)

text: Java lacks native unsigned integer types. Unsigned data are often generated from programs written in C and the lack of these types prevents direct data interchange between C and Java. Unsigned large numbers are also used in many numeric processing fields, including cryptography, which can make Java less convenient to use for these tasks.


title: Java (software platform)

text: Although it is possible to partially circumvent this problem with conversion code and using larger data types, it makes using Java cumbersome for handling the unsigned data. While a 32-bit signed integer may be used to hold a 16-bit unsigned value with relative ease, a 32-bit unsigned value would require a 64-bit signed integer. Additionally, a 64-bit unsigned value cannot be stored using any integer type in Java because no type larger than 64 bits exists in the Java language. If abstracted using functions, function calls become necessary for many operations which are native to some other languages. Alternatively, it is possible to use Java's signed integers to emulate unsigned integers of the same size, but this requires detailed knowledge of complex bitwise operations.


title: Java (software platform)

text: While Java's floating point arithmetic is largely based on IEEE 754 ("Standard for Binary Floating-Point Arithmetic"), certain features are not supported even when using the codice_3 modifier, such as Exception Flags and Directed Roundings capabilities mandated by IEEE Standard 754. Additionally, the extended precision floating-point types permitted in 754 and present in many processors are not permitted in Java.


title: Java (software platform)

text: In the early days of Java (before the HotSpot VM was implemented in Java 1.3 in 2000) there were some criticisms of performance. Benchmarks typically reported Java as being about 50% slower than C (a language which compiles to native code).


title: Java (software platform)

text: Java's performance has improved substantially since the early versions. Performance of JIT compilers relative to native compilers has in some optimized tests been shown to be quite similar.


title: Java (software platform)

text: Java bytecode can either be interpreted at run time by a virtual machine, or it can be compiled at load time or runtime into native code which runs directly on the computer's hardware. Interpretation is slower than native execution, and compilation at load time or runtime has an initial performance penalty for the compilation. Modern performant JVM implementations all use the compilation approach, so after the initial startup time the performance is equivalent to native code.


title: Java (software platform)

text: The Java platform provides a security architecture which is designed to allow the user to run untrusted bytecode in a "sandboxed" manner to protect against malicious or poorly written software. This "sandboxing" feature is intended to protect the user by restricting access to certain platform features and APIs which could be exploited by malware, such as accessing the local filesystem, running arbitrary commands, or accessing communication networks.


title: Java (software platform)

text: In recent years, researchers have discovered numerous security flaws in some widely used Java implementations, including Oracle's, which allow untrusted code to bypass the sandboxing mechanism, exposing users to malicious attacks. These flaws affect only Java applications which execute arbitrary untrusted bytecode, such as web browser plug-ins that run Java applets downloaded from public websites. Applications where the user trusts, and has full control over, all code that is being executed are unaffected.


title: Java (software platform)

text: On August 31, 2012, Java 6 and 7 (both supported back then) on Microsoft Windows, OS X, and Linux were found to have a serious security flaw that allowed a remote exploit to take place by simply loading a malicious web page. was later found to be flawed as well.


title: Java (software platform)

text: On January 10, 2013, three computer specialists spoke out against Java, telling Reuters that it was not secure and that people should disable Java. Jaime Blasco, Labs Manager with AlienVault Labs, stated that "Java is a mess. It's not secure. You have to disable it."


title: Java (software platform)

text: This vulnerability affects and it is unclear if it affects , so it is suggested that consumers disable it. Security alerts from Oracle announce schedules of critical security-related patches to Java.


title: Java (software platform)

text: On January 14, 2013, security experts said that the update still failed to protect PCs from attack. This exploit hole prompted a response from the United States Department of Homeland Security encouraging users to disable or uninstall Java. Apple blacklisted Java in limited order for all computers running its OS X operating system through a virus protection program.


title: Java (software platform)

text: In 2014 and responding to then-recent Java security and vulnerability issues, security blogger Brian Krebs has called for users to remove at least the Java browser plugin and also the entire software. "I look forward to a world without the Java plugin (and to not having to remind readers about quarterly patch updates) but it will probably be years before various versions of this plugin are mostly removed from end-user systems worldwide." "Once promising, it has outlived its usefulness in the browser, and has become a nightmare that delights cyber-criminals at the expense of computer users." "I think everyone should uninstall Java from all their PCs and Macs, and then think carefully about whether they need to add it back. If you are a typical home user, you can probably do without it. If you are a business user, you may not have a choice."


title: Java (software platform)

text: The Oracle-distributed Java runtime environment has a history of bundling sponsored software to be installed by default during installation and during the updates which roll out every month or so. This includes the "Ask.com toolbar" that will redirect browser searches to ads and "McAfee Security Scan Plus". These offers can be blocked through a setting in the Java Control Panel, although this is not obvious. This setting is located under the "Advanced" tab in the Java Control Panel, under the "Miscellaneous" heading, where the option is labelled as an option to suppress "sponsor offers".


title: Java (software platform)

text: Java has yet to release an automatic updater that does not require user intervention and administrative rights unlike Google Chrome and Flash player.


title: Sirolimus

text: Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin kinase (mTOR) inhibitor that inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2).


title: Sirolimus

text: It is produced by the bacterium "Streptomyces hygroscopicus" and was isolated for the first time in 1972, from samples of "Streptomyces hygroscopicus" found on Easter Island. The compound was originally named rapamycin after the native name of the island, Rapa Nui. Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the U.S. Food and Drug Administration (FDA) in September 1999.


title: Sirolimus

text: Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis (LAM).


title: Sirolimus

text: Sirolimus (Fyarro), as protein-bound particles, is indicated for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).


title: Sirolimus

text: The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use. In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus. A 2019 cohort study of nearly 10,000 lung transplant recipients in the US demonstrated significantly improved long-term survival using sirolimus + tacrolimus instead of mycophenolate mofetil + tacrolimus for immunosuppressive therapy starting at one year after transplant.


title: Sirolimus

text: Sirolimus can also be used alone, or in conjunction with a calcineurin inhibitor (such as tacrolimus), and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimens. Impaired wound healing and thrombocytopenia are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.


title: Sirolimus

text: In May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease. LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2). Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors. Sirolimus blocks this pathway.


title: Sirolimus

text: The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.


title: Sirolimus

text: While sirolimus was considered for treatment of LAM, it received orphan drug designation status because LAM is a rare condition.


title: Sirolimus

text: The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher. However, this kind of stent may also increase the risk of vascular thrombosis.


title: Sirolimus

text: Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels. Sirolimus is a relatively new medical therapy for the treatment of vascular malformations in recent years, sirolimus has emerged as a new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for "proliferative" vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent.


title: Sirolimus

text: Sirolimus has been used as a topical treatment of angiofibromas with tuberous sclerosis complex (TSC). Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation.


title: Sirolimus

text: The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.


title: Sirolimus

text: The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.


title: Sirolimus

text: The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:


title: Sirolimus

text: While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin. Sirolimus treatment may additionally increase the risk of type 2 diabetes. In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.


title: Sirolimus

text: Lung toxicity is a serious complication associated with sirolimus therapy, especially in the case of lung transplants. The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway. The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.


title: Sirolimus

text: There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.


title: Sirolimus

text: Sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma. In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors, and lower than under placebo.


title: Sirolimus

text: Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a body mass index in excess of 30 kg/m (classified as obese).


title: Sirolimus

text: Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.


title: Sirolimus

text: Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.


title: Sirolimus

text: The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).