title: Carli Lloyd

text: During the championship match of the CONCACAF Women's Olympic Qualifying Tournament, Lloyd scored the U.S.' only goal during stoppage time on a free-kick. The U.S. eventually defeated Canada 6–5 in penalty kicks. She scored two goals during the 2008 Olympics: the game-winning goal in the team's 1–0 defeat of Japan during the tournament's group stage and another game-winning goal in extra time against Brazil during the final helping the U.S. win gold.


title: Carli Lloyd

text: Lloyd was named the 2008 U.S. Soccer Athlete of the Year along with Tim Howard. She was on the starting lineup in all 35 games in which she played in 2008, tying for the team lead in matches started during the year. Her 2,781 minutes on the pitch for the U.S. ranked third on the team in minutes played. Her nine goals and nine assists resulted in her best scoring year yet on the national team.


title: Carli Lloyd

text: In 2009, the U.S. national team competed in eight games, of which Lloyd was on the starting lineup in five. At the 2010 Algarve Cup, Lloyd scored the game-opening goal in the final helping the U.S. clinch the championship title after defeating Germany 3–2.


title: Carli Lloyd

text: Although she suffered a broken ankle in the fourth game of the 2010 WPS Season while playing for Sky Blue FC, she played in 15 matches for the United States in 2010, starting 14. Lloyd started all five games at the 2010 CONCACAF Women's World Cup Qualifying Tournament, scoring two goals, including the United States' lone goal during the championship match. She ended the tournament with five assists and was named the Player of the Match three times during the tournament. After the U.S. finished third at the tournament, they traveled to Italy to vie for a place at the 2011 FIFA Women's World Cup in the UEFA-CONCACAF play-off against Italy. Playing every minute of the series, Lloyd scored three goals with five assists during the series. She earned her 100th career cap during the second leg of the series.


title: Carli Lloyd

text: 2011 saw the U.S. team making preparations for the 2011 FIFA Women's World Cup and training starting with the Four Nations Tournament. Lloyd scored the lone goal for the U.S. in the opening match loss to Sweden. In the championship match, the U.S. defeated Canada 2–0 with Lloyd scoring the first goal and being named Player of the Match.


title: Carli Lloyd

text: At the 2011 Algarve Cup, Lloyd scored three goals including the first goal in the championship match; subsequently named best goal for the tournament. She was named player of the match for the 2nd time in the tournament. The team won the cup, making it their eighth title win.


title: Carli Lloyd

text: At the 2011 FIFA Women's World Cup, Lloyd scored the final goal in a 3–0 win against Colombia for her first World Cup goal. Throughout the tournament, she tallied an assist, a goal, and one successful penalty kick in the shootout against Brazil to send the U.S. to the semi-finals vs. France. In the World Cup final, after finishing the game tied 2–2 the U.S. went on to penalty kicks with Japan. Along with two teammates who failed to convert their penalty kicks, Lloyd mishit the ball over the crossbar. The U.S. won the silver medal at the tournament.


title: Carli Lloyd

text: The national team opened 2012 with the Olympic Qualifiers in Vancouver, British Columbia, Canada. The U.S. was placed in Group B with the Dominican Republic, Guatemala, and Mexico. In the first match, the United States routed the Dominican Republic by a score of 14–0 with Lloyd tallying one goal and one assist. In the second match, the U.S. again defeated Guatemala 13–0 with Lloyd again finding the back of the net and providing an assist.


title: Carli Lloyd

text: The game to win the group and thus play the second place team from Group A occurred between the U.S. and Mexico. The U.S. was previously defeated 2–1 by Mexico during the 2010 CONCACAF Women's Gold Cup. This time, the U.S. beat Mexico 4–0 with Lloyd netting her first career hat trick. She was subsequently named player of the match.


title: Carli Lloyd

text: In the semi-final, the U.S. faced Costa Rica. During the second half, the U.S. scored two goals, the second coming from Lloyd. The U.S. beat Costa Rica 3–0 with Lloyd named player of the match for the second game in a row. During the final match against Canada, the U.S. defeated Canada at home 4–0 to move on to the Olympics as the CONCACAF champions. Lloyd finished the tournament with six goals and three assists and tied for the team lead in goals scored.


title: Carli Lloyd

text: At the 2012 Summer Olympics in London, Lloyd scored the go-ahead goal in the 56th minute of the team's opening match against France, to boost the U.S. to a 3–2 lead; the match ended with a final score of 4–2. She scored her second goal of the tournament against Colombia during the group stage.


title: Carli Lloyd

text: During the Olympic gold medal match against Japan, played at London's Wembley Stadium, Lloyd scored both American goals in the team's 2–1 victory. Her four goals in the tournament tied for the second highest on the U.S. squad. She is the only player (of either gender) in history to score the game-winning goal in two separate Olympic gold medal matches; her first occurred during the Beijing 2008 final against Brazil.


title: Carli Lloyd

text: After scoring her 46th international goal in the 13th minute of a friendly against New Zealand in October 2013, Lloyd became the highest-scoring midfielder in the team's history, passing Julie Foudy, who finished her career with 45 goals.


title: Carli Lloyd

text: In April 2015, Lloyd was named by head coach Jill Ellis to the 23-player roster for the 2015 FIFA Women's World Cup in Canada. Lloyd captained the team during four of the team's matches, including the quarterfinal against China, in which she scored the winning goal on her 200th cap, semi-final against Germany and final against Japan, and scored six goals during the tournament, finishing the tournament on a four-game goalscoring streak that spanned the knockout stage and that culminated in a hat trick in the game's opening 16 minutes during the final against Japan. The last goal was hailed by Reuters as "one of the most remarkable goals ever witnessed in a Women's World Cup", and featured Lloyd catching Japanese goalkeeper Ayumi Kaihori off her line and chipping her virtually from the halfway line.


title: Carli Lloyd

text: For her efforts in leading the United States to a record third World Cup title, and first since 1999, she won the Golden Ball as the best player of the tournament. While Lloyd's six goals were enough to match Celia Sasic as the tournament's top scorer, Sasic won the Golden Boot for playing fewer minutes and Lloyd was awarded the Silver Boot. Lloyd also became the first woman to score a hat trick in a World Cup final and the first player, male or female, to do so since Geoff Hurst did so for England against West Germany at Wembley in 1966. Only one player has since replicated the feat – Kylian Mbappé for France against Argentina in Lusail, Qatar in 2022. Furthermore, her third goal earned her a nomination for the Puskás Award, FIFA's annual award for Goal of the Year.


title: Carli Lloyd

text: Lloyd scored in her first two games of the 2019 FIFA Women's World Cup; one against Thailand and two against Chile. Hence, she became the first player to score in six straight Women's World Cup matches.


title: Carli Lloyd

text: On April 10, 2021, Lloyd earned her 300th cap in a friendly match against Sweden to become the third player to achieve that feat after Kristine Lilly and Christie Pearce. On June 14, 2021, she became the oldest player at 38 years and 332 days to score for the United States in a 4–0 win over Jamaica at the BBVA Stadium, and thereby beating the record previously held by Kristine Lilly (38 years, 264 days).


title: Carli Lloyd

text: On August 5, 2021, she scored twice in a 4–3 win over Australia in the bronze medal match of the 2020 Summer Olympics, to set the U.S. women's record for most Olympic goals, 10 goals in total, surpassing Abby Wambach. Following the Olympics, Lloyd announced she would be retiring from the national team in 2021.


title: Carli Lloyd

text: In early 2022, she partnered with Teqball USA and one of her retirement plans is to make Teqball an Olympic sport by 2028. She also developed CL10 Soccer Clinic, a program  to help people improve their soccer skills. In October 2022, she co-conducted the draw for the 2023 Women's World Cup in Australia and New Zealand held at the Aotea Centre in Auckland.


title: Carli Lloyd

text: Although she was criticised for being inconsistent at the beginning of career, and for losing possession too easily, Lloyd later developed into one of the best players in the world, and is highly regarded for her outstanding determination, mental strength, and work-ethic. A tenacious, energetic, and hard-working player, she also is known for her control, technique, and passing accuracy, and is capable of aiding her team both defensively and offensively, due to her stamina, strength, and tackling, as well as her ability to get into good attacking positions, and either score goals or create chances for teammates. These abilities, coupled with her tactical versatility, enable her to be deployed in several midfield positions; although she began her career in the centre, as a defensive midfielder, she is most comfortable when moved to a more advanced role, as an attacking midfielder behind the forwards. Lloyd has earned a reputation as a "clutch player", due to her tendency to score decisive goals. A powerful striker of the ball, she is capable of scoring from any position on the pitch, and can finish well both with her head and with her feet inside the area.


title: Carli Lloyd

text: Lloyd lives with her husband, golfer Brian Hollins, in Mount Laurel, New Jersey. They married on November 4, 2016, in Puerto Morelos, Mexico.


title: Carli Lloyd

text: Lloyd has had an endorsement deal with Nike for several years. In 2011, she was the focus of a promotional feature for the sports company entitled, "Pressure Makes Us: Carli Lloyd". Following the 2015 FIFA Women's World Cup, Lloyd starred in a commercial for Xfinity and signed an endorsement deal with Visa. In August 2015, she co-starred in a Nike commercial called "Snow Day" also featuring Rob Gronkowski and teammate Sydney Leroux. In April 2016, she was named brand ambassador for Lifeway Foods and appeared in a television commercial for Heineken the same year. She has a partnership with Whole Foods Market and appeared in a television commercial for United Airlines. In June 2016, she joined Michael Phelps in partnership deals with Krave Jerky. She also has endorsement deals with Beats by Dre, Kind, and NJM Insurance.


title: Carli Lloyd

text: Lloyd has been featured in "Glamour", "Shape", and "Sports Illustrated" magazines. She was on the covers of Howler Magazine and Sports Illustrated. In 2012, she appeared in an ESPN feature called "Title IX is Mine: USWNT". Lloyd has made appearances on numerous television shows including: "Good Morning America", "The Daily Show with Jon Stewart", "Live with Kelly and Michael", "The Today Show", "Late Night with Seth Meyers", "Fox and Friends", "Late Late Show with James Corden".


title: Carli Lloyd

text: Lloyd was featured along with her national teammates in the EA Sports' FIFA video game series in "FIFA 16", the first time women players were included in the game. In September 2015, she was ranked by EA Sports as the No. 1 women's player in the game.


title: Carli Lloyd

text: Following the United States' win at the 2015 FIFA Women's World Cup, Lloyd and her teammates became the first women's sports team to be honored with a ticker tape parade in New York City. Each player received a key to the city from Mayor Bill de Blasio. In October of the same year, the team was honored by President Barack Obama at the White House.


title: Cat-scratch disease

text: Cat-scratch disease (CSD) or felinosis is an infectious disease that most often results from a scratch or bite of a cat. Symptoms typically include a non-painful bump or blister at the site of injury and painful and swollen lymph nodes. People may feel tired, have a headache, or a fever. Symptoms typically begin within 3–14 days following infection.


title: Cat-scratch disease

text: Cat-scratch disease is caused by the bacterium "Bartonella henselae" which is believed to be spread by the cat's saliva. Young cats pose a greater risk than older cats. Occasionally dog scratches or bites may be involved. Diagnosis is generally based on symptoms. Confirmation is possible by blood tests.


title: Cat-scratch disease

text: The primary treatment is supportive. Antibiotics speed healing and are recommended in those with severe disease or immune problems. Recovery typically occurs within 4 months but can require a year. About 1 in 10,000 people are affected. It is more common in children.


title: Cat-scratch disease

text: Cat-scratch disease commonly presents as tender, swollen lymph nodes near the site of the inoculating bite or scratch or on the neck, and is usually limited to one side. This condition is referred to as regional lymphadenopathy and occurs 1–3 weeks after inoculation. Lymphadenopathy most commonly occurs in the axilla, arms, neck, or jaw, but may also occur near the groin or around the ear. A vesicle or an erythematous papule may form at the site of initial infection.


title: Cat-scratch disease

text: Most people also develop systemic symptoms such as malaise, decreased appetite, and aches. Other associated complaints include headache, chills, muscular pains, joint pains, arthritis, backache, and abdominal pain. It may take 7 to 14 days, or as long as two months, for symptoms to appear. Most cases are benign and self-limiting, but lymphadenopathy may persist for several months after other symptoms disappear. The disease usually resolves spontaneously, with or without treatment, in one month.


title: Cat-scratch disease

text: In rare situations, CSD can lead to the development of serious neurologic or cardiac sequelae such as meningoencephalitis, encephalopathy, seizures, or endocarditis. Endocarditis associated with "Bartonella" infection has a particularly high mortality. Parinaud's oculoglandular syndrome is the most common ocular manifestation of CSD, and is a granulomatous conjunctivitis with concurrent swelling of the lymph node near the ear. Optic neuritis or neuroretinitis is one of the atypical presentations.


title: Cat-scratch disease

text: People who are immunocompromised are susceptible to other conditions associated with "B. henselae" and "B. quintana", such as bacillary angiomatosis or bacillary peliosis. Bacillary angiomatosis is primarily a vascular skin lesion that may extend to bone or be present in other areas of the body. In the typical scenario, the patient has HIV or another cause of severe immune dysfunction. Bacillary peliosis is caused by "B. henselae" that most often affects people with HIV and other conditions causing severe immune compromise. The liver and spleen are primarily affected, with findings of blood-filled cystic spaces on pathology.


title: Cat-scratch disease

text: The cat was recognized as the natural reservoir of the disease in 1950 by Robert Debré. Kittens are more likely to carry the bacteria in their blood, so may be more likely to transmit the disease than adult cats. However, fleas serve as a vector for transmission of "B. henselae" among cats, and viable "B. henselae" are excreted in the feces of "Ctenocephalides felis", the cat flea. Cats could be infected with "B. henselae" through intradermal inoculation using flea feces containing "B. henselae".


title: Cat-scratch disease

text: As a consequence, a likely means of transmission of "B. henselae" from cats to humans may be inoculation with flea feces containing "B. henselae" through a contaminated cat scratch wound or by cat saliva transmitted in a bite. Ticks can also act as vectors and occasionally transmit the bacteria to humans. Combined clinical and PCR-based research has shown that other organisms can transmit Bartonella, including spiders. Cryptic "Bartonella" infection may be a much larger problem than previously thought, constituting an unrecognized occupational health hazard of veterinarians.


title: Cat-scratch disease

text: The best diagnostic method available is polymerase chain reaction, which has a sensitivity of 43-76% and a specificity (in one study) of 100%. The Warthin–Starry stain can be helpful to show the presence of "B. henselae", but is often difficult to interpret. "B. henselae" is difficult to culture and can take 2–6 weeks to incubate.


title: Cat-scratch disease

text: Cat-scratch disease is characterized by granulomatous inflammation on histological examination of the lymph nodes. Under the microscope, the skin lesion demonstrates a circumscribed focus of necrosis, surrounded by histiocytes, often accompanied by multinucleated giant cells, lymphocytes, and eosinophils. The regional lymph nodes demonstrate follicular hyperplasia with central stellate necrosis with neutrophils, surrounded by palisading histiocytes (suppurative granulomas) and sinuses packed with monocytoid B cells, usually without perifollicular and intrafollicular epithelioid cells. This pattern, although typical, is only present in a minority of cases.


title: Cat-scratch disease

text: Cat-scratch disease can be primarily prevented by taking effective flea control measures; since cats are mostly exposed to fleas when they are outside, keeping cats inside can help prevent infestation. Strictly-indoor cats without exposure to indoor-outdoor animals are generally at negligible risk of infestation. Cats which are carrying the bacterium, "B. henselae," are asymptomatic, thus thoroughly washing hands after handling a cat or cat feces is an important factor in preventing potential cat-scratch disease transmission from possibly infected cats to humans.


title: Cat-scratch disease

text: Most healthy people clear the infection without treatment, but in 5 to 14% of individuals, the organisms disseminate and infect the liver, spleen, eye, or central nervous system. Although some experts recommend not treating typical CSD in immunocompetent people with mild to moderate illness, treatment of all people with antimicrobial agents (Grade 2B) is suggested due to the probability of disseminated disease. The preferred antibiotic for treatment is azithromycin, since this agent is the only one studied in a randomized controlled study.


title: Cat-scratch disease

text: Azithromycin is preferentially used in pregnancy to avoid the teratogenic side effects of doxycycline. However, doxycycline is preferred to treat "B. henselae" infections with optic neuritis due to its ability to adequately penetrate the tissues of the eye and central nervous system.


title: Cat-scratch disease

text: Cat-scratch disease has a worldwide distribution, but it is a nonreportable disease in humans, so public health data on this disease are inadequate. Geographical location, present season, and variables associated with cats (such as exposure and degree of flea infestation) all play a factor in the prevalence of CSD within a population. In warmer climates, the CSD is more prevalent during the fall and winter, which may be attributed to the breeding season for adult cats, which allows for the birth of kittens." B henselae," the bacterium responsible for causing CSD, is more prevalent in younger cats (less than one year old) than it is in adult cats.


title: Cat-scratch disease

text: To determine recent incidence of CSD in the United States, the Truven Health MarketScan Commercial Claims and Encounters database was analyzed in a case control study from 2005 to 2013. The database consisted of healthcare insurance claims for employees, their spouses, and their dependents. All participants were under 65 years of age, from all 50 states. The length of the study period was 9 years and was based on 280,522,578 person-years; factors such as year, length of insurance coverage, region, age, and sex were used to calculate the person-years incidence rate to eliminate confounding variables among the entire study population.


title: Cat-scratch disease

text: A total of 13,273 subjects were diagnosed with CSD, and both in- and outpatient cases were analyzed. The study revealed an incidence rate of 4.5/100,000 outpatient cases of cat-scratch disease. For inpatient cases, the incidence rate was much lower at 0.19/100,000 population. Incidence of CSD was highest in 2005 among outpatient cases and then slowly declined. The Southern states had the most significant decrease of incidence over time. Mountain regions have the lowest incidence of this disease because fleas are not commonly found in these areas.


title: Cat-scratch disease

text: Distribution of CSD among children aged 5–9 was of the highest incidence in the analyzed database, followed by women aged 60–64. Incidence among females was higher than that among males in all age groups. According to data on social trends, women are more likely to own a cat over men; which supports higher incidence rates of this disease in women. Risk of contracting CSD increases as the number of cats residing in the home increases. The number of pet cats in the United States is estimated to be 57 million. Due to the large population of cats residing in the United States, the ability of this disease to continue to infect humans is vast. Laboratory diagnosis of CSD has improved in recent years, which may support an increase in incidence of the disease in future populations.


title: Cat-scratch disease

text: Historically, the number of reported cases of CSD has been low, there has been a significant increase in reports in urban and suburban areas in the northeast region of United States. An example of the increased incidence can be found in Essex County, New Jersey. In 2016, there were 6 reported cases. In 2017, there were 51 reported cases. In 2018, there were 263 reported cases. Although usually treated with antibiotics and minimal long-term effects, there have been 3 reported case of tachycardia more than one year after exposure. Pathologists believe that the increased incidence of CSD is due to cat owners neglecting to vaccinate their cats.


title: Cat-scratch disease

text: Symptoms similar to CSD were first described by Henri Parinaud in 1889, and the clinical syndrome was first described in 1950 by Robert Debré. In 1983, the Warthin-Starry silver stain was used to discover a Gram-negative bacillus which was named "Afipia felis" in 1991 after it was successfully cultured and isolated. The causative organism of CSD was originally believed to be "Afipia felis", but this was disproved by immunological studies in the 1990s demonstrating that people with cat-scratch fever developed antibodies to two other organisms, "B. henselae" (originally known as "Rochalimea henselae" before the genera "Bartonella" and "Rochalimea" were combined) and "B. clarridgeiae", which is a rod-shaped Gram-negative bacterium.


title: Fallujah

text: Fallujah (, Iraqi pronunciation: ) is a city in the Iraqi province of Al Anbar, located roughly west of Baghdad on the Euphrates. Fallujah dates from Babylonian times and was host to important Jewish academies for many centuries.


title: Fallujah

text: The city grew from a small town in 1947 to having a population of 275,128 inhabitants in 2011. Within Iraq, it is known as the "city of mosques" for the more than 200 mosques found in the city and the surrounding villages.


title: Fallujah

text: The city became a major center of resistance against the Iraqi government during the Iraqi insurgency and the city was the scene of fierce fighting during the First and Second Battles of Fallujah. These battles left much of the city heavily damaged. In January 2014, the city was captured by the Islamic State and suffered major population loss. On 23 May 2016, Iraqi forces announced the beginning of their attempt to retake Fallujah from IS. On 26 June 2016 the city was declared fully liberated by the Iraqi army.


title: Fallujah

text: The region has been inhabited for many millennia. There is evidence that the area surrounding Fallujah was inhabited in Babylonian times. The current name of the city is thought to come from its Syriac name, Pallgutha, which is derived from the word "division" or "canal regulator" since it was the location where the water of the Euphrates River divided into a canal. Classical authors cited the name as "Pallacottas". The name in Aramaic is Pumbedita.


title: Fallujah

text: The region of Fallujah lies near the ancient Sassanid Persian town of "Anbar", in the Sassanid province of Asōristān . The word "anbar" is Persian and means "warehouse". It was known as Firuz Shapur or Perisapora during the Sassanian Era. There are extensive ruins north of Fallujah which are identified with the town of Anbar. Anbar was located at the confluence of the Euphrates River with the King's Canal, today the Saqlawiyah Canal, known in early Islamic times as the Nahr Isa and in ancient times as the Nahr Malka. Subsequent shifts in the Euphrates River channel have caused it to follow the course of the ancient Pallacottas canal. The town at this site in Jewish sources was known as Nehardea and was the primary center of Babylonian Jewry until its destruction by the Palmyran ruler Odenathus in 259. The Medieval Jewish traveller Benjamin of Tudela in 1164 visited "el-Anbar which is Pumbeditha in Nehardea" and said it had 3,000 Jews living there.


title: Fallujah

text: The region played host for several centuries to one of the most important Jewish academies, the Pumbedita Academy, which from 258 to 1038 along with Sura (ar-Hira) was one of the two most important centers of Jewish learning worldwide.


title: Fallujah

text: Under the Ottoman Empire, Fallujah was a minor stop on one of the country's main roads across the desert west from Baghdad.


title: Fallujah

text: In the spring of 1920, the British, who had gained control of Iraq after the collapse of the Ottoman Empire, sent Lieut.-Colonel Gerard Leachman, a renowned explorer and a senior colonial officer, to meet with local leader Shaykh Dhari, perhaps to forgive a loan given to the sheikh. Exactly what happened depends on the source, but according to the Arab version, Gerard Leachman was betrayed by the sheikh who had his two sons shoot him in the legs, then behead him by the sword.


title: Fallujah

text: During the brief Anglo-Iraqi War of 1941, the Iraqi Army was defeated by the British in a battle near Fallujah. In 1947 the town had only about 10,000 inhabitants. It grew rapidly into a city after Iraqi independence with the influx of oil wealth into the country. Its position on one of the main roads out of Baghdad made it of central importance.


title: Fallujah

text: Under Saddam Hussein, who ruled Iraq from 1979 to 2003, Fallujah came to be an important area of support for the regime, along with the rest of the region labeled by the US military as the "Sunni Triangle". Many residents of the primarily Sunni city were employees and supporters of Saddam's government, and many senior Ba'ath Party officials were natives of the city. Fallujah was heavily industrialised during the Saddam era, with the construction of several large factories, including one closed down by United Nations Special Commission (UNSCOM) in the 1990s that may have been used to create chemical weapons. A new highway system (a part of Saddam's infrastructure initiatives) circumvented Fallujah and gradually caused the city to decline in national importance by the time of the Iraq War.


title: Fallujah

text: During the Gulf War, Coalition warplanes repeatedly attacked a bridge in Fallujah which was used as part of an Iraqi military supply line. On 14 February 1991, a Royal Air Force (RAF) fighter jet fired two laser-guided missiles which were aimed at the bridge, but malfunctioned and instead struck Fallujah's largest marketplace (which was situated in a residential area), killing between 50 and 150 non-combatants and wounding many more. After news of the mistake became public, an RAF spokesman, Group Captain David Henderson, issued a statement noting that the missile had malfunctioned but admitted that the Royal Air Force had made an error. Coalition warplanes subsequently launched another attack on the bridge, with one missile hitting its target while two others fell into the river and a fourth struck another marketplace in Fallujah, due to its laser guidance system once again malfunctioning.


title: Fallujah

text: Fallujah was one of the least affected areas of Iraq immediately after the 2003 invasion by the US-led Coalition. Iraqi Army units stationed in the area abandoned their positions and disappeared into the local population, leaving unsecured military equipment behind. Fallujah was also the site of a Ba'athist resort facility called "Dreamland", located a few kilometers outside the city proper.


title: Fallujah

text: The damage the city had avoided during the initial invasion was negated by damage from looters, who took advantage of the collapse of Saddam Hussein's government. The looters targeted former government sites, the Dreamland compound, and the nearby military bases. Aggravating this situation was the proximity of Fallujah to the infamous Abu Ghraib prison, from which Saddam, in one of his last acts, had released all prisoners.


title: Fallujah

text: The new mayor of the city—Taha Bidaywi Hamed, selected by local tribal leaders—was strongly pro-American. When the US Army entered the town in April 2003, they positioned themselves at the vacated Ba'ath Party headquarters. A Fallujah Protection Force composed of local Iraqis was set up by the US-led occupants to help fight the rising resistance.


title: Fallujah

text: On the evening of 28 April 2003, a crowd of about two hundred people defied a curfew imposed by the Americans and gathered outside a secondary school used as a military HQ to demand its reopening. Soldiers from the 82nd Airborne stationed on the roof of the building fired upon the crowd, resulting in the deaths of 17 civilians and the wounding of over 70. American forces claim they were responding to gunfire from the crowd, while the Iraqis involved deny this version. Human Rights Watch also disputed the American claims, and says that the evidence suggests the US troops fired indiscriminately and used disproportionate force. A protest against the killings two days later was also fired upon by US troops, resulting in two more deaths.


title: Fallujah

text: On 31 March 2004, Iraqi insurgents in Fallujah ambushed a convoy containing four American private military contractors from Blackwater USA, who were conducting delivery for food caterers ESS.


title: Fallujah

text: The four armed contractors, Scott Helvenston, Jerry (Jerko) Zovko, Wesley Batalona, and Michael Teague, were dragged from their cars, beaten, and set on fire. Their charred corpses were then dragged through the streets before being hung from a bridge spanning the Euphrates River. This bridge is unofficially referred to as "Blackwater Bridge" by Coalition Forces operating there. Photographs of the event were released to news agencies worldwide, causing outrage in the United States, and prompting the announcement of a campaign to reestablish American control over the city.


title: Fallujah

text: This led to an abortive US operation to recapture control of the city in Operation Vigilant Resolve, and a successful recapture operation in the city in November 2004, called Operation Phantom Fury in English and Operation Al Fajr in Arabic. Operation Phantom Fury resulted in the reputed death of over 1,350 insurgent fighters. Approximately 95 American troops were killed, and 560 wounded. After the successful recapture of the city, U.S. forces discovered a room in which they claimed to find evidence of a beheading, and bomb-making factories, which were shown to the media as evidence of Fallujah's important role in the insurgency against U.S. forces. They also found two hostages—an Iraqi and a Syrian. The Syrian was the driver for two French journalists, Christian Chesnot and Georges Malbrunot, who had been missing since August 2004. The Iraqi's captors were Syrian; he thought he was in Syria until found by the Marines. Chesnot and Malbrunot were released by their captors, the Islamic Army in Iraq, on 21 December 2004.


title: Fallujah

text: The U.S. military first denied that it has used white phosphorus as an anti-personnel weapon in Fallujah, but later retracted that denial, and admitted to using the incendiary in the city as an offensive weapon. According to George Monbiot, reports following the events of November 2004 have alleged war crimes, human rights abuses, and a massacre by U.S. personnel. This point of view is presented in the 2005 documentary film, "Fallujah, The Hidden Massacre".


title: Fallujah

text: On 17 May 2011, AFP reported that twenty-one bodies, in black body-bags marked with letters and numbers in Latin script had been recovered from a mass grave in al-Maadhidi cemetery in the center of the city. Fallujah police chief Brigadier General Mahmud al-Essawi said that they had been blindfolded, their legs had been tied and they had suffered gunshot wounds. The Mayor, Adnan Husseini said that the manner of their killing, as well as the body bags, indicated that US forces had been responsible. Both al-Essawi and Husseini agreed that the dead had been killed in 2004. The US military declined to comment.


title: Fallujah

text: Residents were allowed to return to the city in mid-December 2004 after undergoing biometric identification, provided they wear their ID cards all the time. US officials report that "more than half of Fallujah's 39,000 homes were damaged during Operation Phantom Fury, and about ten thousand of those were destroyed" while compensation amounts to twenty percent of the value of damaged houses, with an estimated 32,000 homeowners eligible, according to Marine Lt Col William Brown. According to NBC, 9,000 homes were destroyed, thousands more were damaged and of the 32,000 compensation claims only 2,500 have been paid as of 14 April 2005.


title: Fallujah

text: According to Mike Marqusee of "Iraq Occupation Focus" writing in the "Guardian", "Fallujah's compensation commissioner has reported that 36,000 of the city's 50,000 homes were destroyed, along with 60 schools and 65 mosques and shrines". Reconstruction mainly consists of clearing rubble from heavily damaged areas and reestablishing basic utility services. 10% of the pre-offensive inhabitants had returned as of mid-January 2005, and 30% as of the end of March 2005. In 2006, some reports say two-thirds have now returned and only 15 percent remain displaced on the outskirts of the city.


title: Fallujah

text: Pre-offensive inhabitant figures are unreliable; the nominal population was assumed to have been 250,000–350,000. Thus, over 150,000 individuals are still living as IDPs in tent cities or with relatives outside Fallujah or elsewhere in Iraq. Current estimates by the Iraqi Ministry of Interior and Coalition Forces put the city's population at over 350,000, possibly closing in on half a million.


title: Fallujah

text: In the aftermath of the offensive, relative calm was restored to Fallujah although almost-daily attacks against coalition forces resumed in 2005 as the population slowly trickled back into the city. From 2005–06, elements of the New Iraqi Army's 2nd and 4th brigades, 1st Division, occupied the city while the Marines maintained a small complex consisting of a security element from RCT8 and a CMOC at the city hall. The Iraqi units were aided by Military Transition Teams. Most Marine elements stayed outside of the city limits.


title: Fallujah

text: In December 2006, enough control had been exerted over the city to transfer operational control of the city from American forces to the 1st Iraqi Army Division. During the same month, the Fallujah police force began major offensive operations under their new chief. Coalition Forces, as of May 2007, are operating in direct support of the Iraqi Security Forces in the city. The city is one of Anbar province's centers of gravity in a newfound optimism among American and Iraqi leadership about the state of the counterinsurgency in the region.


title: Fallujah

text: In June 2007, Regimental Combat Team 6 began Operation Alljah, a security plan modeled on a successful operation in Ramadi. After segmenting districts of the city, Iraqi Police and Coalition Forces established police district headquarters in order to further localize the law enforcement capabilities of the Iraqi Police. A similar program had met with success in the city of Ramadi in late 2006 and early 2007 (See Battle of Ramadi).


title: Fallujah

text: In January 2014, a variety of sources reported that the city was controlled by al-Qaeda and/or the Islamic State of Iraq and the Levant (ISIS; sometimes called ISIL). On a broadcast of National Public Radio's "All Things Considered", Middle East analyst Kirk Sowell stated that while ISIS was occupying parts of the city, most of the ground lost was to the tribal militias who are opposed to both the Iraqi government and al-Qaeda. More than 100 people were killed as Iraqi police and tribesmen battled militants who took over parts of two cities on Anbar province. On the same day, the Iraqi Army shelled the city of Fallujah with mortars to try to wrest back control from Sunni Muslim militants and tribesmen, killing at least eight people, tribal leaders and officials said. Medical sources in Fallujah said another 30 people were wounded in shelling by the army.


title: Fallujah

text: Despite various reports stating that the ISIS was behind the unrest, "The Christian Science Monitor" journalist Dan Murphy disputed this allegation and claimed that while ISIS fighters have maintained a presence in the city, various tribal militias who sympathized with the ideas of nationalism and were opposed to both the Iraqi government and the ISIS controlled the largest share of area in Fallujah. A report from Al Arabiya also backed this claim and alleged that the relationship between the tribesmen and the ISIS militants was only logistical. On 14 January, various tribal chieftains in the province acknowledged "revolutionary tribesmen" were behind the uprising in Fallujah and other parts of Anbar and announced they would support them unless Maliki agreed to cease the ongoing military crackdowns on tribesmen.


title: Fallujah

text: Speaking on condition of anonymity at the end of May 2014, an Anbar-based Iraqi government security officer told Human Rights Watch that ISIS controlled several neighborhoods of southeast Fallujah as well as several northern and southern satellite communities, while local militias loyal to the Anbar Military Council controlled the central and northern neighborhoods of the city; however, Human Rights Watch stated that they could not confirm these claims. Despite the discussion over which groups initially controlled the city, Fallujah was mostly referred to as under ISIL/ISIS control during the occupation.


title: Fallujah

text: After beginning a campaign to liberate Anbar Governorate from ISIL in July 2015, in February 2016, the Iraqi army and its allies started to encircle the city in the Siege of Fallujah. On 22 May 2016, "Operation Breaking Terrorism" was launched to recapture Fallujah, marking the beginning of the Battle of Fallujah.


title: Fallujah

text: On 22 May 2016, the Iraqi Army notified the remaining Fallujah residents of its plans to retake the city, and that such residents should either evacuate, or if not possible, to minimally raise a white flag over their roofs.


title: Fallujah

text: Over the next several days, the army made advances on the city, capturing several surrounding villages on the outskirts on the town, killing a total of ~270 ISIL fighters, at least 35 members of Iraqi forces, ~40 civilians, and 1 Basij member, as of 1 June 2016.


title: Fallujah

text: On 30 May 2016, the military began to enter the city of Fallujah itself, but began to be stalled on 1 June, trying to attack ISIL members, but keeping the tens of thousands of civilians still trapped inside the city safe. However, by 3 June they began to make further advances on the city, killing 62 more ISIL militants. On 26 June, the Iraqi army reported that it had fully liberated the city, while fighting was ongoing in some pockets northwest of Fallujah which remained under ISIL control.


title: Fallujah

text: Fallujah's western boundary is the Euphrates River. The Euphrates flows from the west (Ramadi), past Fallujah, and into the Baghdad area. When the river reaches the western edge of Fallujah, it turns north, then quickly south, forming what is commonly referred to as the 'peninsula' area. There are two bridges that cross the Euphrates at Fallujah.


title: Fallujah

text: The city's eastern boundary is Highway 1, a four-lane, divided superhighway that travels from Baghdad past Fallujah towards the west. After the sanctions imposed by the UN after the 1991 Gulf War, this highway became the main supply route for the country. Truckers and travelers from Saudi Arabia, Jordan and southern Syria all merge onto this highway prior to entering the Eastern Al Anbar province. The highway has a prominent 'cloverleaf' interchange with Highway 10 on the eastern edge of Fallujah. Highway 10, which also runs through Fallujah. It is a two-lane highway that turns into a four lane highway once inside of Fallujah. The highway runs east-west from Baghdad through Fallujah then west towards Ramadi. A 'cloverleaf' on-ramp allows for traffic on/off Highway 1. The highway basically splits the city into two halves, north and south.


title: Fallujah

text: The northern boundary is a railroad line that runs east-west just along the northern edge of the city. The line sits atop a 10–15 ft high berm all along the northern edge of the city, except where it crosses Highway 1.


title: Fallujah

text: There are three major hospital locations in Fallujah. The main hospital (formerly Saddam General) is located downtown, near the west end. The second is located across the Euphrates River in an area of west Fallujah commonly referred to as the 'peninsula', (due to its shape). The third hospital is the Jordanian Field Hospital located east of the Highway 10/Highway 1 interchange.


title: Fallujah

text: In 2010, it was reported that an academic study had shown "a four-fold increase in all cancers and a 12-fold increase in childhood cancer" since 2004. In addition, the report said the types of cancer were "similar to that in the Hiroshima survivors who were exposed to ionising radiation from the bomb and uranium in the fallout", and an 18% fall in the male birth ratio (to 850 per 1,000 female births, compared to the usual 1,050) was similar to that seen after the Hiroshima bombing. The authors cautioned that while "the results seem to qualitatively support the existence of serious mutation-related health effects in Fallujah, owing to the structural problems associated with surveys of this kind, care should be exercised in interpreting the findings quantitatively".


title: La Défense

text: La Défense () is a major business district in Europe, located west of the city limits of Paris. It is part of the Paris metropolitan area in the Île-de-France region, located in the department of Hauts-de-Seine in the communes of Courbevoie, La Garenne-Colombes, Nanterre, and Puteaux.


title: La Défense

text: La Défense is Europe's largest purpose-built business district, covering , for 180,000 daily workers, with 72 glass and steel buildings (of which 19 are completed skyscrapers), and of office space. Around its Grande Arche and esplanade ("le Parvis"), La Défense contains many of the Paris urban area's tallest high-rises. Les Quatre Temps, a large shopping mall in La Défense, has 220 stores, 48 restaurants and a 24-screen movie theatre.


title: La Défense

text: The district is located at the westernmost extremity of the "Axe historique" ("historical axis") of Paris, which starts at the Louvre in Central Paris and continues along the Champs-Élysées, well beyond the Arc de Triomphe along the Avenue de la Grande Armée before culminating at La Défense. The district is centred in an orbital motorway straddling the Hauts-de-Seine department communes of Courbevoie, La Garenne-Colombes, Nanterre and Puteaux. La Défense is primarily a business district and hosts a population of 25,000 permanent residents and 45,000 students. La Défense is also visited by 8,000,000 tourists each year and houses an open-air museum.


title: La Défense

text: La Défense is named after the statue "La Défense de Paris" by Louis-Ernest Barrias, which was erected in 1883 to commemorate the soldiers who had defended Paris during the Franco-Prussian War.


title: La Défense

text: In September 1958, the (EPAD) buildings (of which the Esso Tower was the very first) were built and began to slowly replace the city's factories, shanties, and even a few farms. The Centre of New Industries and Technologies (CNIT) was built and first used in 1958. These "first generation" skyscrapers were all very similar in appearance, limited to a height of . In 1966, the Nobel Tower was the first office skyscraper built in the area. In 1970, the RER line A railway was opened from La Défense to Étoile. In 1974, a contract for a Défense-Cergy high-speed hovercraft train was signed and soon abandoned.


title: La Défense

text: In the early 1970s, in response to great demand, a second generation of buildings began to appear, but the economic crisis in 1973 nearly halted all construction in the area. A third generation of towers began to appear in the early 1980s. The biggest shopping centre in Europe (at the time), the "Quatre Temps", was created in 1981. In 1982, the EPAD launched the "Tête Défense" competition to find a monument to complete the "Axe historique", which eventually led to the construction of Grande Arche at the west end of the quarter. During the same period, hotels were constructed, the CNIT was restructured, and in 1992, Line 1 of the Paris Métro was extended to La Défense, which made the area readily accessible to even more of the city.


title: La Défense

text: On Bastille Day 1990, French electronic composer Jean-Michel Jarre staged an ambitious concert at the site, using the Grande Arche and three of the area's towers as projection screens, and building a pyramidal stage above the road. The free concert, titled simply Paris la Defense, attracted two million spectators, stretching all the way back to the Arc de Triomphe. This beat Jarre's own previous world record for the largest attendance for a musical concert.


title: La Défense

text: After Jean Michel Jarre, German DJ Sash! and the singer La Trec have set at La Défense the video clip for their song "Stay" in 1997.


title: La Défense

text: After a stagnation in new development in the mid-1990s, La Défense is once again expanding and is now the largest purpose-built business district in Europe.


title: La Défense

text: Important corporations headquartered at La Défense include Neuf Cegetel, Société Générale, TotalEnergies, Aventis, Areva, and Arcelor. The tallest skyscraper, the Tour First belongs to AXA, constructed in 1974. It is high, has 50 floors, and is the highest inhabited building in the Paris area (a title previously held by the Tour Montparnasse, which was the tallest inhabited building until the Tour First was renovated between 2007 and 2011, bringing it to its current height from a previous ; the tallest structure in Paris is the Eiffel Tower).


title: La Défense

text: In December 2005, , CEO & Chairman of EPAD (La Defense Management & Development Office) announced an ambitious 9-year development plan called . This important modernisation plan has to give a new dimension to the district and focuses on four main axes: regenerate outdated skyscrapers, allow new buildings, improve the balance between offices and residential housing and make the transport of local employees from their homes to La Défense easier. There are 3 aims: building of offices within demolition/rebuilding projects, building of offices within new projects, and building of housing.


title: La Défense

text: The government confirmed in July 2006 this plan, which has to be carried out around 2015. It is justified by the strong estate pressure, which plays in favour of building new skyscrapers near Paris. Those constructions have also the advantage to be more economical than little buildings. But it will have to overcome some difficulties: French economy faces a short-term slowdown; the government tries to balance tertiary sector employment in the whole region again, because La Défense today concentrates a major part of those jobs; and traffic is already saturated in the district, while it would need huge investments to extend transport infrastructures.


title: La Défense

text: It launched high-profile international competitions and/or construction greenlight of several key tall sustainable development-style skyscrapers such as Tour Signal, Tour Phare, Hermitage Plaza, and Tour Generali. During said December 2005 Press Conference, EPAD released to the public an elaborate 3D animation film titled "La Défense 2016".


title: La Défense

text: Paris La Défense brings together the cluster of Leonardo da Vinci University Center and 5 business schools: EDC Paris Business School, ESSEC Business School, ICN Graduate Business School, IESEG School of Management and SKEMA Business School. It is also home to the European School of Paris-La Défense, an international primary and secondary school that was accredited as a European School in 2020.


title: La Défense

text: Besides the representative architecture, the area also houses an open-air museum with 70 statues and pieces of modern art, including the following works:


title: IHOP

text: IHOP ( ; acronym for International House of Pancakes) is an American multinational pancake house restaurant chain that specializes in American breakfast foods. It is owned by Dine Brands Global—a company formed after IHOP's purchase of Applebee's, with 99% of the restaurants run by independent franchisees.


title: IHOP

text: While IHOP's focus is on breakfast foods, it also offers a menu of lunch and dinner items. The company has 1,841 locations in the Americas (United States, Canada, Mexico, Peru, Ecuador and Guatemala), the Middle East (United Arab Emirates, Kuwait, Saudi Arabia and Qatar) and the Indian Subcontinent (India and Pakistan), including 161 that are owned by area licensees and 1,680 that are franchised. While many of its locations are open 24 hours a day, 7 days a week, the chain's minimum operating hours are 7:00 a.m. to 10:00 p.m.


title: IHOP

text: Jerry Lapin, Al Lapin, and Albert Kallis founded International House of Pancakes in the Los Angeles, California area in 1958 with the help of Sherwood Rosenberg and William Kaye. The first restaurant opened at 4301 W. Riverside Drive in Burbank, California. The second and third locations at 8555 Vesper Avenue in Panorama City, California and 3625 Stocker Avenue in Baldwin Hills, California (a former Brown Derby restaurant) are still open for business.


title: IHOP

text: The first prototype design for IHOP building was a steep-roofed A-frame building with a distinctive blue roof; the last such location to be built was completed in 1979. While most IHOP locations no longer use the A-frame buildings, several still exist around the U.S.


title: IHOP

text: In 1973, the chain's name was shortened to "IHOP" for marketing purposes, using a cartoon kangaroo in its commercials at the time, and since then the full name and acronym have been officially interchangeable.


title: IHOP

text: The breakfast food menu later expanded (especially in the 1980s) to include standard lunch and dinner items found in similar restaurant chains such as Sambo's and Denny's. In 1976, at the same time as reorganization International Industries became IHOP. In December 2019, IHOP announced plans to launch a chain of fast casual breakfast restaurants called Flip'd.


title: IHOP

text: On July 16, 2007, IHOP Corporation announced a plan to acquire the bar-and-grill chain Applebee's in an all-cash transaction, valued at approximately US$2.1 billion. In the arrangement, Applebee's stock holders will receive $25.50 a share. IHOP stated it would franchise most of Applebee's 500 company-owned facilities. Applebee's had 1,943 restaurants worldwide at the time, including those operated by franchisees.


title: IHOP

text: Applebee's shareholders approved the acquisition with a 70% vote, which closed on November 29, 2007. A number of executives from Applebee's voted against the offer. The chain's largest individual shareholder, Applebee's director Burton "Skip" Sack, called the IHOP offer unfair to its shareholders and stated he planned to sue IHOP for a higher price be paid to him. As part of the purchase, a brand remarketing scheme and revitalization of the Applebee's image was intended. The buyout successfully closed on November 29, 2007, and the corporate entity IHOP changed its name to DineEquity on June 2, 2008. A franchisee opened a hybrid Applebee's/IHOP restaurant in downtown Detroit in mid-2018.


title: IHOP

text: While IHOP's focus is on breakfast, serving pancakes, waffles, French toast, and omelettes, it also offers a menu of lunch and dinner items such as sandwiches, burgers, and salads.


title: IHOP

text: Franchising agreements with M.H. Alshaya, an international restaurant-franchising firm, resulted in an agreement for Alshaya to open as many as forty IHOP locations in the Middle East, beginning in 2012. By the end of 2018, IHOP restaurants operated in six Middle Eastern countries: Kuwait, Qatar, Bahrain, the United Arab Emirates, Saudi Arabia and Lebanon. In 2019, IHOP began its foray into South America, opening three locations in Ecuador. and one location in Peru.


title: IHOP

text: IHOP Express' first location opened in 2011; they are a quick service version of the chain offered at locations such as airports,<ref name"D/FW"></ref> school campuses, military food courts and travel centers. The first standalone public location of the concept opened in downtown San Diego in 2011.


title: IHOP

text: In 2019, IHOP announced plans to open a fast-casual restaurant, Flip'd by IHOP. Flip'd will include a menu serving pancake bowls, burgers, and fried chicken.


title: IHOP

text: In June 2015, IHOP introduced an updated logo, removing its decorative elements and adding a curved line under the "O" and "P" letters to resemble a smiley face. The company argued that the previous logo looked too much like a frown.


title: IHOP

text: In June 2018, an IHOP marketing campaign announced they would "flip" their name to "IHOb"; it was ultimately revealed to be a marketing campaign for its hamburgers, in an effort to address perceptions that IHOP was still primarily oriented towards breakfast food. The tease of the campaign led to speculation via social media regarding the intent of the change. IHOP parodied the campaign the following year to promote a new hamburger that includes a pancake as an ingredient, jokingly stating that they would refer to their burgers as "pancakes" because people wanted IHOP to "stick to pancakes".


title: IHOP

text: In early September 2010, IHOP filed a lawsuit in U.S. District Court in Los Angeles against International House of Prayer and six other defendants alleging trademark dilution and infringement. The lawsuit was dropped on December 21, 2010, with the dispute resolved out of court.


title: Paclitaxel

text: Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered by intravenous injection. There is also an albumin-bound formulation.


title: Paclitaxel

text: Common side effects include hair loss, bone marrow suppression, numbness, allergic reactions, muscle pains, and diarrhea. Other serious side effects include heart problems, increased risk of infection, and lung inflammation. There are concerns that use during pregnancy may cause birth defects. Paclitaxel is in the taxane family of medications. It works by interference with the normal function of microtubules during cell division.


title: Paclitaxel

text: Paclitaxel was first isolated in 1971 from the Pacific yew and approved for medical use in 1993. It is on the World Health Organization's List of Essential Medicines. It has been made from precursors, and more recently through cell culture.


title: Paclitaxel

text: Paclitaxel is approved in the UK for ovarian, breast, lung, bladder, prostate, melanoma, esophageal, and other types of solid tumor cancers as well as Kaposi's sarcoma.


title: Paclitaxel

text: It is recommended in National Institute for Health and Care Excellence (NICE) guidance of June 2001 that it should be used for non-small-cell lung cancer in patients unsuitable for curative treatment, and in first-line and second-line treatment of ovarian cancer. In September 2001, NICE recommended paclitaxel should be available for the treatment of advanced breast cancer after the failure of anthracyclic chemotherapy, but that its first-line use should be limited to clinical trials. In September 2006, NICE recommended paclitaxel should "not" be used in the adjuvant treatment of early node-positive breast cancer. In 2018, it is approved in the United States for the treatment of breast, pancreatic, ovarian, Kaposi's sarcoma and non-small-cell lung cancers.


title: Paclitaxel

text: Albumin-bound paclitaxel (trade name Abraxane, also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to albumin nanoparticles. Much of the clinical toxicity of paclitaxel is associated with the solvent Cremophor EL in which it is dissolved for delivery.


title: Paclitaxel

text: Abraxis BioScience developed Abraxane, in which paclitaxel is bonded to albumin as an alternative delivery agent to the often toxic solvent delivery method. This was approved by the FDA in January 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within six months of adjuvant chemotherapy. It has since been approved for locally advanced or metastatic non-small cell lung cancer and metastatic adenocarcinoma of the pancreas as well.


title: Paclitaxel

text: Synthetic approaches to paclitaxel production led to the development of docetaxel. Docetaxel has a similar set of clinical uses to paclitaxel, and it is marketed under the brand name Taxotere.


title: Paclitaxel

text: Taxanes, including paclitaxel, 10-deacetylbaccatin III, baccatin III, paclitaxel C, and 7-epipaclitaxel, have been found in the leaves and shells of hazel. The finding of these compounds in shells, which are considered discarded material and are mass-produced by many food industries, is of interest for the future availability of paclitaxel.


title: Paclitaxel

text: Paclitaxel is used as an antiproliferative agent for the prevention of restenosis (recurrent narrowing) of coronary and peripheral stents; locally delivered to the wall of the artery, a paclitaxel coating limits the growth of neointima (scar tissue) within stents. Paclitaxel drug-eluting stents for coronary artery placement are sold under the trade name Taxus by Boston Scientific in the United States. Paclitaxel drug-eluting stents for femoropopliteal artery placement are also available.


title: Paclitaxel

text: Common side effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, pain in the joints of the arms or legs lasting two to three days, changes in the color of the nails, and tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain, redness or swelling at the injection site, hand-foot syndrome, change in normal bowel habits for more than two days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing, female infertility by ovarian damage, and chest pain can also occur. Neuropathy may also occur.


title: Paclitaxel

text: A number of these side effects are associated with the excipient used, Cremophor EL, a polyoxyethylated castor oil. Allergies to cyclosporine, teniposide, and other drugs delivered in polyoxyethylated castor oil may increase the risk of adverse reactions to paclitaxel.


title: Paclitaxel

text: Paclitaxel is one of several cytoskeletal drugs that target tubulin. Paclitaxel-treated cells have defects in mitotic spindle assembly, chromosome segregation, and cell division. Unlike other tubulin-targeting drugs, such as colchicine, that inhibit microtubule assembly, paclitaxel stabilizes the microtubule polymer and protects it from disassembly. Chromosomes are thus unable to achieve a metaphase spindle configuration. This blocks the progression of mitosis and prolonged activation of the mitotic checkpoint triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division.


title: Paclitaxel

text: The ability of paclitaxel to inhibit spindle function is generally attributed to its suppression of microtubule dynamics, but other studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At the higher therapeutic concentrations, paclitaxel appears to suppress microtubule detachment from centrosomes, a process normally activated during mitosis. Paclitaxel binds to the beta-tubulin subunits of microtubules.


title: Paclitaxel

text: The nomenclature for paclitaxel is structured on a tetracyclic 17-atom skeleton. There are a total of 11 stereocenters. The active stereoisomer is (−)-paclitaxel (shown here).


title: Paclitaxel

text: From 1967 to 1993, almost all paclitaxel produced was derived from bark of the Pacific yew, "Taxus brevifolia", the harvesting of which kills the tree in the process. The processes used were descendants of the original isolation method of Monroe Wall and Mansukh Wani; by 1987, the U.S. National Cancer Institute (NCI) had contracted Hauser Chemical Research of Boulder, Colorado, to handle bark on the scale needed for phase II and III trials. While both the size of the wild population of the Pacific yew and the magnitude of the eventual demand for paclitaxel were uncertain, it was clear that an alternative, sustainable source of the natural product would be needed. Initial attempts to broaden its sourcing used needles from the tree, or material from other related "Taxus" species, including cultivated ones, but these attempts were challenged by the relatively low and often highly variable yields obtained. Early in the 1990s, coincident with increased sensitivity to the ecology of the forests of the Pacific Northwest, paclitaxel was successfully extracted on a clinically useful scale from these sources.


title: Paclitaxel

text: Concurrently, synthetic chemists in the U.S. and France had been interested in paclitaxel, beginning in the late 1970s. As noted, by 1992 extensive efforts were underway to accomplish the total synthesis of paclitaxel, efforts motivated by the desire to generate new chemical understanding rather than to achieve practical commercial production. In contrast, the French group of Pierre Potier at the Centre national de la recherche scientifique (CNRS) addressed the matter of overall process yield, showing that it was feasible to isolate relatively large quantities of the compound 10-deacetylbaccatin from the European yew, "Taxus baccata", which grew on the CNRS campus and whose needles were available in large quantity. By virtue of its structure, 10-deacetylbaccatin was seen as a viable starting material for a short semisynthesis to produce paclitaxel. By 1988, Poitier and collaborators had published a semisynthetic route from needles of the European yew to paclitaxel.


title: Paclitaxel

text: The view of the NCI, however, was that even this route was not practical. The group of Robert A. Holton had also pursued a practical semisynthetic production route; by late 1989, Holton's group had developed a semisynthetic route to paclitaxel with twice the yield of the Potier process. Florida State University, where Holton worked, signed a deal with Bristol-Myers Squibb (BMS) to license their semisynthesis and future patents. In 1992, Holton patented an improved process with an 80% yield, and BMS took the process in-house and started to manufacture paclitaxel in Ireland from 10-deacetylbaccatin isolated from the needles of the European yew. In early 1993, BMS announced that it would cease reliance on Pacific yew bark by the end of 1995, effectively terminating ecological controversy over its use. This announcement also made good their commitment to develop an alternative supply route, made to the NCI in their cooperative research and development agreement (CRADA) application of 1989.


title: Paclitaxel

text: As of 2013, BMS was using the semisynthetic method utilizing needles from the European yew to produce paclitaxel. Another company which worked with BMS until 2012, Phyton Biotech, Inc., uses plant cell fermentation (PCF) technology. By cultivating a specific "Taxus" cell line in fermentation tanks, they no longer need ongoing sourcing of material from actual yew tree plantations. Paclitaxel is then captured directly from the suspension broth by a resin allowing concentration to highly enriched powder containing about 40% paclitaxel. The compound is then purified by one chromatographic step followed by crystallization. Compared to the semisynthesis method, PCF eliminates the need for many hazardous chemicals and saves a considerable amount of energy.


title: Paclitaxel

text: In 1993, paclitaxel was discovered as a natural product in a newly described endophytic fungus living in the yew tree. It has since been reported in a number of other endophytic fungi, including "Nodulisporium sylviforme", "Alternaria taxi", "Cladosporium cladosporioides" MD2, "Metarhizium anisopliae", "Aspergillus candidus" MD3, "Mucor rouxianus", "Chaetomella raphigera", "Phyllosticta tabernaemontanae", "Phomopsis", "Pestalotiopsis pauciseta", "Phyllosticta citricarpa", "Podocarpus" sp., "Fusarium solani", "Pestalotiopsis terminaliae", "Pestalotiopsis breviseta", "Botryodiplodia theobromae", "Gliocladium" sp., "Alternaria alternata" var. "monosporus", "Cladosporium cladosporioides", "Nigrospora" sp., "Pestalotiopsis versicolor", and "Taxomyces andreanae". However, there has been contradictory evidence for its production by endophytes, with other studies finding independent production is unlikely.


title: Paclitaxel

text: Taxol is a tetracyclic diterpene, and the biosynthesis of diterpenes starts with a FPP molecule being elongated by the addition of an IPP molecule in order to form geranylgeranyl diphosphate (GGPP). The biosynthesis of Taxol contains nineteen steps. These 19 steps can be considered in several steps, with the first step being the formation of the taxane skeleton, which then undergoes a series of oxygenations. Following the oxygenations, two acetylations and a benzoylation occur on the intermediate. The oxygenation of the taxane core is believed to occur on C5 and C10, C2 and C9, C13 followed by C7, and a C1 hydroxylation later on in the pathway. Later in the pathway, an oxidation at C9 forms a ketone functional group and an oxetane, forming the intermediate baccatin III. The final steps of the pathway include the formation of a C13-side chain which is attached to baccatin III. The biosynthesis of Taxol is illustrated in more detail in the figure, with steps 1-7 all occurring in the enzyme taxadiene synthase (TS on the figure). Taxol's biosynthesis begins with E,E,E-GGPP losing pyrophosphate via an SN1 mechanism (step 1 in the figure). The double-bond attacks the cation via electrophilic addition, yielding a tertiary cation and creating the first ring closure (step 2). Another electrophilic attack occurs, further cyclizing the structure by creating the first 6-membered ring and creating another tertiary cation (step 3). An intramolecular proton transfer occurs, attacking the verticillyl cation (step 4) and creating a double bond, yielding a tertiary cation. An electrophilic cyclization occurs in step 5, and an intramolecular proton transfer attacks the taxenyl cation (step 6). This forms the fused ring structure intermediate known as taxadiene. Taxadiene then undergoes a series of 10 oxidations via NADPH, forming the intermediate taxadiene-5α-acetoxy-10β-ol (multiple steps later in the figure). A series of hydroxylations and esterficiations occur, forming the intermediate 10-deacetyl-baccatin III, which undergoes a further series of esterifications and a side-chain hydroxylation. This finally yields the product taxol.


title: Paclitaxel

text: By 1992, at least thirty academic research teams globally were working to achieve a total synthesis of this natural product, with the synthesis proceeding from simple natural products and other readily available starting materials. This total synthesis effort was motivated primarily by the desire to generate new chemical understanding, rather than with an expectation of the practical commercial production of paclitaxel. The first laboratories to complete the total synthesis from much less complex starting materials were the research groups of Robert A. Holton, who had the first article to be accepted for publication, and of K. C. Nicolaou who had the first article to appear in print (by a week, on 7 February 1994). Though the Holton submission preceded the Nicolaou by a month (21 December 1993 versus 24 January 1994), the near coincidence of the publications arising from each of these massive, multiyear efforts—11–18 authors appearing on each of the February 1994 publications—has led the ending of the race to be termed a "tie" or a "photo finish", though each group has argued that their synthetic strategy and tactics were superior.


title: Paclitaxel

text: As of 2006, five additional research groups had reported successful total syntheses of paclitaxel: Wender et al. in 1997, and Kuwajima et al. and Mukaiyama et al. in 1998 with further linear syntheses, and Danishefsky et al. in 1996 and Takahashi et al. in 2006 with further convergent syntheses. As of that date, all strategies had aimed to prepare a 10-deacetylbaccatin-type core containing the ABCD ring system, followed generally by last stage addition of the "tail" to the 13-hydroxyl group.


title: Paclitaxel

text: While the "political climate surrounding [paclitaxel] and [the Pacific yew] in the early 1990s ... helped bolster [a] link between total synthesis and the [paclitaxel] supply problem," and though total synthesis activities were a requisite to explore the structure-activity relationships of paclitaxel via generation of analogs for testing, the total synthesis efforts were never seen "as a serious commercial route" to provide significant quantities of the natural product for medical testing or therapeutic use.


title: Paclitaxel

text: The discovery of paclitaxel began in 1962 as a result of a NCI-funded screening program. A number of years later it was isolated from the bark of the Pacific yew, "Taxus brevifolia", hence its name "taxol".


title: Paclitaxel

text: The discovery was made by Monroe E. Wall and Mansukh C. Wani at the Research Triangle Institute, Research Triangle Park, North Carolina, in 1971. These scientists isolated the natural product from the bark of the Pacific yew tree, determined its structure and named it "taxol", and arranged for its first biological testing. The compound was then developed commercially by BMS, who had the generic name assigned as "paclitaxel".


title: Paclitaxel

text: In 1955, the NCI in the United States set up the Cancer Chemotherapy National Service Center (CCNSC) to act as a public screening center for anticancer activity in compounds submitted by external institutions and companies. Although the majority of compounds screened were of synthetic origin, one chemist, Jonathan Hartwell, who was employed there from 1958 onwards, had experience with natural product derived compounds, and began a plant screening operation. After some years of informal arrangements, in July 1960, the NCI commissioned the United States Department of Agriculture (USDA) botanists to collect samples from about 1,000 plant species per year. On 21 August 1962, one of those botanists, Arthur S. Barclay, collected bark from a single Pacific yew tree in a forest north of the town of Packwood, Washington, as part of a four-month trip to collect material from over 200 different species. The material was then processed by a number of specialist CCNSC subcontractors, and one of the tree's samples was found to be cytotoxic in a cellular assay on 22 May 1964.


title: Paclitaxel

text: Accordingly, in late 1964 or early 1965, the fractionation and isolation laboratory run by Monroe E. Wall in Research Triangle Park, North Carolina, began work on fresh "Taxus" samples, isolating the active ingredient in September 1966 and announcing their findings at an April 1967 American Chemical Society meeting in Miami Beach. They named the pure compound taxol in June 1967. Wall and his colleague Wani published their results, including the chemical structure, in 1971.


title: Paclitaxel

text: The NCI continued to commission work to collect more "Taxus" bark and to isolate increasing quantities of taxol. By 1969, of crude extract had been isolated from almost of bark, although this ultimately yielded only of pure material, but for several years, no use was made of the compound by the NCI. In 1975, it was shown to be active in another "in vitro" system; two years later, a new department head reviewed the data and finally recommended taxol be moved on to the next stage in the discovery process. This required increasing quantities of purified taxol, up to , and in 1977 a further request for of bark was made.


title: Paclitaxel

text: In 1978, two NCI researchers published a report showing taxol was mildly effective in leukaemic mice. In November 1978, taxol was shown to be effective in xenograft studies. Meanwhile, taxol began to be well known in the cell biology, as well as the cancer community, with a publication in early 1979 by Susan B. Horwitz, a molecular pharmacologist at Albert Einstein College of Medicine, showing taxol had a previously unknown mechanism of action involving the stabilization of microtubules. Together with formulation problems, this increased interest from researchers meant that, by 1980, the NCI envisaged needing to collect of bark. Animal toxicology studies were complete by June 1982, and in November NCI applied for the IND necessary to begin clinical trials in humans.


title: Paclitaxel

text: Phase I clinical trials began in April 1984, and the decision to start Phase II trials was made a year later. These larger trials needed more bark and collection of a further 12,000 pounds was commissioned, which enabled some phase II trials to begin by the end of 1986. But by then it was recognized that the demand for taxol might be substantial and that more than 60,000 pounds of bark might be needed as a minimum. This unprecedentedly large amount brought ecological concerns about the impact on yew populations into focus for the first time, as local politicians and foresters expressed unease at the program.


title: Paclitaxel

text: The first public report from a phase II trial in May 1988 showed promising effects in melanoma and refractory ovarian cancer. At this point, Gordon Cragg of the NCI's Natural Product Branch calculated the synthesis of enough taxol to treat all the ovarian cancer and melanoma cases in the US would require the destruction of 360,000 trees annually. For the first time, serious consideration was given to the problem of supply.


title: Paclitaxel

text: Because of the practical and, in particular, the financial scale of the program needed, the NCI decided to seek association with a pharmaceutical company, and in August 1989, it published a Cooperative Research and Development Agreement (CRADA) offering its current stock and supply from current bark stocks, and proprietary access to the data so far collected, to a company willing to commit to providing the funds to collect further raw material, isolate taxol, and fund a large proportion of clinical trials. In the words of Goodman and Welsh, authors of a substantial scholarly book on taxol, "The NCI was thinking, not of collaboration, ... but of a hand-over of taxol (and its problems)".


title: Paclitaxel

text: Although the offer was widely advertised, only four companies responded to the CRADA, including the American firm Bristol-Myers Squibb (BMS),


title: Paclitaxel

text: which was selected as the partner in December 1989. The choice of BMS later became controversial and was the subject of Congressional hearings in 1991 and 1992. While it seems clear the NCI had little choice but to seek a commercial partner, there was also controversy about the terms of the deal, eventually leading to a report by the General Accounting Office in 2003, which concluded the NIH had failed to ensure value for money. In related CRADAs with the USDA and Department of the Interior, Bristol-Myers Squibb was given exclusive first refusal on all Federal supplies of "Taxus brevifolia".


title: Paclitaxel

text: Eighteen months after the CRADA, BMS filed a new drug application (NDA), which was given FDA approval at the very end of 1992.


title: Paclitaxel

text: Although there was no patent on the compound, the provisions of the Waxman-Hatch Act gave Bristol-Myers Squibb five years exclusive marketing rights.


title: Paclitaxel

text: In 1990, BMS applied to trademark the name taxol as "Taxol(R)". This was controversially approved in 1992. At the same time, paclitaxel replaced taxol as the generic (INN) name of the compound. Critics, including the journal "Nature", argued the name taxol had been used for more than two decades and in more than 600 scientific articles and suggested the trademark should not have been awarded and the BMS should renounce its rights to it. BMS argued changing the name would cause confusion among oncologists and possibly endanger the health of patients. BMS has continued to defend its rights to the name in the courts.


title: Paclitaxel

text: BMS has also been criticized for misrepresentation by Goodman and Walsh, who quote from a company report saying "It was not until 1971 that ... testing ... enabled the isolation of paclitaxel, initially described as 'compound 17". This quote is, strictly speaking, accurate: the objection seems to be that this misleadingly neglects to explain that it was the scientist doing the isolation who named the compound taxol and it was not referred to in any other way for more than twenty years. Annual sales peaked in 2000, reaching US$1.6 billion; paclitaxel is now available in generic form.


title: Paclitaxel

text: , the cost to the NHS per patient in early breast cancer, assuming four cycles of treatment, was about £4,000 (approx. $6,000).


title: Paclitaxel

text: Aside from its direct clinical use, paclitaxel is used extensively in biological and biomedical research as a microtubule stabilizer. In general, in vitro assays involving microtubules, such as motility assays, rely on paclitaxel to maintain microtubule integrity in the absence of the various nucleating factors and other stabilizing elements found in the cell. For example, it is used for in vitro tests of drugs that aim to alter the behavior of microtubule motor proteins, or for studies of mutant motor proteins. Moreover, Paclitaxel has been used in vitro to inhibit insulin fibrillation; in a molar ratio of 10:1 (insulin:paclitaxel), it hindered insulin fibrillation near 70%. Iso-thermal titration calorimetry (ITC) findings indicated a spontaneous tendency of paclitaxel to interact with insulin through hydrogen bonds and van der Waal's forces. Also, the inhibitory role of paclitaxel is attributed to its impact on the colloidal stability of protein solution, as it was observed that paclitaxel inhibited lysozyme fibrillation by inducing the formation of "off-pathway" oligomeric intermediates and increasing the colloidal stability subsequently. Paclitaxel is sometimes used for in vivo studies as well; it can be fed to test organisms, such as fruit flies, or injected into individual cells, to inhibit microtubule disassembly or to increase the number of microtubules in the cell. Paclitaxel induces remyelination in a demyelinating mouse in vivo and inhibits hPAD2 in vitro though its methyl ester side chain. Angiotech Pharmaceuticals Inc. began phase II clinical trials in 1999 as a multiple sclerosis treatment but in 2002, reported that the results showed no statistical significance.


title: Paclitaxel

text: In 2016 "in vitro" multi-drug resistant mouse tumor cells were treated with paclitaxel encased in exosomes. Doses 98% less than common dosing had the same effect. Also, dye-marked exosomes were able to mark tumor cells, potentially aiding in diagnosis.


title: The Billion Dollar Code

text: The Billion Dollar Code is a 2021 German television miniseries starring Björn Freiberg, Seumas F. Sargent and Leonard Scheicher. Based on true events, the series was developed for Netflix, where it was first aired in October 2021 along with an additional feature story episode.


title: The Billion Dollar Code

text: The plot follows two interconnected timelines. In Berlin of the 1990s, a group of young hackers and art students had founded the collaboration to play at the cutting edge of computer programming and digital art. They had developed a planet browser in 1991 which was used by Joachim Sauter to get funding from Deutsche Telekom in 1993 to start the successful development of Terravision. In the series, the ART+COM beginnings were dropped, while several of the real persons and stakeholders were fused to a smaller cast, with the fictional Carsten Schlüter as the main artist and Juri Müller as the main programmer.


title: The Billion Dollar Code

text: The other storyline revolves around the 2014 patent infringement dispute against Google, alleging that TerraVision was used to develop Google Earth. The fictional character Brian Anderson is based on Brian McClendon and Michael T Jones who did found Keyhole Inc to develop a planet browser. That company was bought by Google in 2004. The movie dramatized facets of the real lawsuit that lasted until 2017, with the script reproducing only parts of the actual court statements to avoid coming into conflict with Google and having key parts of the proceedings fictionalized or omitted.


title: The Billion Dollar Code

text: The miniseries dramatizes the lawsuit, the proceedings of which lasted until 2017. Art+Com lost at trial and on appeal. The filmmakers used portions of the trial transcript to avoid coming into conflict with Google, but key aspects of the trial were entirely fictionalized or omitted. The actual decision of the court was in fact based on other findings.


title: Petunia

text: Petunia is genus of 20 species of flowering plants of South American origin. The popular flower of the same name derived its epithet from the French, which took the word "petun", meaning "tobacco," from a Tupi–Guarani language. A tender perennial, most of the varieties seen in gardens are hybrids ("Petunia" × "atkinsiana", also known as "Petunia" × "hybrida").


title: Petunia

text: "Petunia" is a genus in the family Solanaceae, subfamily Petunioideae. Well known members of Solanaceae in other subfamilies include tobacco (subfamily Nicotianoideae), and the cape gooseberry, tomato, potato, deadly nightshade and chili pepper (subfamily Solanoideae). Some botanists place the plants of the genus "Calibrachoa" in the genus "Petunia", but this is not accepted by others. "Petchoa" is a hybrid genus derived from crossing "Calibrachoa" and "Petunia".


title: Petunia

text: Petunias are generally insect pollinated, with the exception of "P. exserta", which is a rare, red-flowered, hummingbird-pollinated species. Most petunias are diploid with 14 chromosomes and are interfertile with other petunia species, as well as with Calibrachoa.


title: Petunia

text: Petunias can tolerate relatively harsh conditions and hot climates, but not frost. They need at least five hours of sunlight every day and flourish in moist soil and conditions of low atmospheric humidity. They are best grown from seed. Watering once a week should be sufficient in most regions. Hanging baskets and other containers need more frequent watering. Maximum growth occurs in late spring. Applying fertilizer monthly or weekly, depending on the variety, will help the plant grow quickly.


title: Petunia

text: In horticulture many terms are used to denote different types of cultivated petunia. These include Grandiflora, Multiflora, Wave (Spreading), Supertunia, Cascadia and Surfinia.


title: Petunia

text: The following is a selection of cultivars which have received the Royal Horticultural Society's Award of Garden Merit:


title: Petunia

text: Many species other than "Petunia" × "atkinsiana" are also gaining popularity in the home garden. A wide range of flower colours, sizes, and plant architectures are available in both "Petunia" × "atkinsiana" and other species, listed below:


title: Petunia

text: The Maya and Inca believed that the scent of petunias had the power to ward off underworld monsters and spirits. Their flower-buds were bunched together for magical drinks. According to New Age folklore, Petunias will only thrive where there is "positive energy" and will not grow in places where there is "negativity".


title: Petunia

text: When given as a gift, Petunias have (in the language of flowers) two mutually exclusive meanings, symbolising on the one hand being comfortable with someone, and on the other anger and resentment.


title: Timber rattlesnake

text: The timber rattlesnake, canebrake rattlesnake, or banded rattlesnake (Crotalus horridus) is a species of pit viper endemic to eastern North America. Like all other pit vipers, it is venomous, with a very toxic bite. "C. horridus" is the only rattlesnake species in most of the populous Northeastern United States and is second only to its relatives to the west, the prairie rattlesnake, as the most northerly distributed venomous snake in North America. No subspecies are currently recognized.


title: Timber rattlesnake

text: The timber rattlesnake was one of the many reptile species originally described by Carl Linnaeus in the landmark 1758 10th edition of his "Systema Naturae", and still bears its original name "Crotalus horridus".


title: Timber rattlesnake

text: The subspecies "C. h. atricaudatus" (Latreille "in" Sonnini and Latreille, 1802), often referred to as the canebrake rattlesnake, is currently considered invalid. Previously, it was recognized by Gloyd (1936) and Klauber (1936). Based on an analysis of geographic variation, Pisani et al. (1972) concluded no subspecies should be recognized. This was rejected by Conant (1975), but followed by Collins and Knight (1980). Brown and Ernst (1986) found evidence for retaining the two subspecies, but state telling them apart without having more information than usual is not possible, including adult size, color pattern, the number of dorsal scale rows, and the number of ventral scales. Dundee and Rossman (1989) recognized "C. h. atricaudatus", but others take a more neutral point of view.


title: Timber rattlesnake

text: The timber rattlesnake is one of 36 species in the genus "Crotalus." This genus can be distinguished from "Sistrurus" by the small scales atop the head, rather than nine large scales found on "Sistrurus."


title: Timber rattlesnake

text: Adults usually grow to total length of . In Pennsylvania, the smallest size females that could produce viable eggs was . Most adult timber rattlesnakes found measure less than in total length and weigh between , often being towards the lower end of that range. The maximum reported total length is (Klauber, 1956). Holt (1924) mentions a large specimen caught in Montgomery County, Alabama, which had a total length of and weighed . Large specimens can reportedly weigh as much as .


title: Timber rattlesnake

text: The dorsal scales are keeled and arranged in 21–26 scale rows at midbody (usually 25 rows in the southern part of its geographic range, and 23 rows in the northern part). The ventral scales number 158–177 in males and 163–183 in females. Males have 20–30 subcaudal scales, while females have 15–26. The rostral scale is normally a little higher than it is wide. In the internasal-prefrontal area there are 4–22 scales that include 2 large, triangular internasal scales that border the rostral, followed by two large, quadrangular prefrontal scales (anterior canthals) that may contact each other along the midline, or may be separated by many small scales. Between the supraocular and internasal scales, only a single canthal scale is present. Five to seven intersupraocular scales are seen. The number of prefoveal scales varies between two and eight. Usually, the first supralabial scale is in broad contact with the prenasal scale, although slightly to moderately separated along its posteroventral margin by the most anterior prefoveals.


title: Timber rattlesnake

text: Dorsally, they have a pattern of dark brown or black crossbands on a yellowish-brown or grayish background. The crossbands have irregular zig-zag edges, and may be V- or M-shaped. Often a rust-colored vertebral stripe is present. Ventrally, they are yellowish, uniform, or marked with black. Melanism is common, and some individuals are very dark, almost solid black.


title: Timber rattlesnake

text: Timber rattlesnakes are present in the eastern United States from southern Minnesota and southern New Hampshire, south to East Texas and North Florida. One hundred and fifteen rattlesnakes have been marked within Brown County State Park in Indiana, one of the few places where they can be found in the state.


title: Timber rattlesnake

text: Its historic range includes southern Ontario and southern Quebec in Canada, but in May 2001, the Canadian Species at Risk Act listed it as extirpated in Canada. A Canadian government sponsored recovery strategy is under study to support the reintroducing of this predator of many pests to its former Canadian habitat.


title: Timber rattlesnake

text: Many were present in some of the thick forest areas of central and southeastern Iowa, mostly within the Mississippi, Skunk, Iowa, and Des Moines River valleys, in several places in these areas; bites from timber rattlesnakes have been widespread, especially in a localized area of Geode State Park, in southeastern Henry County, along Credit Island Park, in southern Scott County, and in the forested areas of southern Clinton County.


title: Timber rattlesnake

text: The museum at Amana Colony, Iowa, asserts that one founding family lost their firstborn, a daughter, at the age of three, due to a rattlesnake bite she received while playing on a woodpile in the 19th century.


title: Timber rattlesnake

text: In Pennsylvania, it is not heavily present west of Chestnut Ridge, which is in the Laurel Highlands, nor is it heavily present in the more urban areas of the southeastern corner of the state. Thus, its range does not include Philadelphia and Pittsburgh, the two largest cities in Pennsylvania.


title: Timber rattlesnake

text: In New York, timber rattlesnakes are "extirpated at 26% of historically known dens, and nearly extirpated at another 5%". Brown (1984, 1988) suggested denning populations in New York have been reduced by 50 to 75% of their historical numbers.


title: Timber rattlesnake

text: "C. horridus" is extirpated from Michigan, Delaware, Maine and Rhode Island, and is considered close to extirpation in New Hampshire.


title: Timber rattlesnake

text: In Massachusetts, the snakes are active from mid-May to mid-October. Early settlers were afraid of the snake, as its population was widespread throughout the state. The town of Westborough paid 13 men two shillings per day to rid a local hill of snakes in 1680. The hill had so many rattlesnakes, it was named "Boston Hill" because the number of snakes killed rivaled the population of the young city of Boston. In Milford, men would hunt the rattlesnakes between May and early June. According to Adin Ballou, when he arrived in town in 1824 snakes were still abundant, by 1881 they were still reported in some areas of town. Since that time their habitat has been reduced to the Blue Hills south of Boston, the Berkshires in Western Massachusetts, and parts of the Connecticut River Valley, notably in the area of the Holyoke Range. The snake is so rare in the state that it is rarely encountered by people and is considered endangered, making it illegal to harass, kill, collect, or possess. In September 2021, a five-foot long timber rattlesnake was recorded on video on a trail in the Blue Hills Reservation.


title: Timber rattlesnake

text: Generally, this species is found in deciduous forests in rugged terrain. During the summer, gravid (pregnant) females seem to prefer open, rocky ledges where the temperatures are higher, while males and nongravid females tend to spend more time in cooler, denser woodland with more closed forest canopy.


title: Timber rattlesnake

text: Female timber rattlers often bask in the sun before giving birth, in open rocky areas known as "basking knolls".


title: Timber rattlesnake

text: During the winter, timber rattlesnakes brumate in dens and limestone crevices, often together with copperheads and black rat snakes.


title: Timber rattlesnake

text: A lifetime reproduction study of a population in the Adirondack Mountains of New York found that the first reproduction occurs at a mean age of 9.6 years. The mean length of reproductive cycles is 4.2 years, the mean reproductive life span is 9.6 years, and the average fecundity is 7.7 offspring per litter. Nonviable offspring were found in 20% of the field litters. Most females only reproduced one. Macrogeographic differences were observed within the population and may have correlated resource levels influencing growth rates and additionally human encounters could influence survival.


title: Timber rattlesnake

text: Their prey are mainly small mammals, but may include small birds, frogs, and other small animals, including other snakes. Although capable of consuming other rattlesnakes, the most common snake they prey upon are garter snakes. Like most rattlesnakes, timber rattlesnakes are known to use chemical cues to find sites to ambush their prey and often strike their prey and track them until they can be consumed. Timber rattlesnakes are known to use fallen logs as a waiting site for prey to pass by, giving them an elevated perch from which to effectively strike their prey, which is almost entirely terrestrial rather than arboreal (even arboreal prey such as squirrels tend to be caught when they come to the ground). If the arboreal prey (squirrels) are in the trees, it was found that the snake might indicate vertical tree posture, meaning it leans up against a tree looking at the squirrel and waiting for it to come down. The primary foods by genera of timber rattlesnakes were as follows: "Peromyscus" (33.3%), "Microtus" (10.9%), "Tamias" (qv) (10.6%), "Sylvilagus" (10.4%), "Sigmodon" (5.3%) and "Sciurus" (4.2%). Based on examination of the snout-to-vent length, juvenile timber rattlesnakes were found to differ slightly in dietary preferences from adult rattlesnakes, being more likely to consume smaller prey such as shrews (averaging and unable to attack subadult eastern cottontail rabbits (averaging but "Peromyscus" was the number one prey item for both young and adult rattlesnakes. Several birds, although always secondary to mammals, are also known to be hunted, mainly ground-dwelling species such as bobwhites, but also a surprising number of passerines.


title: Timber rattlesnake

text: Potentially, this is one of North America's most dangerous snakes, due to its long fangs, impressive size, and high venom yield. This is to some degree offset by its relatively mild disposition and long brumation period. Before striking, they often perform a good deal of preliminary rattling and feinting. Cist (1845) described how he lived in western Pennsylvania for many years, and the species was quite common there, but in all that time, he heard of only a single death resulting from its bite.


title: Timber rattlesnake

text: Considerable geographic and ontogenetic variation occurs regarding the toxicity of the venom, which can be said for many rattlesnake species. Four venom patterns have been described for this species: Type A is largely neurotoxic, and is found in various parts of the southern range. One effect of the toxin can be generalized myokymia. Type B is hemorrhagic and proteolytic, and is found consistently in the north and in parts of the southeast. Type A + B is found in areas where the aforementioned types apparently intergrade in southwestern Arkansas and northern Louisiana. Type C venom has none of the above components and is relatively weak.


title: Timber rattlesnake

text: The neurotoxic component of the type A venom is referred to as canebrake toxin, and is a phospholipase A. It is analogous to the neurotoxins found in the venoms of several other rattlesnake species, and when present, contributes significantly to the overall toxicity. Other components found in the venom include a small basic peptide that works as a myotoxin, a fibrinogen-clotting enzyme that can produce defibrination syndrome, and a bradykinin-releasing enzyme.


title: Timber rattlesnake

text: CroFab antivenom, while not specific for "C. horridus", is used to treat envenomations from this species.


title: Timber rattlesnake

text: The timber rattlesnake was designated the state reptile of West Virginia in 2008. That state's legislature praised "...a proud contribution by the eighth grade class at Romney Middle School, from West Virginia's oldest county, in West Virginia's oldest town, to have been instrumental in making the timber rattlesnake the state reptile..."


title: Timber rattlesnake

text: This snake became a prominent symbol of American anger and resolve during the American Revolution due to its fearsome reputation. In the 18th century, European-trained doctors and scientists had little firsthand experience with or information on timber rattlesnakes, and treatment of their bites was poorly effective. The motto "Nemo me impune lacesset" (with the verb in the future tense) appears above a "Crotalus horridus" on a 1778 $20 bill from Georgia as an early example of the colonial use of the coiled rattlesnake symbol, which later became famous on the Gadsden flag.