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Amygdaloideae

Amygdaloideae is a subfamily within the flowering plant family Rosaceae. It was formerly considered by some authors to be separate from Rosaceae, and the family names Prunaceae and Amygdalaceae have been used. Reanalysis from 2007 has shown that the previous definition of subfamily Spiraeoideae was paraphyletic. To solve this problem, a larger subfamily was defined that includes the former Amygdaloideae, Spiraeoideae, and Maloideae. This subfamily, however, is to be called Amygdaloideae rather than Spiraeoideae under the International Code of Nomenclature for algae, fungi, and plants as updated in 2011.

As traditionally defined, the Amygdaloideae includes such commercially important crops as plum, cherry, apricot, peach, and almond. The fruit of these plants are known as stone fruit (drupes), as each fruit contains a hard shell (the endocarp) called a stone or pit, which contains the single seed.

The expanded definition of the Amygdaloideae adds to these commercially important crops such as apples and pears that have pome fruit, and also important ornamental plants such as Spiraea and Aruncus that have hard dry fruits.

Taxonomic history
The name Prunoideae is sometimes used, but is incorrect. The 1835 publication of that name by Gilbert Thomas Burnett (Burnett) is invalid because it lacks a description (or diagnosis or reference to an earlier description or diagnosis). Paul Fedorowitsch Horaninow (Horan.) published the name in 1847, but Amygdaloideae, published in 1832 by George Arnott Walker-Arnott, has priority and is therefore the correct name.

The taxonomy of this group of plants within the Rosaceae has recently been unclear. In 2001 it was reported that Amygdaloideae sensu stricto consists of two distinct genetic groups or "clades", Prunus–Maddenia and Exochorda–Oemleria–Prinsepia. Further refinement shows that Exochorda–Oemleria–Prinsepia is somewhat separate from Prunus–Maddenia–Pygeum, and that the traditional subfamilies Maloideae and Spiraeoideae must be included in Amygdaloideae if a paraphyletic group is to be avoided. With this classification, the genus Prunus is considered to include Armeniaca, Cerasus, Amygdalus, Padus, Laurocerasus, Pygeum, and Maddenia.

Robert Frost alluded to the merging of Amygdalaceae into Rosaceae in his poem The Rose Family, when he wrote "The rose is a rose and was always a rose / But the theory now goes that the apple's a rose, / and the pear is, and so's the plum, I suppose." In the next line he wrote, "The dear [i.e., "the dear Lord", euphemized] only knows what will next prove a rose." This referred to shifting botanical opinion which had recently reunited Amygdalaceae, Spiraeaceae, and Malaceae into Rosaceae (which matches de Jussieu's 1789 classification).

Classification
A recent classification places the following genera in the subfamily:

 * Adenostoma
 * Amelanchier
 * Aria here considered a subgenus of Sorbus
 * Aronia
 * Aruncus
 * Chaenomeles
 * Chamaebatiaria
 * Chamaemeles
 * Chamaemespilus here considered a subgenus of Sorbus
 * Coleogyne
 * Cormus here considered a subgenus of Sorbus
 * Cotoneaster
 * Crataegus
 * Cydonia
 * Dichotomanthes
 * Docynia
 * Docyniopsis
 * Eriobotrya
 * Eriolobus
 * Exochorda
 * Gillenia
 * Hesperomeles
 * Heteromeles
 * Holodiscus
 * Kageneckia
 * Kelseya
 * Kerria
 * Lindleya
 * Luetkea
 * Lyonothamnus
 * Malacomeles
 * Malus (Apples and crabapples)
 * Mespilus
 * Neillia
 * Neviusia
 * Oemleria
 * Osteomeles
 * Peraphyllum
 * Petrophytum
 * Photinia
 * Physocarpus
 * Prinsepia
 * Prunus (Peaches and almonds)
 * Pseudocydonia
 * Pyracantha
 * Pyrus (Pears)
 * Rhaphiolepis
 * Rhodotypos
 * Sibiraea
 * Sorbaria
 * Sorbus
 * Spiraea
 * Spiraeanthus
 * †Stonebergia (Early Eocene; Allenby Formation, Canada)
 * Stranvaesia
 * Torminalis here considered as Sorbus subgenus Torminaria
 * Vauquelinia
 * Xerospiraea

title: Amygdaloideae


text:
Rosoideae

The rose subfamily Rosoideae consists of more than 850 species, including many shrubs, perennial herbs, and fruit plants such as strawberries and brambles. Only a few are annual herbs.

The circumscription of the Rosoideae is still not wholly certain; recent genetic research has resulted in several changes at the genus level and the removal from Rosoideae of some genera (notably Cercocarpus, Cowania, Dryas and Purshia) previously included in the subfamily.

Genera

 * Acaena – bidibidis
 * Agrimonia – agrimonies
 * Alchemilla – lady's mantles
 * Aphanes – parsley-pierts (sometimes in Alchemilla )
 * Aremonia
 * Argentina – silverweeds (sometimes in Potentilla)
 * Bencomia
 * Chamaerhodos Bunge – little-rose
 * Cliffortia
 * Coluria
 * Comarum (formerly in Potentilla)
 * Dasiphora – woody cinquefoils (formerly in Potentilla)
 * Dendriopoterium (currently in Sanguisorba )
 * Drymocallis – sticky cinquefoils (formerly in Potentilla)
 * Fallugia
 * Filipendula
 * Fragaria – strawberries
 * Geum – avenses
 * Hagenia – African redwood
 * Leucosidea – oldwood
 * Marcetella
 * Margyricarpus – pearlfruit
 * Polylepis
 * Potaninia
 * Potentilla – typical cinquefoils
 * Poteridium
 * Poterium
 * Purpusia (sometimes in Potentilla )
 * Rosa – roses
 * Rubus – brambles and raspberries
 * Sanguisorba – burnets
 * Sarcopoterium
 * Sibbaldia
 * Sibbaldianthe
 * Sibbaldiopsis – three-toothed cinquefoil (formerly in Potentilla)
 * Sieversia
 * Spenceria
 * Tetraglochin
 * Waldsteinia (sometimes in Geum )

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Rosoideae


text:
Len Deighton

Leonard Cyril Deighton (born 18 February 1929) is a British author. His publications have included cookery books and works on history, but he is best known for his spy novels.

After completing his national service in the Royal Air Force, Deighton attended the Saint Martin's School of Art and the Royal College of Art in London; he graduated from the latter in 1955. He had several jobs before becoming a book and magazine illustrator and designed the cover for the first UK edition of Jack Kerouac's 1957 work On the Road. He also worked for a period in an advertising agency. During an extended holiday in France he wrote his first novel, The IPCRESS File, which was published in 1962 and was a critical and commercial success. He wrote several spy novels featuring the same central character, an unnamed working-class intelligence officer, cynical and tough. Between 1962 and 1966 Deighton was the food correspondent for The Observer and drew cookstrips—black and white graphic recipes with a limited number of words. A selection of these was collected and published in 1965 as Len Deighton's Action Cook Book, the first of five cookery books he wrote. Other topics of non-fiction include military history.

Many of Deighton's books have been best sellers and he has been favourably compared both with his contemporary John le Carré and his literary antecedents W. Somerset Maugham, Eric Ambler, Ian Fleming and Graham Greene. Deighton's fictional work is marked by a complex narrative structure, extensive research and an air of verisimilitude.

Several of Deighton's works have been adapted for film and radio. Films include The Ipcress File (1965), Funeral in Berlin (1966), Billion Dollar Brain (1967) and Spy Story (1976). In 1988 Granada Television produced the miniseries Game, Set and Match based on his trilogy of the same name, and in 1995 BBC Radio 4 broadcast a real time dramatisation of his 1970 novel Bomber.

Early life and early career: 1929–1961
Leonard Cyril Deighton was born in Marylebone, London, on 18 February 1929. His birth was in the infirmary of a workhouse as the local hospital was full. His father was the chauffeur and mechanic for Campbell Dodgson, the Keeper of Prints and Drawings at the British Museum; Deighton's mother was a part-time cook. At the time the family lived in Gloucester Place Mews near Baker Street. In 1940, during the Second World War, the eleven-year-old Deighton witnessed the arrest of Anna Wolkoff, a British subject of Russian descent for whom his mother cooked; Wolkoff was detained as a Nazi spy and charged with stealing correspondence between Winston Churchill and Franklin D. Roosevelt. Deighton said that observing her arrest was "a major factor in my decision to write a spy story at my first attempt at fiction".

Deighton was educated at St Marylebone Grammar and William Ellis schools, but was moved to an emergency school for part of the Second World War. After leaving school Deighton worked as a railway clerk before being conscripted for national service at the age of 17, which he completed with the Royal Air Force (RAF). While in the RAF he was trained as a photographer, often recording crime scenes with the Special Investigation Branch (SIB) as part of his duties. During his work with the SIB he learned to fly and became an experienced scuba diver.

After two and a half years with the RAF, Deighton received a demobilisation grant, enabling him to study at Saint Martin's School of Art where he won a scholarship to the Royal College of Art; he graduated from the college in 1955. While studying he held a temporary job in 1951 as a pastry chef at the Royal Festival Hall. He worked as a flight attendant for British Overseas Airways Corporation (BOAC) between 1956 and 1957 before becoming a professional illustrator. Much of his work as an illustrator was in advertising—he worked for agencies in New York and London—but he also illustrated magazines and over 200 book covers, including for the first UK edition of Jack Kerouac's 1957 work On the Road.

Writing career: 1961–
While he was working at the Royal Festival Hall, Deighton would make sketches to remember some of the steps he took preparing dishes. He developed the idea into the concept of the "cookstrip", a full recipe within a cartoon-style illustration. Following the publication of one of Deighton's cookstrips in the Daily Express in 1961, The Observer commissioned him to provide a weekly series for its own magazine, which he did between March 1962 and August 1966. He later explained:

"I was buying expensive cookbooks. I'm very messy, and didn't want to take them into the kitchen. So I wrote out the recipes on paper, and it was easier for me to draw three eggs than write 'three eggs'. So I drew three eggs, then put in an arrow. For me it was a natural way to work."

In 1962 Deighton's first novel, The IPCRESS File, was published; it had been written in 1960 while he was staying in the Dordogne, south west France. The book was soon a commercial success and was a best-seller in the UK, France and the US; the novel sold more than 2.5 million copies in three years. The story—written as a first-person narrative—introduced a working-class protagonist, cynical and tough. Deighton did not want to invent a name for the character and later explained "Some people felt that a contrivance, but I kept putting off inventing a name for him until I got to the end of the book and realised I could finish the book without giving him a name".

In 2017 Deighton described how he did not consider the character an anti-hero, but "a romantic, incorruptible figure in the mould of Philip Marlowe". Deighton described the inspiration of using a working-class spy among the Oxbridge-educated members of the Establishment as coming from his time at the advertising agency, when he was the only member of the company's board not to have been educated at Eton. He said "The IPCRESS File is about spies on the surface, but it's also really about a grammar school boy among public school boys and the difficulties he faces."

Deighton published two further novels with his unnamed protagonist—Horse Under Water (1963) and Funeral in Berlin (1964). Funeral in Berlin stayed on The New York Times best-seller list for twenty weeks and sold over forty thousand copies in hardback in 1965. He published two cookbooks in 1965, Len Deighton's Action Cook Book (a collection of his cookstrips from The Observer) and Où est le garlic (Where is the garlic), a collection of French recipes. Two further novels in the spy series followed—Billion-Dollar Brain (1966) and An Expensive Place to Die (1967)—after which he published his first historical non-fiction work, The Assassination of President Kennedy (1967), co-written with Michael Rand and Howard Loxton. During 1967 he also edited and contributed to Len Deighton's London Dossier, a work that described itself as "a real London guidebook". The book suggested the Rowton Houses owned by Rowton Hotels Ltd were doss-houses for the homeless. He and the publishers Jonathan Cape were sued for libel; they apologised, withdrew the suggestions made in the book by amending the claim in unsold editions and paid substantial damages.

In September 1967 he wrote an article in The Sunday Times Magazine about Operation Snowdrop, an SAS attack on Benghazi during the Second World War. Deighton wrote that the raid "suffered a lack of security" because David Stirling, the leader of the raid, "had insisted upon talking about the raid during two social gatherings at the British Embassy in Cairo although warned not to do so". Stirling sued Deighton and Times Newspapers for libel the following year as the implication was that his indiscretion had endangered the lives of his men. Stirling explained in court that one of the social gatherings was a dinner with Winston Churchill, Field Marshal Jan Smuts, General Sir Alan Brooke, General Sir Claude Auchinleck and General Harold Alexander; the second occasion was a private conversation with Churchill. Deighton and Times Newspapers apologised, published a correction and paid damages.

During the mid-1960s Deighton wrote for Playboy as a travel correspondent, and he provided a piece on the boom in spy fiction; An Expensive Place to Die  was serialised in the magazine in 1967. In 1968 Deighton was the producer of the film Only When I Larf, which was based on his novel of the same name. He was the writer and co-producer of Oh! What a Lovely War in 1969, but did not enjoy the process of making films, and had his name removed from the film's credits. In 1970 Deighton wrote Bomber, a fictional account of an RAF Bomber Command raid that goes wrong. To produce the novel he used an IBM MT/ST, and it is possible that this was the first novel to be written using a word processor. Deighton was interviewed on Desert Island Discs in June 1976 by Roy Plomley.

Deighton wrote Fighter: The True Story of the Battle of Britain, published in 1977, after being advised to do so by the historian A. J. P. Taylor. The book was well received by readers and reviewers, although the inclusion of interviews with German participants led to criticism from some. Taylor wrote the introduction for the book, describing it as a "brilliant analysis"; Albert Speer, once the Minister of Armaments for Adolf Hitler, thought it "an excellent, most thorough examination".

Fighter was followed in 1978 by another novel, SS-GB, the idea for which came from Ray Hawkey, Deighton's friend from art school and the designer of the covers of several of his books. While the two were discussing what would have happened if the Germans had won the Second World War, Hawkey asked Deighton if he thought there could be an alternative history novel. Blitzkrieg, Deighton's 1979 history of the rise of the Nazis and the fall of France, has a foreword written by General Walther Nehring, Chief of Staff to General Heinz Guderian. As at 2023 his last history book is Blood, Tears and Folly: An Objective Look at World War II (1993), which examined the events of the war up until 1942. Reviewing for The Times, Henry Stanhope considers the work "extremely readable", although he questions the structure of the book which focuses on different theatres of war, rather than using a purely chronological history. This approach, Stanhope considers, "presents a less complete picture to the reader". The historian Allan R. Millett considers that the book would have been improved by wider research into the Russian, Japanese and American aspects of the war.

Beginning in 1983 Deighton wrote three connected trilogies: Berlin Game (1983), Mexico Set (1984) and London Match (1985); Spy Hook (1988), Spy Line (1989) and Spy Sinker (1990); and Faith (1994), Hope (1995) and Charity (1996). Winter, a companion novel dealing with the lives of a German family from 1899 to 1945, which also provides an historical background to several of the characters from the trilogies, was published in 1987. The trilogies are centred on Bernard Samson, a tough, cynical and disrespectful MI6 intelligence officer.

Personal life
Deighton married the illustrator Shirley Thompson in 1960; the couple were divorced in 1976, having not lived together for over five years. He left Britain in 1969, and has lived abroad since, including in Ireland, Austria, France, the US and Portugal. He lived for a while in Blackrock, County Louth, where he married Ysabele de Ranitz in February 1980, the daughter of a Dutch diplomat. The couple have two sons.

Deighton does not like giving interviews, and these have been rare throughout his life; he also avoids appearing at literary festivals. He says that he does not enjoy being a writer and that "The best thing about writing books is being at a party and telling some pretty girl you write books, the worst thing is sitting at a typewriter and actually writing the book." After completing Faith, Hope and Charity in 1996, he decided to take a year off writing; at the end of the period, he decided that writing was "a mug's game" that he did not miss and did not have to do. By 2016 Deighton had retired from writing.

Works
According to the Gale Contemporary Novelists monographs, Deighton and fellow author John le Carré follow in the same literary tradition of British espionage writers as W. Somerset Maugham, Eric Ambler and Graham Greene. Deighton provides an "energetic style" and his fictional work is marked by a complex narrative structure, according to Gale. Deighton extensively researched the background and technical aspects of his storylines, and enjoyed this side of producing work; in 1976 he said "I like the research better than I like writing books". The literary analyst Gina Macdonald observes that the technical aspect of Deighton's work can overshadow the plots and characterisation in the novel when Deighton provides too much detail in a short passage, leading to what she calls "banal conversations, stilted and unconvincing". Deighton was elected to the Detection Club in 1969 and their work Howdunit, published in 2020, was dedicated to him.

Novels
According to the film and media historian Alan Burton, The IPCRESS File—along with le Carré's 1963 novel The Spy Who Came in from the Cold—"changed the nature of British spy fiction" as it brought in "a more insolent, disillusioned and cynical style to the espionage story". The novel used appendices and footnotes which, according to Burton, gave verisimilitude to the work. The academic George Grella considers Deighton's novels to be "stylish, witty [and] well-crafted", and that they provide "a convincingly detailed picture of the world of espionage while carefully examining the ethics and morality of that world". Deighton has expressed his admiration for the police procedural, which he considers has an authentic feel, and approaches his fiction writing as a "spy procedural". Burton considers The IPCRESS File to be "a marker of a new trend in mature, realistic espionage fiction".

The academic Clive Bloom considers that after Funeral in Berlin was published in 1964, Deighton "established a place for himself ... in the front rank of the spy genre, along with Graham Greene, Ian Fleming and John le Carré". Deighton's later works were less oblique than the earlier ones, and had, according to Bloom, "more subtlety and deeper characterization". Oliver Buckton, the professor of literature, also considers Deighton to be in the forefront of post-war spy writers. The crime writer and poet Julian Symons writes that "[t]he constant crackle of his dialogue makes Deighton a kind of poet of the spy story".

Grella considers Deighton to be "the angry young man of the espionage novel", with the central characters of his main novels—the unnamed protagonist from the IPCRESS series and Bernard Samson from the nine novels in which he appears—both working-class, cynical and streetwise, in contrast to the upper-class and ineffective senior members of the intelligence service in their respective novels. His working-class heroes also stand in contrast to Fleming's Eton and Fettes-educated smooth, upper-class character James Bond.

Adaptations
Several of Deighton's novels have been adapted as films, which include The Ipcress File (1965), Funeral in Berlin (1966), Billion Dollar Brain (1967) and Spy Story (1976). All feature the books' unnamed character, but they were given the full name "Harry Palmer" for the films; either the actor Michael Caine—who played Palmer in the films—or the producer for two of the three films, Harry Saltzman, came up with the name. Two television films also featured Palmer: Bullet to Beijing (1995) and Midnight in Saint Petersburg (1996); they were not based on Deighton's stories. All the films except Spy Story feature Caine as Palmer. Deighton's hands were used in The Ipcress File in place of Caine's for a scene in which Palmer breaks eggs into a bowl and whisks them. In March 2022 The Ipcress File, a television adaptation of Deighton's novel, was broadcast on UK television. Joe Cole was Palmer; Lucy Boynton and Tom Hollander also appeared in major roles.

Berlin Game, Mexico Set and London Match, the first trilogy of his Bernard Samson novel series, were made into Game, Set and Match, a thirteen-part television series by Granada Television in 1988. Although Quentin Tarantino expressed interest in adapting the trilogy, the project did not materialise. The nine Samson novels were in pre-production with Clerkenwell Films in 2013, with a script by Simon Beaufoy.

In 2017 the BBC adapted Deighton's novel SS-GB for a five-part miniseries, broadcast in one-hour episodes; Sam Riley played the lead role of Detective Superintendent Douglas Archer. In 1995 BBC Radio 4 broadcast a real-time dramatisation of Bomber. The drama was in four broadcasts, each of two hours, from 2:30 pm to midnight, threaded through the station's schedule of news and current affairs.

Legacy and influence
Deighton's work has been acknowledged by the thriller writer Jeremy Duns as being an influence on his own work. In Letters from Burma, the politician Aung San Suu Kyi mentions reading Deighton's books, while under house arrest. Suu Kyi wrote that she was passionate about Arthur Conan Doyle's tales of Sherlock Holmes and the spy novels of le Carré and Deighton. When asked by Christie's about his love for Indian art and how he started his collection, the writer V. S. Naipaul credited Deighton. "I met Len Deighton, the thriller writer, at dinner many years ago. He demonstrated to me that Indian art could really be approachable. I bought from ... Maggs because of Len Deighton pushing me onto [them] as being a very fair dealer, saying that they do not charge you much more than they should. That's a marvellous thing to be told".

Deighton's 1970 novel Bomber was listed in Anthony Burgess's 1984 work Ninety-Nine Novels as one of the 99 best novels in English since 1939. Bomber, the third album of the rock group Motörhead, was named after the novel, as the band's singer, Lemmy, was reading it at the time they were recording the album.

title: Len Deighton


text:
Reciprocal

Reciprocal may refer to:

In mathematics

 * Multiplicative inverse, in  mathematics, the number 1/x, which multiplied by x gives the product 1, also known as a reciprocal
 * Reciprocal polynomial, a polynomial obtained from another polynomial by reversing its coefficients
 * Reciprocal rule, a technique in calculus for calculating derivatives of reciprocal functions
 * Reciprocal spiral, a plane curve
 * Reciprocal averaging, a statistical technique for aggregating categorical data

In science and technology

 * Reciprocal aircraft heading, 180 degrees (the opposite direction) from a stated heading
 * Reciprocal lattice, a basis for the dual space of covectors, in crystallography
 * Reciprocal length, a measurement used in science
 * Reciprocating engine or piston engine
 * Reciprocating oscillation in physical wave theory

Life sciences and medicine

 * Hybrid (biology), in genetics, the result of a reciprocal pair of crossings, forming reciprocal hybrids
 * Reciprocal altruism, a form of symbiotic relationship in evolutionary biology
 * Reciprocal cross, a breeding experiment in genetics
 * Sherrington's law of reciprocal innervation in the theory of muscle activation

Social sciences

 * Reciprocal determinism, a theory in psychology

Linguistics

 * Reciprocal construction, a construction in which agent and patient are in a mutual relationship

In reciprocal relationships

 * Reciprocal license, a type of software licenses also known as copyleft
 * Reciprocal link between two web pages
 * Reciprocal obligation, in law, a type of agreement between two individuals
 * Reciprocal Public License (RPL), a software license

title: Reciprocal


text:
Spiraeoideae

The subfamily Spiraeoideae was traditionally a subfamily of flowering plants within the family Rosaceae. The taxonomy of this subfamily has changed several times in the last century as more detailed studies have been carried out. Spiraeoideae as defined before 2007 is paraphyletic, leading some authors to define a broader subfamily which includes the Spiraeoideae as well as the Maleae (plants such as pears and apples whose fruits are pomes), and the Amygdaloideae (including almonds and plums, whose fruits are drupes). Such an expanded subfamily is to be called Amygdaloideae under the International Code of Nomenclature for algae, fungi, and plants.

The traditional Spiraeoideae are shrubs. Most have simple leaves, but the genera Aruncus and Sorbaria have pinnately compound leaves. Carpels are usually 2–5. Most genera traditionally placed in the Spiraeoideae produce flowers with distinct follicles that, upon seed-set, mature to form fruits that are aggregates of follicles.

A traditional classification places the following genera in the subfamily:
 * Aruncus
 * Eriogynia
 * Euphronia
 * Exochorda
 * Gillenia
 * Holodiscus
 * Kageneckia
 * Lindleya
 * Neillia
 * Physocarpus
 * Quillaja
 * Sibiraea
 * Spiraea
 * Spiraeanthus
 * Sorbaria

Examples

 * Aruncus dioicus
 * False spirea, Sorbaria sorbifolia
 * Japanese spiraea, Spiraea japonica

title: Spiraeoideae


text:
Harry Palmer

Harry Palmer is the name given to the anti-hero protagonist of several films based on spy novels written by Len Deighton, in which the main character is an unnamed intelligence officer. For convenience, the novels are also often referred to as the "Harry Palmer" novels.

Michael Caine played Harry Palmer in three films based on published novels featuring this character: The Ipcress File (1965), Funeral in Berlin (1966) and Billion Dollar Brain (1967). Caine also starred as this character in two other films not directly based on Deighton's novels.

The Times called Caine "the epitome of Sixties cool in his first outing as the secret agent Harry Palmer". A trailer for his second role as Palmer described him as possessing "horn rims, cockney wit and an iron fist". The character's thick horn-rimmed glasses, girls, and disregard for authority was cited by Mike Myers as an influence for Austin Powers; Caine would later star in Austin Powers in Goldmember (2002), with his portrayal of Nigel Powers, father of secret agent Austin Powers, a spoof of Palmer.

Origin of the 'Harry Palmer' name
When developing the 1965 film The Ipcress File, based on Len Deighton's 1962 novel of the same name, the production team needed a name for the previously anonymous protagonist, a rough-edged, petty crook turned spy. They chose "Harry Palmer", because they wanted a mundane name, 'one that means absolutely nothing, a common name', to distance him from Ian Fleming's James Bond, the stereotypical sophisticated, swashbuckling spy. Caine says he knew a dull kid at school called "Palmer", with Harry Saltzman saying 'good, and what about a first name', with Caine innocently remarking "Harry", not realising his gaffe until seeing Saltzman's stare.

Early novels
Len Deighton introduced the lead character in The IPCRESS File, his first novel, published in November 1962. In that first-person novel, the intelligence officer is anonymous, although at one point he is greeted by someone saying "Hello, Harry"; he later says, "Now my name isn't Harry, but in this business it's hard to remember whether it ever had been." Deighton's character is described as working class, living in a back street flat and seedy hotels, and shopping in supermarkets. He wears glasses, is hindered by bureaucracy, and craves a pay rise. It is revealed in passing that he is from Burnley, Lancashire, and that he was born in 1922 or 1923.

Further novels featuring this character followed, including Horse Under Water (1963), Funeral in Berlin (1964), Billion-Dollar Brain (1966), and An Expensive Place to Die (1967). Again, the lead character is never named, but they appear to be the same character in all of the books. In his 2009 afterword to Horse Under Water, Deighton noted "Now, writing a second book, I found it an advantage to have an anonymous hero. He might be the same man; or maybe not. I was able to make minor changes to him and his background...I realized that...identifying him as a northerner would make demands on my knowledge that I could not sustain. It would be more sensible to give him a background closer to my own."

From the first novel onwards, the narrator shows knowledge of fine food and drink, painting, classical and 20th-century music, jazz, military history, and Latin. In Horse Under Water, he is described as an expert on world currency.

Later novels and discrepancies
In 1974, the novel Spy Story was published, followed by Yesterday's Spy (1975), and Twinkle, Twinkle, Little Spy (1976) (also known as Catch a Falling Spy in North America). As the protagonist also remains anonymous in these novels, it is still open to debate whether the narrator of these last three novels as the same as in the earlier books. There is conflicting evidence for either view. Despite this, and despite the lead protagonist being unnamed, all eight books have been unofficially called the Harry Palmer novels, based on the protagonist's name given in the subsequent film adaptations of The IPCRESS File and its sequels.

Evidence for this narrator being different from the earlier novels comes from Deighton himself, who is quoted as saying that the narrator of Spy Story is not the same character as the narrator of The IPCRESS File; in fact, for most of Spy Story, the narrator is named and addressed as "Patrick Armstrong" – although, as another character says, "We have so many different names." Additionally, he is reported to be in his late 30s, whereas the narrator of The IPCRESS File was born in 1922 or 1923 (making him in his 40s), and thus implying that this protagonist is different from that of the earlier novels.

Encouraging the unitary concept – that the later novels feature the same narrator – is the 1974 dust jacket to the Harcourt, Brace & Jovanovich American edition of Spy Story, in which the cover blurb states, "He is back, after five long-years' absence, the insubordinate, decent, bespectacled English spy who fought, fumbled, and survived his outrageous way through the best-selling Horse Under Water, Funeral in Berlin, and the rest of those marvellous, celebrated Len Deighton spy thrillers." Likewise, on the 1976 edition dust jacket to Catch a Falling Spy, the novel features "Deighton's familiar hero, our bespectacled Englishman". A number of minor characters from the earlier novels also appear in Spy Story, further connecting the books.

The Ipcress File
The IPCRESS File novel came out just after the release of the first James Bond film Dr. No (1962). When the novel reached best-seller status, Eon Productions film producers Harry Saltzman and Albert R. Broccoli approached Deighton to write the script for the second Bond film, From Russia with Love (1963). Little of Deighton's screenplay was actually used on the shoot. Saltzman decided instead to make use of The IPCRESS File in the expectation of beginning a new secret agent film series. Unlike the Bond films, The Ipcress File was designed to have a somewhat different, mostly rather naturalistic style, with hints of the kitchen sink school, film adaptations of which Saltzman had produced. Saltzman, however, also contracted crew members who had worked on the Bond films, including production designer Ken Adam, film editor Peter Hunt, and film score composer John Barry. Michael Caine was chosen to play the lead role.

In the film version, Harry Palmer is a British Army sergeant forcibly drafted into the security services to work away a prison sentence for black marketeering. He worked first for Army Intelligence, then the Foreign Office. He works for the brilliant but slightly duplicitous Colonel Ross. Harry Palmer has much in common with Deighton, including passions for military history (Harvey Newbegin complains about his bookshelf contents in Billion Dollar Brain), cooking, and classical music.

Sequels
After the release of The Ipcress File (1965), Saltzman's production company made Funeral in Berlin (1966) and Billion Dollar Brain (1967), both starring Michael Caine. The second Harry Palmer novel Horse Under Water was not used. In 1976, Deighton's novel Spy Story was filmed with Michael Petrovitch as 'Patrick Armstrong'; it is unrelated to Saltzman's Harry Palmer films.

In the mid-1990s, two further Harry Palmer films were released, this time with original screenplays and with Michael Caine returning to the role. These were Bullet to Beijing (1995) and Midnight in Saint Petersburg (1996). Despite sometimes being titled Len Deighton's Bullet to Beijing and Len Deighton's Midnight in St Petersburg, Deighton did not participate in the production of these films.

Allusions
Evidence of Michael Caine's popular identification as Harry Palmer can be seen in films such as Blue Ice (1992), where he plays an ex-spy named 'Harry', and who has many similarities to Harry Palmer.

Caine's Harry Palmer character (with the glasses, the girls, and disregard for authority) was an influence for Mike Myers’ spy action comedy films Austin Powers. At Myers request, Caine starred in Austin Powers in Goldmember (2002), with his portrayal of Nigel Powers, father of secret agent Austin Powers, a spoof of Harry Palmer.

In Kingsman: The Secret Service (2014), Caine portrays the bespectacled head of a secret espionage unit.

Television
In 2022, ITV released a six-part television adaptation of The Ipcress File, starring Joe Cole as Palmer.

title: Harry Palmer


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List of tram and light rail transit systems

The following is a list of cities that have current tram/streetcar (including heritage trams/heritage streetcars), or light rail systems as part of their regular public transit systems. In other words, this list only includes systems which operate year-round and provide actual transit service, not ones that are primarily tourist services, are seasonal-only, or are excursion-type tram operations.

Some transit systems branded as "light rail" such as the Docklands Light Railway in London, Ampang Line and Kelana Jaya Line of Kuala Lumpur, Malaysia qualify as metro systems (see medium-capacity rail system) and thus are not listed here – see List of metro systems.

Only currently operational tram and LRT systems are included in this listing – tram and LRT systems that have "suspended operation" or are presently under construction are excluded.

Legend

 * Location: Primary city served by the tram/streetcar or light rail system.
 * Country: Sovereign state in which the tram/streetcar or light rail system is located.
 * System:The English name of the tram system or overview article for city.
 * Year opened: The year the system opened for passenger service. For older systems, this may refer to horsecar service for those systems continuously in operation since their horsecar era.
 * Stations: The number of stations in the network, as quoted by the system's operator.
 * System length: The system length of a tram/streetcar or light rail network is the sum of the lengths of all routes in the rail network in kilometers (or miles). Each section of track is counted only once, regardless of how many lines pass over it, and regardless of whether it is single-track or multi-track, single carriageway or dual carriageway.
 * Type: Defines whether the system in question is a tram/streetcar system or a light rail transit system (or, in a few cases, whether the system is a heritage streetcar system).

Asia
All systems in Russia, including those in Asia, are listed together, for convenience, in the Europe section of this article, similarly all systems in Egypt are listed in the Africa section.

Europe
All systems in Kazakhstan and Turkey, including those in Europe, are listed together, for convenience, in the Asia section of this article. All systems in Russia, including those in Asia, are listed together, for convenience, in this section.

North America
The following systems provide regular transit service daily and year-round in North America, including those systems or lines using vintage or faux-vintage streetcars. For other heritage streetcar lines, ones with more limited service, see Streetcars in North America. North America, specifically more so the United States, once had extensive tram networks in almost all cities, but nearly all were removed for bus operations between the 1940s and the 1960s. These systems are listed at List of streetcar systems in the United States.


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Pantothenic acid

Pantothenic acid (vitamin B5) is a B vitamin and an essential nutrient. All animals need pantothenic acid in order to synthesize coenzyme A (CoA), which is essential for cellular energy production and for the synthesis and degradation of proteins, carbohydrates, and fats.

Pantothenic acid is the combination of pantoic acid and β-alanine. Its name comes from the Greek πάντοθεν pantothen, meaning "from everywhere", because pantothenic acid, at least in small amounts, is in almost all foods. Deficiency of pantothenic acid is very rare in humans. In dietary supplements and animal feed, the form commonly used is calcium pantothenate, because chemically it is more stable, and hence makes for longer product shelf-life, than sodium pantothenate and free pantothenic acid.

Definition
Pantothenic acid is a water-soluble vitamin, one of the B vitamins. It is synthesized from the amino acid β-alanine and pantoic acid (see biosynthesis and structure of coenzyme A figures). Unlike vitamin E or vitamin K, which occurs in several chemically related forms known as vitamers, pantothenic acid is only one chemical compound. It is a starting compound in the synthesis of coenzyme A (CoA), a cofactor for many enzyme processes.

Use in biosynthesis of coenzyme A
Pantothenic acid is a precursor to CoA via a five-step process. The biosynthesis requires pantothenic acid, cysteine, and four equivalents of ATP (see figure).
 * 1) Pantothenic acid is phosphorylated to 4′-phosphopantothenate by the enzyme pantothenate kinase. This is the committed step in CoA biosynthesis and requires ATP.
 * 2) A cysteine is added to 4′-phosphopantothenate by the enzyme phosphopantothenoylcysteine synthetase to form 4'-phospho-N-pantothenoylcysteine (PPC). This step is coupled with ATP hydrolysis.
 * 3) PPC is decarboxylated to 4′-phosphopantetheine by phosphopantothenoylcysteine decarboxylase
 * 4) 4′-Phosphopantetheine is adenylated (or more properly, AMPylated) to form dephospho-CoA by the enzyme phosphopantetheine adenylyl transferase
 * 5) Finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase. This final step also requires ATP.

This pathway is suppressed by end-product inhibition, meaning that CoA is a competitive inhibitor of pantothenate kinase, the enzyme responsible for the first step.

Coenzyme A is necessary in the reaction mechanism of the citric acid cycle. This process is the body's primary catabolic pathway and is essential in breaking down the building blocks of the cell such as carbohydrates, amino acids and lipids, for fuel. CoA is important in energy metabolism for pyruvate to enter the tricarboxylic acid cycle (TCA cycle) as acetyl-CoA, and for α-ketoglutarate to be transformed to succinyl-CoA in the cycle. CoA is also required for acylation and acetylation, which, for example, are involved in signal transduction, and various enzyme functions. In addition to functioning as CoA, this compound can act as an acyl group carrier to form acetyl-CoA and other related compounds; this is a way to transport carbon atoms within the cell. CoA is also required in the formation of acyl carrier protein (ACP), which is required for fatty acid synthesis. Its synthesis also connects with other vitamins such as thiamin and folic acid.

Dietary recommendations
The US Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for B vitamins in 1998. At that time there was not sufficient information to establish EARs and RDAs for pantothenic acid. In instances such as this, the Board sets Adequate Intakes (AIs), with the understanding that at some later date, AIs may be replaced by more exact information.

The current AI for teens and adults ages 14 and up is 5 mg/day. This was based in part on the observation that for a typical diet, urinary excretion was approximately 2.6 mg/day, and that bioavailability of food-bound pantothenic acid was roughly 50%. AI for pregnancy is 6 mg/day. AI for lactation is 7 mg/day. For infants up to 12 months the AI is 1.8 mg/day. For children ages 1–13 years the AI increases with age from 2 to 4 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).

While for many nutrients, the US Department of Agriculture uses food composition data combined with food consumption survey results to estimate average consumption, the surveys and reports do not include pantothenic acid in the analyses. Less formal estimates of adult daily intakes report about 4 to 7 mg/day.

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the US. For women and men over age 11 the Adequate Intake (AI) is set at 5 mg/day. AI for pregnancy is 5 mg/day, for lactation 7 mg/day. For children ages 1–10 years the AI is 4 mg/day. These AIs are similar to the US AIs.

Safety
As for safety, the IOM sets Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of pantothenic acid there is no UL, as there is no human data for adverse effects from high doses. The EFSA also reviewed the safety question and reached the same conclusion as in United States – that there was not sufficient evidence to set a UL for pantothenic acid.

Labeling requirements
For US food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For pantothenic acid labeling purposes 100% of the Daily Value was 10 mg, but as of May 2016 it was revised to 5 mg to bring it into agreement with the AI. Compliance with the updated labeling regulations was required by January 2020 for manufacturers with US$10 million or more in annual food sales, and by January 2021 for manufacturers with lower volume food sales. A table of the old and new adult daily values is provided at Reference Daily Intake.

Dietary
Food sources of pantothenic acid include animal-sourced foods, including dairy foods and eggs. Potatoes, tomato products, oat-cereals, sunflower seeds, avocado are good plant sources. Mushrooms are good sources, too. Whole grains are another source of the vitamin, but milling to make white rice or white flour removes much of the pantothenic acid, as it is found in the outer layers of whole grains. In animal feeds, the most important sources are alfalfa, cereal, fish meal, peanut meal, molasses, rice bran, wheat bran, and yeasts.

Supplements
Dietary supplements of pantothenic acid commonly use pantothenol (or panthenol), a shelf-stable analog, which is converted to pantothenic acid once consumed. Calcium pantothenate – a salt – may be used in manufacturing because it is more resistant than pantothenic acid to factors that deteriorate stability, such as acid, alkali or heat. The amount of pantothenic acid in dietary supplement products may contain up to 1,000 mg (200 times the Adequate Intake level for adults), without evidence that such large amounts provide any benefit. According to WebMD, pantothenic acid supplements have a long list of claimed uses, but there is insufficient scientific evidence to support any of them.

As a dietary supplement, pantothenic acid is not the same as pantethine, which is composed of two pantothenic acid molecules linked by a disulfide bridge. Sold as a high-dose supplement (600 mg), pantethine may be effective for lowering blood levels of LDL cholesterol – a risk factor for cardiovascular diseases – but its long-term effects are unknown, so use should be supervised by a physician. Dietary supplementation with pantothenic acid does not have the cholesterol-lowering effect as pantethine.

Fortification
According to the Global Fortification Data Exchange, pantothenic acid deficiency is so rare that no countries require that foods be fortified.

Absorption, metabolism and excretion
When found in foods, most pantothenic acid is in the form of CoA or bound to acyl carrier protein (ACP). For the intestinal cells to absorb this vitamin, it must be converted into free pantothenic acid. Within the lumen of the intestine, CoA and ACP are hydrolyzed into 4'-phosphopantetheine. The 4'-phosphopantetheine is then dephosphorylated into pantetheine. Pantetheinase, an intestinal enzyme, then hydrolyzes pantetheine into free pantothenic acid. Free pantothenic acid is absorbed into intestinal cells via a saturable, sodium-dependent active transport system. At high levels of intake, when this mechanism is saturated, some pantothenic acid may also be additionally absorbed via passive diffusion. As a whole, when intake increases 10-fold, absorption rate decreases to 10%.

Pantothenic acid is excreted in urine. This occurs after its release from CoA. Urinary amounts are on the order of 2.6 mg/day, but decreased to negligible amounts when subjects in multi-week experimental situations were fed diets devoid of the vitamin.

Deficiency
Pantothenic acid deficiency in humans is very rare and has not been thoroughly studied. In the few cases where deficiency has been seen (prisoners of war during World War II, victims of starvation, or limited volunteer trials), nearly all symptoms were reversed with orally administered pantothenic acid. Symptoms of deficiency are similar to other vitamin B deficiencies. There is impaired energy production, due to low CoA levels, which could cause symptoms of irritability, fatigue, and apathy. Acetylcholine synthesis is also impaired; therefore, neurological symptoms can also appear in deficiency; they include sensation of numbness in hands and feet, paresthesia and muscle cramps. Additional symptoms could include restlessness, malaise, sleep disturbances, nausea, vomiting and abdominal cramps.

In animals, symptoms include disorders of the nervous, gastrointestinal, and immune systems, reduced growth rate, decreased food intake, skin lesions and changes in hair coat, and alterations in lipid and carbohydrate metabolism. In rodents, there can be loss of hair color, which led to marketing of pantothenic acid as a dietary supplement which could prevent or treat graying of hair in humans (despite the lack of any human trial evidence).

Pantothenic acid status can be assessed by measuring either whole blood concentration or 24-hour urinary excretion. In humans, whole blood values less than 1 μmol/L are considered low, as is urinary excretion of less than 4.56 mmol/day.

Animal nutrition
Calcium pantothenate and dexpanthenol (D-panthenol) are European Food Safety Authority (EFSA) approved additives to animal feed. Supplementation is on the order of 8–20 mg/kg for pigs, 10–15 mg/kg for poultry, 30–50 mg/kg for fish and 8–14 mg/kg feed for pets. These are recommended concentrations, designed to be higher than what are thought to be requirements. There is some evidence that feed supplementation increases pantothenic acid concentration in tissues, i.e., meat, consumed by humans, and also for eggs, but this raises no concerns for consumer safety.

No dietary requirement for pantothenic acid has been established in ruminant species. Synthesis of pantothenic acid by ruminal microorganisms appears to be 20 to 30 times more than dietary amounts. Net microbial synthesis of pantothenic acid in the rumen of steer calves has been estimated to be 2.2 mg/kg of digestible organic matter consumed per day. Supplementation of pantothenic acid at 5 to 10 times theoretical requirements did not improve growth performance of feedlot cattle.

Biosynthesis
Bacteria synthesize pantothenic acid from the amino acids aspartate and a precursor to the amino acid valine. Aspartate is converted to β-alanine. The amino group of valine is replaced by a keto-moiety to yield α-ketoisovalerate, which, in turn, forms α-ketopantoate following transfer of a methyl group, then D-pantoate (also known as pantoic acid) following reduction. β-alanine and pantoic acid are then condensed to form pantothenic acid (see figure).

Industrial synthesis
The industrial synthesis of pantothenic acid starts with the aldol condensation of isobutyraldehyde and formaldehyde. The resulting hydroxypivaldehyde is converted to its cyanohydrin derivative. which is cyclised to give racemic pantolactone. This sequence of reactions was first published in 1904.
 * Pantothenic acid synthesis.svg

Synthesis of the vitamin is completed by resolution of the lactone using quinine, for example, followed by treatment with the calcium or sodium salt of β-alanine.

History
The term vitamin is derived from the word vitamine, which was coined in 1912 by Polish biochemist Casimir Funk, who isolated a complex of water-soluble micronutrients essential to life, all of which he presumed to be amines. When this presumption was later determined not to be true, the "e" was dropped from the name, hence "vitamin". Vitamin nomenclature was alphabetical, with Elmer McCollum calling these fat-soluble A and water-soluble B. Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with pantothenic acid as vitamin B5.

The essential nature of pantothenic acid was discovered by Roger J. Williams in 1933 by showing it was required for the growth of yeast. Three years later Elvehjem and Jukes demonstrated that it was a growth and anti-dermatitis factor in chickens. Williams dubbed the compound "pantothenic acid", deriving the name from the Greek word pantothen, which translates as "from everywhere". His reason was that he found it to be present in almost every food he tested. Williams went on to determine the chemical structure in 1940. In 1953, Fritz Lipmann shared the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism", work he had published in 1946.

authors: حسن علي البط

title: Pantothenic acid


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Vitamin E

Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitamin E, can cause nerve problems. Vitamin E is a fat-soluble antioxidant which may help protect cell membranes from reactive oxygen species. Worldwide, government organizations recommend adults consume in the range of 3 to 15 mg per day. As of 2016, consumption was below recommendations according to a worldwide summary of more than one hundred studies that reported a median dietary intake of 6.2 mg per day for alpha-tocopherol. Foods rich in vitamin E include seeds and nuts, seed oils, peanut butter, and vitamin E-fortified foods, such as margarine.

Population studies suggested that people who consumed foods with more vitamin E, or who chose on their own to consume a vitamin E dietary supplement, had lower incidence of cardiovascular diseases, cancer, dementia, and other diseases. However, placebo-controlled clinical trials using alpha-tocopherol as a supplement, with daily amounts as high as 2,000 mg per day, could not always replicate these findings. In the United States vitamin E supplement use peaked around 2002, but has declined by more than half by 2006. The authors theorized that declining use may have been due to publications of large placebo-controlled studies that showed either no benefits or actual negative consequences from high-dose vitamin E.

Both natural and synthetic tocopherols are subject to oxidation, so dietary supplements are esterified, creating tocopheryl acetate for stability purposes. Tocopherols and tocotrienols both occur in α (alpha), β (beta), γ (gamma), and δ (delta) forms, as determined by the number and position of methyl groups on the chromanol ring. All eight of these vitamers feature a chromane double ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals, and a hydrophobic side chain that allows for penetration into biological membranes.

Vitamin E was discovered in 1922, isolated in 1935, and first synthesized in 1938. Because the vitamin activity was first identified as essential for fertilized eggs to result in live births (in rats), it was given the name "tocopherol" from Greek words meaning birth and to bear or carry. Alpha-tocopherol, either naturally extracted from plant oils or, most commonly, as the synthetic tocopheryl acetate, is sold as a popular dietary supplement, either by itself or incorporated into a multivitamin product, and in oils or lotions for use on skin.

Chemistry
The nutritional content of vitamin E is defined by equivalency to 100% RRR-configuration α-tocopherol activity. The molecules that contribute α-tocopherol activity are four tocopherols and four tocotrienols, within each group of four identified by the prefixes alpha- (α-), beta- (β-), gamma- (γ-), and delta- (δ-). For alpha(α)-tocopherol each of the three "R" sites has a methyl group (CH3) attached. For beta(β)-tocopherol: R1 = methyl group, R2 = H, R3 = methyl group. For gamma(γ)-tocopherol: R1 = H, R2 = methyl group, R3 = methyl group. For delta(δ)-tocopherol: R1 = H, R2 = H, R3 = methyl group. The same configurations exist for the tocotrienols, except that the hydrophobic side chain has three carbon-carbon double bonds whereas the tocopherols have a saturated side chain.

Stereoisomers
In addition to distinguishing tocopherols and tocotrienols by position of methyl groups, the tocopherols have a phytyl tail with three chiral points or centers that can have a right or left orientation. The naturally occurring plant form of alpha-tocopherol is RRR-α-tocopherol, also referred to as d-tocopherol, whereas the synthetic form (all-racemic or all-rac vitamin E, also dl-tocopherol) is equal parts of eight stereoisomers RRR, RRS, RSS, SSS, RSR, SRS, SRR and SSR with progressively decreasing biological equivalency, so that 1.36 mg of dl-tocopherol is considered equivalent to 1.0 mg of d-tocopherol, the natural form. Rephrased, the synthetic has 73.5% of the potency of the natural.

Tocopherols
Alpha-tocopherol is a lipid-soluble antioxidant functioning within the glutathione peroxidase pathway, and protecting cell membranes from oxidation by reacting with lipid radicals produced in the lipid peroxidation chain reaction. This removes the free radical intermediates and prevents the oxidation reaction from continuing. The oxidized α-tocopheroxyl radicals produced in this process may be recycled back to the active reduced form through reduction by other antioxidants, such as ascorbate, retinol or ubiquinol. Other forms of vitamin E have their own unique properties; for example, γ-tocopherol is a nucleophile that can react with electrophilic mutagens.

Tocotrienols
The four tocotrienols (alpha, beta, gamma, delta) are similar in structure to the four tocopherols, with the main difference being that the former have hydrophobic side chains with three carbon-carbon double bonds, whereas the tocopherols have saturated side chains. For alpha(α)-tocotrienol each of the three "R" sites has a methyl group (CH3) attached. For beta(β)-tocotrienol: R1 = methyl group, R2 = H, R3 = methyl group. For gamma(γ)-tocotrienol: R1 = H, R2 = methyl group, R3 = methyl group. For delta(δ)-tocotrienol: R1 = H, R2 = H, R3 = methyl group. Palm oil is a good source of alpha and gamma tocotrienols.

Tocotrienols have only a single chiral center, which exists at the 2' chromanol ring carbon, at the point where the isoprenoid tail joins the ring. The other two corresponding centers in the phytyl tail of the corresponding tocopherols do not exist as chiral centers for tocotrienols due to unsaturation (C-C double bonds) at these sites. Tocotrienols extracted from plants are always dextrorotatory stereoisomers, signified as d-tocotrienols. In theory, levorotatory forms of tocotrienols (l-tocotrienols) could exist as well, which would have a 2S rather than 2R configuration at the molecules' single chiral center, but unlike synthetic dl-alpha-tocopherol, the marketed tocotrienol dietary supplements are extracted from palm oil. A number of health benefits of tocotrienols have been proposed, including decreased risk of age-associated cognitive impairment, heart disease and cancer. The evidence is not conclusive.

Functions
Vitamin E may have various roles as a vitamin. Many biological functions have been postulated, including a role as a fat-soluble antioxidant. In this role, vitamin E acts as a radical scavenger, delivering a hydrogen (H) atom to free radicals. At 323 kJ/mol, the O-H bond in tocopherols is about 10% weaker than in most other phenols. This weak bond allows the vitamin to donate a hydrogen atom to the peroxyl radical and other free radicals, minimizing their damaging effect. The thus-generated tocopheryl radical is recycled to tocopherol by a redox reaction with a hydrogen donor, such as vitamin C.

Vitamin E affects gene expression and is an enzyme activity regulator, such as for protein kinase C (PKC) – which plays a role in smooth muscle growth – with vitamin E participating in deactivation of PKC to inhibit smooth muscle growth.

Biosynthesis
Photosynthesizing plants, algae and cyanobacteria synthesize tocochromanols, the chemical family of compounds made up of four tocopherols and four tocotrienols; in a nutrition context this family is referred to as Vitamin E. Biosynthesis starts with formation of the closed-ring part of the molecule as homogentisic acid (HGA). The side chain is attached (saturated for tocopherols, polyunsaturated for tocotrienols). The pathway for both is the same, so that gamma- is created and from that alpha-, or delta- is created and from that the beta- compounds. Biosynthesis takes place in the plastids.

As to why plants synthesize tocochromanols, the major reason appears to be for antioxidant activity. Different parts of plants, and different species, are dominated by different tocochromanols. The predominant form in leaves, and hence leafy green vegetables, is α-tocopherol. Location is in chloroplast membranes, in close proximity to the photosynthetic process. The function is to protect against damage from the ultraviolet radiation of sunlight. Under normal growing conditions the presence of α-tocopherol does not appear to be essential, as there are other photo-protective compounds, and plants that through mutations have lost the ability to synthesize α-tocopherol demonstrate normal growth. However, under stressed growing conditions such as drought, elevated temperature or salt-induced oxidative stress, the plants' physiological status is superior if it has the normal synthesis capacity.

Seeds are lipid-rich, to provide energy for germination and early growth. Tocochromanols protect the seed lipids from oxidizing and becoming rancid. The presence of tocochromanols extends seed longevity, and promotes successful germination and seedling growth. Gamma-tocopherol dominates in seeds of most plant species, but there are exceptions. For canola, corn and soy bean oils, there is more γ-tocopherol than α-tocopherol, but for safflower, sunflower and olive oils the reverse is true. Of the commonly used food oils, palm oil is unique in that tocotrienol content is higher than tocopherol content. Seed tocochromanols content is also dependent on environmental stressors. In almonds, for example, drought or elevated temperature increase α-tocopherol and γ-tocopherol content of the nuts. The same article mentions that drought increases the tocopherol content of olives, and heat likewise for soybeans.

Vitamin E biosynthesis occurs in the plastid and goes through two different pathways: the Shikimate pathway and the Methylerythritol Phosphate pathway (MEP pathway). The Shikimate pathway generates the chromanol ring from the Homogentisic Acid (HGA) and the MEP pathway produces the hydrophobic tail which differs between tocopherol and tocotrienol. The synthesis of the specific tail is dependent on which molecule it originates from. In a tocopherol, its prenyl tail emerges from the geranylgeranyl diphosphate (GGDP) group, while the phytyl tail of a tocotrienol stems from a phytyl diphosphate.

Industrial synthesis
The synthetic product is all-rac-alpha-tocopherol, also referred to as dl-alpha tocopherol. It consists of eight stereoisomers (RRR, RRS, RSS, RSR, SRR, SSR, SRS and SSS) in equal quantities. "It is synthesized from a mixture of toluene and 2,3,5-trimethyl-hydroquinone that reacts with isophytol to all-rac-alpha-tocopherol, using iron in the presence of hydrogen chloride gas as catalyst. The reaction mixture obtained is filtered and extracted with aqueous caustic soda. Toluene is removed by evaporation and the residue (all rac-alpha-tocopherol) is purified by vacuum distillation." The natural alpha tocopherol extracted from plants is RRR-alpha tocopherol, referred to as d-alpha-tocopherol. The synthetic has 73.5% of the potency of the natural. Manufacturers of dietary supplements and fortified foods for humans or domesticated animals convert the phenol form of the vitamin to an ester using either acetic acid or succinic acid because the esters are more chemically stable, providing for a longer shelf-life.

Deficiency
Vitamin E deficiency is rare in humans, occurring as a consequence of abnormalities in dietary fat absorption or metabolism rather than from a diet low in vitamin E. One example of a genetic abnormality in metabolism is mutations of genes coding for alpha-tocopherol transfer protein (α-TTP). Humans with this genetic defect exhibit a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED) despite consuming normal amounts of vitamin E. Large amounts of alpha-tocopherol as a dietary supplement are needed to compensate for the lack of α-TTP. Vitamin E deficiency due to either malabsorption or metabolic anomaly can cause nerve problems due to poor conduction of electrical impulses along nerves due to changes in nerve membrane structure and function. In addition to ataxia, vitamin E deficiency can cause peripheral neuropathy, myopathies, retinopathy, and impairment of immune responses.

Drug interactions
The amounts of alpha-tocopherol, other tocopherols and tocotrienols that are components of dietary vitamin E, when consumed from foods, do not appear to cause any interactions with drugs. Consumption of alpha-tocopherol as a dietary supplement in amounts in excess of 300 mg/day may lead to interactions with aspirin, warfarin and cyclosporine A in ways that alter function. For aspirin and warfarin, high amounts of vitamin E may potentiate anti-blood clotting action. In multiple clinical trials, vitamin E lowered blood concentration of the immunosuppressant medication, cyclosporine A. The US National Institutes of Health, Office of Dietary Supplements, raises a concern that co-administration of vitamin E could counter the mechanisms of anti-cancer radiation therapy and some types of chemotherapy, and so advises against its use in these patient populations. The references it cited reported instances of reduced treatment adverse effects, but also poorer cancer survival, raising the possibility of tumor protection from the intended oxidative damage by the treatments.

Dietary recommendations
The U.S. National Academy of Medicine updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin E in 2000. RDAs are higher than EARs so as to identify amounts that will cover people with higher than average requirements. Adequate intakes (AIs) are identified when there is not sufficient information to set EARs and RDAs. The EAR for vitamin E for women and men ages 14 and up is 12 mg/day. The RDA is 15 mg/day. As for safety, tolerable upper intake levels ("upper limits" or ULs) are set for vitamins and minerals when evidence is sufficient. Hemorrhagic effects in rats were selected as the critical endpoint to calculate the upper limit via starting with the lowest-observed-adverse-effect-level. The result was a human upper limit set at 1000 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes.

The European Food Safety Authority (EFSA) refers to the collective set of information as dietary reference values, with population reference intakes (PRIs) instead of RDAs, and average requirements instead of EARs. AIs and ULs are defined the same as in the United States. For women and men ages 10 and older, the PRIs are set at 11 and 13 mg/day, respectively. PRI for pregnancy is 11 mg/day, for lactation 11 mg/day. For children ages 1–9 years the PRIs increase with age from 6 to 9 mg/day. The EFSA used an effect on blood clotting as a safety-critical effect. It identified that no adverse effects were observed in a human trial as 540 mg/day, used an uncertainty factor of 2 to derive an upper limit of half of that, then rounded to 300 mg/day.

The Japan National Institute of Health and Nutrition set adult AIs at 6.5 mg/day (females) and 7.0 mg/day (males), and 650–700 mg/day (females), and 750–900 mg/day (males) for upper limits, amounts depending on age. India recommends an intake of 8–10 mg/day and does not set an upper limit. The World Health Organization recommends that adults consume 10 mg/day. The United Kingdom is an outlier, in that it recommends 4 mg/day for adult men and 3 mg/day for adult women.

Consumption is below these government recommendations. Government survey results in the United States reported average consumption for adult females at 8.4 mg/d and adult males 10.4 mg/d. Both are below the RDA of 15 mg/day. A worldwide summary of more than one hundred studies reported a median dietary intake of 6.2 mg/d for alpha-tocopherol.

Food labeling
For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of daily value. For vitamin E labeling purposes 100% of the daily value was 30 international units, but as of 27 May 2016, it was revised to 15 mg to bring it into agreement with the RDA. A table of the old and new adult daily values is provided at Reference Daily Intake.

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of daily values, amounts are shown as percent of reference intakes (RIs). For vitamin E, 100% RI was set at 12 mg in 2011.

The international unit measurement was used by the United States in 1968–2016. 1 IU is the biological equivalent of about 0.667 mg d (RRR)-alpha-tocopherol (2/3 mg exactly), or of 0.90 mg of dl-alpha-tocopherol, corresponding to the then-measured relative potency of stereoisomers. In May 2016, the measurements have been revised, such that 1 mg of "Vitamin E" is 1 mg of d-alpha-tocopherol or 2 mg of dl-alpha-tocopherol. The change was originally started in 2000, when forms of Vitamin E other than alpha-tocopherol was dropped from dietary calculations by the IOM. The UL amount disregards any conversion. The EFSA has never used an IU unit, and their measurement only considers RRR-alpha-tocopherol.

Supplements
Vitamin E is fat soluble, so dietary supplement products are usually in the form of the vitamin, esterified with acetic acid to generate tocopheryl acetate, and dissolved in vegetable oil in a softgel capsule. For alpha-tocopherol, amounts range from 100 to 1000 IU per serving. Smaller amounts are incorporated into multi-vitamin/mineral tablets. Gamma-tocopherol and tocotrienol supplements are also available from dietary supplement companies. The latter are extracts from palm oil.

Fortification
The World Health Organization does not have any recommendations for food fortification with vitamin E. The Food Fortification Initiative does not list any countries that have mandatory or voluntary programs for vitamin E. Infant formulas have alpha-tocopherol as an ingredient. In some countries, certain brands of ready-to-eat cereals, liquid nutrition products and other foods have alpha-tocopherol as an added ingredient.

Non-nutrient food additives
Various forms of vitamin E are common food additive in oily food, used to deter rancidity caused by peroxidation. Those with an E number include:
 * 1) E306 Tocopherol-rich extract (mixed, natural, can include tocotrienol)
 * 2) E307 Alpha-tocopherol (synthetic)
 * 3) E308 Gamma-tocopherol (synthetic)
 * 4) E309 Delta-tocopherol (synthetic)

These E numbers include all racemic forms and acetate esters thereof. Commonly found on food labels in Europe and some other countries, their safety assessment and approval are the responsibility of the European Food Safety Authority.

Absorption, metabolism, excretion
Tocotrienols and tocopherols, the latter including the stereoisomers of synthetic alpha-tocopherol, are absorbed from the intestinal lumen, incorporated into chylomicrons, and secreted into the portal vein, leading to the liver. Absorption efficiency is estimated at 51% to 86%, and that applies to all of the vitamin E family – there is no discrimination among the vitamin E vitamers during absorption. Bile is necessary for chylomicron formation, so disease conditions such as cystic fibrosis result in biliary insufficiency and vitamin E malabsorption. When consumed as an alpha-tocopheryl acetate dietary supplement, absorption is promoted when consumed with a fat-containing meal. Unabsorbed vitamin E is excreted via feces. Additionally, vitamin E is excreted by the liver via bile into the intestinal lumen, where it will either be reabsorbed or excreted via feces, and all of the vitamin E vitamers are metabolized and then excreted via urine.

Upon reaching the liver, RRR-alpha-tocopherol is preferentially taken up by alpha-tocopherol transfer protein (α-TTP). All other forms are degraded to 2'-carboxethyl-6-hydroxychromane (CEHC), a process that involves truncating the phytic tail of the molecule, then either sulfated or glycuronidated. This renders the molecules water-soluble and leads to excretion via urine. Alpha-tocopherol is also degraded by the same process, to 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychromane (α-CEHC), but more slowly because it is partially protected by α-TTP. Large intakes of α-tocopherol result in increased urinary α-CEHC, so this appears to be a means of disposing of excess vitamin E.

Alpha-tocopherol transfer protein is coded by the TTPA gene on chromosome 8. The binding site for RRR-α-tocopherol is a hydrophobic pocket with a lower affinity for beta-, gamma-, or delta-tocopherols, or for the stereoisomers with an S configuration at the chiral 2 site. Tocotrienols are also a poor fit because the double bonds in the phytic tail create a rigid configuration that is a mismatch with the α-TTP pocket. A rare genetic defect of the TTPA gene results in people exhibiting a progressive neurodegenerative disorder known as ataxia with vitamin E deficiency (AVED) despite consuming normal amounts of vitamin E. Large amounts of alpha-tocopherol as a dietary supplement are needed to compensate for the lack of α-TTP. The role of α-TTP is to move α-tocopherol to the plasma membrane of hepatocytes (liver cells), where it can be incorporated into newly created very low density lipoprotein (VLDL) molecules. These convey α-tocopherol to cells in the rest of the body. As an example of a result of the preferential treatment, the US diet delivers approximately 70 mg/d of γ-tocopherol and plasma concentrations are on the order of 2–5 μmol/L; meanwhile, dietary α-tocopherol is about 7 mg/d but plasma concentrations are in the range of 11–37 μmol/L.

Affinity of α-TTP for vitamin E vitamers

Testing for levels
A worldwide summary of more than one hundred human studies reported a median of 22.1 μmol/L for serum α-tocopherol, and defined α-tocopherol deficiency as less than 12 μmol/L. It cited a recommendation that serum α-tocopherol concentration be ≥30 μmol/L to optimize health benefits. In contrast, the U.S. Dietary Reference Intake text for vitamin E concluded that a plasma concentration of 12 μmol/L was sufficient to achieve normal ex vivo hydrogen peroxide-induced hemolysis. A 2014 review defined less than 9 μmol/L as deficient, 9-12 μmol/L as marginal, and greater than 12 μmol/L as adequate.

Serum concentration increases with age. This is attributed to the fact that vitamin E circulates in blood incorporated into lipoproteins, and serum lipoprotein concentrations increase with age. Infants and young children have a higher risk of being below the deficiency threshold. Cystic fibrosis and other fat malabsorption conditions can result in low serum vitamin E. Dietary supplements will raise serum vitamin E.

Medical applications
For the conditions described below, the results of randomized clinical trials (RCTs) do not always concur with the observational evidence. This could be a matter of amount. Observational studies compare low consumers to high consumers based on intake from food. Diets higher in vitamin E may contain other compounds that convey health benefits, or be consumed by people who make non-diet lifestyle choices that lower disease risk, so that the observed effect may not be due to the vitamin E content. Meanwhile, many of the published RCTs used amounts of alpha-tocopherol 20X to 30X higher than what can be achieved from food.

Declining supplement use
In the United States, vitamin E supplement use by female health professionals was 16.1% in 1986, 46.2% in 1998, 44.3% in 2002, but decreased to 19.8% in 2006. Similarly, for male health professionals, rates for same years were 18.9%, 52.0%, 49.4% and 24.5%. The authors theorized that declining use in these populations may have been due to publications of studies that showed either no benefits or negative consequences from vitamin E supplements. Within the U.S. military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%. A report on vitamin E sales volume in the US documented a 50% decrease between 2000 and 2006, with a potential reason being a meta-analysis that concluded high-dosage (≥400 IU/d for at least 1 year) vitamin E was associated with an increase in all-cause mortality.

All-cause mortality
Two meta-analyses concluded that as a dietary supplement, vitamin E neither improved nor impaired all-cause mortality. An older meta-analysis had concluded high-dosage (≥400 IU/d for at least 1 year) vitamin E was associated with an increase in all-cause mortality. The authors acknowledged that the cited high-dose trials were often small and performed with people who already had chronic diseases. A meta-analysis of long-term clinical trials reported a non-significant 2% increase in all-cause mortality when alpha-tocopherol was the only supplement used. The same meta-analysis reported a statistically significant 3% increase for results when alpha-tocopherol was used in combination with other nutrients (vitamin A, vitamin C, beta-carotene, selenium).

Age-related macular degeneration
No changes seen for risk of developing age-related macular degeneration from long-term vitamin E suplementation.

Alzheimer's disease
An older review of dietary intake studies reported that higher consumption of vitamin E from foods lowered the risk of developing Alzheimer's disease (AD) by 24%. A 2017 Cochrane review reported on vitamin E as a potential dietary benefit for mild cognitive impairment (MCI) and Alzheimer's disease. Based on evidence from one trial in each of the categories, the study found insufficient evidence for supplemental vitamin E to prevent progression from MCI to dementia, but it did indicate slowing of functional decline in people with AD. Given the small number of trials and subjects, the authors recommended further research. A 2018 meta-analysis found lower vitamin E blood levels in AD people compared to healthy, age-matched people. In 2017, a consensus statement from the British Association for Psychopharmacology concluded that, until further information is available, vitamin E cannot be recommended for treatment or prevention of Alzheimer's disease.

Cancer
In a 2022 update of an earlier report, the United States Preventive Services Task Force recommended against the use of vitamin E supplements for the prevention of cardiovascular disease or cancer, concluding there was insufficient evidence to assess the balance of benefits and harms, yet also concluding with moderate certainty that there is no net benefit of supplementation.

As for literature on different types of cancer, an inverse relationship between dietary vitamin E and kidney cancer and bladder cancer is seen in observational studies. The risk reduction was 19% when highest and lowest intake groups were compared. The authors concluded that randomized controlled trials are needed. A large study comparing placebo to an all rac-alpha-tocopherol group consuming 400 IU/day reported no difference in bladder cancer cases. An inverse relationship between dietary vitamin E and lung cancer was reported in observational studies. The relative risk reduction was 16% when highest and lowest intake groups were compared. The benefit was progressive as dietary intake increased from 2 mg/day to 16 mg/day. The authors noted that the findings need to be confirmed by prospective studies. One such large trial, which compared 50 mg alpha-tocopherol to placebo in male tobacco smokers, reported no impact on lung cancer. A trial which tracked people who chose to consume a vitamin E dietary supplement reported an increased risk of lung cancer for those consuming more than 215 mg/day.

For prostate cancer, there are also conflicting results. A meta-analysis based on serum alpha-tocopherol content reported an inverse correlation, with the difference between lowest and highest a 21% reduction in relative risk. In contrast, a meta-analysis of observational studies reported no relationship for dietary vitamin E intake. There were also conflicting results from large RCTs. The ATBC trial administered placebo or 50 mg/day alpha-tocopherol to male tobacco smokers for 5 to 8 years and reported a 32% decrease in the incidence of prostate cancer. Conversely, the SELECT trial of selenium and vitamin E for prostate cancer enrolled men ages 55 or older, mostly non-smokers, to consume a placebo or a 400 IU/day dietary supplement. It reported relative risk as a statistically significant 17% higher for the vitamin group.

For colorectal cancer, a systematic review identified RCTs of vitamin E and placebo followed for 7–10 years. There was a non-significant 11% decrease in relative risk. The SELECT trial (men over 55 years, placebo or 400 IU/day) also reported on colorectal cancer. There was a non-significant 3% increase in adenoma occurrence compared to placebo. The Women's Health Study reported no significant differences for incidences of all types of cancer, cancer deaths, or specifically for breast, lung or colon cancers.

Potential confounding factors are the form of vitamin E used in prospective studies and the amounts. Synthetic, racemic mixtures of vitamin E isomers are not bioequivalent to natural, non-racemic mixtures, yet are widely used in clinical trials and as dietary supplement ingredients. One review reported a modest increase in cancer risk with vitamin E supplementation while stating that more than 90% of the cited clinical trials used the synthetic, racemic form dl-alpha-tocopherol.

Cancer health claims
The U.S. Food and Drug Administration initiated a process of reviewing and approving food and dietary supplement health claims in 1993. Reviews of petitions results in proposed claims being rejected or approved. If approved, specific wording is allowed on package labels. In 1999, a second process for claims review was created. If there is not a scientific consensus on the totality of the evidence, a Qualified Health Claim (QHC) may be established. The FDA does not "approve" qualified health claim petitions. Instead, it issues a Letter of Enforcement Discretion that includes very specific claim language and the restrictions on using that wording. The first QHCs relevant to vitamin E were issued in 2003: "Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer." In 2009, the claims became more specific, allowing that vitamin E might reduce the risk of renal, bladder and colorectal cancers, but with required mention that the evidence was deemed weak and the claimed benefits highly unlikely. A petition to add brain, cervical, gastric and lung cancers was rejected. A further revision, May 2012, allowed that vitamin E may reduce risk of renal, bladder and colorectal cancers, with a more concise qualifier sentence added: "FDA has concluded that there is very little scientific evidence for this claim." Any company product label making the cancer claims has to include a qualifier sentence.

Cataracts
A meta-analysis from 2015 reported that for studies which reported serum tocopherol, higher serum concentration was associated with a 23% reduction in relative risk of age-related cataracts (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract – the three major classifications of age-related cataracts. However, this article and a second meta-analysis reporting on clinical trials of alpha-tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo.

Cardiovascular diseases
In an 2022 update of an earlier report, the United States Preventive Services Task Force recommended against the use of vitamin E supplements for the prevention of cardiovascular disease or cancer, concluding there was insufficient evidence to assess the balance of benefits and harms, yet also concluding with moderate certainty that there is no net benefit of supplementation.

Research on the effects of vitamin E on cardiovascular disease has produced conflicting results. In theory, oxidative modification of LDL-cholesterol promotes blockages in coronary arteries that lead to atherosclerosis and heart attacks, so vitamin E functioning as an antioxidant would reduce oxidized cholesterol and lower risk of cardiovascular disease. Vitamin E status has also been implicated in the maintenance of normal endothelial cell function of cells lining the inner surface of arteries, anti-inflammatory activity and inhibition of platelet adhesion and aggregation. An inverse relation has been observed between coronary heart disease and the consumption of foods high in vitamin E, and also higher serum concentration of alpha-tocopherol. In one of the largest observational studies, almost 90,000 healthy nurses were tracked for eight years. Compared to those in the lowest fifth for reported vitamin E consumption (from food and dietary supplements), those in the highest fifth were at a 34% lower risk of major coronary disease. The problem with observational studies is that these cannot confirm a relation between the lower risk of coronary heart disease and vitamin E consumption because of confounding factors. Diet higher in vitamin E may also be higher in other, unidentified components that promote heart health, or people choosing such diets may be making other healthy lifestyle choices.

There is some supporting evidence from randomized clinical trials (RCTs). A meta-analysis on the effects of alpha-tocopherol supplementation in RCTs on aspects of cardiovascular health reported that when consumed without any other antioxidant nutrient, the relative risk of heart attack was reduced by 18%. The results were not consistent for all of the individual trials incorporated into the meta-analysis. For example, the Physicians' Health Study II did not show any benefit after 400 IU every other day for eight years, for heart attack, stroke, coronary mortality or all-cause mortality. The HOPE/HOPE-TOO trial, which enrolled people with pre-existing vascular disease or diabetes into a multi-year trial of 400 IU/day, reported a higher risk of heart failure in the alpha-tocopherol group.

The effects of vitamin E supplementation on incidence of stroke were summarized in 2011. There were no significant benefits for vitamin E versus placebo. Subset analysis for ischemic stroke, haemorrhagic stroke, fatal stroke, non-fatal stroke – all no significant difference in risk. Likewise for subset analysis of natural or synthetic vitamin E, or only above or below 300 IU/day, or whether the enrolled people were healthy or considered to be at higher than normal risk. The authors concluded that there was a lack of clinically important benefit of vitamin E supplementation in the prevention of stroke. One large, multi-year study in which post-menopausal women consumed either placebo or 600 IU of natural-sourced vitamin E on alternate days reported no effect on stroke, but did report a 21% reduction in relative risk of developing a deep vein clot or pulmonary embolism. The beneficial effect was strongest is the subset of women who had a history of a prior thrombotic event or who were genetically coded for clot risk (factor V Leiden or prothrombin mutation).

Cardiovascular health claims
In 2001, the U.S. Food and Drug Administration rejected proposed health claims for vitamin E and cardiovascular health. The U.S. National Institutes of Health reviewed literature published up to 2008 and concluded "In general, clinical trials have not provided evidence that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality." The European Food Safety Authority (EFSA) reviews proposed health claims for the European Union countries. In 2010, the EFSA reviewed and rejected claims that a cause and effect relationship has been established between the dietary intake of vitamin E and maintenance of normal cardiac function or of normal blood circulation.

Nonalcoholic fatty liver disease
Meta-analyses reported that supplemental vitamin E significantly reduced elevated liver enzymes, steatosis, inflammation and fibrosis, suggesting that the vitamin may be useful for treatment of nonalcoholic fatty liver disease (NAFLD) and the more extreme subset known as nonalcoholic steatohepatitis (NASH) in adults, but not in children.

Parkinson's disease
For Parkinson's disease, there is an observed inverse correlation seen with dietary vitamin E, but no confirming evidence from placebo-controlled clinical trials.

Pregnancy
Antioxidant vitamins as dietary supplements have been proposed as having benefits if consumed during pregnancy. For the combination of vitamin E with vitamin C supplemented to pregnant women, a Cochrane review concluded that the data do not support vitamin E supplementation – majority of trials alpha-tocopherol at 400 IU/day plus vitamin C at 1,000 mg/day – as being efficacious for reducing risk of stillbirth, neonatal death, preterm birth, preeclampsia or any other maternal or infant outcomes, either in healthy women or those considered at risk for pregnancy complications. The review identified only three small trials in which vitamin E was supplemented without co-supplementation with vitamin C. None of these trials reported any clinically meaningful information.

Skin care
Vitamin E is included in some skincare and wound-treatment products, but a 2015 meta-review found only "limited clinical evidence" of efficacy. However the authors noted a dearth of research, stating that 23 of the 39 studies reviewed were "of limited quality with individual flaws, including low patient numbers, poor randomization, blinding, and short follow-up periods."

Topical
Although there is widespread use of tocopheryl acetate as a topical medication, with claims for improved wound healing and reduced scar tissue, reviews have repeatedly concluded that there is insufficient evidence to support these claims. There are reports of vitamin E-induced allergic contact dermatitis from use of vitamin-E derivatives such as tocopheryl linoleate and tocopherol acetate in skin care products. Incidence is low despite widespread use.

Vaping-associated lung injury
On 5 September 2019, the US Food and Drug Administration announced that 10 out of 18, or 56% of the samples of vape liquids sent in by states, linked to recent vaping related lung disease outbreak in the United States, tested positive for vitamin E acetate which had been used as a thickening agent by illicit THC vape cartridge manufacturers. On 8 November 2019, the Centers for Disease Control and Prevention identified vitamin E acetate as a very strong culprit of concern in the vaping-related illnesses, but has not ruled out other chemicals or toxicants as possible causes. These findings were based on fluid samples from the lungs of 29 patients with vaping-associated pulmonary injury, which provided direct evidence of vitamin E acetate at the primary site of injury in all the 29 lung fluid samples tested. Vitamin E acetate was confirmed as a causitive agent. Pyrolysis of vitamin E acetate produces a range of toxic gases.

History
Vitamin E was discovered in 1922 by Herbert McLean Evans and Katharine Scott Bishop and first isolated in a pure form by Evans and Gladys Anderson Emerson in 1935 at the University of California, Berkeley. Because the vitamin activity was first identified as a dietary fertility factor in rats, it was given the name "tocopherol" from the Greek words "τόκος" [tókos, birth], and "φέρειν", [phérein, to bear or carry] meaning in sum "to carry a pregnancy," with the ending "-ol" signifying its status as a chemical alcohol. George M. Calhoun, Professor of Greek at the University of California, was credited with helping with the naming process. Erhard Fernholz elucidated its structure in 1938 and shortly afterward the same year, Paul Karrer and his team first synthesized it.

Nearly 50 years after the discovery of vitamin E, an editorial in the Journal of the American Medical Association titled "Vitamin in search of a disease" read in part "...research revealed many of the vitamin's secrets, but no certain therapeutic use and no definite deficiency disease in man." The animal discovery experiments had been a requirement for successful pregnancy, but no benefits were observed for women prone to miscarriage. Evidence for vascular health was characterized as unconvincing. The editorial closed with mention of some preliminary human evidence for protection against hemolytic anemia in young children.

A role for vitamin E in coronary heart disease was first proposed in 1946 by Evan Shute and colleagues. More cardiovascular work from the same research group followed, including a proposal that megadoses of vitamin E could slow down and even reverse the development of atherosclerosis. Subsequent research showed no association between vitamin E supplementation and cardiovascular events such as nonfatal stroke or myocardial infarction, or cardiovascular mortality.

There is a long history of belief that topical application of vitamin E containing oil benefits burn and wound healing. This belief persists even though scientific reviews refuted this claim.

The role of vitamin E in infant nutrition has a long research history. From 1949 onward there were trials with premature infants suggesting that oral alpha-tocopherol was protective against edema, intracranial hemorrhage, hemolytic anemia and retrolental fibroplasia. A more recent review concluded that vitamin E supplementation in preterm infants reduced the risk of intercranial hemorrhage and retinopathy, but noted an increased risk of sepsis.

title: Vitamin E