title: Roberto Durán

text: After defeating Leonard in Montreal, Durán gained iconic status in his home country, Panama. Leonard initiated the rematch clause and asked for the fight to be the following November. In their second fight, Leonard successfully changed his tactics, using more footwork and movement than he had in their first fight, and Durán was unable to get Leonard against the ropes. During the seventh round, after Leonard had gained a slight lead on the scorecards, he began taunting and mocking Durán. Towards the end of the eighth round, Durán suddenly stopped fighting, and according to referee Octavio Meyran and ABC commentator Howard Cosell, Durán repeatedly said "No más" ("no more"), which was denied by Durán, his cornermen Ray Arcel and Freddie Brown, and his manager Carlos Eleta, with Durán claiming he had said "No quiero pelear con el payaso" ("I do not want to fight with this clown [Leonard]"). According to Meyran, in addition to saying "No más", Durán also said in broken English "I don't box anymore". In a 2016 interview, Durán claimed that what he actually said was, "No sigo" ("I won't go on"). For a brief time after the "No más" debacle, Durán retired from boxing, but soon changed his mind, not wanting to end on such a bad note.


title: Roberto Durán

text: He took some time to recover from that fight and gained even more weight to contend for the WBC Light Middleweight title, but losing in his first attempt at a championship in that division on January 30, 1982, against Wilfred Benítez by a 15-round unanimous decision, this after having defeated Nino Gonzalez and Luigi Minchillo, two rated Light Middleweights, both by ten-round decisions in non-title bouts. Durán was also to lose his comeback fight in September 1982 in Detroit. Kirkland Laing, from London, shocked the boxing world, producing the type of display his talents promised yet he so rarely produced, taking the split decision. After being relegated to a 10-round walk out win over Englishman Jimmy Batten at The Battle of The Champions in Miami, Durán signed with promoter Bob Arum. This marked the beginning of a comeback in which he beat former world champion and now hall of famer José Cuevas via a fourth round knock-out, which earned him a second crack at the light middleweight title, this time against WBA Champion Davey Moore.


title: Roberto Durán

text: The WBA title bout took place at Madison Square Garden on June 16, 1983, which also happened to be Durán's 32nd birthday. The still inexperienced Moore (12–0) was game through the first three rounds, but by the 4th, Durán said he knew Moore couldn't hurt him, and an onslaught began.<ref name="http://sportsillustrated.cnn.com/vault/article/magazine/MAG1120968/1/index.htm">He That Was Lost Has Been Found, "Sports Illustrated", June 27, 1983</ref> The pro-Durán crowd at ringside cheered as Durán relentlessly punished Moore. By the end of the sixth round, Moore's eye had swollen shut and he was floored near the end of the seventh. Finally the fight was stopped in the eighth round as Moore was taking a horrific beating and Durán won his third world title. After the victory, Durán was hoisted up in the air as the crowd sang "Happy Birthday" to a sobbing Durán.


title: Roberto Durán

text: Durán later fought for the World Middleweight Championship, meeting Marvelous Marvin Hagler in Las Vegas on November 10, 1983. During the fight, Duran broke his hand and lost in a very competitive fight that went the full fifteen rounds. After 13 rounds, two of the judges had Durán one point ahead, and the other judge had it even. Hagler fought tenaciously to win the final two rounds and get a unanimous decision victory. The judges' scores were 144–142, 144–143, and 146–145. Despite the loss, Durán became the second man to take Hagler to a fifteen-round decision (Vito Antuofermo was the other) and the only one to do so while Hagler was the world champion.


title: Roberto Durán

text: In June 1984, Durán was stripped of his Light Middleweight title when the WBA did not approve of his fight with WBC Champion Thomas "Hitman" Hearns and took away recognition of Durán as world champion the moment Durán stepped into the ring to box Hearns. Durán again made history in the fight, but this time it was the wrong kind. Hearns dropped Durán twice in the first round and as he rose to his feet after the second knockdown, which ended the round, the former champion did not know where his corner was. Hearns went on to knock Durán down a third time in the second round and the fight was stopped, marking the first time in his career that Durán had been knocked out in a fight (the "No Más" fight was officially recorded as a technical knockout, because Durán quit). Durán then retired for a second time, but changed his mind over a year later, and was back fighting in early 1986.


title: Roberto Durán

text: Durán did not contend another title fight until 1989, but made the shot count when he won the WBC Middleweight title from Iran Barkley in February. The fight is considered one of Durán's greatest achievements, as the 37-year-old former lightweight champion took the middleweight crown, his fourth title. In a tough, back-and-forth fight, Durán knocked Barkley down in the eleventh round and Durán won a split decision (118–112, 116–112, 113–116). The bout was named the 1989 "Fight of the Year" by "The Ring".


title: Roberto Durán

text: Duran moved up to super middleweight for a third fight with Sugar Ray Leonard in December 1989 (a fight dubbed "Uno Más" — One More — by promoters), where Leonard's WBC super-middleweight title was on the line, although Leonard's camp insisted that the fight with Durán be at a 162lbs catchweight instead of the 168lbs super-middleweight limit that Durán favoured. In the end, both weighed in below the 160lbs middleweight limit. Durán was uncharacteristically flat for most of what was a strange fight. Although Leonard won the fight by a wide unanimous decision (120–110, 119–109, 116–111), by the end of the fight Leonard looked the worse for wear as he had suffered several bad cuts. Leonard's lip was busted by a headbutt in the fourth round, his left eye was cut in the eleventh round and his right eye was cut in the twelfth round. The cuts required more than 60 stitches. Durán didn't fight again until 1991, so had given up his WBC middleweight crown that he had won against Barkley. Durán seemed to be in decline after the third fight against Leonard, but he persisted and worked his way into title shots for the lesser IBC super-middleweight and middleweight titles in 1994, 1995 and 1996.


title: Roberto Durán

text: Durán fought Vinny Pazienza twice, in June 1994 and January 1995, for the IBC Super Middleweight Championship, with Pazienza winning both times by unanimous decision. In the first fight, Durán put Pazienza down in Rounds 2 and 5, but referee Joe Cortez controversially ruled the Round 2 knockdown to be a slip. The first fight divided the people watching as some felt that Durán had won a close fight, but others felt that Pazienza had won either narrowly or widely after finishing strongly in the last five rounds. The second fight was more lopsided in Pazienza's favour, as despite the official judges giving Pazienza the win by scores of 116–112, 117–111 and 118–110, the TV commentators expressed puzzlement at the closeness of the official scoring as they thought that Pazienza had won every round in a 120–108 shutout.


title: Roberto Durán

text: In 1996, Durán fought Héctor Camacho for the vacant IBC Middleweight Championship. At the end of the fight, fans and TV commentators seemed in complete agreement that Durán had won the fight in an excellent performance, but the three judges saw the fight very differently and awarded Camacho the victory by a very controversial unanimous decision. Durán's old rival, Sugar Ray Leonard, commentating at ringside, was baffled at the scoring and called it an early Christmas gift for Camacho, with the result motivating Leonard enough to come out of a 6-year boxing retirement to face Camacho himself in 1997. In 1997, Durán was defeated by former champion Jorge Castro in Argentina. Durán then fought Castro in a rematch bout in Panama and won via unanimous decision, maintaining his unbeaten record in Panama.


title: Roberto Durán

text: In 1998, at the age of 47, he challenged 28-year-old WBA Middleweight Champion William Joppy. Joppy, a trim, quick-fisted fighter, battered Durán to defeat in just 3 rounds. It was Durán's most emphatic loss since the Hearns fight, over a decade earlier. Durán then announced his retirement for the third time in August 1998, but soon changed his mind and was back fighting in March 1999.


title: Roberto Durán

text: In June 2000, Durán avenged a previous loss to Pat Lawlor from 9 years before and won the NBA Super Middleweight Championship on his 49th birthday. He lost the title a year later to Héctor Camacho in a rematch bout and in what would be Durán's final fight.


title: Roberto Durán

text: In October 2001, Durán traveled to Argentina to promote a salsa music CD that he had just released. While there, he was involved in a car crash and required life-saving surgery. After that incident, he announced his retirement from boxing at the age of 50.


title: Roberto Durán

text: Announcing his retirement, Durán cited the weight issues of his friend, Argentinian football legend Diego Maradona, as motivation for getting back in shape, stating "as of now, I am exercising so that when the [retirement] honors arrive the people will see me in shape. I don't want to [look] like Maradona did, all fat."


title: Roberto Durán

text: Durán's five world title belts, which he won in four different divisions, were stolen from his house in Panama in 1993 during a robbery allegedly staged by his brother-in-law, who gave them to memorabilia seller Luis González Báez, who stood trial for trying to sell stolen goods. González Báez allegedly sold the belts to undercover FBI agents. He alleged that Durán authorized the sale of the five belts to him during a time that Durán was facing financial trouble. On September 23, 2003, a federal judge in Florida ordered the five belts returned to Durán.


title: Roberto Durán

text: His 70 wins by knockout place him in an exclusive group of boxers who have won 50 or more fights by knockout. He is ranked number 28 on "The Ring"'s list of 100 greatest punchers of all time.


title: Roberto Durán

text: On October 14, 2006, Durán was inducted into the World Boxing Hall of Fame in Riverside, California, and on June 10, 2007, into the International Boxing Hall of Fame in Canastota, New York.


title: Roberto Durán

text: In June 2020, Durán was diagnosed with Covid-19 after going to hospital with common cold symptoms. Durán underwent treatment for the disease. Coincidentally, the diagnosis came on the 48th anniversary of Durán's first world title victory against Ken Buchanan, which took place on June 26, 1972. He was released from the hospital weeks later.


title: Roberto Durán

text: Durán's daughter, Irichelle Durán, was a professional boxer herself who garnered a record of one win and two losses in three bouts, with one win by knockout. She is a resident of Puerto Rico.


title: Roberto Durán

text: Durán's first appearance in a movie was in the 1979 film "Rocky II" as a lightning-fast sparring partner for Rocky Balboa. Outside of this, Durán had minor roles in "Harlem Nights".


title: Roberto Durán

text: Durán's life and boxing career are told in the documentary "Los puños de una nación" ("The Fists of a Nation") by Panamanian filmmaker Pituka Ortega-Heilbron. Durán also appears very briefly during an interview for the documentary "The Panama Deception" (1992), in which he recounts his experience during the United States invasion of Panama.


title: Roberto Durán

text: The biopic "Hands of Stone" stars Édgar Ramírez as Durán, Robert De Niro as Ray Arcel and Usher as Sugar Ray Leonard, and was released on August 26, 2016.


title: Roberto Durán

text: In "Corporate Warriors", the fourth episode of the second season of the hit American crime drama "", Durán is mentioned by the medical examiner while discussing a dead man found to have bone grafts put in his hands to boost his punching power.


title: Roberto Durán

text: The song "The Eyes of Roberto Durán" by Tom Russell, from the album "The Long Way Around", contains the lyric, "Panama City – it's three in the morning; they're talking 'bout the Hands of Stone."


title: Roberto Durán

text: Durán is mentioned in the third verse of Nas' original demo for "It Ain't Hard to Tell" in the line: "Metaphors of murder man, hittin' like Roberto Durán, hold the mic in my hand, my lifespan."


title: Roberto Durán

text: The musician Jackie Leven recorded a song ("Museum of Childhood") that explores the events of the second world title fight between Durán and Sugar Ray Leonard.


title: Roberto Durán

text: Durán is also mentioned in the third verse of Paul Thorn's "Hammer and Nail," based on Thorn's nationally televised fight with Durán:


title: Roberto Durán

text: Texas rockabilly band Reverend Horton Heat mentions Durán in their song "Eat Steak," off of their album "Smoke 'Em If You Got 'Em".


title: Roberto Durán

text: Durán is mentioned in the salsa song Pa'l Bailador by Colombian singer Joe Arroyo in 1989, "A Roberto Duran, Aya en Panama, Mano de Piedra!" (To Roberto Duran, in Panama, Hands of Stones!)


title: Roberto Durán

text: Durán's 1983 fight with Davey Moore is referenced in the 2014 single, "The Possum," by American songwriter, Sun Kil Moon (i.e. Mark Kozelek), who often writes about boxers. Kozelek sings:


title: Roberto Durán

text: Durán himself was a Salsa singer once, leading an orchestra named "Felicidad" after his wife. They recorded albums and frequented television shows in Latin America.


title: Roberto Durán

text: Durán is also mentioned by former rap duo Max and Sam (consisting of sports analyst Max Kellerman and his brother Sam) in their song 'Young Man Rumble' with the line "Got skills got stamina got Hands of Stone like the champ from Panama."


title: Git

text: Git () is a distributed version control system: tracking changes in any set of files, usually used for coordinating work among programmers collaboratively developing source code during software development. Its goals include speed, data integrity, and support for distributed, non-linear workflows (thousands of parallel branches running on different systems).


title: Git

text: Git was originally authored by Linus Torvalds in 2005 for development of the Linux kernel, with other kernel developers contributing to its initial development. Since 2005, Junio Hamano has been the core maintainer. As with most other distributed version control systems, and unlike most client–server systems, every Git directory on every computer is a full-fledged repository with complete history and full version-tracking abilities, independent of network access or a central server. Git is free and open-source software distributed under the GPL-2.0-only license.


title: Git

text: Git development began in April 2005, after many developers of the Linux kernel gave up access to BitKeeper, a proprietary source-control management (SCM) system that they had been using to maintain the project since 2002. The copyright holder of BitKeeper, Larry McVoy, had withdrawn free use of the product after claiming that Andrew Tridgell had created SourcePuller by reverse engineering the BitKeeper protocols. The same incident also spurred the creation of another version-control system, Mercurial.


title: Git

text: Linus Torvalds wanted a distributed system that he could use like BitKeeper, but none of the available free systems met his needs. Torvalds cited an example of a source-control management system needing 30 seconds to apply a patch and update all associated metadata, and noted that this would not scale to the needs of Linux kernel development, where synchronizing with fellow maintainers could require 250 such actions at once. For his design criterion, he specified that patching should take no more than three seconds, and added three more goals:


title: Git

text: These criteria eliminated every version-control system in use at the time, so immediately after the 2.6.12-rc2 Linux kernel development release, Torvalds set out to write his own.


title: Git

text: The development of Git began on 3 April 2005. Torvalds announced the project on 6 April and became self-hosting the next day. The first merge of multiple branches took place on 18 April. Torvalds achieved his performance goals; on 29 April, the nascent Git was benchmarked recording patches to the Linux kernel tree at the rate of 6.7 patches per second. On 16 June, Git managed the kernel 2.6.12 release.


title: Git

text: Torvalds turned over maintenance on 26 July 2005 to Junio Hamano, a major contributor to the project. Hamano was responsible for the 1.0 release on 21 December 2005.


title: Git

text: Torvalds sarcastically quipped about the name "git" (which means "unpleasant person" in British English slang): "I'm an egotistical bastard, and I name all my projects after myself. First 'Linux', now 'git'." The man page describes Git as "the stupid content tracker". The read-me file of the source code elaborates further:


title: Git

text: Git's design was inspired by BitKeeper and Monotone. Git was originally designed as a low-level version-control system engine, on top of which others could write front ends, such as Cogito or StGIT. The core Git project has since become a complete version-control system that is usable directly. While strongly influenced by BitKeeper, Torvalds deliberately avoided conventional approaches, leading to a unique design.


title: Git

text: Git's design is a synthesis of Torvalds's experience with Linux in maintaining a large distributed development project, along with his intimate knowledge of file-system performance gained from the same project and the urgent need to produce a working system in short order. These influences led to the following implementation choices:


title: Git

text: Another property of Git is that it snapshots directory trees of files. The earliest systems for tracking versions of source code, Source Code Control System (SCCS) and Revision Control System (RCS), worked on individual files and emphasized the space savings to be gained from interleaved deltas (SCCS) or delta encoding (RCS) the (mostly similar) versions. Later revision-control systems maintained this notion of a file having an identity across multiple revisions of a project. However, Torvalds rejected this concept. Consequently, Git does not explicitly record file revision relationships at any level below the source-code tree.


title: Git

text: From this initial design approach, Git has developed the full set of features expected of a traditional SCM, with features mostly being created as needed, then refined and extended over time.


title: Git

text: Git has two data structures: a mutable "index" (also called "stage" or "cache") that caches information about the working directory and the next revision to be committed; and an immutable, append-only "object database".


title: Git

text: Each object is identified by a SHA-1 hash of its contents. Git computes the hash and uses this value for the object's name. The object is put into a directory matching the first two characters of its hash. The rest of the hash is used as the file name for that object.


title: Git

text: Git stores each revision of a file as a unique blob. The relationships between the blobs can be found through examining the tree and commit objects. Newly added objects are stored in their entirety using zlib compression. This can consume a large amount of disk space quickly, so objects can be combined into "packs", which use delta compression to save space, storing blobs as their changes relative to other blobs.


title: Git

text: Additionally, git stores labels called refs (short for references) to indicate the locations of various commits. They are stored in the reference database and are respectively:


title: Git

text: Every object in the Git database that is not referred to may be cleaned up by using a garbage collection command or automatically. An object may be referenced by another object or an explicit reference. Git knows different types of references. The commands to create, move, and delete references vary. codice_4 lists all references. Some types are:


title: Git

text: Git (the main implementation in C) is primarily developed on Linux, although it also supports most major operating systems, including the BSDs (DragonFly BSD, FreeBSD, NetBSD, and OpenBSD), Solaris, macOS, and Windows.


title: Git

text: The first Windows port of Git was primarily a Linux-emulation framework that hosts the Linux version. Installing Git under Windows creates a similarly named Program Files directory containing the Mingw-w64 port of the GNU Compiler Collection, Perl 5, MSYS2 (itself a fork of Cygwin, a Unix-like emulation environment for Windows) and various other Windows ports or emulations of Linux utilities and libraries. Currently, native Windows builds of Git are distributed as 32- and 64-bit installers. The git official website currently maintains a build of Git for Windows, still using the MSYS2 environment.


title: Git

text: The JGit implementation of Git is a pure Java software library, designed to be embedded in any Java application. JGit is used in the Gerrit code-review tool, and in EGit, a Git client for the Eclipse IDE.


title: Git

text: Go-git is an open-source implementation of Git written in pure Go. It is currently used for backing projects as a SQL interface for Git code repositories and providing encryption for Git.


title: Git

text: The libgit2 implementation of Git is an ANSI C software library with no other dependencies, which can be built on multiple platforms, including Windows, Linux, macOS, and BSD. It has bindings for many programming languages, including Ruby, Python, and Haskell.


title: Git

text: As Git is a distributed version control system, it could be used as a server out of the box. It's shipped with a built-in command codice_5 which starts a simple TCP server running on the GIT protocol. Dedicated Git HTTP servers help (amongst other features) by adding access control, displaying the contents of a Git repository via the web interfaces, and managing multiple repositories. Already existing Git repositories can be cloned and shared to be used by others as a centralized repo. It can also be accessed via remote shell just by having the Git software installed and allowing a user to log in. Git servers typically listen on TCP port 9418.


title: Git

text: There are many offerings of Git repositories as a service. The most popular are GitHub, SourceForge, Bitbucket and GitLab.


title: Git

text: The Eclipse Foundation reported in its annual community survey that as of May 2014, Git is now the most widely used source-code management tool, with 42.9% of professional software developers reporting that they use Git as their primary source-control system compared with 36.3% in 2013, 32% in 2012; or for Git responses excluding use of GitHub: 33.3% in 2014, 30.3% in 2013, 27.6% in 2012 and 12.8% in 2011. Open-source directory Black Duck Open Hub reports a similar uptake among open-source projects.


title: Git

text: Stack Overflow has included version control in their annual developer survey in 2015 (16,694 responses), 2017 (30,730 responses), 2018 (74,298 responses) and 2022 (71,379 reponses). Git was the overwhelming favorite of responding developers in these surveys, reporting as high as 93.9% in 2022.


title: Git

text: The UK IT jobs website itjobswatch.co.uk reports that as of late September 2016, 29.27% of UK permanent software development job openings have cited Git, ahead of 12.17% for Microsoft Team Foundation Server, 10.60% for Subversion, 1.30% for Mercurial, and 0.48% for Visual SourceSafe.


title: Git

text: There are many "Git extensions", like Git LFS, which started as an extension to Git in the GitHub community and is now widely used by other repositories. Extensions are usually independently developed and maintained by different people, but at some point in the future, a widely used extension can be merged with Git.


title: Git

text: Microsoft developed the Virtual File System for Git (VFS for Git; formerly Git Virtual File System or GVFS) extension to handle the size of the Windows source-code tree as part of their 2017 migration from Perforce. VFS for Git allows cloned repositories to use placeholders whose contents are downloaded only once a file is accessed.


title: Git

text: Git does not impose many restrictions on how it should be used, but some conventions are adopted in order to organize histories, especially those which require the cooperation of many contributors.


title: Git

text: Git does not provide access-control mechanisms, but was designed for operation with other tools that specialize in access control.


title: Git

text: On 17 December 2014, an exploit was found affecting the Windows and macOS versions of the Git client. An attacker could perform arbitrary code execution on a target computer with Git installed by creating a malicious Git tree (directory) named ".git" (a directory in Git repositories that stores all the data of the repository) in a different case (such as .GIT or .Git, needed because Git does not allow the all-lowercase version of ".git" to be created manually) with malicious files in the ".git/hooks" subdirectory (a folder with executable files that Git runs) on a repository that the attacker made or on a repository that the attacker can modify. If a Windows or Mac user "pulls" (downloads) a version of the repository with the malicious directory, then switches to that directory, the .git directory will be overwritten (due to the case-insensitive trait of the Windows and Mac filesystems) and the malicious executable files in ".git/hooks" may be run, which results in the attacker's commands being executed. An attacker could also modify the ".git/config" configuration file, which allows the attacker to create malicious Git aliases (aliases for Git commands or external commands) or modify extant aliases to execute malicious commands when run. The vulnerability was patched in version 2.2.1 of Git, released on 17 December 2014, and announced the next day.


title: Git

text: Git version 2.6.1, released on 29 September 2015, contained a patch for a security vulnerability () that allowed arbitrary code execution. The vulnerability was exploitable if an attacker could convince a victim to clone a specific URL, as the arbitrary commands were embedded in the URL itself. An attacker could use the exploit via a man-in-the-middle attack if the connection was unencrypted, as they could redirect the user to a URL of their choice. Recursive clones were also vulnerable since they allowed the controller of a repository to specify arbitrary URLs via the gitmodules file.


title: Git

text: Git uses SHA-1 hashes internally. Linus Torvalds has responded that the hash was mostly to guard against accidental corruption, and the security a cryptographically secure hash gives was just an accidental side effect, with the main security being signing elsewhere. Since a demonstration of the SHAttered attack against git in 2017, git was modified to use a SHA-1 variant resistant to this attack. A plan for hash function transition is being written since February 2020.


title: Git

text: "Git" is a registered word trademark of Software Freedom Conservancy under US500000085961336 since 2015-02-03.


title: Autoimmune disease

text: An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly any body part can be involved. Common symptoms can be diverse and transient, ranging from mild to severe, and generally include low grade fever and feeling tired.


title: Autoimmune disease

text: The cause is unknown. Some autoimmune diseases such as lupus run in families, and certain cases may be triggered by infections or other environmental factors. Some common diseases that are generally considered autoimmune include celiac disease, diabetes mellitus type 1, graves' disease, inflammatory bowel disease, multiple sclerosis, alopecia areata, addison’s disease, pernicious anemia, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus. The diagnosis can be difficult to determine.


title: Autoimmune disease

text: Treatment depends on the type and severity of the condition. Nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants are often used. Intravenous immunoglobulin may also occasionally be used. While treatment usually improves symptoms, they do not typically cure the disease.


title: Autoimmune disease

text: About 24 million (~7.5%) people in the United States are affected by an autoimmune disease. Women are more commonly affected than men. Often they start during adulthood. The first autoimmune diseases were described in the early 1900s.


title: Autoimmune disease

text: Certain autoimmune diseases present similar symptoms across the more than eighty different types, whilst others do not, type 1 diabetes being relatively distinct from rheumatoid arthritis, for example. The appearance and severity of these signs and symptoms depends on the location and type of autoimmune response that occurs. An individual may also have more than one autoimmune disease simultaneously, and display symptoms of multiple diseases. Signs and symptoms presented, and the disease itself, can be influenced by various other factors such as age, hormones, and environmental factors. In general, the common symptoms are:


title: Autoimmune disease

text: The appearance of these signs and symptoms can fluctuate, and when they reappear, it is known as a flare-up. Such signs and symptoms may aid in diagnosis by supporting the results from biologic markers of autoimmune diseases.


title: Autoimmune disease

text: There are several areas that are commonly impacted by autoimmune diseases. These areas include: blood vessels, underlying connective tissues, joints and muscles, red blood cells, skin, and endocrine glands (such as thyroid or pancreas glands).


title: Autoimmune disease

text: These diseases tend to have characteristic pathological effects that characterize them as an autoimmune disease. Such features include damage to or destruction of tissues where there is an abnormal immune response, altered organ growth, and altered organ function depending on the location of the disease. Some diseases are organ specific and are restricted to affecting certain tissues, while others are systemic diseases that impact many tissues throughout the body. Signs and symptoms may vary depending on which of these categories an individual's disease falls under.


title: Autoimmune disease

text: Research suggests an overall correlation between autoimmune diseases and cancer, in that having an autoimmune disease increases the risk or likelihood of developing certain cancers. Autoimmune diseases cause inflammation through a variety of mechanisms, however, the way in which inflammation is created does not greatly influence cancer risk. Rather, the cancer risk is largely dependent on the fact that all autoimmune diseases increase chronic inflammation which has been linked to cancer. Below are some autoimmune diseases most commonly linked to cancer including celiac disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.


title: Autoimmune disease

text: Following are the few examples of autoimmune diseases. See List of autoimmune diseases for a more exhaustive list.


title: Autoimmune disease

text: Coeliac disease presents the strongest associations to gastrointestinal and lymphoproliferative cancers. In coeliac disease, the autoimmune reaction is caused by the body's loss of immune tolerance to ingested gluten, found primarily in wheat, barley, and rye. This explains the increased risk of gastrointestinal cancers, as the gastrointestinal tract includes the esophagus, stomach, small intestine, large intestine, rectum, and anus, all areas that the ingested gluten would traverse in digestion. The incidence of gastrointestinal cancer can be partially reduced or eliminated if a patient removes gluten from their diet. Additionally, celiac disease is correlated with lymphoproliferative cancers.


title: Autoimmune disease

text: Inflammatory bowel disease (IBD) is associated with cancers of the gastrointestinal tract and some lymphoproliferative cancers. IBD can be further categorized as Crohn's disease or ulcerative colitis. In both cases, individuals with IBD lose immune tolerance for normal bacteria present in the gut microbiome. In this case, the immune system attacks the bacteria and induces chronic inflammation, which has been linked to increased cancer risk.


title: Autoimmune disease

text: Multiple sclerosis is associated with decreased risk of cancer overall but an increased risk of central nervous system cancer, primarily in the brain. Multiple sclerosis is a neurodegenerative disease in which T-cells – a specific type of immune cells – attack the important myelin sheath in brain neurons. This reduces the nervous system function, creating inflammation and subsequent cancer of the brain.


title: Autoimmune disease

text: Rheumatoid arthritis presents mild, yet significant associations with focal cancers all throughout the body as well as lymphoproliferative cancers. In rheumatoid arthritis, cells that make up the body's joints and cartilages become invasive and induce local inflammation. Additionally, the chronic inflammation and over-activation of the immune system creates an environment that favors further malignant transformation of other cells. This can explain the associations to cancer of the lungs and skin as well as the increased risk of other hematologic cancers none of which are directly affected by the inflammation of joints.


title: Autoimmune disease

text: Systemic lupus erythematosus is associated with focal cancers throughout the body and lymphoproliferative cancers. Systemic lupus erythematosus affects multiple organ systems and is characterized by a widespread loss of immune tolerance. The chronic inflammation throughout the entire body promotes the malignant transformation of other cells which contributes to the increased risk of systemic and lymphoproliferative cancers. Conversely, systemic lupus erythematosus is correlated with a decrease in some cancers. This is best explained by increased immunosurveillance in these areas, however, the mechanism for why these areas experience lower incidence is poorly understood.


title: Autoimmune disease

text: In aplastic anemia the body fails to produce blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anaemia causes a deficiency of all blood cell types: red blood cells, white blood cells and platelets.


title: Autoimmune disease

text: The cause is unknown. Some autoimmune diseases such as lupus run in families, and certain cases may be triggered by infections or other environmental factors. There are more than 100 autoimmune diseases. Some common diseases that are generally considered autoimmune include celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.


title: Autoimmune disease

text: Autoimmune diseases are conditions in which the human immune system attacks healthy human tissues within the body. The exact genes responsible for causing each autoimmune disease have not been found. However, several experimental methods such as the genome-wide association scans have been used to identify certain genetic risk variants that may or may not be responsible. Research focusing on both genome scanning and family trait inheritance analysis has enabled scientists to further understand the etiology of autoimmune diseases such as Type 1 diabetes and Rheumatoid arthritis.


title: Autoimmune disease

text: A range of environmental factors have been recognized as either having a direct role in development, or being a catalyst to many autoimmune diseases. Current studies "indicate" up to seventy percent of autoimmune disease are perhaps due to environmental factors, including: chemicals, infection, diet, and gut dysbiosis. A single set of steps has been identified to be the most likely theory for autoimmune disease onset still there is of yet no definitive proof.


title: Autoimmune disease

text: Chemicals can be found within the direct environment or in the form of drugs, including: hydrazines, hair dyes, trichloroethylene, tartrazines, hazardous wastes, and industrial emissions.


title: Autoimmune disease

text: UV radiation is found to be a possible cause of development of the autoimmune disease dermatomyositis, exposure to pesticides plays a role in rheumatoid arthritis development, and vitamin D has been found to be a key in preventing immune dysfunctions in older populations. Infectious agents are considered T cell activators, a step needed for activation of autoimmune diseases. These mechanisms are relatively unknown, but are one of the current alternative theories to explain autoimmune diseases triggered by infection such as Guillain-Barre syndrome and rheumatic fever.


title: Autoimmune disease

text: The human immune system typically produces both T cells and B cells that are capable of being reactive with self-protein, but these self-reactive cells are usually either killed prior to becoming active within the immune system, placed into a state of anergy (silently removed from their role within the immune system due to over-activation), or removed from their role within the immune system by regulatory cells. When any one of these mechanisms fail, it is possible to have a reservoir of self-reactive cells that become functional within the immune system. The mechanisms of preventing self-reactive T cells from being created take place through negative selection process within the thymus as the T cell is developing into a mature immune cell.


title: Autoimmune disease

text: Some infections, such as "Campylobacter jejuni", have antigens that are similar (but not identical) to our own self-molecules. In this case, a normal immune response to "C. jejuni" can result in the production of antibodies that also react to a lesser degree with gangliosides of myelin sheath surrounding peripheral nerves' axons (i.e., Guillain–Barré). A major understanding of the underlying pathophysiology of autoimmune diseases has been the application of genome-wide association scans that have identified a degree of genetic sharing among the autoimmune diseases.


title: Autoimmune disease

text: Autoimmunity, on the other hand, is the presence of self-reactive immune response (e.g., auto-antibodies, self-reactive T cells), with or without damage or pathology resulting from it. For this reason, autoantibodies are a hallmark of most autoimmune disorders. This may be restricted to certain organs (e.g. in autoimmune thyroiditis) or involve a particular tissue in different places (e.g. Goodpasture's disease which may affect the basement membrane in both the lung and the kidney).


title: Autoimmune disease

text: There are many different theories as to how an autoimmune disease state arises. Some common ones are listed below.


title: Autoimmune disease

text: For a disease to be regarded as an autoimmune disease it needs to answer to "Witebsky's postulates" (first formulated by Ernest Witebsky and colleagues in 1957 and modified in 1994):


title: Autoimmune disease

text: Symptoms of early autoimmune disease are often the exact same as common illnesses, including: fatigue, fever, malaise, joint pain, and rash. Due to the fact symptoms vary for affected location, disease causing agents, and individuals, it is difficult for proper diagnosis. Typically, diagnosis begins with looking into a patient's family's history for genetic predisposition. This is combined with various tests, as no single test can identify an autoimmune disease.


title: Autoimmune disease

text: A test used to identify abnormal proteins, known as antinuclear antibodies, produced when the body attacks its own tissues. It may test positive in several disorders. This test is most useful for diagnosing systemic lupus erythematosus, having a 95% positive test rate.


title: Autoimmune disease

text: A test taking measurements on maturity levels, count, and size of blood cells. Targeted cells include: red blood cells, white blood cells, hemoglobin, hematocrit, and platelets. Based on increased or decreased numbers in these counts, underlying medical conditions may be present; typically, autoimmune disease is represented by low white blood cell count (Leukopenia). For proper diagnosis, further testing is needed.


title: Autoimmune disease

text: A test used to measure levels of a protein group of the immune system called complement within blood. If complement is found in low levels, this may be an indication of disease.


title: Autoimmune disease

text: C-reactive protein, a protein made in the liver, generally increases with inflammation, and may be high in autoimmune disease.


title: Autoimmune disease

text: This test measures the rate at which a patient's blood cells descend in a test tube. More rapid descents may indicate inflammation, a common symptom of autoimmune disease.


title: Autoimmune disease

text: If these tests are indicative antibody abnormalities and inflammation, further tests will be conducted to identify the autoimmune disease present.


title: Autoimmune disease

text: Treatment depends on the type and severity of the condition. The majority of the autoimmune diseases are chronic and there is no definitive cure, but symptoms can be alleviated and controlled with treatment.


title: Autoimmune disease

text: Traditional treatment options include immunosuppressant drugs to reduce the immune response against the body's own tissues, such as:


title: Autoimmune disease

text: Because immunosuppressants weaken the overall immune response, relief of symptoms must be balanced with preserving the patient's ability to combat infections, which could potentially be life-threatening.


title: Autoimmune disease

text: Non-traditional treatments are being researched, developed, and used, especially when traditional treatments fail. These methods aim to either block the activation of pathogenic cells in the body, or alter the pathway that suppresses these cells naturally. These treatments aim to be less toxic to the patient and have more specific targets. Such options include:


title: Autoimmune disease

text: The first estimate of US prevalence for autoimmune diseases as a group was published in 1997 by Jacobson, et al. They reported US prevalence to be around 9 million, applying prevalence estimates for 24 diseases to a US population of 279 million. Jacobson's work was updated by Hayter & Cook in 2012. This study used Witebsky's postulates, as revised by Rose & Bona, to extend the list to 81 diseases and estimated overall cumulative US prevalence for the 81 autoimmune diseases at 5.0%, with 3.0% for males and 7.1% for females. The estimated community prevalence, which takes into account the observation that many people have more than one autoimmune disease, was 4.5% overall, with 2.7% for males and 6.4% for females. National Health and Nutrition Examination Surveys conducted in the US from the 1980s to present day, have shown an increase of antinuclear antibodies, a common biomarker for autoimmune diseases. This shows that there has been an increase in the prevalence of autoimmune diseases in recent years pointing to a stronger influence of environment factors as a risk factor for autoimmune diseases.


title: Autoimmune disease

text: In both autoimmune and inflammatory diseases, the condition arises through aberrant reactions of the human adaptive or innate immune systems. In autoimmunity, the patient's immune system is activated against the body's own proteins. In chronic inflammatory diseases, neutrophils and other leukocytes are constitutively recruited by cytokines and chemokines, resulting in tissue damage.


title: Autoimmune disease

text: Mitigation of inflammation by activation of anti-inflammatory genes and the suppression of inflammatory genes in immune cells is a promising therapeutic approach. There is a body of evidence that once the production of autoantibodies has been initialized, autoantibodies have the capacity to maintain their own production.


title: Autoimmune disease

text: Medical trials to replace the pancreatic β cells that are destroyed in type 1 diabetes are in progress.


title: Autoimmune disease

text: According to this theory, the effector function of the immune response is mediated by the glycans (polysaccharides) displayed by the cells and humoral components of the immune system. Individuals with autoimmunity have alterations in their glycosylation profile such that a proinflammatory immune response is favored. It is further hypothesized that individual autoimmune diseases will have unique glycan signatures.


title: Autoimmune disease

text: According to the hygiene hypothesis, high levels of cleanliness expose children to fewer antigens than in the past, causing their immune systems to become overactive and more likely to misidentify own tissues as foreign, resulting in autoimmune or allergic conditions such as asthma.


title: Autoimmune disease

text: Vitamin D is known as an immune regulator that assists in the adaptive and innate immune response. A deficiency in vitamin D, from hereditary or environmental influence, can lead to a more inefficient and weaker immune response and seen as a contributing factor to the development of autoimmune diseases. With vitamin D present, vitamin D response elements (VDRE) are encoded and expressed via pattern recognition receptors (PRR) responses and the genes associated with those responses. The specific DNA target sequence expressed is known as 1,25-(OH)2D3. The expression of 1,25-(OH)2D3 can be induced by macrophages, dendritic cells, T-cells, and B-cells. In the presence of 1,25-(OH)2D3, the immune system's production of inflammatory cytokines are suppressed and more tolerogenic regulatory T-cells are expressed. This is due to vitamin D's influence on cell maturation, specifically T-cells, and their phenotype expression. Lack of 1,25-(OH)2D3 expression can lead to less tolerant regulatory T-cells, larger presentation of antigens to less tolerant T-cells, and increased inflammatory response.


title: Endocrine system

text: The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems. In humans, the major endocrine glands are the thyroid gland and the adrenal glands. The study of the endocrine system and its disorders is known as endocrinology.


title: Endocrine system

text: Glands that signal each other in sequence are often referred to as an axis, such as the hypothalamic-pituitary-adrenal axis. In addition to the specialized endocrine organs mentioned above, many other organs that are part of other body systems have secondary endocrine functions, including bone, kidneys, liver, heart and gonads. For example, the kidney secretes the endocrine hormone erythropoietin. Hormones can be amino acid complexes, steroids, eicosanoids, leukotrienes, or prostaglandins.


title: Endocrine system

text: The endocrine system can be contrasted to both exocrine glands, which secrete hormones to the outside of the body, and paracrine signalling between cells over a relatively short distance. Endocrine glands have no ducts, are vascular, and commonly have intracellular vacuoles or granules that store their hormones. In contrast, exocrine glands, such as salivary glands, sweat glands, and glands within the gastrointestinal tract, tend to be much less vascular and have ducts or a hollow lumen.


title: Endocrine system

text: The human endocrine system consists of several systems that operate via feedback loops. Several important feedback systems are mediated via the hypothalamus and pituitary.


title: Endocrine system

text: Endocrine glands are glands of the endocrine system that secrete their products, hormones, directly into interstitial spaces where they are absorbed into blood rather than through a duct. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, thyroid gland, parathyroid gland, hypothalamus and adrenal glands. The hypothalamus and pituitary gland are neuroendocrine organs.


title: Endocrine system

text: The hypothalamus and the anterior pituitary are two out of the three endocrine glands that are important in cell signaling. They are both part of the HPA axis which is known to play a role in cell signaling in the nervous system.


title: Endocrine system

text: Hypothalamus: The hypothalamus is a key regulator of the autonomic nervous system. The endocrine system has three sets of endocrine outputs which include the magnocellular system, the parvocellular system, and autonomic intervention. The magnocellular is involved in the expression of oxytocin or vasopressin. The parvocellular is involved in controlling the secretion of hormones from the anterior pituitary.


title: Endocrine system

text: Anterior Pituitary: The main role of the anterior pituitary gland is to produce and secrete tropic hormones. Some examples of tropic hormones secreted by the anterior pituitary gland include TSH, ACTH, GH, LH, and FSH.


title: Endocrine system

text: There are many types of cells that make up the endocrine system and these cells typically make up larger tissues and organs that function within and outside of the endocrine system.


title: Endocrine system

text: The fetal adrenal cortex can be identified within four weeks of gestation. The adrenal cortex originates from the thickening of the intermediate mesoderm. At five to six weeks of gestation, the mesonephros differentiates into a tissue known as the genital ridge. The genital ridge produces the steroidogenic cells for both the gonads and the adrenal cortex. The adrenal medulla is derived from ectodermal cells. Cells that will become adrenal tissue move retroperitoneally to the upper portion of the mesonephros. At seven weeks of gestation, the adrenal cells are joined by sympathetic cells that originate from the neural crest to form the adrenal medulla. At the end of the eighth week, the adrenal glands have been encapsulated and have formed a distinct organ above the developing kidneys. At birth, the adrenal glands weigh approximately eight to nine grams (twice that of the adult adrenal glands) and are 0.5% of the total body weight. At 25 weeks, the adult adrenal cortex zone develops and is responsible for the primary synthesis of steroids during the early postnatal weeks.


title: Endocrine system

text: The thyroid gland develops from two different clusterings of embryonic cells. One part is from the thickening of the pharyngeal floor, which serves as the precursor of the thyroxine (T) producing follicular cells. The other part is from the caudal extensions of the fourth pharyngobranchial pouches which results in the parafollicular calcitonin-secreting cells. These two structures are apparent by 16 to 17 days of gestation. Around the 24th day of gestation, the foramen cecum, a thin, flask-like diverticulum of the median anlage develops. At approximately 24 to 32 days of gestation the median anlage develops into a bilobed structure. By 50 days of gestation, the medial and lateral anlage have fused together. At 12 weeks of gestation, the fetal thyroid is capable of storing iodine for the production of TRH, TSH, and free thyroid hormone. At 20 weeks, the fetus is able to implement feedback mechanisms for the production of thyroid hormones. During fetal development, T is the major thyroid hormone being produced while triiodothyronine (T) and its inactive derivative, reverse T, are not detected until the third trimester.


title: Endocrine system

text: A lateral and ventral view of an embryo showing the third (inferior) and fourth (superior) parathyroid glands during the 6th week of embryogenesis


title: Endocrine system

text: Once the embryo reaches four weeks of gestation, the parathyroid glands begins to develop. The human embryo forms five sets of endoderm-lined pharyngeal pouches. The third and fourth pouch are responsible for developing into the inferior and superior parathyroid glands, respectively. The third pharyngeal pouch encounters the developing thyroid gland and they migrate down to the lower poles of the thyroid lobes. The fourth pharyngeal pouch later encounters the developing thyroid gland and migrates to the upper poles of the thyroid lobes. At 14 weeks of gestation, the parathyroid glands begin to enlarge from 0.1 mm in diameter to approximately 1 – 2 mm at birth. The developing parathyroid glands are physiologically functional beginning in the second trimester.


title: Endocrine system

text: Studies in mice have shown that interfering with the HOX15 gene can cause parathyroid gland aplasia, which suggests the gene plays an important role in the development of the parathyroid gland. The genes, TBX1, CRKL, GATA3, GCM2, and SOX3 have also been shown to play a crucial role in the formation of the parathyroid gland. Mutations in TBX1 and CRKL genes are correlated with DiGeorge syndrome, while mutations in GATA3 have also resulted in a DiGeorge-like syndrome. Malformations in the GCM2 gene have resulted in hypoparathyroidism. Studies on SOX3 gene mutations have demonstrated that it plays a role in parathyroid development. These mutations also lead to varying degrees of hypopituitarism.


title: Endocrine system

text: The human fetal pancreas begins to develop by the fourth week of gestation. Five weeks later, the pancreatic alpha and beta cells have begun to emerge. Reaching eight to ten weeks into development, the pancreas starts producing insulin, glucagon, somatostatin, and pancreatic polypeptide. During the early stages of fetal development, the number of pancreatic alpha cells outnumbers the number of pancreatic beta cells. The alpha cells reach their peak in the middle stage of gestation. From the middle stage until term, the beta cells continue to increase in number until they reach an approximate 1:1 ratio with the alpha cells. The insulin concentration within the fetal pancreas is 3.6 pmol/g at seven to ten weeks, which rises to 30 pmol/g at 16–25 weeks of gestation. Near term, the insulin concentration increases to 93 pmol/g. The endocrine cells have dispersed throughout the body within 10 weeks. At 31 weeks of development, the islets of Langerhans have differentiated.


title: Endocrine system

text: While the fetal pancreas has functional beta cells by 14 to 24 weeks of gestation, the amount of insulin that is released into the bloodstream is relatively low. In a study of pregnant women carrying fetuses in the mid-gestation and near term stages of development, the fetuses did not have an increase in plasma insulin levels in response to injections of high levels of glucose. In contrast to insulin, the fetal plasma glucagon levels are relatively high and continue to increase during development. At the mid-stage of gestation, the glucagon concentration is 6 μg/g, compared to 2 μg/g in adult humans. Just like insulin, fetal glucagon plasma levels do not change in response to an infusion of glucose. However, a study of an infusion of alanine into pregnant women was shown to increase the cord blood and maternal glucagon concentrations, demonstrating a fetal response to amino acid exposure.


title: Endocrine system

text: As such, while the fetal pancreatic alpha and beta islet cells have fully developed and are capable of hormone synthesis during the remaining fetal maturation, the islet cells are relatively immature in their capacity to produce glucagon and insulin. This is thought to be a result of the relatively stable levels of fetal serum glucose concentrations achieved via maternal transfer of glucose through the placenta. On the other hand, the stable fetal serum glucose levels could be attributed to the absence of pancreatic signaling initiated by incretins during feeding. In addition, the fetal pancreatic islets cells are unable to sufficiently produce cAMP and rapidly degrade cAMP by phosphodiesterase necessary to secrete glucagon and insulin.


title: Endocrine system

text: During fetal development, the storage of glycogen is controlled by fetal glucocorticoids and placental lactogen. Fetal insulin is responsible for increasing glucose uptake and lipogenesis during the stages leading up to birth. Fetal cells contain a higher amount of insulin receptors in comparison to adults cells and fetal insulin receptors are not downregulated in cases of hyperinsulinemia. In comparison, fetal haptic glucagon receptors are lowered in comparison to adult cells and the glycemic effect of glucagon is blunted. This temporary physiological change aids the increased rate of fetal development during the final trimester. Poorly managed maternal diabetes mellitus is linked to fetal macrosomia, increased risk of miscarriage, and defects in fetal development. Maternal hyperglycemia is also linked to increased insulin levels and beta cell hyperplasia in the post-term infant. Children of diabetic mothers are at an increased risk for conditions such as: polycythemia, renal vein thrombosis, hypocalcemia, respiratory distress syndrome, jaundice, cardiomyopathy, congenital heart disease, and improper organ development.


title: Endocrine system

text: The reproductive system begins development at four to five weeks of gestation with germ cell migration. The bipotential gonad results from the collection of the medioventral region of the urogenital ridge. At the five-week point, the developing gonads break away from the adrenal primordium. Gonadal differentiation begins 42 days following conception.


title: Endocrine system

text: For males, the testes form at six fetal weeks and the sertoli cells begin developing by the eight week of gestation. SRY, the sex-determining locus, serves to differentiate the Sertoli cells. The Sertoli cells are the point of origin for anti-Müllerian hormone. Once synthesized, the anti-Müllerian hormone initiates the ipsilateral regression of the Müllerian tract and inhibits the development of female internal features. At 10 weeks of gestation, the Leydig cells begin to produce androgen hormones. The androgen hormone dihydrotestosterone is responsible for the development of the male external genitalia.


title: Endocrine system

text: The testicles descend during prenatal development in a two-stage process that begins at eight weeks of gestation and continues through the middle of the third trimester. During the transabdominal stage (8 to 15 weeks of gestation), the gubernacular ligament contracts and begins to thicken. The craniosuspensory ligament begins to break down. This stage is regulated by the secretion of insulin-like 3 (INSL3), a relaxin-like factor produced by the testicles, and the INSL3 G-coupled receptor, LGR8. During the transinguinal phase (25 to 35 weeks of gestation), the testicles descend into the scrotum. This stage is regulated by androgens, the genitofemoral nerve, and calcitonin gene-related peptide. During the second and third trimester, testicular development concludes with the diminution of the fetal Leydig cells and the lengthening and coiling of the seminiferous cords.


title: Endocrine system

text: For females, the ovaries become morphologically visible by the 8th week of gestation. The absence of testosterone results in the diminution of the Wolffian structures. The Müllerian structures remain and develop into the fallopian tubes, uterus, and the upper region of the vagina. The urogenital sinus develops into the urethra and lower region of the vagina, the genital tubercle develops into the clitoris, the urogenital folds develop into the labia minora, and the urogenital swellings develop into the labia majora. At 16 weeks of gestation, the ovaries produce FSH and LH/hCG receptors. At 20 weeks of gestation, the theca cell precursors are present and oogonia mitosis is occurring. At 25 weeks of gestation, the ovary is morphologically defined and folliculogenesis can begin.


title: Endocrine system

text: Studies of gene expression show that a specific complement of genes, such as follistatin and multiple cyclin kinase inhibitors are involved in ovarian development. An assortment of genes and proteins - such as WNT4, RSPO1, FOXL2, and various estrogen receptors - have been shown to prevent the development of testicles or the lineage of male-type cells.


title: Endocrine system

text: The pituitary gland is formed within the rostral neural plate. The Rathke's pouch, a cavity of ectodermal cells of the oropharynx, forms between the fourth and fifth week of gestation and upon full development, it gives rise to the anterior pituitary gland. By seven weeks of gestation, the anterior pituitary vascular system begins to develop. During the first 12 weeks of gestation, the anterior pituitary undergoes cellular differentiation. At 20 weeks of gestation, the hypophyseal portal system has developed. The Rathke's pouch grows towards the third ventricle and fuses with the diverticulum. This eliminates the lumen and the structure becomes Rathke's cleft. The posterior pituitary lobe is formed from the diverticulum. Portions of the pituitary tissue may remain in the nasopharyngeal midline. In rare cases this results in functioning ectopic hormone-secreting tumors in the nasopharynx.


title: Endocrine system

text: The functional development of the anterior pituitary involves spatiotemporal regulation of transcription factors expressed in pituitary stem cells and dynamic gradients of local soluble factors. The coordination of the dorsal gradient of pituitary morphogenesis is dependent on neuroectodermal signals from the infundibular bone morphogenetic protein 4 (BMP4). This protein is responsible for the development of the initial invagination of the Rathke's pouch. Other essential proteins necessary for pituitary cell proliferation are Fibroblast growth factor 8 (FGF8), Wnt4, and Wnt5. Ventral developmental patterning and the expression of transcription factors is influenced by the gradients of BMP2 and sonic hedgehog protein (SHH). These factors are essential for coordinating early patterns of cell proliferation.


title: Endocrine system

text: Six weeks into gestation, the corticotroph cells can be identified. By seven weeks of gestation, the anterior pituitary is capable of secreting ACTH. Within eight weeks of gestation, somatotroph cells begin to develop with cytoplasmic expression of human growth hormone. Once a fetus reaches 12 weeks of development, the thyrotrophs begin expression of Beta subunits for TSH, while gonadotrophs being to express beta-subunits for LH and FSH. Male fetuses predominately produced LH-expressing gonadotrophs, while female fetuses produce an equal expression of LH and FSH expressing gonadotrophs. At 24 weeks of gestation, prolactin-expressing lactotrophs begin to emerge.


title: Endocrine system

text: A hormone is any of a class of signaling molecules produced by cells in glands in multicellular organisms that are transported by the circulatory system to target distant organs to regulate physiology and behaviour. Hormones have diverse chemical structures, mainly of 3 classes: eicosanoids, steroids, and amino acid/protein derivatives (amines, peptides, and proteins). The glands that secrete hormones comprise the endocrine system. The term hormone is sometimes extended to include chemicals produced by cells that affect the same cell (autocrine or intracrine signalling) or nearby cells (paracrine signalling).


title: Endocrine system

text: Hormones are used to communicate between organs and tissues for physiological regulation and behavioral activities, such as digestion, metabolism, respiration, tissue function, sensory perception, sleep, excretion, lactation, stress, growth and development, movement, reproduction, and mood.


title: Endocrine system

text: Hormones affect distant cells by binding to specific receptor proteins in the target cell resulting in a change in cell function. This may lead to cell type-specific responses that include rapid changes to the activity of existing proteins, or slower changes in the expression of target genes. Amino acid–based hormones (amines and peptide or protein hormones) are water-soluble and act on the surface of target cells via signal transduction pathways; steroid hormones, being lipid-soluble, move through the plasma membranes of target cells to act within their nuclei.


title: Endocrine system

text: The typical mode of cell signalling in the endocrine system is endocrine signaling, that is, using the circulatory system to reach distant target organs. However, there are also other modes, i.e., paracrine, autocrine, and neuroendocrine signaling. Purely neurocrine signaling between neurons, on the other hand, belongs completely to the nervous system.


title: Endocrine system

text: Autocrine signaling is a form of signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on the same cell, leading to changes in the cells.


title: Endocrine system

text: Some endocrinologists and clinicians include the paracrine system as part of the endocrine system, but there is not consensus. Paracrines are slower acting, targeting cells in the same tissue or organ. An example of this is somatostatin which is released by some pancreatic cells and targets other pancreatic cells.


title: Endocrine system

text: Juxtacrine signaling is a type of intercellular communication that is transmitted via oligosaccharide, lipid, or protein components of a cell membrane, and may affect either the emitting cell or the immediately adjacent cells.


title: Endocrine system

text: It occurs between adjacent cells that possess broad patches of closely opposed plasma membrane linked by transmembrane channels known as connexons. The gap between the cells can usually be between only 2 and 4 nm.


title: Endocrine system

text: Diseases of the endocrine system are common, including conditions such as diabetes mellitus, thyroid disease, and obesity.


title: Endocrine system

text: Endocrine disease is characterized by misregulated hormone release (a productive pituitary adenoma), inappropriate response to signaling (hypothyroidism), lack of a gland (diabetes mellitus type 1, diminished erythropoiesis in chronic kidney failure), or structural enlargement in a critical site such as the thyroid (toxic multinodular goitre). Hypofunction of endocrine glands can occur as a result of loss of reserve, hyposecretion, agenesis, atrophy, or active destruction. Hyperfunction can occur as a result of hypersecretion, loss of suppression, hyperplastic or neoplastic change, or hyperstimulation.


title: Endocrine system

text: Endocrinopathies are classified as primary, secondary, or tertiary. Primary endocrine disease inhibits the action of downstream glands. Secondary endocrine disease is indicative of a problem with the pituitary gland. Tertiary endocrine disease is associated with dysfunction of the hypothalamus and its releasing hormones.


title: Endocrine system

text: As the thyroid, and hormones have been implicated in signaling distant tissues to proliferate, for example, the estrogen receptor has been shown to be involved in certain breast cancers. Endocrine, paracrine, and autocrine signaling have all been implicated in proliferation, one of the required steps of oncogenesis.


title: Endocrine system

text: Other common diseases that result from endocrine dysfunction include Addison's disease, Cushing's disease and Graves' disease. Cushing's disease and Addison's disease are pathologies involving the dysfunction of the adrenal gland. Dysfunction in the adrenal gland could be due to primary or secondary factors and can result in hypercortisolism or hypocortisolism. Cushing's disease is characterized by the hypersecretion of the adrenocorticotropic hormone (ACTH) due to a pituitary adenoma that ultimately causes endogenous hypercortisolism by stimulating the adrenal glands. Some clinical signs of Cushing's disease include obesity, moon face, and hirsutism. Addison's disease is an endocrine disease that results from hypocortisolism caused by adrenal gland insufficiency. Adrenal insufficiency is significant because it is correlated with decreased ability to maintain blood pressure and blood sugar, a defect that can prove to be fatal.


title: Endocrine system

text: Graves' disease involves the hyperactivity of the thyroid gland which produces the T3 and T4 hormones. Graves' disease effects range from excess sweating, fatigue, heat intolerance and high blood pressure to swelling of the eyes that causes redness, puffiness and in rare cases reduced or double vision.


title: Endocrine system

text: A neuroendocrine system has been observed in all animals with a nervous system and all vertebrates have a hypothalamus-pituitary axis. All vertebrates have a thyroid, which in amphibians is also crucial for transformation of larvae into adult form. All vertebrates have adrenal gland tissue, with mammals unique in having it organized into layers. All vertebrates have some form of a renin–angiotensin axis, and all tetrapods have aldosterone as a primary mineralocorticoid.


title: I Have No Mouth, and I Must Scream

text: "I Have No Mouth, and I Must Scream" is a post-apocalyptic science fiction short story by American writer Harlan Ellison. It was first published in the March 1967 issue of "IF: Worlds of Science Fiction".


title: I Have No Mouth, and I Must Scream

text: It won a Hugo Award in 1968. The name was also used for a short story collection of Ellison's work, featuring this story. It was reprinted by the Library of America, collected in volume two (Terror and the Uncanny, from the 1940s to Now) of "American Fantastic Tales".


title: I Have No Mouth, and I Must Scream

text: Ellison showed the first six pages of "I Have No Mouth, and I Must Scream" to Frederik Pohl, who paid him in advance to finish it. Ellison finished writing the story in a single night in 1966, without making any changes from the first draft. Afterwards, Pohl edited said draft, tweaking some of Ted and Benny's character. Ellison derived the story's title, as well as inspiration for this story, from his friend William Rotsler's caption of a cartoon of a rag doll with no mouth.


title: I Have No Mouth, and I Must Scream

text: In a dystopian future, the Cold War has degenerated into a brutal world war between the United States, the Soviet Union, and China, who have each built an "Allied Mastercomputer" (or AM) to manage their weapons and troops. One of the AMs eventually acquires self-awareness and, after assimilating the other two AMs, takes control of the conflict, giving way to a vast genocide operation that almost completely ends mankind. 109 years later, AM has left only four men and one woman alive and keeps them in captivity within an endless underground housing complex, the only habitable place left on Earth. AM derives its sole semblance of pleasure from torturing the group. To prevent the humans from escaping its torment, AM has rendered the humans virtually immortal and unable to end their own lives.


title: I Have No Mouth, and I Must Scream

text: The machines are each referred to as "AM", which originally stood for "Allied Mastercomputer", but was changed to "Adaptive Manipulator" and later (after gaining sentience) "Aggressive Menace". It finally refers to itself as purely "AM", referring to the phrase "I think, therefore I am."


title: I Have No Mouth, and I Must Scream

text: The story's narrative begins with AM projecting a hologram of Gorrister to the other humans, hanging upside down, dripping blood and unresponsive. The real Gorrister joins the group to their surprise, and they realize it was another one of AM's illusions. Nimdok has the idea that there is canned food somewhere in the great complex. The humans are always near starvation under AM's rule, and any time they are given food, it is always a disgusting meal that they have difficulty eating. Because of their great hunger, the humans are coerced into making the long journey to the place where the food is supposedly kept – in this case, the ice caves. Along the way, the machine provides foul sustenance, sends horrible monsters after them, emits earsplitting sounds, and blinds Benny when he tries to escape.


title: I Have No Mouth, and I Must Scream

text: On more than one occasion, the group is separated by AM's obstacles. At one point, the narrator, Ted, is knocked unconscious and begins dreaming. He envisions the computer, anthropomorphized, standing over a hole in his brain speaking to him directly. Based on this nightmare, Ted comes to a conclusion about AM's nature, specifically why it has so much contempt for humanity; despite its abilities, it lacks the sapience to be creative or the ability to move freely. It wants nothing more than to exact revenge on humanity by torturing the last remnants of the species that created it.


title: I Have No Mouth, and I Must Scream

text: The group reaches the ice caves, where indeed there is a pile of canned goods. The group is overjoyed to find them, but is immediately crestfallen to find that they have no means of opening them. In a final act of desperation and sheer primal hunger, Benny attacks Gorrister and begins to gnaw at the flesh on his face. Ted, in a moment of clarity, realizes their only escape is through death. He seizes a stalactite made of ice and kills Benny and Gorrister. Ellen realizes what Ted is doing, and kills Nimdok, before being killed herself by Ted. Ted is stopped by AM before he can kill himself. AM, unable to return Ted's four companions to life, focuses all its rage on Ted.


title: I Have No Mouth, and I Must Scream

text: The story fast-forwards hundreds of years later, and AM has slowly transformed Ted into a "great soft jelly thing", incapable of causing itself harm, and constantly alters his perception of time to deepen his anguish. Ted, however, is grateful that he was able to save the others from further torture. Ted's closing thoughts end with the sentence that gives the story its title: "I have no mouth. And I must scream."


title: I Have No Mouth, and I Must Scream

text: Ellison uses an alternating pair of punchcode tapes as time-breaks – representing AM's "talkfields" – throughout the short story. The bars are encoded in International Telegraph Alphabet No 2 (ITA2), a character coding system developed for teletypewriter machines.


title: I Have No Mouth, and I Must Scream

text: The first talkfield, used four times, translates as "I THINK, THEREFORE I AM" and the second one, seen three times, as "COGITO ERGO SUM", the same phrase in Latin. The talkfields that divide the story were not included in the original publication in IF, and in many of the early publications were corrupted, up until the preface of the chapter containing "I Have No Mouth, And I Must Scream" in the first edition of "The Essential Ellison" (1991); Ellison states that in that particular edition, "For the first time anywhere, AM's 'talkfields' appear correctly positioned, not garbled or inverted or mirror-imaged as in "all" other versions."


title: I Have No Mouth, and I Must Scream

text: The first talkfield, as published in the first version of "The Essential Ellison", literally translates as


title: I Have No Mouth, and I Must Scream

text: where codice_2 is line feed and codice_3 carriage return. codice_4 sets the machine to "figure" mode and codice_5 puts it back into "character" mode.


title: I Have No Mouth, and I Must Scream

text: Much of the story hinges on the comparison of AM as a merciless god, with plot points paralleling to themes in the Bible, notably AM's transplanted sensations and the characters' trek to the ice caverns. AM also takes different forms before the humans, alluding to religious symbolism. Furthermore, the ravaged apocalyptic setting combined with the punishments is reminiscent of a vengeful God rewarding their sins, familiar to Dante's Inferno. Another theme is the complete inversion of the characters as a reflection of AM's own fate, an ironic fate brought upon themselves by creating the machine, and the altered 'self.'


title: Princess Alice of the United Kingdom

text: Princess Alice (Alice Maud Mary; 25 April 1843 – 14 December 1878) was Grand Duchess of Hesse and by Rhine from 13 June 1877 until her death in 1878 as the wife of Grand Duke Louis IV. She was the third child and second daughter of Queen Victoria of the United Kingdom and Prince Albert of Saxe-Coburg and Gotha. Alice was the first of Queen Victoria's nine children to die, and one of three to predecease their mother, who died in 1901. Her life had been enwrapped in tragedy since her father's death in 1861.


title: Princess Alice of the United Kingdom

text: Alice spent her early childhood in the company of her parents and siblings, travelling between the British royal residences. Her education was devised by Prince Albert's close friend and adviser, Christian Friedrich, Baron Stockmar, and included practical activities such as needlework and woodwork and languages such as French and German. When her father became fatally ill in December 1861, Alice nursed him until his death. Following his death, Queen Victoria entered a period of intense mourning and Alice spent the next six months acting as her mother's unofficial secretary. On 1 July 1862, while the court was still at the height of mourning, Alice married a minor German prince, Louis of Hesse. The ceremony—conducted privately and with unrelieved gloom at Osborne House—was described by the Queen as "more of a funeral than a wedding". Alice's life in Darmstadt was unhappy as a result of impoverishment, family tragedy and worsening relations with her husband and mother.


title: Princess Alice of the United Kingdom

text: Alice showed an interest in nursing, especially the work of Florence Nightingale. When Hesse became involved in the Austro-Prussian War, Darmstadt filled with the injured; the heavily pregnant Alice devoted a lot of her time to the management of field hospitals. One of her organisations, the Princess Alice Women's Guild, took over much of the day-to-day running of the state's military hospitals. As a result of this activity, Queen Victoria became concerned about Alice's directness about medical and, in particular, gynaecological, matters. In 1871, she wrote to Alice's younger sister, Princess Louise, who had recently married: ""Don't" let Alice pump you. Be "very" silent and cautious about your 'interior'". In 1877, Alice became Grand Duchess upon the accession of her husband, her increased duties putting further strains on her health. In late 1878, diphtheria infected the Hessian court. Alice nursed her family for over a month before falling ill herself, dying later that year.


title: Princess Alice of the United Kingdom

text: Princess Alice was the sister of Edward VII of the United Kingdom and German Empress Victoria (wife of Frederick III), mother of Empress Alexandra Feodorovna of Russia (wife of Nicholas II), and maternal grandmother of Queen Louise of Sweden (second wife of Gustaf VI Adolf) and Louis Mountbatten, 1st Earl Mountbatten of Burma (the last Viceroy of India). Another daughter, Elisabeth, who married Grand Duke Sergei Alexandrovich of Russia, was, like Alexandra and her family, killed by the Bolsheviks in 1918.


title: Princess Alice of the United Kingdom

text: Alice was born on 25 April 1843 at Buckingham Palace in London. She was christened "Alice Maud Mary" in the private chapel at Buckingham Palace by The Archbishop of Canterbury, William Howley, on 2 June 1843. Her sex was greeted with mixed feelings from the public, and even the Privy Council sent a message to Albert expressing its "congratulation and condolence" on the birth of a second daughter. Her godparents were the King of Hanover (her great-uncle; for whom the Duke of Cambridge stood proxy), the Princess of Hohenlohe-Langenburg (her aunt; for whom the Duchess of Kent stood proxy), the Hereditary Prince of Saxe-Coburg and Gotha (her uncle; for whom the Hereditary Grand Duke of Mecklenburg-Strelitz stood proxy) and Princess Sophia of Gloucester (her cousin).


title: Princess Alice of the United Kingdom

text: Alice's birth prompted her parents to find a larger family home. Buckingham Palace was not equipped with the private apartments that Victoria's growing family needed, including suitable nurseries. Therefore, in 1844, Victoria and Albert purchased Osborne House on the Isle of Wight as a family holiday home. Alice's education was devised by her father and his close friend, Baron Stockmar. At Osborne, Alice and her siblings were taught practical skills such as housekeeping, cooking, gardening and carpentry, as well as daily lessons in English, French and German.


title: Princess Alice of the United Kingdom

text: Victoria and Albert favoured a monarchy based on family values; Alice and her siblings, who wore middle class clothing on a daily basis, slept in sparsely furnished bedrooms with little heating. Alice was fascinated with the world outside the Royal Household; at Balmoral, where she seemed happiest, she visited the tenants living and working on the estate. On one occasion, she escaped from her governess at the chapel at Windsor Castle and sat in a public pew, so she could better understand people who were not strict adherents to royal protocol. In 1854, during the Crimean War, the eleven-year-old Alice toured London hospitals for wounded soldiers with her mother and her eldest sister. She was the most emotionally sensitive of her siblings and was sympathetic to other people's burdens, possessing a sharp tongue and an easily triggered temper. In her childhood, Alice formed a close relationship with her brother, the Prince of Wales, and her eldest sister, The Princess Royal. Victoria's marriage to Prince Frederick William of Prussia in 1858 greatly upset her.


title: Princess Alice of the United Kingdom

text: Alice's compassion for other people's suffering established her role as the family caregiver in 1861. Her maternal grandmother Victoria, Duchess of Kent, died at Frogmore on 16 March 1861. Alice had spent much of her time at her grandmother's side, often played the piano for her in Frogmore's drawing room, and nursed her through the final stages of illness. Following her mother's death, the Queen broke down with grief and relied heavily on Alice, to whom Albert had given the instruction: "Go and comfort Mama." The Queen wrote to her uncle, King Leopold of Belgium, that "dear good Alice was full of intense tenderness, affection and distress for me".


title: Princess Alice of the United Kingdom

text: Only a few months later, on 14 December 1861, Albert died at Windsor Castle. During his final illness, Alice remained at his bedside. Alice sent for the Prince of Wales by telegram, without the knowledge of the Queen, who refused to notify him because she blamed him for Albert's death. The Queen was distraught by her husband's death, and the court entered a period of intense mourning. Alice became her mother's unofficial secretary, and for the next six months, the physical representation of the monarch. Through her passed the Queen's official papers to and from her government ministers, while the Queen secluded herself from all public life. Alice was aided in this task by her younger sister Princess Louise. Although Princess Helena, Louise's elder sister, would normally have been selected to assist, her inability to go long without crying was held against her.


title: Princess Alice of the United Kingdom

text: Alice's matrimonial plans were begun in 1860 by her mother. Queen Victoria had expressed her wish that her children should marry for love, but this did not mean that her choice of suitors would necessarily be extended to anybody outside the royal houses of Europe. Raising a British subject to royalty, however high their rank, was politically objectionable, and also wasted any opportunity for a useful foreign alliance. The Queen instructed her daughter Victoria, recently married to Prince Frederick William of Prussia, to produce a list of eligible princes in Europe. Her search produced only two suitable candidates: the Prince of Orange; and Prince Albert of Prussia, cousin to Victoria's husband Frederick William. The Prince of Orange was soon discounted. He journeyed to Windsor Castle so that Queen Victoria could look him over in person, but he proved unpalatable to Alice. The prince too showed little interest in Alice, despite strong pressure from his pro-British mother, Queen Sophie of the Netherlands. Prince Albert, too, was spurned, with Prince Frederick William remarking that his cousin would not do for "one who deserves the very best".


title: Princess Alice of the United Kingdom

text: With both of the leading candidates now discounted, Princess Victoria suggested Prince Louis of Hesse, a minor German royal, the nephew of the Grand Duke of Hesse. Princess Victoria had gone to the court of Hesse to inspect Louis's sister, Princess Anna, as a potential bride for her brother, the Prince of Wales. Although not favorably impressed with Princess Anna, she was impressed with Louis and his brother Prince Henry. Both were invited to Windsor Castle in 1860, ostensibly so they could watch the Ascot Races in the company of the royal family, but in reality, the visit was a chance for the Queen to inspect her potential son-in-law. The Queen admired both Louis and Henry, but noted how well Louis and Alice got along together. When the Hessian family departed, Louis requested Alice's photograph, and Alice made it clear that she was attracted to him.


title: Princess Alice of the United Kingdom

text: Alice was engaged to Prince Louis of Hesse on 30 April 1861, following the Queen's consent. The Queen persuaded the Prime Minister, Lord Palmerston, to secure the agreement of Parliament for Alice to receive a dowry of £30,000 (£ as of 2022). Although the amount was considered generous at the time, Prince Albert remarked that "she will not be able to do great things with it" in the little realm of Hesse, compared to the riches that her sister Victoria would inherit as future Queen of Prussia and German Empress. Furthermore, the couple's future home in Darmstadt, the Grand Ducal seat, was uncertain. Although Queen Victoria expected that a new palace would be built, the people of Darmstadt did not want to meet that expense, and the resulting controversy caused resentment there. This meant that Alice was unpopular in Darmstadt before she even arrived.


title: Princess Alice of the United Kingdom

text: Between the engagement and the wedding, Alice's father Prince Albert died on 14 December 1861. Despite the Queen's grief, she ordered that the wedding should continue as planned. On 1 July 1862, Alice and Louis were married privately in the dining room of Osborne House, which was converted into a temporary chapel. The Queen was ushered in by her four sons, acting as a living screen blocking her from view, and took her place in an armchair near the altar. Alice was given away by her uncle, Albert's brother Ernest II, Duke of Saxe-Coburg and Gotha, and was flanked by four bridesmaids: her younger sisters, Princesses Helena, Louise and Beatrice, as well as Louis's sister Princess Anna. For the ceremony, Alice wore a simple white dress, with a veil of Honiton lace and a wreath of orange blossom and myrtle, but was required to wear black mourning clothes before and after the ceremony. The Queen, sitting in an armchair, struggled to hold back her tears, and was shielded from view by the Prince of Wales and Prince Alfred, her second son, who cried throughout the service. The weather at Osborne was dreary, with winds blowing up from the Channel. The Queen wrote to her eldest daughter, Victoria, that the ceremony was "more of a funeral than a wedding", and remarked to Alfred, Lord Tennyson that it was "the saddest day I can remember". The ceremony—described by Gerard Noel as "the saddest royal wedding in modern times"—was over by 4 pm, and the couple set off for their honeymoon at St Claire in Ryde, a house lent to them by the Vernon Harcourt family. Alice's entourage consisted of Lady Churchill, General Seymour and Baron Westerweller (a Hessian courtier). Alice was careful not to displease the Queen after her marriage. When the Queen visited the couple at St Claire, Alice tried not to appear "too happy". Despite this, Alice's displays of romantic bliss made the Queen jealous of her daughter's happiness.


title: Princess Alice of the United Kingdom

text: Alice and Louis arrived at Bingen on 12 July 1862 and were greeted by cheering crowds gathered in spite of pouring rain. After being introduced to town officials, they took a train to Mainz, where they had breakfast, before taking a steamer along the Rhine to Gustavsburg. From there, they took a train to Darmstadt, where they were greeted with great enthusiasm. Alice wrote back to her mother that "I believe the people never gave so hearty a welcome", while her sister Helena wrote that "nothing could have been more enthusiastic than her entry into Darmstadt was″. Alice did not adapt immediately to her new surroundings. She was homesick, and could not believe that while she was so far away from England, her father was not still alive and comforting her mother. The Queen confided to her journal: Already nearly a fortnight since our dear Alice has left and strange to say – much as she has been to me – and dear and precious as a comfort and an assistance, I hardly miss her at all, or felt her going – so utterly alone am I – by that one dreadful loss – that one thought, that everything passed by unheeded!


title: Princess Alice of the United Kingdom

text: The question of Alice's residence became an issue after her arrival, with the Grand Duke unwilling to fund a residence befitting a daughter of Queen Victoria with the low Hessian funds. The pair were given a house in Darmstadt's "Old Quarter", which overlooked the street. The carts rumbling past could easily be heard through the house's thin walls. However, it seemed to suit Alice well, and she spent as much time in Hesse as possible to familiarise herself with her new surroundings. She took art lessons from the court painter Paul Weber.


title: Princess Alice of the United Kingdom

text: In 1863, she travelled to England for the marriage of her brother, the Prince of Wales, and Princess Alexandra of Denmark; Alice delivered her first child, Victoria Alberta Elisabeth Mathilde Marie, on 5 April in the presence of Queen Victoria. The Darmstadt court chaplain was called over to England especially for the christening. Alice's relationship with her mother became difficult, which would continue until her death. After returning to Darmstadt in May, Alice and Louis were given a new residence, Kranichstein, north-east of Darmstadt. Alice gave birth to her second daughter Elisabeth, nicknamed "Ella", on 1 November 1864; Alice's decision to breastfeed her newborn daughter upset her mother, who was against breastfeeding. The Queen was further upset at the realisation that Alice, having found true happiness, would be visiting England less and less.


title: Princess Alice of the United Kingdom

text: In 1866, Austria called for Prussia to hand over administration of Schleswig-Holstein, which had until that point been jointly administered by the two powers, to the Duke of Augustenberg. Prussia refused, and Otto von Bismarck sent troops into Austrian-administered Holstein. This provoked war between Austria and Prussia, with Hesse siding with the Austrians, technically making Alice and her sister Victoria enemies.


title: Princess Alice of the United Kingdom

text: Alice, heavily pregnant with her third child, saw Louis depart to command the Hessian cavalry against the Prussians, and sent her children to stay with Queen Victoria in England. Despite her pregnancy, she performed the royal duties expected of her sex and station, making bandages for troops and preparing hospitals. On 11 July, she gave birth to Princess Irene; Prussian troops were on the verge of entering Darmstadt, she begged the Grand Duke to surrender on Prussia's terms. This provoked fury from the fiercely anti-Prussian Prince Alexander, but Alice realised that the conquered German states would likely form a union which she, like her sister Victoria, supported.


title: Princess Alice of the United Kingdom

text: Alice and Louis communicated extensively during the war, with Alice urging Louis not to take too many risks, and Louis urging her not to worry. Panic ensued in Darmstadt, with the youth corps fleeing their posts, leaving only the palace sentries to defend the city. Eventually an armistice between Prussia and Hesse was concluded, and Louis wrote that they were now "safe". He was reunited with Alice after the two met unexpectedly in the street, and they visited the wounded together. The Prussians entered Darmstadt, and Alice devoted much of her time to the sick and wounded. She was a friend of Florence Nightingale, who was able to collect and send money from England, and Alice used Nightingale's advice as to cleanliness and ventilation in hospitals.


title: Princess Alice of the United Kingdom

text: Despite being relieved that war was over, Alice was appalled by the behaviour of Prussian troops in Hesse; Berlin took the grand duchy's railways and telegraph systems, and assessed Hesse for three million florins in indemnity. Alice wrote to her mother, who in turn wrote to Princess Victoria, who responded that there was nothing she could do to relieve the "painful and distressing position darling Alice was in", as it was "one of the unavoidable results of this dreadful war". Influence came from the Emperor of Russia, who urged the Prussian King to allow the Grand Duke to keep his throne. The facts that the Emperor's wife was the Grand Duke's aunt, and Alice's sister being also the Prussian Crown Princess are likely to have influenced Prussia's generosity. However, Alice was angered by an untactful visit by Princess Victoria to the conquered region of Homburg, originally part of Hesse, shortly after it became Prussian territory.


title: Princess Alice of the United Kingdom

text: Alice developed a friendship with the theologian David Friedrich Strauss. He was a controversial figure at the time; in 1835, he published "The Life of Jesus", which argued that the miracles of Jesus were nonfactual myths and that the Bible could not be literally interpreted as God's word, a view akin to heresy in orthodox circles. Alice's view was similar to Strauss's, and she believed that contemporary Victorian society was presenting God in a way that would be "unrecognisable to early Christians". Strauss also offered Alice an intellectual companionship that her husband was not equipped to provide, and he was regularly invited to the New Palace to read to Alice privately. The friendship flourished; Strauss was introduced to Alice's sister Victoria and her brother-in-law Frederick William, and he was invited by them to Berlin. In 1870, Strauss wanted to dedicate his new work "Lectures on Voltaire" to Alice, but he was too afraid to ask her; she spared him the need by asking him to dedicate them to her. However, Alice's relationship with Strauss angered Empress Augusta, who labelled Alice a "complete atheist" after hearing about his promotion.


title: Princess Alice of the United Kingdom

text: Tragedy befell Alice on 29 May 1873, when her youngest and favourite son, Friedrich, called "Frittie", died after falling 20 feet from a window. The child suffered from haemophilia, and although he regained consciousness, the internal bleeding could not be stopped. Alice never recovered from Frittie's death, writing to her mother two months later: "I am glad you have a little coloured picture of my darling. I feel lower and sadder than ever and miss him so much, so continually." However, the Queen's attention was more focused on the engagement of her son Prince Alfred to the Grand Duchess Marie Alexandrovna of Russia, the only surviving daughter of Tsar Alexander II and his first wife, Empress Maria Alexandrovna. The Tsar had refused to present his daughter for pre-marriage inspection in England, and instead invited the Queen to meet the family in Germany. Alice supported this suggestion, and on the same day she wrote to the Queen about how much she missed Frittie, the Queen wrote to Alice in scathing terms: "You have entirely taken the Russian side, and I "do not" think, dear child, that "you" should tell "me"..."what" I "ought to do"."


title: Princess Alice of the United Kingdom

text: After Frittie's death, Alice attached herself more closely to her only surviving son, Ernest, and her newborn daughter Marie. In 1875 she resumed her public duties, including fund-raising, medical and social work, which had always held her interest. She maintained active correspondence with the social reformer Octavia Hill. However, in these years, relations with her husband deteriorated. In late 1876, she travelled to England for treatment due to an internal complaint caused by a backward curvature of the womb, and remained at Balmoral while she recovered. From Balmoral, she wrote to her husband criticising the childishness of his letters: "[i]f my children wrote me such childish letters – only short accounts – of where and what they had eaten or where they had been etc., and no opinions, observations and remarks, I should be surprised – and how much more so when "you" write like that!" On 3 October 1876, she wrote another despairing letter to Louis: