title: Thiruvalluvar

text: The poem "Kapilar Agaval", purportedly written by Kapilar, describes its author as a brother of Valluvar. It states that they were children of a Pulaya mother named Adi and a Brahmin father named Bhagwan. The poem claims that the couple had seven children, including three sons (Valluvar, Kapilar, and Atikaman) and four sisters (Avvai, Uppai, Uruvai, and Velli). However, this legendary account is spurious. Kamil Zvelebil dates "Kapilar Agaval" to 15th century CE, based on its language. Various biographies mention the name of Valluvar's wife as Vasuki, but such details are of doubtful historicity.


title: Thiruvalluvar

text: The traditional biographies are not only inconsistent, they contain claims about Valluvar that are not credible. Along with various versions of his birth circumstances, many state he went to a mountain and met the legendary Agastya and other sages. During his return journey, he sits under a tree whose shadow sits still over Valluvar and does not move the entire day, he kills a demon, performs miracles such as causing floods and making them retreat, he touches a grounded ship which miraculously then floats and sails off, his bride Vasuki cooks sand which comes out as boiled rice, and many more. Scholars consider these and all associated aspects of these hagiographic stories to be fiction and ahistorical, a feature common to "international and Indian folklore". The alleged low birth, high birth, and being a pariah in the traditional accounts are also doubtful.


title: Thiruvalluvar

text: By 1904, Purnalingam Pillai – an ardent Dravidianist, had analyzed and called these traditional accounts and stories as myths. Pillai's analysis and arguments are robust, according to Blackburn. These fictional accounts of Valluvar's life have become popular because aspects of the traditional accounts were selectively accepted by Christian missionaries such as George Pope and other European writers, were widely published and then became a required reading about Tamil history.


title: Thiruvalluvar

text: The exact date of Valluvar is unclear. His work ' has been dated variously from 300 BCE to about the sixth century CE. According to traditional accounts, it was the last work of the third Sangam and was subjected to a divine test (which it passed). The scholars who believe this tradition, such as Somasundara Bharathiar and M. Rajamanickam, date the text to as early as 300 BCE. Historian K. K. Pillay assigned it to the early first-century CE. These early dates such as 300 BCE to 1 BCE are unacceptable and not supported by evidence within the text, states Zvelebil. The diction and grammar of the ', his indebtedness to some earlier Sanskrit sources, suggest that he lived after the "early Tamil bardic poets", but before Tamil bhakti poets era.


title: Thiruvalluvar

text: In 1959, S. Vaiyapuri Pillai assigned the work to around or after the sixth-century CE. His proposal is based on the evidence that the ' contains a large proportion of Sanskrit loan words, shows awareness and indebtedness to some Sanskrit texts best dated to the first half of the first-millennium CE, and the grammatical innovations in the language of '. Pillai published a list of 137 Sanskrit loan words in '. Later scholars Thomas Burrow and Murray Barnson Emeneau show that 35 of these are of Dravidian origin, and not Sanskrit loan words. Zvelebil states that an additional few have uncertain etymology and future studies may prove those to be Dravidian. The 102 remaining loan words from Sanskrit are "not negligible", and some of the teachings in the ' states Zvelebil are "undoubtedly" based on the then extant Sanskrit works such as the "Arthashastra" and "Manusmriti" (also called the "Manavadharmasastra").


title: Thiruvalluvar

text: According to Kamil Zvelebil, the ' does not belong to the (Sangam) period. In the 1970s, Zvelebil dated the text to somewhere between 450 and 500 CE. His estimate is based on the dates of Tamil texts with similar Tamil language features, and by placing it after some of the Tamil and Sanskrit treatises that are evidenced in the '. Zvelebil notes that the text features several grammatical innovations, that are absent in the older Sangam literature. The text also features a higher number of Sanskrit loan words compared with these older texts. According to Zvelebil, besides being part of the ancient Tamil literary tradition, the author was also a part of the "one great Indian ethical, didactic tradition", as a few of his verses are "undoubtedly" translations of the verses in Sanskrit classics.


title: Thiruvalluvar

text: In the 19th century and early 20th century, European writers and missionaries variously dated the text and Valluvar to between 400 and 1000 CE. According to Blackburn, the "current scholarly consensus" dates the text and the author to approximately 500 CE.


title: Thiruvalluvar

text: In January 1935, the Tamil Nadu government officially recognized 31 BCE as the year of Valluvar. As suggested by Maraimalai Adigal, the Valluvar Year was added to the calendar. Thus, the Valluvar year is calculated by adding 31 to any year of the common era.


title: Thiruvalluvar

text: As with most other details about Valluvar, the exact place of his birth remains uncertain. Valluvar is believed to have lived in Madurai and later in the town of Mayilapuram or Thirumayilai (present-day Mylapore in Chennai). There are also accounts that say he was born in Mayilapuram and later moved to Madurai in order to publish his work at the royal court. The poem "Kapilar Akaval" states that Valluvar was born on the top of an oil-nut or "iluppai" tree ("Madhuca indica") in Mayilapuram,


title: Thiruvalluvar

text: In 2005, a three-member research team from the Kanyakumari Historical and Cultural Research Centre (KHCRC) claimed that Valluvar was born in Thirunayanarkurichi, a village in present-day Kanyakumari district. Their claim was based on an old Kani tribal leader who told them that Valluvar was a king who ruled the "Valluvanadu" territory in the hilly tracts of the Kanyakumari district.


title: Thiruvalluvar

text: Valluvar is generally thought to have belonged to either Jainism or Hinduism. Hinduism, Jainism, and Buddhism were the three religions that flourished in the Indian subcontinent during the time of Valluvar. Early 19th-century writers proposed that Valluvar may have been a Jain. The 1819 translation by Francis Whyte Ellis mentions that the Tamil community debates whether Valluvar was a Jain or Hindu. If Valluvar was indeed a Jain, it raises questions about the source of the traditional Valluvar legends and the mainstream colonial debate about his birth.


title: Thiruvalluvar

text: Kamil Zvelebil believes that the ethics of the "" reflects the Jain moral code, particularly moral vegetarianism (couplets 251–260), and ahimsa, that is, "abstention from killing" (couplets 321–333); scholars also note the articulation of Thiruvalluvar in one of the couplets of Tirukkuṟaḷ on the liberation ("Moksha") from the cycle of rebirth ("Saṃsāra") through living a life with a compassionate heart. Zvelebil states that the text contains epithets for God that reflect Jain ideology:


title: Thiruvalluvar

text: These, according to Zvelebil, are "very much Jaina-like" because the arhat is seen as "standing on the lotus", or where the "arhat" in the Jain conception is the god with the lotus as his vehicle. There are exceptions, adds Zvelebil, when Valluvar treats this God with epithets found in the Hindu text "Manusmriti" (1.6), that is, "the Primeval Lord" and "the King, the Monarch". Zvelebil states that his proposal is supported by the 13th-century Hindu scholar Parimelalhagar, who wrote a commentary on the Kural text, who admitted that these epithets are "very well applicable" to a Jain Arhat. However, according to P. S. Sundaram – a scholar who has translated the text in the late 20th century, Parimelalhagar's commentary explicitly states that there are no [Jaina] heretical beliefs in the texts either.


title: Thiruvalluvar

text: Some other epithets mentioned in the text also reflect a "strong ascetic flavour" of Jainism in Zvelebil's view:


title: Thiruvalluvar

text: Zvelebil further states that Valluvar seems to have been "cognizant of the latest developments" in Jainism. Zvelebil theorizes that he was probably "a learned Jain with eclectic leanings", who was well-acquainted with the earlier Tamil literature and also had knowledge of the Sanskrit texts. Early Digambara or Svetambara Jaina texts do not mention Valluvar. The first claim of Valluvar as an authority appears in a 16th-century Jain text, about 1,100 years after his life.


title: Thiruvalluvar

text: According to other scholars, Valluvar's writings suggest that he belonged to Hinduism. Hindu teachers have mapped his teachings in "" to the teachings found in Hindu texts. Valluvar's treatment of the concept of ahimsa or non-violence, which is the principal concept in both Jainism and Hinduism, bolsters this argument. While the text extols the virtue of non-violence, it also dedicates many of 700 "porul" couplets to various aspects of statecraft and warfare in a manner similar to "Arthasastra": "An army has a duty to kill in battle, and a king must execute criminals for justice." This non-mystic realism and the readiness for just war teachings are similar to those found in Hinduism. According to M. S. Purnalingam Pillai, Valluvar has not condemned Saiva Siddhanta or its principles anywhere in the text, which he says is the crucial test to be applied in determining his religion. Matthieu Ricard believes Valluvar belonged to the Shaivite tradition of South India.


title: Thiruvalluvar

text: The three parts that the Kural literature is divided into, namely, "aram" (virtue), "porul" (wealth) and "inbam" (love), aiming at attaining "vitu" (ultimate salvation), follow, respectively, the four foundations of Hinduism, namely, dharma, artha, kama and moksha. According to Norman Cutler, the prodigious 13th-century Tamil scholar Parimelalakar – who wrote the most influential commentary on "" – interprets the layout and focus on the Valluvar to be synonymous with the Sanskritic concept of Puruṣārtha (the objectives of human life). According to Parimelalakar, the Valluvar text covers primarily and directly the first three aspects, but not "vitu" ("moksha", release). The text, however, does cover "turavaram" (renunciation) – the means to attain spiritual release. Thus, "vitu" is indirectly discussed.


title: Thiruvalluvar

text: In the introductory chapters of the Kural, Valluvar cites Indra, the king of heaven, to exemplify the virtue of conquest over one's senses. According to Tamil Hindu scholars such as Parimelalakar, other concepts and teachings found in Valluvar's text and also found in Hindu texts include Vedas, gods ("Trimurti"), sattva, guṇa, munis and sadhus (renouncers), rebirth, affirmation of a primordial God, among others. According to Purnalingam Pillai, who is known for his critique of Brahminism, a rational analysis of the Valluvar's work suggests that he was a Hindu, and not a Jain. Similarly, J. J. Glazov, a Tamil literature scholar and the translator of the Kural text into the Russian language, sees "Thiruvalluvar as a Hindu by faith", according to a review by Kamil Zvelebil.


title: Thiruvalluvar

text: Valluvar's mentioning of God Vishnu in couplets 610 and 1103 and Goddess Lakshmi in couplets 167, 408, 519, 565, 568, 616, and 617 hints at the Vaishnavite beliefs of Valluvar. Shaivites have characterised Valluvar as a devotee of Shiva and have installed his images in their temples. According to Zvelebil, Valluvar sometimes uses epithets for God that are found in Hindu "Dharmasastras" and not in Jaina texts. Further, in some teachings about politics, economics, and love, Valluvar undoubtedly has translated into Tamil the verses found in Sanskrit texts such as "Arthasastra".


title: Thiruvalluvar

text: According to Stuart Blackburn, the ' is not a bhakti text, and it neither satirizes nor eulogizes Brahmins or ritualism. It is a practical, pragmatic text and "certainly not a Shaivite or Vaishnavite" text. According to Norman Cutler, ' is an aphoristic text and the influential Parimelalakar's commentary interprets it within his own context, grounded in Hindu concepts and theological agenda. His elegantly written interpretations have made his commentary a Tamil classic and maneuvered Valluvar as consistent within the framework of Parimelalakar's Hinduism. His commentary on Valluvar's teachings reflects both the cultural values and textual values in the 13th-to-14th-century Tamil Nadu. Valluvar's text can be interpreted and maneuvered in other ways.


title: Thiruvalluvar

text: Despite scholars suggesting that Valluvar is either a Jain or a Hindu, owing to the Kural text's non-denominational nature, almost every religious group in India, including Christianity, has claimed the work and its author as one of their own. However, these claims are not supported academically and are constantly refuted by scholars. For example, the Christian claims have cropped up only after the colonial missionaries came to India. The Tamil Scholar Mu. Varadarajan suggests Valluvar must have "practised religious eclecticism, maintained unshakeable faith in dharma but should have rejected religious symbols and superstitious beliefs."


title: Thiruvalluvar

text: The Dalit activist Iyothee Thass, who converted to Buddhism, claimed that Valluvar was originally called "Tiruvalla Nayanar", and was a Buddhist. Thass further contended that the name "Tirukkuṟaḷ" is a reference to the Buddhist "Tripiṭaka". He claims that Valluvar's book was originally called "Tirikural" ("Three Kurals"), because it adhered to the three Buddhist scriptures "Dhamma Pitaka", "Sutta Pitaka", and "Vinaya Pitaka". According to Thass, the legend that presents Valluvar as the son of a Brahmin father and a Paraiyar mother was invented by Brahmins in 1825, who wanted to Hinduise a Buddhist text. According to Geetha, the deconstruction and reinterpretation of the history of Valluvar into a Buddhist framework by Thass shows the significance and appropriation of Valluvar's text by all sections of Tamil society.


title: Thiruvalluvar

text: The 19th-century Christian missionary George Uglow Pope claimed that Valluvar must have come in contact with Christian teachers such as Pantaenus of Alexandria, imbibed Christian ideas and peculiarities of Alexandrian teachers and then wrote the "wonderful Kurral" with an echo of the "Sermon of the Mount". According to Pope, Valluvar must have lived in the ninth century CE because that would fit the historical chronology to his theory. Nevertheless, scholars, including Zvelebil, J. M. Nallaswamy Pillai, Sundaram Pillai, Kanakasabai Pillai, and Krishnaswamy Aiyengar, and even missionaries such as John Lazarus refute such claims. Pillai declares Pope's claim as "an absurd literary anachronism" and says that the first two books of the Kural, in particular, are "a stumbling block which can browbeat the most sublime ideas of Christian morality." According to John Lazarus, the Kural's chapter on "no killing" applies to both humans and animals, in stark contrast to the Bible's concept of killing, which refers only to the taking away of human life. He observes, "None of the ten epithets by which the Deity is described in the opening chapter of the Kural have the remotest connection with Christ or God, that is to say, as they are designated in the Bible". He also says that the chapter on love "is quite different from the Apostle’s eulogium in 1 Cor. xiii".


title: Thiruvalluvar

text: In the 1960s, some South Indian Christians led by M. Deivanayagam at the Madras Christian College, presented Valluvar as a disciple of Thomas the Apostle. According to this theory, Thomas visited present-day Chennai, where Valluvar listened to his lectures on the Sermon of the Mount. However, later scholars refute this claim. According to Zvelebil, the ethics and ideas in Valluvar's work are not Christian ethics, but those found in Jainism doctrine. Zvelebil points out to the Kural's unwavering emphasis on the ethics of moral vegetarianism (Chapter 26) and non-killing (Chapter 33), as against any of the Abrahamic religious texts.


title: Thiruvalluvar

text: "" is the primary work credited to Valluvar. It contains 1330 couplets, which are divided into 133 sections of 10 couplets each. The first 38 sections are on moral and cosmic order ("Tamil: aram", Skt: dharma), the next 70 are about political and economic matters ("Tamil: porul", Skt: artha), and the remaining 25 are about pleasure ("Tamil: inbam", Skt: kama).


title: Thiruvalluvar

text: Of the three sections, Valluvar's second section ("porul") is about twice the size of first section, and three times that of the third. In the 700 couplets on "porul" (53% of the text), Valluvar mostly discusses statecraft and warfare. Valluvar's work is a classic on realism and pragmatism, and it is not a mystic, purely philosophical document. Valluvar teachings are similar to those found in "Arthasastra", but differ in some important aspects. In Valluvar's theory of state, unlike Kautilya, the army ("patai") is most important element. Valluvar recommends that a well kept and well trained army ("patai") led by an able commander and ready to go to war is necessary for a state. Valluvar presents his theory of state using six elements: army ("patai"), subjects ("kuti"), treasure ("kul"), ministers ("amaiccu"), allies ("natpu"), and forts ("aran"). Valluvar also recommends forts and other infrastructure, supplies and food storage in preparation for siege.


title: Thiruvalluvar

text: The ' text has been translated into several Indian and international languages. It was translated into Latin by Constanzo Beschi in 1730, which helped make the work known to European intellectuals. ' is one of the most revered works in the Tamil language.


title: Thiruvalluvar

text: "" is generally recognized as the only work by Valluvar. However, in the Tamil literary tradition, Valluvar is attributed to be the author of many other later-dated texts including two Tamil texts on medicine, "Gnana Vettiyan" (1500 verses) and "Pancharathnam" (500 verses). Many scholars state that these are much later era texts (16th and 17th centuries), possibly by an author with the same name as Valluvar. These books, 'Pancharathnam' and 'Gnana Vettiyan', contribute to Tamil science, literature and other Siddha medicines. In addition to these, 15 other Tamil texts have been attributed to Valluvar, namely, "Rathna Sigamani" (800 verses), "Karpam" (300 verses), "Nadhaantha Thiravukol" (100 verses), "Naadhaantha Saaram" (100 verses), "Vaithiya Suthram" (100 verses), "Karpaguru Nool" (50 verses), "Muppu Saathiram" (30 verses), "Vaadha Saathiram" (16 verses), "Muppu Guru" (11 verses), "Kavuna Mani" (100 verses), "Aeni Yettram" (100 verses), "Guru Nool" (51 verses), "Sirppa Chinthamani" (a text on astrology), "Tiruvalluvar Gyanam", and "Tiruvalluvar Kanda Tirunadanam". Several scholars, such as Devaneya Pavanar, deny that Thiruvalluvar was the author of these texts.


title: Thiruvalluvar

text: George Uglow Pope called Valluvar "the greatest poet of South India", but according to Zvelebil, he does not seem to have been a poet. According to Zvelebil, while the author handles the metre very skillfully, the " does not feature "true and great poetry" throughout the work, except, notably, in the third book, which deals with love and pleasure. This suggests that Valluvar's main aim was not to produce a work of art, but rather an instructive text focused on wisdom, justice, and ethics.


title: Thiruvalluvar

text: Valluvar is revered and highly esteemed in the Tamil culture, and this is reflected in the fact that his work has been called by nine different names: " (the sacred kural), "Uttaravedam" (the ultimate Veda), "Thiruvalluvar" (eponymous with the author), "Poyyamoli" (the falseless word), "Vayurai valttu" (truthful praise), "Teyvanul" (the divine book), "Potumarai" (the common Veda), "Muppal" (the three-fold path), and "Tamilmarai" (the Tamil Veda).


title: Thiruvalluvar

text: Its influence and historic use is legendary. In 1708, the German missionary, Bartholomaus Ziegenbalg, remarked that the Malabaris "think very highly of it", they make it "their handbook" often quoting from it to prove the validity of their traditions and arguments, and such books are "not just read but learned by heart" by the learned among them. According to Blackburn, it is hard to outdo the "hyperbolic honors" heaped on Valluvar and his work by the early Europeans in colonial India. Gover, for example, praised it as "Tamil Homer, The Ten Commandments, and Dante rolled into one". During the colonial era, it was the text the Hindus used to respond to the "Christian allegations of Hindu superstition and barbarity".


title: Thiruvalluvar

text: Valluvar is traditionally worshiped as a god and saint by various communities across the Southern region of India. Many communities, including those in Mylapore, and Tiruchuli, worship Valluvar as the 64th Nayanmar of the Saivite tradition. There are various temples exclusively dedicated to Valluvar across South India. The most famous of these is the temple at Mylapore, Chennai. Built in the early 16th century, the temple is located within the Ekambareeswara-Kamakshi (Shiva-Parvati) temple complex in Mylapore. The locals believe that this is where Valluvar was born, underneath a tree within the shrines complex. A Valluvar statue in a seated posture holding a palm leaf manuscript of "" sits under the tree. In the shrine dedicated to him, Valluvar's wife Vasuki is patterned after the Hindu deity Kamakshi inside the sanctum. The temple shikhara (spire) above the sanctum shows scenes of Hindu life and deities, along with Valluvar reading his couplets to his wife. The "sthala vriksham" (holy tree of the temple) is the "iluppai" tree under which Valluvar is believed to have been born. The temple was extensively renovated in the 1970s.


title: Thiruvalluvar

text: At the Valluvar temple at Tiruchuli near Aruppukkottai in Virudhunagar district of the Indian state of Tamil Nadu, Valluvar is taken in a procession as the 64th Nayanmar on his death anniversary in the Tamil month of "Maasi" (February–March) by the Valluvar community, who are into fortune-telling, chiefly in the Periya Pudupatti village. The same practice can be found in other communities as well, including Mylapore.


title: Thiruvalluvar

text: Other temples for Valluvar are located at Periya Kalayamputhur, Thondi, Kanjoor Thattanpady, Senapathy, and Vilvarani.


title: Thiruvalluvar

text: A temple-like memorial to Valluvar, Valluvar Kottam, was built in Chennai in 1976. This monument complex consists of structures usually found in Dravidian temples, including a temple car carved from three blocks of granite, and a shallow, rectangular pond. The auditorium adjoining the memorial is one of the largest in Asia and can seat up to 4,000 people.


title: Thiruvalluvar

text: A 133-foot tall statue of Valluvar was unveiled on January 1, 2000, at Kanyakumari at the southern tip of the Indian subcontinent, where the Arabian Sea, the Bay of Bengal, and the Indian Ocean converge. The 133 feet denote ""'s 133 chapters or "athikarams" and the show of three fingers denote the three themes "Aram", "Porul", and "Inbam", that is, the sections on morals, wealth and love. The statue was designed by V. Ganapati Sthapati, a temple architect from Tamil Nadu. On 9 August 2009, a statue was unveiled in Ulsoor, near Bengaluru, also making it the first of its kind in India for a poet of a local language to be installed in its near states other than his own home land. A 12-foot statue of Valluvar was also installed in Haridwar, Uttarakhand. There is also a statue of Valluvar outside the School of Oriental and African Studies in Russell Square, London. A life-size statue of Valluvar is one among an array of statues installed by the Tamil Nadu government on the stretch of the Marina.


title: Thiruvalluvar

text: The Government of Tamil Nadu celebrates the 15th (16th on leap years) of January (the second of the month of 'Thai' as per Tamil Calendar) as "Thiruvalluvar Day" in the poet's honour, as part of the Pongal celebrations. Thiruvalluvar Day was first celebrated on 17 and 18 May 1935.


title: Thiruvalluvar

text: Valluvar's works have also influenced the South Indian classical music and popular culture. Carnatic musicians and composers such as Mayuram Vishwanatha Shastri and M. M. Dandapani Desigar have tuned select couplets in the 19th and 20th centuries. In January 2016, Chitravina N. Ravikiran set music to the entire 1330 verses using over 169 Indian ragas. The Kural couplets have also been recorded by various Tamil film music composers.


title: Thiruvalluvar

text: a. The period of Valluvar is dated variously by scholars from c. fourth century BCE to c. fifth century CE, based on various methods of analysis, including traditional accounts and linguistics analyses. The officially accepted date, however, is 31 BCE, as ratified by the government in 1921, and the Valluvar Year is being followed ever since. For more in-depth analysis, see Dating the Tirukkural.


title: Thiruvalluvar

text: b. "Valluvanadu" was a Taluk in erstwhile Madras Presidency as part of Malabar District. Currently, that area is part of Palakkad and Malappuram districts of Kerala adjoining the Nilgiri District of Tamil Nadu. The Valluvanadu kings claim that they descended from Pallava Kings and were ruling earlier from the Nilgiri area.


title: Neuroblastoma

text: Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in the abdomen, neck, or chest, or a painless bluish lump under the skin.


title: Neuroblastoma

text: Typically, neuroblastoma occurs due to a genetic mutation occurring during early development. Rarely, it may be due to a mutation inherited from a person's parents. Environmental factors have not been found to be involved. Diagnosis is based on a tissue biopsy. Occasionally, it may be found in a baby by ultrasound during pregnancy. At diagnosis, the cancer has usually already spread. The cancer is divided into low-, intermediate-, and high-risk groups based on a child's age, cancer stage, and what the cancer looks like.


title: Neuroblastoma

text: Treatment and outcomes depends on the risk group a person is in. Treatments may include observation, surgery, radiation, chemotherapy, or stem cell transplantation. Low-risk disease in babies typically has a good outcome with surgery or simply observation. In high-risk disease, chances of long-term survival, however, are less than 40%, despite aggressive treatment.


title: Neuroblastoma

text: Neuroblastoma is the most common cancer in babies and the third-most common cancer in children after leukemia and brain cancer. About one in every 7,000 children is affected at some time. About 90% of cases occur in children less than 5 years old, and it is rare in adults. Of cancer deaths in children, about 15% are due to neuroblastoma. The disease was first described in the 1800s.


title: Neuroblastoma

text: The first symptoms of neuroblastoma are often vague, making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:


title: Neuroblastoma

text: Neuroblastoma often spreads to other parts of the body before any symptoms are apparent, and 50 to 60% of all neuroblastoma cases present with metastases.


title: Neuroblastoma

text: The most common location for neuroblastoma to originate (i.e., the primary tumor) is in the adrenal glands. This occurs in 40% of localized tumors and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% nonadrenal), or pelvis (1%). In rare cases, no primary tumor can be discerned.


title: Neuroblastoma

text: Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), Horner's syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or kidney artery compression, 1.3% of cases).


title: Neuroblastoma

text: The cause of neuroblastoma is not well understood. The great majority of cases are sporadic and nonfamilial. About 1–2% of cases run in families and have been linked to specific gene mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the anaplastic lymphoma kinase ("ALK") gene. Germline mutations in the "PHOX2B "or "KIF1B" gene have been implicated in familial neuroblastoma, as well. Neuroblastoma is also a feature of neurofibromatosis type 1 and the Beckwith-Wiedemann syndrome.


title: Neuroblastoma

text: "MYCN" oncogene amplification within the tumor is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution: either 3- to 10-fold, or 100- to 300-fold. The presence of this mutation is highly correlated to advanced stages of disease.


title: Neuroblastoma

text: Duplicated segments of the "LMO1" gene within neuroblastoma tumor cells have been shown to increase the risk of developing an aggressive form of the cancer.


title: Neuroblastoma

text: Neuroblastoma has been linked to copy-number variation within the "NBPF10" gene, which results in the 1q21.1 deletion syndrome or 1q21.1 duplication syndrome.


title: Neuroblastoma

text: Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset, many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy, and birth factors; however, results have been inconclusive.


title: Neuroblastoma

text: Other studies have examined possible links with atopy and exposure to infection early in life, use of hormones and fertility drugs, and maternal use of hair dye.


title: Neuroblastoma

text: The diagnosis is usually confirmed by a surgical pathologist, taking into account the clinical presentation, microscopic findings, and other laboratory tests. It may arise from any neural crest element of the sympathetic nervous system (SNS).


title: Neuroblastoma

text: Esthesioneuroblastoma, also known as olfactory neuroblastoma, is believed to arise from the olfactory epithelium and its classification remains controversial. However, since it is not a sympathetic nervous system malignancy, esthesioneuroblastoma is a distinct clinical entity and is not to be confused with neuroblastoma.


title: Neuroblastoma

text: In about 90% of cases of neuroblastoma, elevated levels of catecholamines or their metabolites are found in the urine or blood. Catecholamines and their metabolites include dopamine, homovanillic acid (HVA), and/or vanillylmandelic acid (VMA).


title: Neuroblastoma

text: Another way to detect neuroblastoma is the meta-iodobenzylguanidine scan, which is taken up by 90 to 95% of all neuroblastomas, often termed "mIBG-avid". The mechanism is that mIBG is taken up by sympathetic neurons, and is a functioning analog of the neurotransmitter norepinephrine. When it is radio-iodinated with I-131 or I-123 (radioactive iodine isotopes), it is a very good radiopharmaceutical for diagnosis and monitoring of response to treatment for this disease. With a half-life of 13 hours, I-123 is the preferred isotope for imaging sensitivity and quality. I-131 has a half-life of 8 days and at higher doses is an effective therapy as targeted radiation against relapsed and refractory neuroblastoma. As mIBG is not always taken up by neuroblastomas, researchers have explored in children with neuroblastoma whether another type of nuclear imaging, fluoro-deoxy-glucose – positron emission tomography, often termed "F-FDG-PET", might be useful. Evidence suggests that this might be advisable to use in children with neuroblastoma for which mIBG does not work, but more research is needed in this area.


title: Neuroblastoma

text: On microscopy, the tumor cells are typically described as small, round and blue, and rosette patterns (Homer Wright pseudorosettes) may be seen. Homer Wright pseudorosettes are tumor cells around the neuropil, not to be confused with a true rosettes, which are tumor cells around an empty lumen. They are also distinct from the pseudorosettes of an ependymoma which consist of tumor cells with glial fibrillary acidic protein (GFAP)–positive processes tapering off toward a blood vessel (thus a combination of the two). A variety of immunohistochemical stains are used by pathologists to distinguish neuroblastomas from histological mimics, such as rhabdomyosarcoma, Ewing's sarcoma, lymphoma and Wilms' tumor.


title: Neuroblastoma

text: Neuroblastoma is one of the peripheral neuroblastic tumors (pNTs) that have similar origins and show a wide pattern of differentiation ranging from benign ganglioneuroma to stroma-rich ganglioneuroblastoma with neuroblastic cells intermixed or in nodules, to highly malignant neuroblastoma. This distinction in the pre-treatment tumor pathology is an important prognostic factor, along with age and mitosis-karyorrhexis index (MKI). This pathology classification system (the Shimada system) describes "favorable" and "unfavorable" tumors by the International Neuroblastoma Pathology Committee (INPC) which was established in 1999 and revised in 2003.


title: Neuroblastoma

text: The "International Neuroblastoma Staging System" (INSS) established in 1986 and revised in 1988 stratifies neuroblastoma according to its anatomical presence at diagnosis:


title: Neuroblastoma

text: Although international agreement on staging (INSS) has been used, the need for an international consensus on risk assignment has also been recognized in order to compare similar cohorts in results of studies. Beginning in 2005, representatives of the major pediatric oncology cooperative groups have met to review data for 8,800 people with neuroblastoma treated in Europe, Japan, USA, Canada, and Australia between 1990 and 2002. This task force has proposed the International Neuroblastoma Risk Group (INRG) classification system. Retrospective studies revealed the high survival rate of 12–18 month-old age group, previously categorized as high-risk, and prompted the decision to reclassify 12–18 month-old children without N-"myc" (also commonly referred to as MYCN) amplification to intermediate risk category.


title: Neuroblastoma

text: The new INRG risk assignment will classify neuroblastoma at diagnosis based on a new International Neuroblastoma Risk Group Staging System (INRGSS):


title: Neuroblastoma

text: The new risk stratification will be based on the new INRGSS staging system, age (dichotomized at 18 months), tumor grade, N-myc amplification, unbalanced 11q aberration, and ploidy into four pre-treatment risk groups: very low, low, intermediate, and high risk.


title: Neuroblastoma

text: Urine catecholamine level can be elevated in pre-clinical neuroblastoma. Screening asymptomatic infants at three weeks, six months, and one year has been performed in Japan, Canada, Austria and Germany since the 1980s. Japan began screening six-month-olds for neuroblastoma via analysis of the levels of homovanillic acid and vanilmandelic acid in 1984. Screening was halted in 2004 after studies in Canada and Germany showed no reduction in deaths due to neuroblastoma, but rather caused an increase in diagnoses that would have disappeared without treatment, subjecting those infants to unnecessary surgery and chemotherapy.


title: Neuroblastoma

text: When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-"cis"-retinoic acid, and frequently immunotherapy with anti-GD2 monoclonal antibody therapy – dinutuximab).


title: Neuroblastoma

text: Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed assignment to risk groups for planning treatment intensity. These criteria include the age of the person, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulates microRNAs), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 people with neuroblastoma and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk. (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)


title: Neuroblastoma

text: People with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70–90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time. The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009, an early analysis of a Children's Oncology Group (COG) study with 226 people that are high-risk showed that two years after stem cell transplant 66% of the group randomized to receive ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all people enrolling on the trial would receive the antibody therapy.


title: Neuroblastoma

text: Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.


title: Neuroblastoma

text: In November 2020, naxitamab was approved for medical use in the United States in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat people one year of age and older with high-risk neuroblastoma in bone or bone marrow whose tumor did not respond to or has come back after previous treatments and has shown a partial response, minor response, or stable disease to prior therapy.


title: Neuroblastoma

text: By data from England, the overall 5-year survival rate of neuroblastoma is 67%. Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory. Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.


title: Neuroblastoma

text: Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss, growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.


title: Neuroblastoma

text: Based on a series of 493 neuroblastoma samples, it has been reported that overall genomic pattern, as tested by array-based karyotyping, is a predictor of outcome in neuroblastoma:


title: Neuroblastoma

text: Earlier publications categorized neuroblastomas into three major subtypes based on cytogenetic profiles:


title: Neuroblastoma

text: Virtual karyotyping can be performed on fresh or paraffin-embedded tumors to assess copy number at these loci. SNP array virtual karyotyping is preferred for tumor samples, including neuroblastomas, because they can detect copy neutral loss of heterozygosity (acquired uniparental disomy). Copy neutral LOH can be biologically equivalent to a deletion and has been detected at key loci in neuroblastoma. ArrayCGH, FISH, or conventional cytogenetics cannot detect copy neutral LOH.


title: Neuroblastoma

text: Neuroblastoma comprises 6–10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.


title: Neuroblastoma

text: The highest number of cases is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults, but only 10% of cases occur in people older than 5 years of age. A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.


title: Neuroblastoma

text: In 1864 German physician Rudolf Virchow was the first to describe an abdominal tumor in a child as a "glioma". The characteristics of tumors from the sympathetic nervous system and the adrenal medulla were then noted in 1891 by German pathologist Felix Marchand. In 1901 the distinctive presentation of stage 4S in infants (liver but no bone metastases) was described by William Pepper. In 1910 James Homer Wright understood the tumor to originate from primitive neural cells, and named it neuroblastoma. He also noted the circular clumps of cells in bone marrow samples which are now termed "Homer Wright rosettes". Of note, "Homer-Wright" with a hyphen is grammatically incorrect, as the eponym refers to just Dr. Wright.


title: Neuroblastoma

text: U.S. Representative Chet Edwards of Waco, Texas, successfully introduced legislation to earmark $150 million toward a cure for neuroblastoma and other cancers. The measure was signed into law in July 2008 by U.S. President George W. Bush. Edwards was inspired in the endeavor by the illness and subsequent death of Erin Channing Buenger (1997–2009) of Bryan, daughter of one of his constituents, Walter L. Buenger, head of the history department at Texas A&M University.


title: Neuroblastoma

text: Neuroblastoma patient derived tumor xenografts (PDXs) have been created by orthotopic implantation of tumor samples into immunodeficient mice. PDX models have several advantages over conventional cancer cell lines (CCL)s. Neuroblastoma PDXs retain the genetic hallmarks of their corresponding tumors and PDXs display infiltrative growth and metastasis to distant organs. PDX models are more predictive of clinical outcome as compared to conventional cancer cell line xenografts. Neuroblastoma PDXs might thus serve as clinically relevant models to identify effective compounds against neuroblastoma.


title: Neuroblastoma

text: Recent focus has been to reduce therapy for low and intermediate risk neuroblastoma while maintaining survival rates at 90%. A study of 467 people that are at intermediate risk enrolled in A3961 from 1997 to 2005 confirmed the hypothesis that therapy could be successfully reduced for this risk group. Those with favorable characteristics (tumor grade and response) received four cycles of chemotherapy, and those with unfavorable characteristics received eight cycles, with three-year event free survival and overall survival stable at 90% for the entire cohort. Future plans are to intensify treatment for those people with aberration of 1p36 or 11q23 chromosomes as well as for those who lack early response to treatment.


title: Neuroblastoma

text: By contrast, focus the past 20 years or more has been to intensify treatment for high-risk neuroblastoma. Chemotherapy induction variations, timing of surgery, stem cell transplant regimens, various delivery schemes for radiation, and use of monoclonal antibodies and retinoids to treat minimal residual disease continue to be examined. Recent phase III clinical trials with randomization have been carried out to answer these questions to improve survival of high-risk disease:


title: Neuroblastoma

text: Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse.


title: Neuroblastoma

text: A haploidentical stem cell transplant, that is, donor cells derived from parents, is being studied in those with refractory or relapsing neuroblastoma as stem cells from the person themselves is not useful.


title: Neuroblastoma

text: It has been shown that neuroblastoma display a high expression of somatostatin receptors and this enables potential therapy using 177Lu-DOTA-TATE, a type of radionuclide therapy that specifically targets the somatostatin receptors. Several early phase clinical trials using Lu-DOTA-TATE for treatment of high-risk refractory/relapsed neuroblastoma have been conducted with promising results.


title: Neuroblastoma

text: Several international initiatives have been recently launched for the sharing of data of electronic health records of patients with neuroblastoma: these data in fact can be analyzed with machine learning and statistics models to infer new knowledge about this disease.


title: Neuroblastoma

text: To this end, the International Neuroblastoma Risk Group (INRG) recently released the INRG Data Commons, while University of Chicago launched the Pediatric Cancer Data Commons. These two repositories contain data of electronic health records of thousands of patients that are available for scientific research, with prior authorization.


title: Arya 2

text: Arya 2 is a 2009 Indian Telugu-language romantic action film directed by Sukumar. Starring Allu Arjun, Kajal Aggarwal, and Navdeep, it is a spiritual sequel to "Arya" (2004). Devi Sri Prasad composed the film's music, while Aditya Babu and B. V. S. N. Prasad produced the film under the Aditya Arts banner. The plot revolves around the complex love–hate relationship between three characters, Arya (Allu Arjun), a suave and hardworking businessman; Ajay (Navdeep), Arya's childhood friend and a huge businessman than Arya; and Geetha (Kajal Aggarwal), a girl who work at Ajay's company, whom both Arya and Ajay loves. The film theatrically released on 27 November 2009.


title: Arya 2

text: Two orphans, Ajay and Arya, meet at an orphanage, where the psychotic Arya forcibly befriends Ajay and grows possessive about him, while Ajay despises him but pretends not to. Ajay is adopted by a rich family, while Arya is left alone. Ajay grows to become a businessman and owner of an IT company. One day, when some rowdies trouble him, Arya enters their house and injured brutally using surgical instruments. He is arrested and Ajay gets him bailed, and soon, their car meets with an accident, leading to Arya saving Ajay from falling off a bridge in exchange, Ajay agrees to make Arya as his business partner, but with a condition that Arya must reform himself. Arya undergoes a transformation and becomes a suave and hardworking businessman. Within a few time, he earns everyone's respect at Ajay's company, including Shanti, who develops a liking for him.


title: Arya 2

text: One day, when Geetha joins the company, both Arya and Ajay fall for her. Ajay keeps his feelings to himself, but Arya constantly keeps confessing his love for Geetha. Soon, she learns of Arya's real behavior and tries to expose him, but in vain. However, one night, she manages to emotionally blackmail Arya into exposing himself. However, when he proposes to her, she, in turn, proposes Ajay to get rid of him. Ajay frames Arya for a car crash so that Geeta will actually love him. As both Geetha and Ajay express their attraction for each other, Arya decides to get them married. However, Geetha gets taken away by her violent family members on the day of her marriage. Her father Raji Reddy is a hardcore criminal who wants her to marry the son of Kashi Reddy, a rival, in order to end the conflict between both gangs. Arya goes to bring Geetha and stays at her house. Arya conspires to get the marriage stopped and is asked by Raji Reddy to marry her after he rescues Geetha from her kidnapping.


title: Arya 2

text: However, he helps Ajay reunite and flee with Geetha, further justifying that he married her to prevent her from marrying someone else. Back home, where everyone is searching for Geetha, Arya reveals that she is at the railway station. Realizing what he has done, he rushes to the railway station and saves Ajay from getting killed by Raji Reddy. Arya reveals to Ajay that he was the one who informed Raji Reddy as he was unable to sacrifice his wife. Later, Ajay is taken hostage by Raji Reddy and Arya makes Kashi Reddy hold Geetha hostage to demand Ajay's freedom. Arya and Subbi (whose marriage with Geetha was stalled) become friends, and the latter helps the trio escape.


title: Arya 2

text: Arya and Shanti arrange for passports and tickets to help Ajay and Geetha flee to America, but Arya demands one friendly day with them, during which Geetha grows closer to Arya. Ajay changes their destination to Australia in order to prevent Arya from stopping them and Geetha looks down on Ajay for betraying Arya. Before they leave, Ajay spots Raji Reddy. Geetha informs Ajay that she called her father, as she wanted to discuss their love matter with him, rather than let Arya take the fall for everything. Raji Reddy arrives and starts thrashing Ajay. Arya threatens to kill Geetha, but Raji Reddy tells Arya to kill her, as Arya cannot kill her. Raji Reddy attempts to stab Ajay. However, Arya covers him, gets stabbed, and is hospitalized. Ajay has a change of heart seeing Arya ready to sacrifice even his own life for his friendship. In the hospital, Arya asks Ajay to press a button in the hospital equipment which causes him to suffocate as the oxygen supply stops. Arya is saved on time, but Ajay, who pressed the button without any ill-intentions, is slapped by Geetha. Arya secretly apologizes to Ajay, who then leaves with a smile, realizing Geetha and Arya's love.


title: Arya 2

text: The soundtrack and background score were composed by Devi Sri Prasad. The music was released on 1 November 2009 at Rock Heights, Madhapur, Hyderabad. The audio rights of the soundtrack were purchased by Sony Music India. It was also recorded in Malayalam and Hindi. The tracks "Ringa Ringa", "Uppenantha Prema" and "My Love Is Gone" topped the music charts. The song "Ringa Ringa" received a cult status. The music of the song was re-used by Devi Sri Prasad in the Salman Khan's film, Ready as "Dhinka Chika". And it was also re-used in Kannada movie 5 Idiots.


title: Arya 2

text: Following the internet phenomenon of "Why This Kolaveri Di" in 2011, "Ringa Ringa" was featured alongside "Oh Podu", "Appadi podu" and "Naaka Mukka" in a small collection of south Indian songs that are considered a "national rage" in India.


title: Arya 2

text: "Oneindia" gave a review stating "For those who go to watch Allu Arjun film with some expectations, the film would be a true feast. What all one could expect from Allu Arjun"s film could be available in this movie. With the excellent dances and melodious audio, the film would surely be a big hit. The film had all kinds of masala that are needed for a commercial formula film and it would definitely ring the box office and would remain another milestone in Allu Arjun"s career." "IndiaGlitz" gave a review stating "Arya-2, though not in any way a second edition of that mature predecessor, is nevertheless both interesting and sympathetic. Its greatest asset is the riveting second half. Its biggest drawback is the slowness Arjun's character takes to grow on us. If its intelligence and humour in the second half make it enjoyable, the drabness, tacky comedy and excruciating scenes make it unwatchable in the first half. Thankfully, everything is undone by the second 80 minutes, which you will want to watch again and again" and called it an "Entertaining, on again, off again" film. "123telugu.com" gave a review stating "The film redefines the word 'Style'! Allu Arjun is back with a totally new look and style. The entire story is woven around Arya's character. The film has its share of brilliance, especially the scenes between Brahmanandam and his team, conversations between Allu Arjun and Navdeep and the entire episode involving Ajay. Arya-2 is the kind of film in which you will either dazzle you or bore you to death, there's no middle way. Either way, we end up hallucinating under its influence!" and rated the film 3/5 terming that it "Redefines Style". "fullhyderabad.com" gave a review stating "As for visuals, Arya 2 is undoubtedly a slickly made production. The overall design is as colourful and as cheerful as the promos have led you to believe, with the title song being one of the smartest portions of the film. For an audience starved of merry-making at the movies, this one could quite be the party whose invitation won't be chucked away so soon" and rated the film 6.5/10.


title: Arya 2

text: "Arya 2" was released in 1000 screens worldwide. It was also dubbed in Malayalam under the same title, in Odia as "I Love You Geeta" & in Hindi as "Arya: Ek Deewana" (2010).


title: Arya 2

text: The film was remade in Indian Bengali in 2014 as Ami Shudhu Cheyechi Tomay starring Ankush Hazra, Subhashree Ganguly, Vikram and Misha Sawdagor and in Bangladeshi Bengali in 2015 as Ajob Prem starring Bappy Chowdhury, Achol, Joy Chowdhury and Misha Sawdagor.


title: Arya 2

text: The film grossed in its first week, including from Nizam area. However the film was affected when its screening was halted in Telangana region due to Telangana Agitation.


title: Arya 2

text: The film was dubbed into Malayalam with the same title, and released across Kerala on 5 February 2010 with 100 prints and was successful in the state.


title: Pfeiffer syndrome

text: Pfeiffer syndrome is a rare genetic disorder characterized by the premature fusion of certain bones of the skull (craniosynostosis) which affects the shape of the head and face. In addition, the syndrome includes abnormalities of the hands (such as wide and deviated thumbs) and feet (such as wide and deviated big toes).


title: Pfeiffer syndrome

text: Pfeiffer syndrome is caused by mutations in the fibroblast growth factor receptors "FGFR1" and "FGFR2". The syndrome is grouped into three types, type 1 (classic Pfeiffer syndrome) being milder and caused by mutations in either gene and types 2 and 3 being more severe, often leading to death in infancy, caused by mutations in "FGFR2".


title: Pfeiffer syndrome

text: There is no cure for the syndrome. Treatment is supportive and often involves surgery in the earliest years of life to correct skull deformities and respiratory function. Most individuals with Pfeiffer syndrome type 1 have a normal intelligence and life span, while types 2 and 3 typically result in neurodevelopmental disorders and early death.


title: Pfeiffer syndrome

text: Pfeiffer syndrome affects about 1 in 100,000 births. The syndrome is named after German geneticist Rudolf Arthur Pfeiffer (1931–2012), who described it in 1964.


title: Pfeiffer syndrome

text: Many of the characteristic facial features result from the premature fusion of the skull bones (craniosynostosis). The head is unable to grow normally, which leads to a high prominent forehead (turribrachycephaly), and eyes that appear to bulge (proptosis) and are wide-set (hypertelorism). In addition, there is an underdeveloped upper jaw (maxillary hypoplasia). More than 50 percent of children with Pfeiffer syndrome have hearing loss; dental problems are also common.


title: Pfeiffer syndrome

text: In people with Pfeiffer syndrome, the thumbs and first (big) toes are wide and bend away from the other digits (pollex varus and hallux varus). Unusually short fingers and toes (brachydactyly) are also common, and there may be some webbing or fusion between the digits (syndactyly).


title: Pfeiffer syndrome

text: Pfeiffer syndrome is strongly associated with mutations of the fibroblast growth factor receptor 1 ("FGFR1") on chromosome 8 or the fibroblast growth factor receptor 2 ("FGFR2") gene on chromosome 10. These genes code for fibroblast growth factor receptors, which are important for normal bone development. Advanced paternal age is thought to be a risk factor for sporadic cases of Pfeiffer syndrome due to an increase in mutations in sperm as men become older.


title: Pfeiffer syndrome

text: The most widely accepted clinical classification of Pfeiffer syndrome was published by M. Michael Cohen in 1993. Cohen divided the syndrome into three possibly overlapping types, all of which are characterized by broad thumbs, broad great toes, brachydactyly and possibly syndactyly:


title: Pfeiffer syndrome

text: The key problem is the early fusion of the skull, which can be corrected by a series of surgical procedures, often within the first three months after birth. Later surgeries are necessary to correct respiratory and facial deformities.


title: Pfeiffer syndrome

text: Children with Pfeiffer syndrome types 2 and 3 "have a higher risk for neurodevelopmental disorders and a reduced life expectancy" than children with Pfeiffer syndrome type 1, but if treated, favorable outcomes are possible. In severe cases, respiratory and neurological complications often lead to early death.


title: Pfeiffer syndrome

text: The syndrome is named after German geneticist Rudolf Arthur Pfeiffer (1931–2012). In 1964, Pfeiffer described eight individuals in three generations of a family who had abnormalities of the head, hands and feet (acrocephalosyndactylia) that were inherited in an autosomal dominant pattern.


title: Aryan Nations

text: Aryan Nations is a North American antisemitic, neo-Nazi, white supremacist organization that was originally based in Kootenai County, Idaho, about miles (4.4 km) north of the city of Hayden Lake. Richard Girnt Butler founded the group in the 1970s.


title: Aryan Nations

text: In 2001 the Federal Bureau of Investigation (FBI) classified Aryan Nations as a "terrorist threat." In a review of terrorist organizations, the RAND Corporation called it the "first truly nationwide terrorist network" in the United States and Canada.


title: Aryan Nations

text: The beliefs of Aryan Nations are based on the teachings of Wesley A. Swift, a leading figure in the early Christian Identity movement. Swift combined British Israelism, extreme antisemitism, and political militancy. He founded his own church in California in the mid-1940s. He hosted a daily radio broadcast in California during the 1950s and 1960s. In 1957, the name of his church was changed to the Church of Jesus Christ–Christian, which continues to be used by Aryan Nations churches.


title: Aryan Nations

text: From 1974 until 2001, Aryan Nations headquarters was located in a 20-acre (8.1 ha) compound 1.8 miles (3 km) north of Hayden, Idaho. The Aryan Nations had a number of state chapters, but it was highly decentralized and the chapters' ties to the organization's headquarters were extremely loose. The group hosted an annual World Congress of Aryan Nations at Hayden Lake for Aryan Nations members and members of similar groups.


title: Aryan Nations

text: Until 1998, the leadership of the Aryan Nations remained firmly in the hands of Richard Girnt Butler. By that time, he was over 80 years old and his health was poor. At the annual Aryan Nations World Congress in 2001, Neuman Britton was appointed to lead the Aryan Nations as Butler's successor. But in August 2001, after Britton died, Butler appointed Harold Ray Redfeairn who was from Ohio to lead the Aryan Nations as his successor; he had been agitating for control of the organization since the mid-1990s. Redfeairn had brought in Dave Hall, an FBI informant who exposed the group's illegal activities. After this was discovered, Redfeairn was distrusted by some in the group. Redfeairn and August Kreis III, the propaganda minister for Aryan Nations, formed a splinter group, and Butler expelled them from Aryan Nations.


title: Aryan Nations

text: A few months later, Redfeairn returned to form an alliance with Butler. Butler's 2002 World Congress drew fewer than 100 people, and when he ran for mayor, he lost, garnering only 50 votes against more than 2,100 votes. Redfeairn died in October 2003, and Butler died of heart failure in September 2004. At the time of Butler's death, Aryan Nations had about 200 actively participating members.


title: Aryan Nations

text: In September 2000, the Southern Poverty Law Center (SPLC) won a $6.3 million judgment against Aryan Nations from an Idaho jury, who awarded punitive and compensatory damages to plaintiffs Victoria Keenan and her son Jason. The two Native Americans had been beaten with rifles by Aryan Nations security guards in Coeur d'Alene, Idaho in July 1998. The woman and her son were driving near the Aryan Nations compound when their car backfired, which the guards claimed to misinterpret as gunfire. The guards fired at the car, striking it several times. The car crashed and one of the Nations guards held the Keenans at gunpoint, beating them.


title: Aryan Nations

text: The SPLC filed suit on behalf of the Keenans. A jury found that Butler and Aryan Nations were grossly negligent in selecting and supervising the guards, and awarded the Keenans $6.3 million. A local attorney from Keenan's legal team said that the large verdict was partly to compensate the Keenans, but largely to punish Butler and his followers, and serve to deter similar conduct in the future.


title: Aryan Nations

text: The $6.3 million verdict caused Butler to file for bankruptcy one month later. As part of the bankruptcy process, the group's property was put up for auction. SPLC loaned the Keenans $95,000 to bid on the 20-acre property. In February 2001, the group's Hayden Lake compound and intellectual property, including the names "Aryan Nations" and "Church of Jesus Christ Christian", were transferred to the Keenans. Idaho native and millionaire philanthropist Greg Carr purchased the property from the Keenans, donating it to the North Idaho College Foundation. It has been converted to a park dedicated to peace.


title: Aryan Nations

text: Local fire departments demolished some of the church's former buildings by burning them during training exercises. Edgar Steele, the attorney who had represented Butler, was later convicted of hiring a handyman to kill his own wife. In 2014, Steele died while serving a 50-year prison sentence.


title: Aryan Nations

text: There are three main Aryan Nations factions. One was led by Charles John Juba, followed by August Kreis III. In 2012, Kreis stepped down as leader and designated Drew Bostwick as his successor. In 2002, Juba's group was based on a compound in the rural town of Ulysses in Potter County, north central Pennsylvania; it hosted the 2002 Aryan Nations World Congress. Juba resigned in March 2005, announcing that Kreis was the group's new leader.


title: Aryan Nations

text: Kreis established a new headquarters in Lexington, South Carolina and eventually moved it to near Union City, Tennessee. In 2005, Kreis received media attention by seeking an Aryan Nations–al Qaeda alliance.


title: Aryan Nations

text: In 2005, the Holy Order of the Phineas Priesthood, formerly in association with the faction operated by Kreis, seceded and formed Aryan Nations Revival, based in New York City. The Holy Order was created in opposition to Kreis's acceptance of adherents of Wicca, Islam, and Odinism. It considered such groups to be a deviation from the core Christian Identity belief of Aryan Nations. This Revival rapidly became the largest faction.


title: Aryan Nations

text: Aryan Nations Revival leaders were listed in the "Congressional Record" as domestic terrorists. The government concluded that the Holy Order of the Brotherhood of the Phinehas Priesthood was the enforcement/terrorist wing of Aryan Nations. Aryan Nations Revival hosted a weekly radio broadcast titled "The Aryan Nations Broadcast". Airing from 1979 to 2009, the radio program was authorized by Richard Butler. The program ended when host Hal Turner was arrested for threatening the lives of federal judges in Chicago. While incarcerated, Turner announced, through his attorney, that he was a federal informant, and that Aryan Nations was among those organizations which had been informed upon.


title: Aryan Nations

text: In 2009, Aryan Nations Revival, which was then based in Texas, merged with Pastor Jerald O'Brien's Aryan Nations, which was based in Coeur d'Alene, Idaho. Both parties were ardent Christian Identity adherents.


title: Aryan Nations

text: In 1983, Robert Jay Mathews, who had visited the Aryan Nations compound many times, formed The Order, along with Aryan Nations members Dan Bauer, Randy Duey, Denver Parmenter, and Bruce Pierce. The Order's mission was to overthrow the Zionist Occupational Government and establish the Northwest Territorial Imperative through an orchestrated plot to commit acts of domestic terrorism, which would include murder, arson, armed robbery, theft, counterfeiting, and extortion between 1983 and 1984. Dennis McGiffen, who also had ties to Aryan Nations, formed a group called "The New Order", inspired by Mathews' group. The members were arrested before they could follow through with their violent plans.


title: Aryan Nations

text: Buford O. Furrow, Jr., who was convicted of both the Los Angeles Jewish Community Center shooting and the murder of Filipino American postal worker Joseph Ileto, had previously worked as a security guard at the Aryan Nations compound for some time.


title: Aryan Nations

text: On April 4, 2004, intending to start a "Race War", Sean Michael Gillespie (former member of Aryan Nations) threw a Molotov cocktail at B'nai Temple Israel in the city of Oklahoma, Oklahoma. There were no casualties, but the building sustained material damage. Gillespie was arrested in Little Rock, Arkansas, on April 16 of the same year, but it was not until August 2005 that he was sentenced to 39 years in prison for attacking the Jewish temple and then trying to send a racist letter to the congregation. The defendant raised his hand in a Nazi salute with stiff arms as the judge left the courtroom.


title: Nina Foch

text: Nina Foch ( ; born Nina Consuelo Maud Fock; April 20, 1924 – December 5, 2008) was a Dutch-born American actress who later became an instructor. Her career spanned six decades, consisting of over 50 feature films and over 100 television appearances. She was the recipient of numerous accolades, including an Academy Award nomination for Best Supporting Actress, and a National Board of Review Award for Best Supporting Actress. Foch established herself as a dramatic actress in the late 1940s, often playing cool, aloof sophisticates.


title: Nina Foch

text: Born in Leiden, Netherlands in 1924, Foch immigrated to the United States with her mother while still a toddler, and was raised in New York City. After signing a contract with Columbia Pictures at age 19, Foch became a regular in the studio's horror pictures and films noir, starring in such films as "The Return of the Vampire" (1943), "Escape in the Fog", and "My Name Is Julia Ross" (1945). She concurrently embarked on a stage career, making her Broadway debut as the titular Mary in 1947's "John Loves Mary". She subsequently starred in several Broadway productions of William Shakespeare plays, including "Twelfth Night" (1949), "King Lear" (1950), and "Measure for Measure" (1955).


title: Nina Foch

text: Foch gained widespread notice for her role as Milo Roberts in the musical film "An American in Paris" (1951); Robert Wise's drama "Executive Suite" (1954), which earned her the Academy Award nomination for Best Supporting Actress; Cecil B. DeMille's "The Ten Commandments" (1956); and Stanley Kubrick's "Spartacus" (1960). In 1967, she made her theatrical directorial debut with a Broadway production of "Ways and Means", a comedy by Noël Coward. Foch also worked extensively in television beginning in the 1950s, with notable roles including the victim in the first of Peter Falk's "Columbo" films in 1968, as well as guest-starring parts in "The Wild Wild West" (1969), "The F.B.I." (1970), and "Hawaii Five-O" (1973). In 1980, she was nominated for a Primetime Emmy Award for Outstanding Supporting Actress for her guest role on an episode of "Lou Grant".


title: Nina Foch

text: Beginning in the 1960s, Foch began a concurrent career as an educator, teaching courses in drama and film directing at the American Film Institute and at the University of Southern California's School of Cinematic Arts, where she was a faculty member for over 40 years. Among her students were directors Randal Kleiser, Edward Zwick, and Amy Heckerling, and performer Julie Andrews. Foch continued to teach until the end of her life, up until her death in December 2008 of myelodysplastic syndrome.


title: Nina Foch

text: Nina Foch was born Nina Consuelo Maud Fock in 1924 in Leiden, South Holland, Netherlands, to American actress and singer Consuelo Flowerton and Dutch classical music conductor Dirk Fock. Her parents divorced when she was a toddler, and she and her mother moved to the United States, settling in New York City.


title: Nina Foch

text: Throughout Foch's childhood, her mother encouraged her artistic talents; she learned piano and enjoyed art but was more interested in acting. After graduating from the Lincoln School, Foch attended the American Academy of Dramatic Arts, studying method acting under Lee Strasberg and Stella Adler.


title: Nina Foch

text: After signing a contract with Columbia Pictures at age 19, Foch made her feature film debut in the studio's horror picture "The Return of the Vampire" (1943) with Bela Lugosi, subsequently appearing in Columbia's "Cry of the Werewolf" the next year. This was followed with a role in the biopic "A Song to Remember" (1945), the drama "I Love a Mystery" (1945); and a string of films noir, including "Escape in the Fog" (1945), in which she starred as a woman who has a premonition of her kidnapping. The same year, she had the titular role in "My Name is Julia Ross", a mystery about a woman who, after taking a new job working as a caretaker in a rural home, awakens one morning to find herself in a new location and with a different identity.


title: Nina Foch

text: Next, Foch appeared in "Johnny O'Clock" (1947), "The Dark Past" (1948), "The Undercover Man" (1948), and "Johnny Allegro" (1949). During this time, she was also a regular in John Houseman's CBS "Playhouse 90" television series.


title: Nina Foch

text: Foch made her Broadway debut in the 1947 production of "John Loves Mary", playing the titular Mary. She subsequently starred in Stratford and Broadway productions of Shakespeare's "Twelfth Night" (1949) and "King Lear" (1950).


title: Nina Foch

text: In 1951, Foch appeared with Gene Kelly in the musical "An American in Paris", which was awarded the Best Picture Oscar that year. Foch also appeared in "Scaramouche" (1952) as Marie Antoinette. She returned to theater in 1955, appearing in a Off-Broadway production of "Measure for Measure", followed by "The Taming of the Shrew". Next, Foch starred in Cecil B. DeMille's "The Ten Commandments" (1956) as Bithiah, the pharaoh's daughter, who finds the infant Moses in the bulrushes, adopts him as her son, and joins him and the Hebrews in their exodus from Egypt. In 1957, Foch was honored by the Maryland State Council of the American Jewish Congress with a special award for her performance in "The Ten Commandments".


title: Nina Foch

text: Foch received a nomination for the Academy Award for Best Supporting Actress for her role as a secretary in the boardroom drama "Executive Suite" (1954), starring William Holden, Fredric March, and Barbara Stanwyck. The same year "Executive Suite" was released, Foch married her first husband, actor James Lipton; their marriage spanned five years before ending in divorce in 1959. The same year, she married television writer Dennis de Brito, with whom she gave birth to one son, Dirk.


title: Nina Foch

text: In "Spartacus" (1960), starring Kirk Douglas and Laurence Olivier, she played a woman who chooses gladiators to fight to the death in the ring simply for her entertainment. In 1961, she guest-starred in the NBC series about the family divisions from American Civil War entitled "The Americans". In 1963, she appeared on the NBC game show "Your First Impression". In 1964, she played the title role in the episode "Maggie, Queen of the Jungle" of Craig Stevens's short-lived CBS drama series, "Mr. Broadway". Also in 1964, Foch divorced her second husband, De Brito. Foch was next cast as Eva Frazier in the "Outer Limits" episode "The Borderland". She appeared in an episode of "Gunsmoke" as the widowed matriarch of a lawless town, and played in an episode on "Combat!" titled episode "The Casket". In 1967, Foch married her third husband, Michael Dewell, in 1967.


title: Nina Foch

text: Also beginning in the 1960s, Foch began working as an instructor, teaching "Directing the Actor" classes at the School of Cinematic Arts at the University of Southern California (USC), as well as at the American Film Institute.


title: Nina Foch

text: She was subsequently cast as the first murder victim of the "Columbo" mystery series starring Peter Falk, appearing in the pilot movie, "Prescription: Murder" (1968), with Gene Barry as her husband, a homicidal psychiatrist. In the early 1970s, she guest-starred on ABC's "That Girl" in the fifth-season episode, "That Script", and NBC's "The Brian Keith Show". In 1975, she appeared in the film "Mahogany", starring Diana Ross, and subsequently supporting roles in the horror film "Jennifer" and the Walt Disney supernatural television film "Child of Glass" (both released in 1978). In 1980, Foch was nominated for a Primetime Emmy Award for Outstanding Supporting Actress for her guest role as Mrs. Pope on the "Lou Grant" episode "Hollywood".


title: Nina Foch

text: Later in her career, Foch appeared in "War and Remembrance" (1988) as the Comtesse de Chambrun, an American collaborationist in WWII Paris who employs Jane Seymour's character, Natalie Henry, as a librarian and suggests that the best place for her and her uncle would be the inaptly named "Paradise Ghetto". She also appeared as Frannie Halcyon in the TV miniseries "Tales of the City" (1993). The same year, Foch divorced her third husband, Michael Dewell. Another notable television role was as the Overseer Commander (or "Kleezantzun") in the first of the "Alien Nation" TV movies, "" (1994).


title: Nina Foch

text: In her final years, Foch appeared on the television series "Just Shoot Me", "Bull", "Dharma & Greg", and "NCIS", the latter portraying Dr. Donald "Ducky" Mallard's elderly mother. She also had minor roles in the independent drama film "Pumpkin" (2002), and the romantic comedy film "How to Deal" (2003).


title: Nina Foch

text: Foch also continued to work as an instructor at USC during this period, and also worked as an independent script-breakdown consultant for many Hollywood directors.


title: Nina Foch

text: Foch died on December 5, 2008, aged 84, at the Ronald Reagan UCLA Medical Center. Her only son, Dirk de Brito, told the "Los Angeles Times" that she died of complications from the blood disorder myelodysplasia. She had become ill the day before, while teaching her course at USC. Foch was cremated by the Neptune Society of Sherman Oaks, California, and her ashes were placed in the custody of her son.


title: Nina Foch

text: Foch has stars on the Hollywood Walk of Fame, located at 6300 Hollywood Boulevard, and 7000 Hollywood Boulevard. Those who studied with her include Rod Stewart, Julie Andrews, John Ritter (with whom she co-starred in "Skin Deep"), Amy Heckerling, Randal Kleiser, Edward Zwick, Ron Underwood, and Marshall Herskovitz. Andrews recalled of Foch: "She was a tough teacher, but in the best sense. She was always brutally frank, she demanded one go the extra mile, and she wouldn't allow one to get away with a thing." Kleiser, who studied with Foch in 1965, reflected: "She was able to take the things she learned working with directors like Vincente Minnelli and Stanley Kubrick and combine them with her own style."


title: Nina Foch

text: Foch was reportedly the inspiration for the character Nina, a washed-up actress teaching acting classes from a seedy motel, in Rufus Butler Seder's film "Screamplay". Seder had studied under Foch years earlier.


title: Barbecue sauce

text: Barbecue sauce (also abbreviated as BBQ sauce) is a sauce used as a marinade, basting, condiment, or topping for meat cooked in the barbecue cooking style, including pork or beef ribs and chicken. It is a ubiquitous condiment in the Southern United States and is used on many other foods as well.


title: Barbecue sauce

text: Ingredients vary, but most include vinegar or tomato paste (or a combination) as a base, as well as liquid smoke, onion powder, spices such as mustard and black pepper, and sweeteners such as sugar or molasses.


title: Barbecue sauce

text: Some place the origin of barbecue sauce at the formation of the first American colonies in the 17th century. References to the sauce start occurring in both English and French literature over the next two hundred years. South Carolina mustard sauce, a type of barbecue sauce, can be traced to German settlers in the 18th century.


title: Barbecue sauce

text: Early homemade barbecue sauces were made with vinegar, salt, and pepper. Sugar, ketchup, and Worcestershire sauce started to be used in the 1920s, but after World War II, the quantity of sugar and the number of ingredients increased dramatically.


title: Barbecue sauce

text: The Georgia Barbecue Sauce Company of Atlanta advertised an early commercially produced barbecue sauce in 1909. Heinz was the first major company to sell bottled barbecue sauce in 1940. Soon afterward, General Foods introduced "Open Pit." Kraft Foods only entered the market in around 1960, but with heavy advertising, succeeded in becoming the market leader. Kraft also started making cooking oils with bags of spice attached, supplying another market entrance of barbecue sauce.


title: Barbecue sauce

text: Different geographical regions have allegiances to their particular styles and variations of barbecue sauce.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis (DH) is a chronic autoimmune blistering skin condition, characterised by intensely itchy blisters filled with a watery fluid. DH is a cutaneous manifestation of coeliac disease, although the exact causal mechanism is not known. DH is neither related to nor caused by herpes virus; the name means that it is a skin inflammation having an appearance (Latin: "-formis") similar to herpes.


title: Dermatitis herpetiformis

text: The age of onset is usually about 15–40, but DH also may affect children and the elderly. Men are slightly more affected than women. Estimates of DH prevalence vary from 1 in 400 to 1 in 10,000. It is most common in patients of northern European and northern Indian ancestry, and is associated with the human leukocyte antigen (HLA) haplotype HLA-DQ2 or HLA-DQ8 along with coeliac disease and gluten sensitivity.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis was first described by Louis Adolphus Duhring in 1884. A connection between DH and coeliac disease was recognized in 1967.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis is characterized by intensely itchy, chronic papulovesicular eruptions, usually distributed symmetrically on extensor surfaces (buttocks, back of neck, scalp, elbows, knees, back, hairline, groin, or face). The blisters vary in size from very small up to 1 cm across. The condition is extremely itchy, and the desire to scratch may be overwhelming. This sometimes causes the affected person to scratch the blisters off before they are examined by a physician. Intense itching or burning sensations are sometimes felt before the blisters appear in a particular area.


title: Dermatitis herpetiformis

text: The signs and symptoms of DH typically appear around 30 to 40 years of age, although all ages may be affected. Although the first signs and symptoms of dermatitis herpetiformis are intense itching and burning, the first visible signs are the small papules or vesicles that usually look like red bumps or blisters. The rash rarely occurs on other mucous membranes, excepting the mouth or lips. The symptoms range in severity from mild to serious, but they are likely to disappear if gluten ingestion is avoided and appropriate treatment is administered.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis symptoms are chronic, and they tend to come and go, mostly in short periods of time in response to the amount of gluten ingested. Sometimes, these symptoms may be accompanied by symptoms of coeliac disease, which typically include abdominal pain, bloating or loose stool, weight loss, and fatigue. However, individuals with DH often have no gastrointestinal symptoms even if they have associated intestinal damage.


title: Dermatitis herpetiformis

text: The rash caused by dermatitis herpetiformis forms and disappears in three stages. In the first stage, the patient may notice a slight discoloration of the skin at the site where the lesions appear. In the next stage, the skin lesions transform into obvious vesicles and papules that are likely to occur in groups. Healing of the lesions is the last stage of the development of the symptoms, usually characterized by a change in the skin color. This may result in areas of the skin turning darker or lighter than the color of the skin on the rest of the body. Because of the intense itching, patients usually scratch, which may lead to the formation of crusts.


title: Dermatitis herpetiformis

text: In terms of pathology, the first signs of the condition may be observed within the dermis. The changes that may take place at this level may include edema, vascular dilatation, and cellular infiltration. It is common for lymphocytes and eosinophils to be seen. The bullae found in the skin affected by dermatitis herpetiformis are subepidermal and have rounded lateral borders.


title: Dermatitis herpetiformis

text: When looked at under the microscope, the skin affected by dermatitis herpetiformis presents a collection of neutrophils. They have an increased prevalence in the areas where the dermis is closest to the epidermis.


title: Dermatitis herpetiformis

text: Direct IMF studies of uninvolved skin show IgA in the dermal papillae and patchy granular IgA along the basement membrane. The jejunal mucosa may show partial villous atrophy, but the changes tend to be milder than in coeliac disease.


title: Dermatitis herpetiformis

text: Immunological studies revealed findings that are similar to those of coeliac disease in terms of autoantigens. The main autoantigen of dermatitis herpetiformis is epidermal transglutaminase (eTG), a cytosolic enzyme involved in cell envelope formation during keratinocyte differentiation.


title: Dermatitis herpetiformis

text: Various research studies have pointed out different potential factors that may play a larger or smaller role in the development of dermatitis herpetiformis. The fact that eTG has been found in precipitates of skin-bound IgA from skin affected by this condition has been used to conclude that dermatitis herpetiformis may be caused by a deposition of both IgA and eTG within the dermis. It is estimated that these deposits may resorb after ten years of following a gluten-free diet. Moreover, it is suggested that this condition is closely linked to genetics. This theory is based on the arguments that individuals with a family history of gluten sensitivity who still consume foods containing gluten are more likely to develop the condition as a result of the formation of antibodies to gluten. These antibodies cross-react with eTG, and IgA/eTG complexes deposit within the papillary dermis to cause the lesions of dermatitis herpetiformis. These IgA deposits may disappear after long-term (up to ten years) avoidance of dietary gluten.


title: Dermatitis herpetiformis

text: Gliadin proteins in gluten are absorbed by the gut and enter the lamina propria where they need to be deamidated by tissue transglutaminase (tTG). tTG modifies gliadin into a more immunogenic peptide. Classical dendritic cells (cDCs) endocytose the immunogenic peptide and if their pattern recognition receptors (PRRs) are stimulated by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular pattern (DAMPs), the danger signal will influence them to secrete IL-8 (CXCL8) in the lamina propria, recruiting neutrophils. Neutrophil recruitment results in a very rapid onset of inflammation. Therefore, co-infection with microbes that carry PAMPs may be necessary for the initial onset of symptoms in gluten sensitivity, but would not be necessary for successive encounters with gluten due to the production of memory B and memory T cells (discussed below).


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis may be characterised based on inflammation in the skin and gut. Inflammation in the gut is similar to, and linked to, celiac disease. tTG is treated as an autoantigen, especially in people with certain HLA-DQ2 and HLA-DQ8 alleles and other gene variants that cause atopy. tTG is up-regulated after gluten absorption. cDCs endocytose tTG-modified gliadin complexes or modified gliadin alone but they only present gliadin to CD4+ T cells on pMHC-II complexes. These T cells become activated and polarised into type I helper T (Th1) cells. Th1 cells reactive towards gliadin have been discovered, but none against tTG. A naive B cell sequesters tTG-modified gliadin complexes from the surface of cDCs in the lymph nodes (LNs) before they become endocytosed by the cDCs. The B cell receptor (membrane bound antibody; BCR) is specific to the tTG portion of the complex. The B cell endocytoses the complex and presents the modified gliadin to the activated Th1 cell's T cell receptor (TCR) via pMHC-II in a process known as epitope spreading. Thus, the B cell presents the foreign peptide (modified gliadin) but produces antibodies specific for the self-antigen (tTG). Once the B cell becomes activated, it differentiates into plasma cells that secrete autoantibodies against tTG, which may be cross-reactive with epidermal transglutanimase (eTG). Class A antibodies (IgA) deposit in the gut. Some may bind to the CD89 (FcαRI) receptor on macrophages (M1) via their Fc region (constant region). This will trigger endocytosis of the tTG-IgA complex, resulting in the activation of macrophages. Macrophages secrete more IL-8, propagating the neutrophil-mediated inflammatory response.


title: Dermatitis herpetiformis

text: The purportedly cross-reactive autoantibodies may migrate to the skin in dermatitis herpetiformis. IgA deposits may form if the antibodies cross-react with epidermal transglutanimase (eTG). Some patients have eTG-specific antibodies instead of tTG-specific cross-reactive antibodies and the relationship between dermatitis herpetiformis and celiac disease in these patients is not fully understood. Macrophages may be stimulated to secrete IL-8 by the same process as is seen in the gut, causing neutrophils to accumulate at sites of high eTG concentrations in the dermal papillae of the skin. Neutrophils produce pus in the dermal papillae, generating characteristic blisters. IL-31 accumulation at the blisters may intensify itching sensations. Memory B and T cells may become activated in the absence of PAMPs and DAMPs during successive encounters with tTG-modified gliadin complexes or modified gliadin alone, respectively. Symptoms of dermatitis herpetiformis are often resolved if patients avoid a gluten-rich diet.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis often is misdiagnosed, being confused with drug eruptions, contact dermatitis, dishydrotic eczema (dyshidrosis), and even scabies. Other diagnoses in the differential diagnosis include bug bites and other blistering conditions such as bullous pemphigoid, linear IgA bullous dermatosis, and bullous systemic lupus erythematosus.


title: Dermatitis herpetiformis

text: The diagnosis may be confirmed by a simple blood test for IgA antibodies against tissue transglutaminase (which cross-react with epidermal transglutaminase), and by a skin biopsy in which the pattern of IgA deposits in the dermal papillae, revealed by direct immunofluorescence, distinguishes it from linear IgA bullous dermatosis and other forms of dermatitis. Additionally, the concomitant diagnosis of Celiac disease can be made without the need for a small-intenstinal biopsy if an individual has biopsy-confirmed dermatitis herpetiformis as well as supporting serologic studies (elevated levels of IgA tissue transglutaminase antibodies, IgA epidermal transglutaminase antibodies, or IgA endomysial antibodies). These tests should be performed before the patient starts on a gluten-free diet, otherwise they might produce false negatives.


title: Dermatitis herpetiformis

text: As with ordinary celiac disease, IgA against transglutaminase disappears (often within months) when patients eliminate gluten from their diet. Thus, for both groups of patients, it may be necessary to restart gluten for several weeks before testing may be done reliably. In 2010, "Cutis" reported an eruption labelled "gluten-sensitive dermatitis" which is clinically indistinguishable from dermatitis herpetiformis, but lacks the IgA connection, similar to gastrointestinal symptoms mimicking coeliac disease but without the diagnostic immunological markers.


title: Dermatitis herpetiformis

text: A strict gluten-free diet must be followed, and usually, this treatment will be a lifelong requirement. Avoidance of gluten will reduce any associated intestinal damage and the risk of other complications. It can be very difficult to maintain a strict gluten-free diet, however, as contamination with gluten is common in many supposedly gluten-free foods and restaurants.


title: Dermatitis herpetiformis

text: Dapsone is an effective initial treatment in most people and is the initial drug of choice to alleviate the rash and itching. Itching is typically reduced within 2–3 days, however, dapsone treatment has no effect on any intestinal damage that might be present. After some time on a gluten-free diet, the dosage of dapsone usually may be reduced or even stopped, although this may take many years. Dapsone is an antibacterial, and its role in the treatment of DH, which is not caused by bacteria, is poorly understood. It may cause adverse effects, especially hemolytic anemia, so regular blood monitoring is required.


title: Dermatitis herpetiformis

text: For individuals with DH unable to tolerate dapsone for any reason, alternative treatment options may include the following:


title: Dermatitis herpetiformis

text: Combination therapy with nicotinamide and tetracyclines has been shown to be effective and well tolerated in some individuals who cannot tolerate dapsone or live in places where dapsone is not readily available. While the mechanism of action of tetracyclines and nicotinamide in DH is unknown, it is speculated to be due to their immune-modulating effects.


title: Dermatitis herpetiformis

text: Topical steroid medications are also sometimes used in combination with dapsone and a gluten-free diet to alleviate the itchiness associated with the rash.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis generally responds well to medication and a strict gluten-free diet. It is an autoimmune disease, however, and thus individuals with DH are more likely to develop other autoimmune conditions such as thyroid disease, insulin-dependent diabetes, lupus erythematosus, Sjögren's syndrome, sarcoidosis, vitiligo, and alopecia areata. There has been an association of non-Hodgkin lymphoma in individuals who have dermatitis herpetiformis, although this risk decreases to less than the population risk with a strict gluten-free diet.


title: Dermatitis herpetiformis

text: Dermatitis herpetiformis does not usually cause complications on its own, without being associated with another condition. Complications from this condition, however, arise from the autoimmune character of the disease, as an overreacting immune system is a sign that something does not work well and might cause problems to other parts of the body that do not necessarily involve the digestive system.


title: Dermatitis herpetiformis

text: Gluten intolerance and the body's reaction to it make the disease more worrying in what concerns the possible complications. This means that complications that may arise from dermatitis herpetiformis are the same as those resulting from coeliac disease, which include osteoporosis, certain kinds of gut cancer, and an increased risk of other autoimmune diseases such as thyroid disease.


title: Dermatitis herpetiformis

text: The risks of developing complications from dermatitis herpetiformis decrease significantly if the affected individuals follow a gluten-free diet.


title: Dermatitis herpetiformis

text: Global estimates of the prevalence of dermatitis herpetiformis range from 1 in 400 to 1 in 10,000 people. Individuals of Northern European descent are most likely to be affected and estimates of the rates of DH in British and Finnish populations range from 30 in 100,000 to 75 in 100,000 people, respectively. The annual incidence rate of DH in these populations range from 0.8 to 2.7 per 100,000.


title: Dermatitis herpetiformis

text: People of all ages may be affected, although the mean age at diagnosis varies between 30 and 40 years of age. There is a slight male predominance in DH for unknown reasons and it is associated with celiac disease and the haplotypes HLA-DQ2 and, less commonly, HLA-DQ8.


title: Dermatitis herpetiformis

text: It has been suggested that French revolutionary Jean-Paul Marat had DH. Marat was known to have a painful skin disease, from which he could only achieve relief by immersing himself in a bathtub filled with an herbal mixture; it was in this tub that he was famously assassinated, as portrayed in "The Death of Marat". A researcher suggested in 1979 that the mysterious skin disease was DH based on these symptoms and this regimen of self-treatment.


title: Octane

text: Octane is a hydrocarbon and an alkane with the chemical formula , and the condensed structural formula . Octane has many structural isomers that differ by the amount and location of branching in the carbon chain. One of these isomers, 2,2,4-trimethylpentane (commonly called iso-octane) is used as one of the standard values in the octane rating scale.


title: Octane

text: Octane is a component of gasoline (petrol). As with all low-molecular-weight hydrocarbons, octane is volatile and very flammable.


title: Octane

text: "Octane" is colloquially used as a short form of "octane rating," particularly in the expression "high octane". "Octane rating" is an index of a fuel's ability to resist engine knock in engines having different compression ratios, which is a characteristic of octane's branched-chain isomers, especially iso-octane.


title: Octane

text: The octane rating of gasoline is not directly related to the power output of an engine. Using gasoline of a higher octane than an engine is designed for cannot increase power output.


title: Octane

text: The octane rating was originally determined by mixing fuels from only normal heptane and iso-octane (2,2,4-trimethylpentane, a highly branched octane), and assigning anti-knock ratings of zero for normal heptane and 100 for pure iso-octane. The anti-knock rating of this mixture would be the same as the percentage of iso-octane in the mix. Different isomers of octane can contribute to a lower or higher octane rating. For example, "n"-octane (the straight chain of 8 carbon atoms with no branching) has a -20 (negative) Research Octane Rating, whereas pure iso-octane has an RON rating of 100. Some fuels have an octane rating higher than 100, notably those containing methanol or ethanol.


title: Octane

text: Octane became well known in American popular culture in the mid- and late 1960s, when gasoline companies boasted of "high octane" levels in their gasoline advertisements.


title: Octane

text: The compound adjective "high-octane", meaning powerful or dynamic, is recorded in a figurative sense from 1944. By the mid-1990s, the phrase was commonly being used as an intensifier and it has found a place in modern English vernacular.


title: Magnus the Good

text: Magnus Olafsson (Old Norse: "Magnús Óláfsson"; Norwegian and Danish: "Magnus Olavsson"; – 25 October 1047), better known as Magnus the Good (Old Norse: "Magnús góði", Norwegian and Danish: "Magnus den gode"), was King of Norway from 1035 and King of Denmark from 1042 until his death in 1047.


title: Magnus the Good

text: Magnus was an illegitimate son of King Olaf II of Norway, and fled with his mother Alfhild when his father was dethroned in 1028. He returned to Norway in 1035 and was crowned king at the age of 11. In 1042, he was also crowned king of Denmark. Magnus ruled the two countries until 1047, when he died under unclear circumstances. After his death, his kingdom was split between Harald Hardrada in Norway and Sweyn Estridsson in Denmark.


title: Magnus the Good

text: Magnus was an illegitimate son of King Olaf Haraldsson (later St. Olaf), by his English concubine Alfhild, originally a slave (thrall) of Olaf's queen Astrid Olofsdotter. Born prematurely, the child was weak and unable to breathe for the first few minutes, and he was probably not expected to survive. Olaf was not present at the child's birth, and his Icelandic skald Sigvatr Þórðarson became his godfather. In a hasty baptism, Sigvatr named Magnus after the greatest king he knew of, also Olaf's greatest role model, "Karla Magnus", or Charlemagne. Against the odds, Magnus went on to grow strong and healthy, and he became of vital importance to Olaf as his only son.