title: Suprachiasmatic nucleus

text: The SCN receives input from specialized photosensitive ganglion cells in the retina via the retinohypothalamic tract. Neurons in the "ventrolateral SCN" (vlSCN) have the ability for light-induced gene expression. Melanopsin-containing ganglion cells in the retina have a direct connection to the ventrolateral SCN via the retinohypothalamic tract. When the retina receives light, the vlSCN relays this information throughout the SCN allowing "entrainment", synchronization, of the person's or animal's daily rhythms to the 24-hour cycle in nature. The importance of entraining organisms, including humans, to exogenous cues such as the light/dark cycle, is reflected by several circadian rhythm sleep disorders, where this process does not function normally.


title: Suprachiasmatic nucleus

text: Neurons in the "dorsomedial SCN" (dmSCN) are believed to have an endogenous 24-hour rhythm that can persist under constant darkness (in humans averaging about 24 hours 11 min). A GABAergic mechanism is involved in the coupling of the ventral and dorsal regions of the SCN.


title: Suprachiasmatic nucleus

text: The SCN sends information to other hypothalamic nuclei and the pineal gland to modulate body temperature and production of hormones such as cortisol and melatonin.


title: Suprachiasmatic nucleus

text: Information about the direct neuronal regulation of metabolic processes and circadian rhythm-controlled behaviors is not well known among either endothermic or ectothermic vertebrates, although extensive research has been done on the SCN in model animals such as the mammalian mouse and ectothermic reptiles, in particular, lizards. The SCN is known to be involved not only in photoreception through innervation from the retinohypothalamic tract but also in thermoregulation of vertebrates capable of homeothermy, as well as regulating locomotion and other behavioral outputs of the circadian clock within ectothermic vertebrates. The behavioral differences between both classes of vertebrates, when compared to the respective structures and properties of the SCN and various other nuclei proximate to the hypothalamus, provide insight into how these behaviors are the consequence of differing circadian regulation. Ultimately, many neuroethological studies must be done to completely ascertain the direct and indirect roles of the SCN on circadian-regulated behaviors of vertebrates.


title: Suprachiasmatic nucleus

text: In general, external temperature does not influence endothermic animal behavior or circadian rhythm because of the ability of these animals to keep their internal body temperature constant through homeostatic thermoregulation; however, peripheral oscillators (see Circadian rhythm) in mammals are sensitive to temperature pulses and will experience resetting of the circadian clock phase and associated genetic expression, suggesting how peripheral circadian oscillators may be separate entities from one another despite having a master oscillator within the SCN. Furthermore, when individual neurons of the SCN from a mouse were treated with heat pulses, a similar resetting of oscillators was observed, but when an intact SCN was treated with the same heat pulse treatment the SCN was resistant to temperature change by exhibiting an unaltered circadian oscillating phase. In ectothermic animals, particularly the ruin lizard "Podacris sicula", temperature has been shown to affect the circadian oscillators within the SCN. This reflects a potential evolutionary relationship among endothermic and ectothermic vertebrates, in how ectotherms rely on environmental temperature to affect their circadian rhythms and behavior and endotherms have an evolved SCN to essentially ignore external temperature and use photoreception as a means for entraining the circadian oscillators within their SCN. In addition, the differences of the SCN between endothermic and ectothermic vertebrates suggest that the neuronal organization of the temperature-resistant SCN in endotherms is responsible for driving thermoregulatory behaviors in those animals differently from those of ectotherms, since they rely on external temperature for engaging in certain behaviors.


title: Suprachiasmatic nucleus

text: Significant research has been conducted on the genes responsible for controlling circadian rhythm, in particular within the SCN. Knowledge of the gene expression of "Clock" ("Clk") and "Period2" ("Per2"), two of the many genes responsible for regulating circadian rhythm within the individual cells of the SCN, has allowed for a greater understanding of how genetic expression influences the regulation of circadian rhythm-controlled behaviors. Studies on thermoregulation of ruin lizards and mice have informed some connections between the neural and genetic components of both vertebrates when experiencing induced hypothermic conditions. Certain findings have reflected how evolution of SCN both structurally and genetically has resulted in the engagement of characteristic and stereotyped thermoregulatory behavior in both classes of vertebrates.


title: Suprachiasmatic nucleus

text: Some of the others are the lateral geniculate nucleus (LGN), the superior colliculus, the basal optic system, and the pretectum:


title: Suprachiasmatic nucleus

text: The circadian rhythm in the SCN is generated by a gene expression cycle in individual SCN neurons. This cycle has been well conserved through evolution and in essence is similar in cells from many widely different organisms that show circadian rhythms. For example, although fruit flies (like all invertebrates) do not have an SCN, the cycle is largely similar to that of mammals. It is currently thought that all animals share a common root in their circadian rhythm.


title: Suprachiasmatic nucleus

text: In the fruitfly "Drosophila", the cellular circadian rhythm in neurons is controlled by two interlocked feedback loops.


title: Suprachiasmatic nucleus

text: These genes encode various transcription factors that trigger expression of other proteins. The products of "clock" and "cycle", called CLK and CYC, belong to the PAS-containing subfamily of the basic helix-loop-helix (bHLH) family of transcription factors, and form a heterodimer. This heterodimer (CLK-CYC) initiates the transcription of "PER" and "TIM", whose protein products dimerize and then inhibit their own expression by disrupting CLK-CYC-mediated transcription. This negative feedback mechanism gives a 24-hour rhythm in the expression of the clock genes. Many genes are suspected to be linked to circadian control by "E-box elements" in their promoters, as CLK-CYC and its homologs bind to these elements.


title: Suprachiasmatic nucleus

text: The 24-hour rhythm could be reset by light via the protein cryptochrome (CRY), which is involved in the circadian photoreception in "Drosophila". CRY associates with TIM in a light-dependent manner that leads to the destruction of TIM. Without the presence of TIM for stabilization, PER is eventually destroyed during the day. As a result, the repression of CLK-CYC is reduced and the whole cycle reinitiates again.


title: Suprachiasmatic nucleus

text: CLOCK (circadian locomotor output cycles kaput) was first cloned in mouse and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1) is the primary homolog of "Drosophila" CYC.


title: Suprachiasmatic nucleus

text: Three homologs of PER (PER1, PER2, and PER3) and two CRY homologs (CRY1 and CRY2) have been identified.


title: Suprachiasmatic nucleus

text: TIM has been identified in mammals; however, its function is still not determined. Mutations in TIM result in an inability to respond to zeitgebers, which is essential for resetting the biological clock.


title: Suprachiasmatic nucleus

text: Recent research suggests that, outside the SCN, clock genes may have other important roles as well, including their influence on the effects of drugs of abuse such as cocaine.


title: Suprachiasmatic nucleus

text: Neurons in the SCN fire action potentials in a 24-hour rhythm. At mid-day, the firing rate reaches a maximum, and, during the night, it falls again. How the gene expression cycle (so-called the core clock) connects to the neural firing remains unknown.


title: Suprachiasmatic nucleus

text: Many SCN neurons are sensitive to light stimulation via the retina, and sustainedly firing action potentials during a light pulse (~30 seconds) in rodents. The photic response is likely linked to effects of light on circadian rhythms. In addition, focal application of melatonin can decrease firing activity of these neurons, suggesting that melatonin receptors present in the SCN mediate phase-shifting effects through the SCN.


title: Panchayati raj

text: The Panchayat raj ("panchayat" "village council", "raj" "rule") is a political system, originating from the Indian subcontinent, found mainly in India, Pakistan, Bangladesh, Sri Lanka, and Nepal. It is the oldest system of local government in the Indian subcontinent, and historical mentions date to the 250 CE period. The word "raj" means "rule" and "panchayat" means "assembly" ("ayat") of five ("panch"). Traditionally, Panchayats consisted of wise and respected elders chosen and accepted by the local community. These assemblies settled disputes between both individuals and villages. However, there were varying forms of such assemblies.


title: Panchayati raj

text: The leader of the Panchayat was often called the president mukhiya, sarpanch, or pradhan, an elected or generally acknowledged position. The modern Panchayati Raj of India and its gram panchayats are neither to be confused with the traditional system nor with the extra-constitutional khap panchayats (or caste panchayats) found in parts of northern India.


title: Panchayati raj

text: Mahatma Gandhi advocated "panchayat raj" as the foundation of India's political system. It would have been a decentralised form of government, where each village would be responsible for its own affairs. The term for such a vision was "Gram Swaraj" ("village self-governance"). Instead, India developed a highly centralised system of government. However, this has been moderated by the delegation of several administrative functions to the local level, empowering elected gram panchayats. There are significant differences between the traditional Panchayati Raj system, the system envisioned by Gandhi, and the system formalised in India in 1992.


title: Panchayati raj

text: In the time of the Rigveda (1700 BC), evidences suggest that self-governing village bodies called 'sabhas' existed. With the passage of time, these bodies became panchayats (council of five persons). Panchayat were functional institutions of grassroots governance in almost every village. The Village Panchayat or elected council had large ers, both executive and judicial. Land was distributed by this panchayat which also collected taxes out of the produce and paid the government's share on behalf of the village. Above a number of these village councils there was a larger panchayat or council to supervise and interfere if necessary. Casteism and feudalistic system of governance under Mughal rule in the medieval period slowly eroded the self-government in villages. A new class of feudal chiefs and revenue collectors (zamindars) emerged between the ruler and the people. And, so began the stagnation and decline of self-government in villages.


title: Panchayati raj

text: A detailed account of how a medieval south Indian village council functioned was carved into a temple wall in Uthiramerur, a village in Tamil Nadu some 85km westof Chennai. Thirty councilmembers were chosen by lot, a form of sortition. Males were eligible for selection if they were of good character and met a set of requirements based on landholdings and knowledge of Hindu scriptures. They were then assigned to various committees in charge of irrigation works, gardens and other matters.


title: Panchayati raj

text: The British were not generally concerned with local administration, but left that to the local rulers, and thus didn't interfere with existing panchayati systems, nor induce the rulers to consider more democratic institutions at the local level. The rulers were interested in the creation of 'controlled' local bodies, which could help them in their trading interests by collecting taxes for them. When the colonial administration came under severe financial pressure after the 1857 uprising, decentralization was sought by transferring responsibility for road and public works to local bodies. However, the thrust of this 'compelled' decentralization was with respect to municipal administration.


title: Panchayati raj

text: "The panchayat was destroyed by the East India Company when it was granted the office of Diwan in 1765 in Bengal by the nawab as part of reparation after his defeat at Buxar. As Diwan the Company took two decisions. The first was that it abolished the village land record office and created a company official called Patwari. The Patwari became the official record keeper for a number of villages. The second was the creation of the office of magistrate and the abolition of village police. The magistrate carried out policing functions through the Darogha who had always been a state functionary under the Faujdar. The primary purpose of these measures was the collection of land revenue by fiat. The depredations of the Patwari and the Darogha are part of our folklore and it led to the worst famine in Bengal. The effects of the famine lingered right to the end of the 18th century. These two measures completely disempowered the village community and destroyed the panchayat. After 1857 the British tried to restore the panchayat by giving it powers to try minor offences and to resolve village disputes. But these measures never restored the lost powers of the village community."


title: Panchayati raj

text: From 1870 when the Viceroy’s Lord Mayo's Resolution (for decentralization of power to bring about administrative efficiency in meeting people's demand and to add to the finances of colonial regime) gave the needed impetus to the development of local institutions. It was a landmark in the evolution of colonial policy towards local government. The real bench marking of the government policy on decentralization can, however, be attributed to Lord Ripon who, in his famous resolution on local self-government on May 18, 1882, recognized the twin considerations of local government: (i) administrative efficiency and (ii) political education.


title: Panchayati raj

text: The Ripon Resolution, which focused on towns, provided for local bodies consisting of a large majority of elected non-official members and presided over by a non-official chairperson. This resolution met with resistance from colonial administrators. The progress of local self-government was tardy with only half- hearted steps taken in setting up municipal bodies. Rural decentralization remained a neglected area of administrative reform.


title: Panchayati raj

text: The Royal Commission on Decentralization (1907) under the chairmanship of Sir H. W. Primrose recognized the importance of panchayats at the village level. The commission recommended that "it is most desirable, alike in the interests of decentralization and in order to associate the people with the local tasks of administration, that an attempt should be made to constitute and develop village panchayats for the administration of local village affairs."


title: Panchayati raj

text: But, the Montague-Chemsford reforms (1919) brought local self-government as a provincial transferred subject, under the domain of Indian ministers in the provinces. Due to organisational and fiscal constraints, the reform was unable to make panchayat institutions truly democratic and vibrant. However, the most significant development of this period was the 'establishment of village panchayats in a number of provinces, that were no longer mere ad hoc judicial tribunal, but representative institutions symbolising the corporate character of the village and having a wide jurisdiction in respect of civic matters'. l By 1925, eight provinces had passed panchayat acts and by 1926, six native states had also passed panchayat laws.


title: Panchayati raj

text: The provincial autonomy under the Government of India Act, 1935, marked the evolution of panchayats in India. Popularly elected governments in provinces enacted legislations to further democratize institutions of local self-government. But the system of responsible government at the grassroots level was least responsible. D.P. Mishra, the then minister for local self-government under the Government of India Act of 1935 in Central Provinces was of the view that 'the working of our local bodies... in our province and perhaps in the whole country presents a tragic picture... 'Inefficiency' and 'local body' have become synonymous terms...'.


title: Panchayati raj

text: In spite of various committees such as the Royal Commission on Decentralization (1907), the report of Montague and Chemsford on constitutional reform (1919), the Government of India Resolution (1919), etc., a hierarchical administrative structure based on supervision and control evolved. The administrator became the focal point of rural governance. The British were not concerned with decentralized democracy but were aiming for colonial objectives.


title: Panchayati raj

text: The Indian National Congress from the 1920s to 1947, emphasized the issue of all-India Swaraj, and organized movements for Independence under the leadership of Mahatma Gandhi. The task of preparing any sort of blueprint for the local level was neglected as a result. There was no consensus among the top leaders regarding the status and role to be assigned to the institution of rural local self-government; rather there were divergent views on the subject. On the one end Gandhi favoured Village Swaraj and strengthening the village panchayat to the fullest extent and on the other end, Dr. B.R. Ambedkar opposed this idea. He believed that the village represented regressive India, a source of oppression. The model state hence had to build safeguards against such social oppression and the only way it could be done was through the adoption of the parliamentary model of politics.


title: Panchayati raj

text: During the drafting of the Constitution of India, Panchayati Raj Institutions were placed in the non-justiciable part of the Constitution, the Directive Principles of State Policy, as Article 40. The Article read 'the State shall take steps to organize village panchayats and endow them with such powers and authority as may be necessary to enable them to function as units of self-government'. However, no worthwhile legislation was enacted either at the national or state level to implement it.


title: Panchayati raj

text: In the four decades since the adoption of the Constitution, panchayat raj institutions have travelled from the non-justiciable part of the Constitution to one where, through a separate amendment, a whole new status has been added to their history.


title: Panchayati raj

text: Panchayat raj had to go through various stages. The First Five Year Plan failed to bring about active participation and involvement of the people in the Plan processes, which included Plan formulation implementation and monitoring. The Second Five Year Plan attempted to cover the entire countryside with National Extensive Service Blocks through the institutions of Block Development Officers, Assistant Development Officers, Village Level Workers, in addition to nominated representatives of village panchayats of that area and some other popular organisations like co-operative societies. But the plan failed to satisfactorily accomplish decentralisation. Hence, committees were constituted by various authorities to advise the Centre on different aspects of decentralisation.


title: Panchayati raj

text: At least in part to provide the Gandhian goal of direct political participation of people at the grass root level, in 1957, the National Development Council appointed a committee under Balwant Rai Mehta, which submitted its report in 1958 in which it recommended:-


title: Panchayati raj

text: 》A 3-tier structure consisting of Zila Parishad at the District level, Panchayat Samiti at the Block level and Gram Panchayat at the village level.


title: Panchayati raj

text: The next major change in the panchayat system of India came in the form of the passage of the Panchayati Raj Act (73rd Amendment) in 1992. A key motivation of this act was the belief that local governments may be better placed than centrally appointed bureaucrats to identify and respond to the needs of the village. Hence, this act was an important part of India's move towards decentralization.


title: Panchayati raj

text: The main features of this act are: (a) a 3-tier system of Panchayati Raj for all States having population of over 20 lakh; (b) Panchayat elections regularly every 5 years; (c) reservation of seats for Scheduled Castes, Scheduled Tribes and women (not less than one-third of seats); (d) appointment of State Finance Commission to make recommendations as regards the financial powers of the Panchayats. Hence, in theory, panchayats have been given sufficient authority to function as institutions of self-governance and aid social justice.


title: Panchayati raj

text: There were several positive effects of this amendment, some of which have been listed above. However, there is also evidence of deeply ingrained vote-trading structures maintained through extra-political means. This can potentially be blamed on the fact that Gram Sabhas have not been sufficiently empowered and strengthened to ensure greater people's participation and transparency in functioning of Panchayats as envisaged in the Panchayat Act.


title: Pseudomyxoma peritonei

text: Pseudomyxoma peritonei (PMP) is a clinical condition caused by cancerous cells (mucinous adenocarcinoma) that produce abundant mucin or gelatinous ascites. The tumors cause fibrosis of tissues and impede digestion or organ function, and if left untreated, the tumors and mucin they produce will fill the abdominal cavity. This will result in compression of organs and will destroy the function of the colon, small intestine, stomach, or other organs. Prognosis with treatment in many cases is optimistic, but the disease is lethal if untreated, with death occurring via cachexia, bowel obstruction, or other types of complications.


title: Pseudomyxoma peritonei

text: This disease is most commonly caused by an appendiceal primary cancer (cancer of the appendix); mucinous tumors of the ovary have also been implicated, although in most cases ovarian involvement is favored to be a metastasis from an appendiceal or other gastrointestinal source. Disease is typically classified as low- or high-grade (with signet ring cells). When disease presents with low-grade histologic features the cancer rarely spreads through the lymphatic system or through the bloodstream.


title: Pseudomyxoma peritonei

text: Signs and symptoms of pseudomyxoma peritonei may include abdominal or pelvic pain and/or bloating, distension, digestive disorders, weight changes, increased girth, and infertility.


title: Pseudomyxoma peritonei

text: The primary tumor appears to arise from the MUC2 expressing goblet cells and most commonly from these cells in the appendix. The K-Ras and p53 genes may be involved in the oncogenesis. It may be diagnosed with a range of conditions. While the majority of these cases are associated with appendiceal carcinomas, other conditions may also be found, including disseminated peritoneal adenomucinosis (DPAM), peritoneal carcinomas, several mucinous tumors (mucinous adenocarcinoma, mucinous cystadenoma, and mucinous cystadenocarcinoma), as well as other disease states. Other primary sites that have been reported include colon, rectum, stomach, gallbladder, bile ducts, small intestine, urinary bladder, lung, breast, fallopian tubes, and the pancreas.


title: Pseudomyxoma peritonei

text: This disease is often discovered during surgery for other conditions, e.g., hernia repair, following which an experienced pathologist can confirm the diagnosis. Advanced stages may present as tumors palpable on the abdomen or distention of the belly ("jelly belly" is sometimes used as a slang term for the condition). Due to the rarity of this disease, it is important to obtain an accurate diagnosis so that appropriate treatment may be obtained from a Gastro intestinal cancer surgeon. Diagnostic tests may include CT scans, examination of tissue samples obtained through laparoscopy, and the evaluation of tumor markers. In most cases a colonoscopy is unsuitable as a diagnostic tool because in most cases appendix cancer invades the abdominal cavity but not the colon (however, spread inside the colon is occasionally reported). PET scans may be used to evaluate high-grade mucinous adenocarcinoma, but this test is not reliable for detecting low-grade tumors because those do not take up the dye which shows up on scans. New MRI procedures are being developed for disease monitoring, but standard MRIs are not typically used as a diagnostic tool. Diagnosis is confirmed through pathology.


title: Pseudomyxoma peritonei

text: There is substantial debate regarding histopathologic classification of pseudomyxoma peritonei. In 1995, Ronnett et al. proposed separating pseudomyxoma peritonei cases into two diagnostic categories: adenoma (disseminated peritoneal adenomucinosis, DPAM) or carcinoma (peritoneal mucinous carcinomatosis, PMCA) with a third category reserved for cases with intermediate features. In this classification system, cases of DPAM were characterized by peritoneal lesions composed of abundant extracellular mucin containing scant simple to focally proliferative mucinous epithelium with little cytologic atypia or mitotic activity (in other words, most cells looked fairly normal and there was no evidence of mitosis which would indicate that cells were rapidly dividing), with or without an associated appendiceal mucinous adenoma. Cases of PMCA were characterized by peritoneal lesions composed of more abundant mucinous epithelium with the architectural and cytologic features of carcinoma (irregular cells, evidence that cells were rapidly dividing, and other criteria), with or without an associated primary mucinous adenocarcinoma. Bradley et al. (2007) argued that continued use of non-malignant terms, i.e., adenoma, for those frequent cases with low-grade features (such as DPAM), is misleading because pseudomyxoma peritonei is a disease state that results from invasion of the abdominal cavity by cells with uncontrolled growth. Bradley states that an adenoma, by definition, is a tumor confined to the appendiceal mucosa with absolutely no evidence of invasion beyond the muscularis mucosae.


title: Pseudomyxoma peritonei

text: The term mucinous adenocarcinoma is used in different contexts depending on the reference material used by the pathologist for disease classification. For example, neoplasms characterized by high-grade features, invasive glands and or signet ring cells, are termed adenocarcinoma in pathology literature. However, some pathologists (e.g., Odze and Goldblum, "Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas", 2nd ed.) also use the term mucinous adenocarcinoma when referring to low-grade, well-differentiated tumors lacking high-grade features. Low-grade mucinous adenocarcinoma is used by the American Joint Committee on Cancer and World Health Organization and is nearly or completely synonymous with the DPAM designation. For low-grade mucinous adenocarcinoma, disease may be designated as "benign" because tumors do not invade deeply into tissue and rarely metastasize to parenchyma of organs; this designation may be misleading and confusing to the layperson because pseudomyxoma peritonei is not a harmless condition, fatal if untreated. High-grade or poorly differentiated mucinous adenocarcinoma has a generally poorer prognosis, though surgical treatment with heated intra-peritoneal chemotherapy (HIPEC) is yielding promising outcomes (see surgical treatment).


title: Pseudomyxoma peritonei

text: Treatment is variable, both due to its rarity and to its frequently slow-growing nature. Treatment ranges from watchful waiting to debulking and hyperthermic intraperitoneal chemotherapy (HIPEC, also called intraperitoneal hyperthermic chemotherapy, IPHC) with cytoreductive surgery.


title: Pseudomyxoma peritonei

text: The standard of care for mucinous adenocarcinoma with clinical condition PMP involves cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), performed by surgical oncologists who specialize in treating PMP. Some surgeons also apply early post-operative intraperitonial chemotherapy (EPIC), adjunct to surgical cytoreduction and HIPEC. In situations where surgery is not required immediately, patients can be monitored via CT scans, tumor marker laboratory tests, and physical symptoms, to determine when, and if, surgery is warranted. Although some surgical procedures may be rather extensive, patients can and do recover from surgery, and the majority of these patients can and do live productive lives.


title: Pseudomyxoma peritonei

text: In debulking, the surgeon attempts to remove as much tumor as possible. CRS or cytoreductive surgery involves surgical removal of the peritoneum and any adjacent organs which appear to have tumor seeding. Since the mucus tends to pool at the bottom of the abdominal cavity, it is common to remove the ovaries, fallopian tubes, uterus, and parts of the large intestine. Depending upon the spread of the tumor, other organs might be removed, including but not limited to the gallbladder, spleen, and portions of the small intestine and/or stomach. For organs that cannot be removed safely (like the liver), the surgeon strips off the tumor from the surface.


title: Pseudomyxoma peritonei

text: Chemotherapy (typically utilising the chemotherapeutic agent Mitomycin C) may be infused directly into the abdominal cavity after cytoreductive surgery (surgery removing all visible disease to kill remaining microscopic cancerous tumors and free floating cells). The heated chemotherapy (HIPEC) is perfused throughout the abdominal cavity for an hour or two as the last step in the surgery, or ports are installed to allow circulation and/or drainage of the chemicals for one to five days after surgery, known as early postoperative intraperitoneal chemotherapy (EPIC). EPIC may be given in multiple cycles for several months after surgery.


title: Pseudomyxoma peritonei

text: Systemic chemotherapy may be administered as additional or adjuvant treatment. Due to the increased availability of new chemotherapies developed for colorectal cancer patients, some patients have experienced stability in tumor growth with systemic chemotherapy. Systemic chemotherapy is generally reserved for patients with advanced disease, recurrent disease, or disease that has spread to the lymph nodes or distant sites.


title: Pseudomyxoma peritonei

text: This disease may recur following surgery and chemotherapy. Periodic post operative CT scans and tumor marker laboratory tests are used to monitor patients for disease progression.


title: Pseudomyxoma peritonei

text: The overall incidence was previously estimated at 0.5 to 1 cases per 100,000 people per year. Recent research in Europe indicates that the previous estimate of 1-2 persons per million may be underestimating the actual rate by approximately half, with the real incidence being approximately 3.2 persons per million, and the prevalence being 22 persons per million. It is slightly more common in women than men (male:female ratio of approximately 1:1.3,), although the actual ratio is difficult to identify due to potential misdiagnoses and possibly inclusion bias in reported studies. The median age at presentation is typically about 50 years with a range of 20–25 years, but PMP may strike persons of any age.


title: Pseudomyxoma peritonei

text: The first case was described by Carl F. Rokitansky in 1842. Werth in 1884 coined the term pseudomyxoma peritonei, describing it in association with a mucinous ovarian tumor. In 1901 Frankel described the first case associated with a cyst of the appendix. Audrey Hepburn died of pseudomyxoma peritonei in 1993.


title: Rakshita Suresh

text: Rakshita Suresh (born 1 June 1998) is one of the Indian playback singers known for her work in Tamil, Hindi, Kannada and Telugu cinema. She was the Winner on "Rhythm Tadheem" aired on ETV Kannada and Title Winner of "Little Star Singer" 2009 aired on Asianet Suvarna (Kannada). She was first runner up in the reality show of Super Singer 6 aired on Star Vijay (Tamil) in 2018 through which she received lots of attention.She is also known as "Golden voice of Super Singer Season 6".She is one of the upcoming popular female vocalist in India


title: Rakshita Suresh

text: Rakshita was born on 1 June 1998, in Mysore Karnataka to Suresh and Anitha Suresh. She is a graduate in B.Sc. Rakshita started learning music at the age of 4 years. She is trained in Carnatic Music, Hindustani Classical music and Light Music.


title: Rakshita Suresh

text: She made her debut as a playback singer for Ilayaraja, she has sung many more singles in Tamil, Hindi, Kannada and Telugu. The first song that she recorded in Telugu was in 2015 for the film Yevade Subramanyam starring Telugu actor Nani. She delivered many solo concerts globally, both in India and abroad, like Mysuru "Yuva Dasara".


title: Rakshita Suresh

text: She started her career with music talent shows. Her first reality show in Kannada was "Yede Thumbi Haduvenu" on ETV and "Junior Super Stars" on Star Vijay (Tamil). Rakshita Suresh was the Winner on "Rhythm Tadheem" aired on ETV Kannada and Title Winner of "Little Star Singer" 2009 aired on Asianet Suvarna (Kannada). She was first runner up in the reality show of Super Singer 6 aired on Star Vijay (Tamil) in 2018 through which she received lots of attention.


title: Rakshita Suresh

text: Rakshita made her Bollywood debut with the composition of A.R Rahman as She sang the song "Yaane Yaane" for the movie Mimi.


title: Tetany

text: Tetany or tetanic seizure is a medical sign consisting of the involuntary contraction of muscles, which may be caused by disorders that increase the action potential frequency of muscle cells or the nerves that innervate them.


title: Tetany

text: Muscle cramps caused by the disease tetanus are not classified as tetany; rather, they are due to a lack of inhibition to the neurons that supply muscles. Tetanic contractions (physiologic tetanus) are a broad range of muscle contraction types, of which tetany is only one.


title: Tetany

text: Tetany is characterized by contraction of distal muscles of the hands (carpal spasm with extension of interphalangeal joints and adduction and flexion of the metacarpophalangeal joints) and feet (pedal spasm) and is associated with tingling around the mouth and distally in the limbs.


title: Tetany

text: Metabolic alkalosis with hypokalemia like Gitelman syndrome and Bartter's syndrome can cause tetany. Vomiting induced alkalosis and hyperventilation induced respiratory alkalosis also cause tetany because of neuronal irritability.


title: Tetany

text: Hypocalcemia is the primary cause of tetany. Low ionized calcium levels in the extracellular fluid increase the permeability of neuronal membranes to sodium ion, causing a progressive depolarization, which increases the possibility of action potentials. This occurs because calcium ions interact with the exterior surface of sodium channels in the plasma membrane of nerve cells and hypocalcemia effectively increases resting potential (rendering the cells more excitable) since less positive charge is present extracellularly. When calcium ions are absent the voltage level required to open voltage gated sodium channels is significantly altered (less excitation is required). If the plasma Ca decreases to less than 50% of the normal value of 9.4 mg/dl, action potentials may be spontaneously generated, causing contraction of peripheral skeletal muscles. Hypocalcemia is not a term for tetany but is rather a cause of tetany.


title: Tetany

text: French Professor Armand Trousseau (1801–1867) devised the maneuver of occluding the brachial artery by squeezing, to trigger cramps in the fingers. This is now known as the Trousseau sign of latent tetany.


title: Tetany

text: Also, tetany can be demonstrated by tapping anterior to the ear, at the emergence of the facial nerve. A resultant twitch of the nose or lips suggests low calcium levels. This is now known as the Chvostek sign.


title: Tetany

text: EMG studies reveal single or often grouped motor unit discharges at low discharge frequency during tetany episodes.


title: Pooja Chopra

text: Pooja Chopra is an Indian actress. She won the title of Femina Miss India World 2009. She is the first Indian to win the "Beauty with a Purpose" title at the Miss World competition for India. As an actress, Chopra was awarded the Times Most Powerful Woman Award for her contribution to the field of acting. She got her breakthrough with and since then, appeared in many films. Pooja Chopra features in the Times list of 50 most beautiful faces of India.


title: Pooja Chopra

text: Chopra was born in Kolkata, West Bengal, India. She was abandoned by her father at birth since he wanted a boy. Chopra's mother, Neera had to leave her marital home since she refused to admit Pooja to an orphanage in Kolkata, and she moved to Mumbai with both kids. She worked and brought up both girls by herself. She is a resident of Pune, Maharashtra. She has an older sister named Shubhra Chopra. She attended Mount Carmel Convent High School and later graduated from Ness Wadia College, both in Pune.


title: Pooja Chopra

text: Pooja Chopra was crowned with the 2009 Femina Miss India East title on 17 February 2009, in Kolkata. She also won Miss Perfect 10, Miss Catwalk, Miss Beautiful Smile, Talwarkars Best Body, and Nakshatra Miss Sparkling Beauty, thus gaining direct entry into the top ten finalists of the Femina Miss India 2009. On 5 April 2009, she was crowned the Pantaloons Femina Miss India-World 2009.


title: Pooja Chopra

text: Chopra sprained her ankle while running down a flight of stairs one week prior to the Miss World Final, which was scheduled to take place on 12 December 2009; still, she participated in the competition and earned a positive response from the public. Doctors advised 3 weeks of complete bed-rest, but she continued with the competition. She finished as one of the top 16 finalists out of 120 contestants.


title: Pooja Chopra

text: During her reign as Miss she endorsed brands such as Tata Docomo, Bajaj Allainz, Richfeel, Body and Soul, Roots Comb, Evolve Med Spa, and Juvederm Voluma.


title: Pooja Chopra

text: Chopra made her acting debut in the 2011 Tamil film "Ponnar Shankar", playing the role of Princess Muthaayi, opposite Prashanth Thiagarajan. Before she made her debut in Bollywood as a leading lady, she had minor roles in Madhur Bhandarkar's films "Fashion" and "Heroine".


title: Pooja Chopra

text: Chopra acted in Vipul Shah's action film "Commando" opposite Vidyut Jammwal, in her first lead role. Chopra starred in Neeraj Pandey's short film "Ouch", a dramatic love story.


title: Pooja Chopra

text: Meena Iyer from "Times of India" said, "Pooja Chopra (Femina Miss India-2009) is super-confident in her film debut and a welcome addition to Bollywood's heroines".


title: Pooja Chopra

text: Pooja has won 8 National and International Titles in 2009. She appeared in Kingfisher Calendar 2020. Pooja features in Times 50 Most beautiful faces India. Chopra's next films Jahaan Chaar Yaar and Jeevan Beema Yojna both releasing in 2022.


title: Pooja Chopra

text: She has given a TED Talk on the subject of "Write your own destiny : Journey of a once abandoned girl child". The talk happened in Krupanidhi Institution of Engineering, Bangalore.


title: Pooja Chopra

text: On 12 December 2009, she won the "Beauty With a Purpose" title at Miss World 2009 based on her charitable work in the India "Nanhi Kali" project. She won US$10,000 for her project, which she donated to the NGO which helps small girls fight poverty.


title: Pooja Chopra

text: Considering their shared interest in fitness, Pooja chopra, along with Akshay Kumar, launched the Asian Heart Institute Initiative "Happy Heart India" campaign for underprivileged children in 2018. Chopra was also invited by the BMC to lead the campaign "#EkChammachKam" alongside Farhan Akhtar to spread awareness about non-communicable diseases.


title: Pooja Chopra

text: Post Pulwama attack in 2019, Pooja Chopra donated part of her Aiyaary earnings to families of Martyred Soldiers.


title: Stacy London

text: Stacy London (born May 25, 1969) is an American stylist, fashion consultant, author, and magazine editor. She is known primarily for her time as co-host on "What Not to Wear", a reality television program that featured wardrobe and appearance makeovers.


title: Stacy London

text: After graduating from Vassar College, London started her career as a fashion editor at "Vogue" and transitioned into being a stylist for celebrities and designers. She moved into television by co-hosting "What Not to Wear" with first Wayne Scot Lukas and then Clinton Kelly, and doing fashion reporting for "Access Hollywood", "The Early Show", and the "Today Show". From 2009 to 2010, she was a celebrity spokesperson for Pantene, Woolite, Dr. Scholl's, and Riders by Lee. She co-owns Style for Hire and is the creative director of Westfield Style.


title: Stacy London

text: London was born in New York City on May 25, 1969. She is of Sicilian descent on her mother's side and Jewish descent on her father's side. Her mother, Joy Weinman, worked as a venture capitalist, and her father, Herbert London, was the president emeritus of the Hudson Institute. Her stepmother, Vicki Pops, is a romance novelist. In an interview with "The Wall Street Journal", she said of her father, "We don't see eye to eye on that much politically [but] he did instill a certain sense of propriety and right and wrong in me, which plays into my fashion sensibility." While going to Vassar College, she double majored in 20th century philosophy and German literature and was a member of Phi Beta Kappa. It was during a summer internship in Paris in Christian Dior's PR department that she took a serious interest in pursuing a career in the fashion industry.


title: Stacy London

text: London began her career as a fashion assistant at "Vogue" magazine and later became the senior fashion editor at "Mademoiselle". She has styled fashion photos for other publications, including Italian "D", "Nylon", and "Contents". London has styled for celebrities such as Kate Winslet and Liv Tyler, and on fashion shows for designers Rebecca Taylor, Ghost, and Vivienne Tam. London has worked on numerous advertising campaigns; her client roster includes Hanes, Wonderbra, Bali, Procter & Gamble, CoverGirl, Suave, Target, Levi Strauss & Co., Maytag, Swatch, Longines, and Calvin Klein.


title: Stacy London

text: London began co-hosting TLC's "What Not to Wear" in its inaugural season in 2003. In 2005, she and co-host Clinton Kelly wrote a book titled "Dress Your Best". London is known for her love of high-heeled shoes, owning over 300 pairs. In a "What Not to Wear" "Best of 2005" look-back show, Clinton Kelly teased London by saying "...there are almost as many great moments as there are high heels in Stacy's wardrobe." In 2008, London also served as the host of her own talk show "Shut Up! It's Stacy London!" which was the pilot episode for "Fashionably Late with Stacy London". London has done fashion reporting for "Weekend Today", "The Early Show", "Good Day Live", and "Access Hollywood". She is a frequent contributor on NBC's "Today Show".


title: Stacy London

text: From 2009 to 2010, London was a spokesperson for Pantene, Woolite, Dr. Scholl's, and Riders by Lee. In addition to her hosting duties and endorsements, London and business partner Cindy McLaughlin co-founded Style for Hire—an online service that matches people with personal stylists that live in their area. The goal of the online agency is to bring personal styling services to average income people. Style for Hire was launched as a pilot on September 13, 2010, in Washington, D.C., to test the idea. The agency launched in its entirety on April 16, 2012. As of that date, there are 135 stylists in 24 cities. London is also the creative director for Westfield Style and the editor-in-chief of "Westfield STYLE" magazine. Westfield's Style Lounges are staffed by professional stylists from Style for Hire who provide free on-demand fashion consultations. There are three Style Lounges located at Westfield Garden State Plaza in New Jersey, Westfield Montgomery in Maryland, and Westfield Trumbull in Connecticut.


title: Stacy London

text: London was the executive producer of "Big Brooklyn Style", a reality show about customer experiences at Lee Lee's Valise boutique in New York. The show premiered May 29, 2012 on TLC. In February 2013, she became an editor-at-large of "Shape" magazine. In her role, she will write a fashion column for the magazine every month. In March 2013, TLC announced that "What Not to Wear" would air its final season starting in July. London said of the experience "This show changed me and the trajectory of my life... I hope we touched [our contributors] as much as they touched me. I hope we touched our viewers." In January 2015, TLC announced that London would host "Love, Lust, or Run", a show similar to her previous work, "What Not to Wear". She was an official contributor on Season 19 of "The View" from 2015 to 2016.


title: Stacy London

text: London lives in the Carroll Gardens neighborhood of New York City's Brooklyn borough. On December 31, 2019, she announced that she was in her first serious relationship with a woman, musician Cat Yezbak, and had been so for over a year. She wrote on Instagram, "So I used to date men. Now I date her."


title: Stacy London

text: London has suffered from psoriasis since childhood. Due to her experience growing up, she became a spokesperson for the National Psoriasis Foundation in 2007 and AbbVie's "Uncover Your Confidence" campaign in 2013. She is well known for her naturally-occurring gray streak in the front of her hair—known in the medical field as poliosis—which she has had since she was 11 years old. Her Pantene contract includes a "gray clause" that allows her to keep it.


title: Stacy London

text: In the early 1990s, London struggled with anorexia, binge eating, and other weight issues. Standing , she was at her lightest weight and at her heaviest. In a 2007 interview with "Sirens" magazine, she said of the experience, "I have been every size in my life. I've been smaller than a zero, up through a size 16. I've had lots of issues with body image and weight my whole life and it really took a great deal of work to recognize that at all those weights, no matter how I felt, I could still find a dress that made me feel sexy and powerful."


title: Stacy London

text: In 2010, London was profiled by "Time Out" magazine in their article/photo series about the most stylish New Yorkers. That same year, she performed in the Off-Broadway play "Love, Loss, and What I Wore", a series of monologues about women's clothes and their relationship to life events/memories. As of 2016, London has never been married and has no children. She discussed being single, the importance of personal style, and her past struggles with eating disorders in her second book, a memoir, titled "The Truth About Style".


title: Stacy London

text: In December 2016, London underwent spinal fusion surgery to correct a chronic back problem, which required a six-month rehabilitation.


title: Anthony Mirra

text: Anthony "Tony" Mirra (July 18, 1927 – February 18, 1982) was an American mobster, soldier and later caporegime for the Bonanno crime family. He is well known for being the individual who introduced FBI Special Agent Joseph "Donnie Brasco" Pistone into the Bonanno family.


title: Anthony Mirra

text: Mirra was born to Albert Mirra and Millie Embarrato in Manhattan. He was the nephew of Bonanno family caporegime Alfred Embarrato, and cousins of street soldier Joseph D'Amico, capo Richard Cantarella, capo Frank Cantarella, and Bonanno family capo Paul Cantarella.


title: Anthony Mirra

text: Mirra was born in the poverty-stricken Lower East Side at Knickerbocker Village where he lived in the same apartment building as Embarrato, Richard Cantarella and D'Amico. The Federal Bureau of Narcotics lists his address of residence at 115 Madison Street (Manhattan) in Lower East Side, New York. Mirra was once a good friend of Benjamin "Lefty" Ruggiero; Mirra owned the Bus Stop Luncheonette in Little Italy, Manhattan not far from Ruggiero's bar. His relatives D'Amico, Embarrato and Cantarella became involved in major racketeering schemes at "The New York Post" distribution center behind their housing complex, but Mirra moved on to more successful and prosperous racketeering endeavours.


title: Anthony Mirra

text: Mirra worked for Bonanno capo Michael Zaffarano, and was involved in extortion, gambling and drug trafficking. During the 1970s, Mirra confessed to the 1959 assassination of Anthony Carfano and comedian Alan Drake's wife, Janice Hansen Drake. "The New York Times" correspondent Ralph Blumenthal described Mirra's appearance as "Zorba-like". Mirra never drank alcohol, only ginger ale.


title: Anthony Mirra

text: Mirra remained a recluse from his fellow mobsters including his own relatives, which included Richard Cantarella, and eventually even became estranged from his uncle Alfred. Mirra was the first contact FBI agent Joseph Pistone made in his undercover operation, which led to his infiltration of the Bonanno family. Pistone was working as an associate for the Colombo family at the time. Mirra introduced Pistone to "Lefty" Ruggiero and offered him a job handling his slot-machine route. Pistone went under the name "Donnie Brasco" and posed as a jewel thief.


title: Anthony Mirra

text: In 1977, Mirra fled New York after being indicted for drug trafficking. The FBI caught up with him three months later and he was sent to federal prison again for eight and a half years. When Mirra got out of jail, Brasco had since become close with Ruggiero and was working under him. Mirra argued that Brasco belonged to him, not Ruggiero. Mirra took the issue right to the top and had several meetings over the situation. In the end, Ruggiero won.


title: Anthony Mirra

text: After the sudden death of his capo, Michael Zaffarano, Mirra took over the Bonanno family pornography empire and worked under the powerful Sicilian capo Cesare Bonventre. Mirra also muscled in on several Little Italy, Manhattan, restaurants and bars. He was involved in a vending machine operation that dealt in slot machines, peanut vending machines, video arcade machines and pinball machines that were distributed all over New York City. He had them installed in stores, luncheonettes, social clubs and after-hours establishments.


title: Anthony Mirra

text: The slot machines, since they were illegal, would be installed in the establishment's back room or basement. The coin collection route produced $2,000 a week, and he would open the machines with a key he carried and give the store owner his cut of the profits (at least $25). Mirra was involved in "strong arm" schemes and extorted from several bars and restaurants. Each of the owners would pay him $5,000 a week in protection money and he would become angry if he did not receive the money.


title: Anthony Mirra

text: In 1979, following the takeover of Philip Rastelli as leader of the Bonanno family, the family divided into two rival factions. The "Red" Team led by capos Alphonse "Sonny Red" Indelicato, Dominick Trinchera and Philip Giaccone, and the "Black" Team led by Dominick "Sonny Black" Napolitano and Joseph Massino. The day before Giaccone, Trinchera and Indelicato were to be ambushed and executed, Mirra announced at the Toyland Social Club to Nicholas Marangello that he was joining the opposition.


title: Anthony Mirra

text: On May 5, 1981, the day of the executions, Napolitano called Mirra's uncle, Albert Embarrato, and told him to come down to The Motion Lounge for a "sit down". At the sit down, Napolitano had two of his soldiers flank Embarrato on either side until Napolitano received confirmation that the executions were followed through. Napolitano would later tell Pistone, "When he (Albert) heard that, he turned ash white. He thought we were going to hit him too. But I just reamed at him about Tony, told him Tony was no good; and that he (Albert) better recognize that and act right himself." Embarrato agreed.


title: Anthony Mirra

text: Joseph Pistone said that Mirra was the nastiest and most intimidating man he had met during his seven years undercover. Due to Mirra's irrational behavior, nobody could ever build a close relationship with him. He would never talk about anything that did not involve criminal activities. Pistone said that, "One day you might ask him, 'How's your mother, Tony?' He might say, 'Okay.' Another day you ask him, and he might answer, 'What the fuck you so nosy about?' "


title: Anthony Mirra

text: He was known among fellow mobsters as a "knife man". It was a common practice for mobsters to carry knives, because they were routinely rousted by police officers and did not want to be caught with firearms. Mirra carried a folding knife with a long blade. Unlike Mirra, it was uncommon for mobsters to ever use their blade, preferring the use of a firearm. Pistone was warned by fellow mobsters that, "If you ever get into an argument with him, make sure you stay an arm's length apart, because he will stick you."


title: Anthony Mirra

text: Although Mirra was despised, he was tolerated because he was a remarkably good moneymaker. Mirra was a hard worker who was out on the street every day from 8:00a.m. to 3:00p.m., making around $5,000 a day for the family. He once bragged to Pistone that since he had been out of prison, he had made over $200,000. He had a reputation for either cheating people out of money or outright stealing, demanding that goods and services be provided to him "on the arm".


title: Anthony Mirra

text: He was known to be violent with women, physically abusing his mistresses and threatening to murder one when she confessed that she was a lesbian. Ruggiero told Pistone that the problem with Mirra was that he was always abusing somebody. Mirra insulted everybody and was always in arguments. Mirra was so loathed by mobsters that when Donnie Brasco was revealed to be an undercover agent, he immediately went into hiding instead of attempting to negotiate for his own life, as he knew that countless mafiosi would be eager to take the opportunity to murder him.


title: Anthony Mirra

text: In mid-1981, when Pistone was revealed as an FBI agent, "Sonny Black" Napolitano, "Lefty" Ruggiero, and Mirra were all in the firing line for initially allowing the infiltration. Mirra went into hiding. Joseph Massino ordered Mirra's uncle Alfred Embarrato and Mirra's two cousins, Richard Cantarella and Joseph D'Amico, to find and kill him. On February 18, 1982, D'Amico lured him to a parking garage in Lower Manhattan. Embarrato and Cantarella were waiting in a getaway car. The pair went to the parking garage, climbed into Mirra's car, and drove up to a locked security gate. D'Amico later described in a testimony, "He took out his key, put it in the box, but he didn’t get a chance to turn the box... I shot him at close range several times on the side of his head."


title: Hereditary angioedema

text: Hereditary angioedema (HAE) is a disorder that results in recurrent attacks of severe swelling. The swelling most commonly affects the arms, legs, face, intestinal tract, and airway. If the intestinal tract is affected, abdominal pain and vomiting may occur. Swelling of the airway can result in its obstruction and trouble breathing. Without preventive treatment, attacks typically occur every two weeks and last for a few days.


title: Hereditary angioedema

text: There are three main types of HAE. Types I and II are caused by a mutation in the "SERPING1" gene, which makes the C1 inhibitor protein, while type III is often due to a mutation in the "F12" (factor XII) gene. The result is increased levels of bradykinin, which promotes swelling. The condition may be inherited from a person's parents in an autosomal dominant manner or occur as a new mutation. Triggers for an attack may include minor trauma or stress, but attacks often occur without any obvious preceding event. Diagnosis of types I and II is based on measurement of C4 and C1-inhibitor levels.


title: Hereditary angioedema

text: Management of HAE involves efforts to prevent attacks and the treatment of attacks if they occur. During an attack, supportive care such as intravenous fluids and airway support may be required. C1 inhibitor medications can be used for both prevention and treatment, while ecallantide and icatibant can be used to treat acute attacks.


title: Hereditary angioedema

text: HAE affects approximately 1 in 50,000 people. The condition is typically first noticed in childhood. Type I and II affected females and males equally, while type III affects females more often than males. When the airway is involved, without treatment, the risk of death is about 25%. With treatment, outcomes are generally good. The condition was first described in 1888 by Canadian physician William Osler.


title: Hereditary angioedema

text: People diagnosed with Hereditary Angioedema have recurrent swelling in the extremities, genitals, face, lips, larynx or GI tract. Some patients describe a sensation of fullness but not pain or itching in the affected area except for those with abdominal swellings who often experience acute abdominal pain. Others experience an intense amount of pain, described as radiating from the bone outward along with intense itching just beneath the skin and intense heat, regardless of the area targeted.


title: Hereditary angioedema

text: Swelling involving the respiratory and gastrointestinal systems can cause significant risk and distress. Involvement of respiratory structures, such as the throat or larynx, can cause difficulties in breathing and life-threatening airway obstruction. Episodes that attack the gastrointestinal tract can cause a number of complications including vomiting, crampy abdominal pain, diarrhea, and dehydration.


title: Hereditary angioedema

text: Some people with HAE experience 'wandering' attacks. These attacks will center around an extremity. For example: Should the affected person's hand swell up, it will go through the normal swelling cycle before 'transferring' to either the connection limb (In this case wrist to forearm) or move to the opposite hand. People with this symptom may find their episodes last longer and may find their triggers more difficult to track.


title: Hereditary angioedema

text: Because HAE is an autosomal dominant disease, there is no sex difference in transmission and both sexes are equally likely to receive the mutated gene from their parents. In an example, a father (individual A) with a mutated gene for HAE, has the disease while his wife (individual B) with 2 non-mutated copies of the C1 inhibitor gene and does not have the disease. The possibility of a cross between them gives the possibilities as shown: two of their offspring will have the disease (HAE) while the others would not.


title: Hereditary angioedema

text: The affected father who has HAE has a mutation on one of his genes (C1-INH). Each one of his children, regardless of sex, will have a 50% chance to inherit the mutated C1-INH gene from him. HAE is generally referred to as a "dominant" condition because it only takes a mutation in one of the two C1-INH genes in a carrier to cause the disease.


title: Hereditary angioedema

text: The prevalence of HAE is relatively low – between 1 in every 10,000 to 1 in every 50,000 persons. Most persons with HAE acquire a C1 esterase inhibitor (C1-INH) mutation from one of their parents. A parent with HAE usually has a 50% probability of transmitting this condition on to one of his/her children of either sex as shown in the figure (HEA Inheritance). People with no previous history of can acquire HAE by spontaneous changes in the sperm or egg cell. In a review of patients who do not have a history of HAE in their family, but who have relatively low levels of mutated C1-INH with persistent angioedema, 25% of new patients who had HAE had C1-INH changes that do not show signs of inheritance.


title: Hereditary angioedema

text: Recognizing HAE is often difficult due to the wide variability in disease expression. The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When HAE is misdiagnosed as an allergy it is most commonly treated with steroids and epinephrine, drugs that are usually ineffective in treating a HAE episode. Other misdiagnoses have resulted in unnecessary exploratory surgery for patients with abdominal swelling and other HAE patients report that their abdominal pain was wrongly diagnosed as psychosomatic.


title: Hereditary angioedema

text: HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be overemphasized.


title: Hereditary angioedema

text: A blood test, ideally taken during an episode, can be used to diagnose the condition. Measure: serum complement factor 4 (C4),


title: Hereditary angioedema

text: C1 inhibitor (C1-INH) antigenic protein, C1 inhibitor (C1-INH) functional level if available. Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components.


title: Hereditary angioedema

text: HAE type I is primarily caused by a deficiency in blood proteins (C1 esterase inhibitors) which normally suppress activation of the complement system. The resultant overstimulation of this system leads to the production of inflammatory anaphylatoxins, which affects the flow of body fluids between the vascular system and body tissues. This deficiency is responsible for approximately 80–85% of cases.


title: Hereditary angioedema

text: HAE type II is a less frequently encountered form of this disorder and accounts for 15–20% of cases. In this type, atypical C1-inhibitor proteins are produced which are less capable of suppressing activation of the complement system. Like HAE type I, this results in overstimulation of this system.


title: Hereditary angioedema

text: HAE type III is rare and has only been documented recently. Unlike types I and II, this form does not appear to be connected with C1-inhibitor deficiency. This type mainly affects females and appears to be influenced by contact with estrogens and also by hormone replacement therapy (e.g. oral contraceptives). Its pathogenesis is credited to increased activity of the enzyme kininogenase, which leads to rise in the levels of bradykinin. Other patients with type III HAE have alterations in gene F12, which encodes a protein which participates in blood coagulation. Some patients with type III HAE have a mutation in the F12 gene which produces a protein involved in blood clotting. Due to the results of a genetic test on 4 affected German families, it is believed that this type of the condition is caused by a disease-causing gene in chromosome 5q.35.2-q35.3.


title: Hereditary angioedema

text: Treatment with ACE inhibitors is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.


title: Hereditary angioedema

text: People in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prevention. There are several phase III clinical trials addressing HAE prophylaxis and therapy. These have led to the licensing of pdC1INH in many parts of the world; bradykinin receptor antagonists (icatibant) in Europe; kallikrein inhibitors (ecallantide and lanadelumab) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa) in Europe. Tranexamic acid has been shown to be relatively ineffective therapy. Danazol prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol's adverse events. For people requiring long-term prophylaxis, home therapy which allows people to self-administer the product, is considered an integral part of allowing patients a normal quality of life.


title: Hereditary angioedema

text: In 2018, the U.S. Food and Drug Administration approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in patients over age 12. Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II.


title: Hereditary angioedema

text: Berotralstat was approved in the United States in December 2020, for the prevention of attacks of hereditary angioedema in people over twelve years of age.


title: Hereditary angioedema

text: Short-term prevention is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.


title: Hereditary angioedema

text: The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1 inhibitor concentrate from donor blood, which must be administered intravenously; however, in most European countries, C1 inhibitor concentrate is only available to patients who are participating in special programs. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor.


title: Hereditary angioedema

text: Other treatment modalities can stimulate the synthesis of C1 inhibitor, or reduce C1 inhibitor consumption. Purified C1 inhibitor, derived from human blood, has been used in Europe since 1979. Several C1 inhibitor treatments are now available in the U.S. Food and Drug Administration and two C1 inhibitor products are now available in Canada. Berinert P (CSL Behring), which is pasteurized, was approved by the F.D.A. in 2009 for acute attacks. Cinryze (ViroPharma), which is nanofiltered, was approved by the F.D.A. in 2008 for prophylaxis. Ruconest (Pharming) is a recombinant C1 inhibitor approved in the US and Europe that does not carry the risk of infectious disease transmission due to human blood-borne pathogens.


title: Hereditary angioedema

text: The medication ecallantide inhibits plasma kallikrein and was approved by the F.D.A. (but not in Europe) for acute attacks in 2009. Icatibant inhibits the bradykinin B2 receptor, and was approved in Europe and the USA.


title: Hereditary angioedema

text: In HAE, specific stimuli that have previously led to attacks may need to be avoided in the future. It does not respond to antihistamines, corticosteroids, or epinephrine.


title: Hereditary angioedema

text: Data regarding the epidemiology of angioedema is limited. The incidence of HAE is one in 10,000–50,000 people in the United States and Canada. Mortality rates are estimated at 15–33%, resulting primarily from laryngeal edema and asphyxiation. HAE leads to 15,000–30,000 emergency department visits per year.


title: Hereditary angioedema

text: There are national associations for HAE patients and their families in a number of countries around the world. These national associations are members of the global organization HAEi - International Patient Organization for C1-Inhibitor Deficiencies. HAEi is dedicated to raising awareness of C1 inhibitor deficiencies around the world. It is a non-profit international network established to promote co-operation, co-ordination and information sharing between HAE specialists and national HAE patient associations in order to help facilitate the availability of effective diagnosis and management of C1 inhibitor deficiencies throughout the world.


title: Hereditary angioedema

text: The Assistance Fund Inc. is an American nonprofit organization that offers co-pay assistance for medications that treat HAE and is open to any American Citizens or landed immigrants who have insurance.


title: Hereditary angioedema

text: A column on puzzling medical cases in The New York Times Magazine featured a 45-year-old woman with intestinal swelling who was ultimately diagnosed as having type III HAE. The patient’s HAE attack had been triggered by exposure to estrogen from her oral contraceptive.


title: Hereditary angioedema

text: Clinical development of several new active substances, which intervene in the disease process in different ways, is currently ongoing.


title: Hereditary angioedema

text: Pharming Group NV announced on 24 June 2010 that the European Medicines Agency has adopted a positive opinion on conestat alfa (trade name Ruconest), a C1-inhibitor for the treatment of acute angioedema attacks.


title: Hereditary angioedema

text: Ecallantide, a peptide inhibitor of kallikrein, has received orphan status for HAE and has shown positive results in phase III trials.


title: Hereditary angioedema

text: Icatibant (marketed as Firazyr) is a selective bradykinin receptor antagonist, which has been approved in Europe and was approved in the US by the FDA in Aug 2011. After initial borderline results this drug was shown to be effective in phase III trials. Cinryze has been approved by the FDA in October 2008.


title: Nintendo 64 accessories

text: Nintendo 64 accessories are first-party Nintendo hardwareand third-party hardware, licensed and unlicensed. Nintendo's first-party accessories are mainly transformative system expansions: the 64DD Internet multimedia platform, with a floppy drive, video capture and editor, game building setup, web browser, and online service; the controller plus its own expansions for storage and rumble feedback; and the RAM-boosting Expansion Pak for big improvements in graphics and gameplay. Third-party accessories include the essential game developer tools built by SGI and SN Systems on Nintendo's behalf, an unlicensed SharkWire online service, and unlicensed cheaper counterparts to first-party items. In the fifth generation of video game consoles, the Nintendo 64 had a market lifespan from 1996 to 2002.


title: Nintendo 64 accessories

text: First-party Nintendo 64 accessories have a product code prefixed with NUS, short for "Nintendo Ultra Sixty-four".


title: Nintendo 64 accessories

text: The Nintendo 64 controller (NUS-005) is an "m"-shaped controller with 10 buttons (A, B, C-Up, C-Down, C-Left, C-Right, L, R, Z, and Start), one analog stick in the center, a digital directional pad on the left side, and an extension port on the back for many of the system's accessories. Initially available in the seven colors of gray, yellow, green, red, blue, purple, and black, and it was later released in translucent versions of those colors except gray.


title: Nintendo 64 accessories

text: The (NUS-004) is the console's memory card, comparable to those of the PlayStation and GameCube. Compatible games can save player data to the Controller Pak, which plugs into the back of the Nintendo 64 controller (as do the Rumble and Transfer Paks). The Controller Pak was marketed for exchanging data between Nintendo 64 owners, because data on the game cartridge can not be transferred.


title: Nintendo 64 accessories

text: The original models from Nintendo have 256 kilobit (32KB) of battery backed SRAM, split into 123 pages with a limitation of 16 save files, but third-party models have much more, often in the form of 4 selectable memory banks of 256kbits. Games occupy varying numbers of pages, sometimes using the entire card. It is powered by a common CR2032 battery.


title: Nintendo 64 accessories

text: Upon launch, the Controller Pak was initially useful, and even necessary for early games. Over time, the Controller Pak lost popularity to the convenience of a battery backed SRAM or EEPROM in some cartridges. Because the Nintendo 64 Game Pak format also allows saving data on supported cartridges, few first-party and second-party games use the Controller Pak. The vast majority are from third-party developers. This is most likely due to the increased production and retail costs which would have been caused by including self-contained data on the cartridge. Some games use it to save optional data that is too large for the cartridge, such as "Mario Kart 64", which uses 121 of the total 123 pages for storing ghost data, or "International Superstar Soccer 64", which uses the entire cartridge's space for its save data. "Tony Hawk's Pro Skater" uses 11 pages. "Quest 64" and "Mystical Ninja Starring Goemon" use the Controller Pak exclusively for saved data. The Japan-only game "Animal Forest" uses the Controller Pak to travel to other towns.


title: Nintendo 64 accessories

text: Following the 1996 Christmas shopping season, "Next Generation" reported "impressive sales of the memory pack cartridges despite the lack of available games to take advantage of the $19.99 units".


title: Nintendo 64 accessories

text: The Jumper Pak (NUS-008) is a filler that plugs into the console's memory expansion port. It serves no functional purpose other than to terminate the Rambus bus in the absence of the Expansion Pak. This is functionally equivalent to a continuity RIMM in a Rambus motherboard filling the unused RIMM sockets until the user upgrades. All Nintendo 64 consoles were shipped with the Jumper Pak installed. Replacement Jumper Paks were not sold individually in stores and could only be ordered through Nintendo's online store. The system requires the Jumper Pak or Expansion Pak, or there is no display.


title: Nintendo 64 accessories

text: The (NUS-007) consists of 4 MB (megabytes) of random access memory (RAM)—which is RDRAM, the same on the console motherboard—increasing the console's RAM from 4 MB to 8 MB of contiguous main memory. It is installed in a port on top of the console and replaces the pre-installed Jumper Pak, which is simply a Rambus terminator. Originally designed for the 64DD disk drive's larger multimedia workstation applications, the Expansion Pak was launched separately in Q4 1998 and then bundled with the 64DD's delayed December 1999 launch package in Japan. The Expansion Pak was bundled with "Donkey Kong 64", and in Japan, the Expansion Pak additionally was bundled with "" and "Perfect Dark".


title: Nintendo 64 accessories

text: Game developers found ways to use the increased memory, including greater visual appeal. The Expansion Pak is required in order to run both "Donkey Kong 64" and "Majora's Mask". "Perfect Dark" blocks access to content, including the single-player campaign, when no Expansion Pak is present, and the game's packaging states that "approximately 35%" of the game is available in that case. It is required for all 64DD software. In "StarCraft 64", it is needed to unlock levels from the "" add-on from the PC version. "Quake II" features higher color depth and better performance, but not a higher resolution, with the Expansion Pak. In the vast majority of games with support, such as "" and "Indiana Jones and the Infernal Machine", the Expansion Pak is merely used as additional frame buffer memory to enable various high-resolution (usually interlaced) mode options at a performance cost, in some cases dramatically so. This use of the Expansion Pak can be attributed to ease of implementation and games that mainly target the stock console; additional RDRAM cannot be easily used to circumvent other bottlenecks of the console, such as the small texture cache. The of "Space Station Silicon Valley" may crash in certain places if the Expansion Pak is present.


title: Nintendo 64 accessories

text: IGN celebrated the Nintendo 64 industry's methods in launching and supporting the Expansion Pak for making a high-impact accessory with "immediate and noticeable", though mostly optional, effects.


title: Nintendo 64 accessories

text: The (NUS-013) provides haptic feedback by vibration. It is powered by two AAA batteries and connects to the controller's expansion port. It was released in 1997 for the new game "Star Fox 64", with which it was originally bundled.


title: Nintendo 64 accessories

text: The Transfer Pak (NUS-019) plugs into the controller to transfer data between supported Nintendo 64 games and Game Boy or Game Boy Color games. It has a Game Boy Color slot and a part that fits into the expansion port of the Nintendo 64 controller. It was first revealed at Nintendo's Space World 1997 trade show as the "64 GB Cable", and was initially designed as a cable that would connect a Game Boy to a Nintendo 64 controller port, allowing for both the transfer of data between games and the use of the Game Boy as a "sub-screen" for certain Nintendo 64 games; this form factor and feature set would later be revisited with the GameCube – Game Boy Advance link cable. The Transfer Pak was released in Japan in August 1998, and was bundled with the game "Pocket Monsters' Stadium", which required the Transfer Pak for many of its features. North America and Europe did not receive the Transfer Pak until February and April 2000 respectively, where it was similarly bundled with "Pokémon Stadium".


title: Nintendo 64 accessories

text: Several games with planned Transfer Pak support went unreleased. One of these was "Cabbage", a Nintendo 64DD virtual pet game developed by Nintendo EAD, which would have featured the Transfer Pak as a major gameplay component. The game was planned to allow players to transfer their pet to the Game Boy and continue to nurture it throughout the day. It was also suggested that special inexpensive Game Boy cartridges would contain new content, such as additional events and items, that could be transferred into "Cabbage". Another 64DD game, "DT Bloodmasters", was a trading card game developed by Marigul Management and Media Factory that would allow for the Game Boy to function as a second screen using the 64 GB Cable; the project was later retooled into the Game Boy Color game "DT: Lords of Genomes".


title: Nintendo 64 accessories

text: Other games were intended to include Transfer Pak features during development, only to remove them prior to release. "Derby Stallion 64" would have used the Game Boy as a second screen to place private bets on horse races, but this ceased to be viable after the 64 GB Cable was retooled into the Transfer Pak. "WWF No Mercy" was meant to use the Transfer Pak to import points earned in its Game Boy Color counterpart, which could be spent on rewards in the Nintendo 64 game's "SmackDown Mall". However, this feature was removed following the cancellation of the Game Boy Color version. "Perfect Dark" was initially going to support transferring photos from the Game Boy Camera to create characters with real-life faces, but this function was removed during development, as a result of both technical issues and a wave of anti-violent video game sentiment after the Columbine High School massacre; the final version only uses the Transfer Pak to immediately unlock four of the game's cheats via "Perfect Dark" on Game Boy Color.


title: Nintendo 64 accessories

text: Developed by Intelligent Systems, the Wide-Boy64 is a series of adapters similar to the Super Game Boy that plays Game Boy games. The device was never sold in retail to general consumers and was only provided to developers and the gaming press. Two major versions of Wide-Boy64 were released: the CGB for Game Boy and Game Boy Color games, and the updated AGB for those and Game Boy Advance Game Paks. The gaming press used it to capture screen shots more easily. Like the Super Game Boy and Game Boy Player, the game screen is surrounded by a template mimicking the appearance of the portable system. It was used for final matches at the "Pokémon" League Summer Training Tour '99. Developers and magazines could purchase one directly from Nintendo at a cost of . The Canadian children's game show "Video & Arcade Top 10" used Wide-Boy64 adapters so contestants could play Game Boy games on some later episodes.


title: Nintendo 64 accessories

text: The S-Video cable provides a better quality picture than composite RCA cables via the MultiAV port. The NTSC cable is identical to and compatible with earlier SNES (NTSC/PAL) and later GameCube (NTSC-only) S-Video cables. The first-party NTSC Nintendo 64 S-Video cable sold by Nintendo, however, was not produced in PAL regions. The PAL Nintendo 64 does natively output S-Video (Luma/Chroma), but require a different cable to NTSC Nintendo 64 due to a design difference in most or all PAL motherboard revisions. Nintendo never released an official S-Video cable for the PAL console. Using an NTSC S-Video cable on a PAL console will usually produce over-bright, garish colors; or it may not produce any video image at all.


title: Nintendo 64 accessories

text: Third-party S-Video cables for NTSC and PAL consoles were produced, though many cheaper S-Video cables do not deliver a true S-Video signal, merely passing the composite video signal (the yellow plug of the standard red/white/yellow AV cables) through the S-Video plug.


title: Nintendo 64 accessories

text: The 64DD (NUS-010) is a floppy drive with real-time clock, font and audio library in ROM, and a bundle of other accessories and custom games. The peripheral was initially announced in 1995, planned for release in 1997, and repeatedly delayed until its release in December 1999. It was launched alongside a now defunct online service called Randnet. With nine games released, it was a commercial failure and so was never released outside Japan.


title: Nintendo 64 accessories

text: The mouse (NUS-017) was developed for the 64DD's GUI-based games and applications, such the "Mario Artist" suite, "SimCity 64", and the web browser for Nintendo's defunct online service Randnet. It was manufactured by Mitsumi and was released only as a bundle with the 64DD's launch game, "". It works with , which was switched from the 64DD to Game Pak.


title: Nintendo 64 accessories

text: The VRU or Voice Recognition Unit (NUS-020, NUS-021, NUS-022, and NUS-025) is compatible with only two games: "Hey You, Pikachu!" and "Densha de Go! 64". "Hey You, Pikachu!" is packaged with the VRU and requires it, but "Densha de Go! 64" does not and is sold separately. The VRU consists of a ballast (NUS-020) connected to controller port 4, a microphone (NUS-021), a yellow foam cover for the microphone, and a clip for clipping the microphone to the controller (NUS-025, bundled with "Hey You, Pikachu!") or a plastic neck holder for hands-free usage (NUS-022, bundled with "Densha de Go! 64"). The VRU is calibrated for best recognition of a high-pitched voice, such as a small child's, and other voices are less likely be recognized properly by the VRU.


title: Nintendo 64 accessories

text: VRUs are region dependent, and foreign region VRUs are not detected by the games. No VRU compatible game was launched in the EUR region (PAL, Europe), so there is no EUR-region VRU. A similar device for the Wii is Wii Speak.


title: Nintendo 64 accessories

text: The cleaning kit (NUS-014, NUS-015, and NUS-016) contains materials to clean the connectors of the Control Deck, controllers, Game Paks, Rumble Paks, and Controller Paks.


title: Nintendo 64 accessories

text: The RF Switch and RF Modulator (NUS-009 and NUS-003) connect the Nintendo 64 and model 2 SNES (redesigned after the launch of the Nintendo 64) to the television through RF. It is primarily intended for older televisions that lack AV cable support. The RF switch itself is identical in every way to the RF switches released for Nintendo's prior systems (the NES and the SNES) and can be interchanged if needed. This set was later re-released for the GameCube to give it RF capability. The cables intended for the GameCube will also work with the Nintendo 64 and SNES.


title: Nintendo 64 accessories

text: The Euro Connector Plug is an adaptor packaged with European releases of the console, which converts RCA composite and stereo cable inputs to Composite SCART.


title: Nintendo 64 accessories

text: The video capture cassette (NUS-028), or cartridge, is for the 64DD game series. The back of the cartridge has audio, video, and microphone input jacks. It was bundled with the 64DD game


title: Nintendo 64 accessories

text: The modem cartridge (NUS-029) connects at up to , for the defunct Randnet service and compatible 64DD games and web browser.


title: Nintendo 64 accessories

text: SmartMedia memory cards for contain images, backgrounds, borders, and other media assets for editing the user's photos.


title: Nintendo 64 accessories

text: The cards are all 3.3 V 2 MB SmartMedia memory cards manufactured by Hagiwara Sys-Com. "Mario no Photopi" was bundled with an empty memory SmartMedia card for storing the user creations.


title: Nintendo 64 accessories

text: The ASCIIWHEEL 64 is an alternate controller shaped as a steering wheel for driving games, with an accessory port.


title: Nintendo 64 accessories

text: The Bio Sensor (NUS-A-BIO-JPN) is an ear clip that plugs into the Controller Pak slot of the controller to measure the user's heart rate. It was manufactured by Seta and released only in Japan. It is compatible only with "Tetris 64", which slows down or speeds up depending on how fast the player's heart is beating. This device is similar to the unreleased Wii Vitality Sensor.


title: Nintendo 64 accessories

text: The (ASC-0905) is a fishing controller manufactured by ASCII Corporation and compatible with a few fishing games released in Japan, like , , or


title: Nintendo 64 accessories

text: A train controller compatible with just one game: It is similar to other controllers for the same game series on different platforms such as Dreamcast and PlayStation. The game optionally supports the VRU.


title: Nintendo 64 accessories

text: Nintendo licensed A.L.S. Industries to make two types of black wooden system organizers. Both feature a plastic drawer, bearing a Nintendo 64 sticker, with slots designed to hold Nintendo 64 game cartridges, controllers, and Controller Paks.


title: Nintendo 64 accessories

text: The Messenger Bag is a black bag to be carried on the left side of the body. It comes with zippered compartments on the outside and inside and with mesh pockets, for a few games and a controller.


title: Nintendo 64 accessories

text: Nintendo licensed a Traveling Case—a black bag, with the Nintendo 64 name stitched on the front. Two plastic buckles on the front keep the bag closed. It carries the Nintendo 64 console, controllers, games, and accessories. They also made a standard black backpack with the Nintendo 64 logo on the top and a zippered compartment on the front.


title: Nintendo 64 accessories

text: A basic 35 mm camera, complete with a timer and flash. Official cameras have a Nintendo 64 logo on the front. They come in different colors such as blue and orange.


title: Nintendo 64 accessories

text: Nintendo's original development environment for Nintendo 64 software is a card made by SGI containing most of a Nintendo 64 console, plus a software development kit (SDK) for self-hosted installation in an SGI Indy workstation.


title: Nintendo 64 accessories

text: The second generation moved to a much cheaper partner model between a normal Nintendo 64 console and a PC by providing a cartridge form factor holding flash storage with a cable connection to a PC. Nintendo officially licensed SN Systems to make the SN Systems dev kit and SN Maestro 64, the second generation of Nintendo 64 SDK in PC partner form to replace the Indy-hosted hardware solution. Unofficial kits include IS-VIEWER 64 and Partner 64. The Monegi Smart Pack is a collection of third-party hardware and software which facilitates real-time development while the game is running on the console.


title: Nintendo 64 accessories

text: Through the decades, many unlicensed third-party peripheral devices have provided many consumer-friendly alternative storage mediums for retail Nintendo 64 consoles. They bypass console security for the purpose of development or for users making backups of game cartridges and save data. The Doctor V64 is a CD-ROM peripheral designed by Bung Enterprises and released in 1996. It plugs into the Nintendo 64's underside expansion slot, and uses a lockout-bypass adaptor that fits into the cartridge port, into which any retail cartridge is inserted for use of its lockout chip by proxy. The Doctor V64 Jr. is a cheaper, condensed version that fits into the cartridge port and provides a parallel port connection to a PC. Bung made the DX 256 Super Game Saver which stores 256 battery EEPROM save states, and the DS1 Super Doctor Save Card. The CD 64 is a CD-ROM drive developed by UFO/Success Company. Mr. Backup Z64 designed by Harrison Electronics, Inc. is a ZIP drive peripheral for creating writable backups and performing playback of any Nintendo 64 cartridge. The modern Everdrive 64, ED64 Plus, N64 Neo Myth, and 64Drive use SD cards for mass storage of ROM image files or USB cables to connect to a PC for transfer.


title: Nintendo 64 accessories

text: DexDrive is a retail consumer product, an adaptor to connect a Nintendo 64 #Controller Pak into a PC serial port, for sharing saved games.


title: Sonoma, California

text: Sonoma is a city in Sonoma County, California, United States, located in the North Bay region of the San Francisco Bay Area. Sonoma is one of the principal cities of California's Wine Country and the center of the Sonoma Valley AVA. Sonoma's population was 10,739 as of the 2020 census, while the Sonoma urban area had a population of 32,679. Sonoma is a popular tourist destination, owing to its Californian wineries, noted events like the Sonoma International Film Festival, and its historic center.


title: Sonoma, California

text: Sonoma's origins date to 1823, when José Altimira established Mission San Francisco Solano, under the direction of Governor Luis Antonio Argüello. Following the Mexican secularization of the missions, famed Californio statesman Mariano G. Vallejo founded Sonoma on the former mission's lands in 1835. Sonoma served as the base of General Vallejo's operations until the Bear Flag Revolt in 1846, when American filibusters overthrew the local Mexican government and declared the California Republic, ushering in the American Conquest of California.


title: Sonoma, California

text: When the first Europeans arrived, the area was near the northeast corner of the Coast Miwok territory, with Southern Pomo to the northwest, Wappo to the northeast, Suisunes and Patwin peoples to the east.<ref name="S/PSHPA">S/PSHPA</ref>


title: Sonoma, California

text: Mission San Francisco Solano is the direct predecessor to the founding of Sonoma. The mission, the only to be constructed not by the Spanish but by the Mexican authorities, was built as part of a larger plan Governor Luis Antonio Argüello had devised to fortify Mexican presence north of San Francisco Bay and thus deter Russian encroachment into the region. Franciscan padre José Altimira worked with Governor Argüello to plan the mission, against the desires of José Francisco de Paula Señan, then the President-General of the Californian missions, who disapproved of government intervention into religious matters.


title: Sonoma, California

text: In 1833 the Mexican Congress passed the Mexican secularization act of 1833, effectively nationalizing all the missions and associated lands of the Catholic church in California, which the goal of diminishing the church's highly influential standing in California's economy and political system. Governor José Figueroa appointed Mariano Guadalupe Vallejo, then the Commandant of the Presidio of San Francisco, as administrator ("comisionado") to oversee the closing of Mission San Francisco Solano and its conversion into a civilian town.


title: Sonoma, California

text: Governor Figueroa had received instructions from the Mexican Congress to establish a strong presence in the region north of the San Francisco Bay to protect the area from encroachments of foreigners. An immediate concern was the further eastward movement of the Russian America Company from their settlements at Fort Ross and Bodega Bay on the California coast.


title: Sonoma, California

text: Figueroa's next step in implementing his instructions was to name Lieutenant Vallejo as Military Commander of the Northern Frontier and to order the soldiers, arms and materiel at the Presidio of San Francisco moved to the site of the recently secularized Mission San Francisco Solano. The Sonoma Barracks were built to house the soldiers. Until the building was habitable, the troops were housed in the buildings of the old Mission. In 1834, George C. Yount, the first Euro-American permanent settler in the Napa Valley, was employed as a carpenter by General Vallejo.


title: Sonoma, California

text: The Governor granted Lieutenant Vallejo the initial lands (approximately ) of Rancho Petaluma immediately west of Sonoma. Vallejo was also named Director of Colonization which meant that he could initiate land grants for other colonists (subject to the approval of the governor) and the "diputación" (Alta California's legislature).


title: Sonoma, California

text: Vallejo had also been instructed by Governor Figueroa to establish a pueblo at the site of the old Mission. In 1835, with the assistance of William A. Richardson, he laid out, in accordance with the Spanish Laws of the Indies, the streets, lots, central plaza and broad main avenue of the new "Pueblo de Sonoma".


title: Sonoma, California

text: Although Sonoma had been founded as a pueblo in 1835, it remained under military control, lacking the political structures of municipal self-government of other Alta California pueblos. In 1843, Lieutenant Colonel Vallejo wrote to the Governor recommending that a civil government be organized for Sonoma. A town council ("ayuntamiento") was established in 1844 and Jacobo Leese was named first "alcalde", and Cayetano Juárez second "alcalde".


title: Sonoma, California

text: Before dawn on Sunday, June 14, 1846, thirty-three Americans, already in rebellion against the Alta California government, arrived in Sonoma. Some of the group had traveled from the camp of U.S. Army Brevet Captain John C. Frémont who had entered California illegally in late 1845 with his exploration and mapping expedition. Others had joined along the way. As the number of immigrants arriving in California had swelled, the Mexican government barred them from buying or renting land and threatened them with expulsion because they had entered without official permission. Mexican officials were concerned about the coming war with the United States coupled with the growing influx of American immigrants into California.


title: Sonoma, California

text: A group of rebellious Americans had departed from Frémont's camp on June 10 and captured a herd of 170 Mexican government-owned horses being moved by Californio soldiers from San Rafael and Sonoma to Alta California's Commandante General José Castro in Santa Clara. The insurgents next determined to seize the weapons and materiel stored in the Sonoma Barracks and to deny Sonoma to the Californios as a rallying point north of San Francisco Bay.


title: Sonoma, California

text: Meeting no resistance, they approached the home of General Vallejo, who invited the filibusters' leaders into his home to negotiate terms. However, when the agreement was presented to those outside they refused to endorse it. Rather than releasing the Mexican officers under parole, they insisted they be held as hostages. William Ide gave an impassioned speech urging the rebels to stay in Sonoma and start a new republic. Afterwards, Vallejo and his three associates were taken as prisoners and placed on horseback and taken to Frémont.


title: Sonoma, California

text: The Sonoma Barracks became the headquarters for the remaining twenty-four rebels, who within a few days created their Bear Flag. After the flag was raised Californios called the insurgents "Los Osos" (The Bears) because of their flag and in derision of their often scruffy appearance. The rebels embraced the expression, and their uprising became known as the Bear Flag Revolt. There were some small unit skirmishes between the Bears and the Californios but no major confrontations.


title: Sonoma, California

text: After hearing reports that General José Castro was preparing to attack Sonoma, Frémont left Sutter's Fort with his forces for Sonoma. There he called a meeting with "the Bears" and united his forces with the revolters to form a single military unit. Frémont then took the majority of the men back to Sutter's Fort and left fifty men to defend Sonoma. The Bear Flag Revolt ended and the California Republic ceased to exist on July 9 when Lieutenant Joseph Warren Revere of the U.S. Navy raised the United States flag in front of the Sonoma Barracks.


title: Sonoma, California

text: Following the American Conquest of California and the advent of the California Gold Rush, local businesses prospered with the business brought by the soldiers as well as miners traveling to and from the gold fields. The prosperity and optimism about Sonoma's future promoted land speculation which was particularly problematic because of the cloudy records regarding land ownership.


title: Sonoma, California

text: Vallejo had granted land by virtue of his office as Director of Colonization before the pueblo was organized. Among the traditional duties of Alta California's "alcaldes" was the selling of town lots. Political factions backed different Sonoma "alcaldes" (John H. Nash, supported by American immigrants, and Lilburn Boggs supported by Vallejo and the Californios) made the situation more complex. Some property was sold more than once. A valid land sale depended on proof of the seller's chain of title. Over thirty years of lawsuits were required before land owners in Sonoma were able to obtain clear titles.