Allopregnanolone known as brexanolone, is a medication and a produced steroid that acts on the brain. As a medication, it is used to treat postpartum depression, it is used by injection into a vein over a 60-hour period under medical supervision. Side effects of brexanolone may include sedation, dry mouth, hot flashes, loss of consciousness, it is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid. Brexanolone was approved for medical use in the United States in 2019, with commercial sales expected to begin in June 2019; the long administration time, as well as the cost of US$34,000, have raised concerns about accessibility for many women. Brexanolone is used to treat postpartum depression in women. Side effects of brexanolone includes sedation, dry mouth, loss of consciousness, flushing, it can produce euphoria to a degree similar to that of alprazolam. Allopregnanolone possesses a wide variety of effects, including, in no particular order, anxiolytic, stress-reducing, prosocial, prosexual, pro-sleep, memory-impairment, anesthetic, anticonvulsant and neurogenic effects.
Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, premenstrual syndrome, catamenial epilepsy, various other neuropsychiatric conditions. During pregnancy and pregnanolone are involved in sedation and anesthesia of the fetus. Allopregnanolone is an endogenous inhibitory pregnane neurosteroid, it is made from progesterone, is a positive allosteric modulator of the action of γ-aminobutyric acid at GABAA receptor. Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic and anticonvulsant activity. Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor. Allopregnanolone acts as a potent positive allosteric modulator of the GABAA receptor. While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.
Allopregnanolone has been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear. In addition to its actions on GABA receptors, like progesterone, is known to be a negative allosteric modulator of nACh receptors, appears to act as a negative allosteric modulator of the 5-HT3 receptor. Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, glycine receptors. Unlike progesterone, allopregnanolone is inactive at the classical nuclear progesterone receptor. However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, for this reason, allopregnanolone can produce PR-mediated progestogenic effects. In addition, allopregnanolone has been found to be an agonist of the newly discovered membrane progesterone receptors, including mPRδ, mPRα, mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.
The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties. Like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor. To many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels, including α1 subtypes Cav1.2 and Cav1.3. However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM, far greater than the concentration of 5 nM, estimated to be produced in the human brain. Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone. Allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor. However, it is only able to do so at micromolar concentrations, which to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.
Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety and aggression. This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases inhibit the activity of the receptor, while lower and higher concentration increases stimulate it; this seems to be a common effect of many GABAA receptor positive allosteric modulators. In accordance, acute administration of low doses of micronized progesterone has been found to have negative effects on mood, while higher doses have a neutral effect; the mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown. Other GABAA receptor PAMs, such as benz
The Electronic Information Exchange System was an early online conferencing bulletin board system that allowed real-time and asynchronous communication. The system was used to deliver courses, conduct conferencing sessions, facilitate research. Funded by the National Science Foundation and developed from 1974-1978 at the New Jersey Institute of Technology by Murray Turoff based on his earlier EMISARI done at the now-defunct Office of Emergency Preparedness, EIES was intended to facilitate group communications that would allow groups to make decisions based on their collective intelligence rather than the lowest common denominator. Conceived as an experiment in computer mediated communication, EIES remained in use for decades because its users "just wouldn't let go" of it adapting it for legislative and spiritual uses. In the mid-1980s, a new version called EIES-2 was developed to research the implementation of group communications in distributed environments, versus the centralized time-sharing environment used for the first version.
EIES-2 had an object database architecture using over 2 dozen classes and implementing a notion of activities, a standardized interface for implementing nonstandard functions such as polls or list-gathering. The activities concept was similar to what would be done in today's message board applications using plug-ins; the standard message-based functions were implemented as activities. EIES-2 was written in the programming languages C and Smalltalk. EIES-2 used the X.400 database standards. Accounts were available to the public for a monthly fee of USD $75 plus connect-time charges. In his book The Virtual Community, Howard Rheingold called EIES "the lively great-great-grandmother of all virtual communities". EIES was one of the earliest instances of groupware, if not the earliest, some users contend it is where the term was coined; the editors of the Whole Earth Software Catalog set up a private conference on EIES where they could collaborate on software reviews from around the US. Along with serious research, there were diversions like the "EIES Soap Opera", a series of stories written collaboratively by the service's users.
The first soap opera was initiated in 1980 by Martin Nisenholtz. Working groups from different corporations used EIES to collaborate, some working from home. EIES gave an early glimpse of the challenges of work–life balance and pointed the way toward hypertext and gamification. Notable users included Alvin Toffler, Peter & Trudy Johnson-Lenz, Barry Wellman, Whole Earth editor-in-chief Stewart Brand, influenced by EIES to develop The WELL. At its peak EIES had more than 2000 subscribers from various government agencies, large corporations and educational institutions; the Western Behavioral Sciences Institute ran a private conference called the School of Management and Strategic Studies, of which Harlan Cleveland was a member. As a legacy system lacking support for multimedia or file attachments, EIES was shut down in 2000, despite NJIT's inability to locate a replacement with equivalent performance. At the time of its shutdown, EIES-2 held 6 GB of stored data, could serve 1,000 concurrent users with an average response time of under 15 seconds.
IRC History -- Electronic Information Exchange System EIES History Dr. Turoff's account Electronic Global University System and Services
Marcel Cas is a Dutch former professional footballer and current fitness coach for Eredivise side Feyenoord. As a player, he was a midfielder from 1995 until 2005, playing in both his native land and in England, notably for RBC, Notts County and FC Den Bosch, as well as turning out in brief spells with Sheffield United and Grimsby Town. Born in Breda in 1972, Cas started his career playing for RBC Roosendaal in 1995 established himself into the team making 121 first team appearances, scoring 13 goals before securing a move to England in 2001. Cas joined Football League Division Two side Notts County in the summer of 2001, he remained at Meadow Lane following 58 appearances and 8 goals. Sheffield United signed Cas in 2003, but found it hard to find his way into the plans of manager Neil Warnock and he was released at the end of the 2002-2003 season, following only 6 league appearances. Cas returned to the Netherlands for preseason training, but began to talk to several clubs back in England, this was confirmed when it was announced that he had flown into Humberside Airport in June 2003 to sign a one-year contract with Grimsby Town, where he joined Tony Crane as the club's first new signings for the 2003–2004 season.
Despite being signed as a right-sided midfielder, a position he had played in all his career, he would come to a disagreement with manager Paul Groves who preferred to play him at right-back, whilst Jason Crowe, a natural of that position, was played in Cas's favoured slot. This was something that unsettled Cas, who fell out with Groves, thus paving the way for his departure from Blundell Park in January 2004. Upon his departure, Cas commented "I'm a midfielder...not a defender" to the media in relation to his spat with Groves that had ended his time at Grimsby. Cas re-signed for RBC Roosendaal in 2004, but in a half-year spell back at the club he was plagued with injuries, he departed in summer 2004 having only featured in 16 league matches. Upon his departure from RBC, he signed for FC Den Bosch in 2004, but decided to retire due to a persistent back injury in November 2005, following 11 years as an active professional footballer. At the beginning of the season 2009/2010 season, Dutch side Feyenoord announced that Cas had joined the club's backroom staff, working in the medical department after spending two years as a fitness coach at RKC.
In 2013, he became the clubs fitness coach. Profile - Dannenburg Physiotherapists
The Diocese of Sabina-Poggio Mirteto a suburbicarian see of the Holy Roman Church and a diocese of the Catholic Church in Italy in the Roman province of the Pope. Sabina has been the seat of such a bishopric since the 6th century, though the earliest names in the list of bishops may be apocryphal; the ancient cathedral of San Salvatore of Sabina was located in Forum Novum. The official papal province of Sabina was established under Pope Paul V in 1605. Since 1842 the Cardinal Bishop of Sabina bears the title of Territorial Abbot of Farfa. Since 1925, the cardinalatial Titular Church of Sabina has been united to that of Poggio Mirteto, named Sabina e Poggio Mirteto, since 1986 Sabina–Poggio Mirteto; the current Cardinal-Bishop is Giovanni Battista Re, while the Ordinary of the Diocese is Bishop Ernesto Mandara. If?, century or c. is given, exact years or dates have not yet been found for his tenure. Mariano Pietro Issa Teodoro Samuele Sergio Leone Gregorio Anastasio Giovanni Giovanni Domenico Benedetto Rainiero Gaetano de Lai Donato Sbarretti Enrico Sibilia Adeodato Giovanni Piazza Marcello Mimmi Giuseppe Ferretto Antonio Samoré Agnelo Rossi Eduardo Francisco Pironio Lucas Moreira Neves Giovanni Battista Re Kehr, Paul Fridolin.
Italia pontificia. Vol. II: Latium. Berlin: Apud Weidmannos. Pp. 53–74. Suburbicarian Diocese of Sabina-Poggio Mirteto Official Website Complete list Konrad Eubel, Hierarchia Catholica Medii Aevi, vol. I-IV
Dominic Waghorn is a British journalist, the Diplomatic Editor of Sky News and presenter of the channel's weekly international affairs analysis programme World View. He was before that US Correspondent of Sky News, the 24-hour television news service operated by Sky Television, part of British Sky Broadcasting, he is based at Sky News' Washington Bureau. He was Sky News' Asia Correspondent, based in Beijing and Middle East Correspondent, based in Jerusalem, he became Sky News' US Correspondent in 2011. Waghorn was born in London and educated at Streete Court School, a former preparatory independent school for boys, in the village of Godstone in Surrey in South East England, from 1976–1982, at Worth School, a Roman Catholic senior boarding independent school for boys, near the village of Turners Hill in West Sussex, from 1982–1987, of which he says he has "very fond memories", boarded at St. Bede's House, he went to the University of Bristol, where he gained a BA in History, followed by the University of the West of England, where he gained a Diploma in Broadcast Journalism.
Waghorn started at LBC Radio in London, where he was an editor and news reporter. He joined the Feature Story News news agency in 1996, was its North America Correspondent, based in Washington, D. C.. He set up the agency's London Bureau, where he was Bureau Chief and television and radio correspondent, it was during this time that he covered the visit of Nelson Mandela in May 1999, when NATO bombed the Chinese Embassy in Belgrade, working on outdated intelligence information which had indicated its previous suspected usage as a munitions storage site for forces loyal to Slobodan Milosevic. For FSN, Waghorn covered the subsequent large demonstrations across Beijing, in which western embassies, including those of some not involved in the conflict, came under siege, his FSN reports were carried by networks in three continents, among, his first report to be shown on Sky News. Waghorn joined Sky News in January 2001, he became Sky News' Asia Correspondent in January 2004, remained there for just under three years, where his exclusive reports won several awards, including RTS Television Journalist of the Year and News Item of the Year in 2007, for a series of investigative reports in China.
He won awards for his China and South East Asia reporting, as Foreign Press Association Journalist of the Year award and One World Media Journalist of the Year and a Golden Nymph for Best TV News Item at the Monte Carlo TV Festival. In late 2006, Waghorn became Sky News' Middle East Correspondent, based in Jerusalem, he worked there for five years, during which time he covered the wars in Iraq, the aftermath of the war in Lebanon and the Arab Spring. Whilst in the Middle East, he reflected on his school experiences: of Streete Court School in the village of Godstone in Surrey, he says that the Middle East's "biblical surroundings remind him on an daily basis of Major James' nightly Oak Room bible readings and the weekly scriptural writing sessions administered by Ellis Parry; the other day he was driving up through the Sinai and Major James' explanation of Moses finding water while leading the Israelites out of Egypt, came to mind", that at Worth School, near the village of Turners Hill in West Sussex, he says he had studied the Crusades "through the barrage of Father Stephen's pipe smoke".
In 2009, Waghorn was the first British journalist to re-enter Gaza after Hamas' takeover in 2007, was praised in the press for his coverage of the 2009 Gaza Conflict. In 2010, he was despatched to the Caribbean to report on the Haiti earthquake. In 2011, he was among the first Western journalists to enter Libya, days after the defeat of Gadaffi forces in the east, reporting from Benghazi and the road to Ras Lanuf. Waghorn was part of Sky's BAFTA-nominated and Golden-Nymph award winning team covering the Egyptian revolution before the downfall of President Hosni Mubarak, from the outbreak of protests, to the'Friday of Rage' protests in Cairo's Tahrir Square, demanding Mubarak's rapid departure, Mubarak's subsequent downfall and the immediate aftermath. Waghorn became Sky News' US Correspondent, based in its Washington, D. C. bureau, in 2011. He has travelled extensively across the United States, covering the US presidential primary campaigns and the re-election of Barack Obama. Waghorn was awarded the RTS Television Journalist of the Year and News Item of the Year in 2007, for a series of investigative reports in China.
He won Foreign Press Association Journalist of the Year Award, the One World Media Journalist of the Year Award, a Golden Nymph for Best TV News Item in the Monte Carlo TV Festival for a story on AIDS in China. He and other colleagues at Sky were nominated for a BAFTA for coverage of the Egyptian Revolution of 2011, his wife Penny is an actress and jewellery designer, they have three children. Dominic Waghorn on Twitter