Cyp1a2(-/-) null mutant mice develop normally but show deficient drug metabolism.

Cytochrome P450 1A2 (CYP1A2) is a predominantly hepatic enzyme known to be important in the metabolism of numerous foreign chemicals of pharmacologic, toxicologic, and carcinogenic significance. CYP1A2 substrates include aflatoxin B1, acetaminophen, and a variety of environmental arylamines. To define better the developmental and metabolic functions of this enzyme, we developed a CYP1A2-deficient mouse line by homologous recombination in embryonic stem cells. Mice homozygous for the targeted Cyp1a2 gene, designated Cyp1a2(-/-), are completely viable and fertile; histologic examination of 15-day embryos, newborn pups, and 3-week-old mice revealed no abnormalities. No CYP1A2 mRNA was detected by Northern blot analysis. Moreover, mRNA levels of Cyp1a1, the other gene in the same subfamily, appear unaffected by loss of the Cyp1a2 gene. Because the muscle relaxant zoxazolamine is a known substrate for CYP1A2, we studied the Cyp1a2(-/-) genotype by using the zoxazolamine paralysis test: the Cyp1a2(-/-) mice exhibited dramatically lengthened paralysis times relative to the Cyp1a2(+/+) wild-type animals, and the Cyp1a2(+/-) heterozygotes showed an intermediate effect. Availability of a viable and fertile CYP1A2-deficient mouse line will provide a valuable tool for researchers wishing to define the precise role of CYP1A2 in numerous metabolic and pharmacokinetic processes.

Accelerated induction of experimental allergic encephalomyelitis in PL/J mice by a non-V beta 8-specific superantigen.

Superantigens such as the staphylococcal enterotoxins can play an important role in exacerbation of autoimmune disorders such as experimental allergic encephalomyelitis (EAE) in mice. In fact, superantigens can reactivate EAE in PL/J mice that have been sensitized to rat myelin basic protein (MBP). The T-cell subset predominantly responsible for disease in PL/J mice bears the V beta 8+ T-cell antigen receptor (TCR). The question arises as to whether T cells bearing other V beta specificities are involved in induction or reactivation of EAE with superantigen. Thus, we have investigated the ability of a non-V beta 8-specific superantigen, staphylococcal enterotoxin A (SEA) (V beta specificities 1, 3, 10, 11, and 17), to induce EAE in PL/J mice that have been previously protected from disease by anergy and deletion of V beta 8+ T cells. PL/J mice were first pretreated with the V beta 8-specific superantigen staphylococcal enterotoxin B (SEB) and then immunized with MBP. These mice exhibited V beta 8-specific anergy and depletion and did not develop EAE, even when further treated with SEB. However, administration of SEA to these same mice induced an initial episode of EAE which was characterized by severe hindleg paralysis and accelerated onset of disease. In contrast to SEB pretreatment, PL/J mice pretreated with SEA did develop EAE when immunized with MBP, and after resolution of clinical signs of disease these mice were susceptible to relapse of EAE induced by SEB but not by SEA. Thus, superantigens can activate encephalitogenic MBP-specific non-V beta 8+ T cells to cause EAE in PL/J mice. These data suggest that superantigens can play a central role in autoimmune disorders and that they introduce a profound complexity to autoimmune diseases such as EAE, akin to the complexity seen in multiple sclerosis.

Emergent Brazil and the Curse of the ‘Hen’s Flight’. CEPS Working Document No. 379, 27 February 2013

The ‘Emergent Brazil’ growth model is reaching its limits. Its main engines have been slowing significantly since the beginning of the global financial and economic crisis. Even its much-praised predictable macroeconomic policy has been eroded by political interference. Inflationary pressures are growing and GDP performance is anaemic. As ominous, Brazil cannot compensate for its domestic deficiencies with an export drive. Commodity exports are suffering with the world economic slow-down and the manufacturing industries’ competitiveness is in sharp decline. Brazil has put all its trade negotiation eggs into the South American and WTO baskets, and now its export market share is threatened by the Doha Round paralysis, the Latin American Alianza del Pacífico, and the US-led initiatives for a Trans-Pacific Partnership and a trade and investment agreement with the EU. Paradoxically, this alarming situation opens a window of opportunity. There is a mounting national consensus on the need to tackle head-on the country’s and its industries’ lack of competitiveness. That means finding a solution to the much-decried ‘Brazil Cost’ and stimulating private-sector investment. It also entails an aggressive trade-negotiating stance in order to secure better access to foreign markets and to foster more competition in the domestic one. The most promising near-term goal would be the conclusion of the EU–Mercosur trade talks. A scenario to overcome the paralysis of these negotiations could trail two parallel paths: bilateral EU–Brazil agreements on ‘anything but trade’ combined with a sequencing of the EU–Mercosur talks where each member of the South American bloc could adopt faster or slower liberalisation commitments and schedules.

Climate Conundrums at High Altitude. EU Diplomacy Paper 01/2014, January 2014

The European Union (EU) was the frontrunner for the establishment of the world’s first multinational emissions trading scheme (ETS). Committed to combating climate change, the EU sought to overcome the multilateral paralysis within the International Civil Aviation Organization (ICAO) to mitigate aviation emissions. Unsuccessful in pushing for a global market-based measure (MBM) within the organisation, the EU was ready for take-off to include the sector in the EU emissions trading system (EU ETS). The geographical scope, however, including all flights from and to Europe in their entire trajectory, caused frictions with the international community about sovereignty issues. Ultimately, Climate Commissioner Connie Hedegaard announced a ‘stop-the-clock’ for international flights, a temporary derogation until the 2013 ICAO Assembly in order to find a global agreement. The ’stop-the-clock’ initiative provides ample opportunity to analyse EU leadership in curbing aviation emissions based on an analytical framework specifying different types of leadership. Its shows the global challenge to the EU’s claim of structural leadership on various levels in and beyond ICAO. The paper aims to analyse to what extent the EU is a global leader in mitigating aviation emissions and to identify the kind of EU leadership according to a threefold analytical framework. In addition, it will factor in the 'stop-the-clock' initiative and to what extent it altered the perception of EU leadership in the field. The paper comes to the conclusion that EU leadership in mitigating aviation emissions is not stalling. On the contrary, the EU, by pursuing the extension of the EU ETS, has put aviation emissions on everybody’s radar – and thus showed idea-based leadership. Proving the scheme’s feasibility further underlined EU leadership, in the form of directional leadership. The 'stop-the-clock' decision, however, already indicated what was later on confirmed in the 38th ICAO Assembly: Unilateral structural leadership of the EU in the field of aviation emissions is not credible at the moment.

Do Institutional Changes Make a Difference? A veto player analysis of how institutional changes in the Council of the EU influence legislative efficiency and outputs. Brugges Political Research Paper No. 31, October 2013

A driving argument behind recent EU treaty reforms was that more qualified majority voting (QMV) was required to reduce the potential dangers of legislative paralysis caused by enlargement. Whilst existing literature on enlargement mostly focuses on the question of what changed in the legislative process after the 2004 enlargement, the question of why these changes occurred has been given far less attention. Through the use of a single veto player theoretical model, this paper seeks to test and explain whether enlargement reduces the efficiency of the legislative process and alters the type of legislation produced, and whether QMV can compensate for these effects. In doing this, it offers a theoretical explanation as to why institutional changes that alter the level of cohesion between actors in the Council have an influence over both the legislative process and its outcomes.

Transnistria – Where to? EPC Policy Brief, 13 March 2014

At the Vilnius summit of the Eastern Partnership in November 2013, Moldova initialled its Association Agreement with the EU, including a Deep and Comprehensive Free Trade Area (DCFTA) agreement, and is expected to sign the documents before the end of August 2014. Meanwhile, Russia has increased its presence and pressure in the region, as a consequence of which Armenia declined the AA and DCFTA with the EU and Ukraine, after months of protests and political paralysis, now has part of its territory occupied by Russia. Moldova is no exception to Russian pressure. As the country gets closer to upgrading relations with the EU, Russia has increased its activities in Moldova, including in the autonomous region of Gagauzia and in the breakaway region of Transnistria. Even though the “5+2” negotiations for the settlement of the Transnistria conflict continue, the number of incidents in and around this region have increased. The window of opportunity created by the involvement of Germany in the settlement of the conflict and the restart of the “5+2” negotiations in late 2011 seems to have closed. Given the recent events in the region and in Moldova/Transnistria, including the potential impact of DCFTA and visa liberalisation, Chisinau finds it increasingly difficult to manage the juggling act between its EU commitment and dialogue with Tiraspol. This Policy Brief presents the background, state of play and prospects of the Transnistria conflict while also focusing on the potential impact of Moldova’s Association Agreement with the EU on the settlement of the conflict.

Bernhardi Verzaschae Exercitatio de apoplexia et paralysi.

Mode of access: Internet.

Paralysies et contractures hystériques.

Mode of access: Internet.

Essai sur l'hémiplégie des vieillards. Les lacunes de désintégration cérébrale. Avec 8 planches.

Plates 1-2 are accompanied by leaf with descriptive letter-press.

Survey of cripples in New York City /

Report of the Committee on Survey of Cripples of the Conference on Cripples held in New York on Apr. 4, 1919.

Traité de l'apoplexie et de ses différentes espèces : avec une nouvelle méthode curative, dont l'utilité est prouvée par l'expérience ... on y traite également de la paralysie et de ses differentes especes particulières /

Mode of access: Internet.

Erregung und lähmung, eine allgemeine physiologie der reizwirkungen,

The greater part of the contents of this book was included in the author's Silliman lectures, delivered at Yale in October, 1911, and published under title: Irritability, a physiological analysis of the general effect of stimuli in living substances, New Haven, 1913; but sufficient material has been added to make a practically new work. cf. Vorwort.

A spectator

Color photograph of a spectator at a showing, pictured between Kevorkian's paintings "Paralysis" and "Four Presidents and a God." Photo dated June 1985. Caption by Ava Janus

Dynamics of motor nerve terminal remodeling unveiled using SNARE-cleaving botulinum toxins: the extent and duration are dictated by the sites of SNAP-25 truncation

Nerve sprouts emerge from motor nerve terminals following blockade of exo-endocytosis for more than 3 days by botulinum neurotoxin (BoNT), and form functional synapses, albeit temporary. Upon restoration of synaptic activity to the parent terminal 7 and 90 days after exposure to BoNT/F or A respectively, a concomitant retraction of the outgrowths was observed. BoNT/E caused short-term neuroparalysis, and dramatically accelerated the recovery of BoNT/A-paralyzed muscle by further truncation of SNAP-25 and its replenishment with functional full-length SNARE. The removal of 9 C-terminal residues from SNAP-25 by BoNT/A leads to persistence of the inhibitory product due to the formation of a nonproductive SNARE complex(es) at release sites, whereas deletion of a further 17 amino acids permits replenishment and a speedy recovery. (C) 2003 Elsevier Science (USA). All rights reserved.

Limitations to global disease control

In October 2000, Australia was declared poliomyelitis-free” by the World Health Organisation. This declaration followed some extensive six years of surveillance of all cases of acute flaccid paralysis, by the Poliomyelitis Expert Surveillance Committee (Centre for Disease Control, Commonwealth Department of Health and Aged Care, Canberra), chaired by the author. There have been seven attempts in the history of the world to eliminate a disease from the earth’s surface. The dramatic failure of five of these, the success of global smallpox eradication, and current successes and difficulties in the case of attempts to eliminate poliomyelitis worldwide, lead one to an analysis of the factors which led both to success and to failure. The global eradication of a specific disease is one of the most important endeavours which the international community can undertake. This audit reviews the details of such approaches; that such might be used as tools for the future.