Dramatic influence of V beta gene polymorphism on an antigen-specific CD8+ T cell response in vivo.

According to recent crystallographic studies, the TCR-alpha beta contacts MHC class I-bound antigenic peptides via the polymorphic V gene-encoded complementarity-determining region 1 beta (CDR1 beta) and the hypervariable (D)J-encoded CDR3 beta and CDR3 alpha domains. To evaluate directly the relative importance of CDR1 beta polymorphism on the fine specificity of T cell responses in vivo, we have taken advantage of congenic V beta a and V beta b mouse strains that differ by a CDR1 polymorphism in the V beta 10 gene segment. The V beta 10-restricted CD8+ T cell response to a defined immunodominant epitope was dramatically reduced in V beta a compared with V beta b mice, as measured either by the expansion of V beta 10+ cells or by the binding of MHC-peptide tetramers. These data indicate that V beta polymorphism has an important impact on TCR-ligand binding in vivo, presumably by modifying the affinity of CDR1 beta-peptide interactions.

Dramatic effect of early clopidogrel administration in reducing mortality and MACE rates in ACS patients. Data from the Swiss registry AMIS-Plus.

BACKGROUND: Patients who have acute coronary syndromes with or without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy of early clopidogrel administration (300 mg) (<24 hours) when given with aspirin in such patients. METHODS: We included 30,243 patients who had an acute coronary syndrome with or without ST segment elevation. Data on early clopidogrel administration were available for 24,463 (81%). Some 15,525 (51%) of the total cohort were administrated clopidogrel within 24h of admission. RESULTS: In-hospital death occurred in 2.9% of the patients in the early clopidogrel group treated with primary PCI and in 11.4% of the patients in the other group without primary percutaneous coronary intervention (PCI) and no early clopidogrel. The unadjusted clopidogrel odds ratio (OR) for mortality was 0.31 (95% confidence interval 0.27-0.34; p <0.001). Incidence of major adverse cardiac death (MACE) was 4.1% in the early clopidogrel group treated with 1°PCI and 13.5% in the other group without primary PCI and no early clopidogrel (OR 0.35, confidence interval 0.32-0.39, p <0.001). Early clopidogrel administration and PCI were the only treatment lowering mortality as shown by mutlivariate analysis. CONCLUSIONS: The early administration of the anti-platelet agent clopidogrel in patients with acute coronary syndromes with or without ST-segment elevation has a beneficial effect on mortality and major adverse cardiac events. The lower mortality rate and incidence of MACE emerged with a combination of primary PCI and early clopidogrel administration.

Ein Instrument der parlamentarischen Mitwirkung im Bereich der schweizerischen Aussenpolitik : die Information und Konsultation gemäss Art. 152 Parlamentsgesetz

Dass der Weg der parlamentarischen Mitwirkung im Bereich der Aussenpolitik steinig werden sollte, widerspiegelte sich bereits in der Entstehungsgeschichte der Aussenpolitischen Kommissionen (APK). Diese haben zum heutigen Zeitpunkt unter anderem dafür zu sorgen, dass das Parlament seine Mitwirkungsrechte in auswärtigen Angelegenheiten frühzeitig und wirk¬sam wahrnehmen kann. Nebst verschiedensten Instrumenten auf Verfassungs- und Gesetzesebene steht den APK ein wichtiges Mitwirkungsinstrument zur Verfügung: die Information und Konsultation gemäss Art. 152 Parlamentsgesetz (ParlG). Seit Inkrafttreten dieser Bestimmung im Dezember 2003 offenbart sich jedoch, dass sich die praktische Umsetzung des Gesetzesartikels mit den damaligen Vorstellungen des Gesetzgebers anlässlich der Erarbeitung dieses parlamentarischen Instrumentes nicht deckt. Der Gesetzgeber wies seiner¬zeit auf das für die Umsetzung bedeutende Vertrauensverhältnis zwischen Bundesrat und Parlament hin. Allerdings beeinflussen nun Spannungen und Konkurrenz zwischen der Exekutive und der Legislative die Umsetzung von Art. 152 ParlG. Die vorliegende Arbeit versucht, die geschichtlichen Hintergründe, die Entstehung, den Sinn und Zweck sowie die Praxis von Art. 152 ParlG vor dem Hintergrund des erwähnten Spannungsfelds und im Zusammenspiel mit den weiteren Mitwirkungsinstrumenten im Bereich der Aussenpolitik darzulegen. Comme le montre déjà l'historique des Commissions de politique extérieure (CPE), la participation du Parlement à la politique extérieure n'est pas dénuée d'obstacles. A l'heure actuelle, les CPE doivent notamment faire en sorte que le Parlement puisse faire valoir, en amont et avec efficacité, son droit de participation dans le domaine de la politique étrangère de la Suisse. Outre divers instruments figurant dans la Constitution et les lois, les CPE disposent d'un important moyen de participation: l'information et la consultation au sens de l'art. 152 de la loi sur le Parlement (LParl). Depuis l'entrée en vigueur de cette disposition en décembre 2003, il s'avère toutefois que l'application concrète de cet article de loi ne ré¬pond pas entièrement aux attentes du législateur lors de l'élaboration de cet instrument parlementaire. En effet, le législateur s'était alors basé sur la relation de confiance entre le Conseil fédéral et le Parlement, relation essentielle à la mise en oeuvre de cet article. La pratique montre cependant que la mise en oeuvre de l'art. 152 LParl est influencée par des tensions et par une relation de concurrence existant entre l'exécutif et le législatif. Le présent travail entend exposer le contexte historique de l'art. 152 LParl, son élaboration, son but et sa mise en oeuvre, tout en tenant compte des éléments de tension et des autres instruments permettant la participation en matière de politique extérieure.

Dramatic malignant progression of a pigmented villonodular synovitis of the knee after 27 years of multimodality treatment

Introduction: Pigmented villonodular synovitis (PVNS) is a rare benign tumour of the synovium, most commonly arising around the knee. Resection remains the treatment of choice. The diffuse variant of the disease is prone to local recurrence (30-50%). However distant dissemination is extremely rare. We report the case of a patient with massive loco-regional and late distant spread to the lungs of PVNS originating in the knee. Case report: A 69 yo women presented to our service 27 years ago with PVNS in her knee. Despite multible surgical resections, synoviorthesis and external beam radiotherapy, no local control was achieved. The disease spread in all thigh compartments. Due to the resistance to all convetional treatment modalities, isolated limb perfusion with TNFα and Melphalan was performed, without any effect on local control. After the disease was diagnosed in iliac lymph nodes, the patient was subjected to a systemic chemotherapy protocol with imitamib, which had to be abandoned, due to intolerance. Due to a giant lymphoedema of the entire limb, making up for a considerable part of the patient's body weight and in view of significant skin invasion, a hip disarticulation was performed. Finally, rapidly growing lung metastases appeared on CT scan, confirmed by core-needle biopsy. Palliative chemotherapy was initiated. Interestingly, histological analysis of the disease throughout the years remained consistent with classic benign PVNS. No sarcomatous dedifferentiation was observed, not even in the pulmonary lesions. Conclusion: PVNS is a benign tumour, with a high risk of local recurrence. Malignant behaviour, with loco-regional and distant metastases remains extremely rare. A histologically benign appearance does not exclude a clinically malignant behaviour with systemic spread.

Phylogeographic patterning of mtDNA in the widely distributed harvest mouse (Micromys minutus) suggests dramatic cycles of range contraction and expansion during the mid- to late Pleistocene

We examined sequence variation in the mitochondrial cytochrome b gene (1140 bp, n = 73) and control region (842-851 bp, n = 74) in the Eurasian harvest mouse (Micromys minutus (Pallas, 1771)), with samples drawn from across its range, from Western Europe to Japan. Phylogeographic analyses revealed region-specific haplotype groupings combined with overall low levels of inter-regional genetic divergence. Despite the enormous intervening distance, European and East Asian samples showed a net nucleotide divergence of only 0.36%. Based on an evolutionary rate for the cytochrome b gene of 2.4%(.)(site(.)lineage(.)million years)(-1), the initial divergence time of these populations is estimated at around 80 000 years before present. Our findings are consistent with available fossil evidence that has recorded repeated cycles of extinction and recolonization of Europe by M. minutus through the Quaternary. The molecular data further suggest that recolonization occurred from refugia in the Central to East Asian region. Japanese haplotypes of M. minutus, with the exception of those from Tsushima Is., show limited nucleotide diversity (0.15%) compared with those found on the adjacent Korean Peninsula. This finding suggests recent colonization of the Japanese Archipelago, probably around the last glacial period, followed by rapid population growth.

State-of-the-art of 3D cultures (organs-on-a-chip) in safety testing and pathophysiology.

Integrated approaches using different in vitro methods in combination with bioinformatics can (i) increase the success rate and speed of drug development; (ii) improve the accuracy of toxicological risk assessment; and (iii) increase our understanding of disease. Three-dimensional (3D) cell culture models are important building blocks of this strategy which has emerged during the last years. The majority of these models are organotypic, i.e., they aim to reproduce major functions of an organ or organ system. This implies in many cases that more than one cell type forms the 3D structure, and often matrix elements play an important role. This review summarizes the state of the art concerning commonalities of the different models. For instance, the theory of mass transport/metabolite exchange in 3D systems and the special analytical requirements for test endpoints in organotypic cultures are discussed in detail. In the next part, 3D model systems for selected organs--liver, lung, skin, brain--are presented and characterized in dedicated chapters. Also, 3D approaches to the modeling of tumors are presented and discussed. All chapters give a historical background, illustrate the large variety of approaches, and highlight up- and downsides as well as specific requirements. Moreover, they refer to the application in disease modeling, drug discovery and safety assessment. Finally, consensus recommendations indicate a roadmap for the successful implementation of 3D models in routine screening. It is expected that the use of such models will accelerate progress by reducing error rates and wrong predictions from compound testing.