Plasminogen activator inhibitor-1 activity and 4G/5G polymorphism in hemodialysis

Introduction: Chronic insufficiency alters homeostasis, in part due to endothelial inflammation. Plasminogen activator inhibitor-1 (PAI-1) is increased in renal disease, contributing to vascular damage. We assessed PAI-1 activity and PAI-1 4G/5G polymorphism in hemodialysis (HD) subjects and any association between thrombotic vascular access (VA) events and PAI-1 polymorphism. Methods: Prospective, observational study in 36 HD patients: mean age: 66.6 +/- 12.5 yr, males n=26 (72%), time on HD: 28.71 +/- 22.45 months. Vascular accesses: 10 polytetrafluoroethylene grafts (PTFEG), 22 arteriovenous fistulae (AVF), four dual lumen catheters (CAT). Control group (CG): 40 subjects; mean age: 60.0 +/- 15 yrs, males n=30 (75%). Group A (GA): thrombotic events (n=12), and group B (GB): No events (n=24). Groups were no different according to age (69.2 +/- 9.12 vs. 65.3 +/- 14.5 yrs), gender (males: 7; 58.3% vs. 18; 81.8%), time on HD (26.1 +/- 14.7 vs. 30.1 +/- 38.7 months), causes of renal failure. Time to follow-up, for access thrombosis: 12 months. Results: PAI-1 levels in HD: 7.21 +/- 2.13 vs. CG: 0.42 +/- 0.27 U/ml (p < 0.000 1). PAI-1 4G/5G polymorphic variant distribution in HD: 5G/5G: 6 (17%),4G/5G: 23 (64%); 4G/4G: 7 (19%) and in CG: 5G/5G: 14 (35%); 4G/5G: 18 (45%); 4G/4G: 8 (20%). C-reactive protein (CRP) in HD: 24.5 +/- 15.2 mg/L vs. in CG 2.3 +/- 0.2 mg/L (p < 0.0001). PAI-1 4G/5G variants: GA: 5G/5G: 3; 4G/5G: 8; 4G/4G: 1; GB: 5G/5G: 3; 4G/5G: 15; 4G/4G: 6. Thrombosis occurred in 8/10 patients (80%) with PTFEG, 3/22 (9%) in AVF, and 1/4 (25%) in CAT. Among the eight PTFEG patients with thrombosis, seven were PAI 4G/5G. Conclusions: PAI-1 levels were elevated in HD patients, independent of their polymorphic variants, 4G/5G being the most prevalent variant. Our data suggest that in patients with PTFEG the 4G/5G variant might be associated with an increased thrombosis risk.

« Saturer les esprits » việt cộng par la propagande : l'incitation à la défection dans le programme chiêu hồi

Lancé en 1963 par le président Ngô Ðình Diệm, le programme chiêu hồi visait à susciter des défections dans les rangs Viêt cộng. Sa première phase, dite de persuasion, consistait en un intense effort de propagande réalisé par le largage de milliards de tracts, la diffusion de messages par haut-parleur aérien, l'affichage de banderoles ou de posters et plus généralement l'utilisation de tous les canaux de communication possibles. S'y ajoutait le déploiement d'unités de propagande armées, composées d'anciens Viêt cộng, chargées de plus particulièrement cibler les groupes prioritairement visés par les messages du programme. Le programme chiêu hồi fut la plus massive des opérations psychologiques conduites lors de la guerre du Vietnam et sans doute la plus importante des actions de guerre psychologique de l'histoire.

Dominant Role of CD80-CD86 Over CD40 and ICOSL in the Massive Polyclonal B Cell Activation Mediated by LAT(Y136F) CD4(+) T Cells.

Coordinated interactions between T and B cells are crucial for inducing physiological B cell responses. Mutant mice in which tyrosine 136 of linker for activation of T cell (LAT) is replaced by a phenylalanine (Lat(Y136F)) exhibit a strong CD4(+) T cell proliferation in the absence of intended immunization. The resulting effector T cells produce high amounts of T(H)2 cytokines and are extremely efficient at inducing polyclonal B cell activation. As a consequence, these Lat(Y136F) mutant mice showed massive germinal center formations and hypergammaglobulinemia. Here, we analyzed the involvement of different costimulators and their ligands in such T-B interactions both in vitro and in vivo, using blocking antibodies, knockout mice, and adoptive transfer experiments. Surprisingly, we showed in vitro that although B cell activation required contact with T cells, CD40, and inducible T cell costimulator molecule-ligand (ICOSL) signaling were not necessary for this process. These observations were further confirmed in vivo, where none of these molecules were required for the unfolding of the LAT CD4(+) T cell expansion and the subsequent polyclonal B cell activation, although, the absence of CD40 led to a reduction of the follicular B cell response. These results indicate that the crucial functions played by CD40 and ICOSL in germinal center formation and isotype switching in physiological humoral responses are partly overcome in Lat(Y136F) mice. By comparison, the absence of CD80-CD86 was found to almost completely block the in vitro B cell activation mediated by Lat(Y136F) CD4(+) T cells. The role of CD80-CD86 in T-B cooperation in vivo remained elusive due to the upstream implication of these costimulatory molecules in the expansion of Lat(Y136F) CD4(+) T cells. Together, our data suggest that CD80 and CD86 costimulators play a key role in the polyclonal B cell activation mediated by Lat(Y136F) CD4(+) T cells even though additional costimulatory molecules or cytokines are likely to be required in this process.

Climate and sea-level variations along the northwestern Tethyan margin during the Valanginian C-isotope excursion: Mineralogical evidence from the Vocontian Basin (SE France)

A high resolution mineralogical study (bulk-rock and clay-fraction) was carried out upon the hemipelagic strata of the Angles section (Vocontian Basin, SE France) in which the Valanginian positive C-isotope excursion occurs. To investigate sea-level fluctuations and climate change respectively, a Detrital Index (DI: (phyllosilicates and quartz)/calcite) and a Weathering Index (WI: kaolinite/(illite + chlorite)) were established and compared to second-order sea-level fluctuations. In addition, the mineralogical data were compared with the High Nutrient Index (HNI, based on calcareous nannofossil taxa) data obtained by Duchamp-Alphonse et al. (2007), in order to assess the link between the hydrolysis conditions recorded on the surrounding continents and the trophic conditions inferred for the Vocontian Basin. It appears that the mineralogical distribution along the northwestern Tethyan margin is mainly influenced by sea-level changes during the Early Valanginian (Pertransiens to Stephanophorus ammonite Zones) and by climate variations from the late Early Valanginian to the base of the Hauterivian (top of the Stephanophorus to the Radiatus ammonite Zones). The sea-level fall observed in the Pertransiens ammonite Zone (Early Valanginian) is well expressed by an increase in detrital inputs (an increase in the DI) associated with a more proximal source and a shallower marine environment, whereas the sea-level rise recorded in the Stephanophorus ammonite Zone corresponds to a decrease in detrital influx (a decrease in the DI) as the source becomes more distal and the environment deeper. Interpretation of both DI and WI, indicates that the positive C-isotope excursion (top of the Stephanophorus to the Verrucosum ammonite Zones) is associated with an increase of detrital inputs under a stable, warm and humid climate, probably related to greenhouse conditions, the strongest hydrolysis conditions being reached at the maximum of the positive C-isotope excursion. From the Verrucosum ammonite Zone to the base of the Hauterivian (Radiatus ammonite Zone) climatic conditions evolved from weak hydrolysis conditions and, most likely, a cooler climate (resulting in a decrease in detrital inputs) to a seasonal climate in which more humid seasons alternated with more arid ones. The comparison of the WI to the HNI shows that the nutrification recorded al: the Angles section from the top of the Stephanophorus to the Radiatus ammonite Zones (including the positive C-isotope shift), is associated with climatic changes in the source areas. At that time, increased nutrient inputs were generally triggered by increased weathering processes in the source areas due to acceleration in the hydrological cycle under greenhouse conditions This scenario accords with the widely questioned palaeoenvironmental model proposed by Lini et al., (1992) and suggests that increasing greenhouse conditions are the main factor that drove the palaeoenvironmental changes observed in the hemipelagic realm of the Vocontian Basin, during the Valanginian positive C-isotope shift. This high-resolution mineralogical study highlights short-term climatic changes during the Valanginian, probably associated to rapid changes in the C-cycle. Coeval Massive Parana-Etendeka flood basalt eruptions may explain such rapid perturbations. (C) 2011 Elsevier B.V. All rights reserved.