Atherogenic Lipid Stress Induces Platelet Hyperactivity Through CD36-Mediated Hyposensitivity To Prostacyclin-; The Role Of Phosphodiesterase 3A

Prostacyclin (PGI2) controls platelet activation and thrombosis through a cyclic adenosine monophosphate (cAMP) signalling cascade. However, in patients with cardiovascular diseases this protective mechanism fails for reasons that are unclear. Using both pharmacological and genetic approaches we describe a mechanism by which oxidised low density lipoproteins (oxLDL) associated with dyslipidaemia promote platelet activation through impaired PGI2 sensitivity and diminished cAMP signalling. In functional assays using human platelets, oxLDL modulated the inhibitory effects of PGI2, but not a PDE-insensitive cAMP analogue, on platelet aggregation, granule secretion and in vitro thrombosis. Examination of the mechanism revealed that oxLDL promoted the hydrolysis of cAMP through the phosphorylation and activation of phosphodiesterase 3A (PDE3A), leading to diminished cAMP signalling. PDE3A activation by oxLDL required Src family kinases, Syk and protein kinase C. The effects of oxLDL on platelet function and cAMP signalling were blocked by pharmacological inhibition of CD36, mimicked by CD36-specific oxidised phospholipids and ablated in CD36-/- murine platelets. The injection of oxLDL into wild type mice strongly promoted FeCl3 induced carotid thrombosis in vivo, which was prevented by pharmacological inhibition of PDE3A. Furthermore, blood from dyslipidaemic mice was associated with increased oxidative lipid stress, reduced platelet sensitivity to PGI2 ex vivo and diminished PKA signalling. In contrast, platelet sensitivity to a PDE-resistant cAMP analogue remained normal. Genetic deletion of CD36, protected dyslipidaemic animals from PGI2 hyposensitivity and restored PKA signalling. These data suggest that CD36 can translate atherogenic lipid stress into platelet hyperactivity through modulation of inhibitory cAMP signalling.  

The mixed problem for the Laplacian in Lipschitz domains

We consider the mixed boundary value problem or Zaremba's problem for the Laplacian in a bounded Lipschitz domain in R^n. We specify Dirichlet data on part of the boundary and Neumann data on the remainder of the boundary. We assume that the boundary between the sets where we specify Dirichlet and Neumann data is a Lipschitz surface. We require that the Neumann data is in L^p and the Dirichlet data is in the Sobolev space of functions having one derivative in L^p for some p near 1. Under these conditions, there is a unique solution to the mixed problem with the non-tangential maximal function of the gradient of the solution in L^p of the boundary. We also obtain results with data from Hardy spaces when p=1.Comment: Version 5 includes a correction to one step of the main proof. Since the paper appeared long ago, this submission includes the complete paper, followed by a short section that gives the correction to one step in the proo

Optimal Design of a Trickle Bed Reactor for Light Fuel Oxidative Desulfurization based on Experiments and Modelling

YesIn this work, the performance of oxidative desulfurization (ODS) of dibenzothiophene (DBT) in light gas oil (LGO) is evaluated with a homemade manganese oxide (MnO2/γ-Al2O3) catalyst. The catalyst is prepared by Incipient Wetness Impregnation (IWI) method with air under moderate operating conditions. The effect of different reaction parameters such as reaction temperature, liquid hour space velocity and initial concentration of DBT are also investigated experimentally. Developing a detailed and a validated trickle bed reactor (TBR) process model that can be employed for design and optimization of the ODS process, it is important to develop kinetic models for the relevant reactions with high accuracy. Best kinetic model for the ODS process taking into account hydrodynamic factors (mainly, catalyst effectiveness factor, catalyst wetting efficiency and internal diffusion) and the physical properties affecting the oxidation process is developed utilizing data from pilot plant experiments. An optimization technique based upon the minimization of the sum of the squared error between the experimental and predicted composition of oxidation process is used to determine the best parameters of the kinetic models. The predicted product conversion showed very good agreement with the experimental data for a wide range of the operating condition with absolute average errors less than 5%

Metal-Poor Stars and the Chemical Enrichment of the Universe

Metal-poor stars hold the key to our understanding of the origin of the elements and the chemical evolution of the Universe. This chapter describes the process of discovery of these rare stars, the manner in which their surface abundances (produced in supernovae and other evolved stars) are determined from the analysis of their spectra, and the interpretation of their abundance patterns to elucidate questions of origin and evolution. More generally, studies of these stars contribute to other fundamental areas that include nuclear astrophysics, conditions at the earliest times, the nature of the first stars, and the formation and evolution of galaxies -- including our own Milky Way. We illustrate this with results from studies of lithium formed during the Big Bang; of stars dated to within ~1 Gyr of that event; of the most metal-poor stars, with abundance signatures very different from all other stars; and of the build-up of the elements over the first several Gyr. The combination of abundance and kinematic signatures constrains how the Milky Way formed, while recent discoveries of extremely metal-poor stars in the Milky Way's dwarf galaxy satellites constrain the hierarchical build-up of its stellar halo from small dark-matter dominated systems. [abridged]Comment: Book chapter, emulated version, 34 pages; number of references are limited by publisher; to appear in Vol. 5 of textbook "Planets, Stars and Stellar Systems", by Springer, in 201

Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

Background. During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary. The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients

Characterization of transport properties variations with magnetic field and temperature of ITER-candidate NbTi strands

While the International Thermonuclear Experimental Reactor (ITER) conceptual design retained the Nb3Sn for toroidal field (TF) and central solenoid (CS) coils, the low working field (around 6 T) promoted the choice of NbTi for the poloidal field (PF) coils. EU has carried out the experimental study of industrial NbTi strands and cables with different internal structures in order to choose the one which generate the lowest losses when used in the PF operating conditions (i.e. pulsed field). CEA has contributed to this project through the experimental study of the transport properties variations with respect to magnetic field and temperature of two candidate strands. One of them contains an internal CuNi barrier and the other is Ni-plated. A homemade cryostat is used to control the temperature of the sample which is wound on a VAMAS-like mandrel. J(c) measurements are presented here and subsequently the parameters deduced from scaling laws and their variation with temperature between 4.2 and 7 K and with field up to I 1 T. A comparison between the two strands characteristics and ITER PF coils criteria is also discussed. The results are in good agreement with literature and lie inside an acceptable range in spite of some discrepancy with the ITER PF criteria: a recent thermo-hydraulic simulation confirmed it. In the future, this study, completed by AC losses measurements on cabled strands, should help to optimise the strands performances below the ITER PF security margins. (C) 2002 Published by Elsevier Science B.V

Contribution to the study of superconducting magnetic systems in the frame of fusion projects

This report is a presentation of all the 55 publications made by the Magnet Group of the "Department de Recherches sur la Fusion Contolee" during the 94-99 period. These publications have been made mainly in the frame of EURATOM contracts and tasks for ITER