Factor V Leiden and thrombosis in patients with systemic lupus erythematosus: a meta-analysis.

The aim of this study was to perform a meta-analysis of the association between the factor V Leiden polymorphism (FVL) and thrombosis among patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibody (aPL) positivity. Included studies recruited patients based on SLE or aPL-positive status, confirmed subjects' SLE diagnosis as defined by the American College of Rheumatology, and documented thrombotic events. Excluded studies were non-English or considered only arterial thrombosis. Individual patient data, available from 5 studies, together with unpublished data from 1210 European-American SLE patients from the UCSF Lupus Genetics Collection genotyped for FVL, were further analyzed. Seventeen studies (n=2090 subjects) were included in the initial meta-analysis. Unadjusted odds ratios (OR) were calculated to assess association of FVL with thrombosis. The OR for association of thrombosis with FVL was 2.88 (95% confidence interval (CI) 1.98-4.20). In the secondary analysis with our individual patient dataset (n=1447 European-derived individuals), SLE subjects with the FVL polymorphism still had more than two times the odds of thrombosis compared to subjects without this polymorphism, even when adjusting for covariates such as gender, age and aPL status. SLE and/or aPL-positive patients with the FVL variant have more than two times the odds of thrombosis compared to those without this polymorphism

A Novel Small Molecule Inhibitor of Hepatitis C Virus Entry

Small molecule inhibitors of hepatitis C virus (HCV) are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp) incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc), blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development

The Very Energetic Radiation Imaging Telescope Array System (VERITAS)

We give an overview of the current status and scientific goals of VERITAS, a proposed hexagonal array of seven 10 m aperture imaging Cherenkov telescopes. The selected site is Montosa Canyon (1390 m a.s.l.) at the Whipple Observatory, Arizona. Each telescope, of 12 m focal length, will initially be equipped with a 499 element photomultiplier camera covering a 3.5 degree field of view. A central station will initiate the readout of 500 MHz FADCs upon receipt of multiple telescope triggers. The minimum detectable flux sensitivity will be 0.5% of the Crab Nebula flux at 200 GeV. Detailed simulations of the array's performance are presented elsewhere at this meeting. VERITAS will operate primarily as a gamma-ray observatory in the 50 GeV to 50 TeV range for the study of active galaxies, supernova remnants, pulsars and gamma-ray bursts

Construction and characterization of a 10-fold genome equivalent rat P1-derived artificial chromosome library.

A rat PAC library was constructed in the vector pPAC4 from genomic DNA isolated from female Brown Norway rats. This library consists of 215,409 clones arrayed in 614,384-well microtiter plates. An average insert size of 143 kb was estimated from 217 randomly isolated clones, thus representing approximately 10-fold genome coverage. This coverage provides a very high probability that the library contains a unique sequence in genome screening. Tests on randomly selected clones demonstrated that they are very stable, with only 4 of 130 clones showing restriction digest fragment alterations after 80 generations of serial growth. FISH analysis using 70 randomly chosen PACs revealed no significant chimeric clones. About 7% of the clones analyzed contained repetitive sequences related to centromeric regions that hybridized to some but not all centromeres. DNA plate pools and superpools were made, and high-density filters each containing an array of 8 plates in duplicate were prepared. Library screening on these superpools and appropriate filters with 10 single-locus rat markers revealed an average of 8 positive clones, in agreement with the estimated high genomic coverage of this library and representation of the rat genome. This library provides a new resource for rat genome analysis, in particular the identification of genes involved in models of multifactorial disease. The library and high-density filters are currently available to the scientific community

Elastin and collagen enhances electrospun aligned polyurethane as scaffolds for vascular graft

Mismatch in mechanical properties between synthetic vascular graft and arteries contribute to graft failure. The viscoelastic properties of arteries are conferred by elastin and collagen. In this study, the mechanical properties and cellular interactions of aligned nanofibrous polyurethane (PU) scaffolds blended with elastin, collagen or a mixture of both proteins were examined. Elastin softened PU to a peak stress and strain of 7.86&nbsp;MPa and 112.28&nbsp;% respectively, which are similar to those observed in blood vessels. Collagen-blended PU increased in peak stress to 28.14&nbsp;MPa. The growth of smooth muscle cells (SMCs) on both collagen-blended and elastin/collagen-blended scaffold increased by 283 and 224&nbsp;% respectively when compared to PU. Smooth muscle myosin staining indicated that the cells are contractile SMCs which are favored in vascular tissue engineering. Elastin and collagen are beneficial for creating compliant synthetic vascular grafts as elastin provided the necessary viscoelastic properties while collagen enhanced the cellular interactions. <br /