bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of recurrent venous thromboembolism after a first oestrogen-associated episode
Authors: Gal Grégoire Le , Kovacs Michael , Carrier Marc , Do Kimberley , Kahn Susan , Wells Philip , Anderson David , Chagnon Isabelle , Solymoss Susan , Crowther Mark , Righini Marc , Lacut Karine , White Richard , Vickars Linda , Rodger Marc 
Published: June 2010

SummaryThe use of exogenous oestrogen in women with otherwise unprovoked venous thromboembolism (VTE) could be considered sufficient explanation to classify VTE as provoked if the risk of recurrent VTE after 3–6 months of anticoagulant treatment is similar to the risk of recurrent VTE observed after a surgery or prolonged immobilisation. Our objective was to assess the risk of recurrent VTE in women after a first unprovoked episode on oestrogen. The REVERSE study is a cohort study of patients with a first unprovoked VTE treated with anticoagulant treatment for 5–7 months. The risk of recurrent VTE during follow-up was compared between women users and non users of oestrogen at the time of index VTE. Among the 646 patients included, 314 were women, of them 67 were current users of oestrogen at the time of their VTE: 49 were on oral contraceptives and 18 on post-menopausal hormone replacement therapy (HRT). No significant association was found between oestrogen exposure, either oral contraceptives or HRT, and a lower risk of recurrent VTE after adjustment for age, or analysis restricted to women in the same age range as oestrogen contraceptives and HRT users, respectively. The risk of recurrent VTE is low in women after a first otherwise unprovoked oestrogen-associated VTE. However, this risk is not significantly lower than in women whose VTE was not related to oestrogen use.
Tissue factor and thrombosis: The clot starts here
Authors: Owens A. Phillip , Mackman Nigel 
Published: June 2010

SummaryThrombosis, or complications from thrombosis, currently occupies the top three positions in the cardiovascular causes of morbidity and mortality in the developed world. There are a limited number of safe and effective drugs to prevent and treat thrombosis. Animal models of thrombosis are necessary to better understand the complex components and interactions involved in the formation of a clot. Tissue factor (TF) is required for the initiation of blood coagulation and likely plays a key role in both arterial and venous thrombosis. Understanding the role of TF in thrombosis may permit the development of new antithrombotic drugs. This review will focus on the role of TF in in vivo models of thrombosis.
Regulation of von Willebrand factor-platelet interactions
Authors: Pegon Julie , Groot Evelyn , de Groot Philip , Lenting Peter 
Published: June 2010

SummaryThe formation of thrombi is a multistep process involving several components, including von Willebrand factor (VWF). VWF is an adhesive multimeric protein, which acts as a molecular bridge between the subendothelial matrix and the glycoprotein Ib/IX/V receptor complex. Furthermore, VWF promotes the expansion of the platelet plug by cross-linking platelets via binding to integrin αIIbβ3. In terms of thrombus formation, it is essential that VWF-platelet interactions occur timely, that is: it should happen not too early or too late. Given the co-existence of VWF and platelets in the circulation, this implies that there must be regulatory mechanisms that prevent premature formation of VWF-rich platelet aggregates that could occlude the vasculature. Indeed, several mechanisms have been identified at the level of VWF, which are dedicated to the prevention of excessive VWF-platelet interactions following endothelial release of VWF (which may include limited exposure to shear stress, the presence of Mg2+ ions, inhibition of VWF-platelet interactions by endothelial proteins, ADAMTS13-mediated proteolysis) and of circulating VWF-platelet aggregates during normal circulation (shielding of the platelet-binding A1 domain by other regions of the VWF molecule, inhibition of VWF-platelet interactions by β2-glycoprotein I). In the present review an overview of these mechanisms will be discussed.
FIX-Triple, a gain-of-function factor IX variant, improves haemostasis in mouse models without increased risk of thrombosis
Authors: Kao Chung-Yang , Lin Chia-Ni , Yu I-Shing , Tao Mi-Hua , Wu Hua-Lin , Shi Guey-Yueh , Yang Yung-Li , Kao Jau-Tsuen , Lin Shu-Wha 
Published: June 2010

SummaryEngineered recombinant factor IX (FIX) with augmented clotting activity may prove useful for replacement therapy, but it has not been studied for risk of thrombosis. We used three mouse models to evaluate thrombosis risk associated with the FIX variant FIX-Triple, which has a 13-fold higher specific activity than wild-type FIX (FIX-WT). Protein infusion of FIX-Triple into haemophilia B mice was not thrombogenic, even at a dose of 13-fold higher than FIX-WT. Gene knock-in to generate mice that constitutively produce FIX-WT or FIX-Triple protein revealed that all mice expressed equal antigen levels. FIX-Triple knock-in mice that exhibited 10-fold higher FIX clotting activity did not show hypercoagulation. Adeno-associated viral (AAV) delivery of the FIX gene into mice was used to mimic gene therapy. Haemophilia B and inbred C57Bl/6 mice injected with different doses of virus particles carrying FIX-WT or FIX-Triple and expressing up to a nearly 13-fold excess (1289% of normal) of FIX clotting activity did not show increased risk of thrombosis compared with untreated wild-type mice in a normal haemostatic state. When challenged with ferric chloride (FeCl3), the mesenteric venules of AAV-treated C57Bl/6 mice that gave a nearly five-fold excess (474%) of FIX clotting activity were not thrombotic; however, thrombosis became obvious in FeCl3-challenged mice expressing extremely high FIX clotting activities (976–1289%) achieved by AAV delivery of FIX-Triple. These studies suggest that FIX-Triple is not thrombogenic at therapeutic levels and is a potential therapeutic substitute for FIX-WT.
A combined immunostimulatory and immunoinhibitory short interference RNA reduces hypercoagulability in a rat model of acute promyelocytic leukaemia
Authors: Sørensen Dag Reidar , Sioud Mouldy , Iversen Per Ole 
Published: June 2010

SummaryAcute promyelocytic leukaemia (APL) confers an increased risk of thrombosis and bleeding. Current treatments are insufficient to inhibit these complications. We recently showed that a combined immunoinhibitory and immunostimulatory short interference (si) RNA effectively inhibited leukaemic growth and metastasis in rats with APL. We now asked if the reported anti-leukaemic effects of siRNA treatment could be explained by inhibition of hypercoagulability. We measured markers of coagulation and fibrinolysis in plasma collected from APL rats with overt leukaemia using conventional assays. Coagulopathy developed in untreated leukaemic rats evidenced by increase in several haemostatic markers. Treatment of leukaemic rats with the siRNA reduced (p < 0.05) the concentration of thrombin-anti-thrombin complex (a marker of coagulation) by 40% compared with rats treated with an inactive, control siRNA. Substantial reductions (p < 0.05) were also obtained for two markers of fibrinolysis: D-dimer (72%) and plasminogen activator inhibitor type 1 (51%). The activity of tissue factor, the main initiator of coagulation, was not increased (p > 0.05) in untreated leukaemic rats compared with healthy rats, and did not change (p > 0.05) upon treatment with the siRNA. The bifunctional siRNA reduces the hypercoagulable state in APL in addition to its direct anti-leukaemic properties, supporting testing of this small molecule in human APL.
Heme oxygenase-1 in neovascularisation: A diabetic perspective
Authors: Grochot-Przeczek Anna , Dulak Jozef , Jozkowicz Alicja 
Published: June 2010

SummaryNeovascularisation is crucial both for physiological processes, like development, wound healing, tissue regeneration, hair growth or menstrual cycle, and for pathological states, such as tumour progression, retinopathy and psoriasis. Blood vessel formation is orchestrated by numerous pro-angiogenic and anti-angiogenic factors, acting together to keep tight rein on this complicated, desirable but also dangerous process. One of the proteins important for neovascularisation is heme oxygenase-1 (HO-1), an enzyme degrading heme. This review focuses on the role of HO-1 in angiogenesis and vasculogenesis, having a closer look at the significance of this system in diabetes.
Phagocytosis of platelet microvesicles and β2– glycoprotein I
Authors: Le Anhquyen , Prakasam Anthony , Abdel-Monem Hanan , Dasgupta Swapan , Thiagarajan Perumal 
Published: June 2010

SummaryThe majority of the antiphospholipid antibodies, present in patients with antiphospholipid syndrome, are directed against conformational epitopes in β2-glycoprotein I. β2-glycoprotein I is an anionic phospholipid- binding 50-kDa plasma protein whose physiological role is not clear. Here we investigate the role of β2-glycoprotein I in the phagocytosis of phosphatidylserine-expressing platelet microvesicles and the effect of autoantibodies to β2-glycoprotein I on this process. We labelled the glycans of β2-glycoprotein I with BODIPY (4,4-difluoro- 4-bora-3a,4a-diaza-s-indacene)-hydrazide without affecting its phospholipid binding capacity. BODIPY-β2-glycoprotein I bound to platelet microvesicles in a concentration-dependent manner and promoted the phagocytosis of platelet microvesicles by THP-1 derived macrophages in vitro at physiological plasma concentrations with a half maximal effect at ∼10 μg/ml. β2-glycoprotein I-stimulated phagocytosis was inhibited by annexin A5 and the phosphatidylserine-binding C1C2 fragment of lactadherin. Furthermore, immunoaffinity purified β2-glycoprotein I-dependent antiphospholipid antibodies from five patients with antiphospholipid syndrome inhibited the phagocytosis in a concentration- dependent manner. These studies suggest that the binding of β2-glycoprotein I to phosphatidylserine-expressing procoagulant platelet microvesicles may promote their clearance by phagocytosis and autoantibodies to β2-glycoprotein I may inhibit this process to induce a procoagulant state.
Evaluation of a new automated panel of assays for the detection of anti-PF4/heparin antibodies in patients suspected of having heparin-induced thrombocytopenia
Authors: Cini Michela , Pili Caterina , Boggian Ottavio , Frascaro Mirella , Palareti Gualtiero , Legnani Cristina 
Published: June 2010

SummaryHeparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin treatment; the prognosis depends on early and accurate diagnosis, and prompt start of alternative anticoagulants. Because of high sensitivity, the commercially available immunologic assays are widely used, though not suited to be run on single samples and with a turnaround time of 2–3 hours. We evaluated two new, rapid, automated, semi-quantitative chemiluminescent immunoassays in HIT suspected patients: HemosIL® AcuStar HIT-IgG(PF4-H) (specific for IgG anti- PF4/heparin antibodies) and HemosIL® AcuStar HIT-Ab(PF4-H) (detecting IgG, IgM and IgA anti-PF4/heparin antibodies) (both from Instrumentation Laboratory). A total of 102 patients with suspected HIT were included; HIT was diagnosed in 17 (16.7%). No false negative cases were observed using either the HemosIL AcuStar HIT-IgG(PF4-H) or the HITAb(PF4-H) assay (sensitivity and negative predictive values = 100%; negative likelihood ratios <0.01). The specificity was higher for the He-mosIL AcuStar HIT-IgG(PF4-H) in comparison with that of the HemosIL AcuStar HIT-Ab(PF4-H) (96.5% vs. 81.2%). Higher values of the HemosIL AcuStar HIT-IgG(PF4-H) were associated with increased probability of HIT. Patients with confirmed HIT and thrombotic complications had significantly higher levels of HemosIL AcuStar HIT-IgG(PF4-H) than those without thrombotic complications. The HemosIL AcuStar HIT-IgG(PF4-H) and HIT-Ab(PF4-H) assays showed a very high sensitivity, and therefore they can reliably be used to rule out HIT in suspected patients. The diagnostic specificity was greatly increased by using the HemosIL AcuStar HITIgG(PF4-H). Both the assays are reproducible (CVs <6%), rapid (turnaround time 30 minutes), automated, and semi-quantitative, and they can be run for single sample testing.
The in vitro effects of niacin on platelet biomarkers in human volunteers
Authors: Malinin Alex , Aradi Daniel , Kuliczkowski Wiktor , Norgard Nicholas , Boden William , Serebruany Victor 
Published: June 2010

SummaryNiacin is a natural pyridine derivative, proven to favorably modulate the blood lipid profile by increasing levels of high-density lipoprotein (HDL) cholesterol, and by reducing total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and Lp (a) lipoprotein concentrations. Considering that platelet activity is important in predicting vascular outcomes, and that HDL heavily constitutes platelet cellular membranes, we sought to evaluate the effect of niacin on human platelet activity indices. The blood obtained from 30 aspirin-naïve volunteers was preincubated with escalating concentrations of niacin in vitro. Platelet tests included whole blood and plasma aggregometry, rapid cartridgebased analyser, expression of major surface receptors by flow cytometry, and plasma prostaglandins by ELISA. Preincubation of blood with niacin at 0.3, 1.0 and 3.0 mM resulted in significant inhibition of maximal adenosine diphosphate (ADP)- (p=0.03), and collagen-induced platelet aggregation (p=0.01), and reduced activity by VerifyNow™ (p=0.007) bedside analyser. Surface platelet PAR-1 (MoAb WEDE-15; p=0.04), and vitronectin (CD51/CD61; p=0.02) receptors were up-regulated. Niacin was associated with a two- to three-fold increase of thromboxane B2, prostaglandins D2, and E2. Formation of platelet-monocyte microparticles (CD14+CD151), and expression of PECAM-1 (CD31), thrombospondin (CD36), GP IIb/IIIa (CD41a) antigen, and activity with MoAb PAC-1, GPIb (CD42b), P-selectin (CD62p), LAMP-3 (CD63), LAMP-1 (CD107a), CD40-ligand (CD154), GP37 (CD165), were not affected by niacin, suggesting no effect on prostacyclin release. In conclusion, niacin in vitro affects platelet activity by mildly inhibiting aggregation, and stimulating significant prostaglandin release, with mostly intact major platelet receptor expression. The effect of niacin is unique, differs from other known antiplatelet agents, and suggests potential opportunities for therapeutic combination, particularly in patients with low levels of HDL-C. These preliminary data, while intriguing, require confirmation in subjects receiving orally dosed extended-release niacin in order to determine whether these findings are clinically relevant.
Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice
Authors: Zufferey Paul , Baylot Denis , Nguyen Philippe , Borg Jeanne-Yvonne , Fontenay Michaela , Deygas Beatrice , Mismetti Patrick , Laporte Silvy , Delavenne Xavier ,   for the GETHCAM study group and POP-A-RIX investigators
Published: June 2010

SummaryFondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.
Future perspective of induced pluripotent stem cells for diagnosis, drug screening and treatment of human diseases
Authors: Lian Qizhou , Chow Yenyen , Esteban Miguel , Pei Duanqing , Tse Hung-Fat 
Published: June 2010

SummaryRecent advances in stem cell biology have transformed the understanding of cell physiology and developmental biology such that it can now play a more prominent role in the clinical application of stem cell and regenerative medicine. Success in the generation of human induced pluripotent stem cells (iPS) as well as related emerging technology on the iPS platform provide great promise in the development of regenerative medicine. Human iPS cells show almost identical properties to human embryonic stem cells (ESC) in pluripotency, but avoid many of their limitations of use. In addition, investigations into reprogramming of somatic cells to pluripotent stem cells facilitate a deeper understanding of human stem cell biology. The iPS cell technology has offered a unique platform for studying the pathogenesis of human disease, pharmacological and toxicological testing, and cell-based therapy. Nevertheless, significant challenges remain to be overcome before the promise of human iPS cell technology can be realised.
An Experimental Study of Small-Scale Variability of Raindrop Size Distribution
Authors: Tokay Ali , Bashor Paul G. 
Published: June 2010

Abstract
An experimental study of small-scale variability of raindrop size distributions (DSDs) has been carried out at Wallops Island, Virginia. Three Joss–Waldvogel disdrometers were operated at a distance of 0.65, 1.05, and 1.70 km in a nearly straight line. The main purpose of the study was to examine the variability of DSDs and its integral parameters of liquid water content, rainfall, and reflectivity within a 2-km array: a typical size of Cartesian radar pixel. The composite DSD of rain events showed very good agreement among the disdrometers except where there were noticeable differences in midsize and large drops in a few events. For consideration of partial beam filling where the radar pixel was not completely covered by rain, a single disdrometer reported just over 10% more rainy minutes than the rainy minutes when all three disdrometers reported rainfall. Similarly two out of three disdrometers reported 5% more rainy minutes than when all three were reporting rainfall. These percentages were based on a 1-min average, and were less for longer averaging periods. Considering only the minutes when all three disdrometers were reporting rainfall, just over one quarter of the observations showed an increase in the difference in rainfall with distance. This finding was based on a 15-min average and was even less for shorter averaging periods. The probability and cumulative distributions of a gamma-fitted DSD and integral rain parameters between the three disdrometers had a very good agreement and no major variability. This was mainly due to the high percentage of light stratiform rain and to the number of storms that traveled along the track of the disdrometers. At a fixed time step, however, both DSDs and integral rain parameters showed substantial variability. The standard deviation (SD) of rain rate was near 3 mm h−1, while the SD of reflectivity exceeded 3 dBZ at the longest separation distance. These standard deviations were at 6-min average and were higher at shorter averaging periods. The correlations decreased with increasing separation distance. For rain rate, the correlations were higher than previous gauge-based studies. This was attributed to the differences in data processing and the difference in rainfall characteristics in different climate regions. It was also considered that the gauge sampling errors could be a factor. In this regard, gauge measurements were simulated employing existing disdrometer dataset. While a difference was noticed in cumulative distribution of rain occurrence between the simulated gauge and disdrometer observations, the correlations in simulated gauge measurements did not differ from the disdrometer measurements.
Effect of Aerosol on the Susceptibility and Efficiency of Precipitation in Warm Trade Cumulus Clouds
Authors: Jiang Hongli , Feingold Graham , Sorooshian Armin 
Published: June 2010

Abstract
Large-eddy simulations of warm, trade wind cumulus clouds are conducted for a range of aerosol conditions with a focus on precipitating clouds. Individual clouds are tracked over the course of their lifetimes. Precipitation rate decreases progressively as aerosol increases. For larger, precipitating clouds, the polluted clouds have longer lifetimes because of precipitation suppression. For clean aerosol conditions, there is good agreement between the average model precipitation rate and that calculated based on observed radar reflectivity Z and precipitation rate R relationships. Precipitation rate can be expressed as a power-law function of liquid water path (LWP) and Nd, to reasonable accuracy. The respective powers for LWP and Nd are of similar magnitude compared to those based on observational studies of stratocumulus clouds. The time-integrated precipitation rate represented by a power-law function of LWP, Nd, and cloud lifetime is much more reliably predicted than is R expressed in terms of LWP and Nd alone. The precipitation susceptibility (So = −dlnR/dlnNd) that quantifies the sensitivity of precipitation to changes in Nd depends strongly on LWP and exhibits nonmonotonic behavior with a maximum at intermediate LWP values. The relationship between So and precipitation efficiency is explored and the importance of including dependence on Nd in the latter is highlighted. The results provide trade cumulus cloud population statistics, as well as relationships between microphysical/macrophysical properties and precipitation, that are amenable for use in larger-scale models.
On the Potential Causes of the Nonstationary Correlations between West African Precipitation and Atlantic Hurricane Activity
Authors: Fink Andreas H. , Schrage Jon M. , Kotthaus Simone 
Published: June 2010

Abstract
For years, various indices of seasonal West African precipitation have served as useful predictors of the overall tropical cyclone activity in the Atlantic Ocean. Since the mid-1990s, the correlation unexpectedly deteriorated. In the present study, statistical techniques are developed to describe the nonstationary nature of the correlations between annual measures of Atlantic tropical cyclone activity and three selected West African precipitation indices (namely, western Sahelian precipitation in June–September, central Sahelian precipitation in June–September, and Guinean coastal precipitation in the preceding year’s August–November period). The correlations between these parameters are found to vary over the period from 1921 to 2007 on a range of time scales. Additionally, considerable year-to-year variability in the strength of these correlations is documented by selecting subsamples of years with respect to various meteorological factors. Broadly, in years when the environment in the main development region is generally favorable for enhanced tropical cyclogenesis (e.g., when sea surface temperatures are high, when there is relatively little wind shear through the depth of the troposphere, or when the relative vorticity in the midtroposphere is anomalously high), the correlations between indices of West African monsoon precipitation and Atlantic tropical cyclone activity are considerably weaker than in years when the overall conditions in the region are less conducive. Other more remote climate parameters, such as the phase of the Southern Oscillation, are less effective at modulating the nature of these interactions.