bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombogenesis with continuous blood flow in the inferior vena cava
Authors: Hawley Angela , Alvarado Christine , Berguer Alexandra , Baker Nichole , Wrobleski Shirley , Wakefield Thomas , Lucchesi Benedict , Myers Daniel , Diaz José 
Published: June 2010

SummarySeveral rodent models have been used to study deep venous thrombosis (DVT). However, a model that generates consistent venous thrombi in the presence of continuous blood flow, to evaluate therapeutic agents for DVT, is not available. Mice used in the present study were wild-type C57BL/6 (WT), plasminogen activator inhibitor-1 (PAI-1) knock out (KO) and Delta Cytoplasmic Tail (ΔCT). An electrolytic inferior vena cava (IVC) model (EIM) was used. A 25G stainless-steel needle, attached to a silver coated copper wire electrode (anode), was inserted into the exposed caudal IVC. Another electrode (cathode) was placed subcutaneously. A current of 250 μAmps over 15 minutes was applied. Ultrasound imaging was used to demonstrate the presence of IVC blood flow. Analyses included measurement of plasma soluble P-selectin (sP-Sel), thrombus weight (TW), vein wall morphometrics, P-selectin and Von Willebrand factor (vWF) staining, transmission electron microscopy (TEM), scanning electron microscopy (SEM); and the effect of enoxaparin on TW was evaluated. A current of 250 μAmps over 15 minutes consistently promoted thrombus formation in the IVC. Plasma sPSel was decreased in PAI-1 KO and increased in ΔCT vs. WT (WT/PAI-1: p=0.003, WT/ΔCT: p=0.0002). Endothelial activation was demonstrated by SEM, TEM, P-selectin and vWF immunohistochemistry and confirmed by inflammatory cell counts. Ultrasound imaging demonstrated thrombus formation in the presence of blood flow. Enoxaparin significantly reduced the thrombus size by 61% in this model. This EIM closely mimics clinical venous disease and can be used to study endothelial cell activation, leukocyte migration, thrombogenesis and therapeutic applications in the presence of blood flow.
Integrins on neutrophils are dispensable for migration into three-dimensional fibrin gels
Authors: Koenderman Leo , van der Linden Jan , Honing Henk , Ulfman Laurien 
Published: June 2010

SummaryThe innate immune system and the blood haemostasis system function cooperatively in many pathological conditions such as acute respiratory distress syndrome, deep venous thrombosis, ischaemia/reperfusion injury and cardiovascular disease. Infiltration of neutrophils into thrombotic substrates such as fibrin clots supports fibrinolysis, tissue damage and inflammation. Despite the importance of integrins in neutrophil attachment to fibrin-coated surfaces under flow conditions, little is known about their role in migration processes in shear free two-dimensional (2D) and three-dimensional (3D) fibrin(ogen) environments. Therefore, the present study was designed to study the role of functional integrins in mediating neutrophil migration on and in fibrin matrices. Time lapse video sequences of neutrophil chemokinesis and chemotaxis were made under conditions of active- or non-active integrins. Interestingly, migration of neutrophils on 2D fibrinogen coated surfaces and 3D fibrin matrices is independent of integrins as the response is not sensitive to αM-(CD11b) and β2-(CD18) blocking antibodies and/or chelation of Ca2+ and Mg2+ by EDTA in bivalent ion-free buffers. The blocking integrin antibodies were shown to be functionally active in regular adhesion assays. Our study shows that integrins are dispensable for migration on 2D and in 3D fibrin matrices, both when neutrophils enter into the fibrin matrix and when captured in the matrix.
BMS-593214, an active site-directed factor VIIa inhibitor: Enzyme kinetics, antithrombotic and antihaemostatic studies
Authors: Luettgen Joseph , Rendina Alan , Kettner Charles , Xin Baomin , Knabb Robert , Wexler Ruth , Priestley E. Scott , Wong Pancras 
Published: June 2010

SummaryFactor (F) VIIa in association with tissue factor (TF) is the primary in vivo initiator of blood coagulation and activates FX and FIX to generate thrombin, which plays a key role in the pathogenesis of thrombosis. We evaluated the enzyme kinetics, antithrombotic and antihaemostatic properties of BMS-593214, an active-site, direct FVIIa inhibitor. Studies were conducted in enzymatic assays, and in anesthetised rabbit models of electrically-induced carotid arterial thrombosis (AT), thread-induced vena cava venous thrombosis (VT) and cuticle bleeding time (BT). Antithrombotic efficacy of BMS-593214 given intravenously was evaluated for both the prevention and treatment of AT and VT. BMS-593214 displayed direct, competitive inhibition of human FVIIa in the hydrolysis of a tripeptide substrate with Ki of 5 nM. However, it acted as a noncompetitive inhibitor of the activation of the physiological substrate FX by TF/VIIa with Ki of 9.3 nM. BMS-593214 showed selectivity for FVIIa and exhibited species differences in TF-FVIIa-dependent anticoagulation with similar potency in human and rabbit plasma. BMS-593214 was efficacious in the prevention and treatment models of AT and VT with ED50 values of 1.1 to 3.1 mg/kg. Furthermore, BMS-593214 exhibited a wide therapeutic window with respect to BT. These results suggest that inhibition of FVIIa with small-molecule active-site inhibitors represents a promising antithrombotic approach for the development of new therapies for the prevention and treatment of AT and VT.
A randomised pilot trial of the anti-von Willebrand factor aptamer ARC1779 in patients with type 2b von Willebrand disease
Authors: Paulinska Petra , Jilma-Stohlawetz Petra , Gilbert James , Hutabarat Renta , Knöbl Paul , Jilma Bernd 
Published: June 2010

SummaryDesmopressin aggravates thrombocytopenia in type 2B von Willebrand disease (VWF type 2B) by release of large and hyper-adhesive von Wille-brand Factor (VWF) multimers. This pilot study investigated whether the anti-VWF aptamer ARC1779 can prevent desmopressin-induced thrombocytopenia and interferes with the excessive VWF turnover in patients with VWF type 2B. Concentration effect curves of ARC1779 were established for five patients in vitro and two patients with VWF type 2B were treated by infusion of ARC1779, desmopressin, or their combination in a randomised, controlled, double-blind design. ARC1779 concentrations in the range of 1–3 μg/ml blocked free A1 domain binding sites by 90% in vitro. In vivo, desmopressin alone induced a profound (-90%) drop in platelet counts in one of the patients. ARC1779 (4–5 μg/ml) completely inhibited VWF A1 domains and prevented this desmopress-in-induced platelet drop. Desmopressin alone increased VWF antigen two- to three-fold, accompanied by concordant changes in VWF Ristocetin cofactor activity (RCo) and coagulation factor VIII activity. ARC1779 substantially enhanced the desmopressin-induced maximal increase in these parameters, and improved multimer patterns. No treatment related adverse events were observed and no bleeding occurred despite marked thrombocytopenia. These data provide first proof of concept in humans and evidence that ARC1779 is a potent inhibitor of VWF. ARC1779 prevented the rapid consumption of VWF multimers together with agglutinated platelets that occurred in response to desmopressin challenge in patients with VWD type 2B.Clinical Trial registration number: NCT00632242.
Reconstruction of Global Monthly Upper-Level Temperature and Geopotential Height Fields Back to 1880
Authors: Griesser Thomas , Brönnimann Stefan , Grant Andrea , Ewen Tracy , Stickler Alexander , Comeaux Joey 
Published: June 2010

Abstract
This work presents statistically reconstructed global monthly mean fields of temperature and geopotential height (GPH) up to 100 hPa for the period 1880–1957. For the statistical model several thousand predictors were used, comprising a large amount of historical upper-air data as well as data from the earth’s surface. In the calibration period (1958–2001), the statistical models were fit using the 40-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-40) as the predictand. After the weighting of the predictors, principal component (PC) analyses were performed on both the predictand and predictor dataset. Multiple linear regression models relate each principal component time series from the predictand with an optimal subset of principal component time series from the predictor. To assess the quality of the reconstructions, statistical split-sample validation (SSV) experiments were performed within the calibration period. Furthermore, the reconstructions were compared with independent historical upper-air and total ozone data. Based on the SSV experiment, this study obtained good reconstructions for temperature and GPH in the Northern Hemisphere; however, the skill in the tropics and the Southern Hemisphere was much lower. The reconstruction skill shows a clear annual cycle with the highest values in January. The lower levels were better reconstructed except in the tropics where the highest levels showed the best skill. With the inclusion of a considerable amount of upper-air data after 1939 the skill increased substantially. The fields were analyzed for selected months in the 1920s and 1930s to demonstrate the usefulness of the reconstructions. It is shown that the reconstructions are able to capture regional-to-global dynamical features.
Regional Climate Model Projections and Uncertainties of U.S. Summer Heat Waves
Authors: Kunkel Kenneth E. , Liang Xin-Zhong , Zhu Jinhong 
Published: June 2010

Abstract
Regional climate model (RCM) simulations, driven by low and high climate-sensitivity coupled general circulation models (CGCMs) under various future emissions scenarios, were compared to projected changes in heat wave characteristics. The RCM downscaling reduces the CGCM biases in heat wave threshold temperature by a factor of 2, suggesting a higher credibility in the future projections. All of the RCM simulations suggest that there is a high probability of heat waves of unprecedented severity by the end of the twenty-first century if a high emissions path is followed. In particular, the annual 3-day heat wave temperature increases generally by 3°–8°C; the number of heat wave days increases by 30–60 day yr−1 over much of the western and southern United States with slightly smaller increases elsewhere; the variance spectra for intermediate, 3–7 days (prolonged, 7–14 days), temperature extremes increase (decrease) in the central (western) United States. If a lower emissions path is followed, then the outcomes range from quite small changes to substantial increases. In all cases, the mean temperature climatological shift is the dominant change in heat wave characteristics, suggesting that adaptation and acclimatization could reduce effects.
A Dynamical Index for the East Asian Winter Monsoon
Authors: Li Yueqing , Yang Song 
Published: June 2010

Abstract
A new index measuring the East Asian winter monsoon is defined using the mean wind shears of upper-tropospheric zonal wind based on the belief that the physical processes of both higher and lower latitudes, and at both lower and upper troposphere, should be considered to depict the variability of monsoon. When the index is high (low), the westerly jet is strong (weak), the East Asian trough is deep (shallow), the Siberian high is strong (weak), and anomalous low-level northerlies (southerlies) prevail over East Asia. As a result, the surface and lower-tropospheric temperature over East Asia decreases (increases) and the cold surges over Southeast Asia and tropical western Pacific are more (less) active. The index, which exhibits distinct interannual variations, is also strongly correlated with the Arctic Oscillation and Niño-3.4 sea surface temperature (SST) index. Compared to previous indexes, this index takes into account more influencing factors and better elucidates the physical processes associated with monsoon, enhancing interpretations of the variability of monsoon and its effects on regional weather and climate. Furthermore, the monsoon index is significantly linked to antecedent tropical Pacific SST and is highly predictable in the NCEP Climate Forecast System, indicating the advantage of the index for operational predictions of monsoon.
Annual Volume and Area Variations in Tropical Cyclone Rainfall over the Eastern United States
Authors: Nogueira Ricardo C. , Keim Barry D. 
Published: June 2010

Abstract
This paper examines tropical cyclone (TC) rainfall in the eastern United States from the perspective of documenting accumulated annual water volumes and areas of the precipitation. Volume is a value that merges both rainfall depth and rainfall area into a single metric for each year that can be directly compared between individual years. Area represents the total land area affected by tropical rains. These TC rainfall metrics were then compared to the ENSO and the Atlantic multidecadal oscillation (AMO). Time series of annual TC water volumes show an annual average of 107 km3. The maximum volume was produced in 1985 with 405.8 km3, driven by Hurricanes Bob, Claudette, Danny, Elena, Gloria, Henri, Juan, and Kate as well as by Tropical Storms Henri and Isabel. The lowest TC volume occurred in 1978 with 8.9 km3. ENSO phases did not show any statistical correlation with TC frequency in the eastern United States. However, AMO showed a significant correlation with volume and the number of storms affecting the region. TC rainfall volume and area in the eastern United States showed a strong correlation. However, there are exceptions, whereby 1985 stands out as an exceptional volume year though the area affected is not as impressive. In contrast, 1979 is an example when TCs covered a large area with a corresponding small rainfall volume, in part because of the rapid forward movement of the storms, for example, Hurricanes David and Frederic. Since 1995, TCs have become more numerous, producing larger volumes and affecting larger areas.
Surface Layer Heat Balance in the Eastern Equatorial Pacific Ocean on Interannual Time Scales: Influence of Local versus Remote Wind Forcing*
Authors: Zhang Xuebin , McPhaden Michael J. 
Published: June 2010

Abstract
The authors use a new and novel heat balance formalism for the upper 50 m of the Niño-3 region (5°N–5°S, 90°–150°W) to investigate the oceanographic processes underlying interannual sea surface temperature (SST) variations in the eastern equatorial Pacific. The focus is on a better understanding of the relationship between local and remote atmospheric forcing in generating SST anomalies associated with El Niño–Southern Oscillation (ENSO) events. The heat balance analysis indicates that heat advection across 50-m depth and across 150°W are the important oceanic mechanisms responsible for temperature variations with the former being dominant. On the other hand, net surface heat flux adjusted for penetrative radiation damps SST. Jointly, these processes can explain most of interannual variations in temperature tendency averaged over the Niño-3 region. Decomposition of vertical advection across the bottom indicates that the mean seasonal advection of anomalous temperature (the so-called thermocline feedback) dominates and is highly correlated with 20°C isotherm depth variations, which are mainly forced by remote winds in the western and central equatorial Pacific. Temperature advection by anomalous vertical velocity (the “Ekman feedback”), which is highly correlated with local zonal wind stress variations, is smaller with an amplitude of about 40% on average of remotely forced vertical heat advection. These results support those of recent empirical and modeling studies in which local atmospheric forcing, while not dominant, significantly affects ENSO SST variations in the eastern equatorial Pacific.
Observational Evaluation of a Convective Quasi-Equilibrium View of Monsoons
Authors: Nie Ji , Boos William R. , Kuang Zhiming 
Published: June 2010

AbstractIdealized dynamical theories that employ a convective quasi-equilibrium (QE) treatment for the diabatic effects of moist convection have been used to explain the location, intensity, and intraseasonal evolution of monsoons. This paper examines whether observations of the earth’s regional monsoons are consistent with the assumption of QE. It is shown here that in local summer climatologies based on reanalysis data, maxima of free-tropospheric temperature are, indeed, nearly collocated with maxima of subcloud equivalent potential temperature, θeb, in all monsoon regions except the North and South American monsoons. Free-tropospheric temperatures over North Africa also exhibit a strong remote influence from the South Asian monsoon. Consistent with idealized dynamical theories, peak precipitation falls slightly equatorward of the maxima in θeb and free-tropospheric temperature in regions where QE seems to hold.Vertical structures of temperature and wind reveal two types of monsoon circulations. One is the deep, moist baroclinic circulation clearly seen in the South Asian monsoon. The other is of mixed type, with the deep moist circulation superimposed on a shallow dry circulation closely associated with boundary layer temperature gradients. While the existence of a shallow dry circulation has been documented extensively in the North African monsoon, here it is shown to also exist in Australia and southern Africa during the local summer. Analogous to moist QE theories for the deep circulation, the shallow circulation can be viewed in a dry QE framework in which shallow ascent occurs just equatorward of the peak boundary layer potential temperature, θb, providing a unified system where the poleward extents of deep and shallow circulations are bounded by maxima in θeb and θb, respectively.
Variations in the Flow of the Global Atmosphere Associated with a Composite Convectively Coupled Oceanic Kelvin Wave
Authors: Roundy Paul E. , Gribble-Verhagen Lynn M. 
Published: June 2010

Abstract
Kelvin waves in the Pacific Ocean occasionally develop and propagate eastward together with anomalies of deep convection and low-level westerly wind. This pattern suggests coupling between the oceanic waves and atmospheric convection. A simple composite analysis based on observed coupled events from October through April demonstrates that this apparent coupled mode is associated with significant large anomalies in the global flow that extend to high latitudes. These high-latitude anomalies are significantly larger than those that are linearly associated with the El Niño–Southern Oscillation (ENSO), and they evolve on time scales between those of the Madden–Julian oscillation and ENSO, potentially providing an opportunity for enhanced subseasonal predictability in the flow of the global atmosphere.
An in vivo model of double-unit cord blood transplantation that correlates with clinical engraftment
Authors: Eldjerou Lamis K. , Chaudhury Sonali , Baisre-de Leon Ada , He Mai , Arcila Maria E. , Heller Glenn , O'Reilly Richard J. , Barker Juliet N. , Moore Malcolm A. 
Published: June 2010

Abstract
Double-unit cord blood transplantation (DCBT) appears to enhance engraftment despite sustained hematopoiesis usually being derived from a single unit. To investigate DCBT biology, in vitro and murine models were established using cells from 39 patient grafts. Mononuclear cells (MNCs) and CD34+ cells from each unit alone and in DCB combination were assessed for colony-forming cell and cobblestone area-forming cell potential, and multilineage engraftment in NOD/SCID/IL2R-γnull mice. In DCB assays, the contribution of each unit was measured by quantitative short tandem repeat region analysis. There was no correlation between colony-forming cell (n = 10) or cobblestone area-forming cell (n = 9) numbers and clinical engraftment, and both units contributed to DCB cocultures. In MNC transplantations in NOD/SCID/IL2R-γnull mice, each unit engrafted alone, but MNC DCBT demonstrated single-unit dominance that correlated with clinical engraftment in 18 of 21 cases (86%, P < .001). In contrast, unit dominance and clinical correlation were lost with CD34+ DCBT (n = 11). However, add-back of CD34− to CD34+ cells (n = 20) restored single-unit dominance with the dominant unit correlating not with clinical engraftment but also with the origin of the CD34− cells in all experiments. Thus, unit dominance is an in vivo phenomenon probably associated with a graft-versus-graft immune interaction mediated by CD34− cells.
Impact of in vivo alemtuzumab dose before reduced intensity conditioning and HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune reconstitution
Authors: Chakraverty Ronjon , Orti Guillermo , Roughton Michael , Shen Jun , Fielding Adele , Kottaridis Panagiotis , Milligan Donald , Collin Matthew , Crawley Charles , Johnson Peter , Clark Andrew , Parker Anne , Bloor Adrian , Pettengell Ruth , Snowden John , Pettitt Andrew , Clark Richard , Hale Geoff , Peggs Karl , Thomson Kirsty , Morris Emma , Mackinnon Stephen 
Published: June 2010

AbstractIn vivo alemtuzumab reduces the risk of graft-versus-host disease (GVHD) and nonrelapse mortality after reduced intensity allogeneic transplantation. However, it also delays immune reconstitution, leading to frequent infections and potential loss of graft-versus-tumor responses. Here, we tested the feasibility of alemtuzumab dose deescalation in the context of fludarabine-melphalan conditioning and human leukocyte antigen (HLA)–identical sibling transplantation. Alemtuzumab was given 1-2 days before graft infusion, and dose reduced from 60 mg to 20 mg in 4 sequential cohorts (total n = 106). Pharmacokinetic studies were fitted to a linear, 2-compartment model in which dose reduction led to incomplete saturation of CD52 binding sites and greater antibody clearance. Increased elimination was particularly evident in the 20-mg group in patients who had CD52-expressing tumors at time of transplantation. The 20-mg dose was also associated with greater risk of severe GVHD (acute grade III-IV or chronic extensive) compared with > 20 mg (hazard ratio, 6.7; 95% CI, 2.5-18.3). In contrast, dose reduction to 30 mg on day −1 was associated with equivalent clinical outcomes to higher doses but better lymphocyte recovery at 12 months. In conclusion, alemtuzumab dose reduction to 30 mg is safe in the context of reduced intensity conditioning and HLA-identical sibling transplantation. This trial was registered at http://www.ncrn.org.uk as UKCRN study 1415.