bluuebunny/crossref_metadata_2025_split huggingface dataset:
An algal sulfated galactan has an unusual dual effect on venous thrombosis due to activation of factor XII and inhibition of the coagulation proteases
Authors: Melo Fábio , Mourão Paulo 
Published: February 2008

SummarySulfated galactan from the red alga Botryocladia occidentalis has a potent anticoagulant activity,due to its ability to enhance thrombin and factor Xa inhibition by antithrombin and/or heparin cofactor II. It is less active than unfractionated heparin in arterial thrombosis,but in a venous thrombosis presents a dual effect,inhibiting thrombosis in low but not in high doses.This dual effect on venous thrombosis is a consequence of two actions, one that inhibits thrombin and factor Xa and one that induces factor XII activation. In order to dissociate these effects, we prepared derivatives of the sulfated galactan with low molecular weights. Two fractions that were similar in size to unfractionated heparin and low-molecular-weight heparin were obtained. As the molec- ular weight decreased, the ability to activate factor XII and to promote inhibition of coagulation proteases in the presence of antithrombin and heparin cofactor II diminished.At ∼5 kDa, the sulfated galactan fragment had no effect on factor XII activation, and showed the same effect as unfractionated heparin in a venous thrombosis model.The ∼5-kDa fragment is an antithrombotic with several advantages: i) It is as active as unfractionated heparin in venous thrombosis, but it has little activity in arterial thrombosis; ii) It inhibits venous thrombosis with very little anticoagulant effect; iii) It does not cause bleeding; and iv) It is not obtained from mammals.
Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases
Authors: Jablonska Ewa , Guenther Andreas , Preissner Klaus , Markart Philipp , Wygrecka Malgorzata 
Published: February 2008

SummaryAcute inflammatory and chronic interstitial lung diseases are characterized by excessive and persistent fibrin deposition in the lung.Intraalveolar fibrin accumulation,observed under these conditions, arises from a leakage of plasma proteins (including fibrinogen) into the alveolar space in combination with a disbalance of alveolar haemostasis. Tissue factor in association with factor VIIa and inhibition of urokinase by plasminogen activator inhibitor-1 are major factors that are responsible for the procoagulant and antifibrinolytic state. In addition, in acute respiratory distress syndrome (ARDS) patients, factor VII-activating protease and extracellular RNA, which may be released into the extracellular milieu from damaged cells during lung injury, may contribute to fibrin formation as well. Fibrin itself can increase vascular permeability, influence the expression of inflammatory mediators and alter the migration and proliferation of various cell types. Additionally, fibrin may inactivate pulmonary surfactant and provide a matrix on which fibroblasts can migrate and produce collagen.Furthermore,cellular activities of haemostatic proteases may also contribute to proinflammatory and fibrotic processes in the lung.The application of coagulation inhibitors, like tissue factor pathway inhibitor, active site-inactivated factor VIIa, activated protein C, antithrombin, heparin or hirudin turned out to be beneficial in experimental models of acute and chronic lung injury. However, the ability of anticoagulant and profibrinolytic agents to improve clinical outcome remains to be elucidated. In the current article, the role of the alveolar coagulation and fibrinolysis systems in acute inflammatory and chronic interstitial lung diseases is discussed with regard to pathomechanisms and modalities of intervention.
P2 receptors, platelet function and pharmacological implications
Authors: Gachet Christian 
Published: February 2008

SummaryADP and ATP play a crucial role in platelet activation and their receptors are potential targets for antithrombotic drugs. The ATP-gated cation channel P2X1 and the two G protein-coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus.Owing to its central role in the growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs like the thienopyridines clopidogrel or prasugrel, or competitive antag-onists such as cangrelor or AZD6140.The optimal inhibition of this receptor to reach clinical efficacy while preserving patients from unacceptable bleeding is a matter of debate. On the other hand, studies in P2Y1 and P2X1 knockout mice and using selective P2Y1 and P2X1 antagonists have shown that these receptors are also attractive targets for new antithrombotic compounds. Finally, the regulation by the P2 receptors of the platelet involvement in inflammatory processes is also briefly discussed.
Individualized antithrombotic therapy in high risk patients after coronary stenting. A double-edged sword between thrombosis and bleeding
Authors: Geisler Tobias , Gawaz Meinrad , May Andreas 
Published: February 2008

SummaryDual antiplatelet therapy with aspirin and clopidogrel is currently the standard therapy after coronary stent implantation to prevent a life-threatening stent thrombosis. However, a variety of procedural and individual factors contribute to the individual patient risk and have to be taken into account to allow for an individual recommendation for both the duration and intensity of the antiplatelet therapy. Obviously, the benefit of the prevention of stent thrombosis by antithrombotic therapy has to outweigh the risk of severe bleeding complications. Depending on the individual clinical situation and procedural characteristics (stent type, length, angiographic result etc.), the recommended duration of the combined antiplatelet therapy currently varies from four weeks to at least one year.These recommendations are mainly based on large, prospective, randomized trials and evidence-based guidelines. However, in a subgroup of high-risk patients there is insufficient evidence for the benefit of conventional dual antiplatelet regimen.These include i) patients with an indication for anticoagulation, ii) patients with urgent need for an operation requiring a perioperative withholding of antiplatelet therapy, as well as iii) clopidogrel low responders.This review aims to provide a stratification to define patient collectives who may benefit from more individualized antithrombotic regimens on behalf of currently available literature and guidelines.
Platelet-vessel wall interactions in atherosclerotic disease
Authors: Langer Harald , Gawaz Meinrad 
Published: February 2008

SummaryDuring the prolonged course of atherosclerotic disease,platelets are of central importance as they contribute to the initiation of the disease, to its progression and acute exacerbation but also provide potential regenerative mechanisms. Platelets secrete chemokines and cytokines that mediate vascular inflammation and are in turn activated by substances released from cells of the vascular wall.These interactions represent positive and negative feedback loops, which in case of dysregulation may lead to development and progression of disease. Furthermore, platelet adhesion to the endothelium is critical for the initiation of atherosclerotic lesion formation in vivo. Even prior to endothelial denudation, platelet adhesion governed by disturbed flow at predilection sites for atherosclerosis induces recruitment of proathe- rosclerotic cells and release of proinflammatory mediators from all involved cell types.Finally,the pathogenetic role of platelets for late atheroclerotic events including plaque rupture, microembolism or spasms within the microcirculation is well established. However, increasing evidence indicates that platelets mediate on the other hand potential regenerative mechanisms. Platelets recruit circulating progenitor cells to sites of vascular injury. Furthermore, they influence their biological activity and maturation. Therefore,platelets contribute at all stages of vascular disease by interfering with highly dynamic processes. Understanding interactions of platelets with other circulating cells and the vascular wall is a prerequisite to understand cardiovascular disease and to identify potential therapeutic targets.
Magnesium maintains endothelial integrity, up-regulates proteolysis of ultra-large von Willebrand factor, and reduces platelet aggregation under flow conditions
Authors: Cruz Miguel , Aboulfatova Khatira , Martin Cecilia , Choi Hiuwan , Bergeron Angela , Martini Sheryl , Kroll Michael , Kent Thomas , Dong Jing-fei 
Published: February 2008

SummaryMg ++ regulates endothelial functions and has anti-inflammatory effects. Its effects on thrombosis have been demonstrated, but the mechanism remains poorly understood.We investigated the roles of MgSO4 in regulating the release and cleavage of the prothrombotic ultra-large (UL) von Willebrand factor (VWF) and VWF-mediated platelet adhesion and aggregation.Washed platelets were perfused over cultured endothelial cells from human umbilical cord veins under a shear stress of 2.5 dyn/cm2. Release and cleavage of ULVWF by ADAMTS-13 was measured in the absence or presence of physiological or therapeutic levels of MgSO4. Whole blood or plasma-free reconstituted blood was perfused over immobilized collagen to measure the effect of MgSO4 on platelet adhesion and aggregation. Also studied were the effects of MgSO4 on ristocetin-induced platelet aggregation andVWF-collagen interaction.Maintenance of endothelial integrity required physiological levels of MgSO4, but exogenous MgSO4 showed no additional benefits.Exogenous MgSO4 significantly enhanced the cleavage of the newly released ULVWF strings by ADAMTS-13 and markedly reduced platelet aggregation on immobilized collagen under flow conditions.This effect is likely to be mediated through VWF as Mg++ partially inhibited ristocetin-induced platelet aggregation andVWF binding to collagen.MgSO4 is critical for maintaining endothelial integrity and regulates ULVWF proteolysis and aggregation under flow conditions. These results provide a new insight into additional mechanisms involved with magnesium therapy.
Platelet GPIb complex as a target for anti-thrombotic drug development
Authors: Clemetson Jeannine , Clemetson Kenneth 
Published: February 2008

SummarySpecific inhibition of platelet function is a major target of antithrombotic drug research. Platelet receptors are both accessible and specific but have multiple functions often linked to a wide range of ligands. GPIb complex is best known as a major platelet receptor for vonWillebrand factor essential for platelet adhesion under high shear conditions found in arteries and in thrombosis. Recent animal studies have supported inhibition of GPIb as a good candidate for anti-thrombotic drug development with several classes of proteins showing important specific effects and the required discrimination between roles in haemo- stasis and thrombosis is important to protect against bleeding complications.These include antibodies, several classes of snake venom proteins, mutant thrombin molecules and peptides affecting subunit interactions.However,due to the nature of its receptor- ligand interactions involving large protein-protein interfaces, the possibility of developing classic pharmaceutical inhibitors for long term (and perhaps oral) treatment is still unclear, and additional information about structural interactions and signalling mechanisms is essential.
Molecular characterization of two novel mutations causing factor XI deficiency: A splicing defect and a missense mutation responsible for a CRM+ defect
Authors: Guella Ilaria , Soldà Giulia , Spena Silvia , Asselta Rosanna , Ghiotto Rossella , Tenchini Maria , Castaman Giancarlo , Duga Stefano 
Published: February 2008

SummarySevere factor XI (FXI) deficiency is a bleeding disorder generally inherited as an autosomal recessive trait and characterized by haemorrhagic symptoms mainly associated with injury or surgery. So far, more than 150 causative molecular defects have been identified throughout the F11 gene. In the present study, we investigated the molecular basis of FXI deficiency in two Italian patients. Mutational screening of the F|| gene disclosed a novel missense substitution (Arg184Gly) in exon 7 and two splicing mutations: a novel G>A transition affecting the last nucleotide of exon 4 (325G>A), and the already known IVS6+3A>G. RT-PCR assays were performed on total RNA extracted from platelets and lymphocytes of each patient. Se- quencing of RT-PCR products demonstrated that both 325G>A and IVS6+3A>G mutations abolish the corresponding donor splice site, causing the skipping of the affected exon; this in turn results in a frameshift introducing a premature termination codon. Expression of recombinant FXI-Arg184Gly revealed a 70% reduction in FXI activity, suggesting that the Arg184Gly mutation might cause a cross-reactive material positive (CRM+) deficiency. In conclusion, the functional consequences of two splicing mutations leading to FXI deficiency have been elucidated. Moreover, we report a novel missense mutation in the FIX-binding region of the FXI A3 domain leading to a CRM+ deficiency.
Atmospheric Horizontal Resolution Affects Tropical Climate Variability in Coupled Models
Authors: Navarra A. , Gualdi S. , Masina S. , Behera S. , Luo J.-J. , Masson S. , Guilyardi E. , Delecluse P. , Yamagata T. 
Published: February 2008

Abstract
The effect of atmospheric horizontal resolution on tropical variability is investigated within the modified Scale Interaction Experiment (SINTEX) coupled model, SINTEX-Frontier (SINTEX-F), developed jointly at Istituto Nazionale di Geofisica e Vulcanologia (INGV), L’Institut Pierre-Simon Laplace (IPSL), and the Frontier Research System. The ocean resolution is not changed as the atmospheric model resolution is modified from spectral resolution 30 (T30) to spectral resolution 106 (T106). The horizontal resolutions of the atmospheric model T30 and T106 are investigated in terms of the coupling characteristics, frequency, and variability of the tropical ocean–atmosphere interactions. It appears that the T106 resolution is generally beneficial even if it does not eliminate all the major systematic errors of the coupled model. There is an excessive shift west of the cold tongue and ENSO variability, and high resolution also has a somewhat negative impact on the variability in the east Indian Ocean. A dominant 2-yr peak for the Niño-3 variability in the T30 model is moderated in the T106 as it shifts to a longer time scale. At high resolution, new processes come into play, such as the coupling of tropical instability waves, the resolution of coastal flows at the Pacific–Mexican coasts, and improved coastal forcing along the coast of South America. The delayed oscillator seems to be the main mechanism that generates the interannual variability in both models, but the models realize it in different ways. In the T30 model it is confined close to the equator, involving relatively fast equatorial and near-equatorial modes, and in the high-resolution model, it involves a wider latitudinal region and slower waves. It is speculated that the extent of the region that is involved in the interannual variability may be linked to the time scale of the variability itself.
The Diurnal Cycle of Precipitation over the North American Monsoon Region during the NAME 2004 Field Campaign
Authors: Becker Emily J. , Berbery Ernesto Hugo 
Published: February 2008

Abstract
The structure of the diurnal cycle of warm-season precipitation and its associated fields during the North American monsoon are examined for the core monsoon region and for the southwestern United States, using a diverse set of observations, analyses, and forecasts from the North American Monsoon Experiment field campaign of 2004. Included are rain gauge and satellite estimates of precipitation, Eta Model forecasts, and the North American Regional Reanalysis (NARR). Daily rain rates are of about the same magnitude in all datasets with the exception of the Climate Prediction Center (CPC) Morphing (CMORPH) technique, which exhibits markedly higher precipitation values.
The diurnal cycle of precipitation within the core region occurs earlier in the day at higher topographic elevations, evolving with a westward shift of the maximum. This shift appears in the observations, reanalysis, and, while less pronounced, in the model forecasts. Examination of some of the fields associated with this cycle, including convective available potential energy (CAPE), convective inhibition (CIN), and moisture flux convergence (MFC), reveals that the westward shift appears in all of them, but more prominently in the latter.
In general, warm-season precipitation in southern Arizona and parts of New Mexico shows a strong effect due to northward moisture surges from the Gulf of California. A reported positive bias in the NARR northward winds over the Gulf of California limits their use with confidence for studies of the moist surges along the Gulf; thus, the analysis is complemented with operational analysis and the Eta Model short-term simulations. The nonsurge diurnal cycle of precipitation lags the CAPE maximum by 6 h and is simultaneous with a minimum of CIN, while the moisture flux remains divergent throughout the day. During surges, CAPE and CIN have modifications only to the amplitude of their cycles, but the moisture flux becomes strongly convergent about 6 h before the precipitation maximum, suggesting a stronger role in the development of precipitation.
Tropical Cyclone–Induced Upper-Ocean Mixing and Climate: Application to Equable Climates
Authors: Korty Robert L. , Emanuel Kerry A. , Scott Jeffery R. 
Published: February 2008

Abstract
Tropical cyclones instigate an isolated blast of vigorous mixing in the upper tropical oceans, stirring warm surface water with cooler water in the thermocline. Previous work suggests that the frequency, intensity, and lifetime of these storms may be functions of the climate state, implying that transient tropical mixing could have been stronger during warmer equable climates with higher concentrations of carbon dioxide. Stronger mixing of the tropical oceans can force the oceans’ meridional heat flux to increase, cooling tropical latitudes while warming higher ones. This response differs significantly from previous modeling studies of equable climates that used static mixing; coupling mixing to climate changes the dynamic response. A parameterization of mixing from tropical cyclones is developed, and including it leads to a cooling of tropical oceans and a warming of subtropical waters compared with control cases with fixed mixing. The mixing penetration depth regulates the magnitude of the response.
The Roles of Atmospheric Stochastic Forcing (SF) and Oceanic Entrainment Temperature (Te) in Decadal Modulation of ENSO
Authors: Zhang Rong-Hua , Busalacchi Antonio J. , DeWitt David G. 
Published: February 2008

AbstractThe El Niño–Southern Oscillation (ENSO) has been observed to exhibit decadal changes in its properties; the cause and implication of such changes are strongly debated. Here the authors examine the influences of two particular attributors of the ocean–atmospheric system. The roles of stochastic forcing (SF) in the atmosphere and decadal changes in the temperature of subsurface water entrained into the mixed layer (Te) in modulating ENSO are compared to one another using coupled ocean–atmosphere models of the tropical Pacific climate system. Two types of coupled models are used. One is an intermediate coupled model (ICM) and another is a hybrid coupled model (HCM), both of which consist of the same intermediate ocean model (IOM) with an empirical parameterization for Te, constructed via singular value decomposition (SVD) analysis of the IOM simulated historical data. The differences in the ICM and HCM are in the atmospheric component: the one in the ICM is an empirical feedback model for wind stress (τ), and that in the HCM is an atmospheric general circulation model (AGCM; ECHAM4.5). The deterministic component of atmospheric τ variability, representing its signal response (τSig) to an external SST forcing, is constructed statistically by an SVD analysis from a 24-member ensemble mean of the ECHAM4.5 AGCM simulations forced by observed SST; the SF component (τSF) is explicitly estimated from the ECHAM4.5 AGCM ensemble and HCM simulations. Different SF representations are specified in the atmosphere: the SF effect can be either absent or present explicitly in the ICM, or implicitly in the HCM where the ECHAM4.5 AGCM is used as a source for SF. Decadal changes in the ocean thermal structure observed in the late 1970s are incorporated into the coupled systems through the Te parameterizations for the two subperiods before (1963–79) and after (1980–96) the climate shift (T63–79e and T80–96e), respectively.The ICM and HCM simulations well reproduce interannual variability associated with El Niño in the tropical Pacific. Model sensitivity experiments are performed using these two types of coupled models with different realizations of SF in the atmosphere and specifications of decadal Te changes in the ocean. It is demonstrated that the properties of ENSO are modulated differently by these two factors. The decadal Te changes in the ocean can be responsible for a systematic shift in the phase propagation of ENSO, while the SF in the atmosphere can contribute to the amplitude and period modulation in a random way. The relevance to the observed decadal ENSO variability in the late 1970s is discussed.
The Influence of Changes in Cloud Cover on Recent Surface Temperature Trends in the Arctic
Authors: Liu Yinghui , Key Jeffrey R. , Wang Xuanji 
Published: February 2008

AbstractA method is presented to assess the influence of changes in Arctic cloud cover on the surface temperature trend, allowing for a more robust diagnosis of causes for surface warming or cooling. Seasonal trends in satellite-derived Arctic surface temperature under clear-, cloudy-, and all-sky conditions are examined for the period 1982–2004. The satellite-derived trends are in good agreement with trends in the European Centre for Medium-Range Weather Forecasts (ECMWF) reanalysis product and surface-based weather station measurements in the Arctic. Surface temperature trends under clear and cloudy conditions have patterns similar to the all-sky trends, though the magnitude of the trends under cloudy conditions is smaller than those under clear-sky conditions, illustrating the negative feedback of clouds on the surface temperature trends. The all-sky surface temperature trend is divided into two parts: the first part is a linear combination of the surface temperature trends under clear and cloudy conditions; the second part is caused by changes in cloud cover as a function of the clear–cloudy surface temperature difference. The relative importance of these two components is different in the four seasons, with the first part more important in spring, summer, and autumn, but with both parts being equally important in winter. The contribution of biases in satellite retrievals is also evaluated.