bluuebunny/crossref_metadata_2025_split huggingface dataset:
C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor α, on human monocytes
Authors: Ropars Armelle , Seguin-Devaux Carole , Poitevin Gaël , Grosjean Sandrine , Latger-Cannard Vèronique , Devaux Yvan , Zannad Faiez , Regnault Vèronique , Lacolley Patrick , Mertes Paul-Michel , Hanriot Didier , Bello Gaëlle , Hess Ketsia , Longrois Dan 
Published: February 2008

SummaryNon-specific markers of inflammation such as C-reactive protein (CRP) are associated statistically with an increased risk of atherosclerosis through mechanisms that have not yet been fully elucidated.We investigated the effects of CRP on several aspects of human monocyte biology, a cell type involved in the initiation and progression of atherosclerosis. Blood monocytes isolated from healthy men and premenopausal women (n=9/group) were exposed to purified CRP (25 μg/ml) for 12 hours. Changes in gene expression were analyzed using a custom-made array containing oligonucleotide sequences of 250 genes expressed by activated monocytes and confirmed by quantitative PCR. CRP increased significantly the expression of the cytokines interleukin (IL)-1α, IL-1β and IL-6, and the chemokines GRO-α, GRO-β and IL-8. CRP also displayed anti-inflammatory effects through upregulation of liver X receptor (LXR) α and activin receptor expression, and down-regulation of alpha 2-macroglobulin expression. Increased LXRα mRNA expression in both monocytes and the monocytic cell lineTHP-1 was associated with increased LXRα protein expression and nuclear translocation, as well as increased ABCA1 mRNA expression, a target gene of LXRα. Western Blot analysis revealed CRP-induced nuclear translocation of NF-κB and activation of p42/44, MAP and Akt kinases. CRP-induced LXRá mRNA expression was inhibited by anti-CD64 (FcγRI) antibodies and by p42/44 and PI3 kinase inhibitors. This hypothesis-generating study demonstrates that CRP modulates the expression of genes that contribute to both pro- and anti-inflammatory responses in human monocytes. Among these novel anti-inflammatory effects, we show clearly that CRP activates the LXRα pathway.
Concentration-dependent roles for heparin in modifying liopolysaccharide-induced activation of mononuclear cells in whole blood
Authors: Hochart Helene , Jenkins Vincent , Preston Roger , Smith Owen , White Barry , O’Donnell James 
Published: February 2008

SummaryIn addition to their anticoagulant activity,unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have important immunomodulatory properties. However, different studies have reported conflicting pro- and anti-inflammatory effects in association with heparin. Moreover, the molecular basis for these heparin effects on inflammation remains unclear.It was the objective of this study to determine how UFH and LMWH regulate lipopolysaccharide (LPS)-induced activation of human mononuclear cells in whole blood, and define the role of lipopolysaccharide- binding protein (LBP) in mediating this effect. Whole blood was pre-treated with UFH or LMWH (0.1–200 IU/ml), prior to stimulation with LPS (10 ng/ml). After six hours, monocyte pro-inflammatory cytokine (interleukin (IL)-1β, IL-6, IL-8, and TNF-α) secretion was determined by plasma ELISA. Parallel experiments using THP-1 cell line and primary monocytes were performed under serum-free conditions, in the presence or absence of LBP (50–100 nM). Under serum-free conditions, heparin demonstrated dose-dependent anti-inflammatory effects,significantly reducing secretion of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and TNF-α) in response to LPSstimulation of THP-1 cells and primary monocytes. In contrast, in the presence of LBP, both UFH and LMWH demonstrated dose-dependent pro-inflammatory effects at all heparin concentrations. In ex-vivo whole blood experiments, pro-inflammatory effects (increased IL-1β and IL-8 following LPS-stimulation) of heparin were also observed,but only at supra-therapeutic doses (10–200 IU/ml). Our data demonstrate that in the absence of LBP, the direct effect of heparin on LPS-stimulated monocytes is anti-inflammatory. However in whole blood, the immunomodulatory effects of heparin are significantly more complex, with either pro- or anti-inflammatory effects dependent upon heparin concentration.
Selective inhibition of the platelet phosphoinositide 3-kinase p110β as promising new strategy for platelet protection during extracorporeal circulation
Authors: Wendel Hans , Dietz Klaus , Schiebold Daniela , Peter Karlheinz , Schoenwaelder Simone , Ziemer Gerhard , Straub Andreas 
Published: February 2008

SummaryExtracorporeal circulation (ECC) is used in cardiac surgery for cardiopulmonary bypass as well as in ventricular assist devices and for extracorporeal membrane oxygenation. Blood contact with the artificial surface and shear stress of ECC activates platelets and leukocytes resulting in a coagulopathy and proinflammatory events. Blockers of the platelet glycoprotein (GP) IIb/IIIa (CD41/CD61) can protect platelet function during ECC, a phenomenon called “platelet anaesthesia”, but may be involved in post-ECC bleeding. We hypothesized that the new selective phosphoinositide 3-kinase p110β inhibitor TGX-221 that inhibits shear-induced platelet activation without prolonging the bleeding time in vivo may also protect platelet function during ECC. Heparinized blood of healthy volunteers (n=6) was treated in vitro with either the GP IIb/IIIa blocker tirofiban, TGX-221 or as control and circulated in an ECC moand after 30 minutes circulation CD41 expression on the ECCtubing as measure for platelet-ECC binding and generation of the platelet activation marker β-thromboglobulin were determined using ELISA. Platelet aggregation and platelet-granulocyte binding were analysed in flow cytometry. After log-transforming the data statistical evaluation was performed using multifactor ANOVA in combination with Tukey’s HSD test (global alpha = 5%).Tirofiban and TGX-221 inhibited platelet-ECC interaction, platelet aggregation and platelet-granulocyte binding. Tirofiban also inhibited ECC-induced β-thromboglobulin release.The observed inhibition of platelet-ECC interaction and platelet activation by tirofiban contributes to explain the mechanism of“platelet anaesthesia”.TGX-221 represents a promising alternative to GP IIb/IIIa blockade and should be further investigated for use during ECC in vivo.
The C242T polymorphism of the p22phox component of NAD (P)H oxidase and vascular risk
Authors: Castelnuovo Augusto , Soccio Manola , Iacoviello Licia , Evangelista Virgilio , Consoli Agostino , Vanuzzo Diego , Diviacco Silvia , Carluccio Marisa , Caterina Raffaele , Rignanese Lucia 
Published: February 2008

SummaryNAD(P)H oxidase is a prominent source of reactive oxygen species in the vasculature.Vascular NAD(P)H oxidase is comprised of several subunits, one of which, p22phox, is encoded by a gene exhibiting several allelic variants. Here the C242T nucleotide transition has been found to alter superoxide anion production and associated with an altered risk of coronary artery disease (CAD). We assessed the role of this variant in two casecontrol studies, and performed a meta-analysis of previously reported investigations relating it to vascular risk. Population I was comprised of 492 subjects with type 2 diabetes, with or without macrovascular disease,matched for age,sex,and duration of diabetes. Population II was comprised of 158 subjects with or without either CAD or cerebro-vascular disease, and matched for age,sex,smoking status,weight category and the presence of hypertension, dyslipidemia, and diabetes. Our findings were metaanalyzed together with additional studies retrieved from the literature. The C242T polymorphism distribution did not differ between cases and controls in populations I and II both at univariate and multivariate analyses, and this was confirmed in a metaanalysis with || previously published populations. The metaanalysis, however, suggested a protective role of the T allele on CAD as an end point in Asian populations. In conclusion, these data suggest a significant heterogeneity for a modulating role of the T allele in the C242T polymorphism of p22-phox for the occurrence of CAD across ethnicities,with the absence of a significant effect in Caucasians.
Antithrombin alfa in hereditary antithrombin deficient patients: A phase 3 study of prophylactic intravenous administration in high risk situations
Authors: Tait R. , Shaffer Don , Baudo Francesco , Boneu Bernard , Dempfle Carl , Horellou Marie , Klamroth Robert , Lazarchick John , Mumford Andrew , Schulman Sam , Shiach Caroline , Bonfiglio Laura , Frieling Johan , Conard Jacqueline , Depka Mario , Tiede Andreas 
Published: February 2008

SummaryDuring surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis,and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditaryAT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days.No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.
Increased thrombin generation in persons with echogenic carotid plaques
Authors: Mathiesen Ellisiv , Østerud Bjarne , Amiral Jean , Vissac Anne , Hansen John-Bjarne , Notø Ann-Trude 
Published: February 2008

SummaryEcholucent carotid plaques are associated with higher risk for future ischemic cerebrovascular events (CVE) than echogenic plaques independent of the degree of stenosis.Elevated markers of thrombin generation are associated with atherosclerotic plaques and are increased in the acute and chronic phases of CVE. The present study was conducted to investigate the influence of plaque morphology on thrombin generation in persons with carotid stenosis. One hundred twenty-eight persons with carotid stenosis (≥35% lumen diameter reduction) and 136 matched controls without stenosis were recruited from the health survey of the Tromsø Study. Blood samples were collected and plaque morphology determined by ultrasonography. Thrombin generation was assessed by thrombin-antithrombin complexes (TAT) and by prothrombin fragment 1+2 (F1+2).Persons with echogenic plaques (n=63) had significantly higher levels of TAT (5.24 μg/l, 4.33–6.14) (mean, 95%CI) than persons with echolucent plaques (n=65) (3.44 μg/l, 2.91–3.96, p<0.001) and controls (n=136) (3.33 μg/l, 3.06–3.60, p<0.001).They also had significantly higher levels of F1+2 (2.14 nM, 1.83–2.45) than persons with echolucent plaques (1.54 nM, 1.38–1.71, p<0.001) and controls (1.49 nM, 1.40–1.58, p<0.001). TAT and F1+2 increased linearly with plaque echogenicity (p=0.002 and p=0.001, respectively) independent of the degree of stenosis. Increased thrombin generation was associated with a significant increase in plasma factorV levels among persons with echogenic plaques compared to echolucent plaques (p=0.049) and controls (p=0.025). The present findings indicate that increasing plaque echogenicity, rather than plaque echolucency and the degree of stenosis, is associated with thrombin generation in persons with carotid stenosis.
Treatment of pulmonary embolism: The use of low-molecularweight heparin in the inpatient and outpatient settings
Authors: Hull Russell 
Published: February 2008

SummaryPulmonary embolism (PE) remains a major clinical problem associated with considerable mortality and morbidity. In patients with PE, appropriate anticoagulant therapy has been shown to significantly reduce both recurrence and mortality. Low-molecular- weight heparin (LMWH) is at least as effective as unfractionated heparin (UFH) in the treatment of PE,with a similar risk of bleeding. Furthermore, LMWH offers more predictable pharmacokinetics and anticoagulant effects. As a result, current guidelines from both the American College of Chest Physicians and the joint American College of Physicians/American Academy of Family Physicians recommend the use of LMWH over UFH (in patients with submassive PE). Outpatient treatment with LMWH has been shown to be feasible in many patients,and offers the potential for cost-savings and improvements in healthrelated quality of life. Further data are needed to support an evidence- based recommendation for the use of LMWH in the outpatient treatment of PE.
The interaction of fragment 1 of prothrombin with the membrane surface is a prerequisite for optimum expression of factor Va cofactor activity within prothrombinase
Authors: Bukys Michael , Orban Tivadar , Kim Paul , Nesheim Michael , Kalafatis Michael 
Published: February 2008

SummaryIncorporation of factor (F) Va into prothrombinase directs prothrombin activation by FXa through the meizothrombin pathway, characterized by initial cleavage at Arg320 We have shown that a pentapeptide with the sequence DYDYQ specifically inhibits this pathway. It has been also established that Hir54–65(SO3 -) is a specific inhibitor of prothrombinase.To understand the role of FVa within prothrombinase at the molecular level, we have studied thrombin formation by prothrombinase in the presence of various prothrombin-derived fragments alone or in combination. Activation of prethrombin 1 is slow with cleavages at Arg320 and Arg271 occurring with similar rates. Addition of purified fragment 1 to prethrombin 1 accelerates both the rate of cleavage at Arg320 and thrombin formation.Both reactions were inhibited by Hir54–65(SO3 -) while DYDYQ had no significant inhibitory effect on prethrombin 1 cleavage in the absence or presence of fragment 1. Similarly, activation of prethrombin 2 by prothrombinase,is inhibited by Hir54–65(SO3 -), but is not affected by DYDYQ.Addition of purified fragment 1•2 to prethrombin 2 accelerates the rate of cleavage at Arg320 by prothrombinase. This addition also results in a significant inhibition of thrombin formation by DYDYQ and is concurrent with the elimination of the inhibitory effect of Hir54–65(SO3 -) on the same reaction. Finally, a membrane-bound ternary complex composed of prethrombin 2/fragment 1•2/Hir54–65(SO3 -) is inhibited by DYDYQ. Altogether,the data demonstrate that membrane- bound fragment 1 is required to promote optimum FVa cofactor activity which in turn is translated by efficient initial cleavage of prothrombin by prothrombinase at Arg320.
Evaluation of a venous-return assist device to treat severe post-thrombotic syndrome (VENOPTS)
Authors: McRae Simon , Kahn Susan , Julian Jim , Kearon Clive , MacKinnon Betsy , Magier Debbie , Strulovich Carla , Lyons Theresa , Robinson Sandra , Hirsh Jack , Ginsberg Jeffrey , O’Donnell Martin 
Published: February 2008

SummarySevere post-thrombotic syndrome (PTS) is responsible for considerable disability, reduced quality of life and increased health care costs. Current therapies are limited and often ineffective. We performed a two-centre,randomized,cross-over controlled trial to evaluate Venowave
TM, a novel lower-limb venous-return assist device, for the treatment of severe PTS. Eligible subjects were allocated to receive, in randomized order, Venowave for eight weeks and a control device for eight weeks. The eightweek treatment periods were separated by a four-week period when no device was used (i.e. wash-out period). The primary outcome measure was a ‘clinical success’ defined as: i) reported benefit from the device; and ii) moderate or greater improvement in symptoms of PTS; and iii) willingness to continue using the device. Secondary outcome measures included quality of life (QOL) as measured by VEINES-QOL questionnaire (higher scores indicate better QOL), and PTS severity as measured by the Villalta PTS scale (higher scores indicate more severe PTS). The study was registered with ClinicalTrials.gov (NCT00182208). Thirty-two patients were enrolled. Of these, 26 (80%) were also using graduated compression stockings. Twenty-six participants completed both trial periods. Clinical success occurred in 10 (31%) participants receiving Venowave and four (13%) participants receiving the control device, with two (6%) participants reporting a clinical success with both devices (P=0.11). Mean VEINES-QOL score at the end of study period was significantly greater (P=0.004) forVenowave (52.5; SD 5.8) compared to control (50.2;SD 6.2).MeanVillalta scale score at the end of study period was significantly decreased (P=0.004) for Venowave (12.2; SD 6.3) compared to control (15.0; SD 6.1). In conclusion,Venowave appears to be a very promising new therapy for patients with severe PTS, which may be used alone or in combination with graduated compression stockings.
Slight differences in sulfation of algal galactans account for differences in their anticoagulant and venous antithrombotic activities
Authors: Fonseca Roberto , Oliveira Stephan-Nicollas , Melo Fábio , Pereira Maria , Benevides Norma , Mourão Paulo 
Published: February 2008

SummaryWe compared sulfated galactans (SGs) from two species of red algae using specific coagulation assays and experimental models of thrombosis.These polysaccharides have an identical saccharide structure and the same size chain, but with slight differences in their sulfation patterns.As a consequence of these differences, the two SGs differ in their anticoagulant and venous antithrombotic activities.SG from G.crinale exhibits procoagulant and prothrombotic effects in low doses (up to 1.0 mg/kg body weight), but in high doses (>1.0 mg/kg) this polysaccharide inhibits both venous and arterial thrombosis in rats and prolongs ex-vivo recalcification time. In contrast, SG from B. occidentalis is a very potent anticoagulant and antithrombotic compound in low doses (up to 0.5 mg/kg body weight), inhibiting venous experimental thrombosis and prolonging ex-vivo recalcification time, but these effects are reverted in high doses. Only at high doses (>1.0 mg/kg) the SG from B. occidentalis inhibits arterial thrombosis. As with heparin, SG from G. crinale does not activate factor XII, while the polysaccharide from B. occidentalis activates factor XII in high concentrations, which could account for its procoagulant effect at high doses on rats. Both SGs do not modify bleeding time in rats.These results indicate that slight differences in the proportions and/or distribution of sulfated residues along the galactan chain may be critical for the interaction between proteases, inhibitors and activators of the coagulation system, resulting in a distinct pattern in anti- and procoagulant activities and in the antithrombotic action.
Clinical presentation and time-course of postoperative venous thromboembolism: Results from the RIETE Registry
Authors: Arcelus Juan , Caprini Joseph , Guisado Javier , Soto Mª , Núñez Manuel , Alvárez Juan , Monreal Manuel ,   the RIETE investigators
Published: February 2008

SummaryThere is little literature about the clinical presentation and timecourse of postoperative venous thromboembolism (VTE) in different surgical procedures. RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic acuteVTE.In this analysis,we analysed the baseline characteristics, thromboprophylaxis and therapeutic patterns, timecourse, and three-month outcome of all patients with postoperative VTE. As of January 2006, there were 1,602 patients with postoperativeVTE in RIETE: 393 (25%) after major orthopaedic surgery (145 elective hip arthroplasty, 126 knee arthroplasty, 122 hip fracture); 207 (13%) after cancer surgery; 1,002 (63%) after other procedures. The percentage of patients presenting with clinically overt pulmonary embolism (PE) (48%, 48%, and 50% respectively), the average time elapsed from surgery toVTE (22 ± 16, 24 ± 16, and 21 ± 15 days, respectively), and the three- month incidence of fatal PE (1.3%, 1.4%, and 0.8%, respectively), fatal bleeding (0.8%, 1.0%, and 0.2%, respectively), or major bleeding (2.3%, 2.9%, and 2.8%, respectively) were similar in the three groups. However, the percentage of patients who had received thromboprophylaxis (96%, 76% and 52%, respectively), the duration of prophylaxis (17 ± 9.6, 13 ± 8.9, and 12 ± 11 days, respectively) and the mean daily doses of low-molecular-weight heparin (4,252 ± 1,016, 3,260 ± 1,141, and 3,769 ± 1,650 IU, respectively), were significantly lower in those undergoing cancer surgery or other procedures. In conclusion, the clinical presentation, time-course, and three-month outcome ofVTE was similar among the different subgroups of patients,but the use of prophylaxis in patients undergoing cancer surgery or other procedures was suboptimal.
Tissue factor pathway inhibitor (TFPI) interferes with endothelial cell migration by inhibition of both the Erk pathway and focal adhesion proteins
Authors: Provençal Mathieu , Michaud Marisol , Beaulieu Édith , Ratel David , Rivard Georges-Étienne , Gingras Denis , Béliveau Richard 
Published: February 2008

SummaryTissue factor pathway inhibitor (TFPI) is a plasma Kunitz-type serine protease inhibitor that is mainly known for its inhibition of tissue factor-mediated coagulation. In addition to its anticoagulant properties, emerging data show that TFPI may also regulate endothelial cell functions via a non-haemostatic pathway. In this work we demonstrate that at concentrations within the physiological range,TFPI inhibits both endothelial cell migration and their differentiation into capillary-like structures in vitro. These effects were specific to endothelial cells since no inhibitory effect was observed on the migration of tumor (glio- blastoma) cells. Inhibition of endothelial cell migration was correlated with a concomitant loss in cell adhesion,suggesting an alteration of focal adhesion complex integrity. Accordingly,we observed thatTFPI inhibited the phosphorylation of focal adhesion kinase and paxillin,two key proteins involved in the scaffolding of these complexes, and that this effect was specific to endothelial cells. These results suggest that TFPI influences the angiogenic process via a non-haemostatic pathway, by downregulating the migratory mechanisms of endothelial cells.