bluuebunny/crossref_metadata_2025_split huggingface dataset:
Management of multinodular goiter in Germany (Papillon 2005)
Authors: Wegscheider K. , Vaupel R. , Schmidt M. , Schicha H. , Dietlein M. 
Published: June 2007

Summary
Aim: Large-scale survey to focus on management of multinodular goiter and to compare the approaches of practitioners in primary care and thyroid specialists in Germany. Methods: Replies to a questionnaire were received from 2,191 practitioners and 297 thyroid specialists between June 1 and September 30, 2005. The hypothetical cases and their modifications described multinodular goiters of different sizes with and without toxic nodules. Results: In the workup, TSH determination and thyroid sonography were found to be standard procedures. Scintigraphy was selected by 80.2% of practitioners and 92.9% of specialists (p <0.001), in preference to fine needle aspiration cytology (17.9% of practitioners and 34.5% of the specialists, p <0.001). Only 6.1% of practitioners and 24.4% of specialists (p <0.001) advocated calcitonin screening. Euthyroid multinodular goiter (50-80 ml) was treated medically by 67.1% of practitioners and 65.6% of specialists, the combination of levothyroxine with iodine being clearly preferred (54.5% of practitioners, 52.3% of specialists). For toxic nodular goiter the preference for radioiodine therapy was significantly higher (p <0.001) among specialists (67.7%) than among practitioners (47.5%). Referral to surgery was recommended for cold nodules with negative cytology by 64.9% of practitioners and 73.5% of specialists (p = 0.004). Conclusions: Treatment and diagnostic procedures are used to nearly the same extent in primary care and specialist institutions, but the opinions diverge over the issues of calcitonin screening and referral for radioiodine therapy.
Tissue factor-enriched vesicles are taken up by platelets and induce platelet aggregation in the presence of factor VIIa
Authors: Lopez-Vilchez Irene , Diaz-Ricart Maribel , Fuste Berta , Galan Ana , White James , Escolar Gines 
Published: June 2007

SummaryWe investigated the interactions of vesicles containing human tissue factor (TF) with platelets and evaluated responses induced by rFVIIa using standard aggregometry, ultrastructural and flow-cytometry techniques. Washed platelets were exposed to a preparation of placental human TF (pTF) or to a relipidated formulation of recombinant humanTF (rTF). Under stirring conditions, pTF induced reversible aggregation with platelets returning to their resting state after 5 minutes. This reversible response to pTF was partially inhibited by antibodies against CD62-P, but not by antithrombin agents, and was not observed with rTF. Sequential ultrastructural studies revealed uptake of both TF preparations by platelets involving traffic of vesicles through channels of the open canalicular system (OCS). Immunocytochemical studies on cryosections identified TF in the OCS, and occasionally in the alpha-granules of the platelets. These processes were faster with pTF than with rTF, but bothTF preparations accumulated in platelets at the end of incubation periods. Flow cytometry studies revealed the presence of other cellular antigens (CD62-P, CD14 and CD45) associated to the pTF. Addition of rFVIIa to washed platelets exposed to pTF or rTF, caused a thrombin dependent irreversible platelet aggregation. Our studies demonstrate that platelets possess mechanisms to capture and incorporate TF-rich vesicles. These processes are accelerated by the presence of other cellular antigens in the vesicles. Our findings may explain the hemostatic action of rFVIIa in severely hemodiluted patients, but are also relevant for the understanding of potential implications of TF-associated to platelets in the propagation of thrombus.
Platelet activation by collagen is increased in retinal vein occlusion
Authors: Bruzzese Debora , Signorello Maria , Armani Ugo , Piana Antonietta , Ghiglione Davidina , Camicione Paola , Leoncini Giuliana 
Published: June 2007

SummaryRetinal vein occlusion (RVO) is the most common retinal vascular disorder second to diabetic retinopathy. The main risk factors in patients with RVO are hypertension, diabetes, hyperlipidemia, increased blood viscosity and glaucoma. The pathogenesis of RVO has not yet been clarified. In these events platelets could play a very important role. In the present study the platelet response to collagen was deeply investigated. Experiments were carried out on a selected group of RVO patients, which were compared to a group of healthy subjects matched for age, sex, clinical and metabolic characteristics. In resting and activated platelets of both groups of subjects p72syk phosphorylation, phospholipase Cγ 2 phosphorylation, protein kinase C activation, intracellular calcium levels and nitric oxide formation were measured. Results show that platelets of patients were more responsive to collagen or ADP than healthy subjects and that the response was significantly different (p < 0.0005) at low concentrations of these agonists. In platelets of patients stimulated with collagen increased phosphorylation of p72syk and phospholipase C γ 2 was found. Also protein kinase C was more activated in patients. In addition intracellular calcium rise induced by collagen was significantly higher in patients than in healthy subjects. RVO patients showed a lower basal level of nitric oxide both in resting and stimulated platelets compared to healthy subjects. Altogether these results suggest that the platelet hyperaggregability described in patients might be an important factor in the development of RVO contributing to the thrombogenic effects.
Thrombin activation of endometrial endothelial cells: A possible role in intrauterine growth restriction
Authors: Huang Se-Te , Schatz Frederick , Salafia Carolyn , Stocco Carlos , Lockwood Charles , Krikun Graciela 
Published: June 2007

SummaryPreeclampsia (PE), intrauterine growth restriction (IUGR) and abruption with or without fetal loss are associated with reduced uteroplacental blood flow, decidual vasculopathy, endothelial cell dysfunction, thrombosis, inflammation and hemorrhage. Our hypothesis is that reduced uteroplacental blood flow causes focal decidual hypoxia that generates vascular endothelial growth factor (VEGF). The latter acts directly on decidual endothelial cells to induce aberrant expression of tissue factor (TF), the primary initiator of coagulation. This in turn generates thrombin that induces: i) further TF expression; and ii) inflammatory cytokines. BothVEGF and TF induce aberrant angiogenesis-vessel maintenance reflected by endothelial cell fenestrations and induction of a prothrombotic surface causing both the decidual hemorrhage (i.e.abruption) and thrombosis (i.e.uteroplacental vascular insuf- ficiency) observed in these adverse pregnancy outcomes. This novel hypothesis is supported by our finding of TF expression in decidual endothelium of pregnancies complicated by IUGR and/ or fetal loss. Moreover, treatment of cultured endometrial endothelial cells with VEGF or thrombin induces TF protein and mRNA expression. Quantitative RT-PCR analysis indicates that thrombin enhances (>10-fold) the output of diverse inflammatory cytokines in these cultures. The greatest effect (>2-log) was seen on macrophage inflammatory protein 3 α (MIP3 α ). In vitro, thrombin results in endometrial endothelial cell aggregations and changes in the apoptotic pathway. Thus, we postulate that reductions in uteroplacental flow initiate a cascade of molecular effects leading to hypoxia, thrombosis, inflammation, and endothelial cell dysfunction resulting in untoward pregnancy outcomes.
Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis
Authors: Murad Sarwa , de Maat Moniek , Tanck Michael , Haagsma Elizabeth , van Hoek Bart , Rosendaal Frits , Janssen Harry , Leebeek Frank , de Bruijne Emile ,   for the Liver and Thrombosis Study Group
Published: June 2007

SummarySplanchnic vein thrombosis (SVT) has been associated with a hypercoagulable state. Thrombin-activatable fibrinolysis inhibitor (TAFI) may contribute to a hypercoagulable state, and therefore we were interested in the role of TAFI in SVT. Since the disease is frequently associated with liver insufficiency, which affects plasma levels ofTAFI, we studied the role of variation in theTAFI gene in SVT. In a multicenter case-control study on 118 patients with SVT (39 Budd-Chiari syndrome and 85 portal vein thrombosis) and 118 population-based controls, the relationship of SVT with single nucleotide polymorphisms (SNPs) and haplotypes in the TAFI gene (- 438G/A, Ala147Thr, Thr325Ile and 1583A/T) was determined. The risk for SVT was decreased (OR 0.2,95% CI 0.1–0.7) in 147Thr/Thr homozygotes and slightly,but not significantly,increased in carriers of the 325Ile allele (OR 1.6, 95%CI 0.9–2.7). Haplotype analysis confirmed that the Ala147Thr SNP has the strongest association with risk of SVT. In conclusion, genetic variation in the TAFI gene is associated with risk of SVT, suggesting a role for TAFI in the pathogenetic mechanism of SVT.
Recombinant human activated factor VII is thrombogenic in a rabbit model of cyclic flow reduction and does not reduce intra-abdominal bleeding
Authors: Charbonneau Sonia , Girard François , Boudreault Daniel , Ruel Monique , Blais Normand , Hardy Jean-François 
Published: June 2007

SummaryRecombinant human activated factor VII (rHuFVIIa) can reduce bleeding but may be associated with arterial thrombosis. We hypothesized that rHuFVIIa would increase the occurrence of cyclic flow reductions (CFR) and reduce intra-abdominal bleeding in an experimental model. An adapted Folts’ model of carotid artery lesion and stenosis was used. Twenty four rabbits were randomized to receive rHuFVIIa (group F) or placebo (group P) in a double-blind fashion. A standardized injury to the common carotid artery resulted in CFR and/or thrombosis. Hematological values, coagulation and thromboelastographic (TEG) variables were compared. Intra-abdominal bleeding was evaluated by measuring blood loss from standardized hepatosplenic lesions. The median number (range) of spontaneous CFR [group P: 6 (0–15); group F: 8 (0–16)] was comparable between groups. The number of induced CFR (by “shaking” of the artery) needed to avert thrombosis (group F: 2; group P: 0 ; p < 0.05) and the incidence of complete carotid artery thrombosis (group F: 3; group P : 0; p < 0.05) were higher in group F. Intra-abdominal bleeding was similar in both groups. TEG analysis demonstrated a hypercoagulable state in both groups but the magnitude of the change was statistically more important in group F. rHuFVIIa increases thrombosis in a rabbit model of carotid artery injury. The bleeding from hepatic and splenic lesions is not reduced by administration of rHuFVIIa despite a hypercoagulable state confirmed by standard TEG analysis.
Inhibition of thrombin-induced platelet aggregation using human single-chain Fv antibodies specific for TREM-like transcript-1
Authors: Chisholm Maia , Quigley Laura , McMahon James , Mori Toshiyuki , Giomarelli Barbara , Washington Valance , McVicar Daniel 
Published: June 2007

SummaryTREM-like transcript-1 (TLT-1) is a novel platelet membrane receptor, which has been recently characterized in mice. TLT-1 is expressed exclusively in platelets and megakaryocytes, and its expression is dramatically upregulated upon platelet activation, suggesting that it plays a unique role in hemostasis and/or thrombosis. In this study we identified and characterized highly specific human monoclonal antibodies that bind to TLT-1 by screening a naïve library of single chain Fv fragments (scFvs) displayed on filamentous phage (Thomlinson I library). These scFvs detected plate-bound TLT-1, captured soluble TLT-1, and readily reacted with cell-bound TLT-1 on transfectants and primary human platelets. Most importantly, anti-TLT-1 scFvs inhibited thrombin-mediated human platelet aggregation. This inhibition was specific for thrombin-induced aggregation and was reversible with higher doses of agonist. These data are the first to demonstrate a biological role for TLT-1 and its potential as a therapeutic target. The human scFvs isolated in this study may represent novel anti-platelet therapeutic agents.
Plasminogen binds to plasmin-modulated factor Xa by Ca2+- and C-terminal lysine-dependent and -independent interactions
Authors: Grundy Jean E. , Hancock Mark A. , Meixner Scott C. , MacKenzie Roger C. , Koschinsky Marlys L. , Pryzdial Edward L. G. 
Published: June 2007

SummaryPlasminogen binding to receptors involves both C-terminal lysine-dependent and -independent interactions. The latter are poorly understood. Our earlier work demonstrated a novel Ca2+-enhanced bivalent interaction between plasmin-cleaved FXa (FXa33/13) and plasminogen truncated at Lys78 (Lys-Pg). Here we hypothesized that the effects of Ca2+may enable dissection of the C-terminal lysine-dependent and -independent interactions. To evaluate the role of the Glu-plasminogen (Glu-Pg) amino acids 1–77, binding of FXa33/13 to immobilized Glu-Pg was compared to Lys-Pg by surface plasmon resonance. Under identical conditions, approximately half the amount of FXa33/13 bound to Glu-Pg. The simplest fit of data suggested a 2:1 plasminogen:FXa33/13 stoichiometry for both, which were proportionately enhanced by Ca2+. Only Lys-Pg demonstrated significant Ca2+-independent binding to FXa33/13. In the presence of Ca2+, weak C-terminal lysine-independent binding could be detected, but only for Glu-Pg. The elastase-generated plasminogen fragment encompassing the angiostatin-like kringle domains 1 to 3 (K1–3) inhibited binding of FXa33/13 to Lys-Pg, whereas fragments corresponding to kringle 4- and kringle 5-protease domain had no effect. Immobilized K1–3 binding to FXa33/13 had both Ca2+-dependent and -independent components. The principal KMd for the interaction was 10-fold higher than Lys-Pg. In the presence of Ca2+, eACA inhibited FXa33/13 binding to K1–3 by 30%, but eliminated binding in the absence of Ca2+. These studies suggest that Ca2+-dependent and -independent binding of Lys-Pg to FXa33/13 are C-terminal lysine-dependent. The N-terminal 1–77 amino acids of Glu-Pg confer significant C-terminal lysine-independent binding, which may play a role during the initiating stages of plasminogen activation.
No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis
Authors: Keijzer Miranda B. A. J. , Borm George F. , Blom Henk J. , Bos Gerard M. J. , Rosendaal Frits R. , den Heijer Martin 
Published: June 2007

SummaryHomocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C, it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies, but not in others. We performed a meta-analysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls. We also investigated the interaction effect of factor V Leiden and hyperhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis. The meta-analysis yielded no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) –1.77 (95%CI –8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)].The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction; RERI 0.13 (95%CI –3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.
Cytokine production by CD4+ T cells specific for coagulation factor VIII in healthy subjects and haemophilia A patients
Authors: Guo Delan , Key Nigel , Conti-Fine Bianca , Hu Genlin 
Published: June 2007

SummaryHaemophiliaA patients treated with human factorVIII (fVIII) may develop antibody (Ab) inhibitors to fVIII. FVIII-specific CD4+ T cells are common in haemophilia A patients, but also in healthy subjects who do not have a sustained anti-fVIII Ab response. Here, we examined the fVIII-induced IFNγ -, IL-4- and TGF- β 1-producing CD4+ T blasts by culturing peripheral blood mononuclear cells (PBMC) from controls and patients with recombinant fVIII. FVIII exposure significantly increased IFNγ - and IL-4-, but not TGF-β 1-producing CD4+ T blasts in patients with inhibitors. Patients without inhibitors had fVIII-induced IFNγ - andTGF-β 1-,but not IL-4-producing CD4+ T blasts.Controls did not have IL-4-producing CD4+ T blasts. However, controls whose PMBC proliferated in response to fVIII had fVIII-induced CD4+ T blasts that produced IFN-γ, the number of which correlated with the intensity of the proliferative response to fVIII of their PMBC, whereas controls whose PMBC did not proliferate to fVIII had predominantly fVIII-induced CD4+ T blasts that producedTGF- β 1.The presence in controls and patients without inhibitors of fVIII-induced IFN-γ -producing CD4 + T cells, but not IL-4-producing CD4+ T cells, which are abundant in inhibitor patients, suggests a role of Th1 cells in initiating the immune response to fVIII, and of Th2 cells in the development of strong inhibitor production. The polarized high ratios of Th3/Th1 and Th3/Th2 in controls and patients without inhibitors suggest that a preponderance ofTh3 cells in the response to fVIII may help to maintain tolerance to fVIII.
Simple and safe exclusion of pulmonary embolism in outpatients using quantitative D-dimer and Wells’ simplified decision rule
Authors: Steeghs Neeltje , Niessen Rene W. L. M. , Jonkers Gé J. P. M. , Dik Hans , Castel Ad , Werker-van Gelder Lies , Vlasveld Tom L. , van Klink Rik C. J. , Planken Erwin V. , Huisman Menno V. , Goekoop Robbert J. 
Published: June 2007

SummaryA safe and effective management strategy is pivotal in excluding pulmonary embolism (PE). The combination of Wells’ simplified dichotomous clinical decision rule and D-dimer test is non-invasive and could be highly efficient, though its safety has not been widely studied. We evaluated safety and efficiency of this combination in excluding PE. Wells clinical decision rule was performed in 941 consecutive patients with suspected PE and, if patients had a score ≤ 4.0 points, a VIDAS D-dimer test followed. Patients with a normal D-dimer concentration had no further tests, PE was considered excluded, and patients did not receive anticoagulant treatment. Patients, in whom PE was excluded, were followed up for three months. Four hundred fifty patients (51.2%) had a clinical decision score ≤ 4.0 points and a normal D-dimer concentration. In 45 of these patients, during the initial diagnostic period additional objective testing, although not indicated, was performed, and PE was established in two patients. During three months of follow up no venous thromboembolic events (VTE) occurred. Therefore, the overall VTE failure rate was two of 450 (0.4% [95%CI 0–1.1]); the overall prevalence of PE was 12.3%. The diagnostic protocol could be completed and allowed a decision to be made in 90% of the study patients. This study has prospectively established the safety of a combination of a dichotomized clinical decision rule and D-dimer test in ruling out PE. The strategy proved highly efficient, since more than 50% of patients could be managed without the need for more invasive and expensive tests.
Crucial roles of GATA-2 and SP1 in adrenomedullin-affected expression of tissue factor pathway inhibitor in human umbilical vein endothelial cells exposed to lipopolysaccharide
Authors: Wang Wen , Zu Shu-Yu , Liu Wei , Zhu Zi-Qiang , Zhu Guang-Jin 
Published: June 2007

SummaryAdrenomedullin (ADM) is a vasodilator peptide that has a variety of effects, including antithrombotic activities and resistant roles to lipopolysaccharide (LPS)-induced septic shock. During sepsis,LPS triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation.It is unknown whether the antithrombotic activities of ADM contribute to its resistance to sepsis. In the present study, we investigated the effects of ADM on tissue factor pathway inhibitor (TFPI) (primary anticoagulant factor) expression in human umbilical vein endothelial cells (HUVECs) exposed to LPS,and the possible underlying mechanism for these effects.Exposure of HUVECs to LPS for 12 hours caused significant decrease of TFPI protein activities and mRNA expression.These effects were abolished by treatment withADM (10–10 to 10–6 M), cAMP analogue and calcium antagonist. Accordingly, cAMP antagonist inhibited the counteraction effect of ADM on LPS in TFPI expression. Electrophoresis mobility shift assay (EMSA) and Western blot analysis showed that the protein level of GATA-2 and SP1 transcriptional factors and their binding to the corresponding regulatory sequences decreased by LPS treatment. And these effects of LPS were antagonized by ADM. Promoter- reporter assays and mutational analysis also confirmed the roles of GATA-2 and SP1 motifs from –1247 to –381bp promoter sequence in TFPI inducible expression. Taken together, these results indicate that ADM antagonizes the effect of LPS on TFPI expression, which is mediated by affecting transcriptional factor GATA-2 and SP1 through cAMP and calcium signaling pathway.
A novel inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) – Part II: Enhancement of both exogenous and endogenous fibrinolysis in animal models of thrombosis
Authors: da Cunha Valdeci , Vincelette Jon , Zhao Lei , Nagashima Mariko , Kawai Kohichi , Yuan Shendong , Emayan Kumar , Islam Imadul , Hosoya Junko , Sullivan Mark E. , Dole William P. , Morser John , Buckman Brad O. , Vergona Ronald , Wang Yi-Xin 
Published: June 2007

SummaryWe have discovered a novel small-molecule TAFIa inhibitor, BX 528, which is potent, highly selective against other carboxypeptidases and safe. The present study was to determine if BX 528 can enhance exogenous and endogenous thrombolysis in four different animal models. In the first three models, a thrombus was induced by FeCl2 (dogs) or laser (rats) injury of the femoral artery, or formed ex vivo and implanted in the jugular vein in rabbits. A low dose of exogenous t-PA was given to induce a lowlevel thrombolysis on an established thrombus. Co-treatment with BX 528 further enhanced the thrombolytic effects induced by the exogenous t-PA and, thus, r educed thrombosis in all three animal models. In a second rat model, fibrin deposition in the lungs was induced by batroxobin, which was spontaneously resolved in 30 minutes due to the activation of endogenous fibrinolysis. Pre-treatment with lipopolysaccharide (LPS) attenuated this spontaneous fibrinolysis. Co-treatment with 10 mg/kg BX 528 prevented the LPS-induced attenuation of endogenous fibrinolysis. Thus, these studies demonstrated that inhibition ofTAFIa by BX 528, our newly discovered small-molecule TAFIa inhibitor, enhanced both the exogenous (induced by a low dose of t-PA) and endogenous (LPS-induced resistance) thrombolysis without increasing the bleeding risk in four different animal models of thrombosis in different species (rat, dog and rabbit) employing different thrombogenic stimuli (FeCl2, laser, ex vivo and batroxobin) to induce thrombus formation in different tissues (artery, vein and lung microcirculation).