bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-oxidant ebselen delays microvascular thrombus formation in the rat cremaster muscle by inhibiting platelet P-selectin expression
Authors: Lindenblatt Nicole , Schareck Wolfgang , Belusa Lorenz , Nickels Ruth , Menger Michael , Vollmar Brigitte 
Published: September 2003

SummaryEbselen, a seleno-organic compound showing glutathione peroxidase-like activity, has potent anti-inflammatory and anti-oxidant effects. Since selenium deficiency is thought to be associated with an increased incidence of vascular thrombosis, we studied the effect of ebselen on blood cell aggregate formation and vessel occlusion in vivo. In individual microvessels of rat cremaster muscle preparations, photochemically induced thrombus formation was analyzed in detail using intravital fluorescence microscopy. In ebselen-pretreated animals (30mg/kg ip), venular thrombus formation was significantly delayed (50% vessel occlusion: 535±34s; initial stasis: 872±82s; complete occlusion: 908±87s) as compared to vehicle-treated controls (416±42; 612±49; 647±51). Moreover, ebselen significantly prolonged the kinetics of arteriolar thrombus formation and even completely prevented blood cell aggregate and thrombus formation in 88.9% of all arterioles studied (p<0.05 vs controls:37.5%). Anti-thrombotic properties of ebselen could also be observed in a model of ferric chloride-induced microvascular thrombosis, with a low dose (5mg/kg ip) being as effective as a high dose pretreatment (30mg/kg ip). As assessed by flow cytometry of platelet P-selectin immunfluorescence, whole blood isolated from ebselen-treated animals revealed a significantly lower fraction of P-selectin expressing platelets when compared with that of DMSO-treated controls. In addition, oxidant stress-induced upregulation of P-selectin on isolated platelets was found dose-dependently inhibited by increasing concentrations of ebselen (10-100µM). Moreover, ebselen dose-dependently inhibited H2O2-induced platelet-leukocyte aggregate formation in whole blood in vitro, suggesting that the anti-thrombotic effect of ebselen is achieved by attenuation of P-selectin dependent platelet-leukocyte aggregation. Thus, ebselen represents preventive and therapeutic value for disorders with increased risk for oxidant stress-associated thrombotic events.
Soluble CD146, a novel endothelial marker, is increased in physiopathological settings linked to endothelial junctional alteration
Authors: Moal Valérie , Anfosso Francine , Daniel Laurent , Brunet Philippe , Sampol José , George Françoise , Bardin Nathalie 
Published: September 2003

SummaryCD146, a novel cell adhesion molecule localized at the endothelial junction, is involved in the control of cell-cell cohesion. It is found as a soluble form in conditioned medium of cultured endothelial cells. We developed an ELISA and report for the first time the presence of a soluble form of CD146 (sCD146) in the plasma of healthy subjects. Mean sCD146 values (260 ± 60 ng/ml) were higher in subjects over 50 years and in men. We therefore investigated sCD146 values in patients with chronic renal failure (CRF), a clinical setting associated with junctional alterations. A significant increase in sCD146 was found in patients with CRF matched with controls (457 ± 181 ng/ml versus 288 ± 82 ng/ml respectively, p<0.0001). This increase was corroborated by increased endothelial expression of CD146 on kidney biopsies from patients with CRF. In contrast, in patients with CRF no modulation was observed for the soluble and cell-associated form of CD31, another junctional molecule. Together these data indicate that sCD146 circulates in the plasma of healthy subjects. Modifications of its basal levels could reflect alterations of junctional functions such as vascular permeability.
Thrombophilia does not increase risk for neonatal complications in preterm infants
Authors: Kenet Gili , Maayan-Metzger Ayala , Rosenberg Nurit , Sela Ben-Ami , Mazkereth Ram , Ifrah Aviyah , Kuint Jacob 
Published: September 2003

SummaryThe association between thrombophilia and neonatal complications was evaluated in a single-center prospective study. Prevalence of genetic prothrombotic markers (FVL, MTHFR, FIIG20210A) and levels of plasma homocysteine were assayed in 166 premature (mean gestational age: 30.9±2.3 weeks) and low birth weight (mean weight: 1327±319 grams) infants. The incidence of any neonatal complications was compared in infants with and without thrombophilia. A total of 38 infants were defined as “thrombophilic” due to heterozygous FVL (n=4) and/or FIIG20210A (n=8, including one case of combination with FVL) or homozygous 677T MTHFR (n=22) or homo-cysteine plasma levels above 15µmole/liter. Neonatal complications included: small for gestational age (28.8%), respiratory distress syndrome (51.8%), broncho-pulmonary dysplasia (10.2%), patent ductus arteriosus (12.7%), intraventricular hemorrhage (17%), periventricular leucomalacia (8.4%), retinopathy of prematurity (15.1%) and necrotizing enterocolitis in 1.2% of infants. No thrombosis was documented. The prevalence of perinatal complications and the severity of diseases were similar among infants with or without thrombophilia (p=0.564). Our data suggest that preterm infants with thrombophilia are not at increased risk for developing neonatal complications.
Paris-Trousseau syndrome : clinical, hematological, molecular data of ten new cases
Authors: Favier Remi , Jondeau Katayoun , Boutard Patrice , Grossfeld Paul , Reinert Philippe , Jones Christopher , Bertoni Francesco , Cramer Elisabeth 
Published: September 2003

SummaryParis-Trousseau syndrome (PTS) is an inherited disorder char-acterized by mild hemorragic tendency associated with 11q chromosome deletion. Here we report ten new patients (5 boys,5 girls) with complete clinical history, biological data, ultra-structural and molecular investigations. Thrombocytopenia is chronic in all the patients except two boys in whom it disappeared during the two first years of life. On Romanovsky stained peripheral blood smears, abnormal platelets with giant granules were detected in all the children and confirmed by electron microscopy (EM). On bone marrow smears, dysmega-karyopoiesis with many micromegakaryocytes was constantly observed. Abnormal alpha-granules were virtually absent from bone marrow and cultured megakaryocytes, while EM detected numerous images of granule fusion within blood platelets. Molecular analyses evidenced that the fli-1 gene is deleted in all the patients except one confirming the crucial role of the transcription factor FLI-1 in megakaryopoiesis. In summary, this study documents ten new cases of PTS with characteristic alpha-granule abnormalities, and shows the putative pathogenic role of fli-1 gene in the pathophysiology of this syndrome.
Aminopeptidase inhibitor bestatin stimulates microvascular endothelial cell invasion in a fibrin matrix
Authors: Hensbergen Yvette , Peters Erna , Rana Sareena , Elderkamp Yvonne , van Hinsbergh Victor , Koolwijk Pieter , Broxterman Henk 
Published: September 2003

SummaryThe aminopeptidase inhibitor bestatin has been shown to have anti-angiogenic effects in a number of model systems. These effects are thought to result from inhibition of CD13 activity. Because tumor angiogenesis can evolve in a fibrin-rich stroma matrix we have studied for the first time the effects of bestatin on microvascular endothelial capillary-like tube formation in a fibrin matrix. Bestatin enhanced the formation of capillary-like tubes dose-dependently. Its effects were apparent at 8 µM; the increase was 3.7-fold at 125 µM; while high concentrations (>250 µM), that were shown to have anti-angiogenic effects in other systems, caused extensive matrix degradation. Specific CD13-blocking antibodies WM15 and MY-7, and the aminopeptidase inhibitors amastatin and actinonin also enhanced capillary-like tube formation (maximally 1.5-fold), but these effects did not reach statistical significance. The effect of bestatin was not due to a change in uPAR availability because the relative involvement of the u-PA/u-PAR activity was not altered by bestatin. In view of the present findings we hypothesize that aminopeptidases other than CD13 predominantly contribute to the observed pro-angiogenic effect of bestatin in a fibrin matrix. The identification of this novel effect of bestatin is important in the light of the proposed use of bestatin as anti-angiogenic and/or anti-tumor agent.
Ultrasound screening for distal vein thrombosis is not beneficial after major orthopedic surgery.
Authors: Michler Ronny , Klein Martin , Faulmann Grit , Weber Christian , Schellong Sebastian , Schmidt Benjamin 
Published: September 2003

SummaryUltrasound screening for deep vein thrombosis (DVT) after orthopedic surgery revealed thrombosis in up to 30% of patients, but the clinical impact of screening for distal thrombosis has not been established.Three hundred and forty six patients after hip or knee replacement and postoperative standard prophylaxis of 10 days low molecular weight heparin (LMWH) were randomized to receive either prolonged prophylaxis with LMWH or postoperative ultrasound screening for proximal and distal thrombosis. All thrombosis found in screening was treated. Patients with a negative screening test did not receive any heparin after day 10. The cumulative rate of proximal thrombosis and symptomatic pulmonary embolism until day 35 postoperatively was determined.In 174 screening patients, ultrasound found 55 cases of distal (31.6%) and 9 cases of proximal (5.1%) in-hospital thrombosis. In 108 screening patients without thrombosis at discharge 7 new distal (6.5%) and 6 new proximal (5.6%) thrombotic events occurred by day 35. In 163 patients with prolonged prophylaxis, 33 cases of distal (20.2%) and 7 cases of proximal (4,3%) thrombotic events occurred by day 35. The cumulative rate of proximal events was 8,7% in the screening group and 4.3% in the prophylaxis group (p=0.12).In conclusion, ultrasound screening for thrombosis does not reduce the rate of proximal thrombosis and symptomatic pulmonary embolism 35 days after hip or knee replacement surgery.
A mutation in the integrin αIIb subunit that selectively inhibits αIIbβ3 receptor function
Authors: Perkins Kim , Loftus Joseph 
Published: September 2003

SummaryThe αIIband αvintegrins have been shown to play a significant role in a variety of disease processes. αIIbβ3is a platelet-specific fibrinogen receptor that is critical for thrombosis and hemo-stasis. Determination of the basis of ligand recognition by αIIbβ3is essential for modulation of platelet function. To identify αIIbresidues involved in αIIbβ3ligand binding function, cells expressing a constitutively active variant of αIIbβ3were randomly mutagenized and selected for loss of αIIbβ3ligand binding function. One mutant isolated in this manner contained a single amino acid substitution at position 96 in αIIb(Ser96→Leu). Cells expressing this αIIbmutant did not bind the ligand mimetic antibody PAC1 or adhere to fibrinogen. In addition, the mutant receptor did not bind to an RGD affinity matrix. Substitution of conserved serine residues at position 1 in β strand A of all seven repeats of αIIbsimilarly inhibited ligand binding to αIIbβ3. αIIbS96 maps to the central cavity of the β–propeller fold of the αIIbsubunit immediately adjacent to a structurally important sequence at the center of the α and β subunit interface. In contrast, substitution of the analogous residues in αvor α4did not disrupt the ligand binding function of αvβ3or α4β1. These data support a potential unique structural or mechanistic role for this residue in αIIbβ3receptor function.
Role of c-kit/Kit ligand signaling in regulating vasculogenesis
Authors: Heissig Beate , Werb Zena , Rafii Shahin , Hattori Koichi 
Published: September 2003

SummaryMobilization into peripheral blood of bone marrow-derived cells including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), is regulated by chemokines/cytokines. These cells can contribute to the formation of new blood vessels (vasculogenesis) under pathological conditions including atherosclerosis, wound healing and tumor growth. We will review how these cells are mobilized into circulation, and supplied to the sites, where vessel formation is needed (i.e. ischemic tissue or tumor bed).We will give evidence that matrix metalloproteinase-9 mediated Kit ligand (Stem cell factor) processing is essential for cell mobilization induced by chemo-/cyto-kines, like vascular endothelial growth factor (VEGF), Placental growth factor (PlGF), stromal cell derived factor-1 (SDF-1). These studies may provide the basis for the development of new therapeutic strategies for vascular diseases through targeting kit ligand mediated mobilization and homing of bone marrow-derived progenitor cells for cell therapy and cancer therapy.This publication was partially financed by Serono Foundation for the Advancement of Medical Science. Financial support: This work was supported by a grant from the Japanese Society for the Promotion of Science (B.H.) and by funds from the National Institutes of Health (CA 72006 and AR46238 to ZW). Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.
Regulation of endothelial cell integrin function and angiogenesis by COX-2, cAMP and Protein Kinase A
Authors: Dormond Olivier , Rüegg Curzio 
Published: September 2003

SummaryAngiogenesis, the development of new blood vessels from preexisting vessels, is a key step in tumor growth, invasion and metastasis formation. Inhibition of tumor angiogenesis is considered as an attractive approach to suppress cancer progression and spreading. Adhesion receptors of the integrin family promote tumor angiogenesis by mediating cell migration, proliferation and survival of angiogenic endothelial cells. Integrins up regulated and highly expressed on neovascular endothelial cells, such as αVβ3 and α5β1, have been considered as relevant targets for anti-angiogenic therapies. Small molecular integrin antagonists or blocking antibodies suppress angiogenesis and tumor progression in many animal models, and some of them are currently being tested in cancer clinical trials as anti-angiogenic agents. COX-2 inhibitors exert anti-cancer effects, at least in part, by inhibiting tumor angiogenesis. We have recently shown that COX-2 inhibitors suppress endothelial cell migration and angiogenesis by preventing αVβ3-mediated and cAMP/PKA-dependent activation of the small GTPases Rac and Cdc42. Here we will review the evidence for the involvement of vascular integrins in mediating angiogenesis and the role of COX-2 metabolites in modulating the cAMP/Protein Kinase A pathway and αVβ3-dependent Rac activation in endothelial cells.The pulication was partially financed by Serono Foundation for the Advancement of Medical Sience.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6–9, 2003 in Geneva, Switzerland.
Lymphangiogenesis and tumor metastasis
Authors: Nisato Riccardo , Tille Jean-Christophe , Pepper Michael 
Published: September 2003

SummaryIn several human cancers, increased expression in primary tumors of vascular endothelial growth factor-C (VEGF-C) is correlated with regional lymph node metastasis. Studies using transgenic mice overexpressing VEGF-C, or xenotransplantation of VEGF-C-expressing tumor cells into immunodeficient mice, have demonstrated a role for VEGF-C in tumor lymphangiogenesis and the subsequent formation of lymph node metastasis. However, at variance with data obtained in animal models, there is at present very little evidence for lymphangiogenesis in human tumors. Nonetheless, the striking correlation between levels of VEGF-C in primary human tumors and lymph node metastases exists, which suggests that VEGF-C may serve functions other than lymphangiogenesis. Thus, VEGF-C may activate pre-existing lymphatics which in turn become directly involved in tumor cell chemotaxis, intralymphatic intravasation and distal dissemination. A reciprocal dialogue is therefore likely to exist between tumor and lymphatic endothelial cells which results in the formation of lymph node metastases.This publication was partially financed by Serono Foundation for the Advancement of Medical Science.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.
Global gene expression profiles in fibroblasts from synovial, skin and lymphoid tissue reveals distinct cytokine and chemokine expression patterns
Authors: Filer Andrew , Ross Ewan , Bofill Margarita , Martin Stuart , Salmon Mike , Parsonage Greg , Falciani Francesco , Burman Angela , Buckley Christopher 
Published: September 2003

SummaryWe investigated the extent to which fibroblasts isolated from diverse tissues differ in their capacity to modulate inflammation by comparing the global gene expression profiles of cultured human fibroblasts from skin, acute and chronically inflamed synovium, lymph node and tonsil. The responses of these fibroblasts to TNF-α, IFN-γ and IL-4 stimulation were markedly different, as revealed by hierarchical cluster analysis and principal component analysis. In the absence of exogenous cytokine, syn-ovial and skin fibroblasts exhibited similar patterns of gene expression. However their transcriptional profiles diverged upon treatment with TNF-α.This proved to be biologically relevant, as TNF-α induced the secretion of different patterns and amounts of IL-6, IL-8 and CCL2 (MCP-1) in the two fibroblast types. Co-culture of skin or synovial fibroblasts with synovial fluid-derived mononuclear cells provided further evidence that these transcriptional differences were functionally significant in an ex vivo setting. Interestingly, the transcriptional response of skin fibroblasts to IL-4 converged with that of TNF-α-treated synovial fibroblasts, suggesting resident tissue fibroblasts and their blood-borne precursors may be imprinted by inflammatory cytokines that are characteristic of different tissues. Our data supports the concept that fibroblasts are heterogeneous, and that they contribute to the tissue-specificity of inflammatory reactions. Fibroblasts are therefore likely to play an active role in the persistence of chronic inflammatory reactions.This publication was partially financed by Serono Foundation for the Advancement of Medical Science.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.
Migration of leukocytes through the vessel wall and beyond
Authors: Yadav Rashmi , Larbi Karen , Young Rebecca , Nourshargh Sussan 
Published: September 2003

SummaryThe migration of leukocytes from the vascular lumen to sites of infection and/or injury in the extravascular tissue involves a series of sequential and coordinated molecular and cellular events with the resultant primary response being that of reduced leukocyte velocity within the blood stream, followed by leukocyte firm adhesion to endothelial cells lining the vessel wall and eventually migration through the vessel wall. Despite the growing knowledge of the mechanisms that mediate initial interaction of leukocytes with the endothelium, very little is known about the mechanisms that mediate and regulate leukocyte migration through the venular wall, the endothelium and its associated perivascular basement membrane. This review, whilst giving a brief outline of the stepwise cascade of molecular interactions involved in this process and the methods employed to investigate leukocyte migration in vivo, focuses primarily on mechanisms of leukocyte transmigration, the final step in the process of leukocyte emigration. Furthermore, special emphasis is placed on discussing the process and the mechanisms involved in leukocyte migration through the basement membrane, a structure that presents significant impedance to transmigrating leukocytes but is seldom investigated in the context of leukocyte transmigration in vivo. The review also discusses the growing evidence supporting the concept that leukocyte transmigration is not only a response that describes the passage of leukocytes through the venular wall, but also acts as a means of regulating leukocyte responsiveness beyond the vessel wall, i.e. within the extravascular tissue.This publication was partially financed by Serono Foundation for the Advancement of Medical Science.Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.
High molecular weight kininogen and factor XII binding to endothelial cells and astrocytes
Authors: Fernando Lawrence , Natesan Snehlatha , Joseph Kusumam , Kaplan Allen 
Published: September 2003

SummaryWe have quantitated the binding of high molecular weight kininogen (HK) to human microvascular endothelial cells of lung and dermal origin as well as to astrocytes and compared the results with those reported for human umbilical vein endothelial cells (HUVEC). We also reassessed parameters of binding to HUVEC employing cells in suspension as well as cells attached to the culture plate and report similar numbers of sites varying from 6.96x105to 7.71x105per cell. The present study shows that HK binds with high specificity and affinity to microvascular endothelial cells (Kd = 1.86 to 4.5 nM) compared to HUVEC (Kd = 10.35nM) but with lower affinity to astrocytes (Kd = 23.73 nM). Human cytokeratin 1, urokinase plasminogen activator receptor and gC1qR were found to be HK binding proteins present at the surface of microvascular endothelial cells and astrocytes analogous to that seen in HUVEC, as assessed by inhibition of binding with antibody to each protein. Lung microvascular endothelial cells had approximately half the number of HK binding sites as HUVEC while dermal micro vascular endothelial cells and astrocytes had only 8-10% of the sites/cell. The affinity of binding to the microvascular endothelial cells was greater than HUVEC, the affinity of binding to astrocytes was considerably less, nevertheless binding to each cell type involves gC1qR, cytokeratin 1 and u-PAR to varying degrees. We also demonstrate, for the first time, that factor XII binds to all of these cell types in a saturable and Zn+2dependent manner. Given that factor XII accelerates the interactions among cell surfaces and proteins of the contact activation cascade to generate bradykinin, binding of factor XII (and the prekallikrein-HK complex) may serve as a mechanism by which these proteins are concentrated locally to facilitate their interactions.