bluuebunny/crossref_metadata_2025_split huggingface dataset:
Platelet dysfunction during Bothrops jararaca snake envenomation in rabbits
Authors: Sano-Martins Ida , Santoro Marcelo 
Published: July 2004

SummaryDespite being well established that snake envenomation causes blood coagulation and fibrinolysis disturbances, scant information is available about blood platelet disorders. Herein we show that experimentally Bothrops jararaca-envenomed rabbits presented thrombocytopenia, hypofibrinogenemia, elevation of von Willebrand factor plasma levels, platelet hypoaggregation in platelet rich plasma and whole blood, normoaggregation in washed platelet suspensions, decreased platelet ATP secretion, normal plasma levels of platelet factor 4, and constant intraplatelet serotonin levels. Furthermore, by flow cytometric analyses, platelets displayed a significant decrease in the expression of a GPIIb-IIIa epitope recognized by P2 monoclonal antibody (p< 0.05) and an increased expression of a ligandinduced binding site (LIBS-1) of GPIIIa (p< 0.05), but total GPIIb-IIIa expression, evaluated with specific polyclonal antibodies, was normal. Fibrinogen and fibrin(ogen) degradation product (FfDP) expression on platelet surface showed no significant alteration. Nonetheless, significant elevations of platelet P-selectin were noticed on circulating platelets. The percentage of circulating reticulated platelets and the survival time of biotinylated platelets of envenomed rabbits were not statistically different from control animals. We suggest that thrombin engendered by procoagulating components of B. jararaca venom has an essential role in the pathogenesis of platelet and coagulation disorders in this experimental model. Increased expression of P-selectin in the experimental group demonstrates that platelets of envenomed rabbits are indeed activated in circulation, and that decreased fibrinogen or increased FfDP levels are not the primary cause of platelet dysfunction. These results imply the existence of an inhibitor in plasma that interferes with platelet aggregation in bothropic envenomation.
Extrinsic coagulation pathway activation and metalloproteinase-2/TIMPs system are related to oxidative stress and atherosclerosis in hemodialysis patients
Authors: Pawlak Dariusz , Mysliwiec Michal , Pawlak Krystyna 
Published: July 2004

SummaryMatrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), together with extrinsic coagulation pathway activation and increased oxidative stress (SOX) have all been implicated as important factors in atherosclerosis and vascular remodelling. The aim of the present study was to investigate whether the MMPs/TIMPs system is associated with activation of the extrinsic coagulation pathway in conditions of increased SOX in hemodialysis (HD) patients. In HD patients, with and without cardiovascular disease (CVD), and in controls, we compared pre-dialysis levels of MMP-2, MMP-9,TIMP-1,TIMP-2; the markers of extrinsic coagulation pathway-tissue factor (TF) and its inhibitor (TFPI), prothrombin fragment F1+2 (F1+2); a marker of SOX-Cu/Zn superoxide dismutase (Cu/Zn SOD) and a surrogate of atherosclerotic disease-intima media thickness (IMT). Hemodialysis patients, particularly those with CVD, showed a significant increase in values of MMP-2/TIMPs, markers of the extrinsic coagulation pathway, Cu/Zn SOD and IMT as compared to controls. The markers of coagulation activation positively correlated with the MMP-2/TIMPs system, whereas they did not correlate with MMP-9. In addition, both MMP-2/TIMPs as well as extrinsic coagulation parameters were related to the prevalence of increased SOX, IMT and CVD. Multiple stepwise regression analysis showed that low TIMP-2 followed by increased Cu/Zn SOD and MMP-2 levels independently and significantly predicted elevated IMT on maintenance HD patients. In conclusion, our data suggest that the MMP-2/TIMPs system and an activated extrinsic coagulation pathway could cooperate in conditions of elevated SOX and could influence arterial remodeling resulting in the presence of CVD in haemodialysis patients.
The catalytic subunit of pseutarin C, a group C prothrombin activator from the venom of Pseudonaja textilis, is structurally similar to mammalian blood coagulation factor Xa
Authors: Rao Veena , Swarup Sanjay , Kini Manjunatha 
Published: July 2004

SummaryPseutarin C, a group C prothrombin activator from Pseudonaja textilis venom, is a large protein complex consisting of catalytic and nonenzymatic subunits, which are functionally similar to the mammalian FXa-FVa complex. Here, we present the complete cDNA sequence of the catalytic subunit of pseutarin C. The cDNA of the catalytic subunit encodes a protein of 449 amino acids, which includes a 22-residue signal peptide, 18-residue propeptide and a mature protein of 409 amino acids. The deduced amino acid sequence shows 74-83% identity to group D prothrombin activators from snake venom and ∼42% identity to mammalian FX and has identical domain structure. The precursor of the catalytic subunit of pseutarin C has several unique features. The activation peptide of the catalytic subunit of pseutarin C is significantly smaller (27 as compared to 52 residues in mammalian FX) and does not contain any glycosylation sites. Unlike coagulation FXa, Ser52 and Asn45 of the light and heavy chains are O- and N-glycosylated in pseutarin C catalytic subunit. There is a 12-residue insertion in pseutarin C catalytic subunit close to the region that is implicated in binding to FVa. This is the first sequence of the catalytic subunit of a group C prothrombin activator.
The potential clinical and economic outcomes of pharmacogenetics-oriented management of warfarin therapy – a decision analysis
Authors: Chan Fredric , Wong Raymond , Cheng Gregory , You Joyce 
Published: July 2004

SummaryVariant cytochrome P450 (CYP) 2C9 genotypes are associated with low maintenance dose requirement of warfarin therapy and increased risk of major bleeding events. The objective of the present study was to evaluate the potential clinical and economic outcomes of using CYP2C9 genotype data to guide the management of anticoagulation therapy and to identify influential factors affecting the cost-effectiveness of this treatment scheme. A decision tree was designed to simulate, over 12 months, the clinical and economic outcomes of patients newly started on warfarin associated with two alternatives: (1) no genotyping (non-genotyped group) and (2) CYP2C9 genotyping prior to initiation of warfarin therapy (genotyped group). Nongenotyped group patients would receive standard care of an anticoagulation clinic (AC). In the genotyped group, patients with at least one variant CYP2C9 allele would receive intensified anticoagulation service. Most of the clinical probabilities were derived from literature. The direct medical costs were estimated from the Diagnosis-Related Group charges and from literature. The total number of events and the direct medical cost per 100 patient-years in the genotyped and non-genotyped groups were 9.58 and USD155,700, and, 10.48 and USD 150,500, respectively. The marginal cost per additional major bleeding averted in the genotyped group was USD 5,778. The model was sensitive to the variation of the cost and reduction of bleeding rate in the intensified anticoagulation service. In conclusion, the pharmacogenetics-oriented management of warfarin therapy is potentially more effective in preventing bleeding with a marginal cost. The cost-effectiveness of this treatment scheme depends on the relative cost and effectiveness of a pharmacogenetics-oriented intensified anticoagulation service comparing to the standard AC care.
Postmenopausal hormone replacement and venous thromboembolism following hip and knee arthroplasty
Authors: Hurbanek Jason , Jaffer Amir , Morra Nariman , Karafa Matthew , Brotman Daniel 
Published: July 2004

SummaryHormone replacement therapy has been associated with venous thromboembolism. Controversy exists regarding the appropriate management of hormone replacement in the perioperative setting and in other situations – such as acute illness – predisposing to acute venous thromboembolism. We performed a case-control study to determine whether perioperative hormone replacement is associated with venous thromboembolism following hip and knee arthroplasty. 108 patients with postoperative venous thrombosis were matched by age, date and type of surgery, and surgeon with 210 controls without thrombosis. Perioperative hormone replacement use was no more prevalent in patients with postoperative thrombosis than those without. Eighteen (16.7%) women with post-operative thrombosis had taken perioperative hormone replacement compared to 49 (23.3%) of controls: odds ratio = 0.66; (95% CI 0.35–1.18; p=0.17). After multivariate analysis, the adjusted odds ratios were similar. Variables predicting post-operative thrombosis included: prior venous thromboembolism (OR = 2.3; p = 0.02), rheumatologic disease (OR = 2.2; p = 0.03), and absence of pharmacologic antithrombotic prophylaxis (OR = 13.4; p = 0.005). Cases and controls were otherwise similar. Users of hormone replacement were similar to non-users except that they were less likely to have coronary disease (OR 0.34; p = 0.03) or prior thrombosis (OR = 0.28; p = 0.04), and were younger (median age 67 versus 74 years; p <0.0001). We found no association between perioperative hormone replacement and post-operative thrombosis in patients undergoing major orthopaedic surgery. Routine discontinuation of these medications preoperatively – and possibly in other situations predisposing to thrombosis, such as acute medical illness – may be unnecessary in patients receiving appropriate pharmacologic antithrombotic prophylaxis.
Extracellular regulation of TGF-β activity in wound repair: growth factor latency as a sensor mechanism for injury
Authors: Blakytny Robert , Brunner Georg 
Published: July 2004

SummaryThe transforming growth factor-β (TGF-β) family of growth factors are major regulators of wound repair, scar formation, and fibrosis. One of the prominent features of TGF-β biology is the fact that this growth factor is secreted as a latent precursor, which may be directed to and stored at specific sites in the cellular microenvironment. Targeting and mobilization, and particularly extracellular activation of latent TGF-β control the biological action of this growth factor. This review will focus on mechanisms of extracellular TGF-β regulation relevant to and potentially operating in wound repair and scarring.
Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis
Authors: Griswold Ian J. , Shen Lei J. , La Rosée Paul , Demehri Shadmehr , Heinrich Michael C. , Braziel Rita M. , McGreevey Laura , Haley Andrea D. , Giese Neill , Druker Brian J. , Deininger Michael W.N. 
Published: July 2004

AbstractInternal tandem duplications (ITDs) of the FMS-like tyrosine kinase 3 (FLT3) receptor tyrosine kinase are found in approximately 30% of patients with acute myelogenous leukemia (AML) and are associated with a poor prognosis. FLT3 ITD mutations result in constitutive kinase activation and are thought to be pathogenetically relevant, implicating FLT3 as a plausible therapeutic target. MLN518 (formerly CT53518) is a small molecule inhibitor of the FLT3, KIT, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases with significant activity in murine models of FLT3 ITD-positive leukemia. Given the importance of FLT3 and KIT for normal hematopoietic progenitor cells, we analyzed the effect of MLN518 on murine hematopoiesis under steady-state conditions, after chemotherapy-induced myelosuppression, and during bone marrow transplantation. In these assays, we show that MLN518 has mild toxicity toward normal hematopoiesis at concentrations that are effective in treating FLT3 ITD-positive leukemia in mice. We also demonstrate that MLN518 preferentially inhibits the growth of blast colonies from FLT3 ITD-positive compared with ITD-negative patients with AML, at concentrations that do not significantly affect colony formation by normal human progenitor cells. In analogy to imatinib mesylate in BCR-ABL–positive acute leukemia, MLN518-induced remissions may not be durable. Our studies provide the basis for integrating this compound into chemotherapy and transplantation protocols.
Apoptotic bodies from endothelial cells enhance the number and initiate the differentiation of human endothelial progenitor cells in vitro
Authors: Hristov Mihail , Erl Wolfgang , Linder Stefan , Weber Peter C. 
Published: July 2004

Abstract
Endothelial progenitor cells (EPCs) play a role in the repair of ischemic or injured tissue. Because endothelial injury can be associated with apoptosis, we have investigated whether apoptotic bodies from mature endothelial cells (ECs) may affect growth and differentiation of EPCs in vitro. A 24-hour incubation of isolated human EPCs with apoptotic bodies-rich medium (ABRM) from ECs led to a significant increase in the number of spindle-shaped attached cells. EPCs were characterized by DiI-Ac-LDL/lectin staining and measurement of CD34 and kinase insert domain receptor (KDR) expression. The treatment with ABRM resulted in a 2-fold increase of DiI-Ac-LDL/lectin-positive cells and up-regulation of CD34 (22% ± 2% versus 13% ± 3%, P &lt; .05 and KDR (49% ± 12% versus 19% ± 7%, P &lt; .05). Fluorescence and confocal laser microscopy demonstrated the uptake of apoptotic bodies by the EPCs. Apoptotic bodies-depleted medium had no effect, whereas the incubation with suspension of apoptotic bodies induced effects similar to those of ABRM. Our results suggest that apoptotic bodies from ECs are taken up by EPCs, increasing their number and differentiation state. Such a mechanism may facilitate the repair of injured endothelium and may represent a new signaling pathway between progenitor and damaged somatic cells. (Blood. 2004;104:2761-2766)
Enhancement of stress-induced apoptosis in B-lineage cells by caspase-9 inhibitor
Authors: Shah Nisha , Asch Rebecca J. , Lysholm Alana S. , LeBien Tucker W. 
Published: July 2004

AbstractWe have established human B-lineage (BLIN) acute lymphoblastic leukemia cell lines that retain a dependency on fibroblast monolayers for survival and proliferation. Eight hours following removal from adherent cell contact BLIN cells undergo a decrease in mitochondrial transmembrane potential and an increase in annexin V binding. Unexpectedly, the caspase-9 inhibitor (C9i) benzyloxycarbonyl-Leu-Glu-His-Asp-fluoromethylketone enhanced the appearance of apoptotic cells within 8 hours following removal of BLIN cells from fibroblast monolayers. C9i enhancement of apoptosis was dose dependent and did not occur with irreversible inhibitors of caspases-2, -3, -6, and -8. C9i also enhanced apoptosis in cord blood-derived CD19+ B-lineage cells (but not myeloid cells) removed from murine stromal cells. Longer exposure (&gt; 18 hours) to C9i culminated in apoptosis in a panel of B-lineage acute lymphoblastic leukemia (ALL) cell lines in the presence or absence of fibroblast monolayers, as well as in 2 proliferating leukemic cell lines (RAMOS and CEM). BLIN-4L cells made deficient in caspase-9 by RNA interference exhibited no resistance to apoptotic signals and actually showed increased apoptotic sensitivity to staurosporine. These collective results suggest that a 4-amino acid caspase inhibitor of caspase-9 can promote apoptosis and that at least some types of apoptotic pathways in B-lineage ALL do not require caspase-9.
Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis
Authors: Chung Ki Young , Morrone Giovanni , Schuringa Jan Jacob , Wong Bryan , Dorn David C. , Moore Malcolm A. S. 
Published: July 2004

Abstract
To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Fms-like tyrosine kinase 3 (Flt3) receptor in leukemogenesis, we introduced the Flt3-ITD, W51, into human cord blood CD34+ cells and evaluated their phenotype in diverse hematopoietic assays. W51 expression resulted in a strong proliferative advantage and enhanced erythropoiesis as determined by immunophenotyping, colony assays, and molecular analyses. In MS-5 stromal cocultures, numerous early cobblestone areas (CAs) were generated within 10 to 14 days. Such W51-associated early CAs disappeared by 4 weeks, yet retained self-renewal properties as demonstrated by generation of secondary and tertiary CAs upon replating. This phenotype appears related to the expression of W51 since it was abolished by exposure to the FLT3 inhibitor, AG1295, but not to the c-kit inhibitor PD16. Wild-type Flt3–overexpressing CD34+ cells exposed to high levels of its physiologic ligand did not produce early CAs, highlighting differences in intracellular signaling between wild-type Flt3 and W51. W51-associated signal transducer and activator of transcription 5 (Stat5) activation plays a major role in this phenotype, although additional downstream targets of W51 may be relevant. Flt3-ITD+ acute myeloid leukemia (AML) blasts from patients invariably generated early AG1295-sensitive CAs in MS-5 cocultures, further validating the phenotype observed in transduced CD34+ cells.
Leukocyte immunoglobulin-like receptors: novel innate receptors for human basophil activation and inhibition
Authors: Sloane David E. , Tedla Nicodemus , Awoniyi Muyiwa , MacGlashan Donald W. , Borges Luis , Austen K. Frank , Arm Jonathan P. 
Published: July 2004

AbstractBasophils, recruited from the blood to tissues, have been implicated by their presence in diverse allergic disorders including bronchial asthma, allergic rhinitis, and cutaneous contact hypersensitivity. We hypothesized that like other leukocytes involved in inflammatory responses, basophils would express members of the leukocyte immunoglobulin-like receptor (LIR) family of immuno-regulatory molecules on their cell surface. We identified LIR7, an activating member coupled to the common Fc receptor gamma chain, and LIR3, an inhibitory member containing cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, on these cells from human peripheral blood. Cross-linking of LIR7 resulted in the concentration-dependent net release of histamine (29.8 ± 10.8%) and cysteinyl leukotrienes (cysLTs) (31.4 ± 8.7 ng/106 basophils) that were maximal at 30 minutes, and of interleukin-4 (IL-4) (410.2 ± 61.6 pg/106 basophils) that was maximal at 4 hours and comparable with the response initiated by cross-linking of the high-affinity receptor for immunoglobulin E (FcϵRI). Coligation of LIR3 to LIR7 or to FcϵRI by means of a second monoclonal antibody significantly inhibited net histamine release, cysLT production, and IL-4 generation. That LIR3 is profoundly counter-regulatory for both adaptive and innate receptors suggests a broad role in containment of the inflammatory response.
E47, IRF-4, and PU.1 synergize to induce B-cell-specific activation of the class II transactivator promoter III (CIITA-PIII)
Authors: van der Stoep Nienke , Quinten Edwin , Rezende Marisa Marcondes , van den Elsen Peter J. 
Published: July 2004

AbstractIn B cells, expression of CIITA and resulting major histocompatibility complex II (MHCII) is mediated exclusively by promoter III (CIITA-PIII) activation. Recent studies have established that CIITA-PIII also participates in the expression of CIITA in activated human T cells, dendritic cells, and monocytes. In this study we characterized the various regulatory elements and interacting factors of CIITA-PIII that account for specific activation in B lymphocytes. We identified 2 E-box motifs and an Ets/ISRE-consensus element (EICE) in CIITA-PIII as playing a crucial role in the B-cell-specific transcriptional regulation of CIITA. Abolishment of factor binding to these elements resulted in a strong reduction of CIITA-PIII activation in B cells only, whereas it did scarcely affect or not affect the activity of CIITA-PIII in activated T cells and monocytes. We show that in B cells, E47 and PU.1/IRF-4 interact with the E-box motifs and the EICE, respectively, and act synergistically in the activation of CIITA-PIII. Moreover, functional inhibition of either E47 or IRF-4 resulted in strong reduction of CIITA-PIII activity in B lymphocytes only. The finding that PU.1, IRF-4, and E47 play an important role in the B-cell-mediated activation of CIITA-PIII provides a link between antigen presentation functions and activation and differentiation events in B lymphocytes.
Lipids from Oxidized Low-Density Lipoprotein Modulate Human Trophoblast Invasion: Involvement of Nuclear Liver X Receptors
Authors: Pavan Laëtitia , Hermouet Axelle , Tsatsaris Vassilis , Thérond Patrice , Sawamura Tatsuya , Evain-Brion Danièle , Fournier Thierry 
Published: July 2004

AbstractHuman embryonic implantation involves major invasion of the uterine wall and remodeling of the uterine arteries by extravillous cytotrophoblast cells (EVCT). Abnormalities in these early steps of placental development lead to poor placentation and fetal growth defects and are frequently associated with preeclampsia, a major complication of human pregnancy. We recently showed that oxidized low-density lipoproteins (oxLDLs) are present in situ in EVCT and inhibit cell invasion in a concentration-dependent manner. The aim of the present study was to better understand the mechanisms by which oxLDL modulate trophoblast invasion. We therefore investigated the presence of oxLDL receptors in our cell culture model of human invasive primary EVCT. We found using immunocytochemistry and immunoblotting that the lectin-like oxLDL receptor-1 was the scavenger receptor mainly expressed in EVCT and was probably involved in oxLDL uptake. We next examined the effect of low-density lipoprotein oxidative state on trophoblast invasion in vitro using EVCT cultured on Matrigel-coated Transwell. We demonstrated that only oxLDL containing a high proportion of oxysterols and phosphatidylcholine hydroperoxide derivatives that provide ligands for liver X receptor (LXR) and peroxisomal proliferator-activated receptor γ (PPARγ), respectively, reduced trophoblast invasion. We next investigated the presence and the role of these nuclear receptors and found that in addition to PPARγ, human invasive trophoblasts express LXRβ, and activation of these nuclear receptors by specific synthetic or natural ligands inhibited trophoblast invasion. Finally, using a PPARγ antagonist, we suggest that LXRβ, rather than PPARγ, is involved in oxLDL-mediated inhibition of human trophoblast invasion in vitro.