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Biomedical subjects

B R Binder

Publications and source records attributed to B R Binder.

At least 55 records · Page 3Linked to original sources
PubMed1999

Coagulation factors II, V, VII, and X, prothrombin gene 20210G-->A transition, and factor V Leiden in coronary artery disease: high factor V clotting activity is an independent risk factor for myocardial infarction.

Increased levels of hemostatic factors and genetic mutations of proteins involved in coagulation may play a role in the pathogenesis of coronary artery disease. We investigated clotting activity of factors II (FII:C), V (FV:C), VII (FVII:C), and X (FX:C), the prothrombin gene 20210G-->A transition, and the factor V Leiden mutation in 200 survivors of myocardial infarction and in 100 healthy controls. FV:C (P<0.0001) and FVII:C (P<0.0001) were found to be independent risk factors for myocardial infarction. High FV:C or high FVII:C combined with smoking or arterial hypertension increased the relative risk for myocardial infarction up to 50-fold. One of 177 patients (0.6%) and 4 of 89 controls (4.5%) had the prothrombin 20210 AG genotype. Eleven of 177 patients (6.2%) and 6 of 89 controls (6.7%) were heterozygous for the factor V Leiden mutation. No homozygous carrier for these mutations was found. Neither the prothrombin gene 20210G-->A transition (odds ratio [OR], 0.1; 95% confidence interval [CI], 0.01 to 1.1) nor the factor V Leiden mutation (OR, 1.0; 95% CI, 0.4 to 2.8) were associated with an increased relative risk for myocardial infarction. In conclusion, our data indicate that neither the prothrombin gene 20210G-->A transition nor the factor V Leiden mutation are risk factors for myocardial infarction. High FVII:C was confirmed to be an independent risk factor for myocardial infarction. Moreover, we describe for the first time that high FV:C is an independent risk factor for myocardial infarction.

Activated Protein C Resistance↗
PubMed1999

Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women.

The increased incidence of cardiovascular diseases in obese subjects could be partially attributed to impaired fibrinolysis due to elevated plasma levels of tissue plasminogen activator inhibitor 1 (PAI-1). The associations between changes in plasma PAI-1, metabolic variables, and adipose tissue during weight loss and regain were studied in 52 healthy, premenopausal, obese women participating in a weight reduction program with a hypocaloric diet. PAI-1, insulin, triglyceride, leptin, and adipsin levels were determined at entry, after the first week, after completion of the program, and after 5 months of follow-up. In the 33 obese women who completed the program, decreases in PAI-1 antigen (-54%), PAI activity (-74%), and leptin (-51%), but not of adipsin, were observed. Changes in PAI-1 were associated with changes in body mass index (BMI), body fat, leptin, and insulin. The decreased level of PAI-1 remained low after follow-up in the 14 women who maintained their reduced weight but increased in the 16 women who regained weight. This increase in PAI-1 was correlated with an increase in body fat and leptin. On multivariate analysis, BMI was the major determinant of PAI-1 level. In conclusion, during weight reduction with a hypocaloric diet, the decrease in PAI-1 is more closely related to changes in adipose tissue than to changes in metabolic variables, suggesting a significant role for adipose tissue in regulating plasma levels of PAI-1.

Adipose Tissue↗
PubMed1999

A transcriptional repressor of the tissue factor gene in endothelial cells.

Tissue factor, the high-affinity receptor and cofactor for the plasma serine protease VII/VIIa, is the primary cellular initiator of the blood coagulation cascade. Inside the vasculature, expression of the tissue factor gene must be tightly controlled. Whereas the endothelium normally does not express tissue factor, on stimulation with inflammatory cytokines or endotoxin the gene is transcriptionally upregulated leading to a procoagulant state. We have now detected a repressive cis-acting element in the tissue factor promoter that downmodulates tissue factor transcription in endothelial cells. In reporter gene assays, deletion of this element leads to an increase of tissue factor transcription and insertion of a trimerized site reduces transcription. Specific protein/DNA complexes are formed on the element with nuclear extracts in electrophoretic mobility shift assays and cross-linking of the proteins followed by SDS-PAGE detects the presence of at least 2 subunits of approximately 40 and 60 kDa, respectively. After transfection of different cell types with the reporter genes, the suppressive effect of the element can only be revealed in endothelial cells. These data suggest that this element represents a novel transcription factor target sequence that functions to suppress expression of the tissue factor gene, preferentially in endothelial cells thereby supporting a noncoagulant state.

Animals↗
PubMed1999

Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells.

The pleiotropic growth factor hepatocyte growth factor/scatter factor (HGF/SF) has been implicated by clinical and experimental studies in repair mechanisms in different organs and tissues. However, no data on the impact of HGF/SF in wound healing in the skin are yet available. Proliferating and migrating keratinocytes play a major role in repair processes in the skin by closing the wound. Recent evidence gathered from studies that used gene-deficient mice has implicated the plasminogen activator (PA)/plasmin system in wound healing, which depends on controlled matrix degradation and deposition during cell migration and proliferation. Furthermore, keratinocytes are an important source of vascular endothelial growth factor (VEGF), which is a potent inducer of angiogenesis. In this study, we show that in human keratinocytes HGF/SF but not the related cytokine macrophage stimulating protein (MSP) significantly increases expression of VEGF and plasminogen activator inhibitor-1 (PAI-1) on the level of protein and mRNA. Furthermore, we demonstrate that HGF/SF increases the expression of the VEGF receptor flk-1 in human endothelial cells and that, in an angiogenesis co-culture assay of endothelial cells and keratinocytes, HGF/SF increases endothelial cell tube formation significantly. Therefore, we propose a role for HGF/SF in wound repair in the skin: HGF/SF--produced by activated fibroblasts--increases in keratinocytes the expression of PAI-1, which leads to increased matrix stability during the repair process and which could also limit activation of HGF/SF by proteases such as urokinase-type PA (u-PA) or tissue-type PA (t-PA). Furthermore HGF/SF also increases the expression of VEGF in these cells, thereby initiating angiogenesis in a paracrine manner. This effect would be enhanced by an increased responsiveness of endothelial cells toward VEGF, resulting from the HGF/SF-induced up-regulation of flk-1 on these cells.

Animals↗
PubMed1999

Predictive value of PAI-1 plasma activity and thallium perfusion imaging for restenosis after percutaneous transluminal angioplasty in clinically asymptomatic patients.

BACKGROUND: The main long-term complication of percutaneous transluminal coronary angioplasty (PTCA) is restenosis that occurs in 30-50 percent of all primary successful cases. The purpose of this study was to evaluate the predictive value of changes in plasminogen activator inhibitor-1 (PAI-1) activity and of thallium dipyridamole perfusion imaging performed 3 months after successful angioplasty. All patients were asymptomatic at evaluation. The results of these two noninvasive tests were compared with the angiographic outcome after 6 months. METHOD AND PATIENTS: Twenty-five patients were included in this prospective study. All patients had single vessel disease, successful angioplasty and were free of clinical symptoms 3 months after angioplasty that would suggest late restenosis. In 12/25 patients (48%) angiographic restenosis (percent diameter stenosis >50%) was determined by follow-up angiography 6 months after angioplasty. PAI-1 plasma activity was determined by a functional titration assay and increase or decrease of PAI-1 plasma activity was evaluated between values obtained before and 3 months after angioplasty. In 7/25 (28%) patients PAI-1 plasma activity increased to more than 90% of pre-angioplasty values. This increase correlated with angiographic restenosis evaluated 6 months after angioplasty (sensitivity 42%, specificity 85%, positive predictive value 71%, and negative predictive value 61%). T1-201-perfusion imaging was performed 3 months after angioplasty. This test was indicative for subsequent restenosis in 5/25 patients (sensitivity 33%, specificity 100%, positive predictive value 62%, and negative predictive value 100%). In 10/25 (40%) patients at least one of the two non-invasive tests performed 3 months after angioplasty predicted angiographic restenosis at 6 months: the combined use of PAI-1 and T1-201-perfusion imaging resulted in increased sensitivity (67%) and high specificity (85%). CONCLUSION: The results of this study indicate that an increase of PAI-1 plasma activity may improve the predictive value for restenosis of T1-201-scintigraphy performed 3 months after angioplasty even in asymptomatic patients.

Angioplasty, Balloon, Coronary↗
PubMed1999

[Pathophysiology of immobilization].

Deep venous thrombosis is initiated primarily in the pockets of the valves of the veins of the lower limbs and the main pelvic veins. In addition to a genetic predisposition there are several acquired conditions associated with deep venous thrombosis such as major surgery, trauma, cancer, pregnancy, and immobilization. While major diseases as well as hormonal changes have been shown to cause changes in blood coagulation and fibrinolytic factors, the impact of immobilization per se is much less clear. It has been shown that in the absence of intermittent pulsatile flow the blood within the valve pockets became rapidly hypoxic when undisturbed during streamline flow (i.e. when "static"). Hypoxia on the other hand has been shown to cause procoagulatory changes of the vascular endothelium (e.g. production of platelet activating factor [PAF], expression of tissue factor), adhesion and activation of leukocytes and expression of tissue factor on their surface, as well as the activation of platelets. Together with reduced removal and/or inactivation of active clotting factors these mechanisms might contribute to the development of deep venous thrombosis during immobilization.

Blood Coagulation Factors↗
PubMed1999

Protease dependent activation of endothelial cells by peritoneal dialysis effluents.

Incubation of cultured human umbilical vein endothelial cells (HUVECs) with dilutions of peritoneal dialysis effluents (PDEs) from 11 individual patients undergoing continuous ambulatory peritoneal dialysis (CAPD) induced cellular procoagulant activity in a dose and time dependent manner. This procoagulant activity could be attributed to tissue factor (TF) expression since it was blocked by rabbit anti-TF IgG. These data was confirmed by FACS analysis yielding surface TF expression; In addition PDEs induced the expression of E-selectin in HUVECs. This TF and selectin inducing activity was heat labile and could be inhibited by protease inhibitors. Partial purification could be achieved using a benzamidine-Sepharose column. The TF inducing activity could not be attributed to LPS, IL-1, TNF-alpha, mast cell tryptase, active thrombin, or complement factor D. We therefore conclude that the peritoneal cavity contains a protease activity that induces a procoagulatory and proinflammatory phenotype in HUVECs.

Animals↗
PubMed1999

Fibrinolytic response to venous occlusion compared to physical stress test in young patients with coronary artery disease.

INTRODUCTION: Venous occlusion (VO) and exercise stress (ES) are stimulators of the fibrinolytic system. Aim of this study was to answer which of both stimulation tests is more useful in patients with symptom-limited coronary artery disease (CAD) to evaluate possible defects in the fibrinolytic system. METHODS AND RESULTS: We investigated 20 patients (M/F = 15/5; mean age = 36.7 years) with angiographically proven CAD for their plasma levels of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-type-1 (PAI-1) at basal conditions as well as after VO and at maximal ES (standardised bicycle stress test) and compared the data to those obtained from 12 sex- and age-matched healthy controls (M/F = 9/3; mean age = 40.4 years). At basal conditions mean t-PA activity and t-PA antigen plasma levels were within the normal range and comparable between the two study groups. After both VO and maximal ES, mean t-PA activity and t-PA antigen levels increased significantly more in the control group as compared to the CAD group. Mean PAI-1 activity plasma levels were significantly higher in the CAD group at basal conditions before VO (patients 7.0 +/- 3.1; controls 3.9 +/- 3.9; IU/ml; p = 0.025) as well as before ES (patients 8.1 +/- 3.5; controls 4.3 +/- 3.8; IU/ml; p = 0.009). PAI-1 activity plasma levels showed a significant decrease for patients and controls only after VO, while PAI-1 activity was not significantly decreased in both study groups at maximal ES. DISCUSSION: The significantly higher increase in mean plasma levels of t-PA activity and t-PA antigen after VO compared to ES in both groups might be explained by the fact that CAD induced symptoms in the patients during ES thus permitting only 80% of their age, sex, and body mass index related optimal work load. CONCLUSION: VO and ES are applicable triggers of the endogenous fibrinolytic system in healthy subjects and patients who are not limited in their physical exercise. Standardised VO appears to be superior to ES as stimulation test of the endogenous fibrinolytic system in patients with symptomatic CAD.

Adult↗
PubMed1998

Analysis of fibrinolytic proteins in relation to DNA ploidy in prostate cancer.

The tissue concentrations of urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (t-PA) were investigated by an ELISA technique in normal and malignant samples of the prostate from 24 patients undergoing radical prostatectomy for organ-confined prostate cancer. The median concentration of u-PA was significantly higher in cancerous than in normal prostate tissue (p = 0.006). No significant increase of u-PAR, PAI-1 and t-PA was found in cancer tissue in comparison with the benign samples (p > 0.05). Assessment of the relationship between fibrinolytic proteins and DNA ploidy revealed an increased u-PA, u-PAR and PAI-1 in diploid prostate cancer as compared with the normal controls. However, in aneuploid cancer u-PA remained high but u-PAR and PAI-1 were decreased. This led to a higher local concentration of u-PA in aneuploid samples than in normal prostate and in diploid prostate cancer. No alteration of median t-PA was found in benign prostate or in diploid or aneuploid prostate cancer. The altered expression of u-PA, u-PAR and PAI-1 in diploid and aneuploid prostate cancer suggests a possible role of fibrinolytic proteins in the different biologic behavior of tumors, and may be one explanation for the higher metastatic potential of aneuploid tumors.

Aged↗
PubMed1998

Nuclear factor (NF)-kappaB-regulated X-chromosome-linked iap gene expression protects endothelial cells from tumor necrosis factor alpha-induced apoptosis.

By differential screening of tumor necrosis factor alpha (TNF-alpha) and lipopolysaccharide (LPS)- activated endothelial cells (ECs), we have identified a cDNA clone that turned out to be a member of the inhibitor of apoptosis (iap) gene family. iap genes function to protect cells from undergoing apoptotic death in response to a variety of stimuli. These iap genes, hiap1, hiap2, and xiap were found to be strongly upregulated upon treatment of ECs with the inflammatory cytokines TNF-alpha, interleukin 1beta, and LPS, reagents that lead to activation of the nuclear transcription factor kappaB (NF-kappaB). Indeed, overexpression of IkappaBalpha, an inhibitor of NF-kappaB, suppresses the induced expression of iap genes and sensitizes ECs to TNF-alpha-induced apoptosis. Ectopic expression of one member of the human iap genes, human X-chromosome-linked iap (xiap), using recombinant adenovirus overrules the IkappaBalpha effect and protects ECs from TNF-alpha- induced apoptosis. We conclude that xiap represents one of the NF-kappaB-regulated genes that counteracts the apoptotic signals caused by TNF-alpha and thereby prevents ECs from undergoing apoptosis during inflammation.

Adenoviridae↗
PubMed1998

Cytokine induced expression of porcine inhibitor of apoptosis protein (iap) family member is regulated by NF-kappa B.

The inhibitor of apoptosis (iap) proteins belong to a gene family that protect certain cell to undergo programmed cell death in response to a variety of stimuli. By differential screening we have identified a cDNA clone, designated piap, in porcine aortic endothelial cells (PAEC) that turned out by sequence comparison to be a porcine member of the iap family. The expression of piap is strongly up-regulated upon treatment of endothelial cells (EC) with inflammatory cytokines TNF-alpha, IL-1 beta, and LPS. In EC these stimuli lead to the activation of nuclear transcription factor kappa B (NF-kappa B) that plays a role in countering TNF-alpha induced apoptosis. We demonstrate that adenovirus mediated overexpression of I kappa B alpha, an inhibitor of NF-kappa B suppresses the expression of piap in response to TNF-alpha suggesting that piap is one of the NF-kappa B regulated genes that operates to prevent programmed cell death of EC in inflammation.

Amino Acid Sequence↗
PubMed1998

Myotonic dystrophy: molecular genetics and diagnosis.

Myotonic dystrophy (DM) is the most common adult muscular dystrophy and follows an autosomal dominant pattern of inheritance. Up to now, the clinical diagnosis of DM was based on symptoms presented such as encephalopathy, facies myopathica, paresthesia, atrophy, myotonia, mental retardation, cataract, diabetes, cardiac conduction defects and electromyography. Since 1991 the specific molecular defect in DM is known and a respective diagnosis is possible. The mutation responsible for DM is the expansion of an unstable trinucleotide repeat, (CTG)n, in the 3'-untranslated region of the myotonin protein kinase gene. It is now generally accepted that the CTG repeat length correlates with the clinical category and the age at onset of the disease; therefore genetic tests are essential in monitoring and management of DM-patients and their family members. Based on the average incidence in Europe about 1000 affected individuals can be expected in Austria, a high percentage of whom is, however, not recognized as carries of the DM-mutation. After having established a genetic diagnosis in Austria allowing the detection of this mutation in DM-patients and their relatives, improvement of the diagnostic procedure should be possible.

Adult↗
PubMed1998

Genotype-phenotype correlation in myotonic dystrophy.

Myotonic dystrophy (DM) is caused by a mutation in the length of a trinucleotide (CTG) repeat in the 3' untranslated region of the myotonin protein kinase gene located on chromosome 19q13.3. The normal gene has between 5 and 36 CTG trinucleotide repeats, whereas minimally affected individuals have 50 copies and severely affected DM-patients have several thousands of such repeats. Since no information on a genotype phenotype correlation in Austrian DM-patients is available, we examined a small group of these patients for the unstable trinucleotide repeat. Molecular analysis was used to clarify equivocal clinical diagnoses and confirm clinical findings. We studied eight DM-families, a total of 57 individuals, of whom 18 were diagnosed with a trinucleotide repeat expansion. Twenty-six unrelated individuals served as a control. Clinical assessment was based on the muscular disability rating scale (MDRS) and a sum of symptoms score (SSS). There was a significant correlation between the clinical scores (MDRS: Spearman r = 0.51; p = 0.029: SSS: Spearman r = 0.538; p = 0.0259) used and the size of the amplification of the trinucleotide repeat. The largest expansion found in our group of patients was 6 kb. Furthermore, we observed both expansion and contraction of the enlarged fragment during transmission from one generation to the next.

Adolescent↗
PubMed1998

Isolation of cDNA clones coding for IgE autoantigens with serum IgE from atopic dermatitis patients.

Recently we demonstrated that a high percentage of atopic dermatitis (AD) patients displayed specific immunoglobulin E reactivity to human proteins. Here we show that IgE autoreactivity is found predominantly in AD patients with severe skin manifestations and reveal the molecular nature of four IgE autoantigens. An expression cDNA library constructed from a human epithelial cell line (A 431) was screened with serum IgE from two AD patients. DNA sequence analysis of three IgE-reactive clones identified the alpha-chain of the nascent polypeptide-associated complex, cytokeratin type II, and the BCL7B oncogen as atopy-related IgE autoantigens (ara). The fourth cDNA coded for an IgE autoantigen containing a typical calcium binding motif that occurred in histogenetically different cells and tissues (keratinocytes, muscle, brain). Recombinant Escherichia coli-expressed IgE autoantigens bound IgE from AD but not from patients with other immunologically mediated disorders (graft vs. host disease, systemic lupus erythematosus) and elicited immediate type skin reactions in AD patients. In serum samples collected from an AD patient over a period of 5 years, IgE anti-ara NAC antibody levels peaked during disease exacerbation. Our finding that ara BCL7B was detected in serum bound to IgE antibodies suggests that intracellular IgE autoantigens can become released after tissue damage and may occur as IgE immune complexes. Via binding to antigen presenting cells as well as to effector cells, IgE autoantigen immune complexes may contribute to exacerbation and/or perpetuation of severe atopic diseases even in the absence of exogenous allergens.

Amino Acid Sequence↗
PubMed1998

What have mast cells to do with edema formation, the consecutive repair and fibrinolysis?

Mast cells (MC) have been implicated in the activation of vascular endothelial cells, capillary leak formation, transmigration of white blood cells, and translocation of fibrinogen (and other plasma molecules) into the tissues, with consecutive edema formation. However, the mechanisms of repair that lead to tissue reconstitution after MC activation and edema formation have not been defined so far. In the present article, the possible contribution of MC to repair, in particular fibrinolysis, is discussed. Thus, accumulating evidence exists that human MC express and release the tissue-type plasminogen activator (tPA) in a constitutive manner. MC also express the urokinase receptor (uPAR) and heparin. Most importantly, however, MC lack plasminogen activator inhibitors (PAI-1, PAI-2, PAI-3). In line with this 'pro-fibrinolytic' profile of antigens, MC supernatants induce plasminogen-to-plasmin conversion and fibrin clot lysis in vitro. The c-kit ligand SCF upregulates uPAR expression, and the release of tPA from MC. These observations point to an important role of MC in endogenous fibrinolysis, a hitherto unrecognized (repair) function of this cell.

Animals↗
PubMed1998

Concentration of endogenous tPA antigen in coronary artery disease: relation to thrombotic events, aspirin treatment, hyperlipidemia, and multivessel disease.

Tissue plasminogen activator (tPA) is the major plasminogen activator responsible for dissolving blood clots found in blood vessels. However, elevated concentrations of tPA antigen were found to be related to adverse events in patients with coronary artery disease (CAD). Considerable controversy about the significance of these results exists. The goal of this cross-sectional study was to identify independent determinants for tPA antigen concentrations in patients with CAD, to possibly clarify the above paradoxical relationship. The baseline tPA antigen concentrations of 366 patients with angiographic evidence of coronary sclerosis were determined. Univariate analysis showed that age (P=0.013), angiographic extent of disease (P<0.001), presence of angina at rest (P<0.001), diabetes mellitus (P=0.004), hypercholesterolemia (P=0. 045), hypertriglyceridemia (P=0.015), and chronic intake of nitrates (P<0.001) were significantly and positively related to tPA antigen concentration, while the chronic intake of aspirin was inversely related to tPA antigen (P<0.001). In addition, plasminogen activator inhibitor type 1 (PAI-1) activity was found to be significantly and positively associated with tPA antigen concentration (P<0.001). A multivariate analysis identified chronic low-dose aspirin therapy (P<0.001), PAI-1 activity (P<0.001), hypertriglyceridemia (P=0.005), the type of angina (P=0.026), multivessel disease (P=0.041), and hypercholesterolemia (P=0.043) as significant and independent determinants of tPA antigen. While hypertriglyceridemia and hypercholesterolemia both are related to the underlying disease, the type of angina and the number of involved vessels are linked to the severity and extent of disease, and all of them are indicators of a prothrombotic state found during the progression of CAD. In contrary, low-dose aspirin rather would decrease the likelihood of thrombotic events. The relation of tPA antigen to PAI-1 activity furthermore underlines the relation between tPA antigen concentration and a prothrombotic state. Therefore, the positive or-in case of aspirin therapy-negative correlation of these parameters with tPA antigen concentration would indicate that thrombus formation and simultaneous endothelial cell activation might be major determinants for tPA antigen concentration in CAD.

Adult↗