bluuebunny/crossref_metadata_2025_split huggingface dataset:
Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin
Authors: Paredes Nethnapha , Thong Bruce , Chindemi Paul , Paes Bosco , Berry Leslie , Monagle Paul , Chan Anthony 
Published: March 2004

SummaryUnfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH’s better bioavailability and more predictable dose response.
Direct attenuation of plasminogen activator inhibitor type-1 expression in human adipose tissue by thiazolidinediones
Authors: Leugers Anne , Lohrmann Jens , Ernst Sandra , Sobel Burton , Bode Christoph , Nordt Thomas , Zirlik Andreas 
Published: March 2004

SummaryAdipose tissue produces substantial amounts of plasminogen activator inhibitor type-1 (PAI-1), an established cardiovascular risk factor. This study evaluated PAI-1 expression in human adipose tissue in response to thiazolidinediones, insulin sensitising drugs activating peroxisome proliferator-activated receptorgamma (PPAR-γ). Troglitazone, rosiglitazone, and ciglitazone significantly reduced PAI-1 protein expression in human preadipocytes under basal conditions and after stimulation of the cells with TGF-β. Pioglitazone had no effect. In human adipocytes all four thiazolidinediones significantly attenuated PAI-1 expression. Signalling appeared to be mediated via PPAR-γ and effects reflected, at least in part, changes in transcription. Accordingly, patients with insulin resistance may benefit from treatment with thiazolidinediones with respect to diminution of PAI-1 expression in adipose tissue and consequent potential reduction of cardiovascular risk.
Orally administered heparins prevent arterial thrombosis in a rat model
Authors: Pinel Cory , M.Wice Sandra , Hiebert Linda 
Published: March 2004

SummaryOur previous studies demonstrated that orally administered heparins prevent thrombosis in a rat jugular vein thrombosis model, where bovine unfractionated heparin (UFH) and the low molecular weight heparin tinzaparin reduced thrombotic incidence by 50% at 7.5 and 0.1 mg/kg, respectively. Our objectives were to determine if similar antithrombotic effects of oral heparin could be observed in an arterial thrombosis model. In this model, filter paper soaked in 30% ferric chloride was applied to the exposed rat carotid artery. A flowmeter recorded blood flow over a 60 min period determining time when the thrombus began forming (TTB) and time till occlusion (TTO). Immediately following, the thrombus was removed, dried and weighed 24 h later. Bovine UFH (7.5 mg/kg), tinzaparin (0.1 mg/kg) or saline was administered by stomach tube at 2, 5 and 25 h prior to thrombus initiation. TTB was significantly increased when UFH was given at 5 and 25 h but not 2 h prior, and when tinzaparin was given at 5 but not 2 or 25 h prior compared to rats given oral saline. TTO was significantly increased for both UFH and tinzaparin when given 5 and 25 h but not 2 h prior (one-way ANOVA). There was no difference in TTO and TTB between UFH and tinzaparin treated groups. A trend in reduction in thrombus weight was observed for UFH at 5 and 25 h prior and tinzaparin at 5 h prior to thrombus initiation (one-way ANOVA). Although no significant changes were observed in activated partial thromboplastin times, Heptest or anti-Xa activity from plasma of heparin treated rats, endothelial heparin concentrations were significantly greater than controls for UFH at 5 h and for tinzaparin at 2, 5, and 24 h. Thus, heparins administered by the oral route are effective antithrombotic agents in arterial as well as venous models.
Localization of heparin and low-molecular-weight heparin in the rat kidney
Authors: Douros Vivian , Podor Thomas , Shaughnessy Stephen , Weitz Jeffrey , Young Edward 
Published: March 2004

SummaryUnfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are cleared, at least in part, by the kidneys through a poorly understood process. This study was undertaken to explore the mechanism of renal clearance of these drugs. Rats were given fluorescein-5-isothiocyanate (FITC)-labeled UFH or LMWH intravenously. At intervals after injection, rats were euthanized and the kidneys were harvested and subjected to immunohistochemical analysis and fluorescence microscopy. Both UFH and LMWH were localized to renal tubular cells and no immunoperoxidase staining or fluorescence was detected in glomeruli. Autoradiography demonstrated similar intracellular distribution of radio-labeled UFH suggesting that this phenomenon is independent of the method used to label heparin. Fluoresence in the tubules increased as a function of time after UFH injection, but reached a plateau after LMWH injection suggesting that the rate of renal tubular uptake depends on the molecular size of the heparin. When administered prior to FITC-labeled UFH or LMWH, probenecid, a renal organic anion inhibitor, decreased the renal tubular uptake of the heparins, whereas cimetidine, a renal organic cation inhibitor, had no effect. These findings suggest that renal excretion of UFH and LMWH primarily reflects tubular uptake via an organic anion transport mechanism.
Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk
Authors: Medina Pilar , Navarro Silvia , Estellés Amparo , Vayá Amparo , Woodhams Barry , Mira Yolanda , Villa Piedad , Migaud-Fressart Martine , Ferrando Fernando , Aznar Justo , Bertina Rogier , España Francisco 
Published: March 2004

SummaryEndothelial cell protein C receptor (EPCR) enhances the generation of activated protein C (APC) by the thrombin-thrombomodulin complex. A soluble form of EPCR (sEPCR), which is generated by metalloprotease activity, is present in plasma. The distribution of sEPCR levels in healthy populations is bimodal. Previously, we described two polymorphisms in exon 4 of the EPCR gene, 4600A/G that encodes the substitution of Ser219 by Gly in the transmembrane region of EPCR and 4678G/C in the 3’-UT region. The aim of this study was to investigate the relationship between these two polymorphisms and plasma sEPCR and APC levels and risk of venous thrombosis. We genotyped 401 healthy controls from the Spanish population and measured their plasma sEPCR and APC levels. Carriers of the 4600AG genotype had significantly higher sEPCR levels than those with the AA genotype, while the 4678CC genotype was associated, to a lesser extent, with elevated APC levels. To assess the effect of these polymorphisms on the risk of thrombosis, we genotyped 405 patients with venous thromboembolism. The frequency of the 4600AG genotype was very similar in patients and controls (p=0.975), whereas the 4678CC genotype was significantly more frequent in controls than in patients (p=0.008). In multivariate analysis, carriers of the 4678CC genotype had a decreased risk of thrombosis (OR=0.61, p=0.009). These data indicate that individuals carrying the 4600AG genotype have high sEPCR levels but do not have an increased risk of thrombosis, whereas individuals carrying the 4678CC genotype have higher APC levels and lower risk of venous thromboembolism.
An enzyme immunoassay of ADAMTS13 distinguishes patients with thrombotic thrombocytopenic purpura from normal individuals and carriers of ADAMTS13 mutations
Authors: Zhou Wenhua , Tsai Han-Mou 
Published: March 2004

SummaryRecent studies demonstrate that assay of ADAMTS13, a circulating zinc metalloprotease that cleaves von Willebrand factor (VWF) at the Y1605-M1606 bond, is an important tool in the diagnosis of thrombotic thrombocytopenic purpura (TTP). In order to develop a method that could be adapted for general use, we describe an enzyme immunoassay (EIA)-based method for measuring the activity of ADAMTS13 in patient plasma samples. A monomeric peptide consisting of the amino acid residues D1596-R1668 of VWF was produced that spanned the ADAMTS13 cleavage site and was franked by glutathione s-transferase (GST) and a 6His sequences at the amino and carboxyl termini respectively. When probed with either anti-GST or anti-6His, the VWF fragment appeared as a 38.1-kDa band. After incubation with normal plasma, the VWF fragment was replaced by a 30.4-kDa band, which was recognized by antiGST but not by anti-6His, consistent with the expected cleavage at the Y1605-M1606 bond. EDTA or plasma samples from patients with TTP inhibited this cleavage. After incubation with normal plasma, the VWF fusion protein immobilized onto antiGST coated microtiter plate wells lost its anti-6His binding activity in a timeand plasma concentration-dependent manner. By using this EIA, the ADAMTS13 activity level was less than 0.12 U/mL in patients with acquired or hereditary TTP, distinguishing these patients from normal individuals or carriers of one copy of mutant ADAMTS13 allele. These results suggest the EIA method based on the VWF fusion protein is a simple but promising alternative for measuring ADAMTS13 activity.
Evidence of a net release of tissue-type plasminogen activator across the human cerebral vasculature
Authors: Blomstrand Christian , Westerlind Anne , Jern Christina 
Published: March 2004

SummaryWe have earlier described models for measuring local net release rates of tissue-type plasminogen activator (t-PA) in vivo across skeletal, coronary, pulmonary, and splanchnic vascular beds. Aim of the present study was to investigate whether there is a net release of t-PA across the human cerebral vascular bed and whether an acute regulated release can be induced by sympathoadrenal activation. Fourteen male subjects undergoing elective coronary artery bypass grafting were investigated prior to surgery and during sternotomy-induced sympathoadrenal activation. Blood samples were obtained simultaneously from the radial artery and the jugular bulb. Blood flow velocity in the middle cerebral artery (VMCA) was determined by transcranial Doppler. Cerebral net release of t-PA was calculated as the arterio-venous concentration gradient times VMCA. Prior to surgery there was a significant cerebral net release of t-PA (131 and 42 ng/min for t-PA antigen and activity, respectively). The release was significantly induced by sternotomy (to 271 and 80 ng/min, respectively). No significant cerebral net release of plasminogen activator inhibitor type 1 (PAI-1) was detected throughout the experiment. The results show that there is a basal net release of t-PA across the human cerebral vascular bed and that sympathoadrenal activation induces a local regulated release of t-PA.
Beyond cholesterol: the enigma of atherosclerosis revisited
Authors: Lackner Karl , Han Shan-Rui , Torzewski Michael , Husmann Matthias , Bhakdi Sucharit 
Published: March 2004

SummaryAtherosclerosis is widely regarded as a chronic inflammatory disease that develops as a consequence of entrapment of low density lipoprotein (LDL) in the arterial intima. Native LDL lacks inflammatory properties, so the lipoprotein must undergo biochemical alterations in order to become atherogenic. Modification is commonly regarded as being dangerous because it bestows inflammatory properties onto the lipoprotein. Most current models consider oxidation to be the decisive modifying event. Here, we submit a different concept for discussion. We propose that modification of tissue-entrapped LDL is required because it enables the lipoprotein to signal to the immune system and effect its own removal. Oxidation would be too haphazard to fulfill this function. We summarize the evidence indicating that modification occurs through the action of ubiquitous hydrolytic enzymes. Enzymatically remodeled LDL binds C-reactive protein. C-reactive protein bound to remodeled LDL not only activates complement but also regulates it by inhibiting activation of the terminal complement cascade. Simultaneously, epitopes are exposed to enable the lipoprotein to be recognized and taken up by macrophages. The high density lipoprotein-dependent reverse transport pathway concludes the sequence of events that clear tissues of cholesterol in a non-inflammatory manner very similar to what has been described for the removal of apoptotic cells. It is proposed that these physiological processes occur throughout life without harm, pathology evolving only when the machinery suffers overload. Detrimental effects are then evoked primarily by the unreigned activation of complement, macrophages, and other effectors of the immune system in the lesions.
Different Paradigms for Choosing Sequential Reweighting Algorithms
Authors: Blanchard Gilles 
Published: March 2004

Analyses of the success of ensemble methods in classification have pointed out the important role played by the margin distribution function on the training and test sets. While it is acknowledged that one should generally try to achieve high margins on the training set, the more precise shape of the empirical margin distribution function one should favor in practice is subject to different approaches. We first present two concurrent philosophies for choosing the empirical margin profile: the minimax margin paradigm and the mean and variance paradigm. The best-known representative of the first paradigm is the AdaBoost algorithm, and this philosophy has been shown by several other authors to be closely related to the principle of the support vector machine. We show that the second paradigm is very close in spirit to Fisher's linear discriminant (in a feature space). We construct two boosting-type algorithms, very similar in their form, dedicated to one or the other philosophy. We consequently derive by interpolation a very simple family of iterative reweighting algorithms that can be understood as different trade-offs between the two paradigms and argue from experiments that this can allow for a suitable adaptivity to different classification problems, particularly in the presence of noise or excessive complexity of the base classifiers.
Time and Uncertainty: A Metaphorical Equation
Authors: Assad Maria 
Published: February 2004

AbstractMy first argument posits that concepts of temporality are discursive strategies to harness uncertainty understood as an innate human condition. Saint Augustine's question of time and some poetic quotes serve as examples to demonstrate the metaphoric use of time in order to attenuate the effects of uncertainty in human affairs. The long history of this substitution is interrupted, however, by Newtonian celestial mechanics, which reduced the metaphoric power of time to quantifiable temporal increments within the construct of differential equations. While classical science continued creating models to explain nature within the conceptual limits of a perfectly reversible and therefore redundant time, poetry, and literature in general, re-discovered the power of time, but through an increasingly radical shift in its relationship to uncertainty. Therefore, using examples from writings by Stéphane Mallarmé and Honoré de Balzac, my second argument explores the possibility that uncertainty is time, not in a metaphoric mode, but as a conceptual identity. Bonding time and uncertainty in this fashion, the examples show further that literary discourse of the 19th Century projects the nonlinear dynamical thinking that dominates late 20th Century scientific debate.
Time and Uncertainty in Elizabeth Bishop's Poems
Authors: Bush Ann Marie 
Published: February 2004

AbstractBishop's poems often link the sense of time to specific emotional tones and levels of awareness of varying degrees. In particular, the poems demonstrate not only the forward movement of linear time, but also the merger of present and past to brighten feelings of loss and to provide a sense of security that counters feelings of uncertainty common in a world where change occurs over time. Feelings of anxiety over loss and uncertainty reside in the poems, but at the same time, a positive feeling of well-being (outright joy or peace and solace) surfaces as the speaker intertwines comforting pleasant past moments with her anxious present, making the past and present indistinguishable and creating an unclear sense of time.
"Brain Death," Death, and Personal Identity
Authors: Steineck Christian 
Published: February 2004

AbstractThe issue of brain death touches directly on questions pertaining to our understanding of what it means to be human. Technological progress made possible the sustaining of signs of life in individuals who seem dead to the world. The concept of brain death was introduced to describe this phenomenon, and to answer some of the normative questions that were raised by it. In my article, I approach the problem of brain death with a focus on its temporal aspects. First I sketch out some general features of human life and death in terms of the theories of time of J. T. Fraser and G. Dux. Then I describe and analyze various definitions of brain death and criteria for its testing.The two most important variants are 'whole brain death' as the death of the organism, and 'cerebral death' as the death of the person. I discuss arguments in favor of, and against these concepts and analyze the framework and structuring of temporalities involved in each of them. I conclude that the extant theories in favor of 'brain death' are unsatisfactory, for factual and conceptual reasons. Most importantly, they neglect essential factors of personal identity. Because they employ a naturalistic concept of the human body, they fail to grasp its expressive quality and its function as a medium of communication. Furthermore, they fail to grasp the social dimension of personal identity. Because the concepts of 'brain death' as a criterion for the determination of death fail, we should regard brain-dead people as living human beings, and decide about their treatment accordingly.
Implementing the Online Learning Community in Africa: A Unisa Case Study
Authors: Heydenrych  , Higgs  , van Niekerk  
Published: March 2004

Abstract
Recent global occurrences are significantly affecting institutions of higher education, particularly on the continent of Africa. In addition, the process of the democratization of education has inevitably led to the explosive demands by the citizens of the different African countries for open admission to institutions of higher education. Against this background this article discusses recent developments at the University of South Africa (UNISA) which have been concerned with the adoption of online distance and open learning approaches in order to achieve greater accessibility and the massification of educational products. This is especially pertinent during this era of technology-driven educational innovation, so as to make university programmes not only accessible but also relevant to the needs and aspirations of African communities.
Pedagogical Issues and Gender in Cyberspace Education: Distance Education in South Africa
Authors: Trevor Sehoole Chika , Moja Teboho 
Published: March 2004

Abstract
The purpose of this paper is to analyse the pedagogical and gender issues embedded in distance and cyberspace education. Pedagogical issues to be addressed relate to access, teaching and learning, quality, and research within distance and cyberspace education. The paper will further analyse the gender dimension in cyberspace education in South Africa. Our paper limits itself to cyberspace teaching and learning as a process that takes place using the Internet or the World Wide Web, or uses some digital information and communications technology (ICT). We understand ICT to be a broad concept that includes all forms of electronic communications in both digital and analogue forms. Pedagogical issues in this paper are covered in a broader context, but our analyses of gender issues is limited to cyberspace education. Some literature refers to latter modes of learning as "e-learning" (Bates 2001). Different people have defined the concept, and the more common definition is that cyberspace is the total interconnectedness of human beings through computers and telecommunications without regard to physical geography. William Gibson is credited with inventing or popularising the concept in his novel.
The Chances for Success of the Francophone Centers for Distance Education of the GDLN Network: The Case of the Centre d'Education à Distance de Côte d'Ivoire
Authors: Yao Kouassi 
Published: March 2004

AbstractThe Centers of Distance Education of francophone Africa in Benin, Côte d'Ivoire, and Senegal were set up under a financial and educational agreement with the World Bank. They were inaugurated on June 21, 2000, at the same time as four other centers in English-speaking Africa and eight others on other continents (Appendix 1). Since September 2003, Mauritania has had its own center, thus increasing the number of centers in French-speaking African countries to four. As of November 2003, more than 60 centers were affiliated with the Global Development Learning Network (GDLN). It has known start-up difficulties because of the socioeconomic environment caused the sociopolitical crisis from December 1999 to the civil war in September 2002. It needs a re-adaptation of its missions by public authorities in order to realize its first mission, which is to improve the capabilities of a large number of government executives and decision-makers at a minimal cost. The strategies and educational approach used at the Center are new methods and tools, precursors of what will be used in the education of tomorrow. In this article, we will briefly present the history of the creation of the Global Development Learning Network (GDLN), and then I will draw up a diagnostic account of the two years' functioning of the CED-CI. Finally, I will give an outline for its future growth.