bluuebunny/crossref_metadata_2025 huggingface dataset:
FUZZY BILEVEL PROGRAMMING: MULTI-OBJECTIVE AND MULTI-FOLLOWER WITH SHARED VARIABLES
Authors: ZHANG GUANGQUAN , LU JIE , GAO YA
Published: September 2008

Bilevel programming deals with hierarchical optimization problems in which the leader at the upper level attempts to optimize his or her objectives, but subject to a set of constraints and the follower's reactions. Typical bilevel programming considers one leader one follower situation and supposes each of them has only one objective. In real world situations, multiple followers may be involved and they may be with different relationships such as sharing decision variables or not, sharing objectives or not. Therefore, the leader's decision will be affected not only by those followers' reactions but also by their relationships. In addition, any of the leader and/or these followers may have multiple conflict objectives that should be optimized simultaneously. Furthermore, the parameters of a bilevel programming model may be described by uncertain values. This paper addresses all these three issues as a whole by particularly focusing on the situation of sharing decision variables among followers. It first proposes a set of fuzzy multi-objective multi-follower bilevel programming (FMMBP) models to describe the complex issue. It then presents an approximation branch-and-bound algorithm to solve the FMMBP problems. Finally, two examples illustrate the proposed models and algorithm.
AN OPTIMIZATION PROBLEM RELATED TO THE BEST SOBOLEV TRACE CONSTANT IN THIN DOMAINS
Authors: BONDER JULIÁN FERNÁNDEZ , ROSSI JULIO D. , SCHÖNLIEB CAROLA-BIBIANE
Published: September 2008

Let Ω ⊂ ℝNbe a bounded, smooth domain. We deal with the best constant of the Sobolev trace embedding W1,p(Ω) ↪ Lq(∂Ω) for functions that vanish in a subset A ⊂ Ω, which we call the hole, i.e. we deal with the minimization problem [Formula: see text] for functions that verify u|A= 0. It is known that there exists an optimal hole that minimizes the best constant SAamong subsets of Ω of the prescribed volume.

In this paper, we look for optimal holes and extremals in thin domains. We find a limit problem (when the thickness of the domain goes to zero), that is a standard Neumann eigenvalue problem with weights and prove that when the domain is contracted to a segment, it is better to concentrate the hole on one side of the domain.
INFINITELY MANY NODAL SOLUTIONS FOR A WEAKLY COUPLED NONLINEAR SCHRÖDINGER SYSTEM
Authors: MAIA L. A. , MONTEFUSCO E. , PELLACCI B.
Published: September 2008

Existence of radial solutions with a prescribed number of nodes is established, via variational methods, for a system of weakly coupled nonlinear Schrödinger equations. The main goal is to obtain a nodal solution with all vector components not identically zero and an estimate on their energies.
THE GINZBURG–LANDAU EQUATION IN THE HEISENBERG GROUP
Authors: BIRINDELLI ISABEAU , VALDINOCI ENRICO
Published: September 2008

We consider a functional related with phase transition models in the Heisenberg group framework. We prove that level sets of local minimizers satisfy some density estimates, that is, they behave as "codimension one" sets. We thus deduce a uniform convergence property of these level sets to interfaces with minimal area.

These results are then applied in the construction of (quasi)periodic, plane-like minimizers, i.e. minimizers of our functional whose level sets are contained in a spacial slab of universal size in a prescribed direction. As a limiting case, we obtain the existence of hypersurfaces contained in such a slab which minimize the surface area with respect to a given periodic metric.
FROM THE BRUNN–MINKOWSKI INEQUALITY TO A CLASS OF POINCARÉ-TYPE INEQUALITIES
Authors: COLESANTI ANDREA
Published: September 2008

We present an argument which leads from the Brunn–Minkowski inequality to a Poincaré-type inequality on the boundary of a convex body K of class [Formula: see text] in Rn. We prove that for every ψ ∈ C1(∂K)[Formula: see text] Here [Formula: see text] denotes the (n - 1)-dimensional Hausdorff measure, νK is the Gauss map of K and DνK is the differential of νK i.e. the Weingarten map.
KRAMERS–WANNIER DUALITIES FOR WZW THEORIES AND MINIMAL MODELS
Authors: SCHWEIGERT CHRISTOPH , TSOUCHNIKA EFROSSINI
Published: September 2008

We study Kramers–Wannier dualities for Wess–Zumino–Witten theories and (super-) minimal models in the Cardy case, i.e. the case with bulk partition function given by charge conjugation. Using the TFT approach to full rational conformal field theories, we classify those dualities that preserve all chiral symmetries. Dualities turn out to exist for small levels only.
EVALUATION OF SMALL- AND MEDIUM-SIZED DISPLAY MARKET FORECASTS
Authors: HUANG JEN-HUNG , HUANG HYLEY , LEE CHENG-FEW
Published: September 2008

The main purpose of this paper is to evaluate small- and medium-sized display market forecasts made by a market research firm. Hypotheses concerning the relationship between stages of technology development and the accuracy of market forecasts are first developed. The hypotheses are then tested and evaluated using the data issued by one market research company, Techno Systems Research (TSR). Kruskal–Wallis rank sum test and nonparametric simple regression are the statistical methods used.

The results of the data analysis showed that the forecasts made by the market research company are dependable for mature technology in mature markets, whereas for a new technology their forecasts are inaccurate. Furthermore, the accuracy of forecasts quite often does not improve over time.

To our knowledge, no prior published works examine the accuracy of the forecasts made by market research firms. This research shows that small- and medium-sized display manufacturers have to be cautious when using forecast data from market research firms.
BRADLEY–TERRY CHOICE PROBABILITY IN MAXIMUM LIKELIHOOD AND EIGENPROBLEM SOLUTIONS
Authors: LIPOVETSKY STAN
Published: September 2008

The Bradley–Terry model (BT) is commonly used for evaluation of choice preferences by paired comparison data in various areas of applied psychology, advertising, and marketing research. The estimation of BT parameters of preference is usually achieved in an iterative procedure based on the maximum likelihood approach. In this paper an easier way of finding these parameters via an eigenproblem is considered. This approach corresponds to solving a Chapman–Kolmogorov system of equations to estimate the steady-state probabilities of the compared items. Both techniques produce very similar results, but the eigenvector solution is simpler for applications and suggests an interpretation of BT preferences as the choice probabilities. The suggested approach can facilitate the paired comparison estimations and be utilized in various practical aims of managerial decision making.
AN EXCEL-BASED DECISION SUPPORT SYSTEM FOR SCORING AND RANKING PROPOSED R&D PROJECTS
Authors: DE PIANTE HENRIKSEN ANNE , PALOCSAY SUSAN W.
Published: September 2008

One of the most challenging aspects of technology management is the selection of research and development (R&D) projects from among a group of proposals. This paper introduces an interactive, user-friendly decision support system for evaluating and ranking R&D projects and demonstrates its application on an example R&D program. It employs the scoring methodology developed by Henriksen and Traynor to provide a practical technique that considers both project merit and project cost in the evaluation process, while explicitly accounting for trade-offs among multiple decision criteria.1 The framework of the Excel-based system, PScore, is presented with an emphasis on the potential benefits of using this methodology with computer-automated extensions that facilitate and enhance managerial review and decision-making capabilities.
ON MERGING CLASSIFICATION RULES
Authors: BOUTSINAS B. , ATHANASIADIS S.
Published: September 2008

One of the main challenges of today's data mining systems is their ability to manage a huge volume of data generated possibly by different sources. On the other hand, inductive learning algorithms have been extensively researched in machine learning using small amounts of judiciously chosen laboratory examples. There is an increasing concern in classifiers handling data that are substantially larger than available main memory on a single processor. One approach to the problem is to combine the results of different classifiers supplied with different subsets of the data, in parallel. In this paper, we present an efficient algorithm for combining partial classification rules. Moreover, the proposed algorithm can be used to match classification rules in a distributed environment, where different subsets of data may have different domains. The latter is achieved by using given concept hierarchies for the identification of matching classification rules. We also present empirical tests that demonstrate that the proposed algorithm has a significant speedup with respect to the analog non-distributed classification algorithm, at a cost of a lower classification accuracy.
DECISION SUPPORT TOOL FOR RETAIL SHELF SPACE OPTIMIZATION
Authors: RAMASESHAN B. , ACHUTHAN N. R. , COLLINSON R.
Published: September 2008

Efficient allocation of shelf space and product assortment can significantly improve a retailer's profitability. This paper addresses the problem from the perspective of an independent franchise retailer. A Category Management Decision Support Tool (CMDST) is proposed that efficiently generates optimal shelf space allocations and product assortments by using the existing scarce resources, resulting in increased profitability. CMDST utilizes two practical integrated category management models that maximize the total net profit in terms of decision variables expressing product assortment, shelf space allocation, review period, and order quantity. The implementation of the models demonstrates their robustness and that the net profit can be significantly increased when compared to the current industry practice.
EVALUATING GOVERNMENT WEBSITE ACCESSIBILITY: A COMPARATIVE STUDY
Authors: HONG SOONGOO , KATERATTANAKUL PAIRIN , JOO SEOK JEONG
Published: September 2008

Because of the aging society, web accessibility will become more important, especially for the disabled people. Even though efforts have been made to reduce the informational gap resulting from web inaccessibility, websites from virtually every type of organization have major accessibility problems. This study used an automated software tool to evaluate the accessibility of four Korean government and four US government websites. The web accessibility problems found were manually verified by both human experts and an assistive technology. Results were compared between the Korean and the US government websites and between the websites published in 2004 and 2007. Finally, how much accessibility of the Korean and the US government websites has improved during 2004–2007, common web accessibility problems, and potential errors from the automated software tool are discussed.
PEOPLE'S LIFE INDICATORS BY FUZZY OUTRANKING
Authors: INOUE HIROSHI , OSHIMA KUNIO , TAKAHASHI SATORU , SHI JIANMING , AMAGASA MICHIHIRO
Published: September 2008

It is getting a hard task to precisely express people's life today when people's senses of values have diversified in a short span of several years. In this paper, as a first step, we look at the past research and have a correct recognition of the situation before we make progress in our research.

People's Life Indicators (PLI) in Japan was made out in order to aim at contributing to the improvement of the quality of people's lives. After several changes and under an investigation committee of National Life Council in Economic Planning Agency PLI was summed up and defined in 1992. Since then PLI was used to show as wealth indicators giving ranking for 47 prefectures in Japan. However, National Life Council discontinued to officially announce the ratings of PLI in 1999 in which some difficulty seems to lie at the root of the changes of economic and social circumstances.

In this paper, we reconsider and analyze PLI by adding another indicator with fuzzy concept to be able to fit more realistic lives using the data from National Life Council.
AN EFFICIENT ALGORITHM FOR SOLVING A QUADRATIC PROGRAMMING MODEL WITH APPLICATION IN CREDIT CARD HOLDERS' BEHAVIOR
Authors: TSENG K.-J. , LIU Y.-H. , HO JOW-FEI
Published: September 2008

A quadratic programming model is developed for predicting the credit card holders' behaviors. This quadratic program is solved by a new algorithm. This algorithm optimizes the objective function along certain directions in the null space of the constraint equations. In this work, the results obtained from the model are compared with the results obtained from the other models for credit card holders' behavior problems. Due to solution algorithm and nature of the model the results are efficient and promising.
SIMILARITY-EXTENSION MODELING METHOD OF MANAGEMENT EXPERIMENTS
Authors: HE BIN , LI ZEYING , QIU YAN
Published: September 2008

In order to overcome the modeling limitations for management experiments, we proposed to integrate the Internet technology with role-playing, and developed a novel modeling method called similarity-extension modeling method. By the novel method, we found a new way to transform an economic experiment into a management one. The basic steps of similarity-extension modeling are presented, and their applications are illustrated by taking Cournot Oligopoly Management Experiment as an example. In the example, the primary Cournot Oligopoly Management Experiment is first established with reference to the basic element model of the Cournot Oligopoly Economic Experiment, and then how to transform the economic experiment into a management one is focused on in detail by introducing management factors. Finally, an improved quantitative process method is delved into for fuzzy management factors based on the Market Quiz Method in psychology.
GEOMETRIC STRUCTURES OF THE CLASSICAL GENERAL RELATIVISTIC PHASE SPACE
Authors: JANYŠKA JOSEF , MODUGNO MARCO
Published: September 2008

This paper is concerned with basic geometric properties of the phase space of a classical general relativistic particle, regarded as the 1st jet space of motions, i.e. as the 1st jet space of timelike 1-dimensional submanifolds of spacetime. This setting allows us to skip constraints.

Our main goal is to determine the geometric conditions by which the Lorentz metric and a connection of the phase space yield contact and Jacobi structures. In particular, we specialize these conditions to the cases when the connection of the phase space is generated by the metric and an additional tensor. Indeed, the case generated by the metric and the electromagnetic field is included, as well.
GEOMETRIC PHASE AND TOPOLOGY QUANTUM GATES USING PARALLEL TRANSPORTATION
Authors: GAO YU-MEI , ZHANG XIN-DING , HU LIAN
Published: September 2008

We present a novel evolution method to obtain pure geometric phase with orthogonal superposed initial state method (OGSM). As examples we illustrate in detail the geometric evolution both in NMR and superconducting Josephson junction systems, which may be further designed to construct fault-tolerant geometric quantum gates. In the end we also propose a simple way to construct topological quantum gates based on OGSM.
f(R) GRAVITY WITH TORSION: A GEOMETRIC APPROACH WITHIN THE $\mathcal{J}$-BUNDLES FRAMEWORK
Authors: CAPOZZIELLO S. , CIANCI R. , STORNAIOLO C. , VIGNOLO S.
Published: September 2008

We discuss the f(R)-theories of gravity with torsion in the framework of [Formula: see text]-bundles. Such an approach is particularly useful since the components of the torsion and curvature tensors can be chosen as fiber [Formula: see text]-coordinates on the bundles and then the symmetries and the conservation laws of the theory can be easily achieved. Field equations of f(R)-gravity are studied in empty space and in presence of various forms of matter as Dirac fields, Yang–Mills fields and spin perfect fluid. Such fields enlarge the jet bundles framework and characterize the dynamics. Finally we give some cosmological applications and discuss the relations between f(R)-gravity and scalar-tensor theories.
GENERAL SOLUTION OF THE QUANTUM DAMPED HARMONIC OSCILLATOR
Authors: ENDO RYUSUKE , FUJII KAZUYUKI , SUZUKI TATSUO
Published: September 2008

In this paper the general solution of the quantum damped harmonic oscillator is given.
NONHOLONOMIC CONSTRAINTS IN k-SYMPLECTIC CLASSICAL FIELD THEORIES
Authors: DE LEÓN M. , MARTÍN DE DIEGO D. , SALGADO M. , VILARIÑO S.
Published: September 2008

A k-symplectic framework for classical field theories subject to nonholonomic constraints is presented. If the constrained problem is regular one can construct a projection operator such that the solutions of the constrained problem are obtained by projecting the solutions of the free problem. Symmetries for the nonholonomic system are introduced and we show that for every such symmetry, there exist a nonholonomic momentum equation. The proposed formalism permits to introduce in a simple way many tools of nonholonomic mechanics to nonholonomic field theories.
Radial Symmetry, the Anterior/Posterior Axis, and Echinoderm Hox Genes
Authors: Mooi Rich , David Bruno
Published: September 2008

The strangeness of echinoderm pentaradiality results from superposition of radial symmetry onto ancestral deuterostome bilaterality. The Extraxial-Axial Theory shows that echinoderms also have an anterior/posterior (A/P) axis developed independently and ontogenetically before radiality. The A/P axis is first established via coelomic stacking in the extraxial region, with ensuing development of the pentamerous hydrocoel in the axial region. This is strongly correlated with a variety of gene expression patterns. The echinoid Hox cluster is disordered into two different sets of genes. During embryogenesis, members of the posterior class demonstrate temporal, spatial, and genetic colinearity within the extraxial region. We suggest that displacement of genes from the more anterior Hox classes toward the 5′ end of the chromosome leads to control of the later-developing, radially symmetric axial region. Genetic disorder is therefore another way of using colinearity to build the unique echinoderm symmetry.
Differential Effects of N-Acetylcysteine, Theophylline or Bicarbonate on Contrast-Induced Rat Renal Vasoconstriction
Authors: Efrati Shai , Berman Sylvia , Ilgiyeav Ilia , Siman-Tov Yariv , Averbukh Zhan , Weissgarten Joshua
Published: September 2008

Background: Vasoconstriction and reactive oxygen species (ROS) accumulation following contrast media (CM) injection are the key factors triggering CM-induced nephropathy. We compared the effects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction and ROS generation in a rat model of CM-induced nephropathy. Methods: Following a 3-day dehydration, Sprague-Dawley rats received CM (Telebrix) or sham ‘CM’ injection of 0.9% saline. Part of them received NAC, theophylline or bicarbonate prior to CM. Medullar renal blood flow was estimated by laser Doppler. The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated and intrarenal STAT-8 isoprostane, PGE2 and NO assessed. Results: Vasoconstriction was significantly attenuated by NAC. Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffective following 30 min. Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE2. NAC, theophylline but not bicarbonate, gradually increased intrarenal NO. In all experimental variables, CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed. Conclusions: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but not bicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE2 synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.
Platelet-derived microparticles and coagulation activation in breast cancer patients
Authors: Toth Bettina , Liebhardt Susanne , Steinig Kerstin , Ditsch Nina , Rank Andreas , Bauerfeind Ingo , Spannagl Michael , Friese Klaus , Reininger Armin J.
Published: September 2008

In the mid 1800s Trousseau observed cancer-associated thrombosis, of which the underlying pathogenesis still remains unknown. We performed a prospective study on platelet-derived microparticles (PMP) and their procoagulant potential in breast cancer patients. Fifty-eight breast cancer patients and 13 women with benign breast tumors were included in the study. Microparticles (MP) were examined by electron microscopy and FACS analysis using labels for annexinV (total numbers), CD61 (PMP), CD62P and CD63 (activated platelets), CD62E (endothelial cells), CD45 (leukocytes) as well as CD142 (tissue factor). Prothrombin fragment 1+2 (F1+2) and thrombin generation were measured as blood coagulation markers. Numbers of annexin V+-MP were highest in breast cancer patients with larger tumor size (T2; median = 5,637×106/l; range = 2,852–8,613) and patients with distant metastases (M1; median = 6,102×106/l; range = 3,350–7,445), and differed significantly from patients with insitu tumor (Tis; median = 3,220×106/l; range = 2,277–4,124; p = 0.019), small tumor size (T1; median = 3,281×106/l; range 2,356–4,861; p = 0.043) and women with benign breast tumor (median = 4,108×106/l; range = 2,530–4,874; p = 0.040). A total of 82.3% of MP were from platelets,14.6 % from endothelial cells and 0.3% from leukocytes. Less than 10% of PMP showed degranulation markers. Larger tumor size (T2) and metastases correlated with high counts of PMP and with highest F1+2 levels. Since prothrombin levels and thrombin generation did not parallel MP levels, we speculate that MP act in the microenvironment of tumor tissue and may thus not be an exclusive parameter reflecting in-vivo procoagulant activity.
Single nucleotide polymorphisms in the VKORC1 gene and the risk of stroke in the Southern German population
Authors: Lichy Christoph , Werner Inge , Radbruch Alexander , Wagner Simone , Grond-Ginsbach Caspar , Arnold Marie-Luise
Published: September 2008

Variation in the gene that encodes the vitamin K epoxide reductase subunit 1 (VKORC1) was recently proposed as a genetic risk factor for stroke in a Chinese population. In this ethnic group, only two common haplotypes were observed, with the C-allele of the polymorphism rs2359612 (VKORC1: c.283+837C>T) associated with stroke and other cardiovascular diseases. Recently, the influence of VKORC1 haplotypes on venous thrombosis and coronary heart disease was analyzed in study populations from France and Northern Germany. We studied the frequencies of theVKORC1 haplotypes in a series of young (<50 years, n = 158) patients with ischemic stroke from Southern Germany. The data were compared with findings from age-matched healthy control subjects from the same population (n = 213). In a replica study we also analysed older stroke patients (>50 years, n = 135) and matched control subjects (n = 113). Neither in the young population, nor in the replica study, we observed significant differences in VKORC1 haplotype distributions between healthy control subjects and patients with ischemic stroke. Our data do not confirm the association between polymorphism in the VKORC1 gene and stroke in the German population.
Protein Z, a protein seeking a pathology
Authors: Vasse Marc
Published: September 2008

Protein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors (factor VII, IX, X, protein C). In contrast to these factors, PZ does not possess any enzymatic activity but is involved as a cofactor in the down-regulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI). ZPI inhibits the activated factor X (FXa) on phospholipid surface. In mice, the disruption of PZ gene is asymptomatic, but the association with the factor V Leiden mutation leads to a quasi complete mortality during the neonatal period with microvascular thrombosis. In humans, PZ is characterized by an unusual wide distribution in plasma, and a major decrease induced by warfarin. Isolated PZ deficiency does not seem to constitute a risk for venous thrombosis, but a severe PZ deficiency could increase the risk of well recognized venous thrombotic risk factors such as factor V Leiden, G20210A mutation or hyperhomocysteinemia. Unexpectedly, a relationship between PZ deficiency and ischemic arterial diseases such as stroke, acute coronary syndromes or peripheral arterial disease was described but not confirmed by all studies. PZ deficiency could be also a risk factor for early fetal losses, and increases the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the various results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.
ADP-induced platelet aggregation frequently fails to detect impaired clopidogrel-responsiveness in patients with coronary artery disease compared to a P2Y12-specific assay
Authors: Weinberger Sarah , Flierl Ulrike , Eigenthaler Martin , Störk Stefan , Walter Ulrich , Ertl Georg , Bauersachs Johann , Schäfer Andreas
Published: September 2008

Incomplete P2Y12-inhibition during clopidogrel treatment is associated with increased cardiovascular events and mortality after coronary intervention. We investigated the incidence of impaired individual clopidogrel-responsiveness using a P2Y12-specific and pre-treatment-independent assay in a real world situation. One hundred consecutive patients with coronary artery disease (CAD) on combined acetylsalicylic acid and clopidogrel treatment (75 mg/d) and 33 patients on aspirin only were screened for platelet ADP-induced signalling by conventional aggregometry, platelet P-selectin expression and the platelet reactivity index (PRI). Impaired P2Y12-specific inhibition by clopidogrel was defined as a PRI>50%. Functional platelet reactivity was significantly lower in clopidogrel-treated patients compared to controls. Impaired individual response to treatment was diagnosed in 69% of clopidogrel-treated patients. Conventional assessment of maximum ADP-induced platelet aggregation failed to detect impaired P2Y12 inhibition in 36% of patients identified by PRI to have an impaired clopidogrel response. Impaired clopidogrel response was associated with lower HDL levels and a history of hyperlipidaemia. In conclusion, PRI as a P2Y12-specific assay to evaluate the treatment effect of clopidogrel in patients with CAD revealed insufficient P2Y12-inhibition in two thirds of patients in a real-world scenario indicating a markedly higher incidence than previously assumed. PRI detected significantly more patients with impaired response than conventional platelet aggregation.
Short-term clinical outcome after acute symptomatic pulmonary embolism
Authors: Conget Francisco , Otero Remedios , Martí David , Escobar Carlos , Rodríguez Consolación , Uresandi Fernando , Cabezudo Miguel , Nauffal Dolores , Oribe Mikel , Yusen Roger , Jiménez David
Published: September 2008

Though studies have identified clinical variables that predict adverse events in patients with acute pulmonary embolism (PE), they have typically not differentiated short-term from long-term predictors.This multicenter prospective cohort study included consecutive outpatients with objectively confirmed symptomatic acute PE.We analyzed the incidence and time course of death, venous thromboembolism (VTE) recurrence, and major bleeding, and we compared event rates during short-term (first week) and long-term (3 months) follow-up after the diagnosis of PE.We also assessed risk factors for short-term mortality. During the first three months after diagnosis of PE, 142 of 1,338 (10.6%) patients died.Thirty-six deaths (2.7%) occurred during the first week after diagnosis of PE,and 61.1% of these were due to PE.Thirty-eight patients (2.8%) had recurrent VTE during the three-month follow-up, though none of the recurrences occurred during the first week after diagnosis of PE. During the three-month follow-up, major bleeding occurred in 48 patients (3.6%). Twenty-one (1.6%) major bleeds occurred during the first week of follow-up,and nine of these were fatal. Short-term mortality was significantly increased in patients who initially presented with systolic arterial hypotension (odds ratio [OR] 3.35; 95% CI, 1.51-5.41) or immobilization due to a medical illness (OR 2.89; 95% confidence interval [CI], 1.31-6.39).In con-clusion,during the first week after the diagnosis of PE, death and major bleeding occur more frequently than recurrent VTE. Patients with systolic arterial hypotension and immobilization at the time of PE diagnosis had an increased isk of short-term mortality.
The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons
Authors: Fontayne Alexandre , Meiring Muriel , Lamprecht Seb , Roodt Jan , Demarsin Eddy , Barbeaux Philippe , Deckmyn Hans
Published: September 2008

The Fab-fragment of 6B4, a murine monoclonal antibody targeting the human platelet glycoprotein (GP) Ibα and blocking the binding of von Willebrand factor (VWF), is a powerful antithrombotic. In baboons, this was without side effects such as bleeding or thrombocytopenia. Recently, we developed a fully recombinant and humanized version of 6B4-Fab-fragment, h6B4-Fab, which maintains its inhibitory capacities in vitro and ex vivo after injection in baboons. We here investigated the antithrombotic properties, the effect on bleeding time and blood loss and initial pharmacokinetics of h6B4-Fab in baboons. The antithrombotic effect of h6B4-Fab on acute platelet-mediated thrombosis was studied in baboons where thrombus formation is induced at an injured and stenosed site of the femoral artery, allowing for cyclic flow reductions (CFRs) which are measured on an extracorporeal femoral arteriovenous shunt. Injection of 0.5 mg/kg h6B4-Fab significantly reduced the CFRs by 80%, whereas two extra injections, resulting in cumulative doses of 1.5 and 2.5 mg/kg, completely inhibited the CFRs. Platelet receptor occupancy, plasma concentrations and effects ex vivo were consistent with what was previously observed. Finally, minimal effects on bleeding time and blood loss, no spontaneous bleeding and no thrombocytopenia were observed. We therefore conclude that h6B4-Fab maintains the antithrombotic capacities of the murine 6B4-Fab, without causing side effects and therefore can be used for further development.
Effects of omega-3 acid ethyl esters and aspirin, alone and in combination, on platelet function in healthy subjects
Authors: Larson Mark K. , Ashmore Joseph H. , Harris Kristina A. , Vogelaar Jessica L. , Pottala James V. , Sprehe Michael , Harris William S.
Published: September 2008

Omega-3 fatty acids (n-3 FA) from oily fish are clinically useful for lowering triglycerides and reducing risk of heart attacks. Accordingly, patients at risk are often advised to take both aspirin and n-3 FA. However, both of these agents can increase bleeding times, and the extent to which the combination inhibits platelet function is unknown. The purpose of this pilot study was to determine the effects of a prescription omega-3 FA product (P-OM3) and aspirin, alone and in combination, on platelet aggregation assessed by whole blood impedance aggregometry (WBA). Ten healthy volunteers provided blood samples on four separate occasions: Day 1, baseline; Day 2, one day after taking aspirin (2 x 325 mg tablets); Day 29, after 28 days of P-OM3 (4 capsules/day); and Day 30, after one day of combined P-OM3 and aspirin. WBA was tested with two concentrations of collagen, with ADP and with a thrombin receptor activating peptide (TRAP). Compared to baseline, aspirin alone inhibited aggregation only with low-dose collagen stimulation;P-OM3 alone did not inhibit aggregation with any agonist; and combined therapy inhibited aggregation with all agonists butTRAP. Significant interactions between interventions were not observed in response to any agonist. In conclusion, P-OM3 alone did not inhibit platelet aggregation, but did (with two agonists) when combined with aspirin. Since previous studies have not reported a clinically significant risk for bleeding in subjects on combined therapy, P-OM3 may safely enhance the anti-platelet effect of aspirin.
Correlation between circulating endothelial cell counts and plasma thrombomodulin levels as markers for endothelial damage
Authors: Rao Chandra , Schmitz Paul I. M. , Kraan Jaco , Lamers Cor H. , Sleijfer Stefan , Terstappen Leon W. M. M. , Gratama Jan W. , Strijbos Michiel H.
Published: September 2008

Increased numbers of circulating endothelial cells (CEC) in peripheral blood have been observed in diseases with vascular involvement, and are considered a promising surrogate marker for vascular damage. It was the objective of this study to evaluate the correlation between putative soluble markers of endothelial injury, activation, and endothelial proliferation, and absolute numbers of CEC. CEC were evaluated in 125 healthy donors and 40 patients with metastatic carcinoma by automated CD146 driven immunomagnetic isolation. Plasma concentrations of E-selectin, endoglin, and thrombomodulin were assessed by ELISA in plasma obtained from 40 healthy donors and 40 patients. CEC numbers in blood were positively correlated with plasma thrombomodulin levels, but not with levels of E-se-lectin and endoglin. Multivariate analysis demonstrated a significant increase in CEC numbers with age. The levels of plasma biomarkers were not influenced by age. Higher levels of thrombomodulin and E-selectin were observed in males when compared to females. In conclusion, CEC numbers correlate positively with plasma levels of thrombomodulin.
Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: Localization, expression and participation in neurodegenerative diseases
Authors: Sokolova Elena , Reiser Georg
Published: September 2008

Emerging evidence demonstrates that thrombin exerts physiological and pathological functions in the central nervous system. Both prothrombin and its active form thrombin have been detected locally in the brain. The cellular functions of thrombin are mainly regulated by G protein-coupled protease-activated receptors (PARs). Thrombin can signal via PAR-1, PAR-3 and PAR-4. Some neurological diseases (e.g. Alzheimer’s disease or Parkinson’s disease) are characterized by increased levels of both active thrombin and PAR-1. This indicates that thrombin and its receptor may be closely involved in the development of neurodegenerative processes. The role of thrombin in brain injury can be either protective or deleterious, depending on the concentration of thrombin. Thrombin at high concentrations exacerbates brain damage. In contrast, low concentrations of thrombin rescue neural cells from death after brain insults. Also thrombin preconditioning has neuroprotective effects. Therefore, thrombin and thrombin receptors represent novel therapeutic targets for treating neurodegenerative diseases.
Metabolism and cell biology of vitamin K
Authors: Newman Paul , Shearer Martin J.
Published: September 2008

Naturally occurring vitamin K compounds comprise a plant form, phylloquinone (vitamin K1) and a series of bacterial menaquinones (MKs) (vitamin K2). Structural differences in the isoprenoid side chain govern many facets of metabolism of K vitamins including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by triglyceride-rich lipoproteins (TRL) and long-chain MKs mainly by low-density lipoproteins (LDL). TRL-borne phylloquinone uptake by osteoblasts is an apoE-mediated process with the LRP1 receptor playing a predominant role. One K2 form, MK-4, has a highly specific tissue distribution suggestive of local synthesis from phylloquinone in which menadione is an intermediate. Both phylloquinone and MKs activate the steroid and xenobiotic receptor (SXR) that initiates their catabolism, but MK-4 specifically upregulates two genes suggesting a novel MK-4 signalling pathway. Many studies have shown specific clinical benefits of MK-4 at pharmacological doses for osteoporosis and cancer although the mechanism(s) are poorly understood. Other putative non-cofactor functions of vitamin K include the suppression of inflammation, prevention of brain oxidative damage and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and thereby the availability of reduced vitamin K. Under extreme blockade, vitamin K can bypass the inhibition of Gla synthesis in the liver but not in the bone and the vessel wall. In humans, MK-7 has a greater efficacy than phylloquinone in carboxylating both liver and bone Gla proteins. A daily supplement of phylloquinone has shown potential for improving anticoagulation control.
Increased platelet adhesion under flow conditions is induced by both thalassemic platelets and red blood cells
Authors: Brill Alexander , Zelig Orly , Goldfarb Ada , Rachmilewitz Eliezer , Goldschmidt Neta , Spectre Galia , Varon David
Published: September 2008

Thromboembolic complications are not uncommon in thalassemia. Previous studies suggest increased platelet aggregation and a potential role of pathological changes in the red blood cell (RBC) lipid membrane, induced by oxidative stress. In the present study,platelet adhesion and the effect of thalassemic RBC on platelet adhesion under flow conditions were evaluated, using the Cone and Plate (let)Analyzer(CPA).Twenty-two β-thalasse-mia patients and 22 blood type-matched healthy controls were studied. An increased platelet adhesion (% surface coverage, SC),was observed in patients as compared to controls (p<0.05). When platelet count and haematocrit were normalized by auto-logous reconstitution, a significant increase in platelet aggregation (average size,AS) was observed (p<0.05). Increased platelet adhesion (SC and AS), was demonstrated in six patients with a history of thrombosis as compared to 16 patients without any history of thrombosis (p≤0.007) and in 17 splenectomized patients as compared to five non-splenectomized patients (p=0.003). In reconstitution studies, thalassemic RBC mixed with normal platelet-rich plasma significantly increased platelet adhesion compared to normal RBC (SC p<0.03, AS p<0.02). Thalassemic platelets reconstituted with normal RBC, had increased aggregation (AS, p<0.004) in comparison with normal platelets.The results indicate that increased platelet adhesion in β-thalassemia is induced by both platelets and RBC. Increased platelet adhesion correlated with clinical thrombotic events and thus may suggest a mechanism of thrombosis in thalassemic patients.The potential application of the CPA in identifying thalassemic patients with high risk for thrombosis should be studied prospectively in a larger cohort of patients.
Protective effects of activated protein C in sepsis
Authors: Toltl Lisa J. , Swystun Laura L. , Pepler Laura , Liaw Patricia C.
Published: September 2008

Sepsis remains a complex syndrome associated with significant morbidity and mortality. It is now widely accepted that the pathways of inflammation, coagulation, apoptosis, and endothelial permeability are intimately linked in sepsis pathophysiology. The clinical success of activated protein C (APC), a natural anticoagulant, in reducing mortality in patients with severe sepsis has fuelled basic and preclinical research on the protective effects of this molecule. Over the past 15 years, impressive research advances have provided novel insights into the multifunctional activities of APC. APC is now viewed not only as an anticoagulant, but also as a cell signaling molecule that dampens the excessive or insufficiently controlled host response during sepsis. This review attempts to summarize the pleiotropic activities of APC with focus on its ability to inhibit coagulation, inflammation, apoptosis, and endothelial barrier breakdown. A comprehensive PUBMED literature review up to May 2008 was conducted.
Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells
Authors: Johnell Matilda , Wickström Malin , Widunder Anna , Siegbahn Agneta , Åberg Mikael
Published: September 2008

Cancer confers a prothrombotic state and statins are associated with a lowered risk for prostate cancer in vivo by unknown mechanisms. Prostate cancer cells release tissue factor (TF)-bearing, cholesterol-rich prostasomes which are procoagulant in vitro and a possible source for the blood-borne TF found in prostate cancer patients. We investigated the effect of cholesterol depletion on the production of prostasomes and on the TF activity in the conditioned medium of simvastatin-treated PC3 cells. Human PC3 prostate cancer cells were treated with high and low concentrations of simvastatin for different time periods. Caspase-3 was detected with the Array Scan microscope, where-asTF mRNA and protein were analyzed by TaqMan and flow cytometry. TF activity was assessed by measuring the cleavage of a chromogenic thrombin substrate. Prostasomes were isolated by repeated centrifugations and detected and quantified by flow cy tometry. A micromolar dose of simvastatin caused reduction of TF expression and induction of apoptosis in the PC3 cells. The levels of TF on the prostasomes were also decreased but the TF activity in the conditioned medium of the simvastatin-treated PC3 cells was increased due to apoptosis-dependent release of prostasomes. Treatment with a nanomolar dose of simvastatin did not induce apoptosis or alter the expression of TF but instead decreased the production and release of the prostasomes. The TF activity was reduced in parity with the decline in prostasome release. In conclusion, in prostate cancer, a nanomolar dose of simvastatin may have an anti-thrombotic effect due to decreased levels of circulating TF-bearing prostasomes.
Tirofiban optimizes platelet inhibition for immediate percutaneous coronary intervention in high-risk acute coronary syndromes
Authors: Keck Frieder , Staritz Peter , Lehrke Stephanie , Katus Hugo A. , Giannitsis Evangelos , Ivandic Boris T. , Kurz Kerstin
Published: September 2008

It was the aim of this study to compare the efficacy of early platelet inhibition by 600 mg clopidogrel and acetylsalicylic acid (ASA) to a triple therapy including a glycoprotein IIb-IIIa receptor blocker. Immediate percutaneous coronary intervention (PCI) is recommended for high-risk acute coronary syndromes. In this setting the efficacy of platelet inhibition is unknown. One hundred patients were randomized to receive ASA and 600 mg clopidogrel, or additional open-label tirofiban (bolus of 10 µg/kg body weight followed by continued infusion of 0.15 µg/kg body weight per minute) as soon as non-ST - segment elevation myocardial infarction was diagnosed. The primary endpoint was the reduction of infarct size determined by post-interventional increases of cardiac troponin T (cTnT). Secondary endpoints included platelet function measured by optical and impedance aggregometry using ADP (5 and 20 µM) and collagen (1 µg/ml) as platelet agonists. Tirofiban maximized platelet inhibition (p<0.0001) immediately and was associated with significantly lower post-interventional cTnT concentrations (p=0.0352). In the dual platelet inhibition arm, clopidogrel was not effective in 69% of patients at the time of coronary intervention, and still in 47%, if pre-treatment time was >120 minutes. The frequency of cardiovascular (death, myocardial infarction, revascularization) and bleeding events was comparable. Platelet aggregation is not adequately inhibited in cTnT - positive patients in the setting of immediate PCI with very short pre-treatment times. Only tirofiban provided consistent and effective inhibition of platelet aggregation at the time of immediate or very early invasive therapy.
Comparison of bivalirudin, enoxaparin, and unfractionated heparin in preventing cardiac catheter thrombosis
Authors: Buerke Michael , Schubert Sebastian , Reindl Iris , Michel Thomas , Hauroeder Baerbel , Carter Justin M. , Peetz Dirk , Werdan Karl , Schlitt Axel , Maegdefessel Lars
Published: September 2008

Bivalirudin, a direct thrombin inhibitor binds specifically and reversibly to both fibrin-bound and unbound thrombin. Bivalirudin is approved for use as an anticoagulant in patients undergoing percutaneous coronary intervention. The OASIS-5 trial presented a significant increase in cardiac catheter thrombosis for the pentasaccharid fondaparinux compared to enoxaparin. Catheter thrombosis has never been reported in any trial using bivalirudin. Our study compared the development of catheter thrombosis for bivalirudin, enoxaparin, and unfractionated heparin in a controlled in-vitro environment. Ten healthy male volunteers were pretreated with aspirin 500 mg 2 hours before venesection of 50 ml of blood. The seven groups of anticoagulant combinations tested were:UFH, UFH + eptifibatide, enoxaparin, enoxaparin + eptifibatide, bivalirudin bolus, bivalirudin + eptifibatide, bivalirudin bolus + continuous infusion. The blood/anticoagulant mix continuously circulated through a cardiac guiding catheter for 60 minutes or until the catheter became blocked with thrombus. Thrombus development was assessed by weighing each catheter before and after the procedure. Electron microscopy was used to quantify the degree of erythrocyte, platelet and fibrin deposition. Following anticoagulation with bolus dose bivalirudin, the catheter was invariably occluded with thrombus after 33 minutes of circulation. However, a continuous infusion of Bivalirudin prevented the development of occlusive catheter thrombosis. In the bolus bivalirudin group the mean thrombus weight was significantly greater than in all other groups (p-value < 0.01 in all analyses). Bivalirudin given as a bolus was not sufficient to prevent cardiac catheter thrombosis in our in-vitro study. However, a continuous infusion of bivalirudin had similar anti-thrombotic efficacy compared to other treatment strategies.
Comparison of the two-year outcomes and costs of prophylaxis in medical patients at risk of venous thromboembolism
Authors: Becker Russ , Lin Jay , Benner Josh , Deitelzweig Steven B.
Published: September 2008

A decision-analytic model incorporating a Markov process to assess the incremental cost and effectiveness of venous throm-boembolism (VTE) prevention strategies was used. Modeling was carried out using a hypothetical cohort of medical patients at risk of VTE.The model compared clinical effectiveness (primary and recurrent VTE, death), safety (adverse events), and direct medical costs between patients receiving enoxaparin prophylaxis, unfractionated heparin (UFH) prophylaxis, and no prophylaxis (n=10,000 for each arm). Monte Carlo simulation was performed to identify changes in inputs that would affect the results.The estimated incidence of VTE at two years (including recurrentVTE) was 6.8% with enoxaparin prophylaxis, 7.9% with UFH prophylaxis,and 17.9% with no prophylaxis.Two-year mortality occurred in 15.7% of enoxaparin patients and 16.0% of UFH patients, with the incidences of major bleeding in these groups being 0.7% and 1.2%, respectively. However, both enoxaparin and UFH prophylaxis were associated with higher rates of major bleeds than no prophylaxis (0.6%).Total average costs per patient were (US dollars) $1,264 (for enoxaparin prophylaxis, $1,585 for UFH prophylaxis,and $2,245 for no prophylaxis).No realistic parameter changes resulted in enoxaparin prophylaxis being more costly than UFH prophylaxis. For the healthcare payer, considering all direct medical costs associated with VTE up to two years after an admission for acute illness, prophylaxis with enoxaparin was more effective and less costly than UFH. This identifies enoxaparin as a potentially favorable VTE prophylaxis regimen compared with UFH and no prophylaxis in at-risk medical patients