bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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

SummaryIn 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

SummaryVariation 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

SummaryProtein 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

SummaryIncomplete 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

SummaryThough 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

SummaryThe 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

SummaryOmega-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

SummaryIncreased 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

SummaryEmerging 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

SummaryNaturally 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

SummaryThromboembolic 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

SummarySepsis 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

SummaryCancer 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.