bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats
Authors: Ostrowska Justyna , Z.Wojtukiewicz Marek , Chabielska Ewa , Buczko Wlodzimierz , Ostrowska Halina 
Published: May 2004

SummaryRecent studies indicate that highly selective proteasome inhibitors can be useful in prevention of some cardiovascular events. Here we demonstrate that proteasome inhibitor, Z-IleGlu (Ot-Bu) Ala-Leucinal (PSI), is active in the prevention of platelet-dependent arterial thrombosis induced in renovascular hypertensive rats (two-kidney, one clip Goldblatt model, and 2K1C, n=5).The administration of PSI intravenously at a single dose of 0.3 mg/kg before induction of arterial thrombosis markedly increased carotid final flow rate, as compared to control (vehicle) group (10.36 ± 1.8 ml/min and 1.2 ± 1.2 ml/min, respectively), significantly decreased the wet (1.23 ± 0.23 mg and 4.1 ± 0.94 mg, respectively), and dry (0.46 ± 0.145 mg and 1.46 ± 0.39, respectively) thrombus weight, and completely prevented arterial occlusion. Moreover, platelets from PSI treated thrombotic 2K1C rats, showed in response to collagen a significant inhibition of aggregation in the whole blood (10.26 ± 0.6 ohms vs. 15.51 ± 0.91ohms in the control group). In contrast, collagen-induced platelet aggregation was not inhibited in vitro, after pre-treatment of the blood with PSI at the concentration of 10μM that effectively inhibited the 20S proteasome activity in platelets, indicating that ex vivo anti-aggregatory effect of PSI proceeds through an indirect mechanism not associated with suppression of 20S proteasome activity in platelets. In conclusion, our in vivo findings demonstrate that proteasome inhibitor, Z-Ile-Glu(Ot-Bu)Ala-Leucinal, prevents the development of arterial thrombosis in renovascular hypertensive rats and effectively suppresses platelet aggregation by an indirect mechanism. Thus the data provide a new insight into the potential role for the proteasome-dependent pathway in cardiovascular events.
Heparin binding protein is increased in chronic leg ulcer fluid and released from granulocytes by secreted products of Pseudomonas aeruginosa
Authors: Lundqvist Katarina , Herwald Heiko , Sonesson Andreas , Schmidtchen Artur 
Published: May 2004

SummaryRecently it was demonstrated by Gautam, et al. that release of neutrophil-borne heparin-binding protein (HBP), also known as CAP37/azurocidin, induced endothelial hyperpermeability and neutrophil efflux. Here, we show that chronic leg ulcer fluid, in contrast to wound fluid from acute wounds, contains highly increased levels of HBP. Immunohistochemistry demonstrated the presence of HBP in chronic ulcer tissues. Furthermore, secreted products of Pseudomonas aeruginosa were found to induce release of HBP from human neutrophils. Our data suggest a possible link between bacterial presence and HBPrelease in chronic ulcers.Thus, targeting HBP offers an interesting option for reduction of endothelial barrier dysfunction in chronic ulcers.
Comparison between ticlopidine and clopidogrel in patients with ST-segment elevation myocardial infarction treated with coronary stenting
Authors: De Luca Giuseppe , van’t Hof Arnoud , Ottervanger Jan , Hoorntje Jan , Gosselink A.T. , Dambrink Jan-Henk , Zijlstra Felix , de Boer Menko-Jan , Suryapranata Harry 
Published: May 2004

SummaryControversy still surrounds the question, which antiplatelet drug should be added to aspirin in patients undergoing coronary stent implantation. The aim of the current study was to compare ticlopidine and clopidogrel in a consecutive series of patients with ST-segment elevation myocardial infarction (STEMI) treated with primary stenting. Our population is represented by 883 consecutive patients with STEMI undergoing primary stenting from April 1997 to October 2001. All clinical, angiographic, and follow-up data were prospectively collected. A total of 523 patients on clopidogrel were compared with 360 patients on ticlopidine after primary stenting. Except for age and statin therapy, no difference in demographic and clinical characteristics was observed between the two groups. Patients on clopidogrel had a higher rate of successful reperfusion (80.7% vs 73.1%, p = 0.008). No difference was observed between the two groups at both 30-day and 1-year follow-up. These data were confirmed after correction for age, successful reperfusion and statin therapy. This study shows no difference in long-term clinical outcome between clopidogrel and ticlopidine as adjunctive antiplatelet therapy in patients with STEMI undergoing stent implantation.
The effects of long-term diet and omega-3 fatty acid supplementation on coagulation factor VII and serum phospholipids with special emphasis on the R353Q polymorphism of the FVII gene
Authors: Pedersen Jan , Hjerkinn Elsa , Arnesen Harald , Veierød Marit , Ellingsen Ingrid , Seljeflot Ingebjørg , Lindman Anja 
Published: May 2004

SummaryThe aim of the present study was to investigate the effect of long-term diet and very long chain n-3 fatty acids (VLC n-3) intervention on plasma coagulation factor VII (FVII), cholinecontaining phospholipids (PC) and triglycerides (TG), especially related to the R353Q polymorphism of the FVII gene. The present investigation included 219 subjects from the Diet and Omega-3 Intervention Trial on atherosclerosis (DOIT), a 2x2 factorial designed study in elderly men with long-standing hypercholesterolemia. The subjects were randomly allocated to receive placebo capsules (corn oil) (control), placebo capsules and dietary advice (“Mediterranean type” diet), VLC n-3 capsules, or VLC n-3 capsules and dietary advice combined. The R353Q genotype and the levels of FVIIc, FVIIag, FVIIa, PC, and TG at baseline and after 6 months were determined. Diet interention was followed by a significant reduction of 5.1% in the levels of FVIIag and 2.4 mU/ml in FVIIa (95% CI −7.4, −2.9, and −3.8, −1.1, respectively) (both p<0.001) compared to the no diet group, independent of genotype. No effects of diet intervention on FVIIc, PC or TG were observed. After VLC n-3 supplementation the TG levels were significantly reduced compared to placebo (p=0.01), whereas all FVII levels and PC remained unchanged. Dietary advice towards a “Mediterranean type” diet, but not VLC n-3 supplementation, was shown to reduce the levels of FVIIag and FVIIa after 6 months, independent of genotype. The results indicate the dietary advice to be more favourable in reducing this risk factor for CVD as compared to specific VLC n-3 supplementation.
Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time
Authors: Graff Jochen , Klinkhardt Ute , von Hentig Nils , Walenga Jeanine , Watanabe Hikari , Osakabe Masanori , Breddin Hans-Klaus , Harder Sebastian 
Published: May 2004

SummaryTreatment with the direct thrombin inhibitor argatroban (ARG) is often followed by vitamin K-antagonist treatment (VKA). Phenprocoumon (PC) and acenocoumarol (AC) are frequently used in Europe. The standard monitoring test for VKA, prothrombin time (PT), is prolonged by direct thrombin inhibitors. Therefore the International Normalized Ratio (INR) obtained during combined treatment does not reflect the true effect of the VKA. A similar interference of the VKA on the activated partial thromboplastin time (aPTT), a monitoring assay for direct thrombin inhibitors, can occur. In 39 healthy volunteers the effect of ARG alone or combined with PC or AC on PT, INR, aPTT, and Ecarin Clotting Time (ECT) was investigated. 6 groups each of 6-8 volunteers received a 5-hour infusion of either 1.0, 2.0 or 3.0 µg/kg/min ARG (days 1, 3, 4 and 5) before initiation of either PC or AC (day 1) and during continued VKA dosing (target INR 2-3). A linear relationship (INR ARG+VKA = intercept + slope * INR VKA alone) was observed between the INR measured “on” and “off” ARG.The slope depended on the argatroban dose and on the International Sensitivity Index (ISI) of the PT reagent, the steepest slope (i.e., the largest difference between INR ARG+VKA and INR VKA alone) was seen with the highest ARG dose and the PT reagent with an ISI of 2.13.There was a close correlation between plasma levels of ARG and aPTT or ECT. Under VKA the ARG-aPTT relationship indicated an increased sensitivity of the aPTT to ARG, VKA treatment had no effect on the prolongation of the ECT induced by argatroban. In conclusion, ARG at doses up to 2 µg/kg/min can be discontinued at an INR of 4.0 on combined therapy with VKA, as this would correspond to an INR between 2.2 and 3.7 for the VKA. If it is necessary to monitor ARG in the critical transition period, the ECT which is not influenced by VKA can be used as an alternative to the aPTT.
Plasma homocysteine concentration is not associated with activated protein C resistance in patients investigated for hypercoagulability
Authors: Houston Donald , Zarychanski Ryan 
Published: May 2004

SummaryHomocysteine and activated protein C (aPC) resistance are known risk factors for thromboembolism, but how elevated homocysteine influences thrombogenicity is not fully understood. The possibility that homocysteine may exert a prothrombotic effect by inducing aPC resistance has been addressed, with conflicting conclusions. The aim of this study is to evaluate the possible relationship of serum homocysteine concentration to aPC resistance in a cohort of patients investigated for hypercoagulability. Laboratory records from 1011 consecutive patients referred to the Haemostasis Laboratory at the Health Sciences Centre (Winnipeg, Canada) were reviewed from February 1997 to November 2002. Homocysteine levels, normalized aPC sensitivity ratio (aPCSR), and Factor V Leiden genotype were recorded for all 1011 patients. 394 patients had aPC-SR determined by mixing the patient plasma in 4 parts FV deficient plasma (FV-deficient-mix assay), and 617 patients had aPC-SR calculated without mixing (neat assay). Homocysteine did not significantly influence the aPC-SR when using the FV deficient assay. When aPC-SR was measured using the neat assay, homocysteine was found to correlate inversely with the degree of aPC resistance. The mean aPC-SR of FV Leiden-negative subjects measured using the neat assay was substantially lower than the expected normalized value of 1.0 that was obtained when aPC-SR was measured with the FV-deficient-mix assay. aPC resistance is common in patients being evaluated for possible hypercoagulability. In these patients, elevated plasma homocysteine levels is not associated with aPC resistance regardless of FV Leiden genotype suggesting that this is not the mechanism by which homocysteine exerts a prothrombotic effect.
New nonlipid effects of statins and their clinical relevance in cardiovascular disease
Authors: Celińska-Löwenhoff Magdalena , Kaczor Marcin , Musial Jacek , Undas Anetta 
Published: May 2004

SummaryInhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, statins, have been demonstrated to reduce cardiovascular morbidity and mortality in patients with a wide range of cholesterol levels. Numerous cholesterol-independent effects of statins that may limit atherosclerosis are probably related to inhibition of the geranylgeranylation of GTP-binding intracellular signaling proteins and involve: improved vasoreactivity, mostly through increased NO bioavailability; decreased expression of proinflammatory cytokines (interleukin-6, interleukin-1β, tumor necrosis factor α), C-reactive protein, chemokines, matrix metalloproteinases, and tissue factor with the subsequent inhibition of thrombin generation; reduced platelet activity; increased thrombomodulin expression; enhanced fibrinolysis, regulation of angiogenesis and immunomodulation. However, the clinical relevance of multiple protective effects induced by statins has not been clarified yet.
The Ser460Pro mutation in recombinant protein S Heerlen does not affect its APC-cofactor and APC-independent anticoagulant activities
Authors: Koenen Rory , Gomes Lucio , Tans Guido , Rosing Jan , Hackeng Tilman 
Published: May 2004

SummaryProtein S is a vitamin K-dependent plasma protein that functions as an APC-cofactor, but also exhibits anticoagulant activity in the absence of APC. The Heerlen polymorphism of protein S is characterized by a Ser460Pro substitution and lacks glycosylation at Asn458. It is associated with decreased protein S levels due to selective deficiency of free protein S Heerlen.To understand the lack of thrombotic complications associated with the protein S Heerlen mutation, we compared recombinant protein S Heerlen, wild type (wt) protein S and plasmaderived protein S. wt-Protein S and protein S Heerlen each bound 1:1 to C4BP with dissociation constants of 0.27 and 0.33 nM, respectively. Both wt-protein S and protein S Heerlen, either free or in complex with C4BP, were equally active as prothrombinase inhibitors in the absence of APC. All three protein S preparations stimulated APC-catalyzed inactivation of normal FVa, FVa Leiden and FVIIIa to the same extent. If extrapolated to plasma, it is not likely that the decreased free protein S levels in carriers of the protein S Heerlen mutation are compensated by an increased anticoagulant activity of protein S Heerlen-C4BP complexes. It is possible that an unrecognized plasma factor selectively enhances the anticoagulant activity of protein S Heerlen. If not, the reduction of free protein S levels in heterozygous protein S Heerlen-carriers combined with (low) normal total protein S levels apparently minimally affects the total anticoagulant activity of protein S (APC-cofactor and APC-independent activity) and hence is not associated with increased risk of venous thrombosis.
Warfarin dosing and cytochrome P450 2C9 polymorphisms
Authors: Johnson F. , Longtine Janina , Kucher Nils , Joffe Hylton , Xu Ruliang , Goldhaber Samuel 
Published: May 2004

SummaryTwo cytochrome P450 2C9 (CYP2C9) polymorphisms, CYP2C9*2 and *3, metabolize warfarin inefficiently. We assessed the extent to which these polymorphisms explain very low warfarin dose requirements and hemorrhagic complications after excluding non-genetic determinants of warfarin dosing. In this retrospective observational study, 73 patients with stable warfarin doses for ≥1 month and International Normalized Ratios (INR) of 2.0–3.0 were enrolled from our Anticoagulation Clinic. Seventeen patients required ≤2 mg (low-dose), 41 required 4–6 mg (moderate-dose), and 15 required ≥10 mg (high-dose) of daily warfarin. CYP2C9 genotyping was assessed by PCR amplification and restriction enzyme digestion analysis of DNA isolated from circulating leukocytes. The CYP2C9 polymorphisms independently predicted low warfarin requirements after adjusting for Body Mass Index, age, acetaminophen use, and race (OR 24.80; 95% CI 3.83–160.78). At least one polymorphism was present in every patient requiring ≤1.5 mg of daily warfarin, and 88%, 37%, and 7% of the low-, moderate-, and high-dose groups, respectively. All homozygotes and compound-heterozygotes for the variant alleles were in the low-dose group. Rates of excessive (INR>6.0) anticoagulation (and bleeding) were 4.5 (6.0), 7.9 (7.9), and 14.7 (0) per 100 patient-years in the wild-types, heterozygotes, and compound heterozygotes/homozygotes, respectively. In conclusion, CYP2C9*2 or *3 compound heterozygotes and homozygotes have low warfarin requirements even after excluding liver disease, excessive alcohol or acetaminophen consumption, low body weight, advancing age, and drug interactions. These polymorphisms increase the rate of excessive anticoagulation, but this risk does not appear to be associated with higher bleeding rates when anticoagulation status is closely monitored.
Admission fibrinolytic profile predicts clot lysis resistance in stroke patients treated with tissue plasminogen activator
Authors: Montaner Joan , Molina Carlos , Arenillas Juan , Santamarina Esteban , Alvarez-Sabín José , Ribo Marc 
Published: May 2004

SummaryEndogenous fibrinolysis inhibitors may be involved in t-PA resistance, decreasing stroke thrombolysis beneficts. We aim to determine the impact of pretreatment levels of plasminogen activator inhibitor (PAI-1), lipoprotein(a), thrombin-activatable fibrinolysis inhibitor (TAFI) and homocysteine on arterial recanalization and outcome. Forty-four consecutive patients with acute proximal middle cerebral artery occlusion were studied, including assessment of transcraneal Doppler artery patency. The neurological status was determined by NIH Stroke Scale (NIHSS) and long-term outcome with modified Rankin Scale (mRS). Patients who recanalized after t-PA infusion had lower PAI-1 levels than those who remained occluded. Similarly, patients who achieved dramatic clinical recovery at 12 hours exhibited significantly lower PAI-1 levels as those independent (mRS≤2) at third month. We observed a trend towards lower lipoprotein p(a) in patients who achieved recanalization at 1 hour, whereas no relation was found between TAFI or homocysteine levels and recanalization. After a regression model was applied the only independent predictor of thrombolysis resistance was baseline PAI-1≤34 ng/ml, such that high PAI-1 levels interfere with tPA-induced recanalization in stroke, predicting a higher susceptibility towards clot-lysis resistance and poor outcome.
The impact of low-dose busulfan on clonal dynamics in nonhuman primates
Authors: Kuramoto Ken , Follman Dean , Hematti Peiman , Sellers Stephanie , Laukkanen Mikko O. , Seggewiss Ruth , Metzger Mark E. , Krouse Allen , Donahue Robert E. , von Kalle Christof , Dunbar Cynthia E. 
Published: May 2004

Abstract
An understanding of the number and contribution of individual pluripotent hematopoietic stem cells (HSCs) to the formation of blood lineages has important clinical implications for gene therapy and stem cell transplantation. We have been able to efficiently mark rhesus macaque long-term repopulating stem and progenitor cells with retroviral vectors, and track their in vivo contributions to hematopoiesis using the linear amplification mediated–polymerase chain reaction (LAM-PCR) technique of insertion site analysis. We assessed the impact of busulfan on contributions of individual retrovirally marked clones to hematopoiesis. There were 2 macaques that received transplants of retrovirally transduced CD34+ cells 2 years previously that were then treated with 4 mg/kg busulfan. Despite only transient and mild suppression of peripheral blood counts, the numbers of individual stem/progenitor clones contributing to granulocyte production decreased dramatically, by 80% in the first monkey and by 60% in the second monkey. A similar impact was seen on clones contributing to T cells. The clone numbers recovered gradually back toward baseline by 5 months following busulfan in the first monkey and by 3 months in the second monkey, and have remained stable for more than one year in both animals. Tracking of individual clones with insertion-site–specific primers suggested that clones contributing to hematopoiesis prior to busulfan accounted for the majority of this recovery, but that some previously undetected clones began to contribute during this recovery phase. These results indicate that even low-dose busulfan significantly affects stem and progenitor cell dynamics. The clonal diversity of hematopoiesis was significantly decreased after even a single, clinically well-tolerated dose of busulfan, with slow but almost complete recovery over the next several months, suggesting that true long-term repopulating stem cells were not permanently deleted. However, the prolonged period of suppression of many clones suggests that transplanted HSCs may have a marked competitive advantage if they can engraft and proliferate during this time period, and supports the use of this agent in nonmyeloablative regimens
Tachykinins regulate the function of platelets
Authors: Graham Gwenda J. , Stevens Joanne M. , Page Nigel M. , Grant Andrew D. , Brain Susan D. , Lowry Philip J. , Gibbins Jonathan M. 
Published: May 2004

AbstractEvidence has been mounting for peripheral functions for tachykinins, a family of neuropeptides including substance P (SP), neurokinin A, and neurokinin B, which are recognized for their roles in the central and peripheral nervous system. The recent discovery of 4 new members of this family, the endokinins (EKA, B, C, and D), which are distributed peripherally, adds support to the notion that tachykinins have physiologic/endocrine roles in the periphery. In the present study we report a fundamental new function for tachykinins in the regulation of platelet function. We show that SP stimulates platelet aggregation, and underlying this is the intracellular mobilization of calcium and degranulation. We demonstrate the presence of the tachykinin receptors NK1 and NK3 in platelets and present evidence for the involvement of NK1 in SP-mediated platelet aggregation. Platelets were found to contain SP-like immunoreactivity that is secreted upon activation implicating SP-like substances in the autocrine/paracrine regulation of these cells. Indeed, NK1-blocking antibodies inhibited aggregation in response to other agonists. Of particular note is the observation that EKA/B cross-react in the SP immunoassay and are also able to stimulate platelet activation. Together our data implicate tachykinins, specifically SP and EKA/B, in the regulation of platelet function.
In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic cytotoxic effects
Authors: Levis Mark , Pham Rosalyn , Smith B. Douglas , Small Donald 
Published: May 2004

AbstractPatients with acute myeloid leukemia (AML) harboring internal tandem duplication mutations of the FLT3 receptor (FLT3/ITD mutations) have a poor prognosis compared to patients lacking such mutations. Incorporation of FLT3 inhibitors into existing chemotherapeutic regimens has the potential to improve clinical outcomes in this high-risk group of patients. CEP-701, an indolocarbazole-derived selective FLT3 inhibitor, potently induces apoptosis in FLT3/ITD-expressing cell lines and primary leukemic blasts. We conducted a series of in vitro cytotoxicity experiments combining CEP-701 with chemotherapy using the FLT3/ITD-expressing cell lines MV4-11 and BaF3/ITD as well as a primary blast sample from a patient with AML harboring a FLT3/ITD mutation. CEP-701 induced cytotoxicity in a synergistic fashion with cytarabine, daunorubicin, mitoxantrone, or etoposide if used simultaneously or immediately following exposure to the chemotherapeutic agent. In contrast, the combination of pretreatment with CEP-701 followed by chemotherapy was generally antagonistic, particularly with the more cell cycle-dependent agents such as cytarabine. This effect appears to be due to CEP-701 causing cell cycle arrest. We conclude that in FLT3/ITD-expressing leukemia cells, CEP-701 is synergistic with standard AML chemotherapeutic agents, but only if used simultaneously with or immediately following the chemotherapy. These results should be considered when designing trials combining chemotherapy with each of the FLT3 inhibitors currently in clinical development. (Blood. 2004; 104:1145-1150)