bluuebunny/crossref_metadata_2025 huggingface dataset:
QT Interval Dispersion as a New Marker of Restenosis after Percutaneous Transluminal Coronary Angioplasty of Isolated Single-Vessel Coronary Artery Stenosis
Authors: Grygier M. , Lesiak M. , Podżerek T. , Kowal J. , Mitkowski P. , Pyda M. , Skorupski W. , Grajek S. , Cieśliński A.
Published: April 2006

Background: There are no reliable non-invasive markers of restenosis after percutaneous transluminal coronary angioplasty (PTCA). The aim of our study was to measure changes in QT interval dispersion after PTCA and to determine whether restenosis subsequently affects QT interval dispersion. Methods and Results: Fifty-six consecutive patients – 41 men and 15 women (mean age: 56.2 ±8.3 years) – with isolated stenosis of the left anterior descending artery who underwent successful PTCA were studied. A symptom-limited treadmill exercise test was performed within 7 days after PTCA and then again before repeated angiography. Repeated coronary angiography revealed restenosis in 15 patients (26.8%) and no signs of significant stenosis in 41 patients (73.2%). QT interval dispersion in the group of patients with restenosis measured before exercise increased from baseline 34 ± 7 to 49 ± 15 ms after 6 months (p < 0.01) and QT interval dispersion measured immediately after exercise increased from baseline 38 ± 4 to 68 ± 21 ms after 6 months (p < 0.001). In contrast, patients without restenosis showed no significant changes in QT interval dispersion measured before (baseline: 34 ± 9 ms; after 6 months 33 ± 12 ms; p = NS) and immediately after exercise (baseline: 34 ± 12 ms; after 6 months: 33 ± 10; p = NS). When QT interval dispersion ≧60 ms (measured 6 months after PTCA procedure) was considered as a potential marker of restenosis, this indicator had very high sensitivity and specificity when measured immediately after exercise (80 and 95% respectively). Conclusions: QT interval dispersion significantly increases in the group of patients with documented restenosis and may be a simple, non-invasive marker of restenosis. However, further studies are needed to confirm this observation.
Spondyloarthropathy-Associated Aortitis and Massive Thickening of the Aortic-Mitral Curtain: Diagnosis by Echocardiography
Authors: Novaro Gian M. , Erim Tolga , Pinski Sergio L.
Published: April 2006

Cardiac involvement in reactive arthritis is well-recognized, and usually results in aortic regurgitation, proximal aortitis, and conduction system abnormalities. Aortitis is usually recognized in conjunction with aortic regurgitation, but can be diagnosed in isolation as aortic root thickening and subaortic fibrous ridging. We report a case of spondyloarthropathy-associated aortitis diagnosed by transesophageal echocardiography. The case illustrates the aortic root pathology and highlights the unique morphologic echocardiographic feature of this condition, prominent thickening of the aortic-mitral curtain.
Therapy with Budesonide in Patients with Refractory Sprue
Authors: Daum Severin , Ipczynski Rainer , Heine Bernhard , Schulzke Jörg-Dieter , Zeitz Martin , Ullrich Reiner
Published: April 2006

Introduction: Refractory sprue (RS) is a rare malabsorption syndrome, which often requires long-term corticosteroid treatment. Locally acting budesonide could replace systemic corticosteroid therapy and reduce toxicity in patients with RS. Aims: To evaluate the efficacy and toxicity of budesonide in patients with RS. Patients and Methods: Clinical and histological data from patients with RS who received budesonide were analyzed. RS was defined as villous atrophy and malabsorption in spite of a strict gluten-free diet persisting for >6 months or requiring earlier therapeutic intervention. Results: We identified 9 patients (1 with autoimmune enteropathy, 4 with RS type I without and 3 with RS type II with signs of early T cell lymphoma and 1 with CD4-positive sprue-like intestinal T cell lymphoma), who received 9 mg/day of budesonide (range 6–12) for 24 months (1–60), and 7 of whom had an initial treatment with 40 mg/day of prednisolone (30–60) for 4 months (1–144). The initial body mass index was 18 (13.1–22.8) and increased similarly under prednisolone [21.5 (14.9–26.7), p < 0.05] and budesonide therapy [21 (18–27.2), p < 0.05]. The stool frequency per day also decreased similarly from 6 (2–8) to 2 (1–3) and 2 (1–5), each p < 0.05, under prednisolone and budesonide therapy, respectively. Two patients with RS type II did not respond and 7, including all 4 with RS type I, were clinically stable with budesonide therapy. Skin fragility in 1 patient was the only adverse effect of budesonide therapy. Conclusions: Budesonide may be an effective treatment option in patients with RS type I, which can stabilize the clinical condition similar to prednisolone.
RF-Assisted Cystectomy and Pericystectomy: A New Technique in the Treatment of Liver Hydatid Disease
Authors: Sahin Mustafa , Kartal Adil , Haykir Rahime , Cakir Murat
Published: April 2006

Background: Radiofrequency (RF) energy has been used for ablation and resection of liver tumors. Purpose: To present a new technique for the treatment of liver hydatid cyst disease. Material and Methods: Two patients with liver hydatid disease treated with RF energy cauterization and surgical resection are presented. Cystectomy was performed in a female patient aged 35 years and pericystectomy was carried out in another female patient aged 55 years using RF energy cauterization. Blood was not needed during the operation. RITA® System (RITA Model 1500 RF Generator, RITA Medical Systems, Inc., USA) was used during the procedure. Conclusion: Cystectomy and pericystectomy in liver hydatid disease can be successfully performed with the assistance of RF energy.
Measurement of Tension-Free Vaginal Tape Trocar Insertion and Exit Forces
Authors: Yip Shing-Kai , Pang Man-Wah , Sahota Daljit Singh
Published: April 2006

Background/Aims: This study aims to establish a model to measure the forces required for tension-free vaginal tape (TVT) trocar application using a pressure transducer. Methods: A 3.5 × 3.5 cm pressure transducer was constructed from piezo-resistive material. The transducer digitally recorded the surface contact pressure (pressure = force/area) profile continuously during TVT trocar application. Recordings were successfully obtained from 24 subjects. Results: The mean (standard error) peak contact pressures during application at the right and left side vaginal walls, and right and left side abdominal walls were 1.05 (0.12) pounds per square inch (psi), 1.08 (0.21) psi, 2.49 (0.3) psi and 2.49 (0.3) psi, respectively. On both the right and left side, pair-wise comparisons between trocar insertion and exit forces were significantly different (p < 0.001). Conclusion: A model has been developed by which TVT trocar application forces can be objectively measured. The TVT trocar exit force is substantially greater than the insertion force, regardless of side.
Endocrine Evidence that Silvering, a Secondary Metamorphosis in the Eel, Is a Pubertal Rather than a Metamorphic Event
Authors: Aroua Salima , Schmitz Monika , Baloche Sylvie , Vidal Bernadette , Rousseau Karine , Dufour Sylvie
Published: April 2006

Silvering (transition from yellow to silver eel) has been traditionally considered as a metamorphosis in view of the numerous morphological, physiological and behavioral changes preparing the eel for the oceanic migration. However, some changes, such as increases in gonad weight and steroidogenesis, suggest that silvering could also be considered as a pubertal event. In order to assess which endocrine axis may be involved in the induction of silvering, we compared the profiles of pituitary and peripheral hormones during the transition from yellow to silver female eels. A strong activation of the gonadotropic axis was shown during silvering. Follicle-stimulating hormone (FSH) mRNA levels increased during the early stages of silvering, followed by a later increase in luteinizing hormone (protein and mRNA) levels. In addition, plasma levels of sexual steroids (estradiol, E2; testosterone, T, and 11-ketotestosterone) and of vitellogenin significantly increased. In contrast, thyrotropin mRNA levels did not change and no or weak variations in plasma thyroid hormones were observed, indicating no or moderate change of the thyrotropic axis during silvering. Similarly, the somatotropic axis was not activated, as shown by pituitary growth hormone expression (protein and mRNA) and plasma levels. In addition, we studied the effects of chronic treatments of female yellow eels with thyroid hormone (thyroxine, T4) and sex steroids (T and E2) on biometrical parameters characteristics of silvering. T induced an increase in eye size and a reduction of digestive tract, whereas T4 and E2 had no effect. These hormonal profiles and experimental data lead to the conclusion that eel silvering should be considered as an onset of puberty rather than a ‘genuine’ metamorphosis.
Thiamine and Cyanocobalamin Relieve Neuropathic Pain in Rats: Synergy with Dexamethasone
Authors: Caram-Salas Nadia L. , Reyes-García Gerardo , Medina-Santillán Roberto , Granados-Soto Vinicio
Published: April 2006

Treatment of neuropathic pain is an area of largely unmet medical need. Therefore, this pain may require the development of novel drug entities. In the search for alternatives, B vitamins have been found to be a clinically useful pharmacological tool for patients with neuropathic pain. However, preclinical studies supporting this use are lacking. In this study, we assessed the possible antiallodynic effects of thiamine, pyridoxine, and cyanocobalamin as well as dexamethasone and their combination on spinal nerve ligation induced allodynia. Sub cutaneous administration of thiamine (75–600 mg/kg), pyridoxine (75–600 mg/kg), cyanocobalamin(0.75–6 mg/kg), and dexamethasone (4–32 mg/kg) significantly reduced tactile allodynia in rats. Maximal antiallodynic effects were reached with 600 mg/kg of thiamine (∼58%), 600 mg/kg of pyridoxine (∼22%), 6 mg/kg of cyanocobalamin (∼73%), and 32 mg/kg of dexamethasone (∼68%). Since a small antiallodynic effect was observed with pyridoxine, this drug was not further analyzed in the combinations. Coadministration of thiamine or cyanocobalamin and dexamethasone remarkably reduced spinal nerve ligation induced allodynia (∼90%), showing a synergistic interaction between either thiamine or cyanocobalamin and dexamethasone. Our data indicate that thiamine and pyridoxine as well as the combination of B vitamins and dexamethasone are able to reduce tactile allodynia in rats and suggest the possible clinical use of these drugs in the treatment of neuropathic pain in human beings.
Health Status Function after Treatment with Thermal Balloon Endometrial Ablation and Levonorgestrel Intrauterine System for Idiopathic Menorrhagia: A Randomized Study
Authors: Tam Wing Hung , Yuen Pong Mo , Shan Ng Doris Pui , Leung Pui Ling , Lok Ingrid Hung , Rogers Michael Scott
Published: April 2006

Aim: To compare patients’ health status function after treatment with thermal balloon endometrial ablation (TBEA) and levonorgestrel intrauterine system (LNG-IUS) for idiopathic menorrhagia. Methods: Forty-four patients were recruited into a randomized trial comparing their health status after treatment with TBEA or LNG-IUS for idiopathic menorrhagia. Results: At 1 year follow-up, the mean haemoglobin was significantly higher in women treated with TBEA (12.6 g/dl vs. 10.3 g/dl, p = 0.018). Iron deficiency occurred in 13.3% from the TBEA arm and in 50% from the LNG-IUS arm (p = 0.026). The women’s mean Short Form 36 Questionnaire general health perception scores (54.9 vs. 40.5, p = 0.024) and mental health scores (49.5 vs. 38.3, p = 0.021) in TBEA arm were significantly higher than in the LNG-IUS arm. The mental health domain score was also significantly lower in the LNG-IUS arm (46.1 vs. 38.3, p = 0.041). Conclusion: TBEA appears to offer better health status function at 1 year follow-up and to be more acceptable to our Chinese population in the treatment of idiopathic menorrhagia following failed medical treatment.
Parental Attachment and Its Impact on the Development of Psychiatric Manifestations in School-Aged Children
Authors: Yoo Han Ik , Kim Boong-Nyun , Shin Min Sup , Cho Soo Churl , Hong Kang-E
Published: April 2006

Background: Few studies have examined the relationship between the attachment styles of the primary caregivers and the behavioral problems of their school-aged children. This study was performed to identify the impact of insecure attachment patterns of parents on the development of their children’s psychiatric manifestations and disorders. Samplings and Methods: We included 494 2nd to 3rd graders and their primary caretakers. A relationship questionnaire was applied to identify the parental attachment patterns. We investigated the children’s mental and behavioral problems by using the Korean Child Behavior Checklist. For objective psychiatric diagnoses, we interviewed 130 high-risk subjects using the Korean Kiddie-Schedule for Affective Disorders and Schizophrenia – Present and Lifetime version. Results: Those parents judged to be preoccupied had children with more internalized symptoms than those who were judged to be secure (p< 0.01); dismissing/avoidant parents had children with higher scores on Attention problems (p = 0002), and fearful/avoidant parents had children with more externalized symptoms (p < 0.01). Moreover, children with insecure attachment type parents revealed more psychiatric morbidity than children with secure parents (p = 0.042). Conclusion: Parental insecure attachment was associated with the development of the psychopathologies and psychiatric illness of their children.
Assessing the Social Behavior of Unipolar Depressives: The Criteria for Typus Melancholicus
Authors: Stanghellini Giovanni , Bertelli Marco
Published: April 2006

Aim: (a) To define the nuclear characteristics of the melancholic type of personality (TM), that in European and Japanese psychopathological tradition is considered the model which most accurately describes the social behavior of unipolar depressives, through clear, valid, and synthetic criteria (criteria for TM = CTM); (b) to evaluate the diagnostic power, reliability, internal consistency, and other psychometric properties of these criteria. Methods: Personality features of 115 unipolar depressives consecutively admitted to 2 psychiatric facilities were assessed with the CTM and with the Kasahara Scale (KS). Four further unipolar depressives were assessed with the CTM by 13 different raters (11 CTM-naive and 2 experienced). Results: The CTM have shown high reliability and internal consistency. They were also highly concordant with the KS scores. Conclusions: The CTM can discriminate between TMs and non-TMs and suggests that the TM kind of personality is not a dimensional concept but a coherent structure in which one feature entails the presence of all the others.
Dystonic Movement Disorders and Spinal Degenerative Disease
Authors: Loher Thomas J. , Bärlocher Christian B. , Krauss Joachim K.
Published: April 2006

The occurrence of degenerative spinal disease subsequent to dystonic movement disorders has been neglected and has received more attention only recently. Spinal surgery is challenging with regard to continuous mechanical stress when treatment of the underlying movement disorder is insufficient. To characterize better the particular features of degenerative spinal disease in patients with dystonia and to analyze operative strategies, we reviewed the available published data. Epidemiologic studies reveal that degenerative spinal disorders in patients with dystonia and choreoathetosis occur much earlier than in the physiological aging process. Dystonic movement disorders more often affect the spine at higher cervical levels (C2–5), in contrast to spinal degeneration with age which manifests more frequently at the middle and lower cervical spine (C5–7). Degenerative changes of the cervical spine are more likely to occur on the side where the chin is rotated or tilted to. Various operative approaches for treatment of spinal pathologies have been advocated in patients with dystonic movement disorders. The available data do not allow making firm statements regarding the superiority of one approach over the other. Posterior approaches were first used for decompression, but additional anterior fusion became necessary in many instances. Anterior approaches with or without instrumented fusion yielded more favorable results, but drawbacks are pseudarthrosis and adjacent-level disease. Parallel to the development of posterior fusion techniques, circumferential surgery was suggested to provide a maximum degree of cord decompression and a higher fusion rate. Perioperative local injections of botulinum toxin were used initially to enhance patient comfort with halo immobilization, but they are also applied in patients without external fixation nowadays. Treatment algorithms directed at the underlying movement disorder itself, taking advantage of new techniques of functional neurosurgery, combined with spinal surgery have recently been introduced and show promising results.
The influence of fibrin polymerization and platelet-mediated contractile forces on citrated whole blood thromboelastography profile
Authors: Chakroun Tahar , Gerotziafas Grigoris , Seghatchian Jerhad , Samama Meyer , Hatmi Mohamed , Elalamy Ismail
Published: April 2006

Thromboelastography analysis providing a global assessment of coagulation is gaining new interest in clinical practice. Minimal TF triggered whole blood thromboelastography provides a valuable tool for studying the kinetics of clot formation (expressed by the parameters R, K and α-angle) and the physical characteristics of the clot, such as its firmness and the elastic modulus shear (expressed by the parameters maximal amplitude MA and G). We studied the influence of fibrin polymerization and platelet functional status on each parameter of thromboelastographic trace obtained by minimal TF activation in WB by employing increasing concentrations of a fibrin polymerization inhibitors (the tetrapeptide Gly-Pro-Arg-Pro-OH. AcOH; Pefabloc-FG®) and an inhibitor of actin polymerization (Cytochalasin D). Pefabloc-FG® at concentrations higher than 5 mg/ml prolonged the R and K times and decreased the α-angle in a concentration-dependent manner but it did not modify MA and G parameters. At the concentration of 5 mg/ml, Pefabloc-FG® completely inhibited clot formation. Cytochalasin D had no effect on R time but decreased the α-angle, MA and G parameters by reachinga plateau at the concentration of 5 µM. The effect of cytochalasin D was more pronounced on MA and G than on the α-angle. A combination of both Pefabloc-FG® (0.5 mg/ml) and cytochalasin D (50 µM) significantly decreased α-angle compared to control as well as their single effect. However, G value was dramatically reduced in the presence of cytochalasin D exposure, without any additional effect when both inhibitors were combined. This study confirms the importance of fibrin polimerization on the kinetics of thrombus formation and demonstrates the close association between the quality of the thrombus and the functional status of platelets. Normal platelet contractile forces are of major importance for the maximum amplitude of TEG which is related to the strength and elastic modulus of the thrombus.
Platelets enhance CD4+ lymphocyte adhesion to extracellular matrix under flow conditions: Role of platelet aggregation, integrins, and non-integrin receptors
Authors: Vitkovsky Yuri , Brill Grigory , Koltakov Alexander , Farzam Nahid , Varon David , Bank Ilan , Solpov Alexey , Shenkman Boris , Savion Naphtali
Published: April 2006

The purpose of this study was to examine the role of platelets in CD4+ T lymphocyte adhesion to subendothelial extracellular matrix (ECM). Herpesvirus saimiri (HVS)-infected CD4+ T cells were incubated on ECM. An image analysis was used to evaluate T cell adhesion. Under static condition, T cell activation with 4-α-Phorbol 12-myristate 13-acetate (PMA) resulted in a 2.6-fold increase in cell adhesion. However, adhesion was not affected by platelets. In contrast, under flow (200s−1), platelets markedly enhanced both resting and PMA-activatedT cell adhesion (33- and 48-fold), forming lymphocyte-platelet co-aggregates that contain approximately 90% of the adherent T cells. Abrogation of platelet aggregation with tirofiban inhibited formation of platelet-T cell co-aggregates under flow and reduced T cell adhesion by 74%. Separate and combined blockade of CD40L and P-selectin glycoprotein-1 (PSGL-1) on PMA-activated lymphocytes reduced adhesion under flow in the presence of platelets by 28%, 33%, and 55%, respectively. Blockade of β1-integrins decreased adhesion under both static and flow conditions (by 35% and 44%, respectively), while blockade of β2-integrin reduced adhesion only under static condition (by 23%). A similar adhesion pattern was observed using CD4+ T cells isolated from normal donor peripheral blood. In conclusion, platelets support CD4+ lymphocyte adhesion to ECM under flow by formation of heterotypic platelet-lymphocyte co-aggregates involving αIIbβ3 integrin and β1-related integrins, as well as CD40L and PSGL-1.
Benefit/risk profile of high-dose antithrombin in patients with severe sepsis treated with and without concomitant heparin
Authors: Hoffmann Johannes , Wiedermann Christian , Juers Mathias , Ostermann Helmut , Kienast Joachim , Briegel Josef , Strauss Richard , Warren Brian , Opal Steven ,   for the KyberSept investigators
Published: April 2006

A randomised, prospective, placebo-controlled phase III multicentre clinical trial (KyberSept) has been performed to test the efficacy of high-dose antithrombin therapy in patients with severe sepsis. Concomitant low-dose heparin has been routinely given in two thirds of patients for deep vein thrombosis prophylaxis.This study analyses heparin – antithrombin interactions in terms of long-term mortality, adverse events, and thromboembolic events. From a total of 2,314 patients with severe sepsis (placebo: n=1,157; antithrombin: n=1,157) 1,616 patients (placebo: 811, antithrombin: 805) received heparin concomitantly with study drug (antithrombin 30,000 IU) over four days, whereas 698 patients (346 and 352, respectively) did not. In patients with no concomitant heparin, 28-day mortality was lower with antithrombin than with placebo (37.8% vs. 43.6%; absolute reduction: 5.8%; risk ratio: 0.860 [0.725–1.019]), which increased until day-90 (44.9% vs. 52.5%; absolute reduction: 7.6%; risk ratio: 0.851 [0.735–0.987]). In patients with concomitant heparin, no effect of antithrombin on mortality was seen (28-day mortality: 39.4% vs. 36.6%; absolute increase: 2.8%; risk ratio: 1.08 [0.96–1.22]). Frequency of use of concomitant heparin increased during conduct of the study. Increased bleeding incidences were reported with antithrombin plus concomitant heparin as compared to antithrombin alone. Rates of thromboembolic events were similar when antithrombin was given with or without concomitant heparin. In the treatment of severe sepsis, high-dose antithrombin may sufficiently protect against development of venous thromboembolism when no concomitant heparin is given. Combined administration of the two increases bleeding risk and probably abolishes efficacy of antithrombin.
Group B streptococcus isolates from septic patients and healthy carriers differentially activate platelet signaling cascades
Authors: Dornieden Catharina , Beyrich Claudia , Schinke Birgitta , Schubert-Unkmeir Alexandra , Abele-Horn Marianne , Speer Christian , Siauw Celine , Kobsar Anna , Eigenthaler Martin
Published: April 2006

Infection with group B streptococcus (GBS) is the most common cause of early onset neonatal sepsis in many countries, leading to neonatal morbidity and mortality.There is much evidence fora direct involvement of platelets in the pathogenesis of inflammation and sepsis. Several bacteria are known to directly interact with platelets leading to activation and aggregation,a phenomenon also observed with GBS. Here, we demonstrate that GBS rapidly bound to platelets; however, only strains isolated from septic patients bound fibrinogen on their surface and induced platelet thromboxane synthesis, platelet aggregation, and P-selectin (CD62P) expression. In contrast, GBS strains isolated from healthy newborns or healthy pregnant women induced only shape change, but not platelet thromboxane synthesis, platelet aggregation, or CD62P expression. All GBS strains investigated were able to activate FcγRIIA receptor signaling pathways including phospholipase C gamma2 (PLCγ2), as well as calcium/calmodulin-dependent myosin kinase II (CaMKII) and phosphorylation of myosin light chain (MLC). In contrast, protein kinase C (PKC) was exclusively activated by GBS strains isolated from septic patients, and p38 mitogen activated protein kinase (p38 MAP kinase) was preferentially activated by septic GBS strains. Furthermore, stress signaling kinase SEK1/MKK4 and focal adhesion kinase (FAK) were activated by all tested GBS strains in a FcγRIIA-independent way.This study demonstrates that septic, but not colonizing, GBS strains bind fibrinogen on their surface, and that septic GBS strains influence platelet function not only via the FcγRIIA receptor, but also via pathways distinct from IgG-mediated signalling. These mechanisms lead to platelet aggregation and secretion, thereby possibly modulating the pathophysiologic course of GBS infections.
Successful silencing of plasminogen activator inhibitor-1 in human vascular endothelial cells using small interfering RNA
Authors: Hecke Anneke , Brooks Hilary , Meryet-Figuière Matthieu , Minne Stephanie , Konstantinides Stavros , Hasenfuss Gerd , Lebleu Bernard , Schäfer Katrin
Published: April 2006

Clinical as well as experimental evidence suggests that vascular overexpression of plasminogen activator inhibitor (PAI)-1, the primary physiological inhibitor of both urokinase and tissuetype plasminogen activator, may be involved in the pathophysiology of atherosclerosis and cardiovascular disease. We investigated the feasibility, efficacy and functional effects of PAI-1 gene silencing in human vascular endothelial cells using small interfering RNA. Double-stranded 21 bp-RNA molecules targeted at sequences within the human PAI-1 gene were constructed. Successful siRNA transfection of HUVEC was confirmed using fluorescence microscopy and flow cytometry. One of five candidate siRNA sequences reduced PAI-1 mRNA and protein in a concentrationand time-dependent manner. Suppression of PAI-1 mRNA was detected up to 72 hours after transfection. Moreover, siRNA treatment reduced the activity of PAI-1 released from HUVEC, and prevented the oxLDL- or LPS-induced upregulation of PAI-1 secretion. Importantly, siRNA treatment did not affect the expression of other endothelial-cell markers. Moreover, downregulation of PAI-1 significantly enhanced the ability of endothelial cells to adhere to vitronectin, and this effect could be reversed upon addition of recombinant PAI-1. SiRNAmediated reduction of PAI-1 expression may be a promising strategy for dissecting the effects of PAI-1 on vascular homeostasis.
Antithrombin reduces reperfusion-induced liver injury in mice by enhancing sensory neuron activation
Authors: Harada Naoaki , Uchiba Mitsuhiro , Kurihara Hiroki , Nakagata Naomi , Okajima Kenji
Published: April 2006

We recently demonstrated that antithrombin (AT) reduces ischemia/reperfusion (I/R)-induced liver injury in rats by increasing hepatic tissue levels of calcitonin gene-related peptide (CGRP),a neuropeptide released from the sensory nerve endings. In the present study, we examined the effect of AT on I/Rinduced liver injury in wild type mice (CGRP+/+) and congenitally αCGRP-deficient mice (CGRP−/−). We also investigated any effects of AT on CGRP release from dorsal root ganglion neurons (DRG) isolated from CGRP+/+. Based on results obtained in the present study, we attempted to determine if the anti-inflammatory activity of AT in vivo is dependent mainly on sensory neuron activation. AT enhanced ischemia/reperfusion-induced increases in hepatic tissue levels of CGRP and 6-keto-PGF1α
, a stable metabolite of PGI2, in CGRP+/+, but it did not enhance these increases in CGRP−/−. AT inhibited reperfusion-induced increases in serum alanine aminotransferase levels by increasing hepatic tissue blood flow and by attenuating increases in hepatic levels of tumor necrosis factor and myeloperoxidase in CGRP+/+,although it showed neither of these therapeutic effects in CGRP−/−. AT increased CGRP release from cultured DRGs only in the presence of anandamide, and AT-induced increase in CGRP release was not observed in the presence KT5720, an inhibitor of protein kinase A (PKA).AT markedly increased intracellular levels of cAMP in the presence of anandamide. These results strongly suggest that AT might reduce I/R-induced liver injury by enhancing activation of the sensory neurons through activation of PKA in sensory neurons.
Serum osteoprotegerin in young survivors of myocardial infarction
Authors: Brodin Ellen , Børvik Trond , Sveinbjørnsson Baldur , Hansen John-Bjarne , Vik Anders
Published: April 2006

Osteoprotegerin (OPG) is a member of the tumour necrosis factor superfamily and is involved in the regulation of bone metabolism and vascular calcification. Increased serum OPG levels have been reported in patients with stable angina pectoris and survivors of myocardial infarction with heart failure. The purpose of the present study was to determine serum OPG levels in young survivors of acute myocardial infarction (MI), and the relationship between OPG, homocysteine, sCD40L and coagulation factors in blood. Fifty-eight patients with verified MI, 40–60 years of age, were recruited 1–4 years after the acute event into an age- and sex- matched case control study with controls recruited from the general population. Serum OPG levels were similar in cases (2.41 ng/ml, 2.11–2.77 ng/ml) (mean, 95% CI) and controls (2.43 ng/ml, 2.11–2.79 ng/ml) (p= 0.92). Significant correlation between OPG and homocysteine was found in patients (r=0.30, p=0.02) and controls (r=0.35, p=0.007). A significant negative correlation was found between OPG and sCD40L in patients (r=-0.51, p<0.001), but not in controls (r=0.001, p=0.96). No associations were found between serum OPG and markers of coagulation activation. The present study shows that serum OPG level was not increased in young survivors of uncomplicated myocardial infarction. Serum OPG levels were not associated with thrombin generation assessed by thrombin-antithrombin complexes (TAT), but a positive association between serum OPG and homocysteine was found.
The influence of sequence variations in factor VII, γ-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement
Authors: Herman Darja , Peternel Polona , Stegnar Mojca , Breskvar Katja , Dolzan Vita
Published: April 2006

The degree of interpatient variability in the warfarin dose required to achieve the desired anticoagulant response can only partly be explained by polymorphisms in the CYP2C9 gene, suggesting that additional genetic factors such as polymorphisms in genes involved in blood coagulation may influence warfarin dose requirement. In total, 165 Caucasian outpatients on stable maintenance warfarin treatment previously genotyped for CYP2C9 were analysed for common polymorphisms in FVII, GGCX and VKORC1 genes. The -402G>A polymorphism and a variable number of repeats in intron 7 of FVII gene did not significantly influence warfarin dose.The mean warfarin doses increased with the number of (CAA) repeats in the GGCX gene, but the differences were significant only in the CYP2C9*1/*1 subgroup of patients (p=0.032). Common polymorphism (6484C>T) in intron 1 of the VKORC1 gene led to lower warfarin dose requirement; the means were 5.70 (95% C.I. 4.95 - 6.45), 3.49 (3.07 - 3.90) and 2.11 (1.80 - 2.42) mg/day for 6484 CC, CT and TT genotypes, respectively (p<0.001). In contrast, 9041G>A polymorphism in 3’UTR of theVKORC1 gene led to higher warfarin dose requirement; the means were 3.09 (2.58 - 3.60), 4.26 (3.69 - 4.82) and 5.86 (4.53 - 7.19) mg/day for 9041 GG, GA and AA genotypes, respectively (p<0.001).With a regression model we explained 60.0% of variability in warfarin dose, which was due to gene polymorphisms (CYP2C9,VKORC1), age and body-surfacearea. When aiming for individualised warfarin therapy, at least VKORC1 polymorphisms should be included in predictive genotyping besides CYP2C9.
Age-dependency of thrombin generation measured by means of calibrated automated thrombography (CAT)
Authors: Haidl Harald , Cimenti Christina , Leschnik Bettina , Zach Doris , Muntean Wolfgang
Published: April 2006

Many coagulation parameters, such as PT or aPTT, show age-dependency. In this study we investigated if the generation of thrombin, possibly better reflecting overall haemostasis, shows an age-dependency.Thrombin generation was measured in platelet poor plasma of 121 children and 86 adults at different ages by means of calibrated automated thrombography (CAT). Correlation analysis shows that endogenous thrombin potential (ETP) (r= 0.702),lag time (r = - 0.266),peak (r = 0.533) and time to peak (r = - 0.214) are significantly correlated with age (p < 0.01).’Younger’ (age limit 35 years) and ‘older’ adults were compared with groups of children and adolescent aged between 0.5 and 6 years, 7 and 11 years and 12 to 17 years by means of the Mann-Whitney-U-Test. ETP values of all children and adolescents were significantly lower than those of adults. In the group of the youngest children,additionally shorter lag times and times to peak and lower peak levels differed significantly from those of adults. In the group of 7to 11-year-old children, lag times were significantly longer than those of both groups of adults, while lower peaks and longer times to peak differed only from the group of the ‘older’ adults. In the group of the 12to 17-yearolds, the values of ETP were lower than those of adults. In addition, both adult groups differed significantly in all studied parameters. Our results show an age-dependency of thrombin generation even beyond the juvenile period. If thrombin generation measurement is to be used asa routine method, age has to be considered. Assuming that thrombin potential is an indicator for the risk of thrombosis, our findings are in accordance with the observation of an increased incidence of thrombembolic disease with higher age.
Local delivery of soluble platelet collagen receptor glycoprotein VI inhibits thrombus formation in vivo
Authors: Bültmann Andreas , Herdeg Christian , Li Zhongmin , Münch Götz , Baumgartner Christine , Langer Harald , Kremmer Elisabeth , Geisler Tobias , May Andreas , Ungerer Martin , Gawaz Meinrad
Published: April 2006

Platelet-mediated thrombus formation at the site of vascular injury isa major trigger for thrombo-ischemic complications after coronary interventions. The platelet collagen receptor glycoprotein VI (GPVI) plays a critical role in the initiation of arterial thrombus formation. Endothelial denudation of the right carotid artery in rabbits was induced through balloon injury. Subsequently, local delivery of soluble, dimeric fusion protein of GPVI (GPVI-Fc) (n=7) or control Fc (n=7) at the site of vascular injury was performed with a modified double-balloon drugdelivery catheter.Thrombus area within the injured carotid artery was quantified using a computer-assisted image analysis and was used as index of thrombus formation.The extent of thrombus formation was significantly reduced in GPVI-Fc- compared with control Fc-treated carotid arteries (relative thrombus area, GPVI-Fc vs. Fc: 9.3 ± 4.2 vs. 2.3 ± 1.7, p<0.001). Local delivery of soluble GPVI resulted in reduced thrombus formation after catheter-induced vascular injury.These data suggest a selective pharmacological modulation of GPVI-collagen interactions to be important for controlling onset and progression of pathological arterial thrombosis, predominantly or even exclusively at sites of injured carotid arteries in the absence of systemic platelet therapy.
Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathway
Authors: Kwak Sang-Hyun , Wang Xue-Qing , He Qianbin , Fang Wen-Feng , Mitra Sanchayita , Bdeir Khalil , Ploplis Victoria , Xu Zhi , Idell Steven , Cines Douglas , Abraham Edward
Published: April 2006

Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor superfamily, modulates fibrinolysis by interacting with proteolytic mediators, including urokinase plasminogen activator (uPA). Although the roles of uPA and PAI-1 in plasmin generation and the degradation of fibrin are well known, recent evidence also suggests that they can participate in acute inflammatory conditions that involve neutrophil activation. In the present experiments, we found that the addition of PAI-1 to LPS-stimulated neutrophils resulted in enhanced nuclear translocation of NF-κB and increased production of the proinflammatory cytokines IL-1β,Tnf-α,and Mip-2.uPA and the kringle domain (KD) of uPA potentiated cytokine expression and NF-κB activation by neutrophils cultured with LPS, and had additive effects when combined with PAI-1. The c-Jun N-terminal kinase (JNK) was activated after exposure of resting neutrophils to PAI-1 or the uPA KD. Enhanced JNK activation, but not that of other kinases induced by LPS, was present in neutrophils cocultured with PAI-1 or uPA KD. Inhibition of JNK activation prevented the potentiation of expression of proinflammatory cytokines induced by PAI-1 or uPA KD in LPS stimulated neutrophils. These results demonstrate that PAI-1 and uPA KD enhance LPSinduced neutrophil responses through their effects on JNK mediated pathways.
In vivo antithrombotic synergy of oral heparin and arginine: Endothelial thromboresistance without changes in coagulation parameters
Authors: Daniels Bruce , Zhang Fuming , Mao Wenjun , Wice Sandra , Hiebert Linda , Linhardt Robert
Published: April 2006

On the basis of suggested clinical efficacy in an uncontrolled study in ninety-seven patients with unstable angina, an animal study was conducted to investigate antithrombotic synergy between orally administered heparin and arginine. A rat venous thrombosis model tested the difference in thrombus formation when heparin (7.5 mg/kg) and arginine (113 mg/kg) were administered, alone or in combination, by stomach tube with a minimum of 20 rats/group. Oral heparin, arginine, and heparin plus arginine reduced thrombus formation by 50%, 75%, and 90%, respectively,when compared to saline administration. Heparin was recovered from endothelium, yet there was little or no observable plasma anticoagulant activity. An orally administered lowmolecular-weight anticoagulant glycosaminoglycan mixture, sulodexide (7.5 mg/kg), showed an 88% reduction in stable thrombus formation when administered alone but showed no synergy with oral arginine. A 28-day study with oral sulodexide (2.9 mg/ kg) and arginine (43.9 mg/kg), 20 rats/group, showed antithrombotic activity with minimal anticoagulant activity indicating suitability for long term treatment. These findings suggest the endothelial localization of heparin and a synergistic antithrombotic effect for orally administered heparin and arginine.
Cleavage of human 7-domain VCAM-1 (CD106) by thrombin
Authors: Barthel Steven , Johansson Mats , Annis Douglas , Mosher Deane
Published: April 2006

Vascular cell adhesion molecule 1 (VCAM-1,CD106) is expressed as a type I transmembrane integrin counter-receptor on activated endothelium and mediates white blood cell attachment. The alternatively spliced 7-domain (7d) form of VCAM-1 contains a potential thrombin cleavage site. Thrombin proteolysis of 7d-VCAM-1 may help regulate adhesive activity of VCAM-1. We determined whether 7d-VCAM-1 is proteolyzed and rendered inactive by thrombin. Recombinant extracellular domain of 7d-VCAM-1 was cleaved by thrombin to generate 33- and 44-kDa products. Cleavage was in the sequence PGPR/IAAQIG near the N-terminal border of the alternatively spliced fourth immunoglobulin (Ig)-like module. There was no cleavage of 6d-VCAM-1 lacking the fourth module. Expression of full-length 7d-VCAM-1 presented on Chinese hamster ovary (CHO) monolayers, as detected by flow cytometry with an antibody directed to Ig-like modules 1–3, was reduced by thrombin treatment whereas there was no reduction in the expression of fulllength 6d-VCAM-1. Adhesion of blood eosinophils to full-length 7d-VCAM-1 was reduced after treatment of CHO cells with thrombin, whereas adhesion to full-length 6d-VCAM-1 was not affected. We conclude that cleavage of 7d-VCAM-1 by thrombin is a potential mechanism for differential regulation of VCAM-1 splice forms in white blood cell adhesion and trafficking.
Air travel and fatal pulmonary embolism
Authors: Bell Melanie , Herbison Peter , Paul Charlotte , Skegg David , Parkin Lianne
Published: April 2006

Although long-distance air travel is commonly regarded as a risk factor for venous thromboembolism, the risk of clinically important events has not been well defined. We estimated the absolute risk of dying from pulmonary embolism following longdistance air travel in a national population-based descriptive study of 121 men and women who were aged 15–59 years (the age range in which the majority of international arrivals are found) and whose underlying cause of death was certified as codes 415.1, 451, or 453 of the International Classification of Diseases (ninth revision). Eleven cases had undertaken longdistance air travel in the four weeks before the onset of the fatal episode. The estimated risks of fatal pulmonary embolism following a flight of at least three hours’ duration were 0.5 (95% CI 0.2–1.2) and 0.6 (95% CI 0.2–1.4) per million arrivals for overseas visitors and New Zealand residents, respectively. For air travel of more than eight hours’ duration, the risk in New Zealand residents was 1.3 (95% CI 0.4–3.0) per million arrivals. We also conducteda case-control study based on those cases who were normally resident in New Zealand and registered on the electoral roll (n=99). For each case, four controls matched for sex, age, and electorate, were randomly selected from the electoral roll. In the key analysis (based on 88 cases and 334 controls), the adjusted odds ratio for travellers who had flown for more than eight hours was 7.9 (95% CI 1.1–55.1) compared with those who did not undertake a long-distance flight. Longdistance air travellers have a higher risk of dying from pulmonary embolism than non-travellers, but the absolute risk in people aged 15–59 years appears to be very small.
Interleukin-6 and interleukin-6 promoter polymorphism (−174) G>C in patients with spontaneous venous thromboembolism
Authors: Vormittag Rainer , Hsieh Kety , Kaider Alexandra , Minar Erich , Bialonczyk Christine , Hirschl Mirko , Mannhalter Christine , Pabinger Ingrid
Published: April 2006

Increased levels of interleukin-6 (IL-6) have been reported in patients with a history of venous thromboembolism (VTE); however, prospective studies did not confirm an association between inflammatory markers that are highly correlated with IL-6 and the risk of VTE. It was the aim of our study to investigate the association of IL-6 and its promoter polymorphism (−174) G>C with the risk of spontaneous VTE. IL-6 was measured in 128 patients with deep venous thrombosis (DVT, 70 w / 58 m),105 with pulmonary embolism (PE, 58w/ 47 m) and 122 healthy controls (60 w / 62 m) with a highly sensitive ELISA (Quantikine− HS Human IL-6 Immunoassay, RnDSystems®). The promoter polymorphism was determined by genotyping, allele specific PCR was followed by high resolution gel-electrophoresis. Median concentrations [interquartile ranges] were 2.37 [1.51–3.89] (pg/ ml) in patients with DVT, 2.83 [1.83–4.87] in those with PE and 2.51 [1.71–4.78] in controls (p = 0.6, p = 0.4). Hetero- or homozygous carriers of the C allele (71% in DVT, 67% in PE and 59% among controls) did not have higher IL-6 levels than homozygous carriers of the G allele (median 2.60 vs. 2.59 pg/ml, p = 0.7). In conclusion, we found no association of IL-6 and its promoter polymorphism (−174) G>C with the risk of spontaneous VTE.
Impaired dimerization of von Willebrand factor subunit due to mutation A2801D in the CK domain results in a recessive type 2A subtype IID von Willebrand disease
Authors: Hommais Antoine , Stépanian Alain , Fressinaud Edith , Mazurier Claudine , Pouymayou Katia , Meyer Dominique , Girma Jean-Pierre , Ribba Anne-Sophie
Published: April 2006

The CK domain of von Willebrand factor (VWF) is involved in the dimerization of the protein.We identified the homozygous substitution A2801D of the CK domain in two siblings. Patients had low levels of VWF in plasma, abnormal ristocetin-induced binding to platelets and abnormal multimeric pattern witha lack of high molecular weight (HMW) forms and the presence of intervening bands between normal multimers. Accordingly, they were classified in type 2A, subtype IID, von Willebrand disease (VWD). Both asymptomatic parents carried the mutation at the heterozygous state.Their plasmaVWF exhibited the full range of multimers found in normal plasma.When analyzed by high resolution gel electrophoresis, very faint bands corresponding to the position of intervening bands of the propositus can be observed. The mutated recombinant (r)VWF-D2801, the hybrid rVWF-A/D2801 and the mutated C-terminal VWF fragment rSPII-D2801 were expressed in COS-7 cells. rVWF-D2801 showed an abnormal multimeric distribution similar to that of the propositus’VWF with intervening bands and a lack of HMW species. rVWF-A/D2801 exhibited the full range of multimers and the aberrant sized forms observed both in propositus’VWF and in rVWF-D2801. rSPII-WT assembled correctly into a dimer of 220 kDa. rSPII-D2801 appeared as a mixture of monomeric and dimeric forms which may be related to the abnormal multimeric pattern of the propositus and both mutated rVWF. We concluded that mutation A2801D disturbs the folding of the CK domain, which may result in a mixture of monomers and dimers of VWF. Multimers containing either an odd or even number of mature subunits are produced, and the presence of monomers appears to limit the degree of multimerization. In the heterozygousVWF,the presence of normal dimers improves the multimerization process. In conclusion, the mutation A2801D appears to be responsible fora recessive type 2A, subtype IID, VWD.
A potent anti-coagulant RNA aptamer inhibits blood coagulation by specifically blocking the extrinsic clotting pathway
Authors: Gopinath Subash , Shikamoto Yasuo , Mizuno Hiroshi , Kumar Penmetcha
Published: April 2006

A potent antidote-controlled aptamer, as an anticoagulant, has reportedly overcome the complications of acute bleeding by the administration of available anticoagulants. In the present study, we provide evidence that the aptamer binds specifically to factors IX and IXa and inhibits their functions. Furthermore, we demonstrated that the aptamer inhibits blood coagulation by interfering with the extrinsic pathway, blocking the complex of factor VIIa and tissue factor interactions with factor IX. The results from the previous and present studies suggest that the aptamer probably binds in the vicinity of the EGF1 and EGF2 domains of factor IX.