bluuebunny/crossref_metadata_2025 huggingface dataset:
Stress Symptoms Induced by Repeated Morphine Withdrawal in Comparison to Other Chronic Stress Models in Mice
Authors: Zelena Dóra , Barna István , Mlynarik Martin , Gupta O.P. , Jezova Daniela , Makara Gábor B.
Published: July 2005

The present study was aimed at evaluating chronic stress models in mice with special attention to morphine treatment. We hypothesized that repeated periods of drug withdrawal induce chronic stress. To verify this hypothesis, mice were made dependent on morphine and then subjected to several types of repeated withdrawal. Body weight reduction, thymus involution, adrenal gland enlargement and activation of the hypothalamo-pituitary-adrenal axis were used as signs of chronic stress. The changes were compared to those induced by ‘laboratory’ models of chronic stress (2 weeks of repeated restraint or rat exposure) and to a disease model of streptozotocin-induced diabetes mellitus (STZ-DM). Mice were made dependent using increasing doses of morphine three times a day for 3 days (10–20–40 mg/kg s.c.). Thereafter, withdrawal was induced either spontaneously (morphine 40 mg/kg injected at 24- or 72-hour time intervals for 2 weeks) or repeatedly precipitated by naloxone (10 mg/kg s.c.) injected daily 3 h after morphine. The results show that repeated periods of spontaneous drug withdrawal (24 or 72 h) in morphine-dependent mice represent a mild stress load. Repeated withdrawal precipitated by naloxone induced clear chronic stress-like changes. Changes observed in the naloxone-precipitated withdrawal model were even more pronounced than those found in laboratory models, namely repeated restraint or exposure to the rat. The most severe chronic stress state developed in mice during untreated STZ-DM. Thus, naloxone-precipitated withdrawal in mice seems to be an appropriate model of chronic stress.
Tegaserod: Long-Term Treatment for Irritable Bowel Syndrome Patients with Constipation in Primary Care
Authors: Layer Peter , Keller Jutta , Mueller-Lissner Stefan , Rüegg Peter , Loeffler Helena
Published: July 2005

Background: Tegaserod, a prokinetic 5-HT4 receptor agonist, has demonstrated efficacy and tolerability in irritable bowel syndrome (IBS) patients with constipation (IBS-C) in controlled clinical trials. Its use in primary care has not been investigated. Aim: To determine whether tegaserod is effective and well tolerated by primary care IBS-C patients. Methods: Patients received tegaserod 6 mg b.i.d. for 12 weeks and were assessed for response, abdominal pain/discomfort, bloating, stool consistency/frequency and straining at weeks 4 and 12. Previous successful treatment with the withdrawn drug, cisapride, was noted. A 9-month study extension was offered to patients completing 12 weeks of tegaserod treatment. Results: 212 patients entered the 12-week treatment period; 166 completed as planned. Response rates were 64.2% at week 4 and 70.3% at week 12. After 12 weeks, abdominal pain/discomfort and bloating were reduced from baseline (p < 0.0001; mean change –1.02 and –0.91 points, respectively), stool frequency increased (0.78–0.97 stools/day) and stool consistency improved (2.45–3.42; lumpy stools became softer). Tegaserod was well tolerated; the most common adverse events were headache (13.2%) and diarrhea (9.4%). One hundred and twenty patients entered the 9-month extension study, 85 completed and tegaserod continued to be well tolerated. Conclusions: In ambulatory primary care IBS-C patients, tegaserod is an effective and well-tolerated long-term treatment.
Introducing Genetic Testing for Adult-Type Hypolactasia
Authors: Büning Carsten , Genschel Janine , Jurga Juliane , Fiedler Thomas , Voderholzer Winfried , Fiedler Eva-Maria , Worm Margitta , Weltrich Renita , Lochs Herbert , Schmidt Hartmut , Ockenga Johann
Published: July 2005

Background and Aims: To evaluate genotyping for two DNA variants (c.1993+327C>T and c.1438+117G>A), recently found to be associated with adult-type hypolactasia, in the diagnosis of lactose intolerance. Methods: In total, 166 consecutive patients with gastrointestinal symptoms mimicking hypolactasia admitted to the clinic between March 2002 and December 2002 were included. Genotyping for the two DNA variants (c.1993+327C>T and c.1438+117G>A) and standard H2 breath test was performed. Results: Among 116 patients with positive H2 breath test, the c.1993+327C variantwas detectablein 106 (91.4%) patients. Among 50 patients with negative H2 breath test, the c.1993+327Cvariantwas seen in 2 patients. Sensitivity, specificity, positive and negative predictive values for the c.1993+327C variant were 91.4, 96.0, 98.1 and 82.8%, respectively. Genotyping for the c.1438+117G variant did not bring any additional information. Among 4 of the 10 patients with positive H2 breath test but negative for the c.1993+327C and the c.1438+117G variant,further evaluation revealed other diseases known to cause secondary hypolactasia such as celiac disease and short bowel syndrome. Conclusion: In symptomatic patients, genotyping for the DNA variant c.1993+327C is a reliable test for adult-type hypolactasia with high sensitivity and specificity and thus provides a new tool in the diagnostic workup of hypolactasia.
Food-Induced Immune Responses as Origin of Bowel Disease?
Authors: Seibold Frank
Published: July 2005

Food-induced immune responses cause or influence a number of intestinal diseases. Food antigens may either directly affect the mucosal immune system, or food modulate the intestinal flora, which may alter the immune response. The system preventing food-induced immune responses is complex: The mucosal barrier is the primary mechanism of host defense. Secondly, the innate immune system can neutralize some of the pathogens or food antigens. Thirdly, the adaptive immune system normally is in a state of unresponsiveness called oral tolerance. Only if these mechanisms fail, can immune reactions be observed. There are diseases where food is the primary factor in the pathogenesis, such as food allergy and gluten-sensitive enteropathy. Both diseases are mediated by different types of immune reactions. Furthermore, allergic reactions may play a role in eosinophilic esophagitis and eosinophilic gastroenteritis. In chronic inflammatory bowel disease food influences the disease by the modulation of various factors such as intestinal bacterial flora or the inflammatory cascade. Yeast antigens, especially in people with a defect in the innate immune system, such as MBL-deficiency may lead to an enhanced immune reactivity to mannan antigens of yeast. This may have some significance in the perpetuation of intestinal inflammatory processes in patients with Crohn’s disease.
Genetic and Environmental Factors in Monozygotic Twins with Crohn’s Disease and Their First-Degree Relatives: A Case Report
Authors: Vind Ida , Jespersgaard Cathrine , Hougs Lotte , Riis Lene , Dinesen Lotte , Andersen Paal Skytt , Locht Henning , Jess Tine , Munkholm Pia
Published: July 2005

Background/Aims: Familial Crohn’s disease has shown concordance concerning location and clinical type of the disease especially among monozygotic twins. Susceptibility to Crohn’s disease is both based on genetic and environmental factors. We investigated polymorphisms of CARD15, TLR4, and OCTN, and environmental factors in a monozygotic twin pair with Crohn’s disease and their first-degree relatives. Methods: 22-year-old monozygotic female twins with ileocolonic Crohn’s disease and their healthy brother and parents were examined. DNA samples from patients and relatives were genotyped for CARD15, TLR4,and OCTN polymorphisms. ASCA and p-ANCA analyses were performed. Additionally, patients and relatives filled out a questionnaire concerning multiple environmental factors. Results: Both twins presented in the same year with identical Vienna Classification phenotypes: stenotic behavior (B2) and localization in terminal ileum and colon (L3). Both carried a CARD15 R702W variant, but had normal alleles in TLR4 and OCTN. They were smokers since the age of 15, used oral contraceptives and had undergone appendectomy. The healthy father and brother were CARD15 R702W positive, were non-smokers and had not undergone appendectomy. Conclusion: This case report is the first to describe complete concordance in CARD15 status, phenotypic appearance, and smoking, appendectomy and oral contraceptive use in a pair of monozygotic twins with CD.
Interaction between CYP19 Aromatase and Butyrylcholinesterase Genes Increases Alzheimer’s Disease Risk
Authors: Combarros Onofre , Riancho José A. , Infante Jon , Sañudo Carolina , Llorca Javier , Zarrabeitia María T. , Berciano José
Published: July 2005

Biological evidence supports a role of aromatase and butyrilcholinesterase (BCHE) enzymes in the disruption of the cholinergic neurotransmission observed in Alzheimer’s disease (AD). Estrogens may reduce the risk of AD through enhancing or preserving cholinergic neurotransmission, and aromatase, the product of the CYP19 gene, is a critical enzyme in the peripheral synthesis of estrogens. BCHE is a hydrolytic enzyme associated with acetylcholine synaptic degradation, and the BCHE K genetic variant confers some protective effect for AD by reducing the activity of the enzyme. We investigated whether a 5′-UTR CYP19 polymorphism and the BCHE K variant might be responsible for susceptibility to AD by studying a clinically well-defined group of 187 sporadic AD patients and 172 control subjects from a Spanish population. We have shown that the CYP19 C/C genotype is overrepresented in AD patients who carry the BCHE non-K allele when compared with controls (OR = 1.85, p = 0.03). Our findings suggest that the CYP19 and BCHE polymorphisms may interact in determining the risk of AD.
Growth Hormone Treatment and Quality of Life among Survivors of Childhood Cancer
Authors: Eiser C. , Vance Y.H. , Glaser A. , Galvin H. , Horne B. , Picton S. , Stoner A. , Butler G.
Published: July 2005

Background: We report the health-related quality of life (QOL) of survivors of childhood cancer (acute lymphoblastic leukaemia, ALL, or central nervous system, CNS, tumour), and whether or not they had growth hormone deficiency (GHD) requiring growth hormone treatment (GHT). Method: We assessed 77 survivors of childhood ALL (n = 51) or CNS tumours (n = 26), aged between 8–18 years, and free from disease for ≧4 years. Survivors and their mothers independently rated survivors’ QOL, and mothers completed semi-structured interviews to determine their views of the benefits and disadvantages of GHT. Results: Survivors, especially those treated for a CNS tumour, reported poorer QOL compared with UK population norms. Although survivors of ALL reported better QOL than survivors of CNS tumours, there were no differences depending on whether or not they were prescribed GHT. However, mothers reported that those prescribed GHT had worse QOL than those not. All but 2 survivors were responsible for their own injections. A minority of mothers were disappointed with the child’s rate of growth, and reported that children experienced pain with injections. Conclusion: We conclude that QOL in survivors of childhood cancer is compromised compared with the normal population, especially following CNS tumours. Longitudinal studies are vital to determine whether GHT can contribute to improved QOL for cancer survivors, especially those who experience more intensive initial therapy regimes.
Addition of Milk Does Not Alter the Antioxidant Activity of Black Tea
Authors: Reddy Vijayakumar C. , Vidya Sagar G.V. , Sreeramulu D. , Venu L. , Raghunath M.
Published: July 2005

Tea is a polyphenol-rich beverage like wine and catechins are its chief polyphenols. Catechins have cardio-protective effects as they can scavenge free radicals and inhibit lipid peroxidation. Epidemiological studies indicate an inverse relation between tea consumption and the risk of cardiovascular and other chronic diseases. Addition of milk to black tea has been reported to adversely affect its beneficial effects, but the data are not unequivocal. Therefore, we assessed the effect of the addition of milk to black tea on its ability to modulate oxidative stress and antioxidant status in adult male human volunteers. Although the area under the curve of plasma catechins was lower on the consumption of tea with milk compared to black tea, it did not affect the beneficial effects of black tea on total plasma antioxidant activity, plasma resistance to oxidation induced ex vivo, and decreased plasma and urinary thiobarbituric acid reactive substance levels. The results suggest that addition of milk may not obviate the ability of black tea to modulate the antioxidant status of subjects and that consumption of black tea with/without milk prevents oxidative damage in vivo.
Risk Factors for Restless Legs Syndrome in Dialysis Patients
Authors: Siddiqui Samira , Kavanagh David , Traynor Jamie , Mak May , Deighan Christopher , Geddes Colin
Published: July 2005

Background: Restless legs syndrome (RLS) is a movement disorder that affects 6.6–62% of dialysis patients. The aims of this multicentre cross-sectional study were to document the frequency, prevalence and severity of RLS in patients attending 5 dialysis centres for chronic hospital haemodialysis (HHD) and to identify associated risk factors. Methods: Thediagnosis of RLS was made using the criteria of The International Restless Legs Study Group. The following data were collected: age; gender; duration of renal replacement therapy (RRT); current smoking status; urea reduction ratio; weekly erythropoietin dose; weekly intravenous iron dose; prescribed beta blocker; prescribed renin/angiotensin system inhibitors and pre-dialysis blood concentrations of haemoglobin, ferritin, total calcium (corrected for albumin), albumin, phosphate, parathyroid hormone. Associations with RLS were analysed by univariate and multivariate logistic regression. Results: Data relating to 277 of 295 patients who had been attending for regular HHD for >3 months were collected. RLS was present in 127 (45.8%). 82 (29.6%), 27 (9.7%) and 18 (6.5%) patients had mild, moderate and severe RLS, respectively. 39 patients (14.1%) were prescribed medicines aimed at reducing RLS. 30 (76.9%) of these 39 patients still had RLS. Female gender (RR 2.17; p = 0.01), increasing duration since first dialysis (RR 1.06 per year; p = 0.03) and increasing body weight(RR 1.02 per kg; p = 0.02) were independent risk factors for RLS by multivariate analysis. In contrast to previous studies, we found no association with iron status, haemoglobin, serum phosphate or smoking. Conclusions: There is a high prevalence of RLS in our population and therapeutic intervention appears to have limited efficacy. The associations with female gender, duration of RRT and body weight deserve further study.
Significant association with location of central venous line placement and risk of venous thrombosis in children
Authors: Male Christoph , Julian Jim A. , Massicotte Patricia , Gent Michael , Mitchell Lesley ,   for the PROTEKT Study Group
Published: July 2005

Venous thromboembolic events (VTE) in children are frequently associated with central venous lines (CVL). Identifying risk factors related to CVL management could potentially minimize CVL-related thrombotic complications. The objectives of the study were to assess whether CVL location, type, size, and duration of placement are associated with the incidence of VTE in children. The study was a prospective, multicentre cohort study in a general pediatric population requiring CVL. Data on CVL characteristics were documented prospectively using standardized case report forms. Outcome assessments were by i) clinical monitoring for symptomatic VTE which were confirmed by appropriate objective test, or ii) screening by venography at study exit. Among 158 children, 21 (13%) hadVTE. The incidence of VTE was increased with femoral CVL (32%) and subclavian CVL (27%) compared to brachial CVL (12%) and jugular CVL (8%;p=0.01). The incidence ofVTE was independent of CVL type (peripherally inserted central catheters, untunneled CVL, tunneled exteriorized CVL, subcutaneous ports; p=0.90), and CVL size (CVL diameter, p=0.42; number of CVL lumen, p=0.58). The incidence of VTE did not increase with duration of CVL placement: 0–5 days (17% VTE), 6–20 days (19%), 21–35 days (10%), and 36–50 days (11%,p=0.68). The incidence of CVL-relatedVTE may be reduced by preferred placement of CVL in brachial or jugular veins. The choice of CVL type and size does not significantly influence the risk of VTE. Short-term CVL are associated with a similar risk of VTE as longer-term CVL.
Quantification of thrombin activatable fibrinolysis inhibitor (TAFI) gene polymorphism effects on plasma levels of TAFI measured with assays insensitive to isoform-dependent artefact
Authors: Frère Corinne , Emmanuel Morange Pierre , Saut Noémie , Tregouet David Alexandre , Grosley Mariana , Beltran Jérôme , Juhan-Vague Irène , Alessi Marie-Christine
Published: July 2005

Reports have reappraised the genotype-dependent variation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI), demonstrating that, in some enzyme-linked immunosorbent assays (ELISA), decreased antibody reactivity towards the TAFI 325 Ile isoform led to erroneous TAFI levels. Assays free of this artefact are required to evaluate the contribution of theTAFI gene polymorphisms toTAFI level variability.TAFI levels were measured in 209 individuals with both immunological and functional assays. Each assay was characterized, in particular for its reactivity towards the 325 Thr and Ile isoforms. Two ELISAs were found to have a lower reactivity towards the Ile isoform, leading to an overesti-mate of the magnitude of variation between two different genotypes. In contrast, one ELISA, as well as functional assays, was found to be free of genotype-dependent artefact constituting a reliable method to detect true quantitative variations of TAFI levels. Using these reliable methods, univariate and haplotype analyses revealed that TAFI gene polymorphisms explain 25% of TAFI level variability. This effect seems to be the consequence of the joint independent action of two polymorphisms, one in the 5’ (G-1102T) and the other in the 3’ region (T+1583A) of the TAFI gene.
Long-term prognostic value of protein C activity, erythrocyte aggregation and membrane fluidity in transmural myocardial infarction
Authors: Saldanha Carlota , Monteiro José , Perdigão Carlota , Martins e Silva J. , Sargento Luis
Published: July 2005

The objective of this study was to evaluate the long-term predictive value of the haemostatic,inflammatory and haemorheologic disturbances in transmural myocardial infarction (MI). Sixty-four (59 male) consecutive survivors of a MI, with a mean age of 58.3 ± 12.0 years, were followed over a period of 36 months. Eighteen patients had a cardiovascular event defined as the composite of death, non-fatal MI, unstable angina and stroke. The haemostatic (protein C activity-PtC, antithrombin III, plasminogen activator inhibitor-1), haemorheologic (blood fluidity and components, erythrocyte membrane fluidity) and inflammatory (polymorphonuclear elastase, leukocyte count) profiles were determined at hospital discharge, using standard methodology. Our results can be summarized as follow: (i) at hospital discharge, the subgroup of patients with events had higher leuko-cyte count (7833.0 ± 1696.0 vs. 10294.0 ± 3129.0; p= 0.011), lower PtC (100.65 ± 19.08 vs.81.25 ± 19.95;p = 0.002),and lower erythrocyte aggregation (14.26 ± 5.94 vs.11.47 ± 3.45;p = 0.031) in relation to the ones without events;(ii) By Cox regression the protein C activity lower tertile (OR 0.169; 0.045 – 0.628; p=0.008); erythrocyte membrane outer layer fluidity upper tertile (OR 0.067; 95% CI 0.011 – 0.393; p=0.003); and erythrocyte aggregation lower tertile (OR 0.182; 0.038 – 0.876; p= 0.034) were independent predictors of the composite endpoint. We can conclude that some haemostatic, haemorheologic and inflammatory disturbances,at hospital discharge,are long-term independent predictors of recurrent cardiovascular events in transmural myocardial infarction survivors.
Genotype-specific increase in plasma concentrations of activated coagulation factor VII in response to experimental inflammation
Authors: Held Claes , Ericsson Carl-Göran , Silveira Angela , Hamsten Anders , Tornvall Per , Bennermo Marie
Published: July 2005

There is evidence that infection and inflammation might trigger an acute coronary event, but the mechanisms are unclear. Activated factor VII (FVIIa) is a potent coagulant that is under genetic control and a potential determinant of the outcome of acute myocardial infarction. This study investigated the acute FVIIa response to experimental inflammation. Forty healthy men and women were vaccinated with 1 ml of Salmonella Typhii vaccine. Plasma levels of FVIIa, FVII antigen (FVIIag), tissue factor (TF) activity and thrombin-antithrombin complex (TAT) were measured at baseline and up to 24 hours after inoculation. All subjects were genotyped for the FVII gene Arg353Gln polymorphism. Plasma concentrations of FVIIa, but not FVIIag, increased significantly with a peak at 10 hrs after vaccination. At 24 hrs FVIIa levels had returned to baseline. The FVIIa response to vaccination was significantly greater in subjects with the ArgArg genotype compared with ArgGln subjects.TAT increased, butTF activity was unchanged after vaccination. The results are of interest from a mechanistic viewpoint, since one explanation for the link between infection and acute myocardial infarction might be activation of coagulation. However, there is a need for further studies of the role of infection and inflammation in haemostasis.
The antiplatelet effect of clopidogrel is not attenuated by statin treatment in stable patients with ischemic heart disease
Authors: Vinholt Pernille , Korsholm Lars , Risom Kristensen Søren , Hallas Jesper , Damkier Per , Mickley Hans , Svenstrup Poulsen Tina
Published: July 2005

Recent studies suggest that cytochrome P450 (CYP) 3A4 metabolized statins attenuate the antiaggregatory effect of clopidogrel. We evaluated how CYP3A4 metabolized statins and non- CYP3A4 metabolized statins influence platelet aggregation when given concomitantly with clopidogrel. Sixty-six stable patients with ischemic heart disease were included in this parallel group study. All patients were on clopidogrel and aspirin. Thirty-three patients received a CYP3A4 metabolized statin (simvastatin or atorvastatin), and 33 were treated with a non- CYP3A4 metabolized statin (pravastatin). The antiplatelet effect of clopidogrel was assessed at inclusion and 21 days after statin discontinuation. Platelet function was evaluated by two methods 1) optical platelet aggregometry after stimulation with 20 and 30 μM ADP, and 2 and 4 mg/l collagen, respectively, 2) a Platelet FunctionAnalyzer-100. The primary effect measure was final platelet aggregation after stimulation with 20 μM ADP. No difference was observed between patients treated with a CYP3A4 metabolized statin and patients receiving a non-CYP3A4 metabolized statin (30% point (7–42) versus 20% point (9–32), p=0.83). Platelet aggregation was not improved by discontinuation of statins for 21 days. Indeed, we found that statin treatment given concomitantly with clopidogrel resulted in an improved platelet inhibition when compared to clopidogrel given alone. The antiplatelet effect of clopidogrel is not attenuated by concomitant treatment with a CYP3A4 metabolized statin in patients with clinical stable ischemic heart disease.
Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells
Authors: Kato Sumie , Pinto Mauricio , Carvajal Andrés , Espinoza Natalia , Monsó Carolina , Bravo Loreto , Villalon Manuel , Cuello Mauricio , Quest Andrew F. , Suenaga Akihiko , Brosens Jan J. , Owen Gareth I.
Published: July 2005

Tissue Factor (TF), the initiator of the extrinsic coagulation cascade, is overexpressed in a variety of cancers. TF is also expressed in normal human endometrium but little is known about its expression or regulation in endometrial cancer. We demonstrate herein that TF is expressed in the endometrial adenocarcinoma cell line Ishikawa. Furthermore, epidermal growth factor (EGF) induces a rapid and sustained increase in TF expression. Estradiol and progesterone had no effect on basal or EGF-induced TF expression in Ishikawa cells. In contrast to the pronounced and sustained upregulation at the protein level,EGF treatment elicited only a modest and transient increase in TF mRNA levels. This activity corresponded to the response observed from an exogenous TF promoter construct. However, the induction of TF was abrogated by cycloheximide as well as actinomycin-D, inhibitors or protein- and mRNA-synthesis, re-spectively, demonstrating that EGF mediates its effect through activation of the TF gene. Fractionation experiments showed that EGF increases TF presence in caveolin-1 containing membrane fractions. Coagulation and invasion assays were used to explore the physiological implications of TF regulation. The results demonstrate that EGF-mediated induction of TF increases the procoagulant activity and invasive potential of Ishikawa cells. Furthermore, immunocytochemistry confirmed that TF is regulated by EGF in primary cultures of normal endometrial epithelial cells and malignant tumor cells. In conclusion, EGF-mediated upregulation ofTF results in accumulation of this glycoprotein in caveolae-like membrane fractions and increased coagulative and invasive potential. Our results suggest that TF may play an integral role in endometrial carcinogenesis.
Prognostic factors for recurrence of venous thromboembolism (VTE) or bleeding during long-term secondary prevention of VTE with ximelagatran
Authors: Lundström Torbjörn , Wåhlander Karin , Billing Clason Solveig , Schulman Sam , Eriksson Henry ,   for the THRIVE III Investigators
Published: July 2005

The oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in theTHRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initialVTE event, and history of previousVTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49, 4.17), and in patients with one or more than one previous VTE event (HR: 1.73, 95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06, 2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.
Congenital erythropoietin over-expression causes “anti-pulmonary hypertensive” structural and functional changes in mice, both in normoxia and hypoxia
Authors: Manz Daniel , Buchspies Daniela , Keller Stephan , Mehling Tanja , Voswinckel Robert , Quanz Karin , Ghofrani Hossein A. , Schermuly Ralph T. , Fink Ludger , Seeger Werner , Gassmann Max , Weissmann Norbert
Published: July 2005

Acute alveolar hypoxia causes pulmonary vasoconstriction that matches lung perfusion to ventilation to optimize gas exchange. Chronic alveolar hypoxia induces pulmonary hypertension, characterized by increased muscularization of the pulmonary vasculature and right ventricular hypertrophy. Elevated erythropoietin (EPO) plasma levels increase hematocrit and blood viscosity and may affect structure and function of the pulmonary circulation. To differentiate between the direct effects of hypoxia and those linked to a hypoxia-induced increase in EPO/hematocrit levels, we investigated the lung vasculature in transgenic mice constitutively over-expressing EPO (termed tg6) upon exposure to normoxia and chronic hypoxia. Despite increased hematocrit levels (∼0.86),tg6 mice kept in normoxia did not develop selective right ventricular hypertrophy. The portion of vessels with a diameter of 51–95 μm and >155 μm was increased whereas the portion of small vessels (30–50 μm) was decreased. Pulmonary vascular resistance and the strength of hypoxic vasoconstriction measured in isolated perfused lungs were decreased. Vasoconstrictions induced by the thromboxane mimetic U46619 tended to be reduced. After chronic hypoxia (FiO2 = 0.10, 21days), vascular resistance and vasoconstrictor responses to acute hypoxia and U46619 were reduced in tg6 mice compared to wildtype controls. Chronic hypoxia increased the degree of pulmonary vascular muscularization in wildtype but not in tg6 mice that already exhibited less muscularization in normoxia. In conclusion, congenital over-expression of EPO exerts an “anti-pulmonary hypertensive” effect, both structurally and functionally, particularly obvious upon chronic hypoxia.
Endocytosis and storage of plasma factor V by human megakaryocytes
Authors: Suehiro Youko , Veljkovic Dragoslava Kika , Fuller Nola , Motomura Yasuaki , Massé Jean Marc , Cramer Elisabeth M. , Hayward Catherine P. M.
Published: July 2005

Factor V is an essential coagulation cofactor that circulates in plasma and platelet α-granules where it is stored complexed to multimerin 1 (MMRN1). To gain insights into the origin and processing of human platelet factor V, and factor V-MMRN1 complexes, we studied factor V in cultured megakaryocytes. Factor V mRNA was detected in all megakaryocyte cultures. However, like albumin, IgG and fibrinogen, factorV protein was detectable only in megakaryocytes cultured with exogenous protein. The amount of factor V associated with megakaryocytes was influenced by the exogenous factorV concentration. Similar to platelet factor V, megakaryocyte factor V was proteolyzed and complexed with megakaryocyte-synthesized MMRN1. With secretagogues, megakaryocytes released factorV, IgG, fibrinogen and MMRN1. Immunofluorescent and electron microscopy confirmed factorV uptake by endocytosis and its trafficking to megakaryocyte α-granules. These data provide direct evidence that human megakaryocytes process plasma-derived factor V into α-granules and generate factor V-MMRN1 complexes from endogenously and exogenously synthesized proteins.
The post-thrombotic syndrome: incidence and prognostic value of non-invasive venous examinations in a six-year follow-up study
Authors: Heijer Martin den , Janssen Mirian C. H. , Vleuten Carine van der , Thien Theo , Wollersheim Hub , Roumen-Klappe Edith M.
Published: July 2005

The ability to predict severity of the post-thrombotic syndrome (PTS) early after acute deep-vein thrombosis (DVT) is limited. The aim of our study was to examine the incidence of PTS prospectively and to evaluate the predictive value of non-invasive venous examinations shortly after DVT for the development of PTS. In 93 patients with DVT thrombosis score (TS), reflux, venous outflow resistance (VOR) and calf muscle pump dysfunction (CMP) were examined prospectively. After one, two and six years patients were evaluated for PTS using the clinical scale of the CEAP-classification (PTS present ≥3 on a scale from 0 to 6). Area under the curves (AUC) were used to evaluate the predictive value of the non-invasive examinations at one and three months after diagnosis of DVT for future PTS. The cumulative incidence of PTS increased from 49% (32/65) after one year to 55% (36/65) and 56% (27/48) after two and six years, whereas the incidence of patients with PTS class 4 progressed from 20% after two years to 33% after six years. The prognostic value to predict PTS was highest for the combination of TS, VOR and reflux measured three months after diagnosis and showed anAUC of 0.77 (0.65−0.90) for PTS after one year. In conclusion, the incidence of PTS after DVT did not increase significantly after one year, whereas during longer follow-up the severity of PTS rose in patients with PTS. Moreover, measurement of TS, VOR and reflux three months after DVT could predict, with reasonable accuracy, the risk of PTS after one year of follow-up.
The contribution of the endothelium to the development of coagulation disorders that characterize Ebola hemorrhagic fever in primates
Authors: Hensley Lisa E. , Geisbert Thomas W.
Published: July 2005

Recently, there have been substantdevelopments ial in the understanding of Ebola hemorrhagic fever pathogenesis, but there are still major gaps. These infections occur in underdeveloped areas of the world,and much of our knowledge of naturally occurring disease is derived from sporadic outbreaks that occurred decades in the past. Recently conducted laboratory animal studies have provided insight into Ebola pathogenesis and may help guide clinical investigations of disease using contemporary methodologies that were not available previously. A better understanding of the relevant host and viral factors that influence clinical and virologic outcome will be critical to our ability to combat this aggressive pathogen. This article reviews the most relevant information relating to the postulated pathogenesis of this disease, focusing on the role of the endothelium in contributing to the coagulation disorders that characterize Ebola hemorrhagic fever in primates. Some of the remaining and key unanswered questions relating to the role of the vascular system in the pathogenesis of this disease, that need to be addressed in further research, are highlighted.
Ethanol inhibits pulse pressure-induced vascular smooth muscle cell migration by differentially modulating plasminogen activator inhibitor type 1, matrix metalloproteinase-2 and -9
Authors: Cullen John P. , Sayeed Shariq , Kim Youngrin , Theodorakis Nicholas G. , Sitzmann James V. , Cahill Paul A. , Redmond Eileen M.
Published: July 2005

We investigated the effect of ethanol on the pulse pressure-induced expression of PAI-1 and MMP-2/9 in human smooth muscle cells (SMC). Human SMC were exposed to static or pulse pressure (25 mL/min; pulse pressure 106/50 mm Hg) conditions for 24 h in the absence or presence of ethanol (0.1-100 mM). SMC migration was then measured byTranswell migration assay. SMC exposed to pulse pressure demonstrated a significant increase in PAI-1 mRNA and protein expression (∼4-fold and ∼3-fold) concomitant with a 3- and 8-fold increase in MMP-2 and MMP-9 protein, respectively. Ethanol dose-dependently inhibited the pulse pressure-induced SMC migration with complete inhibition observed at 20 mM. There was no effect of ethanol on basal PAI-1 or MMP-2/9 in SMC under static conditions. However, ethanol significantly enhanced the pulse pressure- induced PAI-1 mRNA and protein expression (2.2±0.52 fold and 2.5±0.27 fold, for 10 mM), respectively. In contrast, ethanol dose-dependently inhibited the pulse pressure-induced increases in MMP-9 protein and pro-MMP-9 activity and to a lesser extent MMP-2 mRNA and protein and pro-MMP-2 activity, with significant inhibition observed at 1 mM. These data provide a molecular mechanism mediating the inhibitory effect of ethanol on pulse-pressure-induced SMC migration and may be relevant to the cardioprotective effects of ethanol in vivo.
Interleukin-1 gene cluster variants and abdominal aortic aneurysms
Authors: Marculescu Rodrig , Sodeck Gottfried , Domanovits Hans , Hobusch Gerhard , Exner Markus , Heinzl Harald , Huber Kurt , Mannhalter Christine , Minar Erich , Wagner Oswald , Schillinger Martin
Published: July 2005

Inflammation is a key factor in the pathogenesis of abdominal aortic aneurysms (AAA). Interleukin 1 (IL-1), a fundamental regulator of the inflammatory cascade, has been shown to be involved in this process. Several functional polymorphisms in the IL-1 gene cluster are known. In this matched case-control study, we investigated a potential association between six genetic variants in IL-1 and IL-1 receptor antagonist (IL-1 RN) withAAA. We enrolled 405 individuals, 135 consecutive patients with AAA were individually age- and sex-matched to 270 patients with coronary artery disease (CAD). Traditional cardiovascular risk factors and IL-1 genotypes were determined, and the distribution of six single nucleotide polymorphisms were compared between patients and controls by multivariable conditional logistic regression analysis: IL-1A (-889) C>T, IL-1A (+4845) G>T, IL-1B (-511) C>T, IL-1B (-31) C>T, IL-1B (+3954) C>T and IL-1RN (+2018) C>T. IL-1A (-889) C>T and IL-1A (+4845) G>T (kappa 0.98, 95% CI 0.96 to 1.00), and IL-1B (-511) C>T and IL-1B (-31) C>T (kappa 0.98, 95% CI 0.96 to 1.00) were closely linked, therefore IL-1A (-889) C>T and IL-1B (-31) C>T were not considered for further analyses. None of the 4 remaining polymorphisms showed a significant association with AAA: IL-1RN (+2018) C>T (p=0.061), IL-1B (+3954) C>T (p=0.51), IL-1B (-511) C>T (p=0.61) and IL-1A (+4845) G>T (p=0.81). No significant first-degree interactions between the genetic variants andAAA were detected. In conclusion, these six genetic variants in the interleukin-1 gene cluster do not seem to play a clinically relevant role in the pathogenesis of AAA, although we cannot rule out the existence of higher degree gene-gene or gene-environment interactions.
Coagulation factor XIII-A
Authors: Simon Ágnes , Katona Éva , Szanto Attila , Nagy László , Kiss Attila , Kiss Csongor , Muszbek László , Kappelmayer János
Published: July 2005

The association of coagulation factors with leukocytes have been demonstrated in several previous studies. This study was designed to study the sensitivity and specificity of factor XIII subunit A (FXIII-A) labelling in cultured myeloblastic and monoblastic cell lines and to investigate the intracytoplasmic expression of FXIII-A in de novo acute myeloid leukemia (AML) samples. Myeloblastic and a monoblastic cell lines were cultured and investigated for lineage specific maturation markers and FXIII-A expression. Furthermore, FXIII-A expression was investigated in 12 normal samples (7 bone marrow and 5 peripheral blood), 86 de novo AML samples and 6 chronic myelomonocytic leukemia (CMML) samples. In the monoblastic MonoMac6 cell line the appearance of FXIII-A preceded that of CD14 while it remained negative in the myeloblastic PLB-985 cell line throughout its maturation period. Among the AML samples the average frequency of FXIII-A positive cells in myeloblastic leukemia samples was below 10%,while in M4 and M5AML samples it was above 50% and was significantly higher than the generally used CD14 marker (p < 0.0001). In the AML M4 and M5 cases, FXIII-A proved sensitive for the identification of monoblasts.FXIII-A can be considered as a reliable intracytoplasmic marker for the monocytic and megakaryocytic series and its presence is highly predictive for mono- and megakaryocytic AML and for CMML
Mechanism and consequences of invasion of endothelial cells by Staphylococcus aureus
Authors: Herrmann Mathias , Sinha Bhanu
Published: July 2005

It has become clear that Staphylococcus aureus is a facultative intracellular microorganism. Adherence and invasion are a prerequisite for endovascular infections caused by S. aureus, such as infective endocarditis. These phenomena may also be involved in the pathogenesis of invasive and metastatic infection upon hematogenous dissemination, such as osteomyelitis and abscess formation. The underlying molecular mechanism has been elucidated in detail, including its likely relevance in vivo. However, the mode of action of recently identified modulators of invasion, such as pls/Pls have not yet been clarified. The potential outcome for host cells and S. aureus following invasion are diverse. Surprisingly, induction of apoptosis in human endothelial cells is more complex than previously thought, since it appears to involve multiple virulence factors. In the light of increasing resistance to antimicrobial therapy, understanding the multifacetted pathogenesis of S. aureus infection in detail is needed for a better prevention and therapy.
Infection of the endothelium by influenza viruses
Authors: Klenk Hans-Dieter
Published: July 2005

Highly pathogenic avian influenza viruses are nonly ot the of cause devastating “bird flu” outbreaks in domestic fowl, but are also occasionally the cause of human disease with a high mortality rate as is being currently observed with the H5N1 viruses in South-East Asia. Infection in birds is systemic with hemorrhages and edema as characteristic symptoms, and virus replication in the endothelium appears to play an important role in pathogenesis. Some of the factors determining endotheliotropism have been elucidated at the molecular and cellular level. They include proteolytic activation of the hemagglutinin,polarity of virus budding, and tissue specific expression of virus receptors.
The relationship between inflammation and venous thrombosis
Authors: Fox Eric A. , Kahn Susan R.
Published: July 2005

During the past decade, the role of inflammation in the pathophysiology of arterial thrombosis has been elucidated. However, comparatively little is known about the relationship between inflammation and venous thrombosis. The aim of this study was to perform a systematic review of clinical studies that have examined the association between inflammation and venous thrombosis, specifically: (1) the value of inflammatory markers in predicting the future development of venous thrombosis; (2) test characteristics of markers of inflammation in the diagnosis of acute venous thrombosis; and (3) effect of venous thrombosis on blood levels of inflammatory markers. Using keywords venous thrombosis, venous thromboembolism, inflammation, acute phase markers, C-reactive protein (CRP), interleukin (IL)-6, IL-8, and monocyte chemotactic protein (MCP)-1, PubMed and Medline computerized databases were searched for English language articles published after 1980. Search results were restricted to clinical studies in humans that used study designs that were appropriate to address the above objectives. Results show that plasma CRP levels do not appear to predict risk
of future venous thtwo (rombosis studies; N=41,308). Four studies (N=562) have examined the utility of plasma CRP in the diagnosis of venous thrombosis; pooled positive and negative predictive values were 53% (95% CI:47%,59%) and 85% (95% CI: 81%, 89%), respectively.A two- to six-fold increase in the risk of deep vein thrombosis (DVT) is associated with elevations in plasma levels of CRP, IL-6, IL-8, MCP-1 orTNF-α (three studies). We can conclude that the nature of the relationship between inflammation and clinical venous thrombosis is not yet established. CRP does not appear to be useful in predicting future venous thrombosis or in the diagnosis of acute venous thrombosis. While several markers of inflammation are elevated in acute venous thrombosis, further research is needed to determine the precise relationship between these markers and venous thrombosis. The identification and elucidation of inflammatory markers relevant to venous thrombosis could provide targets for future therapy.
Dynamic Cerebral Autoregulation in Acute Ischemic Stroke Assessed From Spontaneous Blood Pressure Fluctuations
Authors: Reinhard M. , Roth M. , Guschlbauer B. , Harloff A. , Timmer J. , Czosnyka M. , Hetzel A.
Published: July 2005

Background and Purpose—

This study investigates dynamic cerebral autoregulation assessed from spontaneous blood pressure (ABP) and cerebral blood flow velocity (CBFV) fluctuations and its time course in acute ischemic stroke.

Methods—

Forty patients admitted with acute ischemic stroke in the territory of the middle cerebral artery (MCA) were enrolled. Admission National Institutes of Health Stroke score was 6±4. Study 1 was performed within 22 (±11) hours and study 2 was performed within 134 (±25) hours of ictus. The final analysis comprised 33 and 29 patients for study 1 and study 2, respectively. Twenty-five age- and sex-matched controls were studied. ABP (Finapres method) and CBFV in both MCAs (transcranial Doppler) were recorded over 10 minutes. Correlations between diastolic and mean ABP and CBFV fluctuations were averaged, yielding the correlation coefficient indices (Dx, Mx). Transfer function analysis was applied to obtain phase shift and gain between ABP and CBFV oscillations.

Results—

No disturbance of autoregulation was indicated by all parameters at study 1. Separate analyses for clinical severity, stroke side, and size did not reveal significant differences for the various autoregulatory indices at study 1 and 2. At study 2, MCA flow velocity was significantly increased on both sides, the autoregulation index Mx was slightly but significantly (
P
<0.05) worse on both sides in comparison to study 1, and phase showed a trend toward poorer values on affected sides. No significant differences to controls occurred. Clinical outcome in patients completing both studies was good in all but one patient.

Conclusions—

Dynamic cerebral autoregulation assessed from spontaneous blood pressure fluctuations does not seem to be relevantly disturbed in early minor MCA stroke. At the subacute stage, slight autoregulatory disturbance may be present.
Hyperbaric Oxygen Reduces Blood–Brain Barrier Damage and Edema After Transient Focal Cerebral Ischemia
Authors: Veltkamp Roland , Siebing Dirk A. , Sun Li , Heiland Sabine , Bieber Katja , Marti Hugo H. , Nagel Simon , Schwab Stefan , Schwaninger Markus
Published: July 2005

Background and Purpose—

Hyperbaric oxygen (HBO) has been shown to protect the brain parenchyma against transient focal cerebral ischemia, but its effects on the ischemic microcirculation are largely unknown. We examined the potential of HBO to reduce postischemic blood–brain barrier (BBB) damage and edema.

Methods—

Wistar rats and C57/BL6 mice underwent occlusion of the middle cerebral artery (MCAO) for 2 hours. Forty minutes after filament introduction, animals breathed either 100% O
2
at 3.0 atmospheres absolute (ata; HBO group) or at 1.0 ata (control) for 1 hour in an HBO chamber. In rats, MRI was performed 15 minutes after MCAO and after 15 minutes and 3, 6, 24, and 72 hours of reperfusion. In mice, BBB permeability for sodium fluorescein was measured after 24-hour reperfusion.

Results—

Increased BBB permeability on postcontrast T1-weighted (T1w) images had a biphasic pattern. HBO reduced volumes and intensity of enhancement. Mean abnormal enhancing volumes were 71±10 mm
3
(control) versus 47±10 mm
3
(HBO) at 15 minutes; 111±21 mm
3
versus 69±17 mm
3
3 hours; 147±44 mm
3
versus 83±21 mm
3
6 hours; 150±37 mm
3
versus 89±14 mm
3
24 hours; and 322±52 mm
3
versus 215±21 mm
3
72 hours (all
P
<0.05). Interhemispheric quotients of mean gray values on T1w were at 1.73±0.11 versus 1.57±0.07 15 minutes; 1.74±0.07 versus 1.60±0.06 at 3 hours; 1.77±0.07 versus 1.62±0.06 at 6 hours; 1.79±0.10 versus 1.60±0.05 at 24 hours; and 1.81±0.10 versus 1.62±0.07 at 72 hours (all
P
<0.05). HBO-treated mice had significantly lower postischemic BBB permeability than mice treated with either normobaric hyperoxia or room air. Vasogenic edema assessed on T2w images and histologic sections was significantly lower in HBO-treated rats.

Conclusions—

Intraischemic HBO therapy reduces early and delayed postischemic BBB damage and edema after focal ischemia in rats and mice.