bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Levels of Pregnancy-Associated Plasma Protein A Are Associated with Mortality in Hemodialysis Patients: Preliminary Results
Authors: Kalousová M. , Hořejší M. , Fialová L. , Soukupová J. , Sulková S. , Malbohan I. , Tesař V. , Zima T.
Published: June 2004

Pregnancy-associated plasma protein A (PAPP-A) is a new prognostic indicator of acute coronary syndrome. This protein is elevated in hemodialysis (HD) patients and is closely related to inflammation and oxidative stress. The aim of our pilot study was to find out whether PAPP-A is related to mortality in HD patients. 40 HD patients in a stable clinical state (20 men and 20 women, mean age 69 ± 12 years) were enrolled in the study and followed up for 20 months. PAPP-A was assessed immunochemically (TRACE method) in serum samples (before the HD session) at the beginning of the observation period. During the follow-up, 22 patients died, 15 of them due to cardiovascular events. PAPP-A levels were significantly higher in the patients who died, compared to living HD patients: 26.8 (21.6–36.8) vs. 20 (14.9–26.6) mU/l, p = 0.034. PAPP-A could also be a new prognostic marker in hemodialysis patients, probably due to its close association with cardiovascular risk. More extensive studies are required to confirm this hypothesis.
Enhancement of Interleukin-4 Production in Activated CD4+ T Cells by Diphthalate Plasticizers via Increased NF-AT Binding Activity
Authors: Lee Mi Hyun , Park Jin , Chung Su Wol , Kang Bok Yun , Kim Seung Hyun , Kim Tae Sung
Published: June 2004

Background: Diethylhexyl phthalate (DEHP) and diisononyl phthalate (DINP), two commonly used plasticizers in flexible polyvinylchloride formulations, have potentially adverse effects on human health. However, the influence of these diphthalates on allergic responses remains unclear. In this study we examined the effects of DEHP and DINP on IL-4 production in CD4+ T cells and the level of IgE in sera, critical hallmarks associated with allergic diseases. Methods: Mouse T cells were exposed to two diphthalates in vitro and in vivo. The levels of IL-4 and IgE were determined by ELISA, and the degree of NF-AT activation was determined by IL-4 gene promoter assay and electrophoretic mobility shift assay. Results and Discussion: Both DEHP and DINP significantly enhanced IL-4 production in activated CD4+ T cells in a concentration-dependent manner. Treatment with DEHP or DINP in vivo resulted in a significant increase of IL-4 production in CD4+ T cells and of IgE levels in sera. Furthermore, DEHP and DINP enhanced the activation of IL-4 gene promoter in EL4 T cells and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for a transcription factor, NF-AT. The activation of T cells resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of DEHP or DINP, indicating that NF-AT was involved in the enhancing effect of DEHP and DINP on IL-4 production. These findings suggest that both DEHP and DINP enhance allergic responses by enhancement of IL-4 production in CD4+ T cells via stimulation of NF-AT-binding activity.
Effects of Hormones Targeting Nuclear Receptors on Transcriptional Regulation of the Growth Hormone Gene in the MtT/S Rat Somatotrope Cell Line
Authors: Iwasaki Yasumasa , Morishita Minako , Asai Masato , Onishi Akiko , Yoshida Masanori , Oiso Yutaka , Inoue Kinji
Published: June 2004

We have examined the effects of nuclear receptor hormones such as glucocorticoid, gonadal steroid hormones, thyroid hormone and retinoids on the transcriptional regulation of the 5′-promoter activity of growth hormone (GH) gene using the MtT/S rat pure somatotrope cell line or MtT/SGL, a subclone of MtT/S in which the rat GH gene 5′-promoter (1.7 Kb)-luciferase fusion gene was stably incorporated. RT-PCR analyses revealed that receptors for all the hormones except androgen receptor were expressed in the cell line. Triiodothyronine (T3, 10 nM) transiently but significantly stimulated the promoter activity of GH gene, whereas retinoic acids (9-cis and all-trans, both 1 µM) showed sustained stimulation. There were no additive effects among the T3, all-trans, and9-cis retinoic acids. Synthetic glucocorticoid hormone dexamethasone (100 nM) showed an inhibitory effect but, interestingly, significantly enhanced T3-stimulated GH promoter activity during long-term incubation. Among the gonadal steroid hormones tested, estradiol and estriol had significant stimulatory effects, and deletion analysis showed that the estrogen effect was maintained with the shortest construct examined (–150 to +6, +1 denotes the transcription start site). These results suggest that thyroid hormone and retinoids stimulate the transcription of GH gene, probably through a common response element, whereas glucocorticoid has both negative and positive effects on GH expression, depending on the combination with other hormones and the time of exposure. Estrogens also have direct stimulatory effects through the proximal promoter region of GH gene.
Genetic Amniocentesis Complications: Is the Incidence Overrated?
Authors: Nassar Anwar H. , Martin Dibe , González-Quintero Victor Hugo , Gómez-Marín Orlando , Salman Fawwaz , Gutierrez Alfredo , O’Sullivan Mary J.
Published: June 2004

Aims: To estimate the complication rate of 2nd-trimester amniocentesis and to determine the associated risk factors. Methods: A retrospective chart review of genetic amniocenteses performed at a single tertiary care institution, from 1996 to 1998, was done. The variables studied included gestational age, indication for amniocentesis, number and site of needle punctures, and amniotic fluid color. Complications included fetal loss, rupture of membranes, and bleeding. Results: Out of the 1,347 procedures analyzed, the most common indications were advanced maternal age (72.3%) and abnormal triple screen (20.3%). Transplacental genetic amniocenteses totaled 234 (17.4%). Clear fluid was observed in 98.2% of the patients. Twenty-two complications (1.6%) were observed: fetal loss (0.22%), bleeding (0.59%), and rupture of membranes (0.82%). An abnormal karyotype was detected in 34 (2.5%) fetuses. In separate univariate logistic regression analyses, complications were significantly associated with gestational age [odds ratio OR = 1.19; 95% confidence interval CI = (1.08, 1.32); p = 0.001], number of punctures [OR = 8.2; 95% CI = (1.76, 37.97); p = 0.007], and ultrasound anomalies [OR = 5.82; 95% CI = (1.65, 20.58); p = 0.006]. Gestational age and number of punctures remained significant in multivariate logistic regression analysis. Conclusions: Genetic amniocentesis performed at a tertiary care institution is rather safe, and the fetal loss rate of 0.22% is significantly lower (p < 0.001) than the previously published incidence of 1/200. The risk of complications is significantly and independently associated with advanced gestational age and number of punctures.
Confocal microscopy analysis of native, full length and B-domain deleted coagulation factor VIII trafficking in mammalian cells
Authors: Becker Sven , Simpson Jeremy , Pepperkok Rainer , Heinz Stefan , Herder Christian , Grez Manuel , Seifried Erhard , Tonn Torsten
Published: June 2004

In mammalian cells, factor VIII (FVIII) secretion depends upon its interaction with chaperones of the endoplasmic reticulum (ER) and requires a unique ATP-dependent step to dissociate aggregates formed within the ER. To further elucidate mechanisms which might account for the inefficient secretion of recombinant FVIII (rFVIII), we have analyzed the pathways of recombinant full length (rFVIII-FL) and B-domain deleted (rFVIIIΔB) FVIII and compared these to the secretion route of native FVIII in primary hepatocytes. Using confocal laser scanning microscopy in combination with a pulse chase of a known secretion marker, we describe the trafficking route of FVIII, which upon release from the ER – where it colocalizes with calnexin – is transported to the Golgi complex in vesiculartubular transport complexes (VTCs) which could be further identified as being COP I coated. However, a large portion of rFVIII is retained in the ER and additionally in structures which could not be assigned to the ER, Golgi complex or intermediate compartment. Moderate BiP transcription levels indicate that this observed retention of FVIII does not reflect cellular stress due to an overexpression of FVIII-protein in transduced cells. Moreover, a pulse of newly synthesized rFVIII protein is released within 4 hrs, indicating that once rFVIII is released from the ER there is no further limitation to its secretion. Our data provide new details about the secretory route of FVIII, which may ultimately help to identify factors currently limiting the efficient and physiological expression of FVIII in gene therapy and manufacture.
Thromboprophylaxis in medical patients: the role of low-molecular-weight heparin
Authors: Norris Timothy , Alexander Turpie
Published: June 2004

Many hospitalised medical patients are at increased risk of venous thromboembolism (VTE). Consensus statements recommend that such patients be assessed for risk of VTE on admission to hospital and receive thromboprophylaxis where appropriate. However, VTE prophylaxis is not widely used in medical patients. One explanation is that assessing medical patients’ risk of VTE is complicated. The risk depends not only on the current illness but also on multiple intrinsic factors, and a variety of strategies for identifying patients who should receive thromboprophylaxis have been suggested. Thromboprophylaxis with unfractionated heparin (UFH) has proved to be effective in reducing the incidence of deep-vein thrombosis and overall mortality in medical patients. Clinical trial evidence, including a meta-analysis, suggests that thromboprophylaxis with low-molecular-weight heparin (LMWH) is at least as effective as with UFH, and also has the advantage of fewer bleeding complications. In particular, two large, randomised clinical trials – Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT) – showed that thromboprophylaxis with the LMWHs enoxaparin (40 mg s.c. once daily) or dalteparin (5,000 IU once daily) is more effective than placebo and well tolerated in medical patients. In addition, the Thromboembolism-Prevention in Cardiopulmonary Diseases with Enoxaparin (THE-PRINCE) trial showed that enoxaparin treatment was as effective as UFH. These studies provide solid evidence for the widespread use of thromboprophylaxis in medical patients.
The epidermal growth factor receptor (EGFR) and proline rich tyrosine kinase 2 (PYK2) are involved in tissue factor dependent factor VIIa signalling in HaCaT cells
Authors: Wiiger Merete , Prydz Hans
Published: June 2004

Binding of the coagulation protease factor VIIa to its receptor Tissue Factor (TF) induces intracellular signals in several cell types including HaCaT keratinocytes. TF belongs to the cytokine receptor family, but is most likely not alone in transferring the complete TF/FVIIa signal over the plasma membrane. The protease activated receptor PAR2 is involved in factor VIIa and factor Xa signal transduction. Our results indicate that the epidermal growth factor receptor (EGFR) and the proline rich tyrosine kinase 2 (PYK2) participate in TF/FVIIa signalling as formation of the TF/FVIIa complex increased the phosphorylation of these proteins. Both FVIIa protease activity and available TF were necessary for generation of the signal. Increased tyrosine phosphorylation of the EGFR was observed following TF/FVIIa complex formation on the cell surface. The EGFR kinase inhibitor tyrphostin AG1478 abrogated the TF/FVIIa-complex induced MAP kinase activation and mRNA increase of egr-1, heparin-binding EGF, and interleukin-8 following FVIIa addition. Using specific antibodies, increased phosphorylation of PYK2 tyrosine residues 402 and 580 was observed.The first site is the major autophosphorylation site and the docking site for Src family kinases. The second site is important for the kinase activity.The Src family kinase Yes and the tyrosine phosphatase SHP-2 were detected in immunoprecipitates using either antiPYK2 or anti-EGFR antibodies.Their coprecipitation with EGFR increased in the presence of FVIIa. Moreover, the coprecipitation of EGFR and PYK2 increased with FVIIa stimulation. Together, these data suggest that EGFR, PYK2, Yes, and SHP-2 are involved in transduction of the TF/FVIIa signal possibly via transactivation of the EGF receptor.
Structural changes in cerebral arteries following nitric oxide deprivation: a comparison between normotensive and hypertensive rats
Authors: Hsieh Nan , Wang Jia , Liu Jiang , Lee Wei , Chen Hsing
Published: June 2004

Chronic inhibition of nitric oxide (NO) synthesis with Nωnitro-L-arginine methyl ester (L-NAME) has become a model of hypertension. The purpose of this study was to evaluate the morphological changes of cerebral arteries in rats with genetic hypertension and hypertension induced by chronic NO deprivation. Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto strain (WKY) were given L-NAME (1 mg·ml-1) from age 5 to 7 or 9 weeks. We assessed vascular remodelling and arteriolar injury score (AIS) in various cerebral arteries using different immunohistochemical staining techniques. In WKY and SHR, L-NAME caused an elevation in tail cuff pressure (TCP). The increase in TCP was larger in SHR than in WKY. L-NAME decreased body weight, but increased heart weight in SHR.The lumen diameter and media cross-section area of internal carotid artery (ICA) in SHR were smaller than those in WKY, and further reduced in SHR and WKY after L-NAME treatment. These findings indicate that cerebral vascular remodelling occurs following chronic hypertension either from genetic origin or NO deprivation. L-NAME increased the media thickness in SHR, but not in WKY. This agent also caused an increase in cell volume density, AIS, and inflammatory cells infiltration in perivascular space with a negative growth index in ICA. The media/lumen ratio was higher in SHR than WKY, and further increased following L-NAME treatment. Diversified vascular remodelling occurred in hypertensive rats, but not in untreated WKY. In summary, these results suggest that NO deprivation and genetic hypertension cause vascular changes in various cerebral arteries.
Antithrombotic effects of saratin on human atherosclerotic plaques
Authors: Vilahur Gemma , Duran Xavier , Juan-Babot Oriol , Casaní Laura , Badimon Lina
Published: June 2004

Platelets play a primary role in thrombus formation after plaque rupture. Platelets recognize the exposed collagen via Von Willebrand factor (VWF) and become activated. Saratin, an inhibitor of the VWF-dependent binding of platelets to collagen, may reduce the thrombotic risk associated to atherosclerosis. Our objective was to evaluate the antithrombotic effects of local treatment with saratin on human atherosclerotic lesions. Thrombus formation was assessed by the deposition of 111Inplatelets on different human atherosclerotic lesions under three local shear conditions (800,1700 and 3400/s) with blood derived from catheterized pigs. Human atherosclerotic lesions were locally treated with saratin (30 µg/ml) at 37ºC for 5 min and placed in the chamber. Under stenotic shear conditions of 800/s, saratin significantly (p<0.05) reduced platelet deposition triggered by human denuded vessel wall (44%), fatty streaks (47%), severely damaged vessel (50%) and atherosclerotic plaque (57%). Thrombus characterization by immunohistochemistry showed also a reduction in fibrin deposition in treated vessels. These results suggest that the local site-specific treatment with saratin inhibits atherosclerotic plaque thrombogenicity at haemodynamic conditions typical of moderately stenotic coronary arteries.
Longitudinal analysis of perfusion lung scintigrams of patients with unoperated chronic thromboembolic pulmonary hypertension
Authors: Skoro-Sajer Nika , Becherer Alexander , Klepetko Walter , Kneussl Meinhard , Maurer Gerald , Lang Irene
Published: June 2004

Chronic thromboembolic pulmonary hypertension (CTEPH) is the result of single or recurrent pulmonary thromboemboli that are thought to develop into organized pulmonary arterial obstructions by recurrent embolism and in situ thrombosis. Radioisotopic ventilation-perfusion scanning (V/Q scan) is a safe and highly sensitive test for pulmonary thromboembolic disease. The aim was to assess the natural history of thrombus expansion. We performed a prospective quantitative evaluation of ventilation/perfusion scintigrams (V/Q scans) in 20 patients with severe unoperated CTEPH. The baseline V/Q scan of each patient served as a reference for the second scan 21.7 ± 8.2 months later. Planar images with intravenous 99mTc-labeled human albumin macroaggregates were reconstructed in six standard projections. Perfusion scans were analyzed by a semiquantitative evaluation. In parallel, hemodynamics and clinical condition were prospectively observed. Lung perfusion scintigrams analyzed by a semi-quantitative method in patients with severe unoperated CTEPH show an apparent decrease of segmental flow abnormalities over time, paralleling right ventricular decline.
The risk of bleeding complications in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon
Authors: Visser Loes , van Schaik Ron , van Vliet Martin , Trienekens Paul , De Smet Peter , Vulto Arnold , Hofman Albert , van Duijn Cornelia , Stricker Bruno
Published: June 2004

The principal enzyme involved in coumarin metabolism is CYP2C9. Allelic variants of CYP2C9, CYP2C9*2 and CYP2C9*3, code for enzymes with reduced activity. Despite increasing evidence that patients with these genetic variants require lower maintenance doses of anticoagulant therapy, there is lack of agreement among studies on the risk of bleeding and CYP2C9 polymorphisms. It was, therefore, our objective to study the effect of the CYP2C9 polymorphisms on bleeding complications during initiation and maintenance phases of coumarin anticoagulant therapy. The design of the study was a population-based cohort in a sample of the Rotterdam Study, a study in 7,983 subjects. All patients who started treatment with acenocoumarol or phenprocoumon in the study period from January 1, 1991 through December 31, 1998 and for whom INR data were available were included. Patients were followed until a bleeding complication, the end of their treatment, death or end of the study period. Proportional hazards regression analysis was used to estimate the risk of a bleeding complication in relation to CYP2C9 genotype after adjustment for several potentially confounding factors such as age, gender, target INR level, INR, time between INR measurements, and aspirin use. The effect of variant genotype on bleeding risk was separately examined during the initiation phase of 90 days after starting therapy with coumarins. The 996 patients with analysable data had a mean follow-up time of 481 days (1.3 years); 311 (31.2%) had at least 1 variant CYP2C9 allele and 685 (68.8%) had the wild type genotype. For patients with the wild type genotype, the rate of minor bleeding, major bleeding and fatal bleeding was 15.9, 3.4 and 0.2 per 100 treatmentyears, respectively. For patients with a variant genotype, the rate of minor, major and fatal bleeding was 14.6, 5.4 and 0.5 per 100 treatment-years. Patients with a variant genotype on acenocoumarol had a significantly increased risk for a major bleeding event (HR 1.83, 95% CI: 1.01-3.32). During the initiation phase of therapy we found no effect of variant genotype on bleeding risk. In this study among outpatients of an anticoagulation clinic using acenocoumarol or phenprocoumon, having a variant allele of CYP2C9 was associated with an increased risk of major bleeding events in patients on acenocoumarol, but not in patients on phenprocoumon. Although one might consider the assessment of the CYP2C9 genotype of a patient for dose adjustment before starting treatment with acenocoumarol, a prospective randomised trial should demonstrate whether this reduces the increased risk of major bleeding events.
Platelet inhibition by aspirin is diminished in patients during carotid surgery: a form of transient aspirin resistance?
Authors: Payne David , Jones Chris , Hayes Paul , Webster Sally , Naylor A. , Goodall Alison
Published: June 2004

The majority of patients who suffer peri-operative thromboembolic complication while undergoing vascular procedures do so despite taking aspirin. This study examined the antiplatelet effect of aspirin during surgery in patients undergoing carotid endarterectomy (CEA). Fifty patients undergoing CEA were standardised to 150 mg aspirin daily for ≥2 weeks. Platelet aggregation in response to arachidonic acid (AA) was measured in platelet rich plasma prepared from blood taken prior to, during, and at the end of surgery. Spontaneous platelet aggregation was also studied, as was the role of physiological agonists (ADP, collagen, thrombin, and epinephrine) in mediating the in vivo and in vitro responses to AA. Eighteen patients undergoing leg angioplasty, also on 150 mg aspirin, without general anaesthesia, served as a control group. In the CEA patients aggregation induced by AA (5 mM) increased significantly from 7.6 ± 5.5% pre-surgery to 50.8 ± 29.5% at the end of surgery (p <0.0001). Aggregation to AA was even greater in samples taken mid-surgery from a sub-set of patients (73.8 ± 7.2%; p = 0.0001), but fell to 45.9 ± 7.4% by the end of surgery. The increased aggregation in response to AA was not due to intra-operative release of physiological platelet agonists since addition of agents that block/neutralise the effects of ADP (apyrase; 4 µg/ml), thrombin (hirudin; 10 units/ml), or epinephrine (yohimbine; 10 µM/l) to the samples taken at the end of surgery did not block the increased aggregation.The patients undergoing angioplasty also showed a significant rise in the response to AA (5 mM), from 5.6 ± 5.5% pre-angioplasty to 32.4 ± 24.9% at the end of the procedure (p <0.0001), which fell significantly to 11.0 ± 8.1% 4 hours later. The antiplatelet activity of aspirin, mediated by blockade of platelet arachidonic acid metabolism, diminished significantly during surgery, but was partially restored by the end of the procedure without additional aspirin treatment.This rapidly inducible and transient effect may explain why some patients undergoing cardiovascular surgery remain at risk of peri-operative stroke and myocardial infarction.
Lepirudin prevents lethal effects of Shiga toxin in a canine model
Authors: Friedman Kenneth , Fenwick Brad , Raife Thomas
Published: June 2004

Microvascular thrombosis is a major cause of organ damage in Shiga toxin-mediated hemolytic uremic syndrome (Stx-HUS). In vitro and clinical studies implicate thrombin-mediated mechanisms in the pathogenesis of Stx microvascular thrombosis. In a greyhound model, administration of 0.03μg/kg to 0.05μg/kg Stx1 or Stx2 causes severe bloody diarrhea and HUS with microvascular thrombosis requiring humane euthanasia within 65 hours. Using a greyhound model of Stx-HUS we analyzed early hemostatic changes, and tested the hypothesis that thrombin blockade with lepirudin would prevent lethal Stx effects. Two Stx1-exposed greyhounds were analyzed for hemostatic changes prior to onset of clinical manifestations. Serial hemostasis studies after Stx1 challenge revealed trends of increased aPTT, fibrinogen levels, and prothrombin fragment 1+2, and appearance of abnormally large von Willebrand factor multimers. Three greyhounds were anticoagulated with lepirudin to maintain activated partial thromboplastin times (aPTT) >2.5-fold normal, followed by administration of Stx2 and observation of clinical responses. Among the 3 lepirudin-treated, Stx2-challenged greyhounds, one developed severe illness requiring euthanasia. Remarkably, 2 of the 3 greyhounds developed only hypersalivation and restlessness that resolved (P <.03 compared to 14 historical controls). These two greyhounds were clinically, hematologically and biochemically normal 74 hours after Stx administration, well beyond the time of euthanasia of any previous greyhound. This study suggests that greyhounds exposed to Stx develop procoagulant changes similar to humans, and that thrombin may be a critical factor in the pathogenesis and treatment of Stx-HUS.
Formation of tissue factor-bearing leukocytes during and after cardiopulmonary bypass
Authors: Shibamiya Aya , Tabuchi Noriyuki , Chung Jihwa , Sunamori Makoto , Koyama Takatoshi
Published: June 2004

During cardiopulmonary bypass (CPB), the extrinsic coagulation system initiated by tissue factor (TF) is a major procoagulant stimulus. TF is present in surgical wounds and could be expressed on activated monocytes. However, recent studies have suggested that collagen stimulation rapidly induces TF by leukocyte-platelet complex formation. Therefore, the appearance of TF-bearing leukocytes and their effect on promoting coagulation were investigated in 5 patients undergoing coronary bypass surgery. Neutrophils and monocytes positive for CD41a and TF increased abruptly in circulating blood during CPB. Their increase was most prominent in blood pooled in the pericardial cavity. Monocytes, but not neutrophils positive for TF showed a second peak one day after operation, which accords with the increase in TF mRNA levels in leukocytes. Similarly, an increase in leukocytes positive for TF accords with the activated factor X generation assay using isolated leukocytes, and with an increase in thrombin-antithrombin complex in circulating blood. The second increase in TF-positive monocytes seems to be responsible for these coagulation parameters that remained high one day after operation. After 10 min of blood incubation stimulated by collagen in vitro, simulating activation in the pericardial cavity, significant increases in neutrophils and monocytes positive for TF and platelet were observed. Our present study suggested the involvement of two distinct mechanisms for the appearance of TF-bearing leukocytes responsible for promoting coagulation: the quick appearance being partly explained by the formation of leukocyte-platelet complex that occurs mainly in the pericardial cavity, and the slow appearance via transcriptional activation in monocytes.
Fibrin-targeted direct factor Xa inhibition: construction and characterization of a recombinant factor Xa inhibitor composed of an anti-fibrin single-chain antibody and tick anticoagulant peptide
Authors: Weirich Uta , Bassler Nicole , Schwarz Meike , Runge Marschall , Bode Christoph , Hagemeyer Christoph , Tomic Ivo , Jaminet Patrick , Peter Karlheinz
Published: June 2004

We investigated whether the direct fXa inhibitor tick anticoagulant peptide (TAP) can be N-terminally coupled to a clot-targeting, single-chain antibody specific for fibrin (scFv59D8). Due to its unique position at the convergence point of the intrinsic and extrinsic pathways early in the coagulation cascade, factor Xa (fXa) represents an attractive therapeutic target. In contrast to indirect inhibitors, direct fXa inhibitors effectively inhibit clotbound and prothrombinase-associated fXa. Targeting of direct fXa inhibitors to clots promises to enhance local anticoagulative potency and to reduce systemic anticoagulation which potentially results in less bleeding complications. TAP is a highly potent fXa inhibitor. Since its N-terminus is essential for antifXa activity, it was a challenging question, whether TAP will be active as a N-terminally coupled fusion molecule. Two step affinity chromatography with Ni2+ and β15-22-peptide of human fibrin results in a pure 36 kDa protein, which was tested for its targeting function and anti-fXa activity. The recombinant fusion did not destroy the function of the fusion partners. Antibody binding function was on a par with the parent molecule. TAP activity was partially reduced, arguing that a free N-terminus is not required for anti-fXa activity, but is important for maximal potency. In human whole blood clots, scFv59D8-TAP revealed anticoagulative properties at concentrations (200 to 500 nM) where non-targeted TAP did not reveal anticoagulative activity at all. In summary, scFv59D8-TAP constitutes a promising new anticoagulant with fibrin-targeted factor Xa inhibition. The production in E. coli and the established purification methods are a solid basis for a modern, large scale production at low cost and reproducible activity.
Histidine-Proline Rich Glycoprotein (HPRG) binds and transduces anti-angiogenic signals through cell surface tropomyosin on endothelial cells
Authors: Guan Xiaojun , Juarez Jose , Qi Xiaoping , Shipulina Natalya , Shaw David , Morgan William , McCrae Keith , Mazar Andrew , Doñate Fernando
Published: June 2004

The anti-angiogenic properties of the histidine-proline–rich (H/P) domain of HPRG have recently been described (Juarez JC, et al. Cancer Research 2002; 62: 5344-50). However, the binding site that mediates these properties is unknown. HPRG is evolutionarily, functionally and structurally related to cleaved high molecular weight kininogen (HKa), an anti-angiogenic polypeptide that stimulates apoptosis of proliferating endothelial cells through binding to cell-surface tropomyosin (Zhang J-C, et al. Proc Natl Acad Sci USA 2002; 99: 12224-9). In this study, we demonstrate that HPRG binds with high affinity to FGF-2–stimulated human umbilical vein endothelial cells (HUVEC) and immobilized tropomyosin in a Zn2+ or pH-dependent manner, and that this interaction is mediated by the H/P domain of HPRG. At least two binding sites for HPRG, tropomyosin and heparan sulfate proteoglycans (HSPs), were identified on the surface of FGF-2–activated endothelial cells. Translocation of tropomyosin to the surface of HUVEC occurred in response to FGF-2, and the anti-angiogenic activity of HPRG in a Matrigel plug model was partially inhibited by soluble tropomyosin. These results suggest that HPRG binds to endothelial cell surface tropomyosin which at least partially mediates the antiangiogenic effects of HPRG.
Association of NOS3 gene with metabolic syndrome in hypertensive patients
Authors: Fernandez Maria , Ruiz Rocio , Gonzalez Maria , Ramirez-Lorca Reposo , Couto Carmen , Ramos Antonio , Gutierrez-Tous Reyes , Rivera Jose , Ruiz Agustin , Grilo Antonio , Real Luis
Published: June 2004

Recent data from animal models indicate that the eNOS null mice present a phenotype that resemble the human metabolic syndrome (hypertension, insulin resistance and hypertriglyceridemia). In this work, we have studied whether NOS3 gene, previously related to endothelial dysfunction, might have a role in metabolic syndrome susceptibility in hypertensive patients. To carry out the study, we genotyped 105 hypertensive patients ≤ 60 years old with two polymorphisms of NOS3 gene: 1132 T>C and 7164 G>T (GeneBank:AF519768.1).To check the allelic frequency of these polymorphisms in our geographical area, we also genotyped 94 unselected healthy controls (control group). To perform sample genotyping, we designed a novel FRET system coupled to real time PCR. There were no differences in genotypic distribution or allelic frequency between hypertensive patients and the control group. However, we observed that 786CC genotype was significantly more frequent in hypertensive patients with metabolic syndrome than in those without the syndrome (p=0.0022). When both polymorphisms were analyzed, we identified the 786C894G as the risk haplotype for metabolic syndrome susceptibility (p=0.011). These data suggest a role of the NOS3 gene in the pathogenesis of metabolic syndrome in hypertensive patients.
Increased platelet activation in young Zucker rats with impaired glucose tolerance is improved by acarbose
Authors: Eigenthaler Martin , Bischoff Hilmar , Ertl Georg , Schäfer Andreas , Widder Julian , Bauersachs Johann
Published: June 2004

Patients with diabetes display increased platelet activation. Recent data show a markedly increased risk for cardiovascular events already in pre-diabetic individuals with impaired glucose tolerance (IGT). We investigated whether IGT is associated with platelet activation. Blood samples were collected from young lean (control) and obese Zucker rats, an established model of IGT, after single oral application of sucrose (4g·kg-1). Platelet-bound fibrinogen and platelet surface-expression of P-selectin were assessed as indices of platelet activation using flow cytometry. In lean Zucker rats, acute sucrose application induced fibrinogen-binding and P-selectin surface-expression, which was prevented by co-administration of acarbose (10mg·kg-1). In obese Zucker rats, platelet activation was already maximally increased under baseline conditions with no significant increase after sucrose application. Chronic treatment with acarbose (15mg·kg-1·day-1) significantly reduced platelet activation in these animals. Acute ingestion of sucrose induces platelet activation which is prevented by acarbose. IGT is associated with marked platelet activation that can be reduced by chronic administration of acarbose.The positive modulation of platelet activation by acarbose may contribute to the reduction of cardiovascular events in patients with IGT.
WSIS: Articulating Information at the Summit
Authors: Sreberny Annabelle
Published: June 2004

This brief article examines WSIS as a staging of transnational political communication. Playing with the acronym, it explores a number of moments of articulation and contradiction within the WSIS process, including gender imbalance, the politics of the inside and the outside, the space between rhetoric and action, and the lack of media coverage of a media-focused event. It suggests that WSIS is as relevant for western publics as for southern publics, and that the articulation of civil society within WSIS can be seen as the globalizing of radical democracy.
The World Summit on the Information Society and Its Legacy for Global Governance
Authors: Raboy Marc
Published: June 2004

The World Summit on the Information Society has highlighted a range of questions about issues and process that characterize communication governance at the start of the 21st century. Without having resolved them, it indicates a new paradigm for global governance generally, in which information and communication issues are central, and in which new actors, particularly global civil society, will have to be involved.
‘MOT Your Life’: Critical Management Studies and the Management of Everyday Life
Authors: Hancock Philip , Tyler Melissa
Published: June 2004

This article attempts to reflect critically on the extent to which the discourses, techniques and imperatives associated with the management of work organizations are increasingly colonizing the everyday sphere of human communication and sense-making. Drawing on critical social theory and particularly Habermas’s account of ‘the rational organization of everyday life’, as well as what has come to be known as critical management studies (CMS), the article begins by locating itself within contemporary debates on management and everyday life. It then proceeds, drawing on recent research involving a critical analysis of post-Excellence management books, to map out the discourse commonly encountered in such texts before going on to explore the presence of a notably similar discourse appearing within contemporary cultural resources such as self-help manuals and, more notably, lifestyle magazines. It is then argued that such texts constitute a material signifier of what is an ongoing managerialist colonization of the everyday life world. This argument is substantiated with reference to a series of (group and individual) semi-structured interviews focusing on the lived experience of management, highlighting the encroachment of management discourse, techniques and imperatives on life outside work organizations. The article concludes by reflecting critically on some of the philosophical and political issues this potentially raises and, in doing so, aims to contribute to a critical discussion of the diffusion of management knowledge and ideology, particularly in relation to the subjective impact of managerialism on human relations.
Efficacy of Oxymorphone Extended Release in Postsurgical Pain: A Randomized Clinical Trial in Knee Arthroplasty
Authors: Ahdieh Harry , Ma Tina , Babul Najib , Lee David
Published: June 2004

Patients with moderate or severe pain following knee arthroplasty and washout from standard patient‐controlled analgesia (PCA) were randomized to receive 20 mg of an extended‐release (ER) oxymorphone formulation (n = 65) or placebo (n = 61) q12h for 1 day. Oxymorphone PCA was used as rescue analgesic. Oxymorphone ER provided significant improvements over placebo for most standard single‐dose analgesic parameters, including mean total pain relief (TOTPAR) over 0 to 12 hours (19.30 vs. 13.72; p = 0.0056), as well as for all multiple‐dose (24‐h) efficacy assessments. Oxymorphone‐treated patients used significantly less rescue PCA than those who received placebo (p < 0.02). Adverse events such as nausea and constipation were typical of opioids, and laboratory and physical findings were similar between groups. Oxymorphone ER was effective and generally well tolerated. A single dose was active from 2 hours until ≥ 12 hours after administration. Comparisons with other oral opioids are warranted, especially in the setting of outpatient and day surgery
What Are We Playing at? Theatre, Organization, and the Use of Metaphor
Authors: Cornelissen Joep P.
Published: June 2004

This article addresses the question of how metaphor works and illustrates this with an explication of the ‘organization as theatre’ metaphor. It is argued that the so-called comparison account of metaphor that has dominated organization studies to date is flawed, misguided, and incapable of accounting for the fact that metaphors generate inferences beyond the similarities required for comprehending the metaphor and that metaphoric understanding is creative, with the features of importance being emergent rather than existing antecedently. A new model of metaphor for organizational theorizing is therefore proposed in this article and illustrated through an extended discussion and explication of the ‘organization as theatre’ metaphor. This explication shows furthermore that the ‘organization as theatre’ metaphor has not broken any new ground or led to any conceptual advances in organization theory, but has just provided a language of theatre (actors, scenes, scripts, and so on) for framing and communicating identity and role enactment within organizations. Constitutive principles and governing rules are derived from this model and from detailing the ‘organization as theatre’ metaphor, which, it is suggested, can guide theorists and researchers in their use of metaphor in organization studies.
Enron Spectacles: A Critical Dramaturgical Analysis
Authors: Boje David M. , Rosile Grace Ann , Durant Rita A. , Luhman John T.
Published: June 2004

Enron shows us dramaturgy gone amuck. In this article, critical theory and postmodern theory are crossed to form a critical dramaturgyresulting in two main contributions. First, critical dramaturgy is differentiated from other forms of dramaturgy, showing how ‘spectacle’ is accomplished through a theatrical performance that legitimates and rationalizes, and casts the public in the role of passive spectators. Second, critical dramaturgy has important connections with public relations theory. While contemporary public relations is concerned with the building of relationships, critical dramaturgy looks at how corporate theatrical image management inhibits relationships by erecting the barrier of the metaphorical proscenium. The Enron scandal is viewed as the collapse of a corporate spectacle illusion into megaspectacle fragments. These fragments include the naming of Enron, the Valhalla Rogue Traders scandal, the Gas Bank, Greenmail, Cowboy Capitalism, the Skilling–Mark rivalry, and the Masters of the Universe theme. Intertextual analysis demonstrates how these fragments contribute to the ‘Greek Mega-tragedy’ of the Enron megaspectacle. The article integrates several corporate theatre processes relevant to understanding four types of spectacle: concentrated, diffused, integrated, and megaspectacle. The value of the critical dramaturgy conceptual work is to lift the romantic veil of spectacle theatrics to reveal the antenarrative fragments of stories marginalized and backgrounded.
Development and the ‘Global War on Terror’
Authors: Tujan Antonio , Gaughran Audrey , Mollett Howard
Published: June 2004

The war on terror is affecting developing countries and development policy and practice. The international focus on counter-terrorism and security has influenced aid allocations and the nature of donor co-operation with developing countries. Counter-terrorism is being used to justify practices that undermine the achievement of development goals and run contrary to international commitments on human rights. Increases in military aid and the export of arms are jeopardising human security and livelihoods in many parts of the world.
Sovereignty vs. Human Rights or Sovereignty and Human Rights?
Authors: Conlon Justin
Published: June 2004

What, post-cold war, are the implications of so-called humanitarian interventions for international law, the nation state and peoples’ rights? Is this a cover for imperialism or, in the era of globalisation, an essential widening of protection for human rights? The provisions of the UN Charter and related instruments are examined, together with the arguments in support of such interventions. That state sovereignty protects human rights by reducing the incidence of war and promoting self-determination and that military intervention can result in atrocities are often overlooked. Somalia, Haiti, Bosnia and the first Gulf war are among the examples discussed.
Gender Roles, Family, and Drinking: Women at the Crossroad of Drinking Cultures
Authors: Bergmark Karin Helmersson
Published: June 2004

During the postwar era, extensive changes in family structure and gender roles have occurred in Western countries. The aim for this study was to see if processes of change and convergence in gender roles have led to new drinking patterns among Swedish women. Data were collected from a survey conducted in 1979 and replicated in 2003. For this study, data on aspects of drinking patterns and problems were combined with demographics and indicators of social situation. For one of the drinking pattern indicators, the assumption of convergence between the sexes was confirmed. Generally, though, differences in drinking patterns are at hand among both women and men in the same direction. Also, social background factors and demographics have weaker explanatory power today compared to the late 1970s.
The Efficacy of Combined Physical and Mental Practice in the Learning of a Foot-Sequence Task after Stroke: A Case Report
Authors: Jackson Philip L. , Doyon Julien , Richards Carol L. , Malouin Francine
Published: June 2004

Objective. To investigate the effect of mental practice on the learning of a sequential task for the lower limb in a patient with a hemiparesis resulting from a stroke. Design. A single-case study. Setting. Research laboratory of a university-affiliated rehabilitation center. Patient. A right-handed 38-year-old man who had suffered a left hemorrhagic subcortical stroke 4 months prior. Intervention. The patient practiced a serial response time task with the lower limb in 3 distinct training phases over a period of 5 weeks: 2 weeks of physical practice, 1 week of combined physical and mental practice, and then 2 weeks of mental practice alone. Main Outcome Measures. Performance on the task measured through errors and response times. Imagery abilities measured through questionnaires. Results . The patient’s average response time improved significantly during the 1st 5 days of physical practice (26%) but then failed to show further improvement during the following week of physical practice. The combination of mental and physical practice during the 3rd week yielded additional improvement (10.3%), whereas the following 2 weeks of mental practice resulted in a marginal increase in performance (2.2%). Conclusion. The findings show that mental practice, when combined with physical practice, can improve the performance of a sequential motor skill in people who had a stroke, and suggest that mental practice could play a role in the retention of newly acquired abilities.
Proximity, Directionality, and the Riddle of Relative Party Extremeness
Authors: Warwick Paul V.
Published: June 2004

Using survey data on European countries, this paper examines the degree of correspondence in left-right policy positions between political parties and the citizens who vote for them through the prism of two competing views on what the ideal correspondence should be. The views are proximity theory, which holds that voters prefer parties to be as close as possible in policy terms, and Rabinowitz-Macdonald (RM) directionality theory, which asserts that voters prefer parties to take positions with greater emotional intensity than the voters themselves feel. It is shown that while the correspondence between party and voter is strong, parties tend to adopt positions that are relatively more extreme than those held by their voters and that the voters, perceptual distortions notwithstanding, are aware of it. This is usually taken as evidence for RM directionality but it is demonstrated that this theory does not and, in fact, cannot explain the discrepancy between what voters want and what parties deliver.
Impact Penetration of Sandwich Panels at Different Velocities - An Experimental Parameter Study: Part I - Parameters and Results
Authors: Kepler J.
Published: June 2004

Part I of this article describes a series of tests of localized, penetrating impact on sandwich panels. The sandwich panel size was 500 500 mm2 with a thickness of 46 mm. Three types of panel configuration were tested. Penetration was carried out in quasi-static conditions and at approximately 70 and 93 m/s. Impactor mass was 1 kg with an impactor diameter of 50 mm and with three different impactor tip geometries. For each of the 27 combinations, the total energy absorption was measured, and the damage patterns are described and quantified.
Work Organization in the Middle Kingdom, Ancient Egypt
Authors: Ezzamel Mahmoud
Published: June 2004

This paper examines original documents from the Middle Kingdom in ancient Egypt (2050-1780 BC), containing material on various practices relating to the organization of work and labour discipline in state projects. The paper explores the roles of accounting and administrative practices in rendering possible the form and functioning of work organization and labour discipline during that historical era. Historical evidence so far removed from the present is clearly open to a variety of readings. Although acknowledging this, the paper argues that, through the compilation of rosters and name lists, the setting of work targets, regular reporting on performance, the application of sanctions against recalcitrant individuals and the determination and distribution of differential wages, accounting and administrative practices established a regime of control that traced workers’ presence and absence at precise temporal points and spatial locations and monitored their achievements. The evidence points to a very strong role for both accounting and administrative practices, lending greater credence to the view that the ‘visible’ hand of administration played a crucial role in the civilization of ancient Egypt.
British Party Members
Authors: Seyd Patrick , Whiteley Paul
Published: June 2004

Party membership and activism is declining among Britain’s three major parties. Using individual membership survey data, evidence of this decline, particularly in party activism, is presented. Reasons for the decline are considered. It is suggested that choice-based rather than structural explanations are more persuasive. The impact of the decline upon the parties and the political system is considered. The article concludes that it is possible for parties to stimulate membership and activism.