bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of human brain microvascular endothelial cells during central nervous system infection
Authors: Adam Rüdiger , Rüssing Daniel , Adams Ortwin , Ailyati Aziz , Kim Kwang Sik , Schroten Horst , Däubener Walter 
Published: July 2005

SummaryThe cerebral endothelium is involved both in regulatinthinflux g e of immune cells into the brain and in modifying immunological reactions within the CNS. A number of human pathogens may cause encephalitis or meningitis when this important protective barrier is impaired. We have previously shown that interferon- γ activated human brain microvascular endothelial cells (HBMEC) restrict the growth of bacteria and parasites. We now provide evidence that HBMEC are also capable of inhibiting viral replication after stimulation with IFN-γ, an effect further augmented by costimulation with IL-1. This antiviral effect was completely blocked in the presence of L-tryptophan, indicating the induction of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO) to be responsible for the observed antiviral effect. Apart from exerting antimicrobial effects tryptophan depletetion has also been described as a regulatory mechanism in T cell responses to both allo- and autoantigens. We were able to demonstrate that IDO mediated degradation of L-tryptohan in HBMEC is responsible for a significant reduction inT lymphocyte proliferation. Resupplementation of L-tryptophan and restoration of initial T cell responses demonstrated the central role of this essential amino acid in the reduction of T-cell proliferation. Brain endothelial cells appear to limit microbial expansion in the CNS by local degradation of tryptophan, thus acting in concert with other IDO-positive cell populations on the parenchymal side of the blood-brain barrier such as astrocytes, microglia and neurons. Since all dietary tryptophan must cross the blood-brain barrier, the microvascular endothelial cells may play a key role in restricting tryptophan influx from the bloodstream into the brain. As deleterious effects of brain infections can often be attributed to subsequently invading immune cells, an IDO-mediated reduction of lymphocyte proliferation may be beneficial for preventing collateral brain damage.
Influence of the 4600A/G and 4678G/C polymorphisms in the endothelial protein C receptor (EPCR) gene on the risk of venous thromboembolism in carriers of factor V Leiden
Authors: Medina Pilar , Navarro Silvia , Estellés Amparo , Vayá Amparo , Bertina Rogier M. , España Francisco 
Published: July 2005

SummaryTwo polymorphisms in the endothelial protein C receptor (EPCR) gene, 4600A/G and 4678G/C, have been reported to influence the risk of venous thromboembolism (VTE). The objective of this study was to assess whether these polymorphisms modify the risk of VTE in carriers of factor V (FV) Leiden. We genotyped 295 carriers of FV Leiden for these polymorphisms: 100 unrelated patients with a history ofVTE (propositi) and 195 relatives (14 of them symptomatic) of 81 of the propositi. Spontaneous VTE events occurred in 71% of propositi carrying the 4678GG genotype, 65% carrying the GC, and 43% with the CC genotype. The mean age at the first onset was significantly higher in propositi carrying the 4678CC than in those with the GC or GG genotype (p=0.046). Among the 276 carriers of FV Leiden from the 81 families studied, the 95 symptomatic members had similar 4600G allele and 4600AG genotype frequencies but significantly lower 4678C allele (p=0.002) and 4678CC genotype (p=0.004) frequencies than the 181 asymptomatic members. The probability of being free of thrombosis at age 40 was significantly higher in the 66 carriers of the 4678CC genotype (94%) than in the 138 carrying the GC (72%) or in the 72 with the 4678GG genotype (60%) (p<0.001). Multivariate analysis showed that the 4678CC genotype reduced the risk of thrombosis in carriers of FV Leiden (OR=0.31;95% CI=0.16–0.83). The incidence ofVTE was higher in the 195 relatives with FV Leiden than in the 133 without FV Leiden (OR=4.7; CI=1.3–7.2). These results show that carriers of FV Leiden with the 4678CC genotype have a significantly reduced risk of VTE compared with those carrying the 4678GG or GC genotype, probably due to the higherAPC levels previously observed in individuals carrying the 4678CC genotype.
The transcriptional response of human endothelial cells to infection with Bartonella henselae is dominated by genes controlling innate immune responses, cell cycle, and vascular remodelling
Authors: Québatte Maxime , Foser Stefan , Certa Ulrich , Dehio Michaela 
Published: July 2005

SummaryThe bacterial pathogen Bartonella henselae (Bh) is for respona sible broad range of clinical manifestations, including the formation of vascular tumours as the result of pathogen-triggered vasoproliferation. In vitro, the interaction of Bh with human umbilical vein endothelial cells (Huvec) involves (i) cytoskeletal rearrangements in conjunction with bacterial internalization, (ii) nuclear factor κB (NFκB)-dependent proinflammatory activation, (iii) the inhibition of apoptosis, and (iv) the modulation of angiogenic properties such as proliferation, migration, and tubular differentiation. To study the transcriptional signature of these pathogen- triggered changes of Huvec, we performed transcriptional profiling with Affymetrix U133 GeneChips. At 6 h or 30 h of infection, a total of 706 genes displayed a clear and statistically significant change of expression (>2.5-fold, t-test p-value<0.05). These included 314 up-regulated genes dominated by the innate immune response. The gene list comprises subsets of tumour necrosis factor α (TNFα, 99 genes) and interferon α (IFNα, 30 genes) inducible genes, which encode components of the NF-κB-dependent proinflammatory response and the type I IFN-dependent anti-infective response, respectively. The remaining set of 197 up-regulated genes mirrors other cellular changes induced by Bh, in particular proliferation and proangiogenic activation. The set of 362 down-regulated genes includes 41TNFα- or IFNα-suppressible genes, and 52 genes involved in cell cycle control or progression. This comprehensive analysis of Bh-triggered changes of the Huvec transcriptome identified candidate genes putatively involved in controlling innate immune responses, cell cycle, and vascular remodelling, and may thus provide the basis for functional studies of the molecular mechanisms underlying these pathogen-induced cellular processes.
Rapid identification of female haemophilia A carriers with deletions in the factor VIII gene by quantitative Real-Time PCR analysis
Authors: Barceló María J. , Baena Manel , Cornet Mónica , Venceslá Adoración , Mateo José , Fontcuberta Jordi , Baiget Montserrat , Tizzano Eduardo F. 
Published: July 2005

SummaryLarge deletions of the factorVIII gene account for approximately 5% of severe haemophilia A patients. Although deletions are readily detectable in males, the identification of heterozygosity in possible carriers of these families still constitutes a challenge. In order to identify a deleted allele over the background of the normal allele in these carriers, we developed a rapid real-time quantitative PCR approach by means of LightCycler technology and SYBR green I for monitoring product formation. The method was applied to families with independent deletions (one in exon 14 and the other in exons 23-24) of the Factor VIII gene, thereby allowing a reliable determination of carrier or non-carrier status. The method is extremely versatile and can be adapted to other deletions within the factor VIII gene as well as to other diseases whose molecular pathology consists of deletions or duplications.
A murine model of deep vein thrombosis Characterization and validation in transgenic mice
Authors: Szema Linda , Chen Chao-Ying , Schwab Jeffrey P. , Schmeling Gregory , Cooley Brian C. 
Published: July 2005

SummaryDeep vein thrombosis (DVT) occurs with high prevalence in association with a number of risk factors, including major surgery, trauma, obesity, bed rest (>5 days), cancer, a previous history of DVT, and several predisposing prothrombotic mutations. A novel murine model of DVT was developed for applications to preclinical studies of transgenically constructed prothrombotic lines and evaluation of new antithrombotic therapies. A transient direct-current electrical injury was induced in the common femoral vein of adult C57Bl/6 mice. A non-occlusive thrombus grew, peaking in size at 30 min, and regressing by 60 min, as revealed by histomorphometric volume reconstruction of the clot. Pre-heparinization greatly reduced clot formation at 10, 30, and 60 min (p<0.01 versus non-heparinized). Homozygous FactorV Leiden mice (analogous to the clinical FactorV Leiden prothrombotic mutation) on a C57Bl/6 background had clot volumes more than twice those of wild-types at 30 min (0.121±0.018 mm3 vs. 0.052±0.008 mm3, respectively; p<0.01). Scanning electron microscopy revealed a clot surface dominated by fibrin strands, in contrast to arterial thrombi which showed a platelet-dominated structure. This new model of DVT presents a quantifiable approach for evaluating thrombosis-related murine transgenic lines and for comparatively evaluating new pharmacologic approaches for prevention of DVT.
ClfA221–550, a fibrinogen-binding segment of Staphylococcus aureus clumping factor A, disrupts fibrinogen function
Authors: Shih Mei-Hsu , Tsai Pei-Jane , Liu Chao-Zong 
Published: July 2005

SummaryClumping factor A (ClfA) is a surface of protein Staphylococcusaureus bacteria known for its ability to bind the C-terminus of plasma fibrinogen γ chain, which participates in mediating fibrinogen- platelet interaction and fibrin cross-linking, resulting in thrombus formation. With an aim to develop agents that block fibrinogen γ chain C-terminus,the fibrinogen-binding segment of ClfA locating at residues 221–550 was produced by recombinant technology and tested for its ability to inhibit platelet functions and fibrin clot formation. Recombinant ClfA221–550 bound fibrinogen and blocked fibrinogen-platelet interaction, resulting in the inhibition of both ADP- and collagen-induced platelet aggregations. ClfA221–550 also affected fibrin clot formation, in which factor XIIIa-mediated cross-linking of fibrinogen γ chains was abrogated by ClfA221–550 leaving the release of fibrinopeptides A and B from fibrinogen by thrombin unaltered, indicating that ClfA221–550 interfered with fibrin clot formation without affecting thrombin’s catalytic activity. Plateletmediated clot retraction depends on both platelet-fibrinogen interaction and fibrin clot formation, which makes platelet thrombus less susceptible to fibrinolysis. At the concentration that reduced platelet aggregation by 40%, ClfA221–550 prevented platelet- mediated clot retraction, whereas the glycoprotein IIb/IIIa antagonist tirofiban needed a higher concentration in inhibiting clot retraction than inhibiting platelet aggregation. By virtue of the multiple effects of ClfA221–550 on platelet aggregation, fibrin clot formation and platelet-mediated clot retraction,the binding of ClfA221–550 to fibrinogen merits further investigation for its potential as a new antithrombotic agent.
Chlamydophila pneumoniae
Authors: Maass Matthias , Suttorp Norbert , Rupp Jan , Krüll Matthias 
Published: July 2005

Summary
Chlamydophila (Chlamydia) pneumoniae, a gram-negative obligate intracellular bacterium, is a widespread respiratory pathogen. Chronic C. pneumoniae infection has been suggested as a trigger/ promoter of inflammation that may result in vascular lesions. Although the genome of C. pneumoniae has been sequenced completely this information has not yet led to an understanding of the mechanisms of acute infection and target cell activation nor to the identification of potential chlamydial virulence factors. Intriguingly, current antibiotic treatment options for acute chlamy- dial infection were proven to be ineffective with respect to clinical outcome in different groups of atherosclerotic patients. The reason might be that primary infection of vascular smooth muscle cells and blood monocytes with C. pneumoniae resembles rather a persistent, antibiotic-resistant, than an active infection. In this review we will focus on the importance of putative host cell receptors for C.pneumoniae and subsequently activated signal transduction pathways.
Consequences of enterohaemorrhagic Escherichia coli infection for the vascular endothelium
Authors: Bielaszewska Martina , Karch Helge 
Published: July 2005

SummaryMicrovascular endothelial damage underlies the pathological changes in haemorrhagic colitis and the haemolytic uraemic syndrome (HUS) caused by enterohaemorrhagic Escherichia coli (EHEC). Shiga toxins (Stxs) are presently the best characterised EHEC virulence factors that can cause the microvascular endothelium injury. Stxs are released by EHEC in the intestine, absorbed across the gut epithelium into the circulation, and transported to small vessel endothelial cells. Then, they presumably injure the host cell by inhibiting protein synthesis, stimulating prothrombotic messages,or inducing apoptosis. The net result is a multi-organ thrombotic process. Moreover, Stxs stimulate a variety of non-endothelial cells to produce and secrete inflammatory mediators (cytokines, chemokines, adhesion molecules) which could potentiate the effects of Stxs on endothelial cells. The association of HUS with Stx-negative E. coli strains stimulated intensive research on putative non-Stx virulence factors, which might also contribute to the pathogenesis of HUS and haemorrhagic colitis. Based on current data, cytolethal distending toxin, EHEC haemolysin, and subtilase cytotoxin might be such candidates.
Impaired wound healing in factor XIII deficient mice
Authors: Inbal Amir , Lubetsky Aharon , Krapp Tanya , Caste David , Shaish Aviv , Dickneitte Gerhardt , Modis Laszlo , Muszbek Laszlo , Inbal Aida 
Published: July 2005

SummaryFactor XIII that stabilizes fibrin clots in the final stages of blood coagulation also participates in wound healing,as can be inferred from a delay in wound repair in some patients with inherited FXIII deficiency. In this study we evaluated the effect of FXIII on wound healing in FXIII-deficient mice. Three groups of mice (n = 10) were employed: control group, FXIII-deficient group and FXIII-deficient group treated with FXIII concentrate. Excisional wounds were left unsutured and undressed, and mice were followed for eleven days. FXIII-deficient mice exhibited impaired wound healing as has been demonstrated by 15%, 27% and 27% decrease in percentage of wound closure on day 4, 8 and 11, respectively. On day 11 complete healing was observed in control (100% closure), 73.23% in FXIII-deficient and 90.06% in FXIII deficient/FXIII-treated groups (p = 0.007 by ANOVA and p = 0.001 by t-test between control and FXIII-deficient groups). Scoring system representing maturation rate of the wounds showed that the scores for the control,FXIII-deficient and FXIIIdeficient/ FXIII treated groups were 94.9 ± 4.7, 61.5 ± 14.5 and 94.5 ± 6.4, respectively (p < 0.001 by ANOVA). Histological analysis of the lesions performed at day 11 disclosed delayed reepithelization and necrotized fissure in FXIII-deficient mice and normal healing in FXIII-deficient/FXIII-treated mice. The findings of this study confirm that in FXIII-deficient mice wound healing is delayed and the cellular and tissue defects can be corrected by treatment with FXIII, providing evidence for the essential role of FXIII in wound repair and remodeling.
Staphylococcus aureus interactions with the endothelium
Authors: Chavakis Triantafyllos , Wiechmann Klaus , Preissner Klaus T. , Herrmann Mathias 
Published: July 2005

SummaryThe intravascular maof nifestation Staphylococcus aureus infection is often associated with a severe, and sometimes catastrophic disease. Many host factors contribute to endothelial tropism of S.aureus including subendothelial matrix proteins,endothelial cell receptors, and platelets that are engaged together with S. aureus cell wall adhesins such as the fibronectin binding proteins. Recently, the role of secreted staphylococcal factors that were initially identified by virtue of their binding function with host proteins and ligands, has been reappraised in this regard. Among these, bacterial proteins without significant homology among each other, coagulase (Coa), the extracellular fibrinogen binding protein (Efb), the extracellular matrix binding protein (Emp), or the extracellular adhesive protein (Eap), are the most prominent ones to be associated with endovascular disease. Newly discovered interactions with host components may account for profound effects on immunmodulation and wound healing which are summarized in this short review and which ascribe an important role of these molecules in acute and chronic endo- and extravascular staphylococcal disease. Further research in the complex functional role of these "secretable expanded repertoire adhesive molecules" (SERAM) may not only help to increase our understanding in the pathogenesis of S. aureus infection but can specify novel targets for preventive or therapeutic strategies.
The role of reverse genetics systems in studying viral hemorrhagic fevers
Authors: Groseth Allison , Neumann Gabriele , Kawaoka Yoshihiro , Ebihara Hideki , Feldmann Heinz 
Published: July 2005

SummaryViral hemorrhagic fever (VHF) is an infectious syndrome in humans often associated with high fatality rates. For most VHFs there are no specific and effective therapies or vaccines available and, in general, there is a lack of knowledge regarding the biology and pathogenesis of the causative agents. Therefore, a more detailed understanding of the molecular basis ofVHF pathogenesis, including the identification of viral virulence determinants and host interactions and responses, will be important to en-hance our ability to control VHF infections. The recently developed “reverse genetics systems” for severalVHF causing viruses have allowed the generation of infectious viruses from cloned cDNA and thus, the generation of virus mutants. Here we review the existing reverse genetics systems for VHF causing viruses and discuss their use in studying viral replication, pathogenesis, and the development of antivirals and vaccines.
Blood-brain barrier breakdown during cerebral malaria: Suicide or murder?
Authors: Pino Paco , Taoufiq Zacharie , Nitcheu Josiane , Vouldoukis Ioanis , Mazier Dominique 
Published: July 2005

SummaryCerebral malaria, one of the most serious complicatiof ons Plasmodium falciparum infection, is characterized by the sequestration of parasitized red blood cells (PRBCs) in cerebral microvascular beds. The precise mechanisms involved in the onset of neuropathology remain unknown, but parasite sequestration in the brain, metabolic disturbances, and host immune responses all play a role. Sequestration of PRBCs is mediated by different endothelial cell surface receptors, mainly ICAM-1 and CD36. In vitro studies demonstrated that PRBC adhesion to endothelial cells induces over-expression of various adhesion molecules including ICAM-1, expression of iNOS, oxidative stress and finally apoptosis in endothelial cells. In vivo studies, in humans and in mice models of cerebral malaria brought striking evidence of the implication of brain infiltrating cytotoxic effector CD8T lymphocytes in the development of murine cerebral malaria pathogenesis. These cells probably act by direct cytotoxicity against endothelial cells. Cytotoxicity and apoptosis potentially lead blood-brain-barrier disruption and could contribute to the development of cerebral malaria. We propose a key role for endothelial cells in the pathogenesis of cerebral malaria, both by suicide / apoptosis, and / or by murder / cytotoxicity.
The nine residue plasminogen-binding motif of the pneumococcal enolase is the major cofactor of plasmin-mediated degradation of extracellular matrix, dissolution of fibrin and transmigration
Authors: Bergmann Simone , Rohde Manfred , Preissner Klaus T. , Hammerschmidt Sven 
Published: July 2005

SummaryThe glycolytic enzyme α-enolase represnts one of the nonclassical cell surface plasminogen-binding proteins of Streptococcus pneumoniae. In this study we investigated the impact of an internal plasminogen-binding motif of enolase on degradation of extracellular matrix and pneumococcal transmigration. In the presence of host-derived plasminogen activators (PA) tissuetype PA or urokinase PA and plasminogen S. pneumoniae expressing wild-type enolase efficiently degraded Matrigel or extracellular matrix (ECM). In contrast, amino acid substitutions in the nine residue plasminogen-binding motif of enolase significantly reduced degradation of ECM or Matrigel by mutated pneumococci. Similarly, recombinant wild-type enolase but not a mutated enolase derivative that lacks plasminogen-binding activity efficiently degraded ECM and Matrigel, respectively. In particular, bacterial cell enolase-bound plasmin potentiated dissolution of fibrin or laminin and transmigration of pneumococci through a fibrin matrix. In conclusion, these results provide evidence that the enolase is the major plasminogen-binding protein of pneumococci and that the nine residue plasminogen-binding motif of enolase is the key cofactor for plasmin-mediated pneumococcal degradation and transmigration through host ECM.
Presence and the Utility of Audio Spatialization
Authors: Bormann Karsten 
Published: July 2005

The primary concern of this paper is whether the utility of audio spatialization, as opposed to the fidelity of audio spatialization, impacts presence. An experiment is reported that investigates the presence-performance relationship by decoupling spatial audio fidelity (realism) from task performance by varying the spatial fidelity of the audio independently of its relevance to performance on the search task that subjects were to perform. This was achieved by having conditions in which subjects searched for a music-playing radio (an active sound source) and having conditions in which the playing radio would be stationary (a passive sound source) while subjects searched for some other object. Independent of this, the music emitted by the radio would be either fully spatialized or directional but nonattenuated. Findings include that for subjects searching for the active sound source, being supplied only nonattenuated audio was detrimental to performance. Even so, this group of subjects consistently had the largest increase in presence scores over the baseline experiment. Further, the Witmer and Singer (1998) presence questionnaire was more sensitive to whether the audio source was active or not, while the presence questionnaire used by Slater and coworkers (see Tromp et al., 1998) was more sensitive to whether audio was fully spatialized or not. Finally, having the sound source active positively impacts the assessment of the audio while negatively impacting subjects' assessment of the visuals.