bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Major Sporulation Proteins of
Myxococcus xanthus
Using a Proteomic Approach
Authors: Dahl John L. , Tengra Farah K. , Dutton David , Yan Jinyuan , Andacht Tracy M. , Coyne Lia , Windell Veronica , Garza Anthony G.
Published: February 2007

Myxococcus xanthus
is a soil-dwelling, gram-negative bacterium that during nutrient deprivation is capable of undergoing morphogenesis from a vegetative rod to a spherical, stress-resistant spore inside a domed-shaped, multicellular fruiting body. To identify proteins required for building stress-resistant
M. xanthus
spores, we compared the proteome of liquid-grown vegetative cells with the proteome of mature fruiting body spores. Two proteins, protein S and protein S1, were differentially expressed in spores, as has been reported previously. In addition, we identified three previously uncharacterized proteins that are differentially expressed in spores and that exhibit no homology to known proteins. The genes encoding these three novel
m
ajor
s
pore
p
roteins (
mspA
,
mspB
, and
mspC
) were inactivated by insertion mutagenesis, and the development of the resulting mutant strains was characterized. All three mutants were capable of aggregating, but for two of the strains the resulting fruiting bodies remained flattened mounds of cells. The most pronounced structural defect of spores produced by all three mutants was an altered cortex layer. We found that
mspA
and
mspB
mutant spores were more sensitive specifically to heat and sodium dodecyl sulfate than wild-type spores, while
mspC
mutant spores were more sensitive to all stress treatments examined. Hence, the products of
mspA
,
mspB
, and
mspC
play significant roles in morphogenesis of
M. xanthus
spores and in the ability of spores to survive environmental stress.
Effects of practitioner education, practitioner payment and reimbursement of patients’ drug costs on smoking cessation in primary care: a cluster randomised trial
Authors: Twardella Dorothee , Brenner Hermann
Published: February 2007

Objective:To evaluate new strategies to enhance the promotion of smoking cessation in general practice.

Design:Cluster randomised trial, 2×2 factorial design.

Setting:82 medical practices in Germany, including 94 general practitioners.

Participants:577 patients who smoked at least 10 cigarettes per day (irrespective of their intention to stop smoking) and were aged 36–75 years.

Interventions:Provision of a 2-h physician group training in smoking cessation methods and direct physician payments for every participant not smoking 12 months after recruitment (TI, training+incentive); provision of the same training and direct participant reimbursements for pharmacy costs associated with nicotine replacement therapy or bupropion treatment (TM, training+medication).

Main outcome measure:Self-reported smoking abstinence obtained at 12 months follow-up and validated by serum cotinine.

Results:In intention-to-treat analysis, smoking abstinence at 12 months follow-up was 3% (2/74), 3% (5/144), 12% (17/140) and 15% (32/219) in the usual care, and interventions TI, TM and TI+TM, respectively. Applying a mixed logistic regression model, no effect was identified for intervention TI (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.65 to 2.43), but intervention TM strongly increased the odds of cessation (OR 4.77, 95% CI 2.03 to 11.22).

Conclusion:Providing cost-free effective drugs to patients along with improved training opportunities for general practitioners could be an effective measure to achieve successful promotion of smoking cessation in general practice.
Residual tobacco smoke: measurement of its washout time in the lung and of its contribution to environmental tobacco smoke
Authors: Invernizzi Giovanni , Ruprecht Ario , De Marco Cinzia , Paredi Paolo , Boffi Roberto
Published: February 2007

Background:Tobacco smoking entails inhaling millions of fine particles with each puff, and it is intuitive that after smoking a cigarette it will take a certain time to washout residual tobacco smoke (RTS) from the lungs with subsequent breaths.

Objectives:To study the washout time of 0.3–1.0 µm particles after the last puff in 10 volunteer smokers by using equipment capable of measuring particle concentration in real time in the exhaled air.

Result:Mean (standard deviation (SD)) lung RTS washout time was 58.6 (23.6) s, range 18–90 s, and corresponded to 8.7 (4.6) subsequent breathings. The contribution of individual and overall RTS to indoor pollution was calculated by subtracting incremental background particle concentration from room concentration after 10 consecutive re-entries of smokers after the last puff into a room of 33.2 m3, with an air exchange rate per hour in the range of 0.2–0.4. Mean (SD) individual RTS contribution consisted of 1402 (1490) million particles (range 51–3611 million), whereas RTS increased room 0.3–1.0 µm particle concentration from a baseline of 22 283 particles/l to a final room concentration of 341 956 particles/l, corresponding to a total increase in particulate matter (2.5) from a background of 0.56 up to 3.32 µg/m3.

Conclusion:These data reveal a definite although marginal, role of RTS as a source of hidden indoor pollution. Further studies are needed to understand the relevance of this contribution in smoke-free premises in terms of risk exposure; however, waiting for about 2 min before re-entry after the last puff would be enough to avoid an unwanted additional exposure for non-smokers.
Occult maternal exposure to environmental tobacco smoke exposure: Table 1
Authors: de Chazeron Ingrid , Llorca Pierre-Michel , Ughetto Sylvie , Coudore François , Boussiron Didier , Perriot Jean , Vendittelli Françoise , Sapin Vincent , Lemery Didier
Published: February 2007

Background:Environmental tobacco smoke (ETS) is a recognised air pollutant. Its harmful effects have been found to be implicated in health disorders, including unfavourable pregnancy outcomes. The discrepancy between self-reported emvironmental tobacco smoke exposure and cotinine levels in pregnant non-smokers in France was examined.

Method:Plasma cotinine was determined by a CPG-SM method on women who had answered a self-questionnaire describing their habits and environment during pregnancy.

Results:Of 698 pregnant women reported as non-smokers, 305 (43.7%) claimed not to be exposed to ETS, yet 196 of these (64.3%) had plasma cotinine levels above the limit of detection.

Conclusion:Self-reported data on ETS exposure in pregnant women therefore underestimate actual exposure. However, cotinine assay cab rectify this misclassification. An accurate identification of this risk factore will help to change attitudes towards ETS and avert its adverse effects on mother and fetus.
A COUNTABLE ECONOMY: AN EXAMPLE
Authors: TASNÁDI ATTILA
Published: February 2007

Weiss (1981) established core equivalence and the existence of competitive equilibria in finitely additive exchange economies. To underline the relevance of finitely additive economies we present in this note an example with a close connection to finite exchange economies.
COALITION FORMATION GAMES: A SURVEY
Authors: HAJDUKOVÁ JANA
Published: February 2007

In this paper we give an overview of various methods used to study cooperation within a set of players. Besides the classical games with transferable utility and games without transferable utility, recently new models have been proposed: the coalition formation games. In these, each player has his own preferences over coalitions to which he could belong and the quality of a coalition structure is evaluated according to its stability. We review various definitions of stability and restrictions of preferences ensuring the existence of a partition stable with respect to a particular stability definition. Further, we stress the importance of preferences over sets of players derived from preferences over individuals and review the known algorithmic results for special types of preferences derived from the best and/or the worst player of a coalition.
A ONE-SHOT PRISONERS' DILEMMA WITH PROCEDURAL UTILITY
Authors: MENESTREL M. LE
Published: February 2007

This article introduces a model of rationality that combines procedural utility over actions with consequential utility over payoffs. It applies the model to the Prisoners' Dilemma and shows that empirically observed cooperative behaviors can be rationally explained by a procedural utility for cooperation. The model characterizes the situations in which cooperation emerges as a Nash equilibrium. When rational individuals are not solely concerned by the consequences of their behavior but also care for the process by which these consequences are obtained, there is no one single rational solution to a Prisoners' Dilemma. Rational behavior depends on the payoffs at stake and on the procedural utility of individuals. In this manner, this model of procedural utility reflects how ethical considerations, social norms or emotions can transform a game of consequences.
A NOTE ON THE EQUIVALENCE OF RATIONALIZABILITY CONCEPTS IN GENERALIZED NICE GAMES
Authors: ZIMPER ALEXANDER
Published: February 2007

Moulin (1984) describes the class of nice games for which the solution concept of point-rationalizability coincides with iterated elimination of strictly dominated strategies. As a consequence nice games have the desirable property that all rationalizability concepts determine the same strategic solution. However, nice games are characterized by rather strong assumptions. For example, only single-valued best responses are admitted and the individual strategy sets have to be convex and compact subsets of the real line ℝ. This note shows that equivalence of all rationalizability concepts can be extended to multi-valued best response correspondences. The surprising finding is that equivalence does not hold for individual strategy sets that are compact and convex subsets of ℝn with n ≥ 2.
GATHERING INFORMATION BY A PARTIALLY INFORMED AGENT
Authors: SHIN DONGSOO , YUN SUNGHO
Published: February 2007

This paper considers an agency contracting with multiple tasks. The agent is privately informed on some tasks, but he must gather information on the other. We show that depending on the cost to gather information, task assignment is employed as an instrument to induce information gathering, or as an instrument to induce a truthful report.
TECHNICAL NOTE: "AN IRRATIONAL-BEHAVIOR-PROOF CONDITION IN COOPERATIVE DIFFERENTIAL GAMES"
Authors: YEUNG DAVID W. K.
Published: February 2007

Under dynamic cooperation a player may use 'irrational' acts to extort additional gains if later circumstances allow. In this article we present a condition under which even if irrational behaviors appear later in the game the concerned player would still be performing better under the cooperative scheme.
A proposed conceptual model for the genesis of the Derbyshire thermal springs
Authors: Brassington F.C.
Published: February 2007

Ten thermal springs occur in seven centres in Derbyshire, England, with temperatures up to 27.5 °C compared with an ambient groundwater temperature of about 9 °C. The springs discharge from a karstic Dinantian limestone aquifer along the boundary with the overlying Namurian strata around the edge of a regional dome structure. The water is heated by deep circulation to as much as 1 km, with the hottest spring being at Buxton spring, where the water is 5000 years old. A comparison of flow data from the Buxton spring with groundwater hydrographs shows seasonality in the thermal flows, suggesting that the loading effects produced by recharge are transmitted through this deep aquifer system. From a review of the geological history and the hydrogeology and the use of measurements on the Buxton spring it is suggested that the thermal flow system may have its roots in ancient convection cells possibly established in the deeply buried aquifer in late Carboniferous–Early Permian times. Subaerial erosion during the Pliocene removed the impermeable cap rocks and allowed both the thermally heated water to form warm springs and this deep groundwater circulation to be recharged by meteoric waters. The location of the individual springs is likely to date from the downcutting during the Late Pleistocene that formed the modern river valley topography.
A guide to the use of volcaniclastic nomenclature in engineering investigations
Authors: Brown D.J.
Published: February 2007

Current good practice in geology is to identify volcaniclastic rocks using a descriptive classification scheme. The terms agglomerate, volcanic breccia and tuff are currently used in both a descriptive and genetic sense, in
BS 5930 (1999)
. However, the definitions used are now considered incorrect in both senses. This technical contribution redefines these terms and places them in a modern geological context. A new descriptive classification scheme for identifying and naming volcaniclastic rocks is proposed that will assist engineering geological descriptions of these rock types.
Water supply maps for northern France created by British military geologists during World War II: precursors of modern groundwater development potential maps
Authors: Robins N.S. , Rose E.P.F. , Clatworthy J.C.
Published: February 2007

Preparatory work for the Allied landings in Normandy on D-Day, 6 June 1944, included the creation of groundwater development potential maps for a large part of coastal northern France at a scale of 1:50 000, followed by summary maps covering coastal and inland areas eastwards into the Low Countries at a scale of 1:250 000. All these maps were compiled from sources available in the UK, almost entirely by the temporary Royal Engineers officers W.B.R. King and F.W. Shotton, under conditions of strict secrecy. Their purpose was to guide military enhancement of water supplies, especially by deployment of Royal Engineers well drilling teams, to sustain the invasion force in Normandy and its advance eastwards to Germany. A uniquely complete set of maps is preserved, together with many associated documents, in the Shotton Archive of the Lapworth Museum of Geology at Birmingham. The maps are more complex than those hastily prepared by German military geologists during the summer of 1940 to guide a cross-Channel amphibious assault in the opposite direction, into southern England. They are significant as the first British attempt to produce groundwater development potential maps for a large area at detailed (1:50 000) scale, and as the precursors of modern-day groundwater harvest potential maps.
Rapid landslides: the importance of understanding mechanisms and rupture surface mechanics
Authors: Fell R. , Glastonbury J. , Hunter G.
Published: February 2007

The paper describes methods for assessing the likelihood of rapid landsliding based on the mechanism of landsliding, the mechanics of the surface of rupture and internal and lateral shear surfaces, ground and surface water, and the landslide geometry. For translational landslides in rock the relationship between the slope of the basal surface of rupture and the shear strength of that surface, whether the surface of rupture is strain weakening and whether there is lateral or toe buttressing are critical for post-failure velocity. For compound slides in rock the most important factors are high loads on the passive wedge; strain weakening on the surface of rupture, internal shears and lateral margins; and toe buttressing. For landslides in soil, the potential for loss of strength on shearing is critical in determination of post-failure velocity. This may occur in drained shear with the soil losing strength from peak to residual, but also in undrained shear. The former is important for soils with a high clay-size content. The latter is critical for loose silty sands and sands, which are contractive on shearing and experience what can be regarded as static liquefaction.
Differential effects of phosphodiesterase PDE-3/PDE-4-specific inhibitors on vasoconstriction and cAMP-dependent vasorelaxation following balloon angioplasty
Authors: Zhao Hong , Quilley John , Montrose David C. , Rajagopalan Swarna , Guan Qizhi , Smith Carolyn J.
Published: February 2007

It is known that cAMP and cGMP are important for vasorelaxation, and cyclic nucleotide phosphodiesterases (PDEs) regulate their levels. Balloon angioplasty (BAL) is associated with reduced cAMP and cGMP levels, and inhibition of PDE-3 reduces restenosis. In this study, we found that BAL increased PDE-3 activity, which affected vasoreactivity of rat aortic rings 24-h post-BAL; these were compared with intact (INT) and ex vivo endothelium-denuded rings (RUB) from sham rats. In BAL and RUB rings, vasorelaxant responses to ACh were abolished. The EC50for phenylephrine (PE) was 1.8-fold less in RUB than in INT or BAL, whereas the maximal contractile effect of PE was greater in BAL than in INT or RUB. PDE-3 inhibitors reduced the maximal response to PE by >65% in BAL compared with 10–30% in INT and RUB; the reduction of the maximal response to U-46619 was 37% in BAL compared with 8% in INT with no reduction in RUB. PDE-4 inhibitors reduced PE-induced tone by <30% in an endothelium-dependent manner. Vasorelaxant responses to agonists that utilize cAMP were greatly impaired in BAL and RUB rings, and inhibition of PDE-3 enhanced the vasorelaxant responses in BAL or RUB. Inhibition of PDE-4 increased vasorelaxant responses to isoproterenol (ISO) to a much lesser degree. Thus PDE-3 and PDE-4 inhibitors exhibited differential effects on PE-induced tone and vasorelaxant responses to ISO. Inhibition of PDE-3 also produced a greater increase in cAMP in BAL than INT or RUB rings. These results suggest that increased PDE-3 activity after BAL may promote a vasospastic state and that the reduction in cAMP may, possibly, influence vessel remodeling.
Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibition of STAT-1 activation
Authors: Torella Daniele , Curcio Antonio , Gasparri Cosimo , Galuppo Valentina , Serio Daniela De , Surace Francesca C. , Cavaliere Anna Lucia , Leone Angelo , Coppola Carmela , Ellison Georgina M. , Indolfi Ciro
Published: February 2007

Drug-eluting stents are increasingly used to reduce in-stent restenosis and adverse cardiac events after percutaneous coronary interventions. However, the race for the ideal drug-eluting stent is still on, with special regard to the best stent-coating system and the most effective and less toxic drug. Fludarabine, a nucleoside analog, has both anti-inflammatory and antiproliferative cellular effects. The aim of the present study was to assess the cellular and molecular effects of fludarabine on vascular smooth muscle cell (VSMC) growth in vitro and in vivo and the feasibility and efficacy of a fludarabine-eluting stent. To study the biomolecular effects of fludarabine on VSMC proliferation in vitro, rat VSMCs were grown in the presence of 50 μM fludarabine or in the absence of the same. To evaluate the in vivo effect of this drug, male Wistar rats underwent balloon injury of the carotid artery, and fludarabine was locally delivered at the time of injury. Finally, fludarabine-eluting stents were in-laboratory manufactured and tested in a rabbit model of in-stent restenosis. Fludarabine markedly inhibited VSMC proliferation in cell culture. Furthermore, fludarabine reduced neointimal formation after balloon angioplasty in a dose-dependent manner, and fludarabine-eluting stents reduced neointimal hyperplasia by ∼50%. These in vitro and in vivo cellular effects were specifically associated with the molecular switch-off of signal transducer and activator of transcription (STAT)-1 activation, without affecting other STAT proteins. Fludarabine abolishes VSMC proliferation in vitro and reduces neointimal formation after balloon injury in vivo through specific inhibition of STAT-1 activation. Fludarabine-eluting stents are feasible and effective in reducing in-stent restenosis in rabbits.
Oxygen sensing and redox signaling: the role of thioredoxin in embryonic development and cardiac diseases
Authors: Kobayashi-Miura M. , Shioji K. , Hoshino Y. , Masutani H. , Nakamura H. , Yodoi J.
Published: February 2007

It is important to regulate the oxygen concentration and scavenge oxygen radicals throughout the life of animals. In mammalian embryos, proper oxygen concentration gradually increases in utero and excessive oxygen is rather toxic during early embryonic development. Reactive oxygen species (ROS) are generated as by-products in the respiratory system and increased under inflammatory conditions. In the pathogenesis of a variety of adult human diseases such as cancer and cardiovascular disorders, ROS cause an enhancement of tissue injuries. ROS promote not only the development of atherosclerosis but also tissue injury during the reperfusion process. The thioredoxin (TRX) system is one of the most important mechanisms for regulating the redox balance. TRX is a small redox active protein distributed ubiquitously in various mammalian tissues and cells. TRX acts as not only an antioxidant but also an anti-inflammatory and an antiapoptotic protein. TRX is induced by oxidative stress and released from cells in response to oxidative stress. In various human diseases, the serum/plasma level of TRX is a well-recognized biomarker of oxidative stress. Here we discuss the roles of TRX on oxygen stress and redox regulation from different perspectives, in embryogenesis and in adult diseases focusing on cardiac disorders.
Extracellular matrix proteins differentially regulate airway smooth muscle phenotype and function
Authors: Dekkers Bart G. J. , Schaafsma Dedmer , Nelemans S. Adriaan , Zaagsma Johan , Meurs Herman
Published: February 2007

Changes in the ECM and increased airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma and chronic obstructive pulmonary disease. It has recently been demonstrated that ECM proteins may differentially affect proliferation and expression of phenotypic markers of cultured ASM cells. In the present study, we investigated the functional relevance of ECM proteins in the modulation of ASM contractility using bovine tracheal smooth muscle (BTSM) preparations. The results demonstrate that culturing of BSTM strips for 4 days in the presence of fibronectin or collagen I depressed maximal contraction (Emax) both for methacholine and KCl, which was associated with decreased contractile protein expression. By contrast, both fibronectin and collagen I increased proliferation of cultured BTSM cells. Similar effects were observed for PDGF. Moreover, PDGF augmented fibronectin- and collagen I-induced proliferation in an additive fashion, without an additional effect on contractility or contractile protein expression. The fibronectin-induced depression of contractility was blocked by the integrin antagonist Arg-Gly-Asp-Ser (RGDS) but not by its negative control Gly-Arg-Ala-Asp-Ser-Pro (GRADSP). Laminin, by itself, did not affect contractility or proliferation but reduced the effects of PDGF on these parameters. Strong relationships were found between the ECM-induced changes in Emaxin BTSM strips and their proliferative responses in BSTM cells and for Emaxand contractile protein expression. Our results indicate that ECM proteins differentially regulate both phenotype and function of intact ASM.
Dysregulation of pulmonary elastin synthesis and assembly in preterm lambs with chronic lung disease
Authors: Bland Richard D. , Xu Liwen , Ertsey Robert , Rabinovitch Marlene , Albertine Kurt H. , Wynn Karen A. , Kumar Vasanth H. , Ryan Rita M. , Swartz Daniel D. , Csiszar Katalin , Fong Keith S. K.
Published: February 2007

Failed alveolar formation and excess, disordered elastin are key features of neonatal chronic lung disease (CLD). We previously found fewer alveoli and more elastin in lungs of preterm compared with term lambs that had mechanical ventilation (MV) with O2-rich gas for 3 wk (MV-3 wk). We hypothesized that, in preterm more than in term lambs, MV-3 wk would reduce lung expression of growth factors that regulate alveolarization (VEGF, PDGF-A) and increase lung expression of growth factors [transforming growth factor (TGF)-α, TGF-β1] and matrix molecules (tropoelastin, fibrillin-1, fibulin-5, lysyl oxidases) that regulate elastin synthesis and assembly. We measured lung expression of these genes in preterm and term lambs after MV for 1 day, 3 days, or 3 wk, and in fetal controls. Lung mRNA for VEGF, PDGF-A, and their receptors (VEGF-R2, PDGF-Rα) decreased in preterm and term lambs after MV-3 wk, with reduced lung content of the relevant proteins in preterm lambs with CLD. TGF-α and TGF-β1expression increased only in lungs of preterm lambs. Tropoelastin mRNA increased more with MV of preterm than term lambs, and expression levels remained high in lambs with CLD. In contrast, fibrillin-1 and lysyl oxidase-like-1 mRNA increased transiently, and lung abundance of other elastin-assembly genes/proteins was unchanged (fibulin-5) or reduced (lysyl oxidase) in preterm lambs with CLD. Thus MV-3 wk reduces lung expression of growth factors that regulate alveolarization and differentially alters expression of growth factors and matrix proteins that regulate elastin assembly. These changes, coupled with increased lung elastase activity measured in preterm lambs after MV for 1–3 days, likely contribute to CLD.
Platelet microparticle membranes have 50- to 100-fold higher specific procoagulant activity than activated platelets
Authors: Kireev Dmitry , Popenko Nadezhda , Pichugin Aleksei , Panteleev Mikhail , Krymskaya Olga , Ataullakhanov Fazoil , Sinauridze Elena
Published: February 2007

Platelet microparticles (PMPs) are small vesicles released from blood platelets upon activation. The procoagulant activity of PMPs has been previously mainly characterized by theirability to bind coagulation factors VIII and Va in reconstructed systems. It can be supposed that PMPs can contribute to the development of thrombotic complications in the pathologic states associated with the increase of their blood concentration. In this study we compared procoagulant properties of calcium ionophore A23187-activated platelets and PMPs using several in-vitro models of hemostasis. Surface densities of phosphatidylserine, CD61, CD62P and factor X bound per surface area unit were determined by flow cytometry. They were 2.7-, 8.4-, 4.3-, and 13-fold higher for PMPs than for activated platelets, respectively. Spatial clot growth rate (Vclot) in the reaction-diffus ion experimental model and endogenous thrombin potential (ETP) were determined in plasma, which was depleted of phospholipid cell surfaces by ultra-centrifugation and supplemented with activated platelets or PMPs at different concentrations. Both Vcllot and ETP rapidly increased with the increase of PMP or platelet concentration until saturation was reached. The plateau values of Vclot and ETP for activated platelets and PMPs were similar. In both assays, the procoagulant activity of one PMP was almost equal to that of one activated platelet despite at least two-orders-of-magnitude difference in their surface areas. This suggests that the PMP surface is approximately 50- to 100-fold more procoagulant than the surface of activated platelets.
Thienopyridines in cardiovascular disease: Focus on Clopidogrel resistance
Authors: Siller-Matula Jolanta , Schrör Karsten , Wojta Johann , Huber Kurt
Published: February 2007

Platelets play an important role in atherothrombotic disease, as well as in the pathogenesis of atherosclerosis and in complications. Antiplatelet therapy with Clopidogrel represents at present an important treatment of coronary artery disease (CAD), especially in and after acute coronary syndromes (ACS), and after coronary interventions when stents are used. Clopidogrel is a potent and specific inhibitor of platelet ADP receptor (P2Y12 receptor) with high antithrombotic activity. Emerging data suggest that a significant percentage of individuals treated with Clopidogrel do not receive the expected therapeutic benefit because of a decreased responsiveness of their platelets, which is caused by several extrinsic and/or intrinsic mechanisms. As long as Clopidogrel is the “gold standard” in combination with aspirin in the treatment of patients undergoing percutaneous coronary intervention and stent implantation, the overall challenge is to develop a fast “point-of-care” assay to detect Clopidogrel resistance early and to enable alternative antithrombotic strategies in non-responders or low-responders. This test should be easily performed (bedside) and reproducible, with a standardized definition of response, which is known to correlate with clinical outcomes. Unfortunately, such a test does not exist at present. As an alternative, new ADP receptor antagonists with better bioavailability and improved pharmacokinetics, e.g. intestinal reabsorption as an active drug or 1:1 conversion into an active metabolite thus reducing individual variations, are in development and have already found their way into clinical use in phase-3 trials. Prasugrel is one of the incoming new drugs with high expectations, but other agents might follow in the near future.
Self-management of oral anticoagulation in the elderly: Rationale, design, baselines and oral anticoagulation control after one year of follow-up
Authors: Rakovac Ivo , Kleespies Caroline , Piso Brigitte , Didjurgeit Ulrike , Siebenhofer Andrea
Published: February 2007

Self-management is safe and reliable in patients with long-term oral anticoagulation (OAC). However, no study has yet assessed the safety and efficacy of OAC self-management in elderly patients with major thromboembolic and haemorrhagic complications as primary outcomes. In this multi-centre, open, randomised controlled trial, patients aged 60 years or more were randomised into the self-management group (SMG) (N=99) or routine care group (RCG) (N=96). We describe the rationale, design, baseline characteristics and interim analyses of oral anticoagulation control quality within the first year of follow-up. The medians of the squared international normalised ratio (INR) value deviations after six and 12 months were significantly lower in the SMG with medians of 0.16 and 0.16 compared to the RCG with medians of 0.25 and 0.25. The percentage of time within target range and the percentage of INR measurements within target range were significantly higher in the SMG versus the RCG within the first six months (medians 71% vs. 58% and 69% vs. 57%), and during the second six months of the study (75% vs. 67% and 72% vs. 57%). The numbers of all thromboembolic events requiring hospitalisation, major bleeding events, and deaths were similar in both groups. These preliminary results suggest that self-management of oral anticoagulation is safe and feasible for elderly patients willing to participate in a structured training programme.
Protein C inhibitor, a serpin with functions in- and outside vascular biology
Authors: Geiger Margarethe
Published: February 2007

Human protein C inhibitor (PCI), a serpin-type protease inhibitor originally described as an inhibitor of activated protein C, has broad protease reactivity. In addition to its activities within the blood clotting and fibrinolytic cascades, it seems to participate in several biological processes including reproductiorn and tumor growth. This review summarizes the current understanding of PCI function, regulation, and potential biological role.
Expression of the serine protease inhibitor neuroserpin in cells of the human myeloid lineage
Authors: Kennedy Sarah , van Diepen Angela , van den Hurk Cecilia , Coates Leigh , Woo Lee Tet , Ostrovsky Lena , Miranda Elena , Perez Juan , Davies Mark , Lomas David , Dunbar Rod , Birch Nigel
Published: February 2007

Myeloid progenitors in the bone marrow differentiate into most of the major cell types of the immune system, including macrophages and dendritic cells. These cells play important roles in both innate and adaptive immunity. They express a number of proteases and protease inhibitors including members of the serine proteinase inhibitor or serpin superfamily. In this study we report the differential expression of neuroserpin in cells of the human myeloid lineage. Neuroserpin was highly expressed and secreted following the differentiation of monocytes to macrophages and dendritic cells. Activation of dendritic cells with lipopolysaccharide resulted in increased neuroserpin mRNA levels but no neuroserpin secretion. Confocal immunofluorescence microscopy showed neuroserpin was differentially localised in human myeloid cells. In macrophages and dendritic cells it was concentrated in vesicles located in close proximity to the plasma membrane. The majority of activated dendritic cells also exhibited an intracellular focal concentration of neuroserpin which co-localised with the lysosomal/late endosomal marker LAMP-1. As neuroserpin inhibits tissue plasminogen activator, a comparative analysis of tPA and plasminogen activator inhibitor-1 (PAI-I) expression was undertaken. This analysis revealed differential expression of PAI-I and neuroserpin suggesting they may have different functions in human immune cells.
Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor
Authors: Perzborn Elisabeth , Friederich Philip , Levi Marcel , Buetehorn Ulf , Büller Harry , Biemond Bart
Published: February 2007

Current anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fon-daparinux (42 Mg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabeled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED50 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondapari-nux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.
The –11377 C>G promoter variant of the adiponectin gene, prevalence of coronary atherosclerosis, and incidence of vascular events in men
Authors: Saely Christoph , Risch Lorenz , Rein Philipp , Koch Lorena , Schmid Fabian , Aczel Stefan , Marte Thomas , Langer Peter , Hoefle Guenter , Muendlein Axel , Drexel Heinz
Published: February 2007

No prospective data demonstrating an association between the –11377 C>G adiponectin gene promoter variant and cardiovascular risk are available. We therefore prospectively evaluated the cardiovascular risk associated with adiponectin gene single nucleotide polmorphisms (SNPs) including SNP –11377 in a consecutive series of men undergoing coronary angiography. We recorded vascular events over four years in 402 men undergoing coronary angiography for the evaluation of coronary artery disease. No significant associations of SNPs +276 G>T and +45 T>G with serum adiponectin, with significant coronary stenoses >50%, or with vascular events were observed. However, for SNP –11377 C>G, serum adiponectin levels significantly decreased (Ptrend = 0.003), and the prevalence of significant coronary stenoses significantly increased from the CC over the GC to the GG genotype (ptrend = 0.004). Prospectively, the risk of vascular events significantly increased from the CC over the CG to the GG genotype of this SNP (adjusted hazard ratios 1.555 [0.957-2.525] and 2.309 [1.067–4.998], respectively; ptrend = 0.014). The –11377 C>G adiponectin gene promoter variant is i) associated with decreased serum adiponectin levels, ii) correlated with the presence of coronary atherosclerosis and iii) significantly predictive of vascular events among men undergoing coronary angiography.
uPAR – uPA – PAI-1 interactions and signaling: A vascular biologist’s view
Authors: Mihaly Judit , Prager Gerald , Binder Bernd
Published: February 2007

The urokinase-type plasminogen activator (uPA), its inhibitor PA I-1 and its cellular receptor (uPAR), play a pivotal role in pericellular proteolysis. In addition, through their interactions with extracellular matrix proteins as well as with transmembrane receptors and other links to the intracellular signaling machinery, they modulate cell migration, cell-matrix interactions and signaling pathways. A large body of experimental evidence from in-vitro and in-vivo data as well as from the clinics indicates an important role of the uPA-uPAR-PAI-1 systems in cancer. In addition to their role in tumor cell biology, the uPA-uPAR-PAI-1 systems are also important for vascular biology by modulating angiogenesis and by altering migration of smooth muscle cells and fibrin deposition in atherosclerosis and restenosis. This review will focus on the general mechanism of uPAR/uPA/PAI-1 interactions and signaling and the possible relevance of this system in vascular biology.
Diabetes Downregulates Large-Conductance Ca
2+
-Activated Potassium β1 Channel Subunit in Retinal Arteriolar Smooth Muscle
Authors: McGahon Mary K. , Dash Durga P. , Arora Aruna , Wall Noreen , Dawicki Jennine , Simpson David A. , Scholfield C. Norman , McGeown J. Graham , Curtis Tim M.
Published: February 2007

Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca
2+
release events (Ca
2+
-sparks), trigger the activation of large-conductance Ca
2+
-activated K
+
(BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca
2+
]
i
release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca
2+
-sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BKα subunit was unchanged. The Ca
2+
-sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BKβ1 subunit confers Ca
2+
-sensitivity to BK channel complexes and both transcript and protein levels for BKβ1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BKβ1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension.
Regulation of Endocytic Recycling of KCNQ1/KCNE1 Potassium Channels
Authors: Seebohm Guiscard , Strutz-Seebohm Nathalie , Birkin Ria , Dell Ghislaine , Bucci Cecilia , Spinosa Maria R. , Baltaev Ravshan , Mack Andreas F. , Korniychuk Ganna , Choudhury Amit , Marks David , Pagano Richard E. , Attali Bernard , Pfeufer Arne , Kass Robert S. , Sanguinetti Michael C. , Tavare Jeremy M. , Lang Florian
Published: February 2007

Stress-dependent regulation of cardiac action potential duration is mediated by the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis. It is accompanied by an increased magnitude of the slow outward potassium ion current,
I
Ks
. KCNQ1 and KCNE1 subunits coassemble to form the
I
Ks
channel. Mutations in either subunit cause long QT syndrome, an inherited cardiac arrhythmia associated with an increased risk of sudden cardiac death. Here we demonstrate that exocytosis of KCNQ1 proteins to the plasma membrane requires the small GTPase RAB11, whereas endocytosis is dependent on RAB5. We further demonstrate that RAB-dependent KCNQ1/KCNE1 exocytosis is enhanced by the serum- and glucocorticoid-inducible kinase 1, and requires phosphorylation and activation of phosphoinositide 3-phosphate 5-kinase and the generation of PI(3,5)P
2
. Identification of KCNQ1/KCNE1 recycling and its modulation by serum- and glucocorticoid-inducible kinase 1-phosphoinositide 3-phosphate 5-kinase -PI(3,5)P
2
provides a mechanistic insight into stress-induced acceleration of cardiac repolarization.
T-Cell Accumulation and Regulated on Activation, Normal T Cell Expressed and Secreted Upregulation in Adipose Tissue in Obesity
Authors: Wu Huaizhu , Ghosh Sudip , Perrard Xiaoyuan Dai , Feng Lili , Garcia Gabriela E. , Perrard Jerry L. , Sweeney John F. , Peterson Leif E. , Chan Lawrence , Smith C. Wayne , Ballantyne Christie M.
Published: February 2007

Background—

Obesity is associated with chronic inflammation, which includes increased macrophage accumulation in adipose tissue (AT) and upregulation of chemokines and cytokines. T cells also play important roles in chronic inflammatory diseases such as atherosclerosis but have not been well studied in obesity.

Methods and Results—

Flow cytometric analysis showed higher numbers of T cells and macrophages in AT of diet-induced obese insulin-resistant male mice than in lean mice and obese females (
P
<0.05). RNase protection assay, ELISA, and flow cytometry indicated gender-dependent upregulation of mRNA and protein levels of regulated on activation, normal T cell expressed and secreted (RANTES) and its receptor CCR5 in AT of obese mice. Adipocytes, stromal/vascular cells from mouse AT, and human and murine adipocytes expressed RANTES. RANTES mRNA levels were negatively correlated with adiponectin in mouse AT. Adiponectin-deficient mice fed high-fat diet showed higher RANTES mRNA levels in AT than wild-type mice. Activated T cells coincubated with preadipocytes in vitro significantly suppressed preadipocyte-to-adipocyte differentiation. Obese humans with metabolic syndrome had higher mRNA levels of RANTES and CCR5 in subcutaneous AT than lean humans. RANTES and CCR5 mRNA levels were significantly higher in visceral than subcutaneous AT of morbidly obese humans. RANTES mRNA levels were positively correlated with CD3 and CD11b in human visceral AT.

Conclusions—

Obesity is associated with increased accumulation of T cells and macrophages in AT, which may play important roles in obesity-related disease by influencing preadipocyte/adipocyte functions. RANTES is an adipokine that is upregulated in AT by obesity in both mice and humans.
Three-Dimensional Mapping of Optimal Left Ventricular Pacing Site for Cardiac Resynchronization
Authors: Helm Robert H. , Byrne Melissa , Helm Patrick A. , Daya Samantapudi K. , Osman Nael F. , Tunin Richard , Halperin Henry R. , Berger Ronald D. , Kass David A. , Lardo Albert C.
Published: February 2007

Background—

The efficacy of cardiac resynchronization therapy (CRT) depends on placement of the left ventricular lead within the late-activated territory. The geographic extent and 3-dimensional distribution of left ventricular (LV) locations yielding optimal CRT remain unknown.

Methods and Results—

Normal or tachypacing-induced failing canine hearts made dyssynchronous by right ventricular free wall pacing or chronic left bundle-branch ablation were acutely instrumented with a nonconstraining epicardial elastic sock containing 128 electrodes interfaced with a computer-controlled stimulation/recording system. Biventricular CRT was performed using a fixed right ventricular site and randomly selected LV sites covering the entire free wall. For each LV site, global cardiac function (conductance catheter) and mechanical synchrony (magnetic resonance imaging tagging) were determined to yield 3-dimensional maps reflecting CRT impact. Optimal CRT was achieved from LV lateral wall sites, slightly more anterior than posterior and more apical than basal. LV sites yielding ≥70% of the maximal dP/dtmax increase covered ≈43% of the LV free wall. This distribution and size were similar in both normal and failing hearts. The region was similar for various systolic and diastolic parameters and correlated with 3-dimensional maps based on mechanical synchrony from magnetic resonance imaging strain analysis.

Conclusions—

In hearts with delayed lateral contraction, optimized CRT is achieved over a fairly broad area of LV lateral wall in both nonfailing and failing hearts, with modest anterior or posterior deviation still capable of providing effective CRT. Sites selected to achieve the most mechanical synchrony are generally similar to those that most improve global function, confirming a key assumption underlying the use of wall motion analysis to optimize CRT.
Exposure to Secondhand Smoke and Biomarkers of Cardiovascular Disease Risk in Never-Smoking Adults
Authors: Venn Andrea , Britton John
Published: February 2007

Background—

Exposure to secondhand smoke has been associated with a disproportionately high risk of coronary heart disease, thought to be mediated through inflammation, platelet aggregation, and/or endothelial dysfunction. The epidemiological association between objectively measured exposure to secondhand smoke and biomarkers of heart disease risk has not been investigated, however.

Methods and Results—

We have investigated the cross-sectional relation between secondhand smoke exposure, measured objectively as cotinine, and recognized biomarkers of heart disease risk, namely C-reactive protein, homocysteine, fibrinogen, and white blood cell count, in 7599 never-smoking adults from the Third National Health and Nutrition Examination Survey. Compared with subjects with no detectable cotinine, those with detectable but low-level cotinine (range, 0.05 to 0.215 ng/mL) had significantly higher levels of both fibrinogen (adjusted mean difference, 8.9 mg/dL; 95% CI, 0.9 to 17.0;
P
=0.03) and homocysteine (0.8 μmol/L; 95% CI, 0.4 to 1.1;
P
<0.001) but not C-reactive protein or white blood cell count. Effect estimates of similar magnitude and significance were seen in subjects in the high category of cotinine exposure (>0.215 ng/mL). The increased levels of fibrinogen and homocysteine seen in relation to secondhand smoke exposure were equivalent to ≈30% to 45% of those seen for active smoking.

Conclusions—

Passive smokers appear to have disproportionately increased levels of 2 biomarkers of cardiovascular disease risk, fibrinogen and homocysteine. This finding provides further evidence to suggest that low-level exposure to secondhand smoke has a clinically important effect on susceptibility to cardiovascular disease.