bluuebunny/crossref_metadata_2025 huggingface dataset:
Quitting cigarettes completely or switching to smokeless tobacco: do US data replicate the Swedish results?
Authors: Zhu S-H , Wang J B , Hartman A , Zhuang Y , Gamst A , Gibson J T , Gilljam H , Galanti M R
Published: January 2009

Background:

Swedish male smokers are more likely than female smokers to switch to smokeless tobacco (snus) and males’ smoking cessation rate is higher than that of females. These results have fuelled international debate over promoting smokeless tobacco for harm reduction. This study examines whether similar results emerge in the United States, one of few other western countries where smokeless tobacco has long been widely available.

Methods:

US data source: national sample in Tobacco Use Supplement to Current Population Survey, 2002, with 1-year follow-up in 2003. Analyses included adult self-respondents in this longitudinal sample (n = 15 056). Population-weighted rates of quitting smoking and switching to smokeless tobacco were computed for the 1-year period.

Results:

Among US men, few current smokers switched to smokeless tobacco (0.3% in 12 months). Few former smokers turned to smokeless tobacco (1.7%). Switching between cigarettes and smokeless tobacco, infrequent among current tobacco users (<4%), was more often from smokeless to smoking. Men quit smokeless tobacco at three times the rate of quitting cigarettes (38.8% vs 11.6%, p<0.001). Overall, US men have no advantage over women in quitting smoking (11.7% vs 12.4%, p = 0.65), even though men are far likelier to use smokeless tobacco.

Conclusion:

The Swedish results are not replicated in the United States. Both male and female US smokers appear to have higher quit rates for smoking than have their Swedish counterparts, despite greater use of smokeless tobacco in Sweden. Promoting smokeless tobacco for harm reduction in countries with ongoing tobacco control programmes may not result in any positive population effect on smoking cessation.
Peroxide generation by p47phox-Src activation of Nox2 has a key role in protein kinase C-induced arterial smooth muscle contraction
Authors: Gupte Sachin A. , Kaminski Pawel M. , George Shimran , Kouznestova Lioubov , Olson Susan C. , Mathew Rajamma , Hintze Thomas H. , Wolin Michael S.
Published: January 2009

Protein kinase C (PKC) stimulation of NAD(P)H oxidases (Nox) is an important component of multiple vascular disease processes; however, the relationship between oxidase activation and the regulation of vascular smooth muscle contraction by PKC remains poorly understood. Therefore, we examined the signaling cascade of PKC-elicited Nox activation and the role of superoxide and hydrogen peroxide in mediating PKC-induced vascular contraction. Endothelium-denuded bovine coronary arteries showed a PKC-dependent basal production of lucigenin (5 μM)-detected Nox oxidase-derived superoxide, which was stimulated fourfold by PKC activation with 10 μM phorbol 12,13-dibutyrate (PDBu). PDBu appeared to increase superoxide generation by Nox2 through both p47phox and peroxide-dependent Src activation mechanisms based on the actions of inhibitors, properties of Src phosphorylation, and the loss of responses in aorta from mice deficient in Nox2 and p47phox. The actions of inhibitors of contractile regulating mechanisms, scavengers of superoxide and peroxide, and responses in knockout mouse aortas suggest that a major component of the contraction elicited by PDBu appeared to be mediated through peroxide derived from Nox2 activation stimulating force generation through Rho kinase and calmodulin kinase-II mechanisms. Superoxide generated by PDBu also attenuated relaxation to nitroglycerin. Peroxide-derived from Nox2 activation by PKC appeared to be a major contributor to the thromboxane A2 receptor agonist U46619 (100 nM)-elicited contraction of coronary arteries. Thus a p47phox and Src kinase activation of peroxide production by Nox2 appears to be an important contributor to vascular contractile mechanisms mediated through activation of PKC.
NADPH oxidase contributes to coronary endothelial dysfunction in the failing heart
Authors: Zhang Ping , Hou Mingxiao , Li Yunfang , Xu Xin , Barsoum Michel , Chen YingJie , Bache Robert J.
Published: January 2009

Increased reactive oxygen species (ROS) produced by the failing heart can react with nitric oxide (NO), thereby decreasing NO bioavailability. This study tested the hypothesis that increased ROS generation contributes to coronary endothelial dysfunction in the failing heart. Congestive heart failure (CHF) was produced in six dogs by ventricular pacing at 240 beats/min for 4 wk. Studies were performed at rest and during treadmill exercise under control conditions and after treatment with the NADPH oxidase inhibitor and antioxidant apocynin (4 mg/kg iv). Apocynin caused no significant changes in heart rate, aortic pressure, left ventricular (LV) systolic pressure, LV end-diastolic pressure, or maximum rate of LV pressure increase at rest or during exercise in normal or CHF dogs. Apocynin caused no change in coronary blood flow (CBF) in normal dogs but increased CBF at rest and during exercise in animals with CHF ( P < 0.05). Intracoronary ACh caused dose-dependent increases of CBF that were blunted in CHF. Apocynin had no effect on the response to ACh in normal dogs but augmented the response to ACh in CHF dogs ( P < 0.05). The oxidative stress markers nitrotyrosine and 4-hydroxy-2-nonenal were significantly greater in failing than in normal myocardium. Furthermore, coelenterazine chemiluminescence for O2− was more than twice normal in failing myocardium, and this difference was abolished by apocynin. Western blot analysis of myocardial lysates demonstrated that the p47phox and p22phox subunits of NADPH were significantly increased in the failing hearts, while real-time PCR demonstrated that Nox2 mRNA was significantly increased. The data indicate that increased ROS generation in the failing heart is associated with coronary endothelial dysfunction and suggest that NADPH oxidase may contribute to this abnormality.
Muscle ring finger 1 mediates cardiac atrophy in vivo
Authors: Willis Monte S. , Rojas Mauricio , Li Luge , Selzman Craig H. , Tang Ru-Hang , Stansfield William E. , Rodriguez Jessica E. , Glass David J. , Patterson Cam
Published: January 2009

Pathological cardiac hypertrophy, induced by various etiologies such as high blood pressure and aortic stenosis, develops in response to increased afterload and represents a common intermediary in the development of heart failure. Understandably then, the reversal of pathological cardiac hypertrophy is associated with a significant reduction in cardiovascular event risk and represents an important, yet underdeveloped, target of therapeutic research. Recently, we determined that muscle ring finger-1 (MuRF1), a muscle-specific protein, inhibits the development of experimentally induced pathological; cardiac hypertrophy. We now demonstrate that therapeutic cardiac atrophy induced in patients after left ventricular assist device placement is associated with an increase in cardiac MuRF1 expression. This prompted us to investigate the role of MuRF1 in two independent mouse models of cardiac atrophy: 1) cardiac hypertrophy regression after reversal of transaortic constriction (TAC) reversal and 2) dexamethasone-induced atrophy. Using echocardiographic, histological, and gene expression analyses, we found that upon TAC release, cardiac mass and cardiomyocyte cross-sectional areas in MuRF1−/− mice decreased ∼70% less than in wild type mice in the 4 wk after release. This was in striking contrast to wild-type mice, who returned to baseline cardiac mass and cardiomyocyte size within 4 days of TAC release. Despite these differences in atrophic remodeling, the transcriptional activation of cardiac hypertrophy measured by β-myosin heavy chain, smooth muscle actin, and brain natriuretic peptide was attenuated similarly in both MuRF1−/− and wild-type hearts after TAC release. In the second model, MuRF1−/− mice also displayed resistance to dexamethasone-induced cardiac atrophy, as determined by echocardiographic analysis. This study demonstrates, for the first time, that MuRF1 is essential for cardiac atrophy in vivo, both in the setting of therapeutic regression of cardiac hypertrophy and dexamethasone-induced atrophy.
Impaired hemodynamics and endothelial vasomotor function via endoperoxide-mediated vasoconstriction in the carotid artery of spontaneously hypertensive rats
Authors: Denniss Steven G. , Rush James W. E.
Published: January 2009

The fact that endothelium removal increases diameter and compliance in the common carotid artery (CCA) of spontaneously hypertensive rats (SHR) and that improving CCA endothelium-dependent vasorelaxation has been shown to normalize a reduced systolic blood flow through the SHR CCA compared with normotensive Wistar-Kyoto rats (WKY) suggests that endothelial vasomotor dysfunction may be linked to altered large artery hemodynamics in hypertension. The experiments herein were designed to further investigate WKY and SHR CCA hemodynamics and endothelium-dependent vasomotor functions. It was hypothesized that CCA blood flow and conductance would be reduced throughout the cardiac cycle in SHR and that endothelium-dependent contractile activity would impair SHR CCA vasorelaxation. We report that mean, maximal systolic, and diastolic blood flow was reduced in SHR vs. WKY CCA, as was vascular conductance. Pressure was augmented in SHR CCA and accompanied by late systolic flow augmentation so that total flow during systole was indeed no different between strains, possibly explained by earlier lower body wave reflection. While ACh stimulation in isolated precontracted WKY CCA caused a robust nitric oxide (NO)-mediated vasorelaxation, endothelium-dependent, cyclooxygenase (COX)-mediated contractile activity stimulated by high ACh concentration impaired NO- and non-NO/non-COX-mediated vasorelaxation in precontracted SHR CCA. In quiescent CCA, this endothelium-dependent contractile response was COX-1 and thromboxane-prostanoid receptor mediated and modulated by the availability of NO. These data collectively suggest that endothelium-dependent, COX-mediated endoperoxide signaling in the CCA of SHR may elicit vasoconstriction, which could shift the mechanical properties of this conduit artery and contribute to reduced CCA blood flow in vivo.
Coronary blood flow responses to physiological stress in humans
Authors: Momen Afsana , Mascarenhas Vernon , Gahremanpour Amir , Gao Zhaohui , Moradkhan Raman , Kunselman Allen , Boehmer John P. , Sinoway Lawrence I. , Leuenberger Urs A.
Published: January 2009

Animal reports suggest that reflex activation of cardiac sympathetic nerves can evoke coronary vasoconstriction. Conversely, physiological stress may induce coronary vasodilation to meet an increased metabolic demand. Whether the sympathetic nervous system can modulate coronary vasomotor tone in response to stress in humans is unclear. Coronary blood velocity (CBV), an index of coronary blood flow, can be measured in humans by noninvasive duplex ultrasound. We studied 11 healthy volunteers and measured beat-by-beat changes in CBV, blood pressure, and heart rate during 1) static handgrip for 20 s at 10% and 70% of maximal voluntary contraction; 2) lower body negative pressure at −10 and −30 mmHg for 3 min each; 3) cold pressor test for 90 s; and 4) hypoxia (10% O2), hyperoxia (100% O2), and hypercapnia (5% CO2) for 5 min each. At the higher level of handgrip, mean blood pressure increased ( P < 0.001), whereas CBV did not change [ P = not significant (NS)]. In addition, during lower body negative pressure, CBV decreased ( P < 0.02; and P < 0.01, for −10 and −30 mmHg, respectively), whereas blood pressure did not change ( P = NS). The dissociation between the responses of CBV and blood pressure to handgrip and lower body negative pressure is consistent with coronary vasoconstriction. During hypoxia, CBV increased ( P < 0.02) and decreased during hyperoxia ( P < 0.01), although blood pressure did not change ( P = NS), suggesting coronary vasodilation during hypoxia and vasoconstriction during hyperoxia. In contrast, concordant increases in CBV and blood pressure were noted during the cold pressor test, and hypercapnia had no effects on either parameter. Thus the physiological stress known to be associated with sympathetic activation can produce coronary vasoconstriction in humans. Contrasting responses were noted during systemic hypoxia and hyperoxia where mechanisms independent of autonomic influences appear to dominate the vascular end-organ effects.
Hydrogen sulfide triggers late-phase preconditioning in postischemic small intestine by an NO- and p38 MAPK-dependent mechanism
Authors: Yusof Mozow , Kamada Kazuhiro , Kalogeris Theodore , Gaskin F. Spencer , Korthuis Ronald J.
Published: January 2009

Hydrogen sulfide (H2S) is one of three endogenous gases, along with carbon monoxide (CO) and nitric oxide (NO), that exert a variety of important vascular actions in vivo. Although it has been demonstrated that CO or NO can trigger the development of a preconditioned phenotype in postischemic tissues, it is unclear whether H2S may also induce protection in organs subsequently exposed to ischemia-reperfusion (I/R). In light of these observations, we postulated that preconditioning with the exogenous H2S donor sodium hydrosulfide (NaHS-PC) would inhibit leukocyte rolling (LR) and adhesion (LA) induced by I/R. We used intravital microscopic techniques to demonstrate that NaHS-PC 24 h, but not 1 h, before I/R causes postcapillary venules to shift to an anti-inflammatory phenotype in wild-type (WT) mice such that these vessels fail to support LR and LA during reperfusion. The protective effect of NaHS-PC on LR was largely abolished by coincident pharmacological inhibition of NO synthase (NOS) in WT animals and was absent in endothelial NOS-deficient (eNOS−/−) mice. A similar pattern of response was noted in WT mice treated concomitantly with NaHS plus p38 mitogen-activated protein kinase (MAPK) inhibitors (SB 203580 or SK-86002). Whereas the reduction in LA induced by antecedent NaHS was attenuated by pharmacological inhibition of NOS or p38 MAPK in WT mice, the antiadhesive effect of NaHS was still evident in eNOS−/− mice. Thus NaHS-PC prevents LR and LA by triggering the activation of an eNOS- and p38 MAPK-dependent mechanism. However, the role of eNOS in the antiadhesive effect of NaHS-PC was less prominent than its effect to reduce LR.
Inhibition of integrin αVβ3prevents urokinase plasminogen activator-mediated impairment of cerebrovasodilation after cerebral hypoxia/ischemia
Authors: Kiessling J. Willis , Cines Douglas B. , Higazi Abd Al-Roof , Armstead William M.
Published: January 2009

Cerebral hypoxia (10 min) followed immediately by ischemia (20 min) (H/I) impairs cerebrovasodilation in response to hypercapnia and hypotension in the newborn pig; exogenous urokinase plasminogen activator (uPA) potentiates this effect, whereas the blockade of endogenous uPA-mediated vasoactivity prevents it completely. This study investigated the role of integrin αVβ3in the uPA-mediated impairment of cerebrovasodilation after H/I in piglets equipped with a closed cranial window. Pial artery dilation induced by hypercapnia (Pco2, 75 mmHg) and hypotension (mean arterial blood pressure, decreased by 45%) was blunted after H/I, reversed to vasconstriction in piglets treated with uPA (10−7M), a concentration observed in cerebrospinal fluid after H/I, but reverted to a dilation no different than preinsult in piglets administered an anti-αVβ3antibody (10 ng/ml) in addition to uPA (26 ± 1, 9 ± 1, −10 ± 3, and 22 ± 3% for hypercapnia before H/I, after H/I, after H/I with uPA, and after H/I with combined uPA and anti-αVβ3antibody, respectively). Responses to isoproterenol were unchanged after H/I and combined uPA and anti-αVβ3antibody. Similar results were obtained for the combined administration of uPA with the αVβ3antagonist Arg-Gly-Asp-d-Phe-Val and Arg-Gly-Asp-Ser, but not for the inactive analog Arg-Gly-Asp-Glu-Ser acetate. These data show that the activation of the integrin αVβ3contributes to the uPA-mediated impairment of pial artery dilation after H/I. These data suggest that the inhibition of uPA and integrin signaling may preserve cerebrohemodynamic control after H/I.
Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances IL-6 and MCP-1 production
Authors: Chen Li , Frister Adrian , Wang Song , Ludwig Andreas , Behr Hagen , Pippig Susanna , Li Beibei , Simm Andreas , Hofmann Britt , Pilowski Claudia , Koch Susanne , Buerke Michael , Rose-John Stefan , Werdan Karl , Loppnow Harald
Published: January 2009

Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein (MCP)-1 and IL-6 are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from the interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMCs) with human mononuclear cells (MNCs) or monocytes on IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-1 production (up to 30- and 10-fold, respectively) compared with separately cultured cells. This enhancement was mediated by CD14-positive monocytes. It was dependent on the SMC-to-MNC/monocyte ratio, and as few as 0.2 monocytes/SMC induced the synergism. Synergistic IL-6 production was observed at the protein, mRNA, and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-1, TNF-α, and IL-6 completely blocked the synergism. IL-1, TNF-α, and IL-6 were present in the cultures. Blockade of the synergism by soluble glycoprotein 130Fc/soluble IL-6 receptor, as well as the induction of synergistic IL-6 production by costimulation of SMCs with IL-1, TNF-α, and hyper-IL-6, suggested the involvement of IL-6 trans-signaling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interactions may augment the proinflammatory status in the tissue, contributing to the acceleration of early atherogenesis.
Properties and ionic mechanisms of action potential adaptation, restitution, and accommodation in canine epicardium
Authors: Decker Keith F. , Heijman Jordi , Silva Jonathan R. , Hund Thomas J. , Rudy Yoram
Published: January 2009

Computational models of cardiac myocytes are important tools for understanding ionic mechanisms of arrhythmia. This work presents a new model of the canine epicardial myocyte that reproduces a wide range of experimentally observed rate-dependent behaviors in cardiac cell and tissue, including action potential (AP) duration (APD) adaptation, restitution, and accommodation. Model behavior depends on updated formulations for the 4-aminopyridine-sensitive transient outward current ( Ito1), the slow component of the delayed rectifier K+ current ( IKs), the L-type Ca2+ channel current ( ICa,L), and the Na+-K+ pump current ( INaK) fit to data from canine ventricular myocytes. We found that Ito1 plays a limited role in potentiating peak ICa,L and sarcoplasmic reticulum Ca2+ release for propagated APs but modulates the time course of APD restitution. IKs plays an important role in APD shortening at short diastolic intervals, despite a limited role in AP repolarization at longer cycle lengths. In addition, we found that ICa,L plays a critical role in APD accommodation and rate dependence of APD restitution. Ca2+ entry via ICa,L at fast rate drives increased Na+-Ca2+ exchanger Ca2+ extrusion and Na+ entry, which in turn increases Na+ extrusion via outward INaK. APD accommodation results from this increased outward INaK. Our simulation results provide valuable insight into the mechanistic basis of rate-dependent phenomena important for determining the heart's response to rapid and irregular pacing rates (e.g., arrhythmia). Accurate simulation of rate-dependent phenomena and increased understanding of their mechanistic basis will lead to more realistic multicellular simulations of arrhythmia and identification of molecular therapeutic targets.
Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic modulation of smooth muscle
Authors: Deaton Rebecca A. , Gan Qiong , Owens Gary K.
Published: January 2009

There is clear evidence that the phenotypic modulation of smooth muscle cells (SMCs) contributes to the pathophysiology of vascular disease. Phenotypic modulation refers to the unique ability of SMCs to alter their phenotype in response to extracellular stimuli and is hallmarked by the loss of SMC marker gene expression. The transcription factor Krüppel-like factor 4 (KLF4) is a known powerful negative regulator of SMC marker gene expression that works, in part, by decreasing the expression of the serum response factor (SRF) myocardin. KLF4 is not expressed in healthy adult SMCs but is increased in SMCs in response to vascular injury in vivo or PDGF-BB treatment in vitro. The aim of the present study was to determine the molecular mechanisms that regulate the expression of KLF4 in phenotypically modulated SMCs. The results demonstrated that the transcription factor stimulating protein-1 (Sp1) regulated the expression of KLF4 in SMCs. The KLF4 promoter contains three consensus Sp1 binding sites. Using a series of truncated KLF4 promoters, we showed that only fragments containing these Sp1 sites could be activated by PDGF-BB. In addition, overexpression of Sp1 alone was sufficient to increase the activity of the KLF4 promoter. Moreover, inhibiting Sp1 expression with small-interfering RNA attenuated the effects of PDGF-BB on KLF4 expression. Mutation of the three Sp1 sites within the KLF4 promoter abolished both baseline and PDGF-BB-induced activity. Finally, the results demonstrated enhanced Sp1 binding to the KLF4 promoter in SMCs treated with PDGF-BB in vitro and following vascular injury in vivo. Taken together, the results suggest a novel role for Sp1 in increasing the expression of KLF4 in phenotypically modulated SMCs.
Curcumin attenuates elastase- and cigarette smoke-induced pulmonary emphysema in mice
Authors: Suzuki Masaru , Betsuyaku Tomoko , Ito Yoko , Nagai Katsura , Odajima Nao , Moriyama Chinatsu , Nasuhara Yasuyuki , Nishimura Masaharu
Published: January 2009

Curcumin, a yellow pigment obtained from turmeric ( Curcumina longa), is a dietary polyphenol that has been reported to possess anti-inflammatory and antioxidant properties. The effect of curcumin against the development of pulmonary emphysema in animal models is unknown. The aim of this study was to determine whether curcumin is able to attenuate the development of pulmonary emphysema in mice. Nine-week-old male C57BL/6J mice were treated with intratracheal porcine pancreatic elastase (PPE) or exposed to mainstream cigarette smoke (CS) (60 min/day for 10 consecutive days or 5 days/wk for 12 wk) to induce pulmonary inflammation and emphysema. Curcumin (100 mg/kg) or vehicle was administrated daily by oral gavage 1 h and 24 h before intratracheal PPE treatment and daily thereafter throughout a 21-day period in PPE-exposed mice and 1 h before each CS exposure in CS-exposed mice. As a result, curcumin treatment significantly inhibited PPE-induced increase of neutrophils in bronchoalveolar lavage fluid at 6 h and on day 1 after PPE administration, with an increase in antioxidant gene expression at 6 h and significantly attenuated PPE-induced air space enlargement on day 21. It was also found that curcumin treatment significantly inhibited CS-induced increase of neutrophils and macrophages in bronchoalveolar lavage fluid after 10 consecutive days of CS exposure and significantly attenuated CS-induced air space enlargement after 12 wk of CS exposure. In conclusion, oral curcumin administration attenuated PPE- and CS-induced pulmonary inflammation and emphysema in mice.
Participation of mitochondrial respiratory complex III in neutrophil activation and lung injury
Authors: Zmijewski Jaroslaw W. , Lorne Emmanuel , Banerjee Sami , Abraham Edward
Published: January 2009

Reactive oxygen species (ROS) produced during mitochondrial activity participate in the regulation of intracellular signaling pathways. However, there is only limited information concerning the role that ROS derived from the mitochondrial respiratory chain play in modulating neutrophil activity and participation in acute inflammatory processes. Because mitochondrial complex III is a major site of ROS formation, we examined whether selective complex III inhibition, through exposure of neutrophils to myxothiazol or antimycin A, would affect LPS-induced activation. Culture of neutrophils with antimycin A or myxothiazol resulted in increased intracellular levels of ROS, including superoxide and hydrogen peroxide (H2O2). Inhibition of complex III activity reduced LPS-induced degradation of IκB-α, nuclear accumulation of NF-κB, and proinflammatory cytokine production. The effects of antimycin A or myxothiazol appeared to be dependent on generation of H2O2since addition of pegylated catalase to neutrophils restored LPS-mediated IκB-α degradation and production of proinflammatory cytokines. Administration of myxothiazol to mice resulted in diminished mitochondrial complex III activity in the lungs and decreased severity of LPS-induced lung injury. These results indicate that inhibition of mitochondrial complex III diminishes Toll-like receptor 4-induced neutrophil activation through a mechanism dependent on H2O2generation and also reduces the severity of lung injury due to LPS exposure, a pathophysiologic process in which neutrophils play a major role.
Targeted inactivation of endothelial lipase attenuates lung allergic inflammation through raising plasma HDL level and inhibiting eosinophil infiltration
Authors: Otera Hiroshi , Ishida Tatsuro , Nishiuma Teruaki , Kobayashi Kazuyuki , Kotani Yoshikazu , Yasuda Tomoyuki , Kundu Ramendra K. , Quertermous Thomas , Hirata Ken-ichi , Nishimura Yoshihiro
Published: January 2009

Endothelial lipase (EL) is a novel phospholipase that determines plasma high-density lipoprotein cholesterol (HDL-C) levels. We have investigated the role of HDL-C in lung allergic inflammation by using EL knockout (EL-KO) mice that are high in HDL-C. EL-KO and wild-type control mice were sensitized and challenged with ovalbumin to evoke eosinophilic inflammation in the lung. EL was expressed in epithelial cells, alveolar type II cells, and endothelial cells in the lung, and its expression was upregulated during inflammation. Concomitant with attenuated hyperresponsiveness of the airway smooth muscles, the number of eosinophils in bronchoalveolar lavage and the expression of VCAM-1 were lower in EL-KO mice than in control mice. HDL reduced cytokine-induced VCAM-1 expression in cultured endothelial cells. When plasma HDL levels were decreased to similar levels in both mouse groups by adenovirus-mediated overexpression of EL, however, eosinophil infiltration was still lower in EL-KO mice. In vitro adhesion assays revealed that EL expression on the cell surface promoted the interaction of eosinophils through the ligand-binding function of EL. In summary, targeted inactivation of EL attenuated allergic inflammation in the lung, and the protective effects in EL-KO mice were associated with high plasma HDL levels, downregulation of VCAM-1, and loss of the direct ligand-binding function of EL. Thus EL is a novel modulator of the progression of allergic asthma.
An Evaluation of Candidate Genes of Inflammation and Thrombosis in Relation to the Risk of Venous Thromboembolism
Authors: Zee Robert Y.L. , Glynn Robert J. , Cheng Suzanne , Steiner Lori , Rose Lynda , Ridker Paul M
Published: January 2009

Background—

Although pathways associated with hemostasis and thrombosis are well documented to have an impact on venous thromboembolism (VTE), whether the inflammatory cascade also influences VTE risk is uncertain.

Methods and Results—

We evaluated 51 polymorphisms from 32 inflammation-related genes (and an additional 19 polymorphisms from 15 thrombosis-related genes) as potential determinants of VTE in a prospective cohort of 22 413 white women followed over a 10-year period. Hazard ratios (HRs) for incident VTE according to the different genotypes were assessed by Cox proportional-hazards models. The false discovery rate (FDR) was used for correction for multiple testing with a 0.20 cut point. During follow-up, 158 idiopathic and 180 secondary VTE events occurred. As anticipated, factor V Leiden (HR, 3.22; 95% CI, 1.92 to 5.40;
P
<0.0001; FDR=0.004) and the prothrombin mutation (HR, 2.57; 95% CI, 1.64 to 4.02;
P
<0.0001; FDR=0.004) were both strongly associated with incident idiopathic VTE, as was the rs6046 polymorphism in the factor VII gene (HR, 0.54; 95% CI, 0.35 to 0.86;
P
=0.008; FDR, 0.12). With regard to polymorphism in the inflammatory genes, variation at rs1143634 in the IL-1β gene was associated with a reduced risk of idiopathic VTE (HR, 0.59; 95% CI, 0.44 to 0.80;
P
=0.0007; FDR=0.02), whereas variation at rs1800872 in the IL-10 gene was associated with increased risk (HR, 1.42; 95% CI, 1.12 to 1.80;
P
=0.004; FDR=0.07). By contrast, no significant associations were found for secondary VTE events.

Conclusion—

In addition to previously reported polymorphisms associated with hemostasis and thrombosis, these prospective cohort data suggest that genetic variation in IL-1 β and IL-10 genes may also influence the risk of idiopathic VTE.
HFE
C282Y Homozygosity Is Associated With Lower Total and Low-Density Lipoprotein Cholesterol
Authors: Adams Paul C. , Pankow James S. , Barton James C. , Acton Ron T. , Leiendecker-Foster Cathie , McLaren Gordon D. , Speechley Mark , Eckfeldt John H.
Published: January 2009

Background—

Previous studies have suggested a positive association of coronary heart disease risk and both serum ferritin concentrations and C282Y heterozygosity. Relationships between serum lipids, C282Y homozygosity, and serum ferritin have not been well established.

Methods and Results—

The Hemochromatosis and Iron Overload Screening study screened 101 168 participants in primary care from 5 field centers in the United States and Canada with serum ferritin, transferrin saturation, and
HFE
genotyping for C282Y and H63D mutations. Serum lipids were measured in a subset of 176 C282Y homozygotes (63 male, 113 female whites) without a prior diagnosis of, family history, or treatment for hemochromatosis and a matched sample of participants with normal transferrin saturation and serum ferritin without C282Y or H63D mutations (wild-type, 123 male, 189 female whites). The proportion of subjects who reported using prescription cholesterol-lowering medications was ≈3 times higher in
HFE
wild-type subjects than C282Y homozygotes among men (22% versus 7%;
P
=0.02) and, in women, 2 times higher (16% versus 8%;
P
=0.07). After excluding subjects taking cholesterol medications, C282Y homozygotes had significantly lower mean total and low-density lipoprotein cholesterol concentrations than wild-type subjects, with larger genotypic differences for low-density lipoprotein in men (−0.62 mmol/L; 95% CI, −0.93 to −0.33) than in women (−0.28 mmol/L; 95%, CI −0.52 to −0.08).

Conclusions—

Total mean serum cholesterol and low-density lipoprotein levels were lower in C282Y homozygotes than in
HFE
wild-type participants. Further studies are required to determine whether this is related to iron overload,
HFE
alleles, or other factors on C282Y-positive chromosome 6p haplotypes.
Genetic Variants Associated With Myocardial Infarction Risk Factors in Over 8000 Individuals From Five Ethnic Groups
Authors: Anand Sonia S. , Xie Changchun , Paré Guillaume , Montpetit Alexandre , Rangarajan Sumathy , McQueen Matthew J. , Cordell Heather J. , Keavney Bernard , Yusuf Salim , Hudson Thomas J. , Engert James C.
Published: January 2009

Background—

Myocardial infarction (MI) is a leading cause of death globally, but specific genetic variants that influence MI and MI risk factors have not been assessed on a global basis.

Methods and Results—

We included 8795 individuals of European, South Asian, Arab, Iranian, and Nepalese origin from the INTERHEART case-control study that genotyped 1536 single-nucleotide polymorphisms (SNPs) from 103 genes. One hundred and two SNPs were nominally associated with MI, but the statistical significance did not remain after adjustment for multiple testing. A subset of 940 SNPs from 69 genes were tested against MI risk factors. One hundred and sixty-three SNPs were nominally associated with a MI risk factor and 13 remained significant after adjusting for multiple testing. Of these 13, 11 were associated with apolipoprotein (Apo) B/A1 levels: 8 SNPs from 3 genes were associated with Apo B, and 3 cholesteryl ester transfer protein SNPs were associated with Apo A1. Seven of 8 of the SNPs associated with Apo B levels were nominally associated with MI (
P
<0.05), whereas none of the 3 cholesteryl ester transfer protein SNPs were associated with MI (
P
≥0.17). Of the 3 SNPs most significantly associated with MI, rs7412, which defines the Apo E2 isoform, was associated with both a lower Apo B/A1 ratio (
P
=1.0�10
−7
) and lower MI risk (
P
=0.0004). Two low-density lipoprotein receptor variants, 1 intronic (rs6511720) and 1 in the 3′ untranslated region (rs1433099) were both associated with a lower Apo B/A1 ratio (
P
<1.0�10
−5
) and a lower risk of MI (
P
=0.004 and
P
=0.003, respectively).

Conclusions—

Thirteen common SNPs were associated with MI risk factors. Importantly, SNPs associated with Apo B levels were associated with MI, whereas SNPs associated with Apo A1 levels were not. The Apo E isoform, and 2 common low-density lipoprotein receptor variants (rs1433099 and rs6511720) influence MI risk in this multiethnic sample.
Association of Regions on Chromosomes 6 and 7 With Blood Pressure in Nigerian Families
Authors: Tayo Bamidele O. , Luke Amy , Zhu Xiaofeng , Adeyemo Adebowale , Cooper Richard S.
Published: January 2009

Background—

Elevated blood pressure (BP) shares a level of heritability similar to many other traits related to cardiovascular risk; however, specific susceptibility loci have been difficult to localize. We conducted a multistage study of BP as a continuous trait in a low-risk West African population in which it was anticipated that environmental exposures would be reduced in complexity and intensity. In our earlier genome-wide linkage study for BP in this population, strong linkage evidence was noted on chromosomes 6 and 7.

Methods and Results—

We subsequently genotyped a total of 3431 tag single-nucleotide polymorphisms (SNPs) in 3 regions (viz, 152.68 to 165.99 Mb on chromosome 6, 0.29 to 20.67 Mb, and 104.09 to 123.06 Mb on chromosome 7) in 713 individuals from 199 families. We conducted a family-based association analysis using individual SNPs and associated haplotypes. After correction for multiple comparisons, 6 intronic and 1 intergenic SNPs achieved nominal statistical significance (
P
<0.05) for the association with BP. The associated intronic SNPs include 2 in the PARK2 gene on chromosome 6; 2 in the KCND2 gene, and 1 each in the C7orf58 and HDAC9 genes on chromosome 7. The intergenic SNP is located between the RPA3 and GLCCI1 genes on chromosome 7. The haplotypes on which these SNPs resided were more strongly associated with BP than their respective single SNPs. The frequency of the “at-risk” haplotypes ranged from 14% to 48%.

Conclusions—

These data provide preliminary evidence that regions on chromosomes 6 and 7 may influence susceptibility to elevations in BP.
Polymorphism in the
CETP
Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction
Authors: Ridker Paul M. , Paré Guillaume , Parker Alex N. , Zee Robert Y.L. , Miletich Joseph P. , Chasman Daniel I.
Published: January 2009

Background—

Recent trial data have challenged the hypothesis that cholesteryl ester transfer protein (CETP) and high-density lipoprotein cholesterol (HDL-C) have causal roles in atherothrombosis. One method to evaluate this issue is to examine whether polymorphisms in the
CETP
gene that impact on HDL-C levels also impact on the future development of myocardial infarction.

Methods and Results—

In a prospective cohort of 18 245 initially healthy American women, we examined over 350 000 singe-nucleotide polymorphisms (SNPs) first to identify loci associated with HDL-C and then to evaluate whether significant SNPs within these loci also impact on rates of incident myocardial infarction during an average 10-year follow-up period. Nine loci on 9 chromosomes had 1 or more SNPs associated with HDL-C at genome-wide statistical significance (
P
<5�10
−8
). However, only SNPs near or in the
CETP
gene at 16q13 were associated with both HDL-C and risk of incident myocardial infarction (198 events). For example, SNP rs708272 in the
CETP
gene was associated with a per-allele increase in HDL-C levels of 3.1 mg/dL and a concordant 24% lower risk of future myocardial infarction (age-adjusted hazard ratio, 0.76; 95% CI, 0.62 to 0.94), consistent with recent meta-analysis. Independent and again concordant effects on HDL-C and incident myocardial infarction were also observed at the
CETP
locus for rs4329913 and rs7202364. Adjustment for HDL-C attenuated but did not eliminate these effects.

Conclusion—

In this prospective cohort of initially healthy women, SNPs at the
CETP
locus impact on future risk of myocardial infarction, supporting a causal role for CETP in atherothrombosis, possibly through an HDL-C mediated pathway.
Prediction of Cardiovascular Disease Outcomes and Established Cardiovascular Risk Factors by Genome-Wide Association Markers
Authors: Ioannidis John P.A.
Published: January 2009

Background—

Genome-wide association (GWA) platforms have yielded a rapidly increasing number of new genetic markers. The ability of these markers to improve prediction of clinically important outcomes is debated.

Methods and Results—

A systematic review was performed of GWA-derived markers associated with cardiovascular outcomes or other phenotypes that represent common established risk factors for cardiovascular outcomes. Sources of information included the National Human Genome Research Institute catalog of published GWA studies, and perusal of the eligible GWA articles, meta-analyses on the respective associations, and articles on the incremental predictive performance of common variants in the GWA era. A total of 95 eligible associations were retrieved from the National Human Genome Research Institute catalogue of published GWA studies as of September 2008. Of those 36 have statistical support of
P
<10
−7
. In depth evaluation of the respective articles shows 28 independent associations with such statistical support, pertaining to coronary artery disease, myocardial infarction, atrial fibrillation/flutter, prolongation of QT interval, as well as type 2 diabetes, body mass index, high-density lipoprotein levels, low-density lipoprotein levels, and nicotine dependence. Between-study heterogeneity is not taken into account usually, but it seems common and it would pose a challenge to generalizability across different populations for these markers. Still limited data are available in non-white populations. Effect sizes are small and may be even smaller in subsequent replications and meta-analysis. Population attributable fractions are substantial, given the large frequency of the risk alleles. However, individualized risk measures are typically very small (proportion of variance explained <1% per marker). When used in conjunction with traditional predictors, improvement in overall prediction (eg, area under the curve) or risk reclassification is limited, and subject to methodological caveats.

Conclusions—

Despite very promising signals in terms of statistical significance, evidence for improvement in cardiovascular prediction by currently available markers derived from GWA studies is sparse. Clinical use of such markers currently would be premature.
Participation, Representation, and Democracy in Contemporary India
Authors: Chandhoke Neera
Published: January 2009

This article analyzes the tensions and paradoxes that are emerging as developing nation governments and civil society organizations alike institutionalize. It examines the prospect for effective representation and for democratic governance in the face of the increasing complexities and professionalization of the public's business and of non-governmental institutions. The article concludes that the challenges are large but not insuperable if approached with openness and imagination.
“Place” as Prepolitical Grounds of Democracy
Authors: Taylor Betsy
Published: January 2009

This article argues for democratization as the crafting of democratic public space. Through ethnography of grassroots contestation in Appalachia, the article examines the social substrate of collective mobilization on environmental issues. It proposes shared stewardship of “place” as important grounds for democratization—helping to overcome divisions of class, culture, and ideology and to encourage integrative deliberation and knowledge. Collective labors to steward particular places create understandings of a shared world arising from civic and environmental commons. Place-stewardship can engender integrative forms of knowledge—multicausal, multiscalar, multitemporal—as people deliberate about complex ecological and social phenomena over time. However, citizens typically face an environmental policy system that displaces integrated, community-centered perspectives into specialized government mandates and scholarly expertise. Against this fragmenting political terrain, civil society develops “counterexpertise” based on multiscalar and multi-issue networking. Such networks are not reliably democratizing, however, unless grounded in democratic public space.
Social Capacity and the Styles of Group Life
Authors: Lichterman Paul
Published: January 2009

This article introduces a concept of social capacity and offers a method of studying it. Social capacity is people's ability to work together to organize public relationships, rather than give responsibility for those relationships wholly to state actors or the flux of market exchange. The article proposes that to study social capacity, we examine the everyday group styles of civic life. Those culturally patterned styles enable and constrain a group's ability to imagine and organize its public relationships with the wider social world. The article applies this approach to the “networking” style of a church alliance in a Midwestern U.S. city, whose members were responding to the welfare policy reforms of 1996. Investigating group style allows a focus on civic relationships, or potential civic relationships, across “sectoral” domains and avoids reifying “civil society,” “state,” or “market.” This analytic approach also avoids the elisions and silences that the popular social capital concept often invites.
Beyond Structures to Democracy as Culture
Authors: Beeman Jennifer , Guberman Nancy , Lamoureux Jocelyne , Fournier Danielle , Gervais Lise
Published: January 2009

This article explores a paradox revealed by our research on the democratic practices of women's groups in Québec. In focus groups and interviews, grassroots members active in these groups suggested that formal decision making structures had little meaning to most grassroots members. Workers and board members also identified a significant distance between members' participation and formal democratic structures. However, these same informants spoke eloquently of the meaning of democracy and its importance in these groups. This article analyses the meaning of democracy and democratic structures for the members of these women's groups. The analysis sits at the intersection of feminist theory on democracy and Alain Touraine's theory of the emergence of the subject through participation in democratic processes. The article explores the nuances, contradictions and richness of the different meanings of democracy for the members of these women's groups.
Placing the Normative Logics of Accountability in “Thick” Perspective
Authors: Ebrahim Alnoor
Published: January 2009

This article provides a critical reflection on the heavily normative nature of current accountability debates. In particular, it explores three streams of normative discourse on nonprofit accountability: improving board governance, improving performance-based reporting, and demonstrating progress toward mission. The article describes how these logics are associated with three basic accountability regimes: coercive, technocratic, and adaptive. It then discusses how a focus on these normative logics and regimes, although important, can mask the realities of social structure and the relations of power that underlie them. The article proposes a more empirical approach to framing accountability—“thick description”—that might enable scholars better understand how social regimes of accountability actually operate in different contexts and in which the instruments of accountability are at least as likely to reproduce relationships of inequality as they are to overturn them.
The Virtues of Virtue
Authors: Weisband Edward
Published: January 2009

Network governance, social capital, and virtue-based forms of corporate social responsibility justify sectoral arrangements organized around reciprocated forms of entrepreneurial accountability to promote best practices of corporate social responsibility benchmarked in near and long terms. Standards of corporate social responsibility require precise elaboration within the contexts of contemporary theories of the firm that specify the normative limits of voluntary business obligations. This article argues that such ethical constraints remain too narrow and suggests how corporate social responsibility might be extended in accordance with eudaimonic principles of social capital and aretaic principles of executive excellence manifested by managerial learning.
The Civic Mission of a Federal Agency in the Age of Networked Governance
Authors: Sirianni Carmen
Published: January 2009

The U.S. Environmental Protection Agency (EPA) has been engaged in a process of organizational learning to build civic capacity for nearly 4 decades, in effect discovering its civic mission. This article examines how EPA has increasingly become a more effective enabler of democratic network governance in the watershed arena and has developed ambitious cross-media initiatives to help transform the culture of the agency. Its very progress, however, highlights significant challenges that the agency must address.
“Can’t C Me”
Authors: Nielson Erik
Published: January 2009

Rap music has always been under surveillance, and the purpose of this article is to explore the most significant ways that the genre has been influenced by it. It begins with an overview of some of the ways in which surveillance has played a crucial role in the emergence of hip hop in general and rap in particular. It then uses a close analysis of 2Pac’s track “Can’t C Me” as a point of departure for a broader discussion of the way many of rap’s lyrical, structural, and thematic features can be interpreted as a response to the perception of being watched. As this article will demonstrate, despite rap’s ostensible emphasis on visibility and recognition, these features indicate a countervailing strain in rap’s aesthetic, one that favors invisibility and anonymity.