J005 Genetic and non-genetic forms of aneurysms of the human ascending aorta share activation and overexpression of Smad2: putative implication of epigenetic mechanisms

Ascending aortic aneurysm (AscAA) development proceeds by multifactorial and chronic processes affecting both vascular extracellular matrix structure and integrity and smooth muscle cell (SMC) survival. These features are associated with all types of AscAA: i) genetic forms associated with mutations in FBN1, TGFBR1 or TGFBR2 (Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS)), ii) aneurysms associated with bicuspid aortic valve (BAV) or iii) degenerative forms. However, the relation between the genotypic variability and the unique aortic phenotype remains unexplained. The common matrix perturbations suggest similar cell dysfunction in both genetic and non-genetic AscAA. In this context, it has been recently proposed that TGF-β1 plays a predominant role in AscAA. Here we investigate TGF-β1 and its intracellular mediator Smad signaling pathway using tissue extracts and cultured SMCs from the media of genetic and non-genetic forms of AscAA. We show an increased activation of Smad2 (phosphorylated-Smad2) and an increased amount of TGF-β1 in AscAA. However, biochemical and histological studies demonstrated an enhancement of TGF-β1 retention within the extracellular matrix but not in its expression and activation, and thus highlight independent dysregulation of TGF-β1 retention and Smad2 signaling in genetic and non-genetic aneurysms. The constitutive Smad2 activation is independent of the extracellular TGF-β1 as well as of TGF-β receptor functionality. Aneurysms bearing TGFBR2 mutations, which induce loss of function, present constitutive Smad2 activation. Moreover, increased Smad2 expression is observed in tissue extracts but also in cultured SMC extracts, where the overexpression is surprisingly maintained during several passages, in AscAA. The study of adventitial fibroblasts shows that Smad2 perturbations are specific to SMCs from the media of aneurysmal aortic wall. A putative regulation of Smad2 expression by epigenetic mechanisms (histone acetylation and/or DNA methylation) is tested. Preliminary results show decreased Smad2 expression induced by deacetylase and methylase inhibitors in aneurysmal SMCs. In contrast, Smad2 expression, in control SMCs, is not affected by these treatments. The constitutive and tissuespecific activation of Smad2 and its maintained expression suggest an implication of epigenetic mechanisms in the development of genetic and non-genetic AscAA

CARBOTRAF: A decision Support system for reducing pollutant emissions by adaptive traffic management

Traffic congestion with frequent “stop & go” situations causes substantial pollutant emissions. Black carbon (BC) is a good indicator of combustion-related air pollution and results in negative health effects. Both BC and CO2 emissions are also known to contribute significantly to global warming. Current traffic control systems are designed to improve traffic flow and reduce congestion. The CARBOTRAF system combines real-time monitoring of traffic and air pollution with simulation models for emission and local air quality prediction in order to deliver on-line recommendations for alternative adaptive traffic management. The aim of introducing a CARBOTRAF system is to reduce BC and CO2 emissions and improve air quality by optimizing the traffic flows. The system is implemented and evaluated in two pilot cities, Graz and Glasgow. Model simulations link traffic states to emission and air quality levels. A chain of models combines micro-scale traffic simulations, traffic volumes, emission models and air quality simulations. This process is completed for several ITS scenarios and a range of traffic boundary conditions. The real-time DSS system uses all these model simulations to select optimal traffic and air quality scenarios. Traffic and BC concentrations are simultaneously monitored. In this paper the effects of ITS measures on air quality are analysed with a focus on BC

Air quality impact of a decision support system for reducing pollutant emissions: CARBOTRAF

Traffic congestion with frequent “stop & go” situations causes substantial pollutant emissions. Black carbon (BC) is a good indicator of combustion-related air pollution and results in negative health effects. Both BC and CO2 emissions are also known to contribute significantly to global warming. Current traffic control systems are designed to improve traffic flow and reduce congestion. The CARBOTRAF system combines real-time monitoring of traffic and air pollution with simulation models for emission and local air quality prediction in order to deliver on-line recommendations for alternative adaptive traffic management. The aim of introducing a CARBOTRAF system is to reduce BC and CO2 emissions and improve air quality by optimizing the traffic flows. The system is implemented and evaluated in two pilot cities, Graz and Glasgow. Model simulations link traffic states to emission and air quality levels. A chain of models combines micro-scale traffic simulations, traffic volumes, emission models and air quality simulations. This process is completed for several ITS scenarios and a range of traffic boundary conditions. The real-time DSS system uses these off-line model simulations to select optimal traffic and air quality scenarios. Traffic and BC concentrations are simultaneously monitored. In this paper the effects of ITS measures on air quality are analysed with a focus on BC

Long-Term Dietary Patterns Are Reflected in the Plasma Inflammatory Proteome of Patients with Inflammatory Bowel Disease

Diet plays an important role in the development and progression of inflammatory bowel disease (IBD, comprising Crohn's disease (CD) and ulcerative colitis (UC)). However, little is known about the extent to which different diets reflect inflammation in IBD beyond measures such as faecal calprotectin or C-reactive protein. In this study, we aimed to unravel associations between dietary patterns and circulating inflammatory proteins in patients with IBD. Plasma concentrations of 73 different inflammation-related proteins were measured in 454 patients with IBD by proximity extension assay (PEA) technology. Food frequency questionnaires (FFQ) were used to assess habitual diet. Principal component analysis (PCA) was performed to extract data-driven dietary patterns. To identify associations between dietary patterns and plasma proteins, we used general linear models adjusting for age, sex, BMI, plasma storage time, smoking, surgical history and medication use. Stratified analyses were performed for IBD type, disease activity and protein intake. A high-sugar diet was strongly inversely associated with fibroblast growth factor-19 (FGF-19) independent of IBD type, disease activity, surgical history and deviance from recommended protein intake (false discovery rate (FDR) < 0.05). Conversely, a Mediterranean-style pattern was associated with higher FGF-19 levels (FDR < 0.05). A pattern characterised by high alcohol and coffee intake was positively associated with CCL11 (eotaxin-1) levels and with lower levels of IL-12B (FDR < 0.05). All results were replicated in CD, whereas only the association with FGF-19 was significant in UC. Our study suggests that dietary habits influence distinct circulating inflammatory proteins implicated in IBD and supports the pro- and anti-inflammatory role of diet. Longitudinal measurements of inflammatory markers, also postprandial, are needed to further elucidate the diet-inflammation relationship

Standardization of measles, mumps and rubella assays to enable comparisons of seroprevalence data across 21 European countries and Australia

The aim of the European Sero-Epidemiology Network is to establish comparability of the serological surveillance of vaccine-preventable diseases in Europe. The designated reference laboratory (RL) for measles, mumps, rubella (MMR) prepared and tested a panel of 151 sera by the reference enzyme immunoassay (rEIA). Laboratories in 21 countries tested the panel for antibodies against MMR using their usual assay (a total of 16 different EIAs) and the results were plotted against the reference results in order to obtain equations for the standardization of national serum surveys. The RL also tested the panel by the plaque neutralization test (PNT). Large differences in qualitative results were found compared to the RL. Well-fitting standardization equations with R20·8 were obtained for almost all laboratories through regression of the quantitative results against those of the RL. When compared to PNT, the rEIA had a sensitivity of 95·3%, 92·8% and 100% and a specificity of 100%, 87·1% and 92·8% for measles, mumps and rubella, respectively. The need for standardization was highlighted by substantial inter-country differences. Standardization was successful and the selected standardization equations allowed the conversion of local serological results into common units and enabled direct comparison of seroprevalence data of the participating countrie

A Global Risk Approach to Identify Patients With Left Main or 3-Vessel Disease Who Could Safely and Efficaciously Be Treated With Percutaneous Coronary Intervention The SYNTAX Trial at 3 Years

ObjectivesThe aim of this study was to assess the additional value of the Global Risk—a combination of the SYNTAX Score (SXscore) and additive EuroSCORE—in the identification of a low-risk population, who could safely and efficaciously be treated with coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention (PCI).BackgroundPCI is increasingly acceptable in appropriately selected patients with left main stem or 3-vessel coronary artery disease.MethodsWithin the SYNTAX Trial (Synergy between PCI with TAXUS and Cardiac Surgery Trial), all-cause death and major adverse cardiac and cerebrovascular events (MACCE) were analyzed at 36 months in low (GRCLOW) to high Global Risk groups, with Kaplan-Meier, log-rank, and Cox regression analyses.ResultsWithin the randomized left main stem population (n = 701), comparisons between GRCLOW groups demonstrated a significantly lower mortality with PCI compared with CABG (CABG: 7.5%, PCI: 1.2%, hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.03 to 0.70, p = 0.0054) and a trend toward reduced MACCE (CABG: 23.1%, PCI: 15.8%, HR: 0.64, 95% CI: 0.39 to 1.07, p = 0.088). Similar analyses within the randomized 3-vessel disease population (n = 1,088) demonstrated no statistically significant differences in mortality (CABG: 5.2%, PCI: 5.8%, HR: 1.14, 95% CI: 0.57 to 2.30, p = 0.71) or MACCE (CABG: 19.0%, PCI: 24.7%, HR: 1.35, 95% CI: 0.95 to 1.92, p = 0.10). Risk-model performance and reclassification analyses demonstrated that the EuroSCORE—with the added incremental benefit of the SXscore to form the Global Risk—enhanced the risk stratification of all PCI patients.ConclusionsIn comparison with the SXscore, the Global Risk, with a simple treatment algorithm, substantially enhances the identification of low-risk patients who could safely and efficaciously be treated with CABG or PCI

Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis.

An estimated one-third of the world population is latently infected with Mycobacterium tuberculosis. These nonreplicating, dormant bacilli are tolerant to conventional anti-tuberculosis drugs, such as isoniazid. We recently identified diarylquinoline R207910 (also called TMC207) as an inhibitor of ATP synthase with a remarkable activity against replicating mycobacteria. In the present study, we show that R207910 kills dormant bacilli as effectively as aerobically grown bacilli with the same target specificity. Despite a transcriptional down-regulation of the ATP synthase operon and significantly lower cellular ATP levels, we show that dormant mycobacteria do possess residual ATP synthase enzymatic activity. This activity is blocked by nanomolar concentrations of R207910, thereby further reducing ATP levels and causing a pronounced bactericidal effect. We conclude that this residual ATP synthase activity is indispensable for the survival of dormant mycobacteria, making it a promising drug target to tackle dormant infections. The unique dual bactericidal activity of diarylquinolines on dormant as well as replicating bacterial subpopulations distinguishes them entirely from the current anti-tuberculosis drugs and underlines the potential of R207910 to shorten tuberculosis treatment. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc