Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model.

Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments

Endarterectomy or carotid artery stenting:the quest continues

Background: Carotid endarterectomy (CEA) is still considered the "gold-standard" of the treatment of patients with significant carotid stenosis and has proven its value during past decades. However, endovascular techniques have recently been evolving. Carotid artery stenting (CAS) is challenging CEA for the best treatment in patients with carotid stenosis. This review presents the development of CAS according to early reports, results of recent randomized trials, and future perspectives regarding CAS. Methods: A literature search using the PubMed and Cochrane databases identified articles focusing on the key issues of CEA and CAS. Results: Early nonrandomized reports of CAS showed variable results, and the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial led to United States Food and Drug Administration approval of CAS for the treatment of patients with symptomatic carotid stenosis. In contrast, recent trials, such as the Stent-Protected Angioplasty Versus Carotid Endarterectomy trial and the Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis trial, (re)fuelled the debate between CAS and CEA. In the Stent-Protected Angioplasty Versus Carotid Endarterectomy trial, the complication rate of ipsilateral stroke or death at 30days was 6.8% for CAS versus 6.3% for CEA and showed that CAS failed the noninferiority test. Analysis of the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial showed a significant higher risk for death or any stroke at 3,0 days for endovascular treatment (9.6%) compared with CEA (3.9%). Other aspects-such as evolving best medical treatment, timely intervention, interventionalists' experience, and analysis of plaque composition-may have important influences on the future treatment of patients with carotid artery stenosis. Conclusions: CAS performed with or without embolic-protection devices can be an effective treatment for patients with carotid artery stenosis. However, presently there is no evidence that CAS provides better results in the prevention of stroke compared with CEA. (C) 2008 Excerpta Medica Inc. All rights reserved

Clinical correlates of change in inflammatory biomarkers:The Framingham Heart Study

<p>Objectives: Traditional clinical risk factors are associated with inflammation cross-sectionally, but associations of longitudinal variation in inflammatory biomarkers with corresponding changes in clinical risk factors are incompletely described. We sought to analyze clinical factors associated with change in inflammation in the community.</p><p>Methods: We studied 3013 Framingham Offspring (n = 2735) and Omni Cohort (n = 278) participants (mean age 59 years, 55% women, 9% ethnic/racial minority) who attended two consecutive examination cycles (mean 6.7 years apart). We selected ten inflammatory biomarkers representing distinctive biological functions: C-reactive protein (CRP), intercellular adhesion molecule-1, interleukin-6, isoprostanes, lipoprotein-associated phospholipase-2 (Lp-PLA2) activity, Lp-PLA2-mass, monocyte chemoattractant protein-1, osteoprotegerin, P-selectin, and tumor necrosis factor receptor II (TNFRII). We constructed multivariable-adjusted regression models to assess the relations of baseline, follow-up and change in clinical risk factors with change in biomarker concentrations over time.</p><p>Results: Baseline, follow-up and change in clinical risk factors explain a moderate amount of the variation in biomarker concentrations across 2 consecutive examinations (ranging from r(2) = 0.28 [TNFRII] up to 0.52 [Lp-PLA2-mass]). In multivariable models, increasing body-mass index, smoking initiation, worsening lipid profile, and increasing waist size were associated with increasing concentrations of several biomarkers. Conversely, hypercholesterolemia therapy and hormone replacement cessation were associated with decreasing concentrations of biomarkers such as CRP, Lp-PLA2-mass and activity.</p><p>Conclusion: Cardiovascular risk factors have different patterns of association with longitudinal change in inflammatory biomarkers and explain modest amounts of variability in biomarker concentrations. Nevertheless, a substantial proportion of longitudinal change in inflammatory markers is not explained by traditional risk factors. (C) 2013 Elsevier Ireland Ltd. All rights reserved.</p>