Objective-To determine the association between leukocyte telomere length (TL) and atherosclerosis and its clinical sequelae stroke and myocardial infarction. Methods and Results-Within the scope of the prospective population-based Bruneck Study, leukocyte TL was measured by quantitative polymerase chain reaction in 800 women and men aged 45 to 84 years (in 1995). The manifestation of cardiovascular disease (CVD) (1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004)(2005) and the progression of atherosclerosis (1995)(1996)(1997)(1998)(1999)(2000) were carefully assessed. In multivariable Cox models, baseline TL emerged as a significant and independent risk predictor for the composite CVD end point and its individual components (myocardial infarction and stroke); however, this was not the case for de novo stable angina and intermittent claudication. Subjects in the top and bottom TL tertile group differed in their CVD risk by a factor of 2.72 (95% CI, 1.41 to 5.28), which is the risk ratio attributable to a 13.9-year difference in chronological age. Remarkably, in our atherosclerosis progression model, TL was strongly associated with advanced, but not early, atherogenesis. All findings were consistent in women and men. Conclusion-Our findings indicate a differential role of telomere shortening in the various stages of atherosclerosis, with preferential involvement in advanced vessel pathology and acute vascular syndromes. (Arterioscler Thromb Vasc Biol.

This is the first comprehensive longitudinal study of individuals who were, on average, 60 at baseline, and who were re-evaluated 10 years later. Our methodology proved to be a reliable tool for a rapid, accurate and cost-efficient determination of RTL with a low amount of DNA.

Hemolytic-uremic syndrome (HUS) is a life-threatening disorder characterized by hemolytic anemia, thrombocytopenia, and renal insufficiency. It is caused mainly by infections with enterohemorrhagic Escherichia coli (EHEC). Recently, Shiga toxin 2, the best-studied virulence factor of EHEC, was reported to interact with complement, implying that complement may be involved in the pathogenesis of EHEC-induced HUS. The aim of the present study was to investigate whether or not the serine protease EspP, an important virulence factor of EHEC, interacts with complement proteins. EspP did not have any effect on the integrity of factor H or factor I. However, EspP was shown to cleave purified C3/C3b and C5. Cleavage of the respective complement proteins also occurred in normal human serum (NHS) as a source of C3/C3b or C5 or when purified complement proteins were added to the supernatant of an EspP-producing wild-type strain. Edman degradation allowed unequivocal mapping of all three main C3b fragments but not of the three main C5 fragments. Complement activation was significantly downregulated in all three pathways for C5-depleted serum to which C5, preincubated with EspP, was added (whereas C5 preincubated with an EspP mutant was able to fully reconstitute complement activation). This indicates that EspP markedly destroyed the functional activity, as measured by a commercial total complement enzyme-linked immunosorbent assay (Wieslab). Downregulation of complement by EspP in vivo may influence the colonization of EHEC bacteria in the gut or the disease severity of HUS.Hemolytic-uremic syndrome (HUS) is the most frequent cause of acute renal failure in children. This disorder is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency (26). HUS may be caused by different etiological agents; infections with enterohemorrhagic Escherichia coli (EHEC) are, however, the leading cause of HUS in childhood worldwide (13). EHEC produces several virulence factors, among which Shiga toxins (Stxs) 1 and 2 are probably the best characterized.The complement system is an important part of innate immunity and consists of more than 30 proteins in plasma and on host cells (25). Complement is activated by three different pathways-the classical pathway (CP), the mannan-binding lectin (MBL) pathway, and the alternative pathway (AP)-based on different recognition mechanisms. Finally, all three pathways converge in the generation of C3 convertases, which cleave the central component C3, creating C3a and C3b. Nascent C3b has the transient ability to form a covalent ester bond with a variety of target surfaces and finally becomes an essential subunit of both the CP and AP C5-cleaving enzymes.C3b is further cleaved to iC3b by factor I (FI) in the presence of factor H (FH), CR1, or membrane cofactor protein. FI cleavage of C3b to iC3b inactivates and prevents C3b from functioning in the C3 or C5 convertase enzymes. Further cleavage of iC3b by FI in the presence of CR1 results in the formation of C3c. When C3b ...

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N-chlorotaurine (NCT), the main representative of long-lived oxidants produced by granulocytes and monocytes, is known to exert broad-spectrum microbicidal activity. Here we show that NCT directly inactivates Shiga toxin 2 (Stx2), used as a model toxin secreted by enterohemorrhagic Escherichia coli (EHEC). Bacterial growth and Stx2 production were both inhibited by 2 mM NCT. The cytotoxic effect of Stx2 on Vero cells was removed by ≥5.5 mM NCT. Confocal microscopy and FACS analyses showed that the binding of Stx2 to human kidney glomerular endothelial cells was inhibited, and no NCT-treated Stx2 entered the cytosol. Mass spectrometry displayed oxidation of thio groups and aromatic amino acids of Stx2 by NCT. Therefore, long-lived oxidants may act as powerful tools of innate immunity against soluble virulence factors of pathogens. Moreover, inactivation of virulence factors may contribute to therapeutic success of NCT and novel analogs, which are in development as topical antiinfectives.