Objective— An increased mean platelet volume (MPV), as an indicator of larger, more reactive platelets resulting from an increased platelet turnover, may represent a risk factor for overall vascular mortality, including myocardial infarction. We intended to identify patients at higher risk of dying from vascular disease in a large, hospital-based cohort. Methods and Results— A total of 206 554 first-ever admissions to the Allgemeines Krankenhaus Wien for determination of MPV between January 1996 and July 2003 were included. Primary end points were overall vascular mortality and death due to ischemic heart disease. Multivariate Cox regression adjusted for sex, age, and platelet count was applied for analysis. MPV values were categorized into quintiles, with the lowest quintile serving as the reference category. Compared with individuals with lower MPV (<8.7 fL), hazard ratios for overall vascular mortality gradually increased to 1.5 in the highest category (≥11.01 fL). The relationship of MPV to ischemic heart disease was even stronger and increased from 1.2 (8.71 to 9.60 fL category) to 1.8 in the highest category (≥11.01 fL). Conclusion— Our results indicate that patients with an increased MPV (≥11.01 fL) are at higher risk of death due to ischemic heart disease, with hazard ratios comparable to those reported for obesity or smoking.

Background: Increased gamma glutamyltransferase (GGT) is associated with cardiovascular disease. To date, however, few studies with sufficient sample size and follow-up have investigated the association of GGT with all-cause mortality. Methods: The relation of GGT to the risk of death was examined in a cohort of 283 438 first attendants (inpatients or outpatients) of the Vienna General Hospital with request for GGT analysis as part of a routine screening panel and was monitored for up to 13 years. To evaluate GGT as a predictor, Cox proportional hazards models were calculated, which were adjusted for age and sex. Results: In both men and women, GGT above the reference category (GGT >9 U/L in women, >14 U/L in men) was significantly (P <0.001) associated with allcause, cancer, hepatobiliary, and vascular mortalities. Hazard ratios (HRs) for men and women were similar in all categories. Among patients who presented with GGT above the reference category, those younger than 30 years had higher all-cause mortality rates than did older individuals (HR 1.5-3.3 vs HR 1-1.3 >80 years, respectively). Conclusions: GGT is associated with mortality in both men and women, especially in patients younger than 30 years, and even high-normal GGT is a risk factor for all-cause mortality.

Data show that carbon monoxide (CO) exerts direct antiinflammatory effects in vitro and in vivo after LPS challenge in a mouse model. We hypothesized that CO may act as an antiinflammatory agent in human endotoxemia. The aim of this trial was to study the effects of CO inhalation on cytokine production during experimental human endotoxemia. The main study was a randomized, double-blinded, placebo-controlled, two-way cross-over trial in healthy volunteers. Each volunteer inhaled synthetic air (as placebo) and 500 ppm CO for 1 hour in random order with a washout period of 6 weeks and received a 2-ng/kg intravenous bolus of LPS after inhalation. Carboxyhemoglobin levels were assessed as a safety parameter. CO inhalation increased carboxyhemoglobin levels from 1.2% (95% confidence interval, 1.0 to 1.4%) to peak values of 7.0% (95% confidence interval, 6.5 to 7.7%). LPS infusion transiently increased plasma concentrations of tumor necrosis factor-alpha, interleukin (IL)-6 (approximately 150-fold increases), and IL-8, as well as IL-1alpha and IL-1beta mRNA levels (an approximately 200-fold increase). These LPS-induced changes were not influenced by CO inhalation. Inhalation of 500 ppm CO for 1 hour had no antiinflammatory effects in a systemic inflammation model in humans, as 250 ppm for 1 hour did in rodents.

Summary. Introduction:The clinical relevance of decreased coagulation factor XII (FXII) plasma activity as a risk factor for both venous and arterial thrombosis is still discussed controversially. The current study evaluated the predictive value of FXII levels for all-cause mortality in a large Viennese patient cohort. Patients and methods: Individuals, whose FXII activity levels were determined for suspected coagulation disorders or thrombophilia screening between 1991-2003 were included in this study (n = 8936, 51% male, 49% female, median age 43 years). Death/survival was determined by record linkage with the Austrian Death Registry. The median observation period was 5 years covering a total of 46 400 person years; the death rate was 17.1%. For Cox regression analysis, FXII plasma activity was divided into 11 categories of 10% steps with the category of > 100% FXII serving as a reference category. Results: With decreasing FXII plasma activity, hazard ratios for all-cause mortality gradually increased linearly from 1.0 in the > 100% category to 1.5 (95% CI: 1.2-1.9) in the 80-90% category to 4.7 (95% CI: 3.4-6.5) in the 10-20% category. Similar results were obtained, when only vascular mortality or death as a result of ischemic heart disease was considered. No significant increase in all-cause mortality (HR: 1.4, 95%CI 0.7-2.8) was observed in the small group of FXII-deficient subjects [0-10% category (n = 58)]. Conclusions: This study first demonstrates a strong and almost linear association of FXII plasma activity between 90% and 10% with all-cause mortality in a large Viennese patient cohort. Interestingly, mortality rates are not increased when FXII activity is below 10%, resulting in a U-shaped survival curve.

Objective-Oxidized phospholipids (OxPLs) that are abundant in atherosclerotic lesions are increasingly recognized as context-dependent lipid mediators demonstrating both pro-and antiinflammatory activities. Molecular mechanisms of their effects are largely unknown. Here we present novel information on the mechanisms whereby OxPLs modulate activation of TLR4 by lipopolysaccharide (LPS). Methods and Results-We show, using several cell types and various inflammatory genes as readouts, that different classes and molecular species of OxPLs do not stimulate TLR4 but exert prominent inhibitory effects on LPS-induced reactions. Our data demonstrate that binding of OxPLs to the LPS-binding protein (LBP) and CD14 prevents recognition of LPS by these proteins, thus impairing activation of TLR4. In addition, OxPLs inhibited LBP-and CD14-independent activation of TLR4 by the synthetic TLR4 agonist E6020 indicating that in parallel with LBP and CD14, OxPLs target cell-associated steps in TLR4 cascade. Conclusions-Our data suggest that OxPLs inhibit action of LPS via a multi-hit mechanism. These results support the notion that OxPLs are endogenous inhibitors of TLR4 produced in response to oxidative stress. O xidized phospholipids (OxPLs) are generated as a result of oxidation of esterified polyunsaturated fatty acids (PUFAs). Oxidized phosphatidylcholines (OxPCs) were identified as proinflammatory components of LDL minimally modified by oxidation (mmLDL) and are increasingly recognized as lipid mediators with a broad spectrum of activities. Apart from OxPCs, oxidation of other classes of PUFA-PLs generates biologically active products that were detected in a number of pathologies including ischemia/reperfusion, radiation injury, cell aging, and apoptosis. [1][2][3][4] OxPCs are especially abundant in human and animal atherosclerotic lesions 5-7 where they are thought to induce inflammatory See accompanying article on page 337 reactions characteristic of atherosclerosis. In particular, OxPCs initiate mononuclear cell recruitment by inducing activation of adhesion molecules and production of MCP-1, IL-8, and other chemokines by endothelial cells (ECs). 8 On the other hand, oxidized LDL and OxPLs demonstrate tissueprotective and antiinflammatory activities including upregulation of antioxidant enzymes or inhibition of inflammation induced by bacterial lipopolysaccharide (LPS, endotoxin) via TLR4. 9,10 The mechanisms of the antiendotoxin effects of OxPLs are only partially understood. In particular, it is not clear which chemical groups are important for the antiendotoxin activity of OxPLs and whether there are strict structural constraints for the activity. Furthermore, the data showing that certain effects of OxPLs are inhibited in TLR4 knockout animals 11,12,13 suggest that OxPLs are not pure inhibitors/antagonists of TLR4 but may possess partial agonistic activity for TLR4. Last but not least, an important open question concerns the molecular targets of the antiendotoxin action of OxPLs. According to one hypothesis, OxPLs ...