http://repub.eur.nl/res/aut/39195/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/31931/ 2012-01-01T00:00:00Z Highly pathogenic avian influenza virus (HPAIV) H5N1 can infect mammals via the intestine; this is unusual since influenza viruses typically infect mammals via the respiratory tract. The dissemination of HPAIV H5N1 following intestinal entry and associated pathogenesis are largely unknown. To assess the route of spread of HPAIV H5N1 to other organs and to determine its associated pathogenesis, we inoculated infected chicken liver homogenate directly into the intestine of cats by use of entericcoated capsules. Intestinal inoculation of HPAIV H5N1 resulted in fatal systemic disease. The spread of HPAIV H5N1 from the lumen of the intestine to other organs took place via the blood and lymphatic vascular systems but not via neuronal transmission. Remarkably, the systemic spread of the virus via the vascular system was associated with massive infection of endothelial and lymphendothelial cells, resulting in widespread hemorrhages. This is unique for influenza in mammals and resembles the pathogenesis of HPAIV infection in terrestrial poultry. It contrasts with the pathogenesis of systemic disease from the same virus following entry via the respiratory tract, where lesions are characterized mainly by necrosis and inflammation and are associated with the presence of influenza virus antigen in parenchymal, not endothelial cells. The marked endotheliotropism of the virus following intestinal inoculation indicates that the pathogenesis of systemic influenza virus infection in mammals may differ according to the portal of entry. © 2012, American Society for Microbiology. http://repub.eur.nl/res/pub/27798/ 2010-05-03T00:00:00Z Background: Lipoprotein-associated phospholipase A2(Lp-PLA2), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA2mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. Methods: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA2or other risk factor. The primary outcome was coronary heart disease. Findings: Lp-PLA2activity and mass were associated with each other (r=0·51, 95% CI 0·47-0·56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA2activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1·10 (95% CI 1·05-1·16) with Lp-PLA2activity and 1·11 (1·07-1·16) with Lp-PLA2mass for coronary heart disease; 1·08 (0·97-1·20) and 1·14 (1·02-1·27) for ischaemic stroke; 1·16 (1·09-1·24) and 1·13 (1·05-1·22) for vascular mortality; and 1·10 (1·04-1·17) and 1·10 (1·03-1·18) for non-vascular mortality, respectively. RRs with Lp-PLA2did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA2mass. Adjusted RRs for coronary heart disease were 1·10 (1·02-1·18) with non-HDL cholesterol and 1·10 (1·00-1·21) with systolic blood pressure. Interpretation: Lp-PLA2activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA2mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. Funding: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.