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These results indicated that estimated cholesterol levels in the large LDL subfraction were not associated with an increased risk of IHD in men and that the cardiovascular risk attributable to variations in the LDL size phenotype was largely related to markers of a preferential accumulation of small dense LDL particles.

Background-Several cross-sectional studies and 3 prospective, nested, case-control studies have indicated that individuals with small, dense low density lipoprotein (LDL) particles are at increased risk for ischemic heart disease (IHD). However, whether LDL particle size is an independent risk factor for future IHD events remains controversial. The objective of the present study was to further analyze the cardiovascular risk associated with various electrophoretic characteristics of LDL particles in men. Methods and Results-LDL particles were characterized by polyacrylamide gradient gel electrophoresis (PAGGE) in a cohort of 2034 men of the Quebec Cardiovascular Study. All men were initially free of IHD and were followed up for a period of 5 years, during which 108 first IHD events were recorded. Among all LDL characteristics investigated by PAGGE, including LDL peak particle size, the cholesterol concentration in LDL particles with a diameter smaller than 255 Å showed the strongest association with the risk of IHD (relative riskϭ4.6 in men in the third vs first tertile of the distribution, PϽ0.001). Multivariate logistic and survival models indicated that the relationship between LDL cholesterol levels in particles with a diameter Ͻ255 Å and IHD risk was independent of all nonlipid risk factors and of LDL cholesterol, high density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels. Conclusions-Results from this large, population-based, prospective study suggest that further characterization of LDL particles by PAGGE, in addition to the traditional lipid profile, may improve our ability to predict IHD events in men.

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Synthetic peptide immunogens that mimic the conformation of a target epitope of pathological relevance offer the possibility to precisely control the immune response specificity. Here, we performed conformational analyses using a panel of peptides in order to investigate the key parameters controlling their conformation upon integration into liposomal bilayers. These revealed that the peptide lipidation pattern, the lipid anchor chain length, and the liposome surface charge all significantly alter peptide conformation. Peptide aggregation could also be mod- The role of immunogen conformation in the specificity and efficacy of the humoral immune response has been recognized in a number of recent therapeutic and prophylactic vaccines (1-4). Conformation-specific antibodies generated by immunization with conformationally restricted immunogens are also important tools for disease diagnosis as biochemical probes for establishing protein structure-function relationships (5, 6) and in affinity purification (7,8). Development of such peptide immunogens, however, has thus far been hindered by the lack of general design strategies to control the conformation of a given peptide sequence. In addition, most naked peptides have low inherent immunogenicity. Although design of peptide templates for the generation of antibodies that selectively recognize protein epitopes with an ␣-helical conformation has been reported (2, 4, 9, 10), general strategies to design short peptide fragments as immunogens for targeting other protein conformations are lacking.Protein aggregation resulting from aberrant folding is characterized by the formation of proteinaceous deposits called amyloid, which exhibit ␤-sheet structure (11). Misfolding is now associated with over 20 human diseases, including Creutzfeldt-Jakob disease, Alzheimer disease (AD), 2 Huntington disease, and Type II diabetes mellitus (12). Vaccines that can elicit antibodies against only the pathological ␤-sheet multimers of these targets would thus be considered advantageous from an efficacy perspective but also particularly from a safety perspective, where the non-folded protein has physiological relevance. In AD, ␤-amyloid peptides (A␤) A␤(1-40) and A␤(1-42) have been associated with disease progression over several decades of research, and the ␤-sheet aggregates of A␤ are one of the major pathological hallmarks of AD (13). Although the molecular pathology of AD has not yet been elucidated, a large variety of soluble and insoluble ␤-sheet A␤(1-40/42) oligomers with different degrees of polymerization have been identified in vitro or in AD brain as synaptotoxic and likely causal agents of cognitive impairment (14 -18).The discovery that active vaccination of transgenic mice overexpressing human amyloid precursor protein (APP) with A␤-derived peptides could be an effective means to modify disease progression has opened up new vistas in AD therapy (19 -21). The importance of immunogen aggregation state upon immune response specificity has been demonstrated by the generation of an...

The aim of the present study was to evaluate the relation among alcohol consumption, the metabolic syndrome, and the risk of ischemic heart disease (IHD). The study was conducted in a cohort of 1966 men from the Quebec Cardiovascular Study. All men were initially free of IHD and, during the follow-up period of 13 y, 219 first cases of IHD were diagnosed. Alcohol consumption was determined by calculating the g/d intake based on standard portions of beer, wine, and spirits. Metabolic syndrome was diagnosed according to a modification of the National Cholesterol Education Program Adult Treatment Panel III definition. Men who consumed >or=15.2 g of alcohol/d (4th quartile of the distribution) were younger (P < 0.001), had elevated plasma HDL-C concentrations (P < 0.001), and lower plasma concentrations of insulin (P = 0.01), CRP (P = 0.01), and fibrinogen (P < 0.001) than men in the 1st quartile (<1.3 g of alcohol/d). After adjustment for a series of coronary risk factors, alcohol consumption >or=15.2 g/d was associated with a 39% reduction in the 13-y risk of IHD [relative risk (RR) of IHD = 0.61, P = 0.02]. Finally, an alcohol consumption <15.2 g/d was associated with an increase of the risk of IHD in men with the metabolic syndrome (RR = 2.24, P < 0.001) but not in men without the metabolic syndrome (RR = 1.31, P = 0.22). These results confirm that moderate daily alcohol consumption has cardioprotective properties and suggest that the effects may be more important in subjects with a deteriorated risk profile, such as those with the metabolic syndrome.

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