T his review will reconsider the current paradigm for understanding the critical, final steps in the progression of atherosclerotic lesions. That scheme, largely an outgrowth of observations of autopsy tissues by Davies and colleagues, 1,2 asserts that the cause of death in atherosclerotic coronary artery disease is rupture of an advanced atherosclerotic lesion. Although this assumption may be partially true, recent autopsy studies suggest that it is incomplete. See p 1177To reconsider this paradigm, we reexamined the morphological classification scheme for lesions proposed by the American Heart Association (AHA). 3,4 This scheme is difficult to use for 2 reasons. First, it uses a very long list of roman numerals modified by letter codes that are difficult to remember. Second, it implies an orderly, linear pattern of lesion progression. This tends to be ambiguous, because it is not clear whether there is a single sequence of events during the progression of all lesions. We have therefore tried to devise a simpler classification scheme that is consistent with the AHA categories but is easier to use, able to deal with a wide array of morphological variations, and not overly burdened by mechanistic implications. The Current ParadigmThe current paradigm is based on the belief that type IV lesions, or "atheromas," described by the AHA are stable because the fatty, necrotic core is contained by a smooth muscle cell-rich fibrous cap. Virchow's analysis 5 in 1858 pointed out that historically, the term "atheroma" refers to a dermal cyst ("Grützbalg"), a fatty mass encapsulated within a cap. Extending Virchow's argument, the fibrous cap over the lipid mass of an atherosclerotic plaque is analogous to the capsule containing an abscess, and like an abscess, the plaque can be ruptured. Rupture of the fibrous cap exposes thrombogenic material, initiating platelet aggregation and coagulation in the infiltrating and overlying blood. These thrombotic changes result from activation of the clotting cascade by tissue factor, and further propagation of the thrombosis results from the interaction of platelets with the active thrombogenic matrix. 6 Platelet activation and thrombin formation combined with the evulsion of thrombogenic plaque contents into the lumen then result in sudden occlusion. 7 This widely held concept of atherosclerotic death is based on morphological data from autopsies as well as clinical angiographic studies, in which the presence of surface irregularities has been interpreted as plaque rupture. 8 -10 Previous pathological studies of sudden coronary death have demonstrated evidence of plaque rupture associated with thrombosis in 73% of cases. 2 Of the remaining cases, 8% consist of plaque fissure with intraplaque fibrin deposition and hemorrhage, while 19% show no evidence of thrombi. 2 Consequently, recent reviews of atherosclerosis have uniformly accepted plaque rupture as the critical event leading to coronary artery death. 6

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5m genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N≤71,225 European ancestry, N=12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N=29,136). We identified association between systolic or diastolic blood pressure and common variants in 8 regions near the CYP17A1 (P=7×10−24), CYP1A2 (P=1×10−23), FGF5 (P=1×10−21), SH2B3 (P=3×10−18), MTHFR (P=2×10−13), c10orf107 (P=1×10−9), ZNF652 (P=5×10−9) and PLCD3 (P=1×10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Early detection represents one of the most promising approaches to reducing the growing cancer burden. It already has a key role in the management of cervical and breast cancer, and is likely to become more important in the control of colorectal, prostate and lung cancer. Early-detection research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the level of the genome or proteome, but how can we harness these new technologies to develop effective and practical screening tests?

Tissue factor (TF)-producing cells were identified in normal human vessels and atherosclerotic plaques by in situ hybridization and immunohistochemistry using a specific riboprobe for TF mRNA and a polyclonal antibody directed against human TF protein. TF mRNA and protein were absent from endothelial cells lining normal internal mammary artery and saphenous vein samples. In normal vessels TF was found to be synthesized in scattered cells present in the tunica media as well as fibroblast-like adventitial cells surrounding vessels. Atherosclerotic plaques contained many cells synthesizing TF mRNA and protein. Macrophages present as foam cells and monocytes adjacent to the cholesterol clefts contained TF mRNA and protein, as did mesenchymalappearing intimal cells. Significant TF protein staining was found deposited in the extracellular matrix surrounding mRNA-positive cells adjacent to the cholesterol clefts and within the necrotic cores. These results suggest that deposition of TF protein in the matrix of the necrotic core of the atherosclerotic plaque may contribute to the hyperthrombotic state of human atherosclerotic vessels.

BACKGROUNDThe incidence of anal cancer has increased among both men (160%) and women (78%) from 1973 to 2000 in the U.S. The authors conducted a population‐based case–control study of anal cancer to examine factors that may account for this increase.METHODSMen (n = 119 patients) and women (n = 187 patients) who were diagnosed with anal cancer between 1986 and 1998 in the Seattle area were ascertained through the local Surveillance, Epidemiology, and End Results registry. Control participants (n = 1700) were ascertained through random‐digit telephone dialing. Participants were interviewed in person and provided blood samples. Archival tumor tissue was tested for human papilloma virus (HPV) DNA, and serum samples were tested for HPV type 16 (HPV‐16).RESULTSOverall, 88% of tumors (all histologies) in the study were found to be positive for HPV. HPV‐16 was the most frequent HPV type detected (73% of all tumors), followed by HPV‐18 (6.9%), regardless of gender. However, 97.7% of tumors from men who were not exclusively heterosexual contained HPV DNA. The risk of anal cancer increased among men (odds ratio [OR], 5.3; 95% confidence interval [95% CI], 2.4–12.0) and women (OR, 11.0; 95% CI, 5.5–22.1) who had ≥ 15 sexual partners during their lifetime. Among men who were not exclusively heterosexual and women, receptive anal intercourse was related strongly to the risk of anal cancer (OR, 6.8 [95% CI, 1.4–33.8] and OR, 2.2 [95% CI, 1.4–3.3], respectively). Current smokers among men and women were at particularly high risk for anal cancer, independent of age and other risk factors (OR, 3.9 [95% CI, 1.9–8.0] and OR, 3.8 [95% CI, 2.4–6.2], respectively).CONCLUSIONSThe high proportion of tumors with detectable HPV suggests that infection with HPV is a necessary cause of anal cancer, similar to that of cervical cancer. Increases in the prevalence of exposures, such as cigarette smoking, anal intercourse, HPV infection, and the number of lifetime sexual partners, may account for the increasing incidence of anal cancer in men and women. Cancer 2004. © 2004 American Cancer Society.

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The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.

Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).