BACKGROUND:Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events.METHODS:A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles.RESULTS:Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile.CONCLUSIONS:Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.

Background: Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events.Methods: A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A(2), C-reactive protein, and fibrinogen levels and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles.Results: Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A(2) (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile.Conclusions: Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A(2) appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk. (N Engl J Med 2000;343:1148-55.) (C) 2000 Massachusetts Medical Society.

Genomics is the study of all the genes in an organism, including their sequence, structure, regulation, interaction and products. Because nearly all diseases have a genetic component, genomics is an important tool for diagnostic medicine, both traditional biochemical testing as well as genetic testing, cDNA/expression (genomic) databases and bioinformatics have emerged as valuable tools within genomic research. These tools have already aided in the discovery of genes related to colorectal cancer, atherosclerosis, osteoporosis and a variety of other diseases. Gene sequence information yields insight into the identity and function of unknown genes, while comparison of gene expression patterns among normal and diseased tissues helps define the role of specific genes in a disease. The concomitant development of new gene analysis technologies, such as DNA arrays for rapid screening of multiple genes, is enhancing the discovery and evaluation of potential diagnostic markers. These technologies allow multiple diagnostic leads to be evaluated at once, thus achieving an economy of scale, as well as allow analysis of complex gene interactions. Several challenges exist for genomics in the area of diagnostics, including the discovery and analysis of low level expression genes and the development of versatile genetic testing instrumentation. As these challenges are overcome, the impact of genomics on diagnostic medicine will increase.

The interaction of genes underpins all physiological processes, in health as well as disease. Diagnostic medicine, which functions to aid in the evaluation of an individual's health, will benefit significantly from genomic research. Genomic databases and bioinformatics are emerging as valuable tools for the discovery of genotypic and phenotypic diagnostic markers. These tools have already led to the discovery of genes related to colorectal cancer, atherosclerosis, osteoporosis, and a variety of other diseases. Gene sequence information yields insight into the identity and function of unknown genes, while comparison of gene expression patterns among normal and diseased tissues helps define the role of specific genes in a disease. The concomitant development of genomic technologies, such as DNA arrays for rapid analysis of multiple genes, are enhancing the discovery and evaluation of potential diagnostic markers. These technologies allow multiple diagnostic leads to be evaluated at once, to achieve an economy of scale as well as allow analysis of complex gene interactions. There are several challenges for genomics in the area of diagnostics, including the discovery and analysis of low‐level expression genes and the development of versatile genetic testing instrumentation. As these challenges are overcome, the impact of genomics on diagnostic medicine will escalate. Drug Dev. Res. 41:193–204, 1997. © 1997 Wiley‐Liss, Inc.

Diacylglycerol contents ofexcised soybean (Glycine maxL.) hypocotyl segments, incubated for4hoursinthepresence or absenceofa growth promoting concentration of2,4-dichloro- phenoxyacetic acid(2,4-D) weremonitored bythreedifferent methods asasensitive measureoftheaction invivoofC-type phospholipases. Byallthreemethods, steadystatelevels of diacylglycerols representing about3%ofthetotal lipids orabout 7%oftheneutral lipids, depending onmethodofassay, declined 18%over4hoursofincubation asdetermined byextraction of total lipids andanalysis bythinlayer chromatography andden- sitometry. Theaverage decline with2,4-D-treated segments was lessbutthedifference fromcontrols wasnotsignificant. Inthose experiments whereasmall effect of2,4-D wasnoted, thefraction showing anelevated diacylglycerol level inresponse to2,4-D, after separation intomembrane andsupematant fractions, was thesupernatant andnotthemembranes. Results wereconfirmed fromanalyses oftotal fatty acidsineachofthemajorlipid fractions andfromdiacylglycerol assays byconversion into phos- phatidic aciduponincubation with(-y-32P)ATP andpurified di- acylglycerol phosphokinase fromEscherichia coli. Inthepres- enceof2,4-D, thediacylglycerol content ofthemembranes was unchanged compared tomembranes fromcontrol segments. As withthedensitometric method, thesmall 2,4-D induced increase indiacylglycerols, whenobserved, wasinsignificant andinthe supernatant. Theonlymembrane-associated lipid fraction con- sistently showing aresponse to2,4-D wasthefraction containing sterols esterified withfatty acids. Either total microsomes or purified plasma membranes whenincubated for10to20minutes with1micromolar 2,4-D showednoaccelerated formation of diacylglycerols compared tomembranesnotincubated. The results donotsupport operation during auxingrowth ofthe animal paradigm wherediacylglycerol activation ofC-type protein kinases occurs inresponse toactivated phospholipase Cbreak- downofphosphoinositides. ofphospholipase action, thediacylglycerols, isusually present only inlowlevels inbiological membranes. Increases insteady state levels ofdiacylglycerols inresponse toaparticular effec- tormight notonlysignal thepossible insitu involvement of aphospholipase intheresponse cascade butmaybeimportant asregulators ofother enzymeactivities. Inmammalian cells, protein kinases oftheC typeareactivated specifically by certain phospholipids anddiacylglycerols incombination (16). Inthis study, steady state levels ofdiacylglycerols inauxin- treated hypocotyl segments werecompared tolevels present insegments incubated without auxin. Membrane diacylglyc- erols werelargely unaltered with2,4-D treatment. Therefore, steady state stimulation ofelongation growth ofsoybean hypocotyls isnotreadily explicable intermsofthesignal- response paradigm involving phospholipid metabolism and diacylglycerol activation ofmembrane-associated C-type pro- tein kinases.