Cardiovascular disease after menopause: a growing epidemic.

Coronary heart disease (CHD) remains the major cause of mortality in women after menopause. At the time of menopause risk factors change to increase the risk of CHD. Although hormone replacement therapy improves some of these risk factors, no overall cardiovascular benefit has been noted with this therapy. There are parallel twin epidemics occurring in postmenopausal women, one being cardiovascular disease and the other metabolic syndrome, in which there appears to be a connection. Metabolic risk factors such as elevated triglyceride levels, decreased HDL-cholesterol levels and glucose abnormalities have been suggested to portend a greater CHD risk in women than men. Also the inflammatory marker, C reactive protein, appears to modify risk at all levels of the metabolic syndrome. Further studies are needed to determine the best strategy to confront the epidemic of cardiovascular morbidity and mortality in the postmenopausal population.

Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

BACKGROUND: The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is the first primary-prevention study in a cohort with average total cholesterol (TC) and LDL cholesterol (LDL-C) and below-average HDL cholesterol (HDL-C). Treatment with lovastatin (20 to 40 mg/d) resulted in a 25% reduction in LDL-C and a 6% increase in HDL-C, as well as a 37% reduction in risk for first acute major coronary event (AMCE), defined as fatal or nonfatal myocardial infarction, unstable angina, or sudden cardiac death. This article describes the relation between baseline and on-treatment lipid and apolipoprotein (apo) parameters and subsequent risk for AMCEs. METHODS AND RESULTS: With all available data from the entire 6605-patient cohort, a prespecified Cox backward stepwise regression model identified outcome predictors, and logistic regression models examined the relation between lipid variables and AMCE risk. Baseline LDL-C, HDL-C, and apoB were significant predictors of AMCE; only on-treatment apoB and the ratio of apoB to apoAI were predictive of subsequent risk; on-treatment LDL-C was not. When event rates were examined across tertiles of baseline lipids, a consistent benefit of treatment with lovastatin was observed. CONCLUSIONS: Persons with average TC and LDL-C levels and below-average HDL-C may obtain significant clinical benefit from primary-prevention lipid modification. On-treatment apoB, especially when combined with apoAI to form the apoB/AI ratio, may be a more accurate predictor than LDL-C of risk for first AMCE.

Plasma lipids and cholesterol esterification in Alzheimer's disease.

Eight patients and eight age matched controls were recruited to study parameters related to plasma lipoprotein metabolism in Alzheimer's disease based on previous studies in Down's syndrome (A.G. Lacko et al., Clin. Chim. Acta, 132 (1983) 133). The fractional rate of cholesterol esterification (% cholesterol esterified per hour) was 16% lower in the patient group compared with controls. Correlational analyses of lecithin/cholesterol acyltransferase (LCAT) activity and plasma lipids revealed additional differences between the Alzheimer's patients and control subjects. These data are strikingly similar to those obtained earlier with Down's syndrome patients. These data, combined with analyses of cholesteryl ester transfer protein (CETP) levels, suggest that reverse cholesterol transport in general and CETP activity in particular may be altered in Alzheimer's disease.

Design & rationale of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS).

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) is a randomized, double-blind, placebo-controlled primary prevention trial. It is designed to test the hypothesis that in addition to a lipid-lowering diet, treatment with lovastatin is more effective than placebo in reducing acute major coronary events (i.e., sudden cardiac death, fatal and nonfatal myocardial infarction, and unstable angina) in a cohort with normal to mildly elevated total (180 to 264 mg/dl) and low-density lipoprotein (LDL) cholesterol (130 to 190 mg/dl) and low high-density lipoprotein (HDL) cholesterol (< or =45 mg/dl for men and < or =47 mg/dl for women). Two sites in Texas, Lackland Air Force Base in San Antonio and the University of North Texas Health Science Center in Fort Worth, will conduct the study. After at least 12 weeks of an American Heart Association Step 1 diet and 2 weeks placebo run-in, 6,605 men and women, ages 45 to 73 and 55 to 73 years, respectively, without clinical evidence of coronary heart disease, are randomized in equal numbers to either lovastatin (20 mg/day) or placebo. Study procedures maintain the blind, allowing titration of lovastatin from 20 to 40 mg/day to achieve an LDL cholesterol goal of < or = 110 mg/dl. All participants are followed until study completion, when 320 participants have had a primary end point or a minimum of 5 years after the last participant is randomized, whichever occurs last. All end points are adjudicated by an independent committee using prespecified criteria. Unique features of this trial are (1) the inclusion of unstable angina in the primary end point to reflect the increasing trend to treat coronary heart disease aggressively before a myocardial infarction has occurred, (2) aggressive pharmacologic intervention, with titration, to attain an LDL cholesterol goal less than the current National Cholesterol Education Panel guidelines for primary prevention, and (3) a cohort that includes women, the elderly, and those with mild to moderate hyperlipidemia and low HDL cholesterol. Compared with earlier studies, results will be applicable to a broader population and may help clarify the role of aggressive LDL cholesterol reduction measures in primary prevention. Treatment of this population is likely to realize the greatest cumulative long-term benefit in the prevention of acute major coronary events.

Effect of lovastatin on cardiovascular resource utilization and costs in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). AFCAPS/TexCAPS Research Group.

This cost-consequences analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study compares the costs of lovastatin treatment with the costs of cardiovascular hospitalizations and procedures. The cost of lovastatin treatment was defined as the average retail price and the cost of drug safety monitoring and adverse experiences. Costs were determined by actual rates of hospitalizations and procedures. Within a trial, lovastatin treatment cost approximately $4,654/patient. Lovastatin treatment significantly reduced the cumulative rate of cardiovascular hospitalizations and procedures (p = 0.002). Over the duration of the study, the cumulative number of cardiovascular hospitalizations and related therapeutic procedures was significantly reduced by 29%. The time to first cardiovascular-related hospitalization or procedure was significantly extended by lovastatin (p = 0.002). Lovastatin reduced the frequency of cardiovascular hospitalization (28%), and cardiovascular therapeutic (32%) and diagnostic procedures (23%). Among therapeutic procedures, treatment reduced coronary artery bypass graft surgery by 19% and percutaneous transluminal coronary angioplasty by 37%. Total cardiovascular-related hospital days were reduced by 26% (p = 0.025). The between-group offset in direct medical costs was $524, which resulted in a 11% cost offset of lovastatin therapy over the mean study duration of 5.2 years. Lovastatin provides meaningful reductions in cardiovascular-related resource utilization and reductions in direct cardiovascular-related costs associated with the onset of coronary disease.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS): additional perspectives on tolerability of long-term treatment with lovastatin.

This study presents the long-term safety data from AFCAPS/TexCAPS, the first primary prevention trial to demonstrate that men and women with average levels of low-density lipoprotein cholesterol (LDL-C) and below average levels of high-density lipoprotein cholesterol (HDL-C) can significantly benefit from long-term treatment to lower LDL-C; lovastatin 20 to 40 mg/day reduced the risk of a first acute major coronary event (fatal or nonfatal myocardial infarction, unstable angina, or sudden death) by 37% (p = 0.00008). This double-blind randomized, placebo-controlled trial, in 6,605 generally healthy middle-aged and older men and women, had prespecified end point and cancer analyses. All analyses were intention-to-treat. Safety monitoring included history, physical examination, and laboratory studies (including hepatic transaminases and creatine phosphokinase [CPK]). All participants, even those who discontinued treatment, were contacted annually for vital status, cardiovascular events, and cancer history. After an average of 5.2 years of follow-up, there were 157 deaths (80 receiving lovastatin and 77 receiving placebo; relative risk [RR] 1.04; 95% confidence interval [CI] 0.76 to 1.42; p = 0.82); of which 115 were noncardiovascular (RR 1.21; CI 0.84 to 1.74; p = 0.31), and of these, 82 were due to cancer (RR 1.41; CI 0.91 to 2.19; p = 0.13). There were no significant differences between treatment groups in overall cancer rates, discontinuations for noncardiovascular adverse experiences, or clinically important elevations of hepatic transaminases or CPK. Among those who used cytochrome P450 isoform (CYP3A4) inhibitors, there were no treatment group differences in the frequency of clinically important muscle-related adverse events. Treatment with lovastatin 20 to 40 mg daily for primary prevention of coronary heart disease was well tolerated and reduced the risk of first acute coronary events without increasing the risk of either noncardiovascular mortality or cancer.

Effect of butylated hydroxyanisole on in vivo and in vitro hepatic aflatoxin B1-DNA binding in rats.

Butylated hydroxyanisole (BHA) pretreatment of male rats has been examined for its effect on in vivo and in vitro hepatic aflatoxin B1-DNA binding (AFB1-DNA) in these animals. No difference either in cytochrome P-450 content or microsome-mediated AFB1-DNA was observed between livers from control and treated rats. However, cytosols from treated animals showed severalfold more inhibition of microsome mediated AFB1 binding to either exogenous or endogenous DNA than cytosols from controls. Presence of 1 mM level of either trichloropropene oxide or styrene oxide partially reversed the cytosolic inhibition of binding. Intraperitoneal administration of AFB1 2h before killing produced 50% less AFB1 binding to nuclear DNA in treated than in control animals. The role of induced glutathione S-transferases in treated rats in modulating hepatic AFB1-DNA binding is discussed.

Antibody inhibition of oxidative activation and inactivation of the carcinogen 2-acetylaminofluorene by purified hepatic cytochrome P-450 from 3-methylcholanthrene pretreated rats.

Immunochemical studies on metabolic N- and ring hydroxylation of 2-acetylaminofluorene (AAF) were performed with total cytochrome P-450 isozymes and with highly purified P-450 D isozyme isolated from liver microsomes from 3-methylcholanthrene (MC)-pretreated rats. In a reconstituted system with rat P-450 D, addition of antibodies against beta-naphthoflavone (BNF) induced rat P-450 B at 15 mg IgG/nmol P-450 inhibited both oxidations completely. With total P-450 isozymes in a reconstituted system, antibody against BNF-rat-P-450 B at 20 mg IgG/nmol P-450 inhibited both oxidations up to 70-80% only. At these concentrations, preimmune antibody or phenobarbital (PB) induced antibody against rat-P-450 B showed no inhibition of AAF oxidations. These results suggest that P-450 D is the predominant cytochrome P-450 isozyme responsible for AAF N- and ring-oxidations in liver microsomes from MC-pretreated rats. Other P-450 isozymes are also suggested to be involved in AAF oxidations.

Oxidative activation and inactivation of the carcinogen 2-acetylaminofluorene by various purified cytochromes P-450 from 3-methylcholanthrene pretreated rats.

Ring- and N-hydroxylations of 2-acetylaminofluorene (AAF) have been examined in a reconstituted system with 4 purified hepatic microsomal cytochromes P-450 isolated from 3-methylcholanthrene (MC)-pretreated rats. Among these 4 isozymes, P-450D showed the most activity whereas P-450C was devoid of any activity; two other P-450s exhibited moderate activity. These and Ouchterlony's double diffusion analyses suggest involvement of multiple cytochromes P-450 in AAF oxidations.

Long-term therapy of coronary artery disease: a vascular biology perspective.

When evaluating a patient with known coronary artery disease or a patient with hypercholesterolemia without overt clinical symptoms of coronary artery disease or other vascular disease, it is helpful to understand the vascular biology behind primary and secondary prevention. This article reviews the progression of the atherosclerotic plaque, endothelial function, and the impact of current modes of therapy.

Comparing medical knowledge of osteopathic medical trainees in DO and MD programs: a random effect meta-analysis.

The authors used random effect meta-analysis to synthesize eight mean score differences of the Part III/Level 3 examinations of the national Board of Osteopathic Medical Examiners (NBOME) between osteopathic medical trainees in DO residency programs and osteopathic medical trainees in MD programs. The analysis involved 6001 trainees and all Part III or Level 3 examinations since 1992. The average mean score difference was not significantly different from zero; however, the estimates of true effect sizes of each examination varied substantially. The findings indicate that, overall, medical knowledge of osteopathic trainees in MD and DO residency programs is compatible at the time they took the examinations. However, a large variation of effect size suggests the need for further investigation of the factors other than difference between osteopathic and allopathic training programs.

The Comprehensive Osteopathic Medical Licensing Examination, COMLEX-USA: a new paradigm in testing and evaluation.

Medical licensure in the United States demands a dynamic and current means to evaluate the competency of physicians seeking to practice medicine. A systematic measuring tool is required--one that is based on actual patient encounters and how physicians should apply their knowledge and skills to the clinical setting according to their level of training and professional development. Osteopathic physicians have a distinctive approach to healthcare, applying the biopsychosocial model with emphasis on the neuromusculoskeletal system. A component of this distinctive approach is a high level of knowledge and skill in the application of osteopathic manipulative treatment. Developed by the National Board of Osteopathic Medical Examiners, COMPLEX-USA is the new sequential three-level examination process for osteopathic medical licensure in the United States. The examination process is interdisciplinary and highly clinical, with even basic science components tested within a clinical context. Examination content is based on wide expert consensus and data consistent with osteopathic medical education, training, and practice. Its design is a novel multidimensional structure that emphasizes clinical problem-solving skills and osteopathic principles and practice within the context of life cycle, gender, ethnicity, and points of service. Design schemata and blueprints are included along with descriptions of strategic research and development. COMPLEX-USA represents the most appropriate pathway for initial licensure for a distinctive and unique professional: the osteopathic physician in the United States.

The role of crawling and walking experience in infant spatial memory.

This research explored infants' use of place learning and cue learning in a locomotor task across the transition from crawling to walking. Novice and expert crawling and walking infants were observed in a novel locomotor task-finding a hidden goal location in a large space. In Experiment 1, infants were tested with distal landmarks. Infants with fewer than 6 weeks of experience, either crawling or walking, could not find the goal location. All infants with more locomotor experience were more successful. Learning did not transfer across the transition to walking. In Experiment 2, novice and expert crawlers and walkers were tested with a direct landmark. Again, novice crawlers and walkers with fewer than 6 weeks of experience could not find the goal, whereas those with more experience could. Taken together, these findings suggest that infants' spatial learning is inextricably linked to mode of locomotion.

Comparative kinetic studies on aflatoxin B1-DNA binding and aflatoxin B1-glutathione conjugation with rat and hamster livers in vitro.

Inhibition of microsome mediated aflatoxin B1 (AFB1) binding to exogenous or endogenous DNA by cytosolic glutathione (GSH) S-transferases is well established from our earlier studies. Correlation between inhibition of AFB1-DNA binding and AFB1-GSH conjugation in vitro using rat and hamster liver subcellular fractions is elucidated in this report. Even though hamster liver microsomes catalyzed AFB1 binding to exogenous DNA three times as much as the rat, hamster cytosol inhibited AFB1-DNA binding catalyzed by either microsomes severalfold more than the rat cytosol. AFB1-DNA binding is found to be inversely related to AFB1-GSH conjugation at all AFB1 concentrations (2-100 microM) studied. Presence of either styrene oxide or 3,3,3-trichloropropene oxide at 1 mM level diminished AFB1-GSH formation in vitro confirming some competition by these epoxides with AFB1-epoxide for cytosolic GSH S-transferases. In a reconstituted system with endogenous DNA, the ratio of AFB1-GSH to AFB1-DNA binding was found to be 10-15 times higher with the hamster in comparison with the rat indicating enhanced inactivation of the ultimate carcinogenic metabolite in the hamster. These results are discussed in relation to AFB1-DNA binding and AFB1 hepatocarcinogenicity in resistant and sensitive species.