Excessive alcohol consumption has long been associated with cardiovascular disorders, including cardiomyopathy, hypertension, coronary artery disease, and stroke. However, recent evidence suggests that moderate alcohol intake can actually provide a measure of cardioprotection, particularly against coronary heart disease and ischemia-reperfusion injury. To explore the various dimensions of these opposing actions of alcohol, the National Institute on Alcohol Abuse and Alcoholism and the National Heart, Lung, and Blood Institute sponsored a state-of-the-art workshop on "Alcohol and the Cardiovascular System: Research Challenges and Opportunities" in Bethesda, Maryland, in May 2003. Speakers discussed the following topics: the epidemiology of alcohol and cardiovascular disease, clinical manifestations of alcohol, genetics of alcohol and cardiovascular disease, mechanisms underlying the molecular and cellular effects of alcohol, the application of new and emerging technology, and translation from discovery to therapeutic modalities of treatment. The panel concluded that future studies are needed to: 1) determine the role of genes and the environment in assessing mechanisms underlying the benefits of alcohol use and cardiovascular disease risk; 2) define the biological mechanisms underlying alcohol-induced peripheral vascular damage; 3) clarify the role of genetic variation in alcohol-metabolizing enzymes, genetic susceptibility, and pharmacogenomics in determining cardiovascular disease risk and effective treatment; 4) determine common mechanisms underlying alcohol-induced cardiovascular disease, such as oxidative stress and inflammation; 5) assess the role of insulin resistance, blood clotting, protein kinase C isoforms, and signal transduction mechanisms mediating alcohol's beneficial effects; and 6) explore the potential of stem cells in myocardial regeneration and repair in hearts damaged by alcohol.

Objective: Evidence from previous studies suggests that heavy alcohol use (HAU) exacerbates the rate of fibrosis progression in the liver and results in increased probability for premature death among patients with hepatitis C virus (HCV) infection. The current study uses population-based mortality data to investigate whether heavy drinking affects the age of death among individuals with HCV and, if so, whether this effect differs between men and women.Methods: A total of 7,263,163 death records in the United States between 2000 and 2002 were drawn from the Multiple Cause of Death (MCD) public-use data files compiled by the National Center for Health Statistics (NCHS). International Classification of Diseases, Tenth Revision (ICD-10) codes were used to identify the presence of HCV (B17.1 and B18.2) and HAU (as indicated by alcohol-induced medical conditions, F10 and K70) either as the underlying cause or as one of the contributing causes of death. The deaths were divided into 4 distinctive cause-of-death categories: HCV without HAU, HAU without HCV, HCV plus HAU, and all others. The mean ages of death and the cumulative probabilities of death derived from multiple-cause life table were compared across these categories.Results: Hepatitis C virus deaths showed an excessive prevalence of HAU when compared with non-HCV deaths. Compared with deaths of HCV without HAU, the mean age of death was shortened for deaths of HCV plus HAU (from 55.1 to 50.0 years among males, and from 61.0 to 49.1 years among females). The cumulative probability of death before age 65 was much higher for the latter than the former group (0.91 vs 0.68 among males, and 0.88 vs 0.47 among females). While HCV alone showed a disproportionate effect on premature death in males, HAU presented a stronger effect in females, resulting in a ''catching-up'' effect that diminished the gender difference in age of HCV death.Conclusions: This study provides mortality-based evidence to further establish heavy alcohol consumption as one of the key risk factors contributing to premature deaths from HCV in the United States. More importantly, this study, for the first time, presents empirical evidence that alcohol consumption affects men and women differently in HCV mortality.

Objective.\p=m-\To assess pairwise differences between placebo, unopposed estrogen, and each of three estrogen/progestin regimens on selected heart disease risk factors in healthy postmenopausal women.Design.\p=m-\A3-year, multicenter, randomized, double-blind, placebo-controlled trial.Participants.\p=m-\A total of 875 healthy postmenopausal women aged 45 to 64 years who had no known contraindication to hormone therapy.Intervention.\p=m-\Participants were randomly assigned in equal numbers to the following groups: (1) placebo; (2) conjugated equine estrogen (CEE), 0.625 mg/d;(3) CEE, 0.625 mg/d plus cyclic medroxyprogesterone acetate (MPA), 10 mg/d for 12 d/mo; (4) CEE, 0.625 mg/d plus consecutive MPA, 2.5 mg/d; or (5) CEE, 0.625

A B S T R A C T In studies with the human promyelocytic leukemia cell line HL-60, we defined changes in intermediary purine metabolism that appear to contribute to the regulation of terminal maturation in myeloid cells. When HL-60 cells were exposed to compounds that induce maturation, consistent alterations in purine metabolism were found to occur within 24 h of culture.Perturbation of guanosine nucleotide synthesis and decreases of up to 50% in intracellular guanylate pool sizes were associated with the induced maturation of these cells in response to diverse inducing agents. While immature HL-60 cells were observed to synthesize purine nucleotides by both de novo and salvage pathways, the activity of both pathways decreased in cells induced to mature, although the relative contribution of purine salvage increased. Moreover, incorporation of the sal-

Infection with hepatitis C and the alcohol abuse that frequently accompanies it, impose major worldwide healthcare burdens. The scientific knowledge base that would inform and direct the development of more effective treatment and intervention strategies for these linked pandemics is inadequate. Therefore, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) organized a workshop in which a multidisciplinary group of experts was asked to review the state-of-the-science specific to alcohol in the context of hepatitis C infection. The panel was charged with identifying newly emerging areas likely to lead to advances in fundamental research and to identify those with the greatest potential for accelerating the development of more effective treatment options. The workshop panel made recommendations for research in four major categories: clinical studies of alcohol and HCV; virology and immunology; liver fibrosis and mechanisms of liver injury; and the development of model systems. This article summarizes the panel's deliberations and their recommendations for future research on alcohol and hepatitis C.