Maurizio Trevisan

Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association? A Scientific Statement From the American Heart Association

A link between oral health and cardiovascular disease has been proposed for more than a century. Recently, concern about possible links between periodontal disease (PD) and atherosclerotic vascular disease (ASVD) has intensified and is driving an active field of investigation into possible association and causality. The 2 disorders share several common risk factors, including cigarette smoking, age, and diabetes mellitus. Patients and providers are increasingly presented with claims that PD treatment strategies offer ASVD protection; these claims are often endorsed by professional and industrial stakeholders. The focus of this review is to assess whether available data support an independent association between ASVD and PD and whether PD treatment might modify ASVD risks or outcomes. It also presents mechanistic details of both PD and ASVD relevant to this topic. The correlation of PD with ASVD outcomes and surrogate markers is discussed, as well as the correlation of response to PD therapy with ASVD event rates. Methodological issues that complicate studies of this association are outlined, with an emphasis on the terms and metrics that would be applicable in future studies. Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes.

Calcium/Vitamin D Supplementation and Cardiovascular Events

Background— Individuals with vascular or valvular calcification are at increased risk for coronary events, but the relationship between calcium consumption and cardiovascular events is uncertain. We evaluated the risk of coronary and cerebrovascular events in the Women’s Health Initiative randomized trial of calcium plus vitamin D supplementation. Methods and Results— We randomized 36 282 postmenopausal women 50 to 79 years of age at 40 clinical sites to calcium carbonate 500 mg with vitamin D 200 IU twice daily or to placebo. Cardiovascular disease was a prespecified secondary efficacy outcome. During 7 years of follow-up, myocardial infarction or coronary heart disease death was confirmed for 499 women assigned to calcium/vitamin D and 475 women assigned to placebo (hazard ratio, 1.04; 95% confidence interval, 0.92 to 1.18). Stroke was confirmed among 362 women assigned to calcium/vitamin D and 377 assigned to placebo (hazard ratio, 0.95; 95% confidence interval, 0.82 to 1.10). In subgroup analyses, women with higher total calcium intake (diet plus supplements) at baseline were not at higher risk for coronary events (P=0.91 for interaction) or stroke (P=0.14 for interaction) if assigned to active calcium/vitamin D. Conclusions— Calcium/vitamin D supplementation neither increased nor decreased coronary or cerebrovascular risk in generally healthy postmenopausal women over a 7-year use period.

The Women's Health Initiative Observational Study: Baseline Characteristics of Participants and Reliability of Baseline Measures

The Women’s Health Initiative (WHI) Observational Study (OS) was established to explore the predictors and natural history of important causes of morbidity and mortality in postmenopausal women, and to serve as a secular control for the WHI Clinical Trial (CT). It enrolled 93,676 ethnically diverse women born in four different decades, from those who came of age in the depression-era, to the first members of the baby boom. Accordingly, this cohort reflects a wide range of socio-cultural influences on opportunities and health behaviors. OS participants will contribute longitudinal data on health status, risk exposures and disease events. The followup interval will be slightly shorter than that in the clinical trial, approximately 7 years. All OS women had a physical examination at baseline and 3 years. Additional data are obtained with annual mailed questionnaires. These forms explore risk exposures, health behaviors, and the prevalence of less common diseases to provide a comprehensive view of both classical and novel risk factors, as well as secular trends in the predictors of healthy aging and disease events. Because of its size, the OS will permit exploration of factors associated with less common diseases. This article describes the demographic, reproductive, dietary, and health characteristics of the OS women by eth-

Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial

Context Research suggests that selenium supplements may improve glucose metabolism. Contribution The investigators examined the incidence of type 2 diabetes among participants in a clinical trial designed to assess the effects of selenium supplementation on skin cancer. Participants randomly assigned to receive selenium were more likely to develop type 2 diabetes than were those assigned to placebo. Cautions Diabetes was a secondary outcome of the original trial. The diagnosis was self-reported, and most participants were older and white. Implication Long-term selenium supplementation appears to increase the risk for type 2 diabetes. The Editors Insulin resistance, impaired glucose tolerance, and type 2 diabetes are all linked to oxidative stress, which may be the pathogenic mechanism that links these conditions to cardiovascular disease (1). Observational epidemiologic studies show a protective association of dietary or plasma antioxidants against the development of type 2 diabetes (2, 3). However, the few clinical trials that have examined the efficacy of antioxidant supplementation in the prevention of type 2 diabetes or its complications have had negative results (46). Experimental evidence from animal models suggests that supplementation with low doses of the antioxidant selenium may exert beneficial effects on glucose metabolism, possibly through many insulin-like actions, and may delay complications of diabetes. The effects of high-dose selenium supplements, however, are less clear (710). Some studies in patients with diabetes suggest that selenium supplementation may help to prevent vascular complications (11) and that diabetic patients may be deficient in selenium relative to healthy persons (12). Conversely, recent findings from the SU.VI.MAX (Supplementation with Antioxidant Vitamins and Minerals) study (13) showed no effect of supplementation with a combination of antioxidants, including selenium (100 g/d), on fasting plasma glucose levels after 7.5 years of follow-up. Because no randomized, placebo-controlled clinical trials to date have tested the effect of long-term supplementation with selenium alone (200 g/d) on the risk for type 2 diabetes, we examined the efficacy of selenium supplementation in preventing new-onset type 2 diabetes in the NPC (Nutritional Prevention of Cancer) trial, a randomized, double-blind clinical trial designed primarily to evaluate the efficacy of selenium supplementation for prevention of cancer (14, 15). Specifically, we assessed the incidence of type 2 diabetes as a secondary end point throughout the blinded phase of the trial (19831996) among participants who did not have type 2 diabetes at baseline (n= 1202). Methods Design and Participants The rationale, design, and methods of the NPC trial are described in detail elsewhere (14). In brief, the NPC trial was a randomized, double-blind, placebo-controlled study of 1312 participants who were recruited in 1983 to 1991 from 7 dermatology clinics in areas of low selenium consumption of the eastern United States. Randomization was blocked by time and stratified by clinic. Persons were eligible if they had a confirmed history of nonmelanoma skin cancer in the year before randomization, had an estimated life expectancy of 5 years, and had no reported internal cancer in the previous 5 years. Participants with a history of clinically important liver or kidney disorders were excluded. Because the primary aim of the trial was to determine the effects of selenium supplementation on nonmelanoma skin cancer, we excluded nonwhite persons. This restriction served to control the effects of skin pigmentation on the risk for skin cancer recurrence. As a result, almost all participants in the NPC trial were non-Hispanic white persons; about 1.4% (n= 18) of persons who were randomly allocated were identified as Hispanic, and some persons were from other ethnic groups. Although recruitment was sex-neutral, about three quarters of the participants were male. Of the 1316 persons recruited, random assignment was successful for 1312. At the end of the blinded treatment period on 1 February 1996, no participant was lost to vital follow-up, generating a total of 9301 person-years of follow-up. Self-reported adherence indicated that 79.3% of participants (80.3% in the placebo group and 78.4% in the selenium group) adhered to the intervention (16). This was corroborated by the fact that plasma selenium levels remained constant throughout the trial in the placebo group but were substantially higher in the selenium group (Figure 1). Figure 1. Mean plasma selenium levels. We analyzed only participants with a valid baseline selenium value obtained within 4 days from the date of randomization (1250 of 1312 participants), a decision that is consistent with previously published studies from the NPC trial (1517). Baseline characteristics of the total NPC cohort of 1312 participants and the subsample of 1250 participants with valid baseline selenium levels did not statistically significantly differ (17), and our findings did not change substantially when analyses were expanded to include all 1312 participants (data not reported). We focus on the 1202 participants who did not have type 2 diabetes at baseline (600 selenium recipients and 602 placebo recipients). Ascertainment of prevalent type 2 diabetes at baseline was based on a self-reported diagnosis of type 2 diabetes before randomization, with subsequent evaluation of medical records (48 cases [21 in the selenium group and 27 in the placebo group]). Figure 2 shows the flow diagram of the NPC participants included in our analysis. Figure 2. Flow diagram of the Nutritional Prevention of Cancer Trial, 19831996. Clinical Examination and Laboratory Methods The intervention agent was 200 g of selenium daily, supplied in a 0.5-g, high-selenium bakers yeast tablet provided by Nutrition 21 (La Jolla, California) through 1995 and by Cypress Systems (Fresno, California) thereafter. The placebo group received a tablet containing yeast only. Selenium and placebo pills were coated with titanium oxide to ensure identical appearance and smell. Each patient was assigned a unique sequential treatment number. Treatment group assignment was made centrally by using sealed identical pill bottles that were distributed at the clinic. The coordinating center held all treatment information in blinded form (14). The selenium content of each batch of pills was determined in the laboratories of Dr. Combs and of I.S. Palmer, MD (South Dakota State University, Brookings, South Dakota), by the diaminonapthalene fluorometric procedure after nitricperchloric acid digestion (18). Plasma selenium level was determined in the laboratory of Dr. Combs by using an automated electrothermal atomic absorption spectrophotometer (Perkin Elmer 3030, Perkin-Elmer, Norwalk, Connecticut) equipped with an electrodeless discharge lamp and automatic Zeeman-effect background correction. Quality control included multiple aliquots of human plasma as external control samples. A coefficient of variation less than 7% (for duplicate analyses) was the criterion for acceptance (19). Participants visited their respective clinics biannually to provide blood samples and report new illnesses and medications. Patient medical records from both study and nonstudy visits were periodically reviewed to ensure completeness and accuracy. At the baseline interview, data were collected on sociodemographic, anthropometric, and behavioral characteristics, including education (0 to 18 years), body mass index (BMI), use of vitamin supplements, alcohol consumption (drinks consumed per day), smoking status (never, former, or current), and pack-years of smoking. For participants who became inactive, annual monitoring was attempted by using the National Death Index and ChoicePoint Services (formerly Equifax, Atlanta, Georgia) to determine vital status and identify diagnoses of new illnesses. Ascertainment of Type 2 Diabetes and Follow-up Participants who had a new diagnosis of type 2 diabetes during the blinded phase of the trial (15 September 1983 to 1 February 1996) were noted. The initial report of diabetes came from 3 sources: self-report during the clinical interview, reported use of drugs for diabetes, and reports in medical record documents. Medical record requests were then sent to the primary physicians for every patient with a report. This process of requesting and reviewing documentation was done in a blinded manner. About 92% of these reports, regardless of source, were corroborated with medical record documentation, as determined by registered nurse reviewers. Person-years of follow-up were accrued from the date of randomization as the start date to the date of an incident case of type 2 diabetes, the date of death, or the end of the blinded period of the trial. Statistical Analysis For continuous and categorical variables, we used t tests and chi-square tests, respectively, to determine the statistical significance of any difference in the distribution of baseline variables between treatment groups. Cumulative incidence curves of type 2 diabetes by treatment group were constructed by comparing NelsonAalen cumulative hazard function estimates that were calculated at different time points of the trial and by using the 2-sided log-rank test (20). In unadjusted analyses, incidence data were statistically analyzed by calculating relative risks as the ratios of the incidence density for the treatment groups, with corresponding 95% CIs. P values were derived from log-rank tests. In adjusted analyses, hazard ratios and 95% CIs were calculated by using the Cox proportional hazard model, which allowed adjustment for age, BMI (continuous variable), sex, and smoking status at baseline as covariates. We decided a priori to adjust for these diabetes risk factors regardless of whether they differed between treatment groups. Tests of proportional hazards assumptions were based on S

National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline.

The National Institute on Aging and the Office of Medical Applications of Research of the National Institutes of Health convened a State-of-the-Science Conference on 26-28 April 2010 to assess the available scientific evidence on prevention of cognitive decline and Alzheimer disease. This article provides the panels assessment of the available evidence.

Effects of Conjugated Equine Estrogen on Stroke in the Women’s Health Initiative

Background— The Women’s Health Initiative (WHI) Estrogen Alone trial assessed the balance of benefits and risks of hormone use in healthy postmenopausal women. The trial was stopped prematurely because there was no benefit for coronary heart disease and an increased risk of stroke. This report provides a thorough analysis of the stroke finding using the final results from the completed trial database. Methods and Results— The WHI Estrogen Alone hormone trial is a multicenter, double-blind, placebo-controlled, randomized clinical trial in 10 739 women aged 50 to 79 years who were given daily conjugated equine estrogen (CEE; 0.625 mg; n=5310) or placebo (n=5429). During an average follow-up of 7.1 years, there were 168 strokes in the CEE group and 127 in the placebo group; 80.3% of strokes were ischemic. For all stroke the intention-to-treat hazard ratio [HR] (95% CI) for CEE versus placebo was 1.37 (1.09 to 1.73). The HR (95% CI) was 1.55 (1.19 to 2.01) for ischemic stroke and 0.64 (0.35, 1.18) for hemorrhagic stroke. The HRs indicate excess risk of ischemic stroke was apparent in all categories of baseline stroke risk, including younger and more recently menopausal women and in women with prior or current use of statins or aspirin. Conclusions— CEE increases the risk of ischemic stroke in generally healthy postmenopausal women. The excess risk appeared to be present in all subgroups of women examined, including younger and more recently menopausal women. There was no convincing evidence to suggest that CEE had an effect on the risk of hemorrhagic stroke.

Estrogen metabolism and risk of breast cancer: A prospective study of the 2:16α-hydroxyestrone ratio in premenopausal and postmenopausal women

Experimental and clinical evidence suggests that 16&agr;-hydroxylated estrogen metabolites, biologically strong estrogens, are associated with breast cancer risk, while 2-hydroxylated metabolites, with lower estrogenic activity, are weakly related to this disease. This study analyzes the association of breast cancer risk with estrogen metabolism, expressed as the ratio of 2-hydroxyestrone to 16&agr;-hydroxyestrone, in a prospective nested case-control study. Between 1987 and 1992, 10,786 women (ages 35–69 years) were recruited to a prospective study on breast cancer in Italy, the “Hormones and Diet in the Etiology of Breast Cancer” (ORDET) study. Women with a history of cancer and women on hormone therapy were excluded at baseline. At recruitment, overnight urine was collected from all participants and stored at −80°C. After an average of 5.5 years of follow-up, 144 breast cancer cases and four matched controls for each case were identified among the participants of the cohort. Among premenopausal women, a higher ratio of 2-hydroxyestrone to 16&agr;-hydroxyestrone at baseline was associated with a reduced risk of breast cancer: women in the highest quintile of the ratio had an adjusted odds ratio (OR) for breast cancer of 0.58 [95% confidence interval (CI) = 0.25−1.34]. The corresponding adjusted OR in postmenopausal women was 1.29 (95% CI = 0.53–3.10). Results of this prospective study support the hypothesis that the estrogen metabolism pathway favoring 2-hydroxylation over 16&agr;-hydroxylation is associated with a reduced risk of invasive breast cancer risk in premenopausal women.

Correlates of short and long sleep duration: a cross-cultural comparison between the United Kingdom and the United States: the Whitehall II Study and the Western New York Health Study.

The authors examined sociodemographic, lifestyle, and comorbidity factors that could confound or mediate U-shaped associations between sleep duration and health in 6,472 United Kingdom adults from the Whitehall II Study (1997-1999) and 3,027 US adults from the Western New York Health Study (1996-2001). Cross-sectional associations between short (<6 hours) and long (>8 hours) durations of sleep across several correlates were calculated as multivariable odds ratios. For short sleep duration, there were significant, consistent associations in both samples for unmarried status (United Kingdom: adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI): 1.15, 1.94; United States: AOR = 1.49, 95% CI: 1.10, 2.02), body mass index (AORs were 1.04 (95% CI: 1.01, 1.07) and 1.02 (95% CI: 1.00, 1.05)), and Short Form-36 physical (AORs were 0.96 (95% CI: 0.95, 0.98) and 0.97 (95% CI: 0.96, 0.98)) and mental (AORs were 0.95 (95% CI: 0.94, 0.96) and 0.98 (95% CI: 0.96, 0.99)) scores. For long sleep duration, there were fewer significant associations: age among men (AORs were 1.08 (95% CI: 1.01, 1.14) and 1.05 (95% CI: 1.02, 1.08)), low physical activity (AORs were 1.75 (95% CI: 0.97, 3.14) and 1.60 (95% CI: 1.09, 2.34)), and Short Form-36 physical score (AORs were 0.96 (95% CI: 0.93, 0.99) and 0.97 (95% CI: 0.95, 0.99)). Being unmarried, being overweight, and having poor general health are associated with short sleep and may contribute to observed disease associations. Long sleep may represent an epiphenomenon of comorbidity.

Risk Factors and Preventive Interventions for Alzheimer Disease: State of the Science

BACKGROUND Numerous studies have investigated risk factors for Alzheimer disease (AD). However, at a recent National Institutes of Health State-of-the-Science Conference, an independent panel found insufficient evidence to support the association of any modifiable factor with risk of cognitive decline or AD. OBJECTIVE To present key findings for selected factors and AD risk that led the panel to their conclusion. DATA SOURCES An evidence report was commissioned by the Agency for Healthcare Research and Quality. It included English-language publications in MEDLINE and the Cochrane Database of Systematic Reviews from 1984 through October 27, 2009. Expert presentations and public discussions were considered. STUDY SELECTION Study inclusion criteria for the evidence report were participants aged 50 years and older from general populations in developed countries; minimum sample sizes of 300 for cohort studies and 50 for randomized controlled trials; at least 2 years between exposure and outcome assessment; and use of well-accepted diagnostic criteria for AD. DATA EXTRACTION Included studies were evaluated for eligibility and data were abstracted. Quality of overall evidence for each factor was summarized as low, moderate, or high. DATA SYNTHESIS Diabetes mellitus, hyperlipidemia in midlife, and current tobacco use were associated with increased risk of AD, and Mediterranean-type diet, folic acid intake, low or moderate alcohol intake, cognitive activities, and physical activity were associated with decreased risk. The quality of evidence was low for all of these associations. CONCLUSION Currently, insufficient evidence exists to draw firm conclusions on the association of any modifiable factors with risk of AD.

Body fat distribution, relative weight, and liver enzyme levels: A population‐based study

Regional body fat distribution may represent an independent risk factor for several conditions, especially metabolic and cardiovascular diseases; recent findings have shown that abdominal fat accumulation can be an independent predictor of hepatic steatosis. Very few studies, mostly using selected clinical samples, have focused on the relationship between indices of abdominal visceral fat accumulation and the most commonly used biochemical liver tests, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma‐glutamyltransferase (GGT). The aim of the present study was to evaluate the relation between central fat accumulation, as assessed by abdominal height, relative weight, as determined by body mass index (BMI), and liver function tests (ALT, AST, and GGT) in a random sample of 2,704 residents of Erie and Niagara Counties in New York State, 35–80 years of age and free from known hepatic disease. Multiple linear regression models were used, with liver enzymes as dependent variables with abdominal height and BMI as independent variables, and the inclusion of several covariates (age, race, education, smoking status, pack‐years of smoking, drinking status, and total ounces of ethanol in the past 30 days). Abdominal height was consistently a better correlate of ALT and GGT levels than BMI in both sexes. In addition, abdominal height was the most powerful independent predictor of ALT in both sexes as well as of GGT among women. In conclusion, these findings support a role for central adiposity independent from BMI in predicting increased levels of hepatic enzymes, likely as a result of unrecognized fatty liver. (HEPATOLOGY 2004;39:754–763.)