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C-reactive protein (CRP) and many fatty acids (FAs) have been linked to cardiovascular disease. Associations of serum CRP with FAs in different populations have not been established.Participants were 926 men aged 40-49 (2002-2006) from a population-based sample; 310 Whites from Pennsylvania, U.S., 313 Japanese from Shiga, Japan, and 303 Japanese Americans from Hawaii, U.S. Serum CRP (mg/L) was measured using immunosorbent assay while serum FAs (%) were measured using capillary-gas-liquid chromatography.Whites had CRP (mg/L) levels higher than Japanese with Japanese Americans in-between (age-adjusted geometric mean "GM" 0.96, 0.38, 0.66, respectively). Whites had also higher levels of total n-6 FAs (%) and trans fatty acids (TFAs) but lower levels of marine-derived n-3 FAs compared to Japanese (41.78 vs. 35.05, 1.04 vs. 0.58, and 3.85 vs. 9.29, respectively). Japanese Americans had FAs levels in-between the other two populations. Whites had significant inverse trends between CRP and tertiles of total n-6 FAs (GM 1.20, 0.91 and 0.80; p=0.002) and marine-derived n-3 FAs (GM 1.22, 1.00 and 0.72; p0.001) but a significant positive trend with TFAs (GM 0.80, 0.95 and 1.15; p=0.007). Japanese had a significant inverse trend between CRP and only total n-6 FAs (GM 0.50, 0.35 and 0.31; p0.001). Japanese Americans had CRP associations with n-3 FAs, n-6 FAs, and TFAs similar to but weaker than Whites.With the exception of consistent inverse association of CRP with total n-6 FAs, there are considerable variations across the three populations in the associations of CRP with different FAs.

Background: Several lines of evidence suggest that inflammatory mechanisms contribute to AD. Objective: To examine whether several markers of inflammation are associated with cognitive decline in African-American and white well-functioning elders. Methods: The authors studied 3,031 African-American and white men and women (mean age 74 years) enrolled in the Health, Aging, and Body Composition Study. Serum levels of interleukin-6 (IL-6) and C-reactive protein (CRP) and plasma levels of tumor necrosis factor-α (TNFα) were measured at baseline; cognition was assessed with the Modified Mini-Mental State Examination (3MS) at baseline and at follow-up. Cognitive decline was defined as a decline of >5 points. Results: In age-adjusted analyses, participants in the highest tertile of IL-6 or CRP performed nearly 2 points lower (worse) on baseline and follow-up 3MS ( p 2 years ( p = 0.01 for IL-6 and p = 0.04 for CRP) compared with those in the lowest tertile. After multivariate adjustment, 3MS scores among participants in the highest tertile of IL-6 and CRP were similar at baseline but remained significantly lower at follow-up ( p ≤ 0.05 for both). Those in the highest inflammatory marker tertile were also more likely to have cognitive decline compared with the lowest tertile for IL-6 (26 vs 20%; age-adjusted odds ratio [OR] = 1.34; 95% CI 1.06 to 1.69) and for CRP (24 vs 19%; OR = 1.41; 95% CI 1.10 to 1.79) but not for TNFα (23 vs 21%; OR = 1.12; 95% CI 0.88 to 1.43). There was no significant interaction between race and inflammatory marker or between nonsteroidal anti-inflammatory drug use and inflammatory marker on cognition. Conclusions: Serum markers of inflammation, especially IL-6 and CRP, are prospectively associated with cognitive decline in well-functioning elders. These findings support the hypothesis that inflammation contributes to cognitive decline in the elderly.

Objective: APOE-ε4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-ε4 and cognitive decline. Method:— As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (≥65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on ≥2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening.Results: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with ε4-negative women, ε4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and ε4 presence (p = 0.037). Among ε4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among ε4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in ε4-negative women but not in ε4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke.Conclusions: Estrogen use was associated with less cognitive decline among ε4-negative women but not ε4-positive women. Potential mechanisms, including carotid atherosclerosis, by which ε4 may interact with estrogen and cognition warrant further investigation.

Cytokines such as interleukin-1 (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha) can influence both bone resorption and bone formation. The objective of this cross-sectional study was to examine the relationship between cytokine production by peripheral blood mononuclear cells (PBMC) and bone mineral density (BMD); the annual rate of change in BMD was examined. Subjects participating in a randomized clinical trial entitled the Women's Healthy Lifestyle Project in Allegheny County, Pennsylvania were used. They included 50 healthy premenopausal women, aged 45-52 years, who had regular menses within the past 3 months and were not on replacement estrogens. Dual-energy X-ray absorptiometry measurements at the AP lumbar spine and femoral neck were made at baseline and at the first annual exam using a Hologic QDR 2000 densitometer. Cytokine production of IL-1beta, IL-6, and TNF-alpha by PBMC was measured at the annual exam. The median values for stimulated cytokine production by PBMC were 3.92 ng/ml, 31.3 ng/ml, and 1.05 ng/ml, for IL-1beta, IL-6, and TNF-alpha, respectively. There were modest correlations between cytokine production and cross-sectional BMD, ranging from r = -0.30 to r = -0.13. Trends of greater spinal bone loss were observed in women with "high" (/=75th percentile) cytokine production of stimulated IL-1beta and IL-6 (IL-1beta: "high" = -1.56% +/- 0.70 versus "low" (75th percentile) = -0.56% +/- 0.35, P = 0.21). In contrast, greater annual gains in femoral neck BMD were observed in those with high cytokine production of IL-1beta and IL-6 (IL-1beta: high = 3.39% +/- 1.16 versus low = -0. 85 +/- 0.58, P = 0.002). There was no association between stimulated TNF production and annual change in BMD. In this population of healthy premenopausal women, the relationship between cytokine production by PBMC and the rate of change in BMD was significantly different for the lumbar spine and femoral neck, possibly reflecting differences in the proportion of trabecular and cortical bone at these sites.

Calcaneal broadband ultrasound attenuation (BUA) is an independent predictor of hip and vertebral fractures. BUA is under genetic control, but the specific genes contributing to BUA are not well defined. We examined the relationship between genetic variation in alpha2HS-glycoprotein (AHSG), an abundant noncollagenous protein of bone matrix, and calcaneal BUA. Genetic polymorphism in AHSG was determined in 222 Caucasian women (age 66-92) enrolled in the Pittsburgh Study of Osteoporotic Fractures clinical center by isoelectric focusing of serum samples. Calcaneal BUA and bone mineral density (BMD) were measured on the same foot with a Walker Sonix UBA 575(+) and single X-ray absorptiometry. Hip and spine BMD were determined with a Hologic QDR-1000 densitometer using dual-energy X-ray absorptiometry. AHSG polymorphism was not significantly related to hip, lumbar spine, or calcaneal BMD. Compared with the homozygous AHSG*2 women, calcaneal BUA was 13% lower in heterozygous (P0.05) and 16% lower in homozygous AHSG*1 women (P0.05). This relationship persisted after controlling for age, weight, height, walks for exercise, and calcaneal BMD. Current and self-reported height were also lowest in homozygous AHSG*1 women, intermediate in heterozygous women, and highest among homozygous AHSG*2 subjects. These results suggest that the AHSG polymorphism may contribute to the genetic influence on calcaneal BUA and stature.

BACKGROUND: Abdominal obesity has an important biological and epidemiological relationship to disease. The gold standard for measurement of visceral adipose tissue (VAT) is assessment by computerized tomography (CT) or magnetic resonance imaging (MRI), but because of simplicity and ease in collection, anthropometric variables are a desirable alternative to estimate VAT. OBJECTIVE: To compare the abilities of a single slice CT scan through the L4-L5 interspace (L4-L5 VAT), sagittal diameter, and body mass index (BMI) to estimate total volume VAT. Total volume VAT (the gold standard) was measured by total abdominal CT scanning, with a mean of 42 CT slices per patient. Estimation of VAT in subjects of similar body size was emphasized. DESIGN: Retrospective study of subjects undergoing complete abdominal and pelvic CT scanning for clinical reasons. SUBJECTS: 40 subjects (20 men and 20 women) mean age 56.5 y, with a balanced selection for BMI 27. RESULTS: In univariate regression models, L4-L5 VAT explained the largest proportion of the variance in total VAT (R 2 a 0.87 (P< 0.001)), though age (R 2 a 0.11 (Pa 0.04)), BMI (R 2 a 0.37 (P< 0.001)), and sagittal diameter (R 2 a 0.50 (P< 0.001)) were also statistically significantly related to total VAT. When limited to individuals with a BMI 27 however, L4-L5 VAT explained a large proportion of the variance in total VAT (R 2 a 0.87 (P< 0.001)) whereas sagittal diameter was only of borderline significance (R 2 a 0.20 (Pa 0.06)), and BMI was not associated with total VAT (R 2 a 0.04 (Pa NS)). In multiple regression analyses, L4-L5 VAT area explained a large proportion of the variance (0.84‐ 0.90), and once in the model, BMI, sagittal diameter, and age did not additionally contribute significantly to the explained variance in total VAT. CONCLUSIONS: Abdominal sagittal diameter is poorly correlated to total VAT for men and women with a BMI 27. Within a 2 cm range of sagittal diameter, there is nearly a three-fold variability in total VAT.

This is the first prospective study of urinary measures of the two major competing pathways of oestrogen metabolism, 16alpha-hydroxyoestrone (16alpha-OHE1) and 2-hydroxyoestrone (2-OHE1), in relation to incident breast cancer risk. Experimental and case-control study results suggest that metabolism favouring the more oestrogenic 16alpha-OHE1 pathway may be linked to higher breast cancer risk. Women aged 35 and older from Guernsey (n = 5104) were surveyed in 1977-85 and have been continuously monitored for breast cancer and mortality up to the present (Guernsey III, Imperial Cancer Research Fund). Incident cases of breast cancer were matched to three control subjects for comparison of urinary oestrogen metabolite levels measured by enzyme immunoassay (EIA) in spot urine samples collected at baseline and stored frozen for up to 19 years. Consistent with case-control study results, post-menopausal (but not premenopausal) women at baseline who went on to develop breast cancer showed about a 15% lower 2:16alpha-OHE1 ratio than matched control subjects. Further, subjects with metabolite ratios in the highest tertile of 2:16alpha-OHE1 had about a 30% lower risk than women with ratios in the lowest two-thirds, although results were not statistically significant (OR = 0.71, 95% CI = 0.29-1.75). It is of potential importance that, in contrast to most risk factors for breast cancer, such as late age at first birth, oestrogen metabolism appears to be modifiable via diet and exercise, offering women the possibility of lowering breast cancer risk through non-pharmacological measures, although this remains to be tested.

SummaryCoagulation factor V Leiden is a risk marker for venous thrombosis. For arterial thrombosis no large study to date has included population-based elderly patients. The Cardiovascular Health Study is a longitudinal study of 5,201 men and women over age 65. With 3.4-year follow-up, we studied 373 incident cases of myocardial infarction (MI), angina, stroke, or transient ischemic attack (TIA), and 482 controls. The odds ratios for each event with heterozygous factor V Leiden were: MI, 0.46 (95% CI 0.17 to 1.25); angina, 1.0 (95% CI 0.45 to 2.23); stroke, 0.77 (95% CI 0.35 to 1.70); TIA, 1.33 (95% CI 0.5 to 3.55); any outcome, 0.83 (95% CI 0.48 to 1.44). Adjustment for cardiovascular risk factors did not change relationships. In older adults factor V Leiden is not a risk factor for future arterial thrombosis.

The genetic influence on bone mineral density (BMD) is thought to be mediated in part by alleles at the vitamin D receptor (VDR) locus. In order to assess the effect of VDR on BMD in premenopausal women, we studied 470 healthy white subjects, aged 44-50 years, participating in the Women's Healthy Lifestyle Project. Each participant was genotyped for the BsmI polymorphism at the VDR gene locus. BMD at the lumbar spine, hip and whole-body, and the whole-body soft tissue composition, were measured cross-sectionally using a Hologic QDR 2000 densitometer. The presence of a polymorphic restriction site at the VDR gene locus was specified as b, whereas absence of this site was B. The frequency distribution of the VDR genotype was: bb, 20.6%; Bb, 39.1%; and BB, 40.2%. Spinal BMD (mean +/- SD) was significantly lower in women with VDR genotype BB (1.038 +/- 0.11 g/cm2) as compared with those with genotype bb (1.069 +/- 0.12 g/cm2, p0.05). Trochanter BMD was 2.7% lower in those with genotype BB versus bb (0.685 +/- 0.10 g/cm2 vs 0.708 +/- 0.09 g/cm2). A similar trend was shown at each subregion of the hip, but not at the whole-body. In premenopausal women, allelic status at the VDR locus contributed to variations in spinal and trochanteric BMDs, but the absolute difference in BMDs was small, amounting to 0.26 and 0.23 standard deviations, respectively. It is concluded that in this population of healthy premenopausal women there was a significant association between polymorphisms at the VDR gene locus and both spinal and trochanteric BMDs, yet no association was demonstrated for the whole-body BMD.

Background . A cross-sectional analysis was conducted to test the feasibility of the National Cholesterol Education Program Adult Treatment Panel I Guidelines (ATPI) in physician office practices. Methods . Twenty-two physician practices in communities from western Pennsylvania and West Virginia were recruited. Using a patient tracking system, 9,171 patients were assessed for cholesterol screening and treatment by their physicians according to the ATPI guidelines. Results . Cholesterol screening was ordered for 1,698 patients or 19% of the population visiting the physician offices. The reasons for not screening included the patient was already under therapy (2,371), screened within the past 5 years (1,714), or acutely ill at the time of the visit (1,691). The frequency of patient refusal for screening was low (444), However, the majority of patient diagnoses were based on a single lipid measurement, and only 817 or 56% of patients evaluated had lipoprotein measures obtained prior to treatment. Follow-up measurement was not performed according to the ATPI schedule, and the magnitude of cholesterol response was inversely related to time to first follow-up measurement. Conclusions . Many patients in these physician practices had initial cholesterol screening. However, repeat measurements as recommended for initial evaluation were not performed routinely, nor were most patients followed within the recommended S-month time period, This lack of follow-up is detrimental to effective, long-term patient management since the magnitude of the cholesterol response is related to time of the first follow-up measurement.

Trends in coronary heart disease mortality and sudden death were studied in 35- to 44-year-old white male residents of Allegheny County, Pennsylvania. Deaths coded as any cardiac or vascular disease, diabetes, unexplained sudden death, and other rubrics were eligible for investigation, and the cause of death was validated by physicians examining multiple data sources about the deaths. During 1970-1990, 1,424 white male deaths were investigated, with 903 validated as coronary heart disease. In that time span, white male coronary heart disease mortality fell from 93.4 to 36.7 per 100,000 population per year, a 60% decline. Little proportionate change was seen in characteristics of the deaths, which were predominantly sudden and out-of-hospital. Diabetes mellitus history increased proportionately over time, largely because diabetics' mortality rates, unlike those of all other subgroups, did not fall. These observations support the contention that the decline in coronary heart disease mortality relates to risk factor modification more than to improvements in the treatment of coronary heart disease. Differences in death certification practices must be considered when interpreting and comparing vital statistics data.

Background. Despite endorsement by a variety of professional societies, screening sigmoidoscopy is performed on a small minority of patients. We performed a survey of primary care physicians in Allegheny County to examine in detail their current practice and attitude toward screening sigmoidoscopy. Methods. Physicians were surveyed by mail or telephone. Eligible respondents were required to practice in the county and perform direct patient care. Results. Of 732 adult primary care physicians in Allegheny County, 400 were randomly selected for sampling and 279, or 70%, responded. Over 88% of physicians agreed completely or partly with current American Cancer Society recommendations for screening sigmoidoscopy, but only 34% (95% CI 29-39%) reported they regularly refer or schedule patients for screening. Physicians who screen were more likely to be from internal medicine or family practice (P < 0.001) and to be trained in (P < 0.001) or to personally perform (P < 0.001) sigmoidoscopy. The greater the number of barriers to screening cited by physicians, including cost, patient discomfort, equipment availability, low probability of finding a lesion, time it takes to do sigmoidoscopy, and the risk of the procedure, the lower the screening rate (P = 0.002). Conclusion. (a) Although primary care physicians in Allegheny County report that they support screening sigmoidoscopy, only one-third regularly refer or schedule patients, (b) physicians who are trained in or who perform sigmoidoscopy are more likely to screen patients, and (c) further education and training of primary care physicians in sigmoidoscopy will be required to increase screening rates.

Tracking of blood pressure was studied in a cohort of 86 men and 116 women, initially examined at mean age 17 years and re-examined at mean ages 34 and 47 years in the Dormont High School Follow-up Study.Correlations for systolic blood pressure (men vs women, P0.05) were r = 0.42 vs r = 0.39 between mean ages 17 and 34 years; r = 0.38 vs r = 0.54 between mean ages 34 and 47 years; and r = 0.27 vs r = 0.24 between mean ages 17 and 47 years. For diastolic blood pressure, the correlations were lower, but were higher among women than men, and were higher between mean ages 34 and 47 years (r = 0.44 for men and r = 0.54 for women, P0.001) than at earlier ages. The correlations for weight were higher than those for blood pressure (men vs women, P0.001): r = 0.64 vs r = 0.59 between mean ages 17 and 34 years; r = 0.88 vs r = 0.81 between mean ages 34 and 47 years; and r = 0.58 vs r = 0.49 between mean ages 17 and 47 years. With increase in age and length of follow-up, there was a stronger tendency for those in the extreme tertiles of the blood pressure distribution to maintain their ranks. The significance and magnitude of the blood pressure correlations remained essentially unchanged after adjustment for weight and its changes. However, weight was related to the changes in blood pressure tracking status, but this varied with age.These data suggest that the age and gender differences in the degree of blood pressure tracking may be a function of the tracking of weight as well as a reflection of the gender difference in the consistency of the relationship of blood pressure to weight at different ages.

In an effort to determine if structural variation in proteins important in bone metabolism might influence bone mineral density (BMD) and thus be a determinant of susceptibility to osteoporosis in older women, the authors typed a group of 258 non-Black women (age 65–90) participating in the Study of Osteoporotic Fractures (SOF) for two polymorphic bone-related proteins, group specific component (Gc), also known as vitamin D-binding protein, and α2HS glycoprotein (AHSG). These two proteins exhibit common structural variation in populations that can be detected by isoelectric focusing/immunoblotting of serum. An important function of Gc is the binding, solubilization, and transport of vitamin D sterols in the bloodstream while AHSG is a glycoprotein constituent of calcified cortical bone matrix. There are six common phenotypes of Gc and four of AHSG. Using Gc or AHSG phenotypes as categorical variables, statistical analyses were done to determine if bone mineral density of the proximal or distal radius or calcaneus differed by phenotype. Neither Gc nor AHSG phenotype demonstrated a statistically significant relationship with BMD at any site. Adjustments for age and degree of obesity did not substantively affect these results. Subsequent analyses to determine if phenotype of either of these proteins was associated with variables related to skeletal size showed an association of AHSG with height (P

Epidemiological techniques have been utilized to accumulate new knowledge about insulin-dependent diabetes mellitus (IDDM), leading to important insights into the disease process and the alteration of these mechanisms when viewed from a geographic or population base. More recently, highly powerful and sophisticated techniques of molecular biology have been added to the research arsenal, extending the knowledge on the genetic basis for IDDM and the probable environmental factors involved. The development and growth of the new discipline of epidemiological genetics promises exciting new developments for the future of our field as well as that of other major medical problems having a genetic base, but significantly influenced by environmental factors. This review stresses the importance of carefully validated diabetes registries in the study of the epidemiology of IDDM. The Children's Hospital of Pittsburgh and the University of Pittsburgh Medical Center have spear-headed the development of such registries, worldwide. The first international meeting on IDDM epidemiology in 1983 gave as a result, i.e., the finding that there were truly remarkable differences in the risk of developing IDDM depending upon the geographic location of the individual. Later collaborative work via the Diabetes Epidemiology Research International (DERI) group has confirmed the previous finding and added the description of secular trends and epidemics of IDDM. It is remarkable that the incidence rate of IDDM in children below 15 years vary from 1/100,000/yr in the Orient to 35/100,000/yr in Finland. The epidemiological approach in the study of IDDM has also stimulated research into the various facets of the etiology of the disease, genetic factors, autoimmune mechanisms and environmental factors.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationships between blood levels of estrogen and lipoprotein lipids and apoproteins were evaluated in 120 women early in the climacteric. Among women who were 1-year amenorrheic, not taking hormone replacement therapy, and with follicle-stimulating hormone levels greater than 720 ng/ml, serum estradiol levels were positively related to concentrations of the high density lipoprotein 2 cholesterol (HDL2c) subfraction. There was a substantial decrease in HDL2c and apoprotein (apo) A-I in women whose estradiol levels decreased to less than or equal to 2.5 pg/ml from the first to the second postmenopausal examination. In a sample of women evaluated during the perimenopause (3-months' amenorrheic), those with the highest concentrations of estradiol or estrone showed a (nonsignificantly) higher level of HDL2c and a lower level of low density lipoprotein cholesterol (LDLc) than did those with the lowest concentration of estradiol or estrone. Estradiol levels declined dramatically between the perimenopausal and the postmenopausal examinations, and this was accompanied by a decrease in HDL2c and a nonsignificant increase in LDLc. HDL2c levels fell substantially in those women whose estradiol decreased below the sensitivity of the assay. The change, however, was not statistically significant. Estrone is the primary postmenopausal estrogen, and levels are directly related to obesity, as are levels of insulin. The interrelationship among obesity, conversion of estrone to estradiol at the tissue level, and insulin (or insulin sensitivity) is probably the primary determinant of HDLc concentration among postmenopausal women.

The apolipoprotein (apo) E structural locus has been shown to influence concentrations of total cholesterol, apo B, and low density lipoprotein (LDL) cholesterol in population studies. Apo E has six phenotypes resulting from three common alleles at this locus. In the present study, we have typed 473 healthy white women for apo E. At baseline in 1984, all women were premenopausal. To date, 109 of these women have become postmenopausal and are not on hormone therapy. Statistical analyses were done on both pre- and postmenopausal groups to assess the influence of menopausal status in combination with the apo E locus on lipid profile. Nine lipoprotein lipids and apolipoproteins were categorized by three apo E phenotypes: apo E3-2, apo E3-3, and apo E4-3. These were compared in analysis of variance. At baseline, the apo E3-2 phenotype showed the lowest average concentrations of total cholesterol (170 mg/dl), apo B (80 mg/dl), and LDL cholesterol (91 mg/dl), while the apo E4-3 phenotype demonstrated the highest average concentrations of total cholesterol (192 mg/dl), apo B (104 mg/dl), and LDL cholesterol (116 mg/dl) (p less than or equal to 0.0004). Apo E3-3 homozygotes were intermediate on all three quantitative variables. The postmenopausal subset showed the same trends by phenotype, with overall increases in total cholesterol, apo B, LDL cholesterol, and triglycerides, regardless of phenotype. Women who remained premenopausal generally showed smaller increases in these same measures. Our results suggest that, on average, the lower lipoprotein values for the apo E3-2 phenotype are maintained through early menopause despite a worsening of lipid profiles for all women as they age.(ABSTRACT TRUNCATED AT 250 WORDS)

Summary. Background: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression. Objectives: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age ≥65 years) from the Cardiovascular Health Study. Methods: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up. Results: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL−1) were 1.3 (1.1–1.4) in men and 1.2 (1.1–1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0–1.5), but not men (1.1; 0.9–1.3). There were no associations of sICAM-1 with non-fatal CVD events. Conclusions: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.

Background —Whether serological evidence of prior infection with Chlamydia pneumoniae , herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy. Methods and Results —We conducted a nested case-control study among participants in the Cardiovascular Health Study, a cohort study of persons aged ≥65 years. Cases experienced an incident MI and CHD death (n=213). Control subjects were matched to cases by age, sex, clinic, year of enrollment, and month of blood draw (n=405). Serum was analyzed for IgG antibodies to C pneumoniae , HSV-1, and CMV. After adjustment for other risk factors, the risk of MI and CHD death was associated with the presence of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95% CI 1.1 to 3.6) but was not associated with the presence of IgG antibodies to either C pneumoniae (OR 1.1, 95% CI 0.7 to 1.8) or CMV (OR 1.2, 95% CI 0.7 to 1.9). Although there was little association with low to moderate C pneumoniae antibody titers (≤1:512), high-titer (1:1024) C pneumoniae antibody was associated with an increased risk (OR 2.2, 95% CI 1.1 to 4.4). Conclusions —Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae , only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.

To investigate the association between fish consumption and subclinical brain abnormalities. In the population-based Cardiovascular Health Study, 3660 participants age > or = 65 underwent an MRI scan in 1992–1994. Five years later, 2313 were scanned. Neuroradiologists assessed MRI scans in a standardized and blinded manner. Food frequency questionnaires were used to assess dietary intakes. Participants with known cerebrovascular disease were excluded from the analyses. After adjustment for multiple risk factors, the risk for having one or more prevalent subclinical infarcts was lower among those consuming tuna/other fish > or 3 times/week, compared to < 1/month (relative risk 0.74, 95% CI = 0.54–1.01, p = 0.06, p trend = 0.03). Tuna/other fish consumption was also associated with trends toward lower incidence of subclinical infarcts. Additionally, tuna/other fish intake was associated with better white matter grade, but not with sulcal and ventricular grades, markers of brain atrophy. No significant association were found between fried fish consumption and any subclinical brain abnormalities. Among older adults, modest consumption of tuna/other fish, but not fried fish, was associated with lower prevalence of subclinical infarcts and white matter abnormalities on MRI examinations. Our results add to prior evidence that suggest that dietary intake of fish with higher eicosapentaenoic acid and docosahexaenoic acid content, and not fried fish intake, may have clinically important health benefits.

Quantitative ultrasound (QUS) assessment of bone is a strong predictor of hip fractures and is currently an FDA-approved tool to identify women at risk of osteoporosis. However, few studies have investigated the lifestyle and genetic correlates of QUS in women. This study investigated the cross-sectional associates of several lifestyle, demographic and genetic factors with calcaneal QUS parameters (broadband ultrasound attenuation (BUA) and speed of sound (SOS)) in 393 women aged 45-53 years. Leisure-time and historical physical activity, dietary calcium and protein, body composition, vitamin D receptor genotypes, menopause status, other health behaviors, calcaneal QUS parameters and bone mineral density (BMD) were assessed at a single clinic visit. Lean mass, recent physical activity and African-American race were the strongest correlates of SOS whereas dietary protein, calcium and recent physical activity were the strongest correlates of BUA. These predictors explained 13% and 6% of the variance in SOS and BUA, respectively. Smoking, alcohol intake, education, hormone replacement therapy, calcium and vitamin D supplements, historical physical activity and vitamin D receptor genotypes were not significantly associated with BUA or SOS. Lean body mass and premenopausal status were the strongest correlates of lumbar BMD whereas lean body mass, physical activity, African-American race and body mass index were significantly related to femoral neck BMD. Physical activity remained predictive of SOS after controlling for lumbar BMD. The spectrum and magnitude of risk factors for SOS and BUA, including lean body mass, physical activity, race, protein and calcium intake, parallel previously observed predictors of BMD.

OBJECTIVE The Hawaii IDDM Registry was created to determine the incidence rate of IDDM among children aged < 15 years of Oahu between 1980 and 1990. Because of the multiracial population living in Hawaii, it is an ideal state in which to study the effect of migration on IDDM incidence. RESEARCH DESIGN AND METHODS Data were collected by a retrospective hospital chart review and physician survey. Registry criteria included 0–14 years of age at IDDM diagnosis and primary residence on Oahu. Children who were military dependents were excluded. Denominator data were compared from two sources. RESULTS A total of 113 new-onset IDDM cases were identified. Case ascertainment was 97%. The unadjusted annual incidence rate was 7.04–7.61 per 100,000 (95% CI 5.83–9.19), depending on which denominator source was used. Race- and ethnicity-specific rates varied greatly (all rates per 100,000): part Hawaiian, 15.34–16.58; Caucasian, 6.21–6.71; Filipino, 3.66–3.96; and Japanese, 2.85–3.08. Temporally, the incidence fluctuated between a low of 2.96 per 100,000 in 1981 to highs of 11.11 and 11.85 per 100,000 in 1985 and 1989, respectively. Ascertainment-corrected rates for these years (3.70, 11.76, and 13.48 per 100,000, respectively) show that the fourfold incidence increase between 1980 and 1989 was not due to ascertainment differences. CONCLUSIONS IDDM incidence among children < 15 years of age in Hawaii was the lowest documented in the U.S. The incidence among part-Hawaiian children was 2.5 times > that of Caucasian children in Hawaii. IDDM incidence rates among Japanese children in Hawaii were comparable with rates in Japan. The temporal variation in IDDM incidence corresponded with a mid-1980s pandemic of IDDM documented elsewhere.

Quantitative ultrasound (QUS) is a simple, inexpensive and non-invasive measure of bone which has been used in research settings for the prediction of osteoporosis. This review summarizes the current status of the epidemiology of QUS analysis, including its relationship with bone mineral density (BMD), risk of osteoporotic fracture and risk factors for osteoporosis. Although only moderately correlated with BMD, QUS appears to be as strong a predictor of osteoporotic fracture as BMD and may predict fracture independent of BMD. Risk factors for low QUS, including age, menopause, body composition and physical inactivity, seem to parallel those of low BMD. More longitudinal research is needed to confirm the clinical utility of QUS and more experimental and population-based studies are needed to determine whether the etiology of low QUS values is different from that of low bone mass.

Background: Previous studies have suggested that IDDM subjects with diabetic autonomic neuropathy (DAN) have a greatly increased risk of mortality which may relate to a specific cardiologic etiology. Objectives: To examine the predictors of DAN in IDDM and its relationship to subsequent mortality. Study population: The Epidemiology of Diabetes Complications Study based on an incident cohort of childhood onset IDDM subjects. Data from two examinations, separated by 2 years, are utilized. Methods: Diabetic autonomic neuropathy was determined by Expiration/Inspiration (E/I ratio). A variety of baseline risk factors were related to its subsequent incidence (n = 57 out of 325 subjects free of DAN at baseline). Two-year mortality by DAN status was also determined for all 479 subjects seen at baseline. Results: Duration of diabetes, the cardiovascular risk profile (hypertension, elevated LDL cholesterol and triglycerides), and other complications (e.g. nephropathy) were all univariately associated with subsequent DAN (P < 0.01). Smoking status and hemoglobin A1 (HbA1), but less strongly, related (P < 0.05). Cox proportional hazards modeling showed diabetes duration and HbA1 to be significant independent predictors. Distal Symmetrical Polyneuropathy also contributed if added to the model. Mortality was increased four-fold in those with DAN (P = 0.005), although this difference no longer was significant after adjustment for baseline nephropathy (P = 0.35) or hypertension (P = 0.42). Conclusions: Duration of diabetes and HbA1 are the major predictors of DAN. However, although DAN is clearly associated with increased mortality, this is largely explained by associations with complications (e.g. nephropathy) and increased cardiovascular risk factors (e.g. hypertension).

A randomized study was conducted to test the feasibility of cholesterol lowering in physician office practices using the National Cholesterol Education Program Adult Treatment Panel 1 guidelines.Twenty-two physician practices in phase 1 and 23 in phase 2 were recruited from communities in Western Pennsylvania and West Virginia. These physicians treated a total of 450 adults in phase 1 (190 men and 260 women) and 480 adults in phase 2 (184 men and 296 women) with hypercholesterolemia. Three models (Usual Care [phase 1], Office Assisted [phase 2], and Nutrition Center [phase 2]) for implementing the National Cholesterol Education Program Adult Treatment Panel 1 guidelines were tested over an 18-month period. The baseline serum cholesterol levels were as follows: 6.51 mmol/L (252 mg/dL) in the Usual Care Model; 6.80 mmol/L (262 mg/dL) in the Office Assisted Model; and 6.96 mmol/L (269 mg/dL) in the Nutrition Center Model.In the patients who were not taking lipid-lowering medication, the mean cholesterol response was significantly different between the 3 models (P.01). Serum cholesterol levels declined by 0.14 mmol/L (5.4 mg/dL) in the Usual Care Model; by 0.31 mmol/L (12 mg/dL) in the Office Assisted Model; and by 0.54 mmol/L (20.9 mg/dL) in the Nutrition Center Model. Two factors-length of time to follow-up measurement and change in weight-were independently related to cholesterol response across all models. African Americans demonstrated a significantly smaller response than whites in the Usual Care Model, while men demonstrated greater declines in serum cholesterol levels than women in the Office Assisted Model. Patient satisfaction was very favorable in both enhanced conditions; however, those treated in the the Nutrition Center Model were more satisfied (P.05) with program components.The impact of nutrition intervention delivered through physician practices on serum cholesterol levels is less than clinically desirable, and new approaches with more aggressive therapy should be tested and implemented.

Background. A number of factors contribute to increased risk of coronary heart disease (CHD) among postmenopausal women, including atherogenic changes in serum cholesterol profiles, weight gain, and decreases in physical activity during the menopause. To date, no study has attempted to prevent elevations in primary CHD risk factors as women experience menopause. Methods. A sample of 535 healthy premenopausal women, ages 44-50, were recruited for an ongoing B-year randomized prevention trial testing whether increases in low-density lipoprotein cholesterol (LDL-C) and body weight can be prevented during the menopause with a dietary and behavioral intervention. The aim was to reduce total dietary and saturated fat and cholesterol, prevent weight gain, and increase physical activity levels. Changes in CHD risk factors after the first 6 months of treatment were analyzed comparing 253 intervention and 267 assessment-only control participants. Results. The intervention group showed significant reductions in total cholesterol (−0.34 mmol/liter), LDL-C (−0.28 mmol/liter), triglycerides (−0.04 mmol/liter), weight (−4.8 kg), waist-hip ratio (−0.008), systolic blood pressure (−3.5 mm Hg), diastolic blood pressure (−2.2 mm Hg), serum glucose levels (−0.06 mmol/liter), and HDL-C (−0.06 mmol/liter) and significant increases in physical activity (+383 kcal). No significant changes were observed in the control group. Conclusion. Six-month results suggested that participants were receptive to the preventive approach to CHD risk reduction and were successful in making initial positive lifestyle changes. Follow-up data will evaluate long-term adherence to the intervention and the interaction between adherence and physiological changes during menopause.

Background The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study. Methods and Results A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes. Conclusions The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

Steady progress has been made in the prevention of cardiovascular disease. There has been a favorable trend in major risk factor reduction and an average 3% annual decline in cardiovascular disease death rates over the past decade. Yet, CVD death rates still exceed that for many countries and not all segments of the U.S. population have benefited equally. Cardiovascular disease remains the leading cause of death and disability in this country. The role of epidemiologic research and prevention strategies in addressing this issue has been underestimated. Unresolved research questions require further epidemiologic research in order to improve application of known preventive measures and explore other approaches toward the prevention of cardiovascular disease. It is well established that attention to life-style changes and pharmacologic approaches can prevent cardiovascular disease in those at high risk and reduce the likelihood of subsequent cardiac events among patients with known cardiovascular disease. Furthermore, small changes in the distribution of risk factors through community intervention can have tremendous impact on cardiovascular disease morbidity and mortality. Preventive research requires an appropriate framework and plan to satisfy or exceed the needs in keeping with the national goals for Healthy People 2000. The National Heart, Lung, and Blood Institute has addressed this issue by creating a Task Force to develop research priorities for epidemiology and prevention.

Some epidemiologic studies have compared the characteristics of individuals who participate, refuse, and are unreachable in population studies, but results have been inconsistent. The Rural Health Promotion Project attempted to recruit all Medicare Part B noninstitutionalized individuals age 65-79 years in a rural community for a trial of preventive health services. Of 962 potential subjects, 360 (37.4%) participated, 253 (26.3%) refused, 176 (18.3%) were ineligible, and 152 (15.8%) were never reached by phone or mail. Approximately 3 years later, we reinterviewed the participants, refusals, and as many of the unreachables as possible. The 3-year mortality was similar for both refusals and participants (approximately 9%) but was much higher for ineligibles (29.0%) and unreachables (23.7%). Participants were more likely to have disease history, to have behavioral risk factors for disease, and to use health screening services. Refusals were the healthiest and possibly chose not to participate because they did not have risk factors targeted by the program. The unreachables had the highest prevalence of disability and health care inpatient reimbursement and may have been ineligible for the demonstration had they volunteered. We conclude that failure to reach potential participants for health promotion services may be a warning of "high risk."

Background . Influenza is responsible for significant morbidity, mortality, and medical costs, but immunization rates in the elderly remain low. Methods . As part of a demonstration project in rural Pennsylvania, 1,989 community-dwelling Medicare beneficiaries, 65-79 years old, completed a health risk appraisal including questions about flu shots. Participants were randomized to two experimental (hospital or physician) or control groups. Experimental groups were offered free flu shots for the 1990-91 flu season. Follow-up interviews to determine vaccination rates were completed about 1 year later. Results . Baseline immunization rates were almost identical for the hospital-based (41.2%), physician-based (41.3%), and control group not offered free immunizations (40.6%). Follow-up rates for the groups offered immunizations rose significantly to 63.6 and 69.1% for hospital and physician groups, respectively, while the control group also increased significantly to 54.1%. Individuals who were more educated, were older, and had greater chronic diseases history (myocardial infarction, hypertension, and pulmonary disease) were more likely to be immunized. Male and married elderly were more likely to be immunized as a result of the demonstration. Conclusions . Increasing community education and providing immunizations free through Medicare will increase immunization rates among elderly. The elderly are more likely to receive flu shots provided through physicians′ offices than through hospital-based clinics.

The relationships between physical activity, obesity, fat distribution and glucose tolerance were examined in the Pima Indians who have the highest documented incidence of non-insulin-dependent diabetes. Fasting and 2-h post-load plasma glucose concentrations, body mass index, and waist-to-thigh circumference ratios were determined in 1054 subjects aged 15–59 years. Current (during the most recent calendar year) and historical (over a lifetime) leisure and occupational physical activity were determined by questionnaire. Current physical activity was inversely correlated with fasting and 2-h plasma glucose concentrations, body mass index and waist-to-thigh ratios for most sex-age groups even when diabetic subjects were excluded. Controlled for age, obesity and fat distribution, activity remained significantly associated with 2-h plasma glucose concentrations in males. In subjects aged 37–59 years, individuals with diabetes compared to those without reported significantly less leisure physical activity during the teenage years (median hours per week of activity, 9.1 vs 13.2 for men; 1.0 vs 2.2 for women). Controlled for body mass index, sex, age and waist-to-thigh ratio, subjects who reported low levels of historical leisure physical activity had a higher rate of diabetes than those who were more active. In conclusion, current physical activity was inversely related to glucose intolerance, obesity and central distribution of fat, particularly in males. Subjects with diabetes were currently less active and reported less historical physical activity than non-diabetic subjects. These findings suggest that activity may protect against the development of non-insulin-dependent diabetes both directly and through an influence on obesity and fat distribution.

Prospective studies of the relatives of people with Type 1 diabetes can provide insights into risk factors for processes leading to the ultimate destruction of the pancreatic islet 8-cells. Relatives ascertained through the Children's Hospital of Pittsburgh diabetes registry were followed and rates of conversion to diabetes were determined. We studied the role of genetic and immunological markers, and used the oral glucose tolerance test (OGTT) to study metabolic disturbances among first-degree relatives. A group of siblings was serotyped for the HLA-A and -B antigens, and the degree of HLA haplotype sharing with the diabetic sibling was established. Later, islet cell antibody (ICA) assays were performed, and subjects were followed to determine the predictive value of ICA testing for the subsequent development of diabetes. The rate of conversion to diabetes among the siblings was 14 times greater than the rate observed in the general population from which they come. This is comparable to rates observed by other centres following relatives of people with Type 1 diabetes. Impaired glucose tolerance (by National Diabetes Data Group (USA) criteria) carried a three-fold greater risk for subsequent Type 1 diabetes than did a normal OGTT. Those relatives with detectable ICA were about 50 times more likely to convert to diabetes than were those without ICA. In a group of siblings in whom HLA haplotype sharing was determined, the prevalence of detectable ICA was greater among those who were HLA-identical to the diabetic sibling (9.9 %) than among those who were haplo-identical (5.3 %) or completely dissimilar (2.4 %) at the HLA-A and -B regions. Similarly, the incidence of Type 1 diabetes was greater among those who were HLA-identical (8.4 per 103 sibling-years), than among those who were not HLA-identical to the proband (4.2 per 103). The greatest risk for subsequent diabetes was found among HLA-identical siblings who were ICA-positive. Approximately 7 % of those who were HLA non-identical or haplo-identical and ICA-positive became diabetic within 5 years, while more than 30 % of HLA-identical siblings who were ICA-positive became diabetic during the 5 years after ICA were detected.

BACKGROUND Aging is associated with an increased risk of women dying from coronary heart disease as well as from all causes combined. Alterations in the major biological risk factors for early coronary heart disease and all-cause mortality are frequently seen in aging. METHODS AND RESULTS The present investigation tested the hypothesis that high levels of physical activity could protect against age-associated changes in biological risk factor levels. In the Healthy Women Study, 507 women were evaluated at study entry and 3 years later. Weekly physical activity level was measured at each examination via the Paffenbarger Physical Activity Questionnaire. During the 3-year period, women increased significantly in weight, blood pressure, levels of total and low-density lipoprotein cholesterol, triglycerides, and insulin and decreased significantly in levels of total high-density lipoprotein cholesterol (HDL-C) and HDL2-C. CONCLUSIONS Consistent with the study hypothesis, women who reported higher levels of activity at baseline had less weight gain over time. Furthermore, women who increased their activity during the 3-year interval had the smallest increases in weight and tended to have the smallest decreases in total HDL-C and HDL2-C. The changes in lipids due to activity were largely independent of changes in body weight.

Waist to hip ratio (WHR) was measured in 487 middle-aged women participating in the Healthy Women Study. Upper body fat distribution was found to be associated with numerous behaviors that affect cardiovascular risk, including smoking, low exercise levels, weight gain during adulthood, and higher caloric intake. Moreover, WHR was also associated with higher levels of anger, anxiety, and depression and lower levels of perceived social support. Women with upper body fat obesity had higher systolic blood pressure, total cholesterol, low density lipoprotein cholesterol, triglycerides, and apolipoprotein B and lower levels of high density lipoprotein (HDL) and the HDL subfractions 2 and 3. These associations remained significant after adjusting for body mass index. Among 108 women who had repeat measurements of WHR, changes in WHR over a 3-year period were significantly correlated with changes in activity and with decreases in HDL2. Thus, WHR appears to be an integral component of the cardiovascular risk profile. WHR is related to those behaviors and psychosocial attributes that influence cardiovascular risk.

A simple method for screening populations for the apolipoprotein E polymorphism which involves isoelectric focusing of delipidated samples on polyacrylamide gels of pH 4.5–5.8 followed by immunoblotting using a double-antibody technique is presented. The method is a synthesis of two previously published procedures and works well on samples that have been stored for as long as 15 years.

The relation between cigarette smoking and mortality was examined prospectively in a population of adult insulin-dependent diabetes mellitus (IDDM) patients. In 1981, information on smoking history and other health and lifestyle factors was obtained by questionnaire from 93% of the 723 patients included in the Children's Hospital of Pittsburgh IDDM registry who were diagnosed between 1950 and 1964. Vital status as of January 1, 1988 was ascertained for 98% of the 548 patients who participated in the baseline survey and were alive as of January 1, 1982. Fifty-four cases died during the 6-year follow-up (32 male, 22 female). Proportional hazards analysis revealed that heavy smoking was a significant independent predictor of all-cause mortality among females but not males. The excess mortality in female diabetics was explained primarily by a marked excess risk of coronary heart disease mortality in smokers. These data strongly suggest that cigarette smoking, especially among diabetic females, should be avoided in order to improve longevity.