Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry.

African ancestry individuals have a more favorable lipoprotein profile than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 Afro-Caribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21-113, 3,426 relative pairs). All lipoproteins were significantly heritable (P<0.05). Gender-specific analysis showed that heritability for triglycerides was much higher (P<0.01) in women than in men (women, 0.62+/-0.18, P<0.01; men, 0.13+/-0.17, P>0.10), but the heritability for LDL cholesterol (LDL-C) was higher (P<0.05) in men than in women (men, 0.79+/-0.21, P<0.01; women, 0.39+/-0.12, P<0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed significant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9) and LDL-C in both the family study and in the replication study. Our findings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals. Future sequencing and functional studies of these loci may advance our understanding of genetic factors contributing to LDL-C in African ancestry populations.

Positive predictive value (PPV) of prostate specific antigen (> ng/ml) and abnormal digital rectal exam for prostate cancer on the Caribbean island of Tobago

OBJECTIVE: To establish and compare the positive predictive values (PPV) for elevated (4 ng/ml) prostate specific antigen (PSA) and abnormal digital rectal exam (DRE) in an Afro-Caribbean population. DESIGN AND METHODS: We screened 728 men aged 40-79 years, recruited from the general population on the Caribbean island of Tobago. Ninety-five percent reported African ancestry. This population had not previously undergone screening for prostate cancer. RESULTS: PSA was elevated (> or = 4 ng/ml) and/or DRE was abnormal in 291 (40 percent) men. Pathological diagnosis of random sextant biopsies was completed in 191 (66 percent) of men. Ninety-two (13 percent) of the screened men were diagnosed with prostate cancer. Among men biopsied for abnormal DRE in the presence of normal PSA, PPV for abnormal DRE was 26 percent (11/43), range 9-50 percent across age groups. Among men with elevated PSA and normal DRE, the PPV for PSA was 46 percent (29/63), range 42-54 percent (no men aged 40-49 years (n=105) fell into this category). When all men with elevated PSA were considered, ignoring DRE status, PPV for PSA was 55 percent (79/144), range 50-60 percent. If both PSA and DRE were abnormal, the PPV was 63 percent. CONCLUSIONS: The PPV of abnormal DRE was similar to that observed in other populations undergoing screening for the first time. We speculate that a lower PSA cut-off point may be appropriate for optima ascertainment of cases in this high-risk population.(Au)

Cholesterol-lowering intervention program. Effect of the step I diet in community office practices.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Clinical infections in the noninstitutionalized geriatric age group: methods utilized and incidence of infections. The Pittsburgh Good Health Study.

Because noninstitutionalized senior citizens comprise over 95% of the population 65 years of age and older, their health needs are a major concern. Data regarding infections in this population including the epidemiology, morbidity, and mortality are lacking. The authors recruited a study population of 417 free-living persons, all 65 years of age or older, from two neighborhoods in Pittsburgh, Pennsylvania. After the collection of self-reported baseline information from these persons, they were monitored for all clinical infections for 2 years, beginning July 1986 and through June 1988, using clinic visits, hospitalizations, or phone calls when needed. The baseline information showed the study population of 417 persons to be comparable with a neighborhood comparison group and with established populations for epidemiologic studies of the elderly in three other states. The 24 months of infection surveillance yielded 494 diagnosed infections in 224 or 54% of the subjects. Respiratory infections were most frequent with 259 or 52% of the total, followed by genitourinary infections with 24%, skin infections with 18%, gastrointestinal infections with 4%, and other types of infection with 2%. By comparing 22 self-reported baseline conditions with the occurrence of infection, 10 historic factors were univariately significant for infection. Of these 10 factors, only history of a lung problem (relative risk = 1.7, 95% confidence interval (CI) 1.1-2.9) and history of difficulty controlling urination (relative risk = 2.7, 95% CI 1.3-4.9) were statistically significant in multivariate analysis. To our knowledge, this study represents the first prospective data on infections in the noninstitutionalized elderly. The data demonstrate the wide variety of infections that occurred in this population and suggest that persons with a history of any one of several medical problems were possibly at greater risk for infection.

Influence of the perimenopause on cardiovascular risk factors and symptoms of middle-aged healthy women.

OBJECTIVE: To determine the changes in cardiovascular risk factors and psychological and physical symptoms that occur during the perimenopause. DESIGN: Cohort study of 541 healthy middle-aged premenopausal women followed up through the menopause. SETTING: General community. PARTICIPANTS: After a baseline evaluation taken at study entry, 152 women ceased menstruating for 3 months (not due to surgery) and were not using hormone replacement therapy, and were reevaluated in a similar protocol (perimenopausal examination); 105 of the 152 were evaluated a third time when they had ceased menstruating for 12 months and were not using hormone replacement therapy (postmenopausal examination). One hundred nine premenopausal women who were repeatedly tested constituted a comparison group. MAIN OUTCOME MEASURES: Levels of lipids and lipoproteins, triglycerides, fasting glucose and insulin, blood pressure, weight, height, and standardized measures of psychological symptoms. RESULTS: Women who became perimenopausal showed increased levels of cardiovascular risk factors, which were similar in magnitude to those experienced by the comparison group of premenopausal women. Perimenopausal women reported a greater number of symptoms, especially hot flashes, cold sweats, joint pain, aches in the skull and/or neck, and being forgetful; reports of hot flashes at the perimenopausal examination were associated with low concentrations of serum estrogens. Menopausal status was not associated with depressive symptoms. Perimenopausal women who became postmenopausal showed a decline in the level of high-density lipoprotein-2-cholesterol (means, 0.53 to 0.43 mmol/L [20.6 to 16.7 mg/dL]) and a gradual increase in the level of low-density lipoprotein cholesterol (means, 3.14 to 3.33 mmol/L [121.3 to 128.8 mg/dL]), whereas symptom reporting declined. CONCLUSIONS: During mid-life, women experience adverse changes in cardiovascular risk factors and a temporary increase in total number of reported symptoms, with no change in depression. Preventive efforts to reduce the menopause-induced increase in cardiovascular risk factors should begin early in the menopausal transition.

Future in lipid and lipoprotein research: from preventing clinical disease to preventing elevated risk factors.

The decline in cardiovascular disease has been a major public health success. The relationship between key risk factors such as blood cholesterol levels, smoking, high blood pressure and clinical disease are universally accepted. The approaches to the prevention of cardiovascular disease are changing to a greater emphasis on the prevention of elevated risk factors by better understanding of the relationship between lifestyle and host susceptibility (genetic attributes) and the risk factor changes with age. The development of new methods to measure vascular disease non-invasively in vivo changes the approaches to evaluation of both risk and definition of endpoints in analytical studies and clinical trials. It is possible now to increase the rate of decline in coronary heart disease.

Selection bias and nonresponse to health promotion in older adults.

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."

Insulin as a predictor of coronary heart disease: interaction with apolipoprotein E phenotype. A report from the Multiple Risk Factor Intervention Trial.

The objective of this study was to examine whether fasting serum insulin is a predictor of coronary heart disease in high-risk US men, and whether any such predictive role explains the enhanced cardiovascular risk seen in subjects with the apolipoprotein (Apo) E 3/2 phenotype. This was a nested case-control study of participants in the Multiple Risk Factor Intervention Trial. Ninety-four subjects who died from coronary heart disease (post-trial follow-up) and 114 case patients with myocardial infarction (during trial) were compared to control subjects (n = 414) matched (1:2) by age, center, randomization date, and intervention group. Overall, fasting serum insulin at baseline was not associated with case-control status. (Means for cases versus controls: 16.8 and 16.6 microU/mL), although serum insulin showed significant correlations with low-density-lipoprotein cholesterol, triglycerides, and uric acid. When stratified by the three Apo E phenotypes, 3/2, 3/3, 3/4, a significant association of fasting insulin with case-control status was seen for Apo E 3/2 individuals (19.9 versus 14.5 microU/mL; P = 0.02) but not for those with the other two phenotypes. Though fasting insulin is not a risk factor overall in this high-risk male population, it appears to contribute to cardiovascular risk in those with the Apo E 3/2 phenotype but does not explain the increased risk seen in these subjects. This new finding, if confirmed, may throw further light on the role of insulin in atherosclerosis.

Pregnancy outcome and anti-cardiolipin antibody in women with systemic lupus erythematosus.

Pregnancies in women with systemic lupus erythematosus are recognized to result in excessive fetal morbidity and mortality. Maternal autoantibody status may explain some of these problems. Anti-cardiolipin antibody has been associated with recurrent pregnancy losses in some women with lupus, but the risk of these losses has not been defined. At the University of Pittsburgh between January 1, 1979, and December 31, 1989, an unmatched case-control study design was used to determine whether patients with lupus and anti-cardiolipin antibody (81 cases) were at increased risk for adverse pregnancy outcomes in comparison with lupus patients without the antibody (174 controls). Cases had 98 of 192 (51%) pregnancies with an adverse outcome, while controls had 212 of 494 (43%). The odds ratio for having any adverse pregnancy outcome was 1.40 (95% confidence interval (CI) 0.98-1.98). When pregnancies were classified according to specific adverse outcome types, the frequency of late miscarriages (14-20 weeks gestation) in cases and controls was 8% and 3%, respectively. The odds ratio for late miscarriage was 2.94 (95% CI 1.31-6.60). When pregnancies were stratified by birth number and by occurrence of pregnancy before or after diagnosis, the increased frequency of late miscarriages in cases was noted only in the first pregnancy when the pregnancy occurred before recognized disease. Preterm births (before 38 weeks gestation) were increased in cases compared with controls in pregnancies that occurred after diagnosis for second and third pregnancies. If a case had one previous adverse outcome, the odds ratio for another adverse outcome was 3.00 (95% CI 1.62-5.57). If a case had two previous adverse outcomes, the odds ratio for a third adverse pregnancy outcome was 4.14 (95% CI 1.62-10.58). Thus, a previous adverse pregnancy outcome was the most important risk factor for an adverse outcome in a subsequent pregnancy.

Sodium-lithium countertransport activity is decreased after weight loss in healthy obese men.

Maximal red blood cell (RBC) sodium-lithium countertransport activity has been consistently related to essential hypertension and may be a marker for risk of developing hypertension. Although there is strong evidence for genetic control of sodium-lithium countertransport, increasing evidence suggests that obesity and insulin-glucose metabolism are related to countertransport activity. This study was performed to determine whether countertransport activity decreases with weight loss in healthy obese adults. Forty-five healthy, white, obese adults were studied at baseline and after 6 months of behavioral dietary intervention. Weight loss was 11.5 kg (25.4 lb) in 24 men and 8.1 kg (17.8 lb) in 21 women. Sodium-lithium countertransport activity decreased 55.0 mumol Li/L RBC/h in men (P < .001, paired t test) and 14.6 mumol Li/L RBC/h in women (NS). Change in countertransport activity was correlated with change in body mass index (BMI) in men (r = .52, P < .01) and women (r = .27, NS) and was also strongly correlated with change in fasting glucose levels in both men and women (r = .50 and r = .56, respectively; P < .01) and with change in fasting insulin levels in men (r = .42, P = .04). Change in countertransport activity was not significantly related to change in physical exercise or serum lipid levels. There was a large decrease in systolic blood pressure in men (10.0 mm Hg, P < .001) and a smaller decrease in women (4.1 mm Hg, P < .05). These changes were significantly correlated with change in weight, but not with change in countertransport or baseline countertransport activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Environmental and familial contributions to insulin levels and change in insulin levels in middle-aged women.

OBJECTIVE: To examine familial and environmental variables associated with elevated insulin levels and changes in insulin levels in healthy, premenopausal women. METHODS: A population-based sample of 518 women (aged 42 to 50 years) completed baseline assessments of weight, cardiovascular risk factors, exercise behaviors, and glucose and insulin levels (fasting and 2 hours after a glucose load); 495 of the women were reevaluated after 3 years. RESULTS: Plasma insulin levels were related to weight, activity level, race, body fat distribution, and weight gain since age 20 years. Parental history of either diabetes or hypertension was also related to elevated insulin levels, independent of body mass index, with the highest insulin levels occurring in those women with a parental history of both diseases. Increases in plasma insulin levels over the years of follow-up were related to weight gain. CONCLUSIONS: This study suggests that importance of using family history to identify women who may have elevated insulin levels and of intervening to prevent weight gain during middle age.

The use of the medical record and financial data to examine the cost of infections in the elderly.

This study demonstrates what can be accomplished when the medical record and other data sources are utilized. By using the medical record as well as financial data and input from the infectious disease department, a detailed analysis of infections in an elderly population in relation to cost and length of stay was completed. This pilot study also enabled the hospital to determine the types of studies that should be done in the future. Quality assessment and improvement studies that examine the effectiveness of infection control procedures over time, the importance of examining both community-acquired and nosocomial infections, and the differences that severity of illness may have on cost and length of stay are all areas that have been identified as needing further study. Future studies in this area and other areas will continue to utilize the medical record. However, the data obtained from the medical record should not be examined alone. It should be analyzed along with other data sources such as severity of illness data, financial data, quality assessment data, infection control data, and risk management data in order to examine epidemiological trends over time. Only when several data sources are used together to investigate a particular aspect of care will that aspect of care be thoroughly and completely examined.

Change in waist-hip ratio with weight loss and its association with change in cardiovascular risk factors.

We investigated whether weight loss decreases the waist-hip ratio (WHR) in overweight men and women, and whether changes in WHR relates to change in cardiovascular risk factors, independent of change in weight. Weight loss correlated significantly with decreases in the circumference of the waist and hips, and decreases in WHR in men and women. At comparable levels of weight loss, men had greater decreases in the waist, and smaller decreases in the hips than women, resulting in greater decreases in WHR. Cardiovascular risk factors improved significantly with weight loss. However, after controlling for weight loss, there was no evidence that change in WHR or change in circumference measures were related to change in risk factors. These data suggest that WHR is modifiable by weight loss, especially in men, but that change in WHR may not be independently related to changes in cardiovascular risk factors.

The impact of the apolipoprotein E polymorphism on the lipoprotein profile in insulin-dependent diabetes: the Pittsburgh Epidemiology of Diabetes Complications Study IX.

The apolipoprotein (apo) E polymorphism has been related to differences in lipoprotein metabolism and lipid/lipoprotein concentrations in a number of studies. Whether these associations are seen in insulin-dependent diabetes mellitus (IDDM), which itself affects many of the same aspects of lipoprotein metabolism as does the apo E polymorphism, is unknown. The present study is an investigation into the influence of apo E phenotype on lipoprotein concentrations in a large group of IDDM patients (n = 433) participating in the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. The frequency of the three apo E alleles 2, 3, and 4 did not differ in this population from that reported in general white populations. Although the diabetic subjects show the same trends as seen in the general population, ie, apo E-2 is associated with lower and apo E-4 with higher low-density lipoprotein cholesterol (LDLc) compared with apo E3 (P less than .03), they also show relationships with glycemic control that influence the relative levels of lipid measures with respect to apo E phenotype. Results also raise the possibility that lipoprotein composition varies according to apo E phenotype in IDDM.

Tracking of blood pressure and anthropometric measures in Nigerian children.

Persistence in ranks (tracking) for blood pressure and anthropometric measures over a one year period was examined in 208 Nigerian children (age 6-17 years). Systolic blood pressure tracked better than diastolic blood pressure (r = 0.52 to 0.72) and r = 0.25 to 0.55, respectively). For systolic blood pressure, 56.5%-70.6% of the Nigerian children remained in the top tertile after one year compared with 45.5%-69.2% for diastolic blood pressure. Weight showed the strongest correlation over the one year period (r = 0.88 to 0.97), whereas skinfolds demonstrated the weakest association (r = 0.54 to 0.82). The association between anthropometric measures at baseline and blood pressure one year later revealed for both males and females that height and weight were positively and significantly correlated with blood pressure.

Cholesterol screening in childhood: sixteen-year Beaver County Lipid Study experience.

To determine the extent to which cholesterol measured in childhood is predictive of values in adulthood, the investigators conducting the second follow-up of the Beaver County Lipid Study tracked the cholesterol values of 295 adults who had initially participated as children (ages 11 to 14 years) in a countywide school screening program. The follow-up study was conducted 16 years after the initial study, when the participants had reached a mean age of 28 years. The overall correlation (r) between baseline (1972-1973) total cholesterol values and the values found at the present follow-up was 0.44 (p less than 0.0001). Women had a higher correlation (r = 0.51) than men (r = 0.38). In addition, the efficacy of childhood screening for cholesterol levels was assessed by considering currently recommended borderline values (greater than 175 mg/dl (4.6 mmol/L) for children and greater than 200 mg/dl (5.2 mmol/L) for adults) as a "positive" test result. The sensitivity of screening at age 12 years for predicting elevated adult total cholesterol concentrations was 63%, specificity was 67%, and the predictive value of a positive test result was 47%. Comparison of false-positive results (above the borderline cutoff point as a child but not as an adult) and false-negative results (below the borderline cutoff point as a child but above it as an adult) showed that male subjects with false-positive results smoked significantly less than those with false-negative results (p less than 0.05) and had a greater improvement during the preceding 7 years in cholesterol-lowering dietary practices (p less than 0.01). Female subjects with false-positive results smoked significantly less than those with false-negative results (p less than 0.05), were less overweight (p less than 0.05), and had a lower prevalence of oral contraceptive use (p less than 0.01). These results support the potential value of screening for hypercholesterolemia in childhood on a population basis. Although some subjects were misclassified as a result of childhood screening, some of this misclassification was associated with adopting changes that a screening and intervention program would be designed to promote--nonsmoking, weight control, and a prudent diet.

Waist to hip ratio in middle-aged women. Associations with behavioral and psychosocial factors and with changes in cardiovascular risk factors.

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.

Psychological, biological and health behavior predictors of blood pressure changes in middle-aged women.

A long-standing hypothesis is that feelings of anger and anxiety increase the risk for essential hypertension. Most studies examining this hypothesis have been cross-sectional in design or undertaken with men only. We tested this hypothesis along with determination of the other behavioral and biological predictors of increases in systolic (SBP) and diastolic (DBP) blood pressure from baseline to a follow-up examination 3 years later in a prospective study of 468 middle-aged women whose blood pressure at the baseline examination was less than 140/90 mmHg. Analyses showed that increases in the Spielberger Trait Anger Scale between the baseline and 3-year follow-up examination, as well as Framingham Tension scores (a measure of anxiety) at baseline, independently predicted an increase in SBP (P less than 0.01). Other factors that independently predicted an increase in SBP were baseline fasting insulin, parental history of hypertension and increases in body mass index and in alcohol intake across the 3 years of follow-up. Increases in the Spielberger Trait Anger Scores independently predicted increases in DBP (P less than 0.02), as did black race, increases in body mass index and hematocrit and decreases in potassium intake. Although menopausal status and hormone replacement therapy were unrelated to changes in blood pressure, postmenopausal women on hormone replacement therapy did show significant increases in DBP in the univariate analysis. Anxiety at baseline, along with parental history of hypertension, baseline fasting insulin and baseline body mass index, predicted a later onset of hypertension, i.e. on pharmacologic treatment for hypertension, in the univariate analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of age, gender, and education on cognitive tests in a rural elderly community sample: norms from the Monongahela Valley Independent Elders Survey.

A random sample of 1,350 persons aged 65 years and older in a rural community underwent cognitive screening as part of a survey to establish a population-based registry of dementing disorders. The screening battery included the neuropsychological tests of the assessment protocol used in the National Institute on Aging multicenter Consortium to Establish a Registry for Alzheimer's Disease (CERAD). This paper reports a large body of normative neuropsychological data from this sample with members of relatively low socioeconomic status. Age, sex, and educational level were found to have statistically significant effects on test scores. The implications of these findings for the establishment of screening cutoff scores are discussed.