OBJECTIVES: Type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) are highly comorbid conditions that are affected by psychological factors, such as self-efficacy. Psychological factors can either hinder or promote medical interventions. Self-efficacy, the belief that one is able to make changes necessary for self-management, is associated with glycemic control and cardiac symptom burden, as well as behaviors that affect CAD prevention and outcomes. METHODS: Using data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, we assessed the relationship between self-efficacy and the treatment, risk factor control, and cardiac outcomes of patients with T2DM and CAD. RESULTS: The first paper (N=889) showed no significant relationships between self-efficacy and randomized treatment for CAD (revascularization vs. medical therapy &beta;=0.06, p=0.66) and T2DM (insulin sensitizers vs. insulin providers &beta;=0.06, p=0.65) in patients with baseline self-efficacy scores &le;8. The second paper (N=1,562) verified a negative association between baseline self-efficacy and follow-up HbA1c (&beta;=-0.03, p<.001) and a positive association with self-efficacy and physical functioning in which time negatively modified the association(interaction p=0.02). A lagged association (feedback loop) was shown between self-efficacy and HbA1c, physical functioning, and BMI over time. The feedback loops were stronger in White non-Hispanic patients compared to minority patients. In the third paper (N=1,817), poor baseline self-efficacy was associated with an increased risk of a composite endpoint of death/myocardial infarction/stroke (hazard ratio [HR] =1.34, p=0.01), subsequent revascularizations (HR=1.30, p=0.004), subsequent PCIs (HR=1.43, p<.001), and angina (odds ratio [OR] =1.11, p<.001) compared to Fair-Excellent self-efficacy, but not after adjusting for baseline covariates. A decrease in self-efficacy from baseline to Year 1 was positively associated with all-cause mortality (adjusted HR=2.32, p<.001) and death/MI/stroke (adjusted HR=1.79, p<.001). CONCLUSIONS: In summary, self-efficacy was associated with clinical risk factors and cardiac outcomes in patients with CAD and T2DM. This is of public health significance because it stresses the importance of improving a patient's confidence in managing their conditions outside of the medical setting.

Ectonucleotide pyrophosphatase/phosphodiesterase 1, which downregulates insulin signaling by inhibiting insulin-receptor tyrosine kinase activity, is encoded by the ENPP1 gene. Common variants in ENPP1 have been associated with body mass index (BMI), diabetes and glycemia related traits in populations of European Ancestry, but data in African ancestry populations are sparse. Our objective was to evaluate common ENPP1 variants for association with diabetes and glycemia related traits in a high risk Afro-Caribbean population. Thirty-four single nucleotide polymorphisms (SNPs) based on pair-wise tagging (r2 > 0.80; MAF > 0.05) were successfully genotyped in 380 cases and 1,455 controls without diabetes. Associations with BMI, fasting glucose, fasting insulin and HOMA-IR were also analyzed in non-diabetic controls. The most interesting association was observed between rs1044498 K121 allele and lower BMI (age-adjusted P = 0.018). Nominal associations were observed with ENPP1 SNPs and fasting glucose (age-and BMI-adjusted P=0.001 to 0.020). Also, six SNPs showed nominal evidence for association (P < 0.05) with diabetes in one or more genotypic model. The most significant associations were observed with SNPs in intron 11 (rs17060836; OR=1.32 [1.04-1.67]; dominant P = 0.019), two SNPs in intron 1 (rs703184, rs7749493; OR= 0.78 to 1.39) and three SNPs in the 3' untranslated region (rs7754561, rs7769993 and rs9373000; OR = 0.69-1.38). In this population of Afro-Caribbean men, the ENPP1-rs1044498 the K121 allele and intronic variants may modulate BMI and glucose. Also, variants in the 3' UTR confer an increased risk of developing diabetes confirming and extending reports in European and African Americans. After accounting for multiple testing, we conclude that ENPP1 is not a major contributor to diabetes related traits; nevertheless, our results reveal that variants in the ENPP1 gene may modulate BMI and maintain glucose homeostasis in this population of Afro-Caribbean men. These studies are of public health relevance or importance because they contribute epidemiologic information to the genetic etiology of type 2 diabetes in men of African ancestry.

INTRODUCTION: Chronic kidney disease is a serious public health concern because of the large physical and economic burden on society. Because of this large burden, it is important to determine what factors are associated with the development and progression of the disease, especially in early stages. Physical activity has been shown to be related to many risk factors for CKD; however, few studies have assessed its direct relationship with kidney function. METHODS: Using data from NHANES, a nationally representative U.S., we described physical activity by various intensities, gender and race/ethnicity (paper 1). We then investigated the cross-sectional relationship between varying intensities of objectively assessed physical activity and kidney function in the same population (paper 2). Using data from the Strong Heart Study, an American Indian cohort at high risk for CKD, we investigated the relationship between subjectively assessed physical activity with kidney function prospectively (paper 3). RESULTS: We showed that Mexican Americans were more physically active than whites and blacks at all levels of intensity, in contrast to findings using questionnaires. We also confirmed that light intensity activity made the largest contribution to total movement. In paper 2, we showed that objectively assessed light intensity physical activity was independently associated with kidney function while objectively and subjectively assessed moderate to vigorous physical activity was not. In paper 3 we showed that physical inactivity was associated with rapid declines and kidney function over a five year period. Physical inactivity was also associated with development of kidney damage over a ten year period. PUBLIC HEALTH SIGNIFICANCE: The results of these three papers show that physical activity of various intensities are related to kidney function and that physical activity may also preserve kidney function over time in a high risk population. Previous recommendations for physical activity and health were unable to discuss the benefits of physical activity on kidney function because the paucity of evidence. This study is of public health significance because it adds to the growing body of evidence for which we can base our future recommendations.

Cardiovascular disease is of public health significance due to its highest rates of mortality. Atherosclerotic cardiovascular events can often result in fatal or disabling non-fatal events. More than half of CHD fatal events do not show earlier symptoms. Early identification of subclinical atherosclerosis and establishment of preventive control are important to reduce CHD mortality and morbidity. The present study aimed to examine: 1) whether n-6 fatty acids are inversely associated with plasminogen activator inhibitor-1 (PAI-1) and fibrinogen; 2) whether vitamin D deficiency is associated with subclinical atherosclerosis; and 3) whether Japanese men have lower incidence or progression of CAC than Caucasian men, and further if marine n-3 fatty acids are inversely associated with incidence or progression of CAC. To test these aims, the Electron-Beam Tomography, Risk Factor Assessment among Japanese and U.S. Men in Post-World War II Birth Cohort (ERA-JUMP) study was utilized. The findings were: 1) in a population-based cross-sectional-sample of 915 men aged 40-49, serum n-6 fatty acids were inversely and significantly associated with PAI-1 but not with fibrinogen; 2) in 295 middle-aged men of a population-based cross-sectional sample, Japanese men showed lower levels of serum vitamin D, despite their habitual fish intake as a major dietary intake, than Caucasian or Japanese-American men. Further, vitamin D deficiency was not associated with subclinical atherosclerosis as measured by intima-media thickness (IMT) and CAC, except for significant associations on IMT in a univariate model among Caucasian men, and on CAC in both univariate and multivariate models among Japanese-American men; and 3) in the follow-up study of 472 men, Japanese men had a significantly lower incidence and progression of CAC than Caucasian men. Japanese men showed significant risk reduction on incident CAC associated with marine n-3 PUFA. However, Japanese and Caucasian men showed no significant associations of marine n-3 PUFA on the progression of CAC. Future studies to examine the causal associations as well as underlying mechanisms are warranted. From the public health importance, these findings extend our understanding of n-3 and n-6 polyunsaturated fatty acids and vitamin D related to subclinical atherosclerosis as well as help to establish public health guidelines.

Adiponectin has been shown to improve insulin sensitivity, regulate glucose and lipid metabolism and exert anti-atherosclerotic effects. This dissertation, designed as three research papers, aimed to examine relationships between diet, weight loss, insulin resistance and adiponectin levels among overweight/obese adults who were participating in a behavioral intervention for weight loss. Data from the ancillary study to the PREFER trial were used for two of the papers and secondary data analysis from the SMART trial was conducted for the third paper. Both parent studies were randomized clinical trials that included a behavioral intervention for weight loss. The first study compared the effect of a standard calorie- and fat-restricted diet and a calorie- and fat-restricted lacto-ovo-vegetarian diet on changes in adiponectin levels at six months (N=143). Weight loss was associated with increased total (â(s.e) = -0.71(0.27); P = 0.003) and high molecular weight (HMW) adiponectin levels (â(s.e) = -1.37(0.47); P = 0.001); however, they were independent of the diet type. The second study examined whether baseline levels or intervention-associated changes in adiponectin levels were associated with insulin resistance after six months (N=143). At baseline, we found significant inverse associations between total (â(s.e) = -0.26(0.05); P < 0.001) and HMW(â(s.e) = -0.38(0.09); P < 0.001) adiponectin levels and homeostasis model assessment of insulin resistance (HOMA) independent of weight. At six months, there was a significant inverse association between changes in total adiponectin and HOMA (â(s.e) = -0.17(0.08); P = 0.04) that was independent of baseline weight and weight loss. However, the association between changes in HMW adiponectin and HOMA was not significant. The third study assessed the longitudinal relationships of weight, waist circumference and body composition with adiponectin levels after six and 12 months (N=133). A significant increase in adiponectin was observed with significant reductions in weight, body mass index, waist circumference, and percent body fat (P for all, < 0.001). Our findings provide evidence for the importance of weight loss as a significant public health preventive measure to enhance adiponectin levels among the studied population, which could impact the progression of atherosclerosis and subsequent cardiovascular disease.

Cardiovascular disease (CVD) is a major public health concern, especially in African ancestry populations, which have greater risk compared with Caucasians. Subclinical CVD measures provide information on the health of the vasculature and are predictive of future risk of clinical events. Vascular health indices have been associated with lower bone mineral density (BMD) and osteoporosis suggesting a potential common etiology. Intima-media thickness (IMT) and arterial diameter (adventitial diameter [AD] and lumen diameter [LD]) are subclinical CVD measures obtained by carotid ultrasound, whereas pulse pressure (PP) and pulse-wave velocity (PWV) are subclinical measures of arterial stiffness. The genetic influence on these subclinical CVD measures and in the link between CVD and osteoporosis has not been well defined in African ancestry populations. Therefore, we have estimated genetic heritability, genetic correlation of CVD and osteoporosis related traits, and performed univariate and bivariate genome-wide linkage analysis of these traits in 7 large, multigenerational families of African ancestry from the Caribbean island of Tobago. A total of 461 individuals aged ¡Ý18 years were included in these analyses from probands and families who were recruited without regard to their health status. After removing the effects of covariates, subclinical CVD traits were all heritable and there was significant phenotypic and genetic correlation between CVD and osteoporosis related traits. The most promising evidence of linkage was detected for AD-BMD trait-pairs on chromosome 14 (max LOD=5.2) in bivariate analysis and for AD and LD on chromosome 11 (max LOD=4.1) in univariate analysis. The linkage regions contain several genes known to be involved in cardiovascular disease including the ApoA1/C3/A4/A5 gene cluster, IL18, BMP4, and ESR2. Further studies of these regions may reveal novel insight into the genetic regulation of subclinical CVD and osteoporosis. These findings have public health significance because determining the genetic regulation of chronic disease may aid in risk prediction and, ultimately, minimize health disparities in African ancestry populations.

Endometrial cancer (EC) is the most common gynecologic malignacy in the United States. In 2010, 43,470 cases were newly diagnosed with 7,950 deaths reported. Certain subtypes of EC are responsible for a disproprtionate number of deaths each year. Specifically, high-grade Type I, papillary serous (PS), and clear cell (CC) tumors account for 60% of all deaths, despite accounting for only 20% of new cases. The molecular mechanisms related to poor survival in these subtypes are unknown. The tumor microenvironment refers to the complex milieu of supporting cells, i.e. stromal cells, which co-exist with the primary tumor. Broad classes of stromal cells including inflammatory cells, endothelial cells, and fibroblasts, support the growth and dissemination of the primary tumor through their interactions with cancer cells. The primary goal of this research was to determine the prognostic roles of two stromal-related pathways [CXCL12 and CXCR4; hepatocyte growth factor (HGF), c-Met, and basic fibroblast growth factor (bFGF)] in a sample of EC cases (N=216) treated at Magee-Womens Hospital. Paraffin-embedded tissue blocks were retrieved from the Pathology Department at Magee-Womens Hospital and protein expression was measured using immunohistochemistry (IHC). Chi-square tests, Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models were used to examine the relationship between tumor and stromal protein expression, clinicopathologic factors, overall survival (OS), and recurrence-free survival (RFS). In the first microenvironmental pathway, positive CXCL12 expression was significantly associated with better OS (hazard ratio, HR: 0.17 95% CI 0.05, 0.59) and RFS (HR: 0.10 95% CI 0.02, 0.57) in high-grade Type I cases. In the second pathway of interest, better OS was detected in HGF positive, stromal bFGF positive patients compared to HGF positive, stromal bFGF negative patients (HR: 0.14, 95% CI 0.03, 0.60). Additionally, worse RFS was observed in HGF positive, tumor bFGF positive patients compared to patients with negative expression of both markers (HR: 9.88, 95% CI 2.63, 37.16). This study provides evidence that tumor microenvironmental proteins can serve as independent prognostic biomarkers in EC. The public health implications include a better understanding of the biology of EC and potential targets for molecularly-targeted treatments in EC.

Introduction: Cholesterol metabolism in the brain is implicated in the development of Alzheimers disease (AD). Understanding the relationship between markers of brain cholesterol metabolism and the structural changes occurring in the aging brain has particular public health relevance to the treatment and prevention of AD. Methods: This dissertation consists of a systematic review of the literature and two papers of original research. Our systematic review: critically evaluates the literature regarding brain cholesterol metabolism and AD, identifies gaps in our current understanding, and proposes directions for future research. The two papers of original research were designed to address these gaps in knowledge. We examined the relationship between plasma oxysterol metabolites and cerebrovascular disease, amyloid deposition in the brain, and incident cognitive impairment using two longitudinal cohorts of older adults with extensive characterization of cognition and brain structure. Quantitative marker of brain structure were prior to clinical disease using magnetic resonance imaging (MRI) and positron emission tomography (PET). Results: Our review found inconsistent associations between brain-derived plasma oxysterols and AD. Epidemiological design issues and methodological limitations may explain these conflicting results; these include: residual confounding, lack of temporal of associations, and inconsistent direction of associations resulting from stage of the disease at which oxysterols were measured. A major methodological limitation is the scarcity of objective measures to quantify underlying structural changes occurring the brain. Our original research examined the longitudinal association between oxysterols, cognition and brain imaging markers in non-demented older adults. We found higher levels of brain-derived oxysterols were associated with MRI markers of cerebrovascular disease and a greater risk of cognitive impairment over 8 years of follow-up. Furthermore, we found that lipid-lowering drugs modify the association between plasma oxysterols levels and amyloid deposition in the brain, visualized using PET. Conclusions: There are important relationships between brain degeneration, cholesterol metabolism and dementia that need to be better understood. Brain-derived metabolites of cholesterol appear to be elevated in the early stages of disease prior to the onset of cognitive impairment. Brain-derived plasma oxysterols may be an important marker of underlying cerebrovascular disease preceding cognitive impairment and risk for developing cognitive impairment.

The number of studies addressing the possible effects of air pollutants on human reproduction, especially prenatal outcomes, has grown extensively. However, the plausible biological mechanisms by which air pollutants influence prenatal outcomes remain unclear. The aims of this dissertation are (1) to determine whether ambient air pollution exposure (including particles of less than 10 µm (PM10) and less than 2.5 µm diameter (PM2.5), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone) contributes to increased inflammatory response by measuring C-reactive protein (CRP) concentrations during early pregnancy, and (2) to examine associations between ambient air pollution exposures and blood pressure changes during pregnancy. In addition, because smoking during pregnancy is a risk factor for some adverse birth outcomes such as preterm delivery, and inflammation has been suggested to increase the risk of preterm delivery, the other aim of this dissertation was to examine whether systemic inflammation mediates the link between smoking and preterm delivery. The study population was selected from the Prenatal Exposures and Preeclampsia Prevention study (PEPP) conducted in Pittsburgh, PA between 1997 and 2001. Space-time Kriging interpolation for ambient station measures at the maternal ZIP code was performed to estimate maternal air pollution exposure. Multiple linear and logistic regressions were employed to evaluate associations between air pollution, CRP concentrations, and blood pressure changes during pregnancy. Positive associations between particulate (both PM2.5 and PM10) and ozone air pollution and elevated CRP concentrations in non-smoking women during early pregnancy were observed. For blood pressure changes, we found that first trimester exposure to PM10 and ozone air pollution was associated to increases in mean systolic and diastolic blood pressure changes during pregnancy. For smoking and preterm study, no evidence that systemic inflammation mediates this association was found. Our findings provide some new evidence that associations between particulate air pollution and adverse birth outcomes may be mediated by systemic inflammation and blood pressure changes. These findings have considerable public health significance to further prevent the adverse birth outcomes associated with air pollution exposure.

Pelvic Inflammatory Disease (PID), the infection and inflammation of the female upper genital tract, can result in serious sequelae. Markers to predict sequelae following PID are greatly needed. The goal of this research is to explore the role of host genetic factors and delayed care seeking in the development of sequelae following clinically suspected PID. We studied the microbial correlates of delayed care and long-term outcomes among 298 women with histologically confirmed endometritis from the PID Evaluation and Clinical Health (PEACH) study. Mean days of pain prior to care were compared by microbial pathogen, with the longest times among women infected by Chlamydia trachomatis (CT) only (12.3±9.4 days) and Mycoplasma genitalium (MG) only (10.9±8.9 days), and the shortest among women infected by Neisseria gonorrhoeae (NG) only (4.6±5 days) or co-infection (5.6±5.1 days, p<0.001). Infertility, recurrent PID, and chronic pelvic pain were frequent (17%, 20%, and 36%), albeit non-significantly elevated after delayed care. PID patients infected with CT or MG were more likely to delay care, possibly increasing persistent inflammation which may permanently damage the reproductive tract before patients seek care. Toll-like receptors (TLR) eliminate microbes through inflammatory responses. As genetic variations may increase TLR signaling, we determined if 18 tagging single nucleotide polymorphisms assayed in 4 TLR genes (TLR1, TLR2, TLR4, TLR6) and 2 adaptor molecules (TIRAP, MyD88) were associated with CT, endometritis, or infertility among 205 African Americans with PID from the PEACH study. An empirical p-value <0.004 was significant. Logistic regression revealed that the TLR4 rs1927911 CC genotype was associated with CT (odds ratio (OR) 3.7, 95% confidence interval (CI) 1.6-8.8, p=0.0021). Further, the TLR1 rs4833095 TT genotype displayed trends towards increased CT (OR 2.8, 95% CI 1.3-6.2, p=0.0084). Predicted carriers of the TLR4 GTC haplotype (p=0.006) and the TLR1 TGT haplotype (p=0.04) were more likely to be CT positive. Genetic variations in TLR genes may play a role in CT pathogenesis. This dissertation yields public health significance by demonstrating the need for increased efforts for early identification and treatment of genital tract infections and providing a novel exploration into the role of genetic variants in CT pathogenesis.