Blacks in the United States have the highest rates of hypertension in the world, and their cardiovascular disease mortality rates are higher than for any other population group as a result of traditional risk factors such as obesity and stronger family history. However, additional underlying factors, such as social determinants of health (e.g., socioeconomic status [SES]) and macrosocial factors (e.g., racism), also correlate with adverse health outcomes. This study investigated whether the interaction between SES mobility over the lifecourse and lifetime racial discrimination influenced the extent to which hypertension contributed to the cardiovascular disease health disparities observed among Blacks in the Jackson Heart Study (JHS). Using a socioecological framework, cross-sectional data collected from the baseline period on a cohort of 5,302 JHS participants were analyzed with multiple regression techniques. The study findings indicated that SES mobility, as measured by education, predicted both the racial discrimination exposure and the burden that individuals experience. However, neither SES mobility nor racial discrimination had any effect in moderating the relationship between hypertension and cardiovascular disease when examined individually or collectively. This study examined a new approach for measuring the influence of racial discrimination on health outcomes. Multidisciplinary public health and research partners should continue to advance understanding of the complex health impact of such experiences on individuals and the dynamics that create racial factors in order to effect social change.

[Truncated abstract] Vitamin E is comprised of a family of tocopherols (TOH) and tocotrienols. The most studied of these is [alpha]-tocopherol ([alpha]-TOH), as this form is retained within the body and any deficiency of vitamin E is corrected with this supplement. [alpha]-TOH is a lipid-soluble antioxidant required for the preservation of cell membranes and potentially acts as a defense against oxidative stress. Individuals who have a primary vitamin E deficiency such as low birth weight infants, secondary vitamin E deficiency due to fat malabsorption such as in abetalipoproteinaemia, or a genetic defect in TOH transport require supplementation. There is debate as to whether vitamin E supplementation in other patient groups is required. Vitamin E supplementation has been recommended for persons with FHBL, a rare disorder of lipoprotein metabolism that leads to low serum [alpha]-TOH and decreased LDL cholesterol and apolipoprotein B concentrations. We examined the effect of truncated apoB variants on vitamin E metabolism and oxidative stress in persons with heterozygous FHBL. We used HPLC with electrochemical detection to measure [alpha]- and [gamma]-TOH in serum, erythrocytes, and platelets, and GC-MS to measure urinary F2-isoprostanes and TOH metabolites as markers of oxidative stress and TOH intake, respectively. Erythrocyte [alpha]-TOH was decreased, but we observed no differences in lipid-adjusted serum TOHs, erythrocyte [gamma]-TOH, platelet [alpha]- or [gamma]-TOH, urinary F2-isoprostanes, or TOH metabolites. Taken together, our findings do not support the recommendation that persons with heterozygous FHBL should receive vitamin E supplementation. ... Sesame lignans are natural components of sesame seed oil and there is evidence that these lignans can inhibit CYP450 enzymes, in particular, those responsible for vitamin E metabolism. We hypothesised that sesame seed ingestion would increase serum [gamma]-TOH, lower plasma lipids and inhibit platelet function in human subjects with at least one cardiovascular risk factor. We used HPLC with electrochemical detection to measure [alpha]- and -TOH in serum and GC-MS to measure F2-isoprostanes and TOH metabolites as markers of oxidative stress and TOH intake, respectively. We used high-sensitive C-reactive protein as a measure of systemic inflammation. Platelet function was assessed using the PFA-100 platelet aggregation assay. Although serum [gamma]-TOH increased by 17%, we observed no effect on lipid metabolism, markers of inflammation, oxidative stress or platelet function following treatment with ~25 g/day sesame seeds for five weeks. Our findings challenge the hypothesis that sesame seed ingestion provides beneficial cardiovascular effects. In summary, we have studied the metabolism and transport of both [alpha]- and [gamma]-TOH in humans to evaluate the requirements for supplementation and the effects of vitamin E on platelet function and CYP3A4 activity. Specialised techniques using HPLC were developed to measure serum and cellular TOH concentrations both in supplemented and un-supplemented individuals. We also used GCMS to provide a sensitive, accurate assessment of TOH metabolites and midazolam pharmacokinetics in humans after vitamin E supplementation. We have examined the role vitamin E has on important biochemical endpoints, with emphasis on the implications for TOH supplementation in subjects at risk of CVD.

<p>Ill health is unevenly distributed across different groups in society, with the disadvantaged groups displaying higher rates of ill health than the more advantaged groups. The aim of the thesis is to study work-related inequalities in health, and to focus on how income, aspects of the physical and psychosocial work environment, and sense of coherence, individually or jointly, generate inequalities in a number of health outcomes in the Swedish working population. The studies are based on survey data and national registers during the period 1990-2003.</p><p>For cardiovascular disease (CVD) prevalence and mortality, the impact of income was stronger than that of work environment factors. The psychosocial work environment (women and men) and income (men only) were associated with psychological distress. Income (women) and the psychosocial work environment (men) were associated with musculoskeletal pain. Thus, both income and work environment are important in generating health inequalities in the working population.</p><p>A strong sense of coherence (SOC) moderated the effect of physical demands on musculoskeletal pain in both genders. SOC moderates, yet not consistently, the impact of adverse working conditions on psychological distress and musculoskeletal pain. Hence, the results do not fully support the hypothesis that sense of coherence is a global health-protective factor. However, differential vulnerability in terms of the strength of SOC contributed to work-related inequalities in health.</p><p>The risk of stroke was higher for women and men in occupations with low job control than for those with high job control. The risk of intracerebral hemorrhage was highest in women in low job-control occupations, while low job control did not significantly increase the risk of brain infarction in women. Job control was related to mortality from stroke in women, but not in men. The effect of job control on stroke mortality in women was consistent in all classes except for upper non-manuals.</p>

<p>The rate at which articles gets published grows exponentially and the possibility to access texts in machine-readable formats is also increasing. The need of an automated system to gather relevant information from text, text mining, is thus growing. </p><p>The goal of this thesis is to find a biologically relevant gene network for atherosclerosis, themain cause of cardiovascular disease, by inspecting gene cooccurrences in abstracts from PubMed. In addition to this gene nets for yeast was generated to evaluate the validity of using text mining as a method. </p><p>The nets found were validated in many ways, they were for example found to have the well known power law link distribution. They were also compared to other gene nets generated by other, often microbiological, methods from different sources. In addition to classic measurements of similarity like overlap, precision, recall and f-score a new way to measure similarity between nets are proposed and used. The method uses an urn approximation and measures the distance from comparing two unrelated nets in standard deviations. The validity of this approximation is supported both analytically and with simulations for both Erd¨os-R´enyi nets and nets having a power law link distribution. The new method explains that very poor overlap, precision, recall and f-score can still be very far from random and also how much overlap one could expect at random. The cutoff was also investigated. </p><p>Results are typically in the order of only 1% overlap but with the remarkable distance of 100 standard deviations from what one could have expected at random. Of particular interest is that one can only expect an overlap of 2 edges with a variance of 2 when comparing two trees with the same set of nodes. The use of a cutoff at one for cooccurrence graphs is discussed and motivated by for example the observation that this eliminates about 60-70% of the false positives but only 20-30% of the overlapping edges. This thesis shows that text mining of PubMed can be used to generate a biologically relevant gene subnet of the human gene net. A reasonable extension of this work is to combine the nets with gene expression data to find a more reliable gene net.</p>

There is an increased risk for cardiovascular (CV) comorbidity among patients with rheumatoid arthritis (RA), with premature atherosclerosis, and a higher incidence of CV events, compared with the general population. Disease related factors add to the CV risk, and interact with the traditional CV risk factors. The underlying mechanism for this is not completely understood. In active RA there is a loss of muscle mass and an increase in body fat content. Production of cytokines, i.e., adipokines, in the adipose tissue could link the inflammation with the CV system. Control of the inflammation has been suggested to modify the CV risk in RA, and the recently introduced biological drugs, such as the tumor necrosis factor inhibitors (TNFi), have opened up new treatment opportunities. The aim of this thesis was to evaluate aspects of the interaction between inflammation and CV comorbidity in RA using biochemical and epidemiological methods. Methods In the first two studies, patients with established RA were examined for clinical disease activity, and blood samples were analysed for cytokines and adipokines using ELISAs and multiplex technology. In Study I (n RA=23) anthropometric measurements were assessed and in Study II (n RA=51) measurements of intima-media thickness (IMT), and endothelial function (FMD). From a subgroup of patients (Study II, n RA=13) samples of abdominal subcutaneous adipose tissue (SAT) were analysed for content of adipokines. In study III and IV associations between treatment with TNFi and acute coronary syndromes (ACS) were analysed using data from the Swedish Rheumatology Register; in Study III regarding early RA (n TNFi exposed=1,271, n bionaïve RA=4,729), and in Study IV comprising patients with RA of all stages (n TNFi exposed=7,213, n bionaïve RA=17,769) and with a matched general population comparator cohort (n=32,161). Associations between response to TNFi therapy and risk for ACS in the early RA cohort were evaluated in a nested case-control design (cases n=24, controls n=81). Results Serum levels of the cytokines/adipokines interleukin-1 receptor antagonist (IL-1Ra), IL-6, osteopontin, visfatin and TNF were increased in patients compared with controls (p≤0.001-0.036). The amount of TNF receptor II extracted from SAT was greater in patients (p=0.006). The serum (s-) levels of IL-1Ra correlated with s-leptin (r=0.71, p≤0.001) and s-haptoglobin in RA patients (r=0.56, p≤0.01). The result from a factor analysis indicated IL-1Ra to be associated with both adipose tissue and inflammation. Levels of s-visfatin (p=0.019) and s-IL-1Ra (p=0.023), respectively, were positively associated with IMT independently of inflammatory activity and CV risk factors. PAI-1 and MCP-1 extracted from SAT showed inverse associations with IMT. Patients with RA, whether exposed to TNFi or bio-naïve, had a doubled risk for ACS compared with the general population; HR 2.09 (95%CI 1.58-2.76) and 1.80 (1.49-2.17), respectively. No significant associations between risk for ACS and TNFi exposure were detected after adjustments; HR 0.80 (0.52-1.24) in early RA and HR 1.08 (0.82-1.41) in RA of any duration. Furthermore, no association between the risk for ACS and response to TNFi treatment in patients with early RA was observed, OR 1.5 (0.3-6.9). Conclusions The results indicate that cytokines/adipokines may have a role in the development of atherosclerosis in RA patients. A continuing increase in the risk of ACS in RA compared with the general population, despite modern therapeutic strategies, was noted. Neither exposure nor response to treatment with TNFi was associated with any modification of the risk for ACS.

Ill health is unevenly distributed across different groups in society, with the disadvantaged groups displaying higher rates of ill health than the more advantaged groups. The aim of the thesis is to study work-related inequalities in health, and to focus on how income, aspects of the physical and psychosocial work environment, and sense of coherence, individually or jointly, generate inequalities in a number of health outcomes in the Swedish working population. The studies are based on survey data and national registers during the period 1990-2003. For cardiovascular disease (CVD) prevalence and mortality, the impact of income was stronger than that of work environment factors. The psychosocial work environment (women and men) and income (men only) were associated with psychological distress. Income (women) and the psychosocial work environment (men) were associated with musculoskeletal pain. Thus, both income and work environment are important in generating health inequalities in the working population. A strong sense of coherence (SOC) moderated the effect of physical demands on musculoskeletal pain in both genders. SOC moderates, yet not consistently, the impact of adverse working conditions on psychological distress and musculoskeletal pain. Hence, the results do not fully support the hypothesis that sense of coherence is a global health-protective factor. However, differential vulnerability in terms of the strength of SOC contributed to work-related inequalities in health. The risk of stroke was higher for women and men in occupations with low job control than for those with high job control. The risk of intracerebral hemorrhage was highest in women in low job-control occupations, while low job control did not significantly increase the risk of brain infarction in women. Job control was related to mortality from stroke in women, but not in men. The effect of job control on stroke mortality in women was consistent in all classes except for upper non-manuals.

The common risk factors for atherosclerosis, such as obesity, high cholesterol levels, sedentary lifestyle, diabetes and high alcohol intake, only explain approximately 50% of cardiovascular disease events. It is thereby important to identify new mechanisms that can stimulate the process of atherosclerosis. During the past decades, a wide range of investigations have demonstrated connections between infections by the respiratory bacterium Chlamydia pneumoniae and atherosclerosis. Earlier studies have focused on the interaction between C. pneumoniae and monocytes/macrophages, T-lymphocytes, smooth muscle cells and endothelial cells, which are present in the atherosclerotic plaque. However, another important player in atherosclerosis and which is also present in the plaques is the platelet. Activation of platelets can stimulate both initiation and progression of atherosclerosis and thrombosis, which is the ultimate endpoint of the disease. The aim of the present thesis was to investigate the capacity of C. pneumoniae to activate platelets and its role in atherosclerosis. The results show that C. pneumoniae at low concentrations binds to platelets and stimulates platelet aggregation, secretion, reactive oxygen species (ROS) production and oxidation of low-density lipoproteins (LDL), and that these effects are mediated by lipopolysaccharide (LPS). Activation of protein kinase C, nitric oxide synthase and 12-lipoxygenase (12-LOX) was required for platelet ROS production, whereas platelet aggregation was dependent on activation of GpIIb/IIIa. Pharmacological studies showed that the C. pneumoniae-induced platelet activation is prevented by inhibitors against 12-LOX, platelet activating factor (PAF) and the purinergic P2Y1 and P2Y12 receptors, but not against cyclooxygenase (COX). These findings were completely opposite to the effects of these inhibitors on collagen-stimulated platelets. We also present data from a clinical study indicating that percutaneous coronary intervention (PCI or balloon dilatation) leads to release of C. pneumoniae into the circulation, which causes platelet activation and LDL oxidation. In conclusion, these data support a role for C. pneumoniae-induced platelet activation in the process of atherosclerosis. Stimulation of platelets by C. pneumoniae leads to release of growth factors and cytokines, oxidation of LDL and platelet aggregation, which are processes that can stimulate both atherosclerosis and thrombosis. Development of novel drugs that prevent C. pneumoniae-platelet interaction by inhibiting 12-LOX and/or PAF, may be important in the future treatment of cardiovascular disease.

Rheumatoid arthritis (RA) is a chronic disabling disease that is associated with a shortened life span. Cardiovascular disease (CVD) contributes to this increased mortality, and also to a great extent to the co-morbidity observed in patients with RA. This thesis aimed to investigate these issues further. The incidence of, and prognosis after an acute myocardial infarction (AMI) /or stroke in a cohort of RA patients was compared with that in the general population within the northern Sweden MONICA register. The standard incidence ratio (SIR) for AMI was 2.9 and for stroke 2.7 in RA patients compared with the general population (p&lt;0.05 for both). During the first 10 years following an event, RA patients had a higher overall case fatality (CF) compared with controls (HR for AMI=1.67, 95%CI [1.02, 2.71], HR for stroke=1.65, 95%CI [1.03, 2.66]). An elevated level of homocysteine is regarded to be a risk marker for CVD. The effects of treatment with B vitamins on the homocysteine level in patients with RA were studied in a consecutive cohort of patients with RA. Sixty-two patients with RA having a homocysteine level of 12 mol were randomized to receive either a placebo or a combination of the vitamins B6, B12 and folic acid. The patients were treated and evaluated in a double-blind manner over 12 months. The homocysteine level was found to be significantly decreased in the B-vitamin treated patients compared with the placebo group (p&lt;0.0001). To evaluate the progression of sub-clinical atherosclerosis in patients with very early RA compared with controls, all patients from the three most northern counties of Sweden newly diagnosed with RA and aged ≤60 years were consecutively recruited. Age and sex matched controls from the general population were also included. Intima media thickness (IMT) of the common carotid artery and endothelium dependent flow mediated dilation (ED-FMD) of the brachial artery were measured using ultrasonography. After 18 months the same measurements were undertaken in a sub-group of the patients with early RA and the relevant controls. There were no differences between patients with early RA and controls in terms of IMT or ED-FMD at inclusion into the study. However, after 18 months there was a significant increase in the IMT among the patients with early RA (p&lt;0.05); no such increase occurred in the control group. Biomarkers of endothelial activation that may reflect the early atherosclerosis that occurs in RA were also evaluated. At inclusion, both IMT and ED-FMD among the patients with early RA related significantly to several of the biomarkers of endothelial activation. Furthermore, markers of inflammation (e.g., DAS28) were significantly related to biomarkers of endothelial activation. In conclusion, RA patients had a higher incidence of CVD and a higher CF after a CV event. The increased homocysteine level among patients with RA was as easy to decrease as in the general population. At the time of diagnosis of RA there were no differences in atherosclerosis between patients and controls, however the patients with RA had a more rapid progression of atherosclerosis than the control subjects. Moreover, there were implications of endothelial activation already in patients with very early RA. Taken together, these results emphasize the necessity of optimizing the preventive, diagnostic and caring strategies for CVD in patients with RA.

Pre-eclampsia is associated with increased risk of cardiovascular disease (CVD) later in life. The ‘gold standard’ for estimating cardiovascular risk - ultrasound assessment of the common carotid artery intima-media thickness (CCA-IMT) - does not convincingly demonstrate this increased risk. The aim of this thesis was to examine whether high-frequency (22 MHz) ultrasound assessment of the individual CCA intima and media layers and calculation of the intima/media (I/M) ratio - can indicate the increased cardiovascular risk after pre-eclampsia. After validation of the method in premenopausal women with systemic lupus erythematosus (SLE) who have a recognized increased risk of CVD, women during and after normal and preeclamptic pregnancies were investigated. Assessment of the individual artery wall layers reliably demonstrated the increased cardiovascular risk in premenopausal women with SLE, while CCA-IMT did not. The artery wall layer dimensions in women with SLE were comparable to those of postmenopausal women without SLE and were 30 years older. Among the women with normal pregnancies negative changes to the artery wall later on in the pregnancy were seen in those with lower serum estradiol, older age, higher body mass index or higher blood pressure early in the pregnancy. About one year postpartum, both the mean intima thickness and the I/M ratio had improved, compared to values during pregnancy. These findings support the theory that normal pregnancy is a stress on the vascular system. Women who developed pre-eclampsia (mean age 31 years) had thicker intima layers, thinner media layers and higher I/M ratios, both at diagnosis and one year postpartum, than women with normal pregnancies, indicating increased cardiovascular risk. Women with a history of severe pre-eclampsia (mean age 44 years; mean 11 years since the last delivery) had thicker intima layers and higher I/M ratios than women with a history of normal pregnancies, indicating long-standing negative vascular effects. Assessment of individual CCA wall layers, but not of CCA-IMT, provided clear evidence of the well-known increased cardiovascular risk in women with SLE or pre-eclampsia. The method has the potential to become an important tool in reducing cardiovascular morbidity and mortality in these women through early diagnosis and intervention.

Cardiovascular disease (CVD) is the leading cause of death among women in the US, and African American women (AAW) have a disproportionately high rate of deaths from CVD. Physical inactivity plays a major role in CVD development. It has been reported that some rural women have low rates of physical activity; 39% of White women and 57% of women of color are reported to be physically inactive. Rural AAW have a high mortality and morbidity rate related to CVD and a high rate of physical inactivity. The purpose of this study was to describe rural AAW’s perception of wellness in conjunction with their stage of change for engaging in exercise. A questionnaire was designed to obtain demographic information and reliable and valid questionnaires were used to measure perceived wellness and current stage of change for exercise. Using a descriptive, cross-sectional design, a convenience sample of 162 rural AAW was recruited from four rural churches in Selma, Alabama. A one-time meeting was conducted and questionnaires were completed by the participants. Statistical analyses including independent samples t-tests and one-way and two-way ANOVA’s were conducted to determine if there were associations among demographic characteristics, self-reported presence of CVD, perceived wellness, and stage of change for exercise. Findings indicated that there was no relationship between perceived wellness and stages of change for exercise among rural AAW; no relationship was found between perceived wellness and CVD, or CVD and stage of change for exercise. However, 51.3% of the sample reported they were physically active, and 21.6% planned to increase their activity within 30 days. Annual household income and employment status were positively correlated with perceived wellness, suggesting a greater sense of wellness is related to income and employment among these rural AAW. These findings have implications for nursing practice in the areas of facilitating health promoting behaviors and development of exercise and wellness programs for rural AAW.