High attrition rates from community participatory research studies need to be explored more by non-traditional methods and participant profiles need to be developed to prevent high attrition rates. The purpose of this dissertation is to characterize compliance and drop out rates using the cardiovascular disease IQ quiz and the life priorities questionnaire. It is important to examine both compliance and dropouts in this context because both diabetes and cardiovascular disease are emerging as a major focus of public health efforts in the United States and abroad. These diseases are accelerating due to the current trends in obesity, which is a preventable, modifiable risk factor for diabetes and cardiovascular disease. Diabetes and cardiovascular disease continue to be the number seven and number one leading causes of death, respectively. We explore these concepts in a largely Hispanic border community in the Southwest, in the small town of Douglas, Arizona. The Hispanic population is increasing in the United States and is now the most populous minority group. Additionally, among this group are some of the highest rates of pre-diabetes, diabetes, and uncontrolled diabetes, all cardiovascular disease risk factors. We found that the cardiovascular disease IQ quiz was a much stronger predictor for compliance and drop out rates in this sample population than the life priorities questionnaire. Compliance did not seem to differ among the study participants who remained in the study. Interestingly, among the participants who were compliant, especially those who kept their eye check-up, were also those more likely to have health insurance and be employed. Though males only represented about 10% of the population sample, they tended to drop out more frequently than females. Dropouts tended to be younger, gainfully employed, and more educated. Qualitative analysis and logistic regression will further help explain the aforementioned associations.

Background Long-term side effects associated with the treatment of Hodgkin’s lymphoma (HL) have frequently been reported during the last decades. Studies have shown increased mortality in HL survivors. Following Hodgkin’s lymphoma, second malignancies (SM) and cardiovascular disease (CVD) are the most common causes of death in individuals treated for HL. This study investigates the incidence of side effects such as SM, CVD and infections in a cohort diagnosed with HL in Sweden between 1965 and 1995. In addition, this study identifies covariate risk factors for late side effects in order to develop strategies that prevent morbidity and mortality in HL survivors. Methods Using the Swedish Cancer Registry (SCR) at the National Board of Health and Welfare and the Multi-Generation Registry at Statistics (MGR) Sweden, we identified 6946 individuals diagnosed with HL between the years 1965 and 1995, and their first degree relatives (FDR) (n=17 858). In addition we identified the malignancies and inpatient care for CVD and infections for the HL cohort and their FDR. The standard incidence ratio (SIR) was calculated for the risk of SM, CVD and infections. For SM and CVD the risk also was stratified and calculated for family history of disease. The Swedish Hodgkin Intervention and Prevention study (SHIP), a prospective study, invited 702 individuals treated for HL at the age of 45 years or younger and who were treated in the region of Skåne, Uppsala or Umeå. The participants completed a questionnaire and were invited to an out-patient visit to an oncologist with clinical examination and blood tests. Any pathological findings were referred for further investigation. Results An increased risk for SM in HL long-term survivors was observed and seems to increase with the number of FDRs with cancer. There was also an increased risk for inpatient care due to congestive heart failure (CHF) and coronary artery disease (CAD). A family history of CHF and CAD further increased the risk for these diseases. The risk for inpatient care due to infections was increased and remained increased after 20 years or longer. The risk for infections was associated with splenectomy and hypothyroidism. Radiotherapy was an independent risk factor for cardiovascular disease in the cohort of the prospective study. ConclusionLong-term survivors from HL have an increased risk for developing late side effects such as SM, CVD and infections. Since many HL patients are young and the cure rate from the disease is high, it is of great importance to offer focused surveillance programs to selected individuals who are at high risk, e.g. individuals who received radiotherapy as part of their treatment and who have other known risk factors for cardiovascular disease such as hypertension, hypercholesterolemia, family history and smoking.

Motivation: Cardiovascular disease (CVD) is one of the leading causes of mortality and morbidity in South Africa and worldwide. Dyslipidaemia and an increased coagulation state contribute to the development of CVD. The quality of fibrin network structure (FNS) may also contribute to the risk for CVD and thrombosis. Changes in fibrinogen concentration directly affect FNS. Management of these risk factors is important and dietary intervention forms an essential part of this management program. An increased intake of vitamin C can lead to a decreased susceptibility to infection and subsequently to decreased levels of haemostatic factors (that give rise to an anti-thrombotic state) and thus reduction in CVD and mortality. Furthermore, vitamin C may prove to be beneficial by increasing the pro-fibrinolytx activities of FNS (formation of thick fibrin fibers and more lysable clots) that could result in a reduction in atherosclerosis and subsequent CVD. Obiective: To investigate the effects of FoodState Vitamin C complex supplementation on haemostatic factors, FNS, serum lipids and lipoprotein (a) (Lp(a)) in hyperlipideamic adults. Methods: Thirty free-living hiperlipidaemic volunteers from the Lipid Clinic, Potchefstroom University for Christian Higher Education (CHE), participated in this randomised placebo controlled double blind crossover study. The subjects were randomly divided into two groups (A or B). After a run-in period of 4 weeks during which the subjects excluded all vitamin supplements, Group A received 2 tablets/day of FoodState Vitamin C complex (500mg vitamin C, 600mg magnesium food complex, 900mg vitamin B complex and 160mg bioflavonoids) and Group B received 2 tablets/day of placebo, for at least 8 weeks. A washout period of 8 weeks followed after which the treatments were crossed-over for a further 8 weeks. Fasting blood samples were drawn 8 times (two samples, one week apart at the beginning and end of each treatment). Results: FoodState Vitamin C complex supplementation did not significantly influence the levels of plasma fibrinogen, plasminogen activator inhibitor 1 activity (PAI-I act), tissue plasminogen activator antigen (tPA ag) or d-dimer. Serum lipids and Lp(a) were also not affected. Median plasmin-antiplasmin complex (PAP) and thrombin-antithrombin complex (TAT) levels, which are markers of plasmin (initiate fibrinolysis) and thrombin (initiate coagulation) generation respectively, were both significantly decreased compared to placebo (PAP: 4.05[-23.39, -0.231% vs 1.81[-8.95, 8.091%; TAT: -5.81[-18,47, 0.391% vs 0.12[-8.03, 13.51%). FoodState Vitamin C complex beneficially affected FNS by significantly increasing compaction (49.95[47.55,53.70]% to 51.85[48.55,56.65]%). Conclusion: The decreases in TAT and PAP are possibly an indication that the FoodState Vitamin C complex decreased the initiation of haemostasis, which in turn led to a compensatory reduction in fibrinolysis. FoodState Vitamin C complex may, therefore be protective of cardiovascular disease by causing a new reduced steady state of hemostatic balance and more lysable clots (increased compaction). / Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2004.

Objective: Glucagon-like peptide-1 receptor (GLP-1R) agonists have been shown to reduce atherosclerosis in non-diabetic mice. We hypothesized that treatment with GLP-1R agonists would reduce the development of atherosclerosis in diabetic Apoe-/- mice. Results: Exendin-4 treatment (10 nmol/kg/day) of high-fat diet-induced glucose-intolerant mice for 22 weeks did not significantly reduce oral glucose tolerance (P=0.62) or HbA1c (P=0.85), and did not reduce plaque size at the aortic sinus (P = 0.35). Taspoglutide treatment for 12 weeks (0.4-mg tablet/month) of diabetic mice reduced body weight (P<0.05), food intake (P<0.05), oral glucose tolerance (P<0.05), intrahepatic triglycerides (P<0.05) and cholesterol (P<0.001), and plasma IL-6 levels (P<0.01); increased insulin:glucose (P<0.05); and unaltered oral lipid tolerance (P=0.21), plasma triglycerides (P=0.45) or cholesterol (P=0.92). Nonetheless, taspoglutide unaltered aortic atherosclerosis (P=0.18, sinus; P=0.19, descending aorta) or macrophage infiltration (P=0.45, sinus; P=0.26, arch). Conclusions: GLP-1R activation in either glucose-intolerant or diabetic mice does not significantly modify the development of atherosclerosis.

Establishing the cellular and molecular basis for cardiovascular disease and the application of tools to manipulate the cardiovascular system genetically provide potential for new forms of treatment against cardiovascular disease, including: atherosclerosis, myocardial ischemia, cardiac hypertrophy and heart failure. Heme oxygenase-1 (HO-1) is an enzyme that has potential for the treatment of cardiovascular diseases (CVD). Atherosclerotic plaques express high levels of HO-1. Advanced plaques are stabilized in part through the separation of plaque constituents from the blood by the fibrous cap made up of smooth muscle cells. Protection of smooth muscle cells from apoptosis in the fibrous cap may be a means of promoting plaque stability in patients. Here we show that expression of HO-1 in human vascular smooth muscle cells renders them resistant to apoptosis mediated by oxidative stress. The cytoprotective mechanism mediated by HO-1 is mediated in part through protein kinase B (Akt). Plaque rupture may lead to myocardial infarction. Tissue recovery after mycocardial infarction requires neovascularization for improved tissue perfusion. A novel cell type recently discovered in the circulation has been characterized as an endothelial progenitor cell (EPC) and appears capable of promoting neovascularization of post-infarct tissue, thereby enhancing tissue recovery and perfusion. Most EPCs transplanted into the infarct environment do not survive or are not retained to function in neovascularization. Here we show that expression of HO-1 and its cytoprotective partner Akt protect EPCs in an infarct environment and promote EPC function in an infarct environment. Oxidative stress can result in maladaptive cardiomyocyte hypertrophy. In a model of oxidative stress-induced myocyte hyperterophy we demonstrate the expression of HO-1 prevents cellular hypertrophy through antioxidant mechanisms and regulation of the transcription nuclear factor kappa B (NF-κB). Atherosclerotic plaque vulnerability is determined by the composition of the lesion. We demonstrate that HO-1 deficient mice have more calcified and fibrotic lesions. This may have implications in the management of late stage atherosclerosis. Collectively, this work demonstrates new insights into the molecular mechanisms of cardiovascular cells under stress that may have implications for strategies aimed at treating CVD using HO-1. / Thesis (Ph.D, Physiology) -- Queen's University, 2009-04-21 15:31:14.05

High plasma concentrations of Lipoprotein(a) (Lp(a)) have been identified as a risk factor for a variety of atherogenic disorders such as cerebrovascular disease, peripheral vascular disease, and coronary heart disease. Lp(a) consists of a lipoprotein moiety containing apolipoproteinB-100 (apoB-100), as well as apolipoprotein(a) (apo(a)), a unique glycoprotein to which the majority of Lp(a) functions are attributed. Variation in the number of identically repeated kringle IV type 2 (KIV2) motifs of apo(a) forms the molecular basis of Lp(a) isoform size heterogeneity, which is a hallmark of this lipoprotein. There is a general inverse correlation between apo(a) size and plasma Lp(a) concentrations, attributed in part to less efficient secretion of larger apo(a) isoforms from hepatic cells. The present study provides a preliminary investigation into processes involved in apo(a) secretion, with respect to isoform size, to understand this inverse correlation at a molecular level. Pulse-chase experiments were performed in human embryonic kidney (HEK 293) cells and human hepatoma (HepG2) cells, both stably expressing differently-sized recombinant apo(a) isoforms representing the range of apo(a) sizes observed in the population. The folding kinetics for the different apo(a) isoforms were determined by changes in the mobility of the non-reduced radiolabelled species on SDS-PAGE gels. In HEK 293 cells, the rate at which apo(a) is folded correlated well with isoform size. In HepG2 cells, however, folding times were comparable regardless of isoform size. Apo(a) secretion from both cell lines exhibited size-dependency. Preliminary experimentation on endoplasmic reticulum (ER)-resident protein modifications of apo(a) was performed, resulting in the identification of apo(a) interactions with PDI, Erp57, Calnexin, Grp78, Grp94, and EDEM. Preliminary experiments indicate a role for intracellular apo(a) degradation in the amount of apo(a) that is secreted from HepG2 cells, although an isoform size dependency of this degradation process cannot be established with current experimental data. Further experimentation is required to confirm enzyme interactions with differently-sized apo(a) isoforms, to identify other chaperones involved in apo(a) secretion, and to confirm the role of proteasomes in intracellular apo(a) degradation. This may, in turn, provide information regarding the mechanism of how apo(a) secretion from hepatic cells is regulated. / Thesis (Master, Biochemistry) -- Queen's University, 2009-09-20 19:10:09.497

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Hypercholesterolemia, a condition of high cholesterol levels in the circulation, poses a major risk for developing cardiovascular disease, such as atherosclerosis. A common method of reducing plasma cholesterol levels relies on the administration of drugs that limit cholesterol synthesis or uptake, many of which have undesirable side effects. Thus, some patients are turning to an alternative treatment, namely natural health products. Natural health products are often equally or even more effective at treating illness than synthetic drugs and may produce fewer side effects. The goal of this study was to identify a natural health product that regulates hepatic cholesterol synthesis by inhibiting HMG-CoA reductase, the enzyme which catalyzes the rate-limiting step of the cholesterol synthesis pathway. Several natural compounds were screened using the human hepatoma cell line HepG2. One compound, berberine, showed great potential as a regulator of cholesterol synthesis and so became the subject of this investigation. Berberine inhibited HMG-CoA reductase activity and decreased cellular accumulation of cholesterol. Berberine was shown to regulate HMG-CoA reductase through activation of metabolic regulator AMP-activated protein kinase, which modifies HMG-CoA reductase post-translationally and thereby decreases its activity. In conclusion, this study demonstrates that the natural health product berberine decreases cholesterol synthesis by activating a cellular signalling pathway to bring about post-translational modification of HMG-CoA reductase, and in doing so, inhibits this enzyme. This novel mechanism supports berberine’s potential for a cholesterol-lowering therapy and its role in reducing the risk for cardiovascular disease.