Background: Breast and Gynecological cancers are a major public health problem. Smoking is associated with several chronic diseases including cancer. Other lifestyles of public health predispose many people to dyslipidemia, hypertension and obesity; risk factors for metabolic syndrome, and are associated with cancer. Objectives: The purpose of this study is to find if those who smoke, and have the metabolic syndrome, are more likely to have breast or gynecological cancers, and to find the distribution by education, having health insurance, race/ethnicity and socio-economic status. Methods: A case-control study of females aged 20 years and above who participated in the United States National Health and Nutrition Examination Survey (NHANES) 2001-2010. Results: Females who have smoked more than hundred cigarettes in life and still smoke; a) have a 42 percent less chance of having a breast cancer diagnosis (OR 0.58; 95% CI 0.36 – 0.93, p-value 0.025), and b) are 2.67 times as likely to report a cervical cancer diagnosis as females who have smoked less than hundred cigarettes in life (OR 2.67; 95% CI 1.72 – 4.13, p-value Conclusion: Smoking and metabolic syndrome are very important indicators of reproductive health and needs further study. Smoking cessation interventions should be an integral part of cervical cancer prevention programs especially targeted at younger females and females who live below the federal poverty level.

MOTIVATION: The increasing prevalence of metabolic syndrome (MetS) is creating immense concern worldwide. In 2009, the International Diabetes Federation (IDF) announced the new MetS definition. MetS is diagnosed by any 3 of the following 5 indicators being present: increased waist circumference (WC), blood pressure (BP), triglycerides, and fasting glucose values, and decreased high–density lipoprotein cholesterol (HDL–C) concentrations. Psychosocial stress relating to an urban environment or acculturation greatly influences the prevalence of both MetS and target organ damage (TOD). Furthermore, in urban Africans, active coping (AC) responses have been associated more with MetS and the related cardiovascular pathology than avoidance. A further synergistic effect of MetS and AC responses was also revealed in African men, in strong association with both subclinical atherosclerosis and renal impairment. Microalbuminuria was four times higher in Africans with MetS, than in those without any MetS indicators. Furthermore, Africans, especially those utilising AC responses, present with greater carotid intima–media thickness (CIMT) than their Caucasian counterparts, although they exhibit a lipid profile that is anti–atherogenic. OBJECTIVES: The objectives were firstly to indicate and compare differences regarding AC responses in the African and Caucasian men, in accord with the prevalence of MetS indicators. Secondly, the extent to which AC responses and MetS indicators predict endothelial dysfunction was investigated. METHODOLOGY: This comparative target population study is nested in the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study, which was conducted from February until the end of May in both 2008 (Africans) and 2009 (Caucasians), avoiding seasonal changes. The Ethics Committee of the North–West University approved the study, and all volunteers gave written informed consent prior to participation. Procedures were conducted according to the institutional guidelines of the Declaration of Helsinki. The participants included 202 male teachers of which 101 were African and 101 Caucasian. Ambulatory blood pressure (BP) measurements were recorded with the Cardiotens CE120 at 30 minute intervals during the day and 60 minutes at night. Actical accelerometers determined physical activity (PA). Registered clinical psychologists supervised completion of the psychosocial questionnaires, including the Coping Strategy Indicator. Participants fasted overnight; after the last BP recording, disconnection of the Cardiotens CE120 and Actical followed. A fasting 8 hour overnight collected urine sample was obtained from each participant. Anthropometric measurements followed, after which a registered nurse commenced blood sampling. The SonoSite Micromaxx was used for the scanning of CIMT. MetS indicators (glucose, triglyceride, and HDL–C), together with gamma glutamyl transferase, cotinine, and ultrahigh–sensitivity C–reactive protein (hs–CRP), were analyzed with Konelab 20i. The albumin–to–creatinine ratio and CIMT determined TOD. Participants were stratified according to ethnicity and median splits of AC response scores (high AC and low AC). Diabetic medication users (n= 8), and participants with renal impairment (n= 2) or HIV positive (n= 13), were excluded from analyses. 2×2 ANCOVA’s determined significant interactions for ethnicity and AC. Partial correlations between MetS indicators and TOD were performed within each ethnic and AC group, independent of age, alcohol consumption and PA. Regression analyses were performed for four models, firstly with microalbuminuria and secondly with CIMT as dependent variables. Significant values were noted as p 0.05, r 0.35, and adjusted R2 0.25. RESULTS: Caucasian men were physically more active than African men, whilst BP, alcohol consumption and hs–CRP levels were significantly higher in African men. Psychological variables revealed higher avoidance scores in Caucasian men and higher social support scores in African men. More MetS indicators exceeded the IDF cut–off points in high AC African men (14.71%) than in their Caucasian counterparts (3.33%). Furthermore, more MetS indicators predicted endothelial dysfunction in African men, especially the high AC responders. CONCLUSION: The following hypotheses were accepted: high AC responses in urban African men were associated with a higher prevalence of MetS indicators than in their Caucasian counterparts, while MetS indicators were associated with a marker of TOD in urban high AC African men, but not in their Caucasian counterparts. / Thesis (M.Sc. (Physiology))--North-West University, Potchefstroom Campus, 2011.

Objectives: The aim of this study was to determine the prevalence of MetS among different African populations using the new Joint Statement Criteria. Hereafter we aimed to determine whether waist or neck circumference is the best predictor of MetS risk after ethnic, gender and age-specific cut-points were developed. Lastly, we aimed to determine whether afore-mentioned cut-point can predict albumin:creatinine ratio as a marker of target organ damage. Methods: The study sample (N=409) comprised of urban African (men, N=101; women, N=99) and Caucasian (men, N=101; women, N=108) teachers from the Dr. Kenneth Kaunda Education district in the North-West Province, South Africa. Participants were aged between 25 and 65 years. Anthropometric measurements, albumin:creatinine ratio and other markers of the metabolic syndrome (MetS) (systolic and diastolic blood pressure [SBP and DBP], glucose, triglycerides [TG] and high density lipoprotein [HDL]) were determined. Results: Africans (65 and 63 % for men and women) and Caucasian men (73%) showed high prevalence of MetS; ROC analysis determined neck circumference (NC) cut-points of 39 and 35 cm for young and older African men, 32 and 35 cm for young and older African women, 40 and 41 cm for Caucasian men and 34 and 33 cm for Caucasian women. This NC cut-point can be used to determine metabolic syndrome risk in all groups, except in African women; ROC developed waist circumference (WC) cut-points were 91 cm for all African male groups, 84, 81 and 84 cm for young, older and total group of African women. Suggested WC cut-points for Caucasian men were 93 cm for the young group and 97 cm for older as well as total Caucasian male groups, while cut-points for Caucasian women were 87 cm, 79 cm and 84 cm for young, older and total Caucasian women. These WC cut-points were good measures of metabolic syndrome risk in all groups; neither cut-point of WC nor NC could increase the risk of albumin:creatinine ratio. Conclusion: African women as a group present with few MetS risk factors and glucose is associated with renal function risk in Africans; NC cut-points may be used as an additional anthropometric marker to predict the metabolic syndrome in a South African cohort, but not in African women; WC cutpoints demonstrated to be good predictors of the metabolic syndrome in the same South African cohort, especially among men; WC would seem to be the best measure of MetS risk in all African populations, although NC can also be used for this purpose in all African populations, except in African women. / Thesis (PhD (Human Movement Science))--North-West University, Potchefstroom Campus, 2012

Emerging evidence suggests that vitamin D may be associated with type 2 diabetes (T2DM), however current data are inconsistent regarding metabolic disorders underlying T2DM. The objectives of this thesis were to investigate the association of vitamin D with the primary pathophysiological disorders of type 2 diabetes: namely insulin resistance (IR) and beta (β)-cell dysfunction, and the metabolic syndrome (MetS). All studies included individuals participating in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, comprising 712 subjects 30 years and older, and at risk of T2DM at baseline. Serum 25-hydroxyvitamin D [25(OH)D] was measured to assess vitamin D nutritional status. Validated oral glucose tolerance test derived indices for IR and β-cell function were calculated. In the first cross-sectional study, multivariate linear regression analyses indicated a significant inverse association of serum 25(OH)D with IR (β=-0.003, p=0.007) and a significant positive association of 25(OH)D with β-cell function (β=0.004, p=0.03) at the baseline PROMISE clinic visit (n=712). In another cross-sectional study also conducted using data from the baseline PROMISE clinic visit, higher 25(OH)D was found to be significantly associated with a reduced presence of the MetS after multivariate adjustment (OR=0.76, 95% CI 0.62-0.93). Low serum 25(OH)D was also significantly associated with various MetS components. In light of the findings in the first cross-sectional study, the third study examined prospective associations of baseline 25(OH)D with 3-year follow-up IR and β-cell function (n=489). Although baseline 25(OH)D was not significantly associated with follow-up IR, a significant positive association of baseline 25(OH)D with β-cell function at follow-up was observed (β=0.005, p=0.015). Lastly, in a longitudinal substudy (n=127), seasonal changes in 25(OH)D over 2.5 years did not significantly affect changes in IR and β-cell function. In conclusion, results indicated that baseline serum 25(OH)D was cross-sectionally related to IR, β-cell function and the MetS, and was prospectively related to β-cell function at the 3-year follow-up. In addition, seasonal changes in 25(OH)D do not adversely affect IR and β-cell function over time. These findings suggest a potential role for higher 25(OH)D levels in reducing diabetes risk, although additional longitudinal studies are warranted.

Emerging evidence suggests that vitamin D may be associated with type 2 diabetes (T2DM), however current data are inconsistent regarding metabolic disorders underlying T2DM. The objectives of this thesis were to investigate the association of vitamin D with the primary pathophysiological disorders of type 2 diabetes: namely insulin resistance (IR) and beta (β)-cell dysfunction, and the metabolic syndrome (MetS). All studies included individuals participating in the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study, comprising 712 subjects 30 years and older, and at risk of T2DM at baseline. Serum 25-hydroxyvitamin D [25(OH)D] was measured to assess vitamin D nutritional status. Validated oral glucose tolerance test derived indices for IR and β-cell function were calculated. In the first cross-sectional study, multivariate linear regression analyses indicated a significant inverse association of serum 25(OH)D with IR (β=-0.003, p=0.007) and a significant positive association of 25(OH)D with β-cell function (β=0.004, p=0.03) at the baseline PROMISE clinic visit (n=712). In another cross-sectional study also conducted using data from the baseline PROMISE clinic visit, higher 25(OH)D was found to be significantly associated with a reduced presence of the MetS after multivariate adjustment (OR=0.76, 95% CI 0.62-0.93). Low serum 25(OH)D was also significantly associated with various MetS components. In light of the findings in the first cross-sectional study, the third study examined prospective associations of baseline 25(OH)D with 3-year follow-up IR and β-cell function (n=489). Although baseline 25(OH)D was not significantly associated with follow-up IR, a significant positive association of baseline 25(OH)D with β-cell function at follow-up was observed (β=0.005, p=0.015). Lastly, in a longitudinal substudy (n=127), seasonal changes in 25(OH)D over 2.5 years did not significantly affect changes in IR and β-cell function. In conclusion, results indicated that baseline serum 25(OH)D was cross-sectionally related to IR, β-cell function and the MetS, and was prospectively related to β-cell function at the 3-year follow-up. In addition, seasonal changes in 25(OH)D do not adversely affect IR and β-cell function over time. These findings suggest a potential role for higher 25(OH)D levels in reducing diabetes risk, although additional longitudinal studies are warranted.

Laminitis is a crippling disease of horses that can result in chronic lameness and debilitation, and sometimes warrants euthanasia. It is a complication of inflammatory conditions such as gastrointestinal disease, and also occurs in obese, insulin-resistant horses with Equine Metabolic Syndrome (EMS). Inflammation and insulin resistance are risk factors for laminitis, and these mechanisms might converge to induce laminitis in susceptible animals. Systemic inflammation is often attributed to endotoxemia, although circulating endotoxin concentrations are not commonly measured in the clinical setting. Although a theoretic basis exists for endotoxemia in the pathogenesis of laminitis, administration of endotoxin alone does not induce the condition. This could be related to differences between experimental models and naturally occurring disease. Studies presented in this dissertation address the overall hypothesis that systemic inflammation causes laminitis and new experimental models can be developed to better represent clinical disease. Associations between systemic inflammation and laminitis were first established by measuring blood inflammatory cytokine expression during a laminitis induction model. A clinically relevant endotoxin model that induced laminitis was then sought, but endotoxin administration alone was insufficient to cause laminitis and endotoxin tolerance developed. Endotoxemia was therefore evaluated in conjunction with predisposing factors such as obesity. In horses with EMS, endotoxin infusion caused exaggerated inflammatory responses, and derangements in glucose homeostasis were more pronounced. Laminitis, however, did not develop. Repeated inflammatory events are implicated in the pathogenesis of sepsis-associated organ failure, so a final study was performed to test whether preexisting endotoxemia increased the risk of laminitis during subsequent carbohydrate overload-induced systemic inflammation. This did not occur, however systemic inflammation was more pronounced in horses that developed laminitis compared to non-responders, and tissues rather than circulating leukocytes appeared to be the major source of inflammatory mediators. Our results do not support a role for endotoxin as the causal agent of laminitis, even when combined with predisposing factors. Tissues appear to be an important source of inflammatory mediators, therefore their role in laminitis should be further characterized. Additionally, future investigations should determine whether exaggerated inflammatory responses and loss of glycemic control increase the risk of laminitis in horses with EMS.

Intestinally derived chylomicron remnants (CM-r) may contribute to atherogenic dyslipidemia during the Metabolic Syndrome (Mets). However, the combined effects of ezetimibe (EZ) and simvastatin (SV) on post-prandial (PP) dyslipidemia during MetS remains unclear, nor is it known whether the combination has a synergistic anti-atherogenic effect on CM-r arterial retention. The first objective was to delineate the effects of EZ+SV therapy on intestinal cholesterol flux and CM PP metabolism in the JCR:LA-cp rat, a model of MetS. The second objective was to quantify the impact of EZ+SV therapy on arterial retention of CM-r and subsequent myocardial lesion development in the JCR:LA-cp rat. EZ+SV therapy decreased net intestinal cholesterol absorption in MetS rats. Furthermore, EZ+SV therapy reduced arterial retention of CM-r and frequency of myocardial lesions in MetS rats. In conclusion, EZ+SV therapy reduces arterial retention of CM-r and myocardial lesion development possibly through its beneficial effects on cholesterol transport and PP-metabolism. / Nutrition and Metabolism

Trans-11 vaccenic acid (VA) is the predominant trans fatty acid in dairy fat and is the major precursor to endogenous synthesis of cis9,trans11-conjugated linoleic acid (CLA) in humans and animals. Epidemiological studies have shown the positive association between trans fat intake and incidence of coronary heart disease. Nevertheless, CLA, categorized as a group of trans fatty acids, has been shown to possess anti-carcinogenic, hypolipidemic and anti-diabetic benefits in several animal models as well as certain human populations, possibly via activating peroxisome proliferator-activated receptor (PPAR) related metabolic pathways. The subsequent effort in enriching CLA in dairy products (e.g. butter) has led to a concomitant increase in VA, whose bioactivity and health implications were not fully appreciated. Interestingly, VA is the major natural trans fat found in the diet. Therefore, the objectives of this thesis were to assess the effect of dietary supplementation of synthetic VA on lipid metabolism especially during conditions of dyslipidemia and metabolic syndrome, and to delineate the intestinal and hepatic metabolic pathways potentially modulated by VA. The JCR:LA-cp rat model, when homozygous for the cp trait (cp/cp), develop leptin receptor deficiency which leads to symptoms of metabolic syndrome and pre-diabetes including obesity, insulin resistance, hepatic steatosis, hypertriglyceridemia and exacerbated production of hepatic very low-density lipoproteins and intestinal chylomicrons (CM). Gas chromatography analysis on nascent lymph shows that VA was effectively absorbed into the intestine. In addition, VA from natural source (i.e. beef fat) showed higher intestinal bioavailability compared to synthetic VA. Dietary supplementation of 1.0% (w/w) synthetic VA to JCR:LA-cp rats (but not lean healthy controls) demonstrated a profound reduction in plasma triglyceride, total cholesterol, low-density lipoprotein-cholesterol, non-esterified fatty acid and haptoglobin concentrations (51%, p<0.001; 40%, p<0.001; 50%, p<0.05; 20%, p<0.05 and 50%, p<0.001; respectively), as well as improvement in hepatic steatosis and postprandial lipaemia. Gastric infusion of VA also resulted in an acute reduction in CM secretion in response to a fat load (p<0.05). We also found that the overall hypolipidemic benefits of VA might be partially contributed by suppression of hepatic de novo lipogenesis, activation of PPAR- activity as well as up-regulation of PPAR- and PPAR- expression in the intestine. In conclusion, VA as a natural trans fat, possesses beneficial properties in a rat model of dyslipidemia and metabolic syndrome, suggesting potential for the prevention of cardiovascular disease risk. / Nutrition and Metabolism

Activation of inducible nitric oxide synthase (iNOS) and oxidative stress have been shown to be associated with compromised cardiovascular function in streptozotocin (STZ)-induced type 1 diabetes. The aim of the project is to investigate cardiovascular abnormalities in a rat model of type 2 diabetes (Zucker diabetes fatty or ZDF rats) and two models of metabolic syndrome (fructose-fed rats and Zucker obese rats), and to provide direct evidence linking iNOS and oxidative stress to abnormal cardiovascular function in these disorders. Blood pressure, cardiac contractility, cardiac index, regional flow, vascular resistance and venous tone were measured in diseased as well as normal rats. Biochemical analyses such as activities of iNOS, immunostaining of iNOS and western-blot analysis of iNOS in the heart tissue were carried out. The results showed that cardiac contractile response to dobutamine was compromised in the ZDF rats, and this was associated with increased myocardial protein expression as well as activity of iNOS. The formation of peroxynitrite was increased in the heart tissue of the ZDF rats. Selective inhibition of iNOS by 1400W (N-3-aminomethyl-benzyl-acetamidine) did not alter responses to dobutamine in the control rats, but augmented the contractile effects of dobutamine in the diabetic rats. The regional blood flow was altered in the ZDF rats, and iNOS played a negligible role in regulating regional flow in the ZDF rats. Although venous response to noradrenaline was also altered in the Zucker obese rats, NOS may not be involved in venous tone regulation. Anti-oxidative treatment with N-acetylcysteine inhibited the development of insulin resistance, blood pressure elevation and the increase of 8-isoprostane formation in the fructose-fed rats. We conclude that heart function is compromised and regional blood flow is altered in the ZDF rats. Activation of iNOS plays an important role in suppressing heart dysfunction but does not affect regional blood flow. In Zucker obese rats with metabolic syndrome, iNOS may not be involved in changes of venous function. Oxidative stress is associated with both abnormality of heart dysfunction in type 2 diabetes (by formation of peroxynitrite due to iNOS activation) and development of hypertension and insulin resistance in metabolic syndrome.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.