Abstract Different metabolic and environmental factors affect the blood pressure level, constituting a cluster, especially in hypertensives, that leads to an increased risk of cardiovascular diseases. The present research was designed to determine the prevalence and the predictors of the metabolic syndrome and the role of insulin and blood pressure in carotid atherosclerosis in 600 treated male and female hypertensives aged 40-59 years and 600 age- and sex-matched controls. The prevalence of the metabolic syndrome in different population-based cohorts varied, depending on the definition, from 0.8% to 35.3%, being lowest in control men and women and highest in hypertensive men. 73.8% of a random, middle-aged, urban population showed at least one cardiovascular risk factor, and 91.3% of all hypertensive subjects showed at least one cardiovascular risk factor in addition to hypertension itself. The independent predictors of the metabolic syndrome were waist circumference, uric acid, total cholesterol and gamma-glutamyl transpeptidase. Hypertension had a significant effect on carotid intima-media thickness and the prevalence of plaques in men, but its effect in women was not significant. A long duration of hypertension resulted in greater intima-media thickness and a higher prevalence of plaques, particularly in men. There were significant associations between gamma-glutamyl transpeptidase and the components of the metabolic syndrome after adjustment for alcohol consumption and also in teetotallers. There were inconsistent associations between the different insulin measures and the intima-media thickness as a measure of carotid atherosclerosis. The exclusion of diabetic subjects did not change the results. In conclusion, a cluster of metabolic abnormalities related to hypertension is frequent among both controls and treated hypertensive subjects. Hypertensive subjects have higher prevalences of carbohydrate and lipoprotein aberrations and structural and functional cardiovascular complications than age- and sex-matched controls.

Objective: To describe the epidemiology and health system impact of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) in Ontario. Methods: Following a review of methods to estimating robust health event rates for small populations, this study described health services use among infants diagnosed with MCADD or received a false positive newborn screening result for MCADD from April 2006 through March 2010. Each cohort was compared with screen negative infants by linking to databases encompassing physician visits, emergency department care, and hospitalizations. Results: Relative to comparison birth cohorts, children with MCADD (n=40) experienced significantly higher rates of all health service types, regardless of age at the time of visit; infants with false positive results for MCADD (n=43) experienced significantly higher rates of physician visits and hospitalizations in the first year of life only. Conclusion: This study makes an important contribution to the limited existing research describing the health system impact of rare diseases.

INTRODUCTION: Alcoholic cirrhosis occurs at a higher rate in female patients, at an earlier age, and with a lower consumption of alcohol compared to male patients. In our study on alcoholic fatty liver disease (AFLD) and adipokine levels, female mice showed a 50% higher mortality rate compared to ethanol fed male mice. The amount of ethanol consumed was similar between sexes when normalized to body weight. This resulted in our hypothesis that female mice are more susceptible to inflammation caused by alcohol consumption. METHODS: 12-week old female mice were fed a Lieber-Decarli alcohol diet (5% ETOH by volume) for 6-weeks and body weight and food intake were measured daily. Serum was collected from the mice and alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum triglycerides, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) levels were measured with the appropriate assays. RESULTS: In response to alcohol feeding, female mice showed significant increases in levels of ALT and AST compared to the male mice, indicating increased damage to the liver. TNF-α and IL-6 were also significantly increased in the ethanol fed female mice, indicating a significant increase in inflammation compared to the male ethanol fed mice. There was no difference found in the levels of serum triglycerides. CONCLUSION: These results indicate chronic alcohol consumption affects mice in a sex dependent manner, and that female mice are more susceptible to the adverse effects of alcohol than male mice. Increased female susceptibility to ethanol-induced damage must be considered in future ethanol-feeding studies.

INTRODUCTION: The liver is the primary organ responsible for the removal of toxic substances from the body by means of a variety of metabolic pathways. One class of proteins responsible for much of the body’s xenobiotic drug and alcohol metabolism is the Cytochrome P450 family of proteins. One protein, Cytochrome P450 Class E Subclass 2 (Cyp2E1), has an integral role in alcohol metabolism by the liver. Cyp2E1 becomes fully activated after an organism has consumed excessive amounts of alcohol excessive alcohol and works with aldehyde dehydrogenase (ALDH) to metabolize ethanol to acetaldehyde. Another metabolic protein, C1q TNF Related Protein 3 (CTRP3), has been shown to effectively prevent alcoholic fatty liver disease (AFLD), specifically with long-term alcohol-induced lipid accumulation. METHODS: In this experiment, 12-week old male mice were fed a Lieber-Decarli alcohol diet (5% ETOH by volume) for 6-weeks. The food intake and body weight of the mice was recorded each day. The mice in the experiment included both wild type and transgenic CTRP3 overexpressing mice. At the end of the 6-week period the mice were euthanized, and the liver was carefully removed, flash-frozen, and prepared for immunoblot analysis of the proteins. RESULTS: Cyp2E1 levels increased significantly in response to ethanol consumption. Cyp2E1 levels were further elevated in ethanol-fed CTRP3 transgenic overexpressing mice. Cyp2E1 levels in CTRP3 transgenic mice were nearly twice that of wild type ethanol-fed mice. CONCLUSIONS: The results of the experiment show a significant increase in Cyp2E1 in mice which overexpress CTRP3. This upregulation of Cyp2E1 with CTRP3 overexpression could explain the mechanism for reduced hepatic lipid accumulation in ethanol-fed CTRP3 transgenic mice.

A Thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in ful lment of the requirements for the degree of Doctor of Philosophy in Medicine Johannesburg, South Africa 2017. / Background: The persistent burden of undernutrition, with increasing prevalence of obesity and metabolic disease risk among children and adolescents, has become a global public health problem. Research has shown that risk factors established in childhood and adolescence may contribute to the development of non-communicable diseases (NCDs) in adulthood. This is of particular concern in South Africa, given its rapid socio-economic, political and epidemiological transitions. Research into the trends of nutrition transition in rural children and adolescents, whose particular health needs have been under-served and poorly delineated in the past, provides a unique opportunity to study the e ects of rapid health transitions on development. Aim: To determine the association of nutrition, body composition and metabolic disease risk in rural South African children and adolescents. Study design: Three cross-sectional studies were undertaken to address the overall aim of this research. The speci c objectives of each study were: (1) to determine the association of nutrition on body composition and metabolic disease risk in children and adolescents; (2) to examine the associations between body mass index (BMI), disordered eating attitude and body dissatisfaction in female adolescents, and descriptive attributes assigned to silhouettes of di ering body habitus in male and female adolescents; and (3) to investigate associations between diet and cardiovascular disease (CVD) risk factors in adolescents. Method: One cross-sectional study, 3 analyses were nested within the Agincourt Health and Socio-demographic Surveillance System (HDSS) site, in the Bushbuckridge subdistrict, Mpumalanga Province, South Africa. In 2009, a random sample of 600 children and adolescents, from age groups 7 to 8 years, 11 to 12 years and 14 to 15 years, were selected from 3489 children who had participated in a 2007 growth survey. These children and adolescents had to have lived in Agincourt at least 80% of the time since birth or since 1992, when enrolment into the Agincourt Health and Socio-Demographic Surveillance System (HDSS) began. Height and weight were measured to determine BMI. Age and sex-speci c cut-o s for underweight and overweight/obesity were determined using those of the International Obesity Task Force. Body image satisfaction using Feel-Ideal Discrepancy (FID) scores, Eating Attitudes Test-26 (EAT-26), perceptual female silhouettes and pubertal assessment were collected through self-administered questionnaires. Blood pressure (systolic (SBP) and diastolic (DBP)) was measured, fasting blood samv ples were collected for the determination of glucose and lipids. Waist to hip ratio cut-o s of (WHR) >0.85 for females, >0.90 for males, waist to height ratio (WHtR) of >0.5 for both sexes, and waist circumference (WC) of >80 cm for females and >94 cm for males were used to determine the risk of adiposity. For abnormal lipids: high density lipoprotein cholesterol (HDL-C) cut-o s of >1.03 mmol/l, low density lipoprotein-cholesterol (LDL-C) of >2.59 mmol/l, triglycerides (TGs) of >1.7 mmol/l and total cholesterol (TC) of >5.17 mmol/l were used. Pre-hypertension prevalence was computed using the average of 2 readings of SBP or DBP, being >90th but <95th percentile for age, sex and height. Dietary intake was assessed using semi-quantitative food frequency questionnaire. T-test and ANOVAs for normally distributed data and Wilcoxon-Mann- Whitney test was used to determine signi cant di erences by sex and by pubertal stages for EAT-26 and EAT-26 sub-scores. Chi square tests were done to determine signi cant associations between the categorical variables. Bivariate linear regression was employed to test associations and signi cant tests were set at the p<0.05 level. Results: Study component (1): Stunting levels were higher in the boys than in the girls in mid to late childhood and combined overweight and obesity prevalence was higher in girls than in boys. The girls' BMI was signi cantly greater at ages 11 and 12 years than that of the boys [girls: 18 3.4, 95% con dence interval (CI): 17.33- 18.69; boys: 17 2, 95% CI: 16.46-17.25; p-value 0.004] and at ages 14-15 years (girls: 22 4.1, 95% CI: 20.82-22.47; boys: 19 2.4, 95% CI: 18.39-19.38; p-value < 0.001). Prehypertension (de ned as < 90th centile for age, sex and height) was higher in girls (15%) than boys (10%). Further, impaired fasting glucose was detected in 5.3% of girls and 5% of boys. High-density lipoprotein cholesterol (>1.03 mmol/l) concentrations were observed in 12% of the girls and 0.7% of the boys, which is indicative of cardiometabolic risk. Study component (2): The prevalence of overweight and obesity was higher in girls than boys in early and mid to post pubertal stages. The majority (83.5%) of the girls reported body image dissatisfaction (a desire to be thinner or fatter). The girls who wanted to be fatter had a signi cantly higher BMI than the girls who wanted to be thinner (p=0.001). There were no di erences in EAT-26 score between pubertal groups, or between boys and girls within the two pubertal groups. The majority of the boys and the girls in both pubertal groups perceived the underweight silhouettes to be \unhappy" and \weak" and the majority of girls in both pubertal groups perceived the normal silhouettes to be the \best". Study component (3): Added sugar and sweets contributed 10% and maize meal and vi bread contributed 7.2% to the total number of food items consumed respectively. Girls had higher intakes of total fat, saturated fat and cholesterol after adjusting for dietary energy intake and age (all p<0.001). The prevalence of combined overweight and obesity was 13.8% in girls and 3.1% in boys (p<0.001). In addition, indicators of adiposity were higher in females, abnormal waist circumference (WC) (6.7%), waist to hip ratio (WHR) (22.0%) and waist to height ratio (WHtR) (18.0%), compared to males, (0%), (3.1%) and (6.2%) respectively (all p<0.001). Girls had higher low-density lipoprotein (LDL) (12(9.3%) vs. 3(2.3%), p=0.01), total cholesterol (17(12.7%) vs. 5(3.5%), p<0.001) and were more pre-hypertensive (28(15.3%) vs.15(8.4%), p=0.04) than the boys. Furthermore, the bivariate associations between dietary intakes (total energy, total carbohydrate (CHO), total dietary fat and saturated fat) and anthropometric indices (BMI and WC) showed that body mass index (BMI) was associated with total energy (p=0.05) and BMI and WC were associated with total fat (p=0.01, p=0.03) and saturated fat (p<0.001, p=0.02) in females respectively. Conclusions: In conclusion, this thesis highlights that girls in rural South Africa had a higher prevalence of combined overweight and obesity than did boys, stunting was more prevalent amongst boys than girls in mid to late childhood and metabolic risk factors that were associated with adiposity, and linked to diet, were higher in girls than in boys. This study has provided useful information for targeting critical health promotion intervention programmes to optimise child nutrition as part of a noncommunicable disease preventative strategy, especially, in remote areas in rapidly transitioning South Africa. / LG2018

With cardiovascular disease, diabetes mellitus, and neurodegenerative conditions on the rise, understanding their pathogenesis is paramount to tackling this public health crisis. Current research indicates that the primary cause of these diseases is mitochondrial dysfunction in the affected patients. While genetics plays a role in these conditions, lifestyle choices and exposure to toxins also significantly contribute to their development. Unfortunately, early-stage diagnosis can be difficult due to overlapping symptoms with other diseases. Developing innovative therapies that can prevent or reverse the deterioration of metabolic dysfunctions is critical to establishing early intervention. My research focused on investigating molecular targets linked with Friedrich's Ataxia, an inherited metabolic disorder, through conducting functional in-vitro studies using human-derived cell samples, as well as developing inventive animal models created via Xenopus laevis tadpoles to evaluate the effects of environmental stressors. My investigations have uncovered promising treatment options that improve mitochondrial function, mitigate oxidative stress, and elucidate critical mechanisms involved in environmentally induced disruptions to mitochondria. / Doctor of Philosophy / Metabolic dysfunction is a widespread health issue that affects millions of individuals each day. Its associated disorders, such as cardiovascular disease, diabetes, and neurodegenerative conditions, are rising due to various factors ranging from genetic predispositions to environmental and lifestyle-related risks. Therefore, there's an urgent need to identify this disorder early on and develop innovative treatment options. Considering this growing public health concern, it has become imperative to establish new methods for detecting metabolic dysfunction at its nascent stage while also exploring potential therapeutic interventions. Our research utilized cells derived from affected patients and animal models in devising novel approaches toward understanding the molecular mechanisms underpinning metabolic dysfunction. Our findings revealed several pathways and molecular targets contributing significantly to this condition, which could effectively be leveraged to develop targeted therapeutic strategies to combat its effects. Expanding our knowledge base will enable us to stay updated with emerging insights on treating metabolic dysfunction effectively while substantially improving patient outcomes.

No description available.

No description available.

Obesity has been on the rise over the last 30 years, reaching worldwide epidemic proportions. Obesity has been linked to multiple metabolic disorders and co-morbidities such as Type 2 Diabetes Mellitus (T2DM), cardiovascular disease, non-alcoholic steatohepatitis and various cancers. Furthermore, obesity is associated with a chronic state of low-grade inflammation in adipose tissue (AT), and it is thought that insulin resistance (IR) and T2DM is associated with the inflammatory state of AT. Endothelial cells (ECs) mediate the migration of immune cells into underlying tissues during times of inflammation, including obesity- and cardiovascular disease-associated inflammation. Cytokines and chemoattractants released from inflamed tissues promote EC activation. Upon activation, ECs increase the expression of leukocyte adhesion molecules (LCAMs) including intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1), E-selectin (E-sel) and P-selectin (P-sel). Increased expression of these LCAMs and increased infiltration of inflammatory cells such as macrophages, have been linked to IR, diabetes and atherosclerosis in obese individuals. Preliminary data from our lab suggests that lipolysis induced by the β-adrenergic receptor agonist CL 316,243 causes an increase in endothelial LCAM gene expression. In addition, histological analyses show increased content of immune cells within AT after the ECs become activated. Here, we demonstrate that CL 316,243-induced lipolysis causes infiltration of neutrophils in wild type (WT) but not E-sel knockout (KO) mice. Following EC activation, there was also a marked increase in cytokine gene expression including IL-1β, MCP-1, and TNF-α in an E-sel-dependent manner. In contrast, fasting-induced lipolysis was associated with increased macrophage infiltration into AT in the absence of EC activation in an E-sel-independent manner. We also examined the role of mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) as a potential contributor to endothelial activation and atherosclerosis. Here we demonstrate that deletion of MAP4K4 in ECs in vitro diminishes TNF-α-induced EC activation. Additionally, MAP4K4 depletion in primary ECs derived from lungs of mice expressing MAP4K4 shRNA decreases EC activation. Finally, endothelial specific depletion or loss of MAP4K4 reduced atherosclerotic plaque formation in vivo. Taken together, these results highlight the importance of the endothelium in modulating obesity-associated comorbidities. Furthermore, these data implicate endothelial MAP4K4 as a novel regulator of EC activation and consequently AT inflammation and atherosclerosis.

<p>Background: The objective of this thesis was to examine the role of psychosocial factors in weight loss success after bariatric surgery. It was proposed that a higher pre-operative body mass index (BMI), greater weight, depression, low self-esteem, and a childhood history of sexual abuse (CSA) would predict poor outcomes one year after Roux-en-y gastric bypass as evidenced by a BMI > 35 kg/m²and a lower percent total weight loss (%TWL). Methods: We administered a battery of psychological screening tools, including the Beck Depression Inventory-II, the Rosenberg Self-Esteem Scale and a self-report measure assessing CSA, to 262 patients seeking bariatric surgery at St. Joseph's Healthcare Hamilton. Patients completed the questionnaires prior to surgery and again one year post-surgery. Results: On average patients (n = 79) achieved good weight loss outcomes (BMI = 32.8 kg/m²) at one-year follow-up. Through multiple regression analysis we found that pre-operative BMI accounted for a significant proportion of variance in postoperative BMI [<em>R²</em> = .60, <em>F</em>(1, 77) = 114.4, <em>p</em> < .001]. Weight before surgery, however, did not predict %TWL after surgery. None of the psychosocial variables significantly predicted post-operative BMI or weight loss. These results are preliminary and are limited by the fact that participants did not present with clinically significant symptomatology and those with active psychopathology were excluded as suitable surgical candidates. Conclusion: These findings indicate that pre-operative BMI is a significant predictor of BMI one year after bariatric surgery, suggesting that more attention should be directed toward managing pre-operative BMI for heavier patients.</p> / Master of Science (MSc)