Dissertations / Theses on the topic 'Cardiovascular system – Diseases – Genetic aspects'

[Truncated abstract] This thesis investigates novel methods for the genetic association analysis of haplotype data in samples of unrelated individuals, and applies these methods to the analysis of coronary heart disease and related phenotypes. Determining the inheritance pattern of genetic variants in studies of unrelated individuals can be problematic because family members of the studied individuals are often not available. For the analysis of individual genetic loci, no problem arises because the unit of interest is the observed genotype. When the unit of interest is the linear combination of alleles along one chromosome, inherited together in a haplotype, it is not always possible to determine with certainty the inheritance pattern, and therefore statistical methods to infer these patterns must be adopted. Due to genotypic heterozygosity, mutliple possible haplotype configurations can often resolve an individual's genotype measures at multiple loci. When haplotypes are not known, but are inferred statistically, an element of uncertainty is thus inherent which, if not dealt with appropriately, can result in unreliable estimates of effect sizes in an association setting. The core aim of the research described in this thesis was to develop and implement a general method for haplotype-based association analysis using multiple imputation to appropriately deal with uncertainty haplotype assignment. Regression-based approaches to association analysis provide flexible methods to investigate the influence of a covariate on a response variable, adjusting for the effects of other variables including interaction terms. ... These methods are then applied to models accommodating binary, quantitative, longitudinal and survival data. The performance of the multiple imputation method implemented was assessed using simulated data under a range of haplotypic effect sizes and genetic inheritance patterns. The multiple imputation approach performed better, on average, than ignoring haplotypic uncertainty, and provided estimates that in most cases were similar to those observed when haplotypes were known. The haplotype association methods developed in this thesis were used to investigate the genetic epidemiology of cardiovascular disease, utilising data for the cholesteryl ester transfer protein gene (CETP), the hepatic lipase (LIPC) gene and the 15- lipoxygenase (ALOX15) gene on a total of 6,487 individuals from three Western Australian studies. Results of these analyses suggested single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were associated with increased plasma high-density lipoprotein cholesterol (HDL-C). SNPs in the LIPC gene were also associated with increased HDL-C and haplotypes in the ALOX15 gene were associated with risk of carotid plaque among individuals with premature CHD. The research presented in this thesis is both novel and important as it provides methods for the analysis of haplotypic associations with a range of response types, while incorporating information about haplotype uncertainty inherent in populationbased studies. These methods are shown to perform well for a range of simulated and real data situations, and have been written into a statistical analysis package that has been freely released to the research community.

Thesis (MSCMedSc)--Stellenbosch University, 2012.
Includes bibliography
ENGLISH ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in the world. The disease spectrum of NAFLD extends from steatosis (types 1,2) to non-alcoholic steatohepatitis (NASH) with inflammation (types 3,4). The aims of the study were 1) to analytically validate high-throughput real time polymerase chain reaction (RT-PCR) assays for three selected single nucleotide polymorphisms (SNPs), FTO rs9939609 (intron 1 T>A), TNF-α rs1800629 (-308 G>A) and PPARγ rs1801282 (Pro12Ala, 34 C>G), and 2) to perform genotype-phenotype association studies in relation to biochemical abnormalities, disease severity and age of onset. A total of 119 patients with fatty liver identified on ultrasound, including 88 histologically confirmed NAFLD patients, and 166 control individuals were genotyped for the three selected SNPs. RT-PCR validated against direct sequencing as the gold standard was used for detection of genetic variation. All three SNPs were in Hardy Weinberg equilibrium in the study population, except for a deviation in genotype distribution detected for PPARγ rs1801282 in the NAFLD patient subgroup (p<0.001). After adjustment for age and gender, the risk-associated FTO rs9939609 A-allele was detected at a significantly higher frequency in the Caucasian compared with Coloured patients (p=0.005). The opposite was detected for the risk-associated TNF-α rs1800629 A-allele, which occurred at a significantly higher frequency in the Coloured compared with Caucasian NAFLD patients (p=0.034). The onset of fatty liver disease symptoms was on average 5 years younger in the presence of each risk-associated TNF-α rs1800629 A-allele (p=0.028). When considered in the context of an inferred genotype risk score ranging from 0-6, disease onset occurred on average 3 years earlier (p=0.008) in the presence of each risk-associated FTO A-allele, TNF-α A-allele or PPARγ C-allele. After adjustment for age, gender and race, no differences in genotype distribution or allele frequencies were observed between histologically confirmed NAFLD (types 1,2) and NASH (types 3,4) patients, while the minor allele frequency for the TNF-α rs1800629 was significantly higher in the total NAFLD (types 1-4) (p=0.047) as well as NASH subgroup (NAFLD types 3,4) (p=0.030) compared with obese patients without a histologically confirmed NAFLD diagnosis. A significant correlation was furthermore observed between the number of TNF-α rs1800629 A-alleles and increasing CRP levels (p=0.029), with a favourable reduced effect in the presence of low- to moderate alcohol intake. The average waist circumference of physically active NAFLD patients was 12% lower than in physically inactive patients (p=0.004). In view of the results presented in this study, the inclusion of the selected SNPs, and in particular the pro-inflammatory TNF-α rs1800629 polymorphism, may be considered as part of a comprehensive cardiovascular risk evaluation of NAFLD patients. Ultimately, early detection of patients with fatty liver disease symptoms and effective intervention based on the underlying disease mechanism may prevent progression from NAFLD to NASH, shown to be an independent risk factor for cardiovascular diseases.
AFRIKAANSE OPSOMMING: Nie-alkoholiese lewervervetting (NALV) is die mees algemene kroniese lewersiekte in die wêreld. Die siektespektrum van NALV strek van steatose (vervette lewer tipes 1,2) tot steatohepatitis met inflammasie (NASH tipes 3,4). Die doel van die studie was 1) om analities die hoë omset polimerase kettingreaksie (RT-PKR) metode te valideer vir die geselekteerde enkel nukleotied polimorfismes (ENPs) FTO rs9939609 (intron 1 T>A), TNF-α rs1800629 (-308 G>A) en PPARγ rs1801282 (Pro12Ala, 34 C>G), en 2) om genotipe-fenotipe assosiasie studies uit te voer ten opsigte van relevante biochemiese abnormaliteite, graad van die siekte en aanvangsouderdom. ’n Totaal van 119 pasiënte met vervette lewers is geïdentifiseer met behulp van ultraklank, insluited 88 histologies-bevestigde NALV pasiënte, en 166 kontrole individue. Hierdie pasiënte is gegenotipeer vir die 3 geselekteerde ENP’s. RT-PKR gevalideer met direkte DNA volgorde bepaling as die goue standaard, is gebruik vir opsporing van genetiese variasie. Al die ENP’s was in Hardy Weinberg ekwilibrium in die studie populasie, behalwe vir ’n afwyking in genotipe verspreiding waargeneem vir PPARγ in die NALV subgroep (p<0.001). Nadat aanpassings gemaak is vir ouderdom en geslag, is die risiko-geassosieerde FTO rs9939609 A-alleel waargeneem teen ’n betekenisvol hoër frekwensie in die Kaukasiese pasiënte in vergelyking met Kleurling pasiënte (p=0.005). Die teenoorgestelde is waargeneem vir die risiko-geassosieerde TNF-α rs1800629 A-alleel wat voorgekom het teen ’n betekenisvol hoër frekwensie in die Kleurling NALV pasiënte, in vergelyking met Kaukasiese NALV pasiënte (p=0.034). Die aanvang van NALV was gemiddeld 5 jaar vroeër in die teenwoordigheid van elke risiko-geassosieerde TNF-α rs1800629 A-alleel (p=0.028). Met inagneming van ’n genotipe risiko telling tussen 0–6, het aanvang van siekte gemiddeld 3 jaar vroeër voorgekom (p=0.008) in die teenwoordigheid van elke toenemende risiko-geassosieerde FTO A-alleel, TNF-α A-alleel en PPARγ C-alleel. Nadat aanpassings gemaak is vir ouderdom, geslag en ras, is geen verskille waargeneem in genotipe verspreiding of alleel frekwensies tussen histologies bevestigde NALV (tipes 1,2) en NASH (tipes 3,4) pasiënte nie, terwyl die minor alleel telling vir die TNF-α rs1800629 betekenisvol hoër was in die totale NALV (tipes 1–4) (p=0.047) asook die NASH subgroep (NALV tipes 3,4) (p=0.03) in vergelyking met vetsugtige pasiënte sonder ’n histologies bevestigde diagnose. ‘n Statisties beteknisvolle korrelasie is verder waargeneem tussen die aantal TNF-α rs1800629 A-allele en toenemende CRP vlakke (p=0.029), met n gunstige verlaagde effek in die teenwoordigheid van lae alcohol gebruik. Die gemiddelde middellyf-omtrek van fisies aktiewe NALV pasiënte was 12% minder as fisies onaktiewe pasiente (p=0.004). Na aanleiding van die resultate van hierdie studie behoort insluiting van geselekteerde ENP’s, en in besonder die pro-inflammatoriese TNF-α rs1800629 polimorfisme, as deel van ’n omvattende kardiovaskulere risiko evaluasie oorweeg te word. Aan die einde van die dag mag vroeë identifikasie van NALV pasiente en effektieve intervensie gebasseer op die onderliggende siekte meganisme, vordering tot NASH verhoed wat getoon is om ’n onafhanklike risiko faktor vir kardiovaskulêre siekte te wees.
Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology

Cardiovascular diseases (CVDs) remain to be the leading causes of morbidity and mortality in Hong Kong and worldwide. Among different modifiable risk factors, dietary pattern is on the major determinant for CVD and overall mortality. Other than pharmacological therapies for cardiovascular risk factors, such as hypertension, hyperlipidemia and diabetes, maintaining a healthy diet is a more sustainable method in general population to prevent CVDs. Current lifestyle intervention in the West countries focus on high intake of fruit and vegetables with more than 400g per day and limited saturated fats with less than 10% of energy, there is very limited data on impact of dietary pattern on CVDs in Chinese. Prior studies among Chinese in Hong Kong have shown that only half of the local population fell within these recommended ranges for fat, saturated fatty acid and cholesterol intakes. Several different dietary patterns have been recommended for CVDs prevention based on: i) food groups, such as Mediterranean diet, the Dietary Approaches to Stop Hypertension (DASH) diet; ii) macronutrients: the low-carbohydrate diet, low glycemic index diet, very-low- fat diet and iii) nutrition or vitamin supplement. However, the effect of different dietary patterns based on modulations of food group, macronutrients and particular micronutrients on vascular structure and function in Chinese subjects is unclear. In the first part of this thesis, the relationships between different dietary pattern and surrogate markers of subclinical atherosclerosis and vascular function in different high risk populations for CVDs were investigated. In Chapter 3, we compared the assessment of dietary pattern in Chinese using different tool, including Food Frequency Questionnaire (FFQ); Dietary Record; and Dietitian assessment. In this study, we demonstrated that suitable dietary assessments tools should be chosen for the assessment of different dietary pattern, according to characteristics of assessments. In Chapter 4, the relationship between the fruit intake and subclinical atherosclerosis as measured by carotid intimal thickness (IMT) was investigated in patient with type II diabetes mellitus (DM). Our results showed that high fruit intake was associated with lower burden of carotid atherosclerosis, independent of level of vitamin intake in patients with type II DM. In Chapter 5, we compared the impact of high carbohydrate diet on arterial stiffness between control subjects without CVDs and patients with high risk for CVDs. Our findings showed that high carbohydrate diet mainly affected patients with established CVDs, and their increased arterial stiffness was associated with an elevation of blood pressure. In Chapter 6, we determined the effect of dietary vitamin intake on oxidative stress in patients with high risk of CVDs. In those high risk patients for CVDs, we demonstrated that increased dietary intake of vitamin A, beta-carotene and alpha tocopherol were associated with decreased oxidative stress, but these relationships were not observed in those control subjects without CVDs. It is likely attributed to the higher systemic oxidative stress levels in patients with high risk of CVDs. On the other hand, food intake may also affect the clinical efficacy of cardiovascular therapies. In particularly, it has been well established that herbal intake which is commonly used by Chinese can affect the anticoagulant effect of warfarin on patients with non-valvular atrial fibrillation (AF). Thus, in this second part of the thesis, we investigated the effect of concomitant herbal intake on anticoagulation control in patients with non-valvular AF treated with warfarin. Our results showed that patients with AF treated with warfarin had limited knowledge on potential interaction between herbal substances in foods and warfarin, in which increased herbal substances intake significantly reduced the percentage time of anticoagulant effect within the therapeutic range. Moreover, a single section of education on knowledge of herbal ingredients did not improve their percentage time of therapeutic range for these patients. In conclusion, these findings suggest that dietary pattern in Chinese might have significant impact of vascular function in patients with type II DM and high risk for CVDs. Moreover, the herbal substances in the diet among Chinese could have significant impact of the therapeutic effects in some of the cardiovascular medications, such as warfarin. Future clinical studies will be needed to confirm these potential beneficial effects of particular diet intake on vascular function in patients with high risks of CVDs as well as potential interaction between herbal substances in Chinese diet and cardiovascular medications.
published_or_final_version
Medicine
Doctoral
Doctor of Philosophy

Background: Research studies in recent years suggested possible role of dark chocolate in preventing cardiovascular diseases due to its high flavonal and procyanidins contents. Whether there is clear clinical benefit and the mechanisms mediating such benefits is controversial. Objective: This systematic review aims to comprehensively examine the current clinical evidence regarding effectiveness and the possible mechanisms of chocolate in reducing the risk and / or surrogate markers of cardiovascular diseases. Methods: Comprehensive electronic literature search was performed using Ovid, Medline and Cochrane database. Only English language literatures published during year 1950 - 2010 were reviewed. All intervention studies and observational studies of adult human subjects taking white or dark chocolate in relation to outcomes of cardiovascular risk were included. All review articles and meta-analysis were also included. Clinical diagnosis of cardiovascular disease and surrogate markers including blood pressure, vascular endothelial function as measured by flowed mediated vasodilation, and blood biomarkers such as lipid profile were studied as outcome variables. Results: The review outlines recent observational and interventional studies and meta-analysis to give an overview of the topic. For observational studies, a cohort studies and two case control studies were found. The observational studies showed that dark chocolate consumption was inversely associated with blood pressure, cardiovascular mortality and C-reactive protein. All interventional studies searched showed that dark chocolate increased FMD and improved platelet function. However, the effects of cocoa on intermediate outcomes such as blood pressure, antioxidant capacity and inflammatory marker changes were inconsistent among interventional studies. Three interventional studies indicated that there was a dose-dependent improvement in immediate outcome variables after 1 month or even 2 hours acute consumption of dark chocolate with procyanidins or cocoa drink with flavonol. However, publication bias and potential conflict of interests may be a potentially important factor in interpreting study results in the current literature. Conclusions: There are some clinical and scientific evidences that consumption of dark chocolate produces positive cardiovascular benefits. A small amount of dark chocolate may be good for the heart. However, gaps in our knowledge such as a lack of long-term RCT in clinical outcomes must be filled in before recommending habitual dark chocolate consumption for reduction of cardiovascular risk.
published_or_final_version
Community Medicine
Master
Master of Public Health

Objective: The review aims to evaluate associations of occasional and moderate drinking with cardiovascular diseases (CVD), specifically to compare results for occasional and moderate drinking, as moderate drinking is widely investigated while occasional drinking is relatively understudied and can potentially inform whether alcohol is causally related to CVD. Methods: A systematic review was conducted by searching for observational and interventional studies from three databases (ScienceDirect, Ebscohost, and PubMed) for alcohol consumption and its association with cardiovascular health. Online internet sources were also used for more supplementary research in this literature review. Patient-oriented outcomes, primarily on heart diseases, including cardiovascular heart disease, myocardial infarction, and coronary heart disease, were extracted from all study groups. Results: Fifteen studies were included, most of which were conducted in the United States of America (9 studies). Generally, moderate alcohol consumption is associated with a reduction in CVD risks, including extensive coronary calcification, sudden cardiac death, congestive heart failure, acute coronary syndrome, ischemic heart disease. Studies also suggests that alcohol may be associated with better endothelial function and lower systolic blood pressure Current occasional alcohol use is found to be associated lower IHD mortality in men, but is not related to IHD mortality in women. Conclusion: We found consistent evidence of protective association of moderate alcohol consumption against cardio-mortality and CVD, while occasional alcohol consumption has relatively less protection against CHD deaths. Such associations were only found in studies with living controls. Only a small number of studies have studied occasional drinking, in relation to cardiovascular health. Further studies that specifically examine occasional drinking, are needed. If the biological effects of occasional drinking towards CVD are limited, then occasional drinking may indicate the magnitude of residual and unobserved confounding in the association with cardiovascular health. This will in turn inform alcohol-related policies such as alcohol duties and minimum alcohol pricing.
published_or_final_version
Public Health
Master
Master of Public Health

Macrophage-derived foam cells play a predominant role in the deposition of arterial plaques during the early stages of atherosclerosis. The deposition of arterial plaques is known to be effected by several factors, including a person’s dietary habits. The consumption of a high-fat (>60% of calories from fat) meal is known to elevate serum LDL and triglycerides, which have been previously implicated in the formation pf foam cells. One limitation of current research models is that it is not possible to directly measure foam cells in vivo. Thus, the purpose of the present study was to validate the use of blood derived monocytes as a proxy measure of foam cells. In order to complete this objective, we evaluated monocyte oxLDL phagocytosis capacity following consumption of a high-fat meal. Eight men and women participated in the present study and venous blood samples were collected prior to the meal, 1-h, 3-h, and 5-h post-meal. Monocytes (CD14+/16- and CD14+/16+) were evaluated for adhesion molecule expression (CD11a, CD11b, and CD18), scavenger R (CD36) expression, and oxLDL phagocytosis using an image-based flow cytometry method developed in our laboratory for this purpose. Data was statistically analyzed for significance using a single-factor ANOVA with repeated measures and a p < 0.05. Consumption of a high-fat meal caused an increase significant increase in the proportion of pro-inflammatory monocytes (CD14+/16+) and a decrease in classic monocytes (CD14+/16-), with the greatest difference occurring at 5 h post prandial (p = 0.038). We also found that pro-inflammatory monocyte expression of adhesion molecules and CD36 increased in a manner that would promote in vivo movement of monocytes into the subendothelial space. Finally, over the course of the 5 h postprandial period, the majority of oxLDL uptake occurred in pro-inflammatory compared to classic monocytes. These results suggest that consuming a high-fat meal increases the potential of monocytes to become foam cells for at least 5 h postprandial.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
FAPESP: 2009/14884-9

Orientador: Eliana Aguiar Petri Nahas
Coorientador: Steven Witkins
Banca: Maria Terezinha Serrão Peraçoli
Banca: Cesar E. Fernandes
Banca: Aarão Mendes Pinto
Banca: Renata D. Jouiliano
Resumo: Não disponível
Abstract: Not available
Doutor

Hereditary Motor and Sensory Neuropathy-Russe (HMSNR) is a rare recessive form of Charcot-Marie-Tooth disease (CMT) that has been identified in the European Gypsy (Roma) population. Clinically, HMSNR manifests with typical CMT symptoms, while no associated features have been detected. Distinct neuropathological features of HMSNR include the presence of numerous clusters of thinly myelinated fibres originating from regenerative activity. HMSNR has been previously mapped to chromosome 10q using a large Bulgarian Gypsy kindred. Subsequent identification of related chromosome 10q haplotypes in Spanish and Romanian Gypsy families suggested a founder mutation in the Gypsy population as the cause of HMSNR. This thesis describes the refined mapping of the HMSNR gene by generating a high-density physical-genetic map of the HMSNR region containing 20 microsatellite markers and 229 SNPs and insertion/deletions which allowed meticulous mapping of recombination breakpoints resulting in a reduction of the HMSNR gene region from 1 Mb to just 63.8 kb. Analysis of positional candidates by direct sequencing included 14 known genes, 7 predicted genes and 42 expressed sequence tags (ESTs) nonoverlapping with the genes. 78 putative HMSNR mutations were identified, two of which exhibit complete segregation with the HMSNR phenotype. Both are located in the so-called testis-specific part of unexpected candidate gene hexokinase 1 (HK1), in a rare alternative untranslated 5’ exon of HK1 and in the adjacent downstream intron. Expression analysis of transcripts containing the alternative exon suggests that the exon is not confined to testis but may be expressed in the nervous system. It remains to be speculated how a gene that functions in the fundamental process of energy generation might be involved in a neuropathy. Further investigations are likely to expand the knowledge about the importance of HK1 in the peripheral nervous system and may elucidate new roles of HK1

The influence of autonomic activation in response to controllable versus noncontrollable stress, anger imagery induction, and relaxation imagery was studied among 80 participants between the ages of 18 and 34. Participants differed in level of trait hostility as assessed by the Irritability Subscale of The Buss-Durkee Hostility Inventory (Buss & Durkee,1957) and the Ho scale of the Cook-Medley Hostility Inventory (Cook & Medley, 1954). Groups were further subdivided with regards to either having a positive family history of cardiovascular disease or having no significant history. Results were obtained through analyses of electrocardiograph R-R intervals which produced an index of autonomic nervous system activation. Findings supported hypotheses involving the relations between autonomic balance and stress and hostility for the female and male populations. Among both populations, parasympathetic regulation was diminished during anger induction for individuals with high levels of trait hostility and having a family history of cardiovascular disease. Similar results were obtained for men during relaxation imagery induction.

Background: Chronic Obstructive Pulmonary Disease (COPD) poses a substantial burden to Hong Kong. Smoking is the single most important risk factor for COPD. Intensive smoking cessation in COPD patients slows disease progression. Community pharmacy based smoking cessation in healthy smokers could forestall COPD onset. Each of these programs has been proven effective and cost-effective worldwide. Currently there are smoking cessation clinics in Hong Kong. But community pharmacy-based smoking cessation services are not available. The present study firstly attempts to identify the disease burden of COPD; secondly, to investigate if community pharmacy-based smoking cessation services are applicable in Hong Kong; finally, to examine if establishing the services would be cost effective in reducing the burden of COPD. Methods: A series of data analysis of mortality, morbidity and cost of hospitalization (length of stay × standard daily ward cost) was conducted to understand the burden of COPD in Hong Kong. Cost effectiveness analysis based on a Markov model evaluated smoking cessation strategies against usual care: (1) minimal counseling in smoking cessation clinics (MiniC) for COPD patients; (2) intensive counseling with pharmacotherapy in smoking cessation clinics (IC_pharm) for COPD patients; (3) community pharmacist-assisted service (CPA) for healthy smokers; (4) combination of CPA and MiniC (CPA+MiniC); (5) combination of CPA and IC_pharm (CPA+IC_Pharm). The Markov model was constructed by sex, smoking status and COPD severity to calculate the lifetime cost of COPD, cost of smoking cessation programs and QALYs. Both effectiveness and cost were discounted at 3%. Incremental cost effectiveness ratios (ICERs), i.e. cost per one QALY gain, served as the decision making rule. One way sensitivity analysis, threshold analysis and probabilistic sensitivity analysis were performed to explore the uncertainty around the parameters. Results: The overall age adjusted mortality of COPD increased from 28.8 per 100 000 in 1981 to 30.14 per 100 000 in 2008. Numbers of people aged 65+ with known COPD was projected to be over 100 000 by 2036. There were 3.8 and 7.8 years of life lost (YLL) and 3.6 and 5.6 QALYs lost due to COPD for male and female smokers respectively. Medical costs of hospitalization were estimated to be over HK$ one billion (US$132 million) in 2008. Seventy one COPD cases could be avoided in the simulated cohort by CPA. If the threshold value was HK$247 332 for one QALY gain, CPA was more cost effective than IC_Pharm, with an ICER of HK$47 717. CPA+MiniC dominated CPA. CPA+IC_Pharm was more cost effective than CPA+MiniC (ICER, HK$36 000). The probability of CPA+ IC_pharm being the most cost effective strategy was approaching 0.8 if one QALY was worth HK$96 000, and it was associated with the maximum expected QALYs if societal value for one QALY was no less than HK$80 000. Conclusion: The model-based economic evaluation demonstrated that CPA+IC_Pharm would be the most cost-effective smoking cessation strategy. Community pharmacy based (CPA) smoking cessation services could be applicable and should be proposed in Hong Kong to reduce the burden of smoking related diseases.
published_or_final_version
Public Health
Doctoral
Doctor of Philosophy

Introduction: Cardiovascular disease affects a greater proportion of females than it does males, and is responsible for an estimated 52 percent of female deaths per annum, globally. Due to the loss of oestrogen associated with the menopause, post-menopausal females are at elevated risk for hypercholesterolaemia which is a primary risk factor for cardiovascular disease. It has not yet been conclusively established whether resistance training can be used to ameliorate hypercholesterolaemia. Aim: This randomized controlled trial investigated what effect 12 weeks of progressive resistance training would have on plasma lipoproteins in a sample of post-menopausal females. Methods: Caucasian women (n=30 intervention and n=18 control) between the ages of 55 and 65 years who were not taking hormone replacement therapy were recruited. Participants did not smoke, were sedentary, were not taking any form of cholesterol-lowering medication, had at least one cholesterol abnormality at baseline but were otherwise healthy and able to participate in a strength training programme. Following extensive medical pre-screening, information dissemination and voluntary consent, the sample was divided into two groups. The exercise sample undertook 12 weeks of resistance training on five days of the week. The control group received no intervention. Measurements were obtained at baseline and every four weeks thereafter and included measures of strength, biochemistry (oestradiol, testosterone, full blood lipid profile, glycated haemoglobin and sex hormone binding globulin), anthropometry, morphology and self-reports (dietary intake, energy expenditure and the profile of mood states questionnaire). Results: There was no change to low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglyceride content or total cholesterol as a result of the intervention. Back, chest and leg strength increased significantly (p<0.01) (increases of 51 percent, 35 percent and 43 percent respectively from baseline); waist circumference dropped (p<0.01) by 5 percent overall and diastolic blood pressure decreased significantly (-9 percent, p<0.01) in the exercise cohort but no change was noted in the matched control. Dietary intake, energy expenditure and body mass remained unchanged in both samples. Morphology (sum of skinfolds, estimated body fat content and girth measures) did not change and nor did other biochemical measures (HbA1c and sex hormone binding globulin) or hormone levels (oestradiol and testosterone). Despite the lack of overall change, an important finding was noted in individual results where a clear indication of ‘responders’ and ‘non-responders’ emerged. Conclusion: Overall mean results suggest that 12 weeks resistance training undertaken five days of the week was ineffective in reducing hypercholesterolaemia in this sample. Despite there being no identifying characteristics determined in this sample, evidence of responders and non-responders to the intervention indicates that reliance on mean data may not be sufficient when analysing data from exercise interventions. Therefore, while progressive resistance training had a positive effect on strength, waist circumference and diastolic blood pressure, it did not positively influence the plasma lipoproteins in this cohort of post-menopausal women.
Maiden name: Kelly, Janet Erica

Associated with physical inactivity and obesity are numerous other health risks which have become a major health concern. A steady decrease in the levels of physical activity during childhood and adolescents have been noted in various parts of the world. The picture of low physical activity levels in developed countries is no different in developing countries. Children spend the majority of their day at school therefore a school setting is ideal to conduct physical activity intervention studies The primary aim of this study was to measure the effect of an intervention programme on the physical activity participation levels among school going children and adolescents. The study was carried out at an urban independent Catholic school. The sample, which was conveniently selected, which included 100 learners from grade 5 to 7 with parental consent. A quantitative approach using a quasi-experimental design was used in this study. Baseline data included levels of physical activity participation, Body Mass Index (BMI), hip-waist ratio, and socio-demographic variables. Physical activity was assessed with the Modifiable Activity Questionnaire for Adolescents. The Promoting Lifestyle activity for Youth (PLAY) programme was implemented at the school. This process-oriented programme shifts the focus from fitness toward regular participation in daily physical activity, and it is not intended to replace a comprehensive physical education programme.

Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2006
Research has shown that the activation of the NO-cGMP pathway leads to myocardial protection from oxidative stress conditions, such as ischaemia and reperfusion. Few of these studies have however combined diet induced oxidative stress with ischaemia/reperfusion injury. Although little is known about the effects of supplements such as red palm oil (RPO) on the NO-cGMP pathway, research has shown that dietary RPO-supplementation improved reperfusion aortic output recovery through mechanisms that may include activation of the NO-cGMP- and inhibition of the cAMP pathway. RPO is an antioxidant-rich oil containing ~carotene and Vitamin E (tocopherols and tocotrienols). The aims of this study were to determine: 1) whether RPO-supplementation of an oxidative risk induced diet (ORD) and a high saturated fat diet (HFD) offers protection against ischaemia/reperfusion injury in the isolated perfused rat heart and 2) the possible mechanisms for this protection. Male Wistar rats were randomly divided into four groups for a period of 14 weeks according to the dietary supplementation they received. The control groups received either an oxidative risk induced diet (ORD) or a high saturated fat diet (HFD), while the experimental groups received an ORD supplemented with RPO (ORD+RPO) or a HFD supplemented with RPO (HFD+RPO).

Expansion of visceral adipose tissue correlates with the metabolic syndrome and increased cardiovascular risk. Hypertrophied visceral fat becomes inflamed, causing increased lipolysis, decreased triglyceride storage, and lipotoxicity in skeletal muscle and liver resulting in insulin resistance. Perivascular adipose tissue is a normal component of the adventitia of arteries in humans and animals. Whether or not perivascular adipose also becomes inflamed in obesity is an important question, as this may be an additional, direct mechanism by which obesity causes vascular inflammation and disease. Thus, for the first part of my thesis, we asked the question: does perivascular adipose in mice become inflamed with high fat feeding? In contrast to visceral adipose, macrophage gene expression was not increased in perivascular adipose in response to high fat diet, and this correlated with reduced F480 antigen positive cells as seen by immunohistochemistry and flow cytometry. Interestingly, perivascular adipose surrounding the thoracic aorta was similar to brown adipose tissue, a highly thermogenic fat depot, as shown by histology and DNA microarrays. Moreover, inter-scapular brown adipose was also resistant to diet induced inflammation in comparison to visceral adipose. These findings suggest that brown adipose in the perivascular niche may serve to protect the vasculature from diet induced inflammation, or from cold exposure, or both; whether or not brown perivascular adipose tissue exists in humans has yet to be determined. In the second part of my thesis, we evaluated the role of perivascular adipose tissue in the apolipoprotein E knockout mouse, which exhibits severe hyperlipidemia and atherosclerosis, but is resistant to diet induced obesity and glucose intolerance. We tested the hypothesis that in this model of severe atherosclerosis, inflammation of perivascular adipose does occur. However, we were surprised to find that macrophage specific gene expression, as determined by either microarray analysis or quantitative polymerase chain reaction, was not increased in either the perivascular or the visceral adipose of high fat diet fed apolipoprotein E knockout mice. While the visceral adipose of wild type mice had extensive alterations in gene expression in response to high fat diet, in particular, enrichment of inflammatory gene expression and broad down regulation of peroxisome proliferator activated receptor gamma target genes, apolipoprotein E knockout visceral adipose did not. Importantly, the apolipoprotein E knockout visceral adipose instead showed increased expression of genes encoding enzymes in fatty acid oxidation pathways. High fat diet fed apolipoprotein E knockout visceral adipose was also characterized by smaller adipocyte size. We conclude that, 1) inflammation in thoracic perivascular adipose does not occur in conjunction with diet induced obesity in normal animals nor with atherosclerosis in apolipoprotein E knockout mice, 2) thoracic perivascular adipose tissue is essentially identical to brown adipose tissue in mice, thus potentially protecting the vasculature from the cold, and 3) apolipoprotein E knockout mice remain lean on a high fat diet, despite hyperlipidemia and atherosclerosis, and the decreased adiposity correlates with decreased adipocyte size and adipose inflammation but increased oxidation of fatty acids. Consistent with previous work showing apolipoprotein E controls adipocyte uptake and deposition of triglyceride, its absence prevents adipocyte hypertrophy and resultant inflammation of visceral adipose tissue. Thus limiting adipocyte acquisition of fatty acids may be advantageous, provided that compensatory mechanisms to prevent sustained hyperlipidemia and peripheral organ lipotoxicity can be activated.

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Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Estudos relacionados às conseqüências metabólicas da ingestão de dietas ricas em sacarose ou frutose ainda são limitados. Assim como os estudos que envolvem a restrição no número de refeições diárias. No presente trabalho foram utilizados 24 ratos machos wistar, de peso inicial médio de 222,69 l 16,49g, divididos aleatoriamente em quatro grupos AD, RT, ADS, RTS com seis ratos cada. O grupo AD foi considerado controle, recebendo dieta basal ad libitum. Os animais do grupo RT receberam a mesma quantidade de dieta ingerida pelo grupo AD, oferecida diariamente no período restrito de duas horas (9:00 às 11:00h). Os animais do grupo ADS receberam ração controle ad libitum e para beber, solução aquosa de sacarose 30% ad libitum. Ratos do grupo RTS foram tratados com a mesma quantidade de ração ingerida pelo grupo ADS, oferecida durante o tempo restrito de 2 horas diárias e solução aquosa de sacarose 30% ad libitum. Após 30 dias de tratamentos os animais foram sacrificados. O soro foi utilizado para determinação do perfil lipídico e marcadores do estresse oxidativo. Restrição no tempo de ingestão alimentar desenvolveu dislipidemia com elevação nos fatores de riscos para aterosclerose, elevação no estresse oxidativo, bem como, diminuição de marcadores de defesa antioxidantes. A elevação na atividade sérica da fosfatase alcalina sugere a existência de alteração hepática. O modelo de dieta rica em carboidratos apresentou característica fenotípica de síndrome metabólica, que foi confirmada pela dislipidemia, acompanhada de hipertrigliceridemia. A restrição no tempo de ingestão alimentar com dieta rica em carboidrato induziu dislipidemia, elevação na ALP sugerindo alteração hepática, bem como elevação nos marcadores de estresse oxidativo e diminuição nas defesas antioxidantes.
Not available.

The primary aim of this study was to investigate the changes in physical fitness characteristics of elite women&rsquo
s rugby union players over the duration of the season. Thirty two elite female rugby players who were identified as members of the South African Rugby Union High Performance Squad were assessed on three separate occasions (pre-season, mid-season and post-season) throughout the competition season. The players were sub-divided into two positional categories consisting of 17 forwards and 15 backs. On all testing occasions, players underwent anthropometric (stature, body mass and sum of 7 skinfolds) and physical performance measurements (sit-and-reach, vertical jump, 10m and 40m speed, 1 RM bench press
pull-ups
1 min push-ups and multi-stage shuttle run test). A two&ndash
factor analysis of variance evaluated differences in the physical fitness variables between and within playing positions over the competition season.

Orientador: Ethel Lourenzi Barbosa Novelli
Banca: Marília Afonso Rabelo Buzalaf
Banca: Rodrigo Cardoso de Oliveira
Banca: Ana Angélica Henrique Fernandes
Banca: Regina Coeli de Miranda Burneiko
Resumo: Estudos relacionados às conseqüências metabólicas da ingestão de dietas ricas em sacarose ou frutose ainda são limitados. Assim como os estudos que envolvem a restrição no número de refeições diárias. No presente trabalho foram utilizados 24 ratos machos wistar, de peso inicial médio de 222,69 l 16,49g, divididos aleatoriamente em quatro grupos AD, RT, ADS, RTS com seis ratos cada. O grupo AD foi considerado controle, recebendo dieta basal ad libitum. Os animais do grupo RT receberam a mesma quantidade de dieta ingerida pelo grupo AD, oferecida diariamente no período restrito de duas horas (9:00 às 11:00h). Os animais do grupo ADS receberam ração controle ad libitum e para beber, solução aquosa de sacarose 30% ad libitum. Ratos do grupo RTS foram tratados com a mesma quantidade de ração ingerida pelo grupo ADS, oferecida durante o tempo restrito de 2 horas diárias e solução aquosa de sacarose 30% ad libitum. Após 30 dias de tratamentos os animais foram sacrificados. O soro foi utilizado para determinação do perfil lipídico e marcadores do estresse oxidativo. Restrição no tempo de ingestão alimentar desenvolveu dislipidemia com elevação nos fatores de riscos para aterosclerose, elevação no estresse oxidativo, bem como, diminuição de marcadores de defesa antioxidantes. A elevação na atividade sérica da fosfatase alcalina sugere a existência de alteração hepática. O modelo de dieta rica em carboidratos apresentou característica fenotípica de síndrome metabólica, que foi confirmada pela dislipidemia, acompanhada de hipertrigliceridemia. A restrição no tempo de ingestão alimentar com dieta rica em carboidrato induziu dislipidemia, elevação na ALP sugerindo alteração hepática, bem como elevação nos marcadores de estresse oxidativo e diminuição nas defesas antioxidantes.
Abstract: Not available.
Doutor

The aim of this research project was to assess and compare cardiovascular disease (CVD) risk in black males and females from an urban, working population in the Makana (Grahamstown) region of the Eastern Cape, South Africa. Two-hundred and ninety one individuals (males: n = 143, females: n = 148) with a mean age of 42.6 (±8.1) years were voluntarily recruited from the greater urban Makana (Grahamstown) area. Eight Cardiovascular disease (CVD) risks were assessed: stature and mass were obtained in order to calculate body mass index (BMI) (mass/stature2). Obesity, defined as a morphological risk, was classified according to the World Health Organisation (WHO) BMI criteria (BMI>30kg.m-2), as well as according to measures of waist circumference (WC) and body composition. Hypertension, hypercholesterolemia and type II diabetes, were grouped as cardiovascular (CV) risks. Hypertension was defined as a blood pressure greater than 140/90mmHg (JNC-7); hypercholesterolemia, as total cholesterol greater than 6.2mmol.L-1 (NCEP); and type II diabetes, as total glucose greater than 12mmol.L-1 (WHO). Physical activity, diet, tobacco use, and alcohol consumption and dependence were grouped as lifestyle-related risks. These were assessed by means of self-reporting through the use of various validated questionnaires. Finally, self-reporting of obesity, hypertension, hypercholesterolemia and type II diabetes was assessed, in addition to perception questions on individuals’ perceived body shape and size (Ziebland figures). Self-reported and perceived responses were then compared to actual measures. Females were significantly (p<0.001) heavier than the males (92.7kg compared to 72.1kg) and had significantly (p<0.001) higher BMIs than their male counterparts (37.6kg.m-2 compared to 25.7 kg.-2). They also recorded significantly (p<0.001) higher waist circumference (WC) values and had significantly (p<0.001) higher percentage and total body fat. Significantly (p<0.001) more females were obese (81%) compared to males (17%). While a higher percentage of males (25 % compared to 22%) presented with stage I hypertension (≥140/90mmHg, <160/95mmHg), significantly (p<0.05) more females (14% compared to 8%) presented with stage II hypertension (>160/95mmHg). The prevalence of hypercholesterolemia at a high level of risk (>6.2mmol.L-1) was relatively low (2.1 % of males, 3.4% of females), but notably more participants (22% of males and 26% of females) presented with the condition at a moderate level of risk (>5mmol.L-1). Type II diabetes was the least prevalent CV risk factor, with no males and only 3% of females presenting with the condition. Males consumed significantly (p<0.05) more in terms of total energy intake (9024 vs. 7234 kJ) and were significantly (p<0.05) more active (3315 compared to 2660 MET-mins.week). A significantly (p<0.05) higher percentage of males smoked (51.1% compared to 3.4%), consumed alcohol (73.4% compared to 46.6%) and were alcohol dependent (40% compared to 33.5%). Both males and females tended to be ignorant of their health status, with both samples under-reporting obesity, hypertension and hypercholesterolemia, while over-reporting type II diabetes. Furthermore, obesity was significantly (p<0.05) underestimated, with both male and female individuals perceiving themselves to be notably smaller than they actually were. Physical activity and diet were important determinants of CVD risk in this black urban sample of individuals. Obesity, in particular central adiposity, was the most notable risk (particularly in females), followed by hypertension (particularly in males). Although some risks presented at a moderate level of risk, a clustering of risk factors was evident in both samples, with 12.6% and 41.2% of males and females presenting with two risk factors, and 2.8% and 8.1% of males and females respectively presenting with three risks.

The purpose of the study was to investigate the cardiovascular disease (CVD) risk profile of black African females in the Makana region, Eastern Cape, South Africa. Baseline measures from 40 participants, who met the criteria, were compared against the 2003 South African Demographic and Health Survey (SADHS) and the 2013 South African National Health and Nutritional Examination Survey (SANHANES-1). The risk factors measured were anthropometric (stature, body mass and body mass index (BMI)), morphological (waist circumference (WC), fat mass and lean mass), cardiovascular (heart rate and blood pressure (BP)), physical activity (step count and energy expenditure), biochemical (glycated haemoglobin and full blood lipid profile) and behavioural (alcohol and tobacco use). Results showed significantly higher (p≤0.05) values for overweight/obesity (BMI 37.60 kg.m⁻²; WC 1130.58 mm; fat mass 45.23%) and high BP (130/88 mmHg) compared to the previous national surveys, highlighting these CVD risk factors as problematic. The subsequent sub-study aimed to assess the efficacy of a pedometer-based walking intervention on high BP. The walking programme (n=25) was based on individual step goals to be completed at a moderate-intensity on five days.week⁻¹ for 12 weeks. The same measurements were taken at monthly intervals, Week 0, Week 4, Week 8 and Week 12, with the addition of dietary intake and fitness level, and the exclusion of the behavioural variables. There were no significant differences (p≤0.05) in systolic and diastolic BP with the exercise intervention, although there was a strong, negative relationship with time for diastolic BP (r²=0.9857). This trend suggests that the lack of significance may be a result of poor compliance and/or the small sample size. Individual results, however, showed no compliance-result relationship for the two risk factors of interest: overweight/obesity and high BP. Future recommendations include supervised or group-based exercise interventions to improve compliance, and the addition of resistance training to the aerobic programme.

Numerous studies focusing on cardiovascular disease risk factors such as obesity, hypertension, smoking, diabetes mellitus, elevated serum lipids, inactivity and lack of physical fitness prevalent in children highlight the importance of the early diagnosis and prevention of conditions that are associated in adulthood with cardiovascular disease. The purpose of this study was to assess the impact of accumulative physical activity on the fitness profile, blood pressure and body composition in 14-16 year old school children in the Western Cape of South Africa.

Thesis (MScMedSc)--Stellenbosch University, 2011.
ENGLISH ABSTRACT: Non-Alcoholic Fatty Liver Disease (NAFLD) is the most prevalent chronic liver disease in Western countries and is considered the hepatic manifestation of the Metabolic Syndrome (MetS). Its heterogeneous nature ranges from hepatic steatosis through steatohepatitis to advanced fibrosis and cirrhosis where the ingestion of significant amounts of alcohol has been excluded. The disease profile of NAFLD and its necro-inflammatory subset Nonalcoholic Steatohepatitis (NASH) were described in the parent study, which provided a clinically well-characterised patient cohort for the present investigation. South African patients with NASH had significantly higher mean serum cholesterol and triglyceride levels than those with fatty liver only. The objective of this study was to implement a high-throughput real-time polymerase chain reaction (PCR) method in our laboratory to enable the assessment of cardiovascular genetic risk factors in NAFLD patients. The specific aims were to determine the clinical utility and perform analytical validation of each mutation included in the multi-gene cardiovascular disease (CVD) screening assay. The Pathology Supported Genetic Testing (PSGT) concept developed at our department provides a practical approach to personalized medicine. The CVD multi-gene screen analyses key metabolic pathways relating to atherogenic dyslipidaemia, chronic inflammation, hypercoagulation and iron dysregulation implicated in insulin resistance, which is known to be a universal factor in the pathogenesis of NAFLD. Deleterious low-penetrance mutations in the APOE (APOE2 and E4 alleles), MTHFR (677C>T and 1298A>C), F2 (20210G>A), FV (1691G>A, Leiden) and HFE (C282Y and H63D) genes were included for analysis due to their important role as genetic contributors to these biological processes. A total of 178 patients diagnosed with NAFLD and 75 controls were studied using direct DNA sequencing and a RT-PCR system for mutation detection. In addition, two patients with high ferritin levels were included as case studies. A significant association was found between HFE mutations and elevated Alanine Transaminase (ALT) levels in the NAFLD population (p = 0.04). This discovery is interpreted as the identification of a subset of patients at greater risk of developing progressive liver damage who would benefit most from genetic testing to direct more aggressive therapy at an earlier stage. The necessity of an integrative, systems-based network approach was demonstrated to more accurately distinguish between Hereditary Haemochromatosis (HH) and Insulin Resistance-associated Hepatic Iron Overload (IR-HIO) syndrome in obese patients. The PSGT approach to personalized medicine facilitates diagnosis of CVD subtypes, prevention of cumulative risk and the formulation of gene-based intervention programs tailored to the needs of the patient. These findings support the clinical utility of the CVD multi-gene test to guide chronic disease risk management in patients with NAFLD. The HFE mutation detection component of this test is of particular relevance in directing an effective treatment strategy in patients with a medical history of CVD and/or high iron stores.
AFRIKAANSE OPSOMMING: Nie-Alkoholiese Vettige Lewer Siekte (NAFLD) is die mees algemene kroniese lewer siekte in Westerse lande en word bestempel as die hepatiese manifestasie van die Metaboliese Sindroom (MetS). Die heterogene natuur van NAFLD strek van hepatiese steatose deur steatohepatietis tot gevorderde fibrose en sirrose waar grootskaalse alkohol inname uitgesluit is. Die siekte-profiel van NAFLD en sy nekro-inflammatoriese subtipe Nie-Alkoholiese Steatohepatietis (NASH) is reeds beskryf in die ouer studie, wat ‗n klinies goed-gekarakteriseerde pasiënt groep vir die huidige ondersoek daar gestel het. Suid-Afrikaanse pasiënte met NASH het beduidend hoër gemiddelde serum cholesterol en trigliseried vlakke in vergelyking met slegs vettige lewer. Die doel van hierdie studie was om ‗n hoë deurvoer rieëltyd polimerase kettingreaksie (RT-PCR) metode in ons laboratorium te implimenteer om kardiovaskulêre genetiese risiko faktore in NAFLD pasiënte te ondersoek. Die spesifieke mikpunte was om die kliniese nut en analitiese geldigheid van elke mutasie wat ingesluit is in die multi-geen kardiovaskulêre siekte (KVS) siftings toets vas te stel. Die Patologie Ondersteunde Genetiese Toetsing (PSGT) konsep wat by ons departement ontwikkel is, verskaf ‗n praktiese benadering tot persoonlike medisyne. Die KVS multi-geen toets analiseer belangrike metaboliese weë verwant aan atherogene dyslipidemie, kroniese inflammasie, oormatige bloedstolling en yster disregulering wat betrokke is by insulien weerstand wat bekend is as ‗n universele factor in the patogenese van NAFLD. Nadelige lae-penetrasie mutasies in die APOE (APOE2 en E4 allele), MTHFR (677C>T en 1298A>C) F2 (20210G>A), FV (1691G>A, Leiden) en HFE (C282Y en H63D) gene was ingesluit vir analise as gevolg van hul belangrike rol as genetiese bydraers tot die bogenoemde biologiese prosesse. ‗n Totaal van 178 pasiënte gediagnoseer met NAFLD en 75 kontroles is bestudeer deur gebruik te maak van direkte DNA volgordebepaling en ‗n RT-PCR metode vir mutasie opsporing. Twee pasiënte met verhoogde ferritien vlakke is ook as gevalle studies ingesluit. ‗n Beduidende assosiasie is gevind tussen HFE mutasies en verhoogde Alanien Transaminase (ALT) vlakke in die NAFLD studiepopulasie (p = 0.04) wat aanduidend is van ‗n subgroup van pasiënte wat die meeste baat sal vind uit genetiese toetsing om meer aggressiewe behandeling te rig op' n vroeër stadium. Die noodsaaklikheid van 'n geïntegreerde, stelsels-gebaseerde netwerk benadering is gewys om meer akkuraat te onderskei tussen Oorerflike Hemochromatose (HH) en Insulien Weerstand-geassosieerde Hepatiese Yster Oorlading (IR-HIO) sindroom in vetsugtige pasiënte. Die PSGT benadering tot persoonlike medisyne formuleer geen-gebaseerde intervensie programme aangepas tot die behoeftes van die pasiënt ek maak diagnose van KVS-subtipes en voorkoming van kumulatiewe risiko moontlik. Hierdie bevindinge ondersteun die kliniese nut van die KVS multi-geen toets om riglyne vir die risikobestuur van kroniese siektes soos NAFLD daar te stel. Die HFE mutasie opsporings komponent van hierdie toets is van besondere belang om 'n effektiewe strategie vir die behandeling van pasiënte met 'n mediese geskiedenis van KVS en/of hoë yster vlakke daar te stel.

Introduction – Objectives. The cardiovascular system is in direct and constant interaction with its environment. Exposure to various environmental parameters, such as low temperature, air pollution and tobacco smoke, has been strongly associated with serious or even fatal cardiovascular outcomes. Arterial stiffening and greater wave reflection are age-related vascular modifications that lead to an increased risk of cardiovascular events. The aim of this work was to explore the relationship between selected environmental factors and arterial elastic properties in an effort to elucidate the underlying mechanisms that link these factors to increased cardiovascular mortality.

Study 1: Effects of cold exposure on central and peripheral vascular tone. Our first study explored the effects of cold exposure on aortic stiffness and peripheral microvascular tone. We observed that cold exposure, in addition to its chronotropic effects, provoked an increase in aortic stiffness, as assessed by aortic pulse wave velocity, as well as significant vasoconstriction of peripheral arterioles in the microcirculation. Moreover, we explored the magnitude of this effect in a different population (Black subjects of African origin), which is traditionally characterized by exaggerated reactions to adrenergic stimuli. We noted that the vascular reactions, in terms of both aortic stiffness and microvascular vasoconstriction, were more profound in Black Africans than in age-matched Caucasian-Whites. These results argue for a direct effect of cold exposure on arterial stiffness and peripheral vascular tone, probably through activation of the orthosympathetic system.

Study 2: Exposure to ambient particulate matter and arterial stiffness. We explored the effects of acute exposure to outdoor particulate matter on aortic stiffness and aortic wave reflection. We studied the relationship between central hemodynamic parameters and ambient concentration of particulate matter in a population of patients who attended the Hypertension Clinics of Athens University. After statistical correction for a number of potential confounders, we did not observe an association between ambient concentrations of particulate matter and aortic stiffness. However, in men, particulate matter concentration was related to the amplitude of the reflected wave reaching the aorta from the periphery. These results suggest a direct acute interaction between particulate matter concentration and vascular tone, leading to an enhanced arterial wave reflection.

Study 3: The role of nicotine on the vascular effects of environmental tobacco smoke. Environmental tobacco smoke is considered as the most important source of particulate matter in the indoor environment. We recently demonstrated that exposure to tobacco smoke augmented wave reflection, an effect that was not seen after equivalent exposure to the smoke of non-tobacco, herbal cigarettes. We also noticed that the increased wave reflection was proportional to the plasma concentrations of nicotine. However, a direct causal effect between nicotine, arterial wave reflection and aortic stiffness has never been clearly demonstrated. We observed that increasing nicotine plasma concentration to levels comparable to those seen after extensive exposure to environmental tobacco smoke, provoked an increase in both aortic stiffness and arterial wave reflection after correction for heart rate and blood pressure changes. These results confirm the significant participation of nicotine in the vascular effects of passive smoking.

Conclusions. Globally, our results reveal the deleterious effects of cold, particulate matter exposure, and nicotinic stimulation on arterial stiffness, peripheral microcirculation and aortic wave reflection. The hemodynamic modifications associated with these effects may at least partially explain the causal relation between cold exposure, ambient air pollution and cardiovascular mortality.

Introduction-Objectifs. Le système cardiovasculaire est en relation directe et constante avec l’environnement. L’exposition au froid, la pollution atmosphérique et le tabagisme passif sont associés à des événements cardiovasculaires aigus graves et même fatals. La rigidification des artères et l’intensification de la réflexion de l’onde de pouls au niveau de l’aorte accompagnent le vieillissement et prédisent un risque cardiovasculaire accru. Nous avons testés l’hypothèse que les effets cardiovasculaires délétères des facteurs environnementaux comportent une altération des propriétés élastiques artérielles. Ceci pourrait être un des mécanismes physiopathologiques qui lie la mortalité cardiovasculaire aux variables environnementales.

Étude 1 :Exposition au froid ;effets centraux et périphériques. Notre première étude portait sur l’effet de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artérioles périphériques. Nous avons démontré que l’exposition au froid, hormis ses effets chronotropes, provoquait une augmentation de la rigidité artérielle – mesuré par la vitesse de l’onde de pouls au niveau de l’aorte - ainsi qu’une vasoconstriction importante au niveau des artérioles de la microcirculation. Nous avons ensuite déterminé l’amplitude de cet effet dans une autre population (sujets Africains-Noirs) qui se caractérise par des réactions plus prononcées aux différentes stimulations adrénergiques. Nous avons observé que les réactions vasculaires, tant au niveau de la rigidité aortique qu’au niveau de la microcirculation, étaient plus marquées chez les Africains-Noirs que chez les Caucasiens. Ces résultats révèlent un effet délétère de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artères périphériques, probablement via une activation du système orthosympathique.

Étude 2 :Exposition aux microparticules atmosphériques et rigidité artérielle. Nous avons ensuite investigué les effets de la pollution atmosphérique sur la rigidité artérielle et la réflexion de l’onde de pouls vers l’aorte. Nous avons étudié la relation entre les paramètres hémodynamiques centraux et la concentration atmosphérique de microparticules dans une population de patients qui ont consulté la Clinique Universitaire d’Hypertension Artérielle d’Athènes. Après correction statistique pour les facteurs confondants, nous n’avons pas observé de corrélation entre la rigidité artérielle et le taux de microparticules atmosphériques dans l’ensemble de la population investiguée. Par contre, si on restreint l’analyse aux résultats obtenus chez les sujets masculins, on s’aperçoit que la concentration atmosphérique de microparticules était associée de façon significative avec l’amplitude de l’onde réfléchie par la périphérie vers l’aorte et la pression pulsée aortique. Ces résultants suggèrent un effet direct des microparticules au niveau de la microcirculation. L’augmentation de l’amplitude de l’onde réfléchie consécutive à une vasoconstriction périphérique, modifie vraisemblablement les pressions au niveau de l’aorte chez le sujet masculin lors de pics de pollution.

Etude 3 :Le rôle de la nicotine dans les effets vasculaires du tabagisme passif. Le tabagisme passif est considéré comme la source la plus importante d’émission de microparticules au niveau domestique. Cependant, la composition chimique des particules semble jouer un rôle essentiel sur les ondes de réflexion. Nous avons démontré récemment que l’exposition passive à la fumée des cigarettes du tabac augmente l’intensité de la réflexion de l’onde de pouls. Ceci n’a pas été observé avec l’exposition à la fumée des cigarettes non tabagiques, en dépit d’une concentration ambiante tout à fait comparable de microparticules. Par ailleurs, nous avons observé que l’augmentation de l’incidence de l’onde de pouls au niveau de l’aorte était fortement associée à la concentration plasmatique de la nicotine. Un lien causal entre la nicotine, réflexion de l’onde de pouls et rigidité artérielle n’avait jamais clairement été établi. Nous avons testé cette hypothèse en administrant la nicotine pure chez des sujets sains. Nous avons observé que l’augmentation des taux plasmatiques de la nicotine à des valeurs comparables à celles qui surviennent après une exposition intensive au tabagisme passif, intensifiait la réflexion de l’onde de pouls et augmentait la rigidité artérielle. La correction statistique pour l’augmentation de la fréquence cardiaque et l’augmentation de la pression artérielle en réponse à la nicotine ne modifiait pas ces conclusions. Nos résultats démontrent ainsi les effets cardiovasculaires importants de faibles concentrations de nicotine, similaires à ceux qui sont atteints en cas d’exposition à un tabagisme passif.

Conclusions. Nos résultats révèlent les effets néfastes de l’exposition au froid et aux microparticules atmosphériques sur la rigidité artérielle, la microcirculation périphérique et la réflexion de l’onde de pouls. Nous avons pu également démontrer le rôle de la stimulation nicotinique dans les effets vasculaires aigus du tabagisme passif, comme en témoigne l’augmentation de la réflexion de l’onde de pouls au niveau aortique. Ces modifications hémodynamiques favorisent l’ischémie myocardique, et constituent un des mécanismes par lesquels l’exposition au froid et à la pollution atmosphérique favorisent la pathologie cardiovasculaire.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished

Although the clinical efficacy of statins has been well established, there is a wide inter-individual variation in the lipid responses to statins. Pharmacogenetic studies have identified some genetic differences that contribute to the variation, but overall the results have been disappointing. The studies described in this thesis were performed to examine whether certain genetic variants predicted the lipid responses to rosuvastatin in Chinese patients. Over 400 Chinese patients with increased risk of cardiovascular disease (CVD) who were treated with rosuvastatin 10 mg daily for at least 4 weeks (more than 97% of patients had at least 6 weeks treatment) were studied, including 166 having familial hypercholesterolaemia (FH) and 36 having rheumatoid arthritis (RA). They were genotyped for 135 polymorphisms in 62 candidate genes/loci potentially related to pharmacokinetics or pharmacodynamics of statins and lipid metabolism. Associations between genetic polymorphisms and the lipid responses to rosuvastatin were analyzed in 386 patients with good compliance. The associations between genetic polymorphisms and some risk factors for CVD including baseline lipid levels, high-sensitivity C-reactive protein (hsCRP), uric acid and bilirubin levels were also analyzed.
Some novel genetic determinants of the LDL-C response to rosuvastatin treatment have been identified in this study. The responses in HDL-C and triglycerides were related more closely to the baseline levels of these lipids than to any of the polymorphisms examined. Genetic associations with baseline lipid parameters, hsCRP, uric acid and bilirubin were identified and generally correspond with some of the previous reports of studies in Chinese and other ethnic groups.
The key findings of the study are as follows: 1. The polymorphisms most highly associated with the low-density lipoprotein cholesterol (LDL-C) response were 421C>A in the ATP-binding cassette G2 (ABCG2) gene (P=9.2x10 -7), followed by 18281G>A (V257M) in the flavin-containing monooxygenase 3 (FMO3) gene (P=0.0002), 1421C>G in the lipoprotein lipase (LPL) gene (P=0.002), and rs4420638 in the apolipoprotein E/C-I/C-IV/C-II (APOE/C1/C4/C2) gene cluster (P=0.004). These genetic polymorphisms and having FH totally explained 13.6% of the variance in percentage change in LDL-C in response to rosuvastatin. The greater percentage reduction in LDL-C in patients with the ABCG2 421AA genotype compared to those with the ABCG2 421CC genotype was equivalent to at least doubling the dose of rosuvastatin. 2. Three SNPs (glucokinase regulator [ GCKR] rs1260326, apolipoprotein AS [APOA5] -1131T>C and the solute carrier organic anion transporter 1B1 [SLCO1B1] 521T>C) tended to be associated with percentage changes in high-density lipoprotein cholesterol (HDL-C) (P<0.05), but none of these reached the overall significance level. In multivariate stepwise regression analysis, baseline HDL-C (P=1.6x10 -6), having diabetes (P=0.0004) or RA (P=0.002) and the SLCO1B1 521T>C polymorphism (P=0.03) were determinants of HDL-C responses, contributing 9.9% of the variance in percentage change in HDL-C, but the genetic factors only contributed to 0.8% of the variance. 3. The triglyceride response to rosuvastatin was highly variable and was strongly related to baseline levels. The diacylglycerol acyltransferase-2 (DGAT2) rs10899113 C>T polymorphism tended to be associated with reduced triglyceride response in a gene-dose dependent manner. However, in multivariate stepwise regression analysis, baseline triglyceride level was the only factor that strongly related to the triglyceride response, explaining 14.4% of the variance. 4. This study has also analyzed relationships between on-treatment plasma hsCRP concentrations and cardiovascular risk factors and 14 single nucleotide polymorphisms in CRP and other candidate genes, which showed that central obesity, low HDL-C and CRP polymorphisms are major determinants of higher hsCRP levels in Chinese patients on treatment with rosuvastatin. 5. The association between genetic polymorphisms and lipid traits were analyzed in FH and non-FH patients separately due to their different lipid profiles. The analysis has shown that there were different genetic predictors of lipid levels in patients with and without FH and that more genetic factors appeared to affect the baseline lipid levels in patients with FH compared to non-FH patients, suggesting complex interactions between genetic and environmental factors and plasma cholesterol levels in patients with and without FH. 6. The SLC2A9 (solute carrier family 2, member 9) rs1014290 T>C was significantly associated with plasma uric acid levels in a gene-dose dependent manner (P=1.0x10-5) and the relationship was more pronounced in women or in patients without hypertension than in men or patients with hypertension. The ABCG2 421 C>A did not show a significant effect on uric acid levels. 7. The UGT1A1 (uridine diphosphate glucuronosyltransferases family, polypeptide A1) variants *28 (P=1.5x10 -9) and *6 (P=2.2x10-7) were independently associated with increased baseline bilirubin levels. Polymorphisms in SLCO1B1 did not appear to affect bilirubin levels in this study.
Hu, Miao.
Adviser: Brian Tomlinson.
Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: .
Thesis (Ph.D.)--Chinese University of Hong Kong, 2010.
Includes bibliographical references (leaves 230-264).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract also in Chinese.

Indiana University-Purdue University Indianapolis (IUPUI)
Neurofibromatosis Type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin is the protein product of NF1 and functions as a negative regulator of Ras activity in both hematopoietic and vascular wall cells, which are critical for maintaining blood vessel homeostasis. NF1 patients are predisposed to chronic inflammation and premature cardiovascular disease, including development of large arterial aneurysms, which may result in sudden death secondary to their rupture. However, the molecular pathogenesis of NF1 aneurysm formation is completely unknown. Utilizing a novel model of Nf1 murine aneurysm formation, we demonstrate that heterozygous inactivation of Nf1 (Nf1+/-) results in enhanced aneurysm formation with myeloid cell infiltration and increased reactive oxygen species in the vessel wall. Using cell lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1+/- aneurysm phenotype in vivo. Additionally, oral administration of simvastatin, a statin with antioxidant and anti-inflammatory effects, significantly reduced aneurysm formation in Nf1+/- mice. Finally, the antioxidant apocynin was administered orally and also resulted in a significant reduction of Nf1+/- aneurysms. These data provide genetic and pharmacologic evidence that neurofibromin-deficient myeloid cells are the central cellular triggers for aneurysm formation in a novel model of NF1 vascular disease, implicated oxidative stress as the key biochemical mechanisms of NF1 aneurysm formation and provide a potential therapeutic target for NF1 vasculopathy.

A thesis submitted to the School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfillment of the requirements for the degree of Doctor of Philosophy June 2017 Johannesburg, South Africa
Non-communicable diseases (NCDs) pose an increasing burden on public health and economic growth worldwide. The highest increase in prevalence and death rates of NCDs has been seen in low and middle-income countries (LMICs). World Health Organization (WHO) estimates that by 2030, NCDs will account for five times as many deaths as communicable diseases in LMICs and that there will be more than 2.16 billion overweight and 1.12 billion obese individuals in the world. It is also estimated that by 2020 NCDs will contribute 80 percent of the global burden of disease and the largest increase in NCD deaths will occur in Africa. Recent reports indicate that six of the ten leading natural causes of death in South Africa are NCDs. There are few studies that have used longitudinal data to understand the effects of life-course childhood adiposity on future health risks and the early life factors responsible for variations in lifecourse childhood obesity. However, it is not known whether there is a genetic basis for the variability in BMI developmental patterns over time. Lack of comprehensive longitudinal and genetic association data for obesity have made it difficult to do such studies in an African setting. It is still not clear whether the same genetic variants associated with obesity in Europeans and other populations are also associated with these traits in African populations. Understanding the genetic contribution to obesity in the black South African population may help to come up with effective interventions to deal with this emerging epidemic in Africa. The aim of this thesis was to better understand the contribution of genetics and explain the longitudinal genetic basis of childhood and adolescence obesity in black South African children. To deal with this, I firstly studied identification of distinct trajectories of BMI and then relate the established BMI trajectories to the future health risks of elevated blood pressure. Secondly, I explored the early life factors behind BMI trajectory membership, this would help to identify factors that may accelerate an individual’s progression from a normal BMI trajectory pattern membership to the one characterized with elevated BMI. Then lastly, I looked at the additive genetic effect for BMI and determine whether genetic risk of obesity in early adulthood was mediated by early life rapid growth. Results showed variation in BMI developmental patterns between boys and girls; three and four distinct sex-specific BMI trajectories were identified in boys and girls respectively. Children belonging to early onset overweight or obese BMI trajectories, characterized by elevated BMI, had an increased risk of elevated blood pressure in late adolescence, compared to their peers in the normal trajectories. Rapid conditional relative weight gain in early life was associated with increased risk of belonging to a BMI trajectory characterized by consistent elevated BMI over time. Individuals in overweight or obese trajectories had a higher chance of being overweight or obese in early adulthood. I found that a genetic risk score, based on known adult BMI Caucasian risk variants, showed significant longitudinal effects of genetic loci with BMI in childhood and adolescent and significant age-GRS interactions were observed. A higher genetic risk score predicted membership of early onset obese or overweight BMI trajectories. The genetic risk of obesity at 18 years of age was mediated by pre-adolescence and adolescence rapid weight gain. The results from this thesis emphasize the importance of studying individual’s BMI developmental patterns when studying development and progression of obesity. These findings also show that the information obtained from GWAS done in other populations can be equally relevant to African populations and this could be used in early identification of individuals at increased risk of obesity and other NCDs risk factors. Combing genetic risk score, BMI trajectories membership and weight status can be used to help improve the screening process of individuals to be targeted in coming up with targeted educational and behavior intervention programmes for obesity. These programmes should target individuals at risk at early stage in order to reduce the adverse health risk outcomes later in life.
MT 2017

Xu Liying.
"April 2004."
Thesis (Ph.D.)--Chinese University of Hong Kong, 2004.
Includes bibliographical references (p. 159-175)
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Mode of access: World Wide Web.
Abstracts in English and Chinese.

Indiana University-Purdue University Indianapolis (IUPUI)
Aniridia, a congenital ocular disorder caused by haploinsufficiency of transcription factor PAX6, is characterized by complete or partial iris hypoplasia with associated foveal hypoplasia. Brain imaging performed in patients heterozygous for PAX6 mutations often reveal absence of the brain anterior or posterior commissure, absence of the pineal gland, and a present but reduced in size corpus callosum. Renal coloboma syndrome, another autosomal dominant inherited disease, is characterized by hypodysplastic kidneys and optic nerve defects, and is caused by haploinsufficiency of transcription factor PAX2. In the first part of this thesis we investigated the role of these Pax genes in neural development, by generating an allelic series of knock-in models at the Pax6 locus. We showed that Pax6(5a) and Pax2 could not replace Pax6 for its auto-regulation in lens induction or for neural differentiation in retina. In brain development, however, we demonstrated that cell proliferation in the cerebral cortex and dorsoventral patterning of the telencephalon and neural tube was partially rescued in either knock-in mutant. We believe our novel findings not only reveal Pax-protein functional specificity during neural development, but may also be utilized to understand the aberrant molecular mechanism that result in aniridia and/or renal coloboma syndrome. Aphakia (lack of lens) is a rare human congenital disorder with its genetic etiology largely unknown. In the second part of this thesis, we show that homozygous deletion of Nf1, the Ras GTPase gene underlying human neurofibromatosis type 1 syndrome, caused lens dysgenesis in mouse. While early lens specification proceeded normally in Nf1 mutants, lens induction was disrupted due to deficient cell proliferation. Further analysis showed that ERK signaling was initially elevated in invaginating lens placode, but by lens vesicle stage, Ras signaling antagonist Sprouty2 was up regulated, followed by rapid decrease in ERK phosphorylation. Only after intraperitoneal treatment of U0126, an inhibitor of ERK phosphorylation, was lens development restored in Nf1 mutants. Hyperactive RAS-MAPK signaling is known to cause neuro-cardiofacial-cutaneous (NCFC) syndromes in human. As a member of NCFC family genes, Nf1 represents the first example that attenuation of Ras-MAPK kinase signaling pathway is essential for normal lens development.

博士
國立中興大學
生命科學系所
101
Sick sinus syndrome (SSS) is a group of abnormal heart rhythm disorders that result from sinus node malfunction. The syndrome accounts for approximately 50% of pacemaker implantations for bradyarrhythmia. The pathologic findings of SSS have revealed fibrotic change over the sinus node and atrium. Evidences suggest genetic mutations in ion channels may lead to familial SSS. However, limited study is available regarding the mechanism of age-related non-familial SSS. Non-familial SSS is frequently associated with an atrial flutter and presents as tachycardia-bradycardia syndrome. The cavotricuspid isthmus (CTI) is a critical and slow conduction zone of the reentry circuit. Atrial fibrosis and the architecture of the atrial musculature have been suggested to be associated with the underlying mechanism of the slow conduction zone. Myocardial fibrosis is related to up-regulation of rennin-angiotensin system (RAS). These findings indicate the role of RAS in the underlying mechanism of atrial flutter. Radiofrequency catheter ablation therapy to block the CTI has been suggested as the method of choice for atrial flutter management. Anatomical variants of CTI have been related to the difficulty of ablation therapy. However, the detailed anatomical predictors of the CTI for the difficult procedure of radiofrequency catheter ablation have not been well described. We utilized transthoracic echocardiography to evaluate the anatomy of the CTI and found that a Eustachian valve variation of the CTI is an independent predictor for the difficult procedure of AFL ablation. The primary objective of the present study is utilizing gene study methods to investigate the possible candidate gene and underlying pathologic mechanism for non-familial SSS. We found that angiotensinogen promoter polymorphisms are associated with susceptibility to non-familial SSS through the modulation of angiotensinogen expression. In a gene association study, we found that the RAS system was associated with susceptibility to non-familial SSS. In addition, the RAS has also been reported to be associated with other cardiovascular disorders. Aortic dissection is a lethal cardiovascular disorder due to intimal tearing. The up-regulation in the RAS has been reported to be related to the underlying mechanism of aortic dissection. Besides, the clinical predictors for the outcome of aortic dissection are important. However, few reports have addressed this issue. We utilized computed tomography imaging to identify the anatomical predictors of the outcomes of aortic dissection. The false lumen size of an aortic dissection was found to be an independent predictor for the outcomes of aortic dissection. In conclusion, susceptibility to non-familial SSS is associated with RAS gene expression. This study identifies a biological predictor for susceptibility to non-familial SSS and clinical predictors for the outcomes of atrial flutter and aortic dissection, which are linked to non-familial SSS and RAS. The RAS is suggested to be closely linked to the pathophysiologic mechanisms of non-familial SSS and related cardiovascular diseases.

Epidemiological studies have suggested that the consumption of fish may reduce the risk of cardiovascular disease. Compared to the number of studies using fish oils, few studies have used fish itself. Those which have used fish have generally used fattier fish such as mackerel and salmon as part of an uncontrolled diet. In this study, 23 healthy men consumed 200g each of Chinook salmon, Dover sole, and sablefish in a three-way crossover design for 18-day periods with three-week washout periods in between. The diets had the approximate composition of the 'Western' diet: 45% carbohydrates, 36% fat, and 16% protein with the sole diet containing 1.95 g omega-3 (n-3) fatty acids, the salmon diet 3.99 g n-3, and the sablefish diet 3.42 g n-3 fatty acids. Serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), bleeding time (BT), blood pressure (BP), platelet aggregation (PA) using ADP and collagen as agonists, platelet fatty acid profiles (FAP), thromboxane B2 (TXB2) , and apolipoprotein B (Apo B) were measured at the beginning and end of each period. TC, and HDL-C, and TG changed significantly when compared to the prefish diet while both LDL-C and apo B demonstrated diet effect. LDL-C increased on both the salmon and sablefish diets (p = 0.08) compared to the sole diet, and increased approximately 15% on the former two diets compared to the prefish diet. Bleeding time was significantly longer when the salmon diet was consumed (p = 0.06). The impact of the three diets on PA depended upon the agonist. With collagen, only the sablefish diet decreased aggregation compared to the prefish diet. When ADP was used, aggregation decreased on both the fattier fish diets compared to the low fat fish (sole). Similar results were demonstrated for TXB₂: the fattier fish produced statistically equivalent decreases (p = 0.06) among the diets, and lowered TXB₂ compared to the prefish diet. There were no significant differences among the diets for either systolic or diastolic BP though there was a significant decrease (p = 0.01) in diastolic pressure compared to the prefish diet when the salmon diet was consumed. Platelet fatty acid profiles reflected diet composition.
Graduation date: 1993

Conclusion 1. The results of the research partly supported hypothesis 1a. There was a significant reduction in both endothelium-dependent arterial relaxation following a surgical menopause. The results of the research partly supported hypothesis 1b. There was a significant reduction in endothelium-dependent arterial relaxation but no significant effect on endothelium-independent arterial relaxation.
Conclusion 2. The results of the research partly supported hypothesis 2a. The addition of unopposed oestrogen significantly improved endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research supported hypothesis 2b. The addition of oestradiol combined with progestogen (norethisterone acetate) reversed the reduction in arterial relaxation caused by a surgical menopause. The results of the research partly supported hypothesis 2c. The addition of tibolone reversed the reduction endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research partly supported hypothesis 2d. The addition of oestradiol combined with a progestogen (norethisterone acetate) reversed the reduction in endothelium-dependent but not endothelium-independent arterial relaxation.
Conclusion 3. The results of the research partly supported hypothesis 3a. Endothelium-dependent arterial relaxation but no endothelium-independent arterial relaxation was improved after the addition of menopausal hormone therapy using oestrogen combined with a progestogen in a continuous manner. The results of the research did not support hypothesis 3b. Neither endothelium-dependent arterial relaxation nor the endothelium-independent arterial relaxation was improved by cyclical menopausal HT.
Conclusion 4. The results of the research did not support hypothesis 4. The addition of menopausal hormone therapy using combined oestrogen with progestogen did not improve arterial relaxation in postmenopausal women with established coronary heart disease.
Hypothesis 2. This hypothesis examined three different types of commonly used menopausal HT. That unopposed oestrogen (2a), oestrogen combined with a progestogen (2b and 2d) or a synthetic steriod that has oestrogenic, progestogenic as well as androgenic activity (tibolone, 2c), reverse the reduction in arterial relaxation following menopause in Hong Kong Chinese women.
Hypothesis 3. That menopausal hormone therapy using oestrogen combined with progestogen given in either continuous (3a) or cyclical (3b) regimens improves arterial relaxation in postmenopausal Hong Kong Chinese women.
Hypothesis 4. That menopausal hormone therapy using combined oestrogen with progestogen improves arterial relaxation in postmenopausal Hong Kong Chinese women with established coronary heart disease.
Menopausal HT can in general at least partially reverse changes in arterial relaxation in postmenopausal women. Different types of menopausal HT exhibit different effects on arterial relaxation. In healthy vessels, menopause HT mainly reverses the endothelium-dependent vascular effect, but it remains unclear how menopausal HT affects the endothelium-independent vascular effect. However, with established coronary heart disease, menopausal HT cannot reverse the changes in vascular reactivity.
Summary. Menopause results in a reduction in arterial relaxation. However, GnRHa temporarily induced menopause in young women, the endothelium-independent vasodilatation was not impaired. This difference can be partly explained by the difference in age as vascular reactivity is age dependent. Secondly, GnRHa works with an initial phase of increase in oestrogen production resulting in a shorter duration of hypo-oestrogenism resulting in the lack of impairment on endothelium-independent vasodilatation.
This thesis tested the following hypotheses: Hypothesis 1. That vascular reactivity decreases after the menopause as shown in premenopausal Hong Kong Chinese women with either a surgical (1a) or a medically induced (1b) menopause.
This thesis will examine the effects of menopause and menopausal HT on arterial reactivity which is an indirect measurement of vascular function. Previous studies have shown that oestrogen is a potent coronary artery vasodilator, and this effect may be mediated via both endothelium-dependent and endothelium-independent mechanisms. One method of assessing vascular reactivity is to use ultrasound measurement of changes in brachial artery diameter in response to certain stimuli. Using this technique, changes in both endothelium-dependent and endothelium-independent vasodilatation can be measured. Increased rather than decreased arterial relaxation after stimulus can be viewed as a favourable response.
Yim, So-fan.
Adviser: C. J. Haines.
Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5873.
Thesis (M.D.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references (p. 159-194).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
School code: 1307.

Cardiovascular disease (CVD) risk behaviors, namely tobacco smoking, hazardous alcohol use, poor diet and sedentary behavior, are more prevalent among people living with HIV (PLWH) than the general population. Qualitative evidence shows that PLWH report adopting unhealthy behaviors as a means of coping with the stress of living with HIV, including the adverse physiological symptoms of HIV infection, the psychological stress of being aware of one’s HIV status, and the physiological and psychological impacts of being on HIV treatment. These observations suggest that being HIV-positive may have a causal influence on CVD risk behaviors and that these causal effects likely differ across stages of the HIV continuum. To date, few quantitative studies have been conducted to examine these causal relationships. The goal of this dissertation was to explore the effects of HIV continuum stage on CVD risk behaviors and assess several plausible stress-coping mechanisms, as motivated by established stress-coping theory. This dissertation consisted of three studies. First, a systematic review was conducted to examine the existing quantitative evidence for the causal effects of HIV continuum stage on CVD risk behaviors. Findings from this review revealed that being HIV-positive is associated with excess smoking and drinking, and that while receipt of a positive HIV diagnosis is associated with short-term improvements in some CVD risk behaviors, these improvements are unlikely to be maintained long-term. Overall, however, the existing studies suffer important methodological limitations, notably inadequate characterization of HIV continuum stage. The second study was an empirical analysis of patterns of self-reported CVD risk behaviors across the HIV continuum among a population-based sample of 4,061 adults aged 40 years and over living in rural Agincourt district in South Africa. Results showed no consistent evidence of an association between HIV continuum stage and hazardous alcohol use or sedentary behavior. However, higher prevalence of smoking was observed specifically among males who were HIV-positive and aware of their status but not on treatment, compared to those who were HIV-negative. There was no evidence of mediation by various measures of physiological and/or psychological stress. The third study was an analysis of whether perceived life expectancy (PLE) modifies the effects of HIV continuum stage on CVD risk behaviors. Observed associations were most prominent among individuals with low PLE and null among those with high PLE. Overall, this dissertation contributed to greater understanding of the relationship between CVD risk behaviors among HIV-infected persons across the HIV continuum. Findings did not support a stress-coping hypothesis; however, PLE was found to be a potentially useful indicator of individuals who are most likely to smoke in the presence of HIV. This dissertation also fills evidence gaps among older adults in sub-Saharan Africa, an under-studied population with high and increasing burdens of both HIV and CVD. As HIV-positive population survive longer on antiretroviral therapy and the prevention of age-related conditions becomes increasingly important, these findings may help inform future research and the development of CVD prevention interventions.

The functional compartmentalization underlying neuronal polarity makes tightly regulated intracellular transport between the cell body, axons, and dendrites essential for proper development and homeostatic maintenance. Disruptions to neuronal trafficking are a major cause of neurodegenerative disease. Pathogenic variants in the microtubule motor protein KIF1A cause KIF1A Associated Neurological Disorder (KAND), a spectrum of rare neurodegenerative conditions. KAND is clinically and genetically heterogeneous, with a broad phenotypic spectrum and over a hundred pathogenic variants identified. KAND is poorly understood at both the clinical and molecular level, and there is currently no treatment. This work characterizes the natural history of KAND and describes a novel heuristic severity score. This severity score is then used to show how the location of pathogenic missense variants within the KIF1A motor domain correlates with disease severity, providing evidence the clinical phenotypic heterogeneity in KAND reflects and parallels the molecular phenotypes. Insights from the neuropathology of deceased KAND patients is used to focus a histopathologic assessment of the C3-Kif1aLgdg mouse model. C3-Kif1aLgdg/Lgdg mice have a cerebellar axonal torpedo phenotype, paralleling some of the pathological changes seen in the patients. Phenotypically, the C3-Kif1aLgdg mice were found to recapitulate some of the symptoms seen in patients including progressive spasticity and gait abnormalities associated with hind limb paralysis. To model the disease at a cellular level, iPSCs were derived from affected individuals and successfully used to generate neural stem cells and neurons. These patient-derived neurons were found to have increased markers of protein aggregates, a cellular phenotype that can be used to test potential treatments. Taken together, these studies provide foundational knowledge for future therapeutic development.

M.A. (Psychology)
The health context of South Africa is on the one hand unique in comparison to the rest of the world. On the other hand does it also. show characteristics of both Third World and First World disease patterns. There is a substantial component of the South African health sector that is negatively affected. This can possibly be ascribed to previous health policies. South Africa has unique characteristics concerning the chronic degenerative aspects of the First World disease pattern. White South Africans have the same cardiovascular disease patterns as the rest of the world with the exception that the South African disease patterns has a much larger incidence and degree of seriousness that the rest of the world. Research in the area of the chronic degenerative nature of heart disease and vascular disease is of great importance. It becomes necessary to address degenerative disease and also lifestyle diseases not only medically but also in terms of an individual's lifestyle. The management of an individual's lifestyle will not only have preventive consequences in the South African context, but it can also be utilised in the treat~ent of cardiovascular disease. Research undertaken at the Clinic and Centre for Behavioral Medicine at the Rand Afrikaans University found that the management or treatment of the Type A behavior pattern for the prevention of recurrent cardiovascular diseases were particularly effective. It therefore seems that technology developed elsewhere proves to be effective for the South African context. According to Johnston (1992) two types of risk factors contribute to the development of cardiovascular disease. The first constitute of classical risk factors which include aspects of blood pressure and cholesterol. The second risk factor includes psychological aspects and in particular the Type A behavior pattern and its components. Johnson and Broman (1987) indicate that the components of anger and hostility of the Type A behavior pattern constitute the most important behavioral factor of Type A coronary-prone behavior and cardiovascular disease. Research also indicate that the component of hostility presents a significant predictor of cardiovascular disease (Helmers et al., 1993) . The role of aggression and its components in the Type A behavior pattern was investigated in this study. An attempt was made to establish whether there is a simultaneous reduction in aggression, its components and the Type A behavior pattern and whether certain components of aggression were more important that others. A group of 39 heart patients were investigated on the following indexes: psychological, cardiological and biochemical in order to establish heart disease risk factors in a biopsychosocial context. A modified Type A treatment progranme was administered to this group over a period of twelve weeks at a local heart rehabilitation centre. A second group of 19 patients served as a no-treatment waitinglist control group, but simultaneously underwent an aerobic exercise and cardiovascular counselling programne. The results of this study indicated that cynical hostility was probably the major risk factor of all the components of aggression in the Type A behavior pattern. The second most important component of aggression in the Type A behavior pattern is the expression of anger in general. The latter also corresponds with results found in research on this subj ect. Ov-ert or specific expression of anger .nd the control of anger also contribute to the psychosocial causation of Type A behavior pattern in cardiovascular disease. Comparisons of the experimental and control groups after the intervention showed statistically significant differences of anger expression in general, specific anger expression, inhibition of anger, control of anger, and hostility. It was concluded that significant differences for the diverse components of aggression have been found due to the experimental intervention programme.

Current dietary recommendations have placed increasing emphasis on dietary fat as an important element to decrease risk of cardiovascular disease (CVD). Although total fat and the fatty acid composition of diets influence the risk of CVD, the optimal amounts of different fatty acids are not well defined, especially if n-6 and n-3 fatty acids are considered. Despite the fact that postmenopausal women are at increased risk of CVD, few studies have investigated the influence of dietary fatty acids on this risk. Therefore, this study was designed to determine the effect of supplementation with different fatty acids on risk factors of CVD in postmenopausal women. Sixteen healthy, postmenopausal women were randomly assigned in a three-period crossover trial to treatments of 15 g/d supplements of oleic acid-rich sunflower oil (TS), linoleic acid-rich safflower oil (SO), and eicosapentaenoic acid- and docosahexaenoic acid-rich fish oil (FO). Each treatment period lasted 5 weeks followed by a 7-week washout interval. When the women were supplemented with FO compared to supplementation with either TS or SO, the concentration of high density lipoprotein cholesterol tended to increase (p=0.07 and 0.05, respectively) as did the size of the low density lipoprotein (LDL) particle (P=0.03 in both instances) while the concentration of triacylglycerol (p=0.0001 and 0.02, respectively) and apolipoprotein B (apo B) (P=0.005 and P=0.01, respectively) decreased. The concentration , i.e., total cholesterol, cholesterol ester, free cholesterol, phospholipids, α- and γ-tocopherol, of the two LDL subfractions was not influenced by any of the oil supplements but was greater in the large (L) subfraction than the small (S). When the oxidation of the two subfractions was measured by monitoring the formation of conjugated dienes, the lag time was shorter in both fractions after supplementation with FO compared to supplementation with SO (P=0.0001) or TS (P=0.0001) but the effect was greater in the L subfraction. The rate of formation of conjugated dienes, which was slower after FO supplementation than supplementation with either TS (P=0.02) or SO (P=0.001), was faster in the L compared to the S subfraction. When oxidation was measured by monitoring the increase in negative charge on apo B over 23 hr, only the 1 hr time point differed. The increase was greater in the FO-supplemented group than either the TS- or SO-supplemented groups (P=0.001 in both instances). The change was greater in S LDL (P=0.007). These findings demonstrate a greater potential antiatherogenic property of dietary n-3-rich oil than n-6- or n-9-rich ones as indicated by changes to plasma lipids, lipoproteins, apo B, and particle size but the influence of the oxidative susceptibility of L and S subfractions is less conclusive.
Graduation date: 2000

Introduction: Gastric cancer (GC) is ranked as the second most common fatal malignancy worldwide. Although Helicobacter pylori is recognized as a major predisposing factor for non-cardia GC, infection alone is not sufficient to cause cancer. This thesis aimed to determine the variation in host genetic polymorphisms in subjects from Malaysia and Singapore and to examine the role of H. pylori infection, host genetic factors and dietary factors in the etiology of non-cardia GC in Chinese subjects resident in Malaysia. Methods: Functional dyspepsia (FD) controls from three ethnic groups in Malaysia, Chinese (123), Indian (110) and Malay (84) and Singaporean Chinese (127) plus Malaysian Chinese gastric cancer cases (55)were examined. Polymorphisms in IL-1B-511, IL-1RN, IL-10 cluster, TNFA-308 and TLR5+1174 were determined by PCR-RFLP or PCR; H. pylori status by serology, dietary intake by questionnaire and gastric IL-1b levels by real time PCR. Results: 1) Significant differences existed in the frequency of all polymorphisms, except IL-1B-1473 and TNFA-308, in the three Malaysian ethnic groups and in the IL-1B-511 polymorphism in Malaysian and Singaporean Chinese FD 2) Globally, two distinct patterns of IL-1B-511, IL-1RN, IL-10-1082, IL-10-592 and TNFA-308 exist, Western and East-Asian 3) In Malaysian Malays, the IL-10 ATA haplotype was associated with H. pylori susceptibility 4) In Malaysian Chinese an increased risk of GC was associated with carriage of the IL-1B-1473 G allele {OR=4.4(1.3-15.3)} and the IL-1B-511 C allele {OR=1.8(0.8-4.1)} 5) Increased levels of IL-1b were observed in Singaporean and Malaysian Chinese FD subjects carrying the IL-1-511C and IL-1-1473G alleles 6) Malaysian Chinese not consuming fresh fruit and vegetables had the highest risk of GC {OR=10.2 (3.4-30.6)} 7) The highest risk of GC {OR=37.3(3.3-424.8)} was observed in H. pylori positive Malaysian Chinese who carried both the IL-1B-511C and IL-1B-1473G alleles and did not consume fresh fruit and vegetables. Conclusions: In Malaysian Chinese, H. pylori infection, host genetic and dietary factors all contribute to the risk of GC. However the significant difference observed in the frequency of host genetic polymorphisms within and between ethnic groups suggests that a single group of risk factors cannot be used to determine GC risk across all populations.