Electronic Theses and Dissertations (PhDs)

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Browsing Electronic Theses and Dissertations (PhDs) by Faculty "Faculty of Health Sciences"

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    Determinant of metabolic syndrome and its cardiovascular complications among people of African ancestry
    (2024) Eluwole, Omotayo Alaba
    Cardiovascular disease is now a leading cause of death globally. However, metabolic syndrome is an extremely critical healthcare issue worldwide due to progressive increase in obesity and its related factors. Obesity is strongly associated with insulin resistance and other components of metabolic syndrome. There is discrepancy in the use of parameters for the diagnostic criteria of metabolic syndrome due to genetic and environmental variability in different ethnicity. Body mass index and waist circumference (WC) are commonly used in the assessment of central obesity and abdominal obesity respectively. Fahed et al observed that waist circumference was employed because measurement was easy, however, waist circumference alone is inconclusive of abdominal adiposity and must be interpreted with body mass index. The two measurements (WC and BMI) have been documented to be strongly related to insulin resistance. (Fahed et al., 2022). However, there is controversial assessment of metabolic syndrome using either waist circumference (WC) or body mass index (BMI) or waist hip ratio (WHR) or combination of two measurements (Kassi et al., 2011; Fahed et al., 2022). Our study assessed the prevalence of metabolic syndrome among apparently healthy 1516 participants from African ancestry using seven established diagnostic criteria (NCEP-ATPIII- National Cholesterol Education Program Adult Treatment Panel III, WHO- World Health Organization, IDF-International Diabetes Federation, AHA/NHLBIAmerican Heart Association/National Heart, Lung and Blood Institute, EGIR - European Group for the study of Insulin Resistance, AACE- American Association of Clinical Endocrinology). The result revealed highest prevalence of metabolic syndrome when modified NCEP-ATPIII [National Cholesterol Education Program Adult Treatment Panel III (ATP III)] was considered. The predictive assessment of blood pressure and arterial stiffness may be useful in achieving early detection and prevention of target organ damage. This study further compared clinic blood pressure, ambulatory blood pressure and central pressure using conventional blood pressure monitor, Spacelabs 90207 (Spacelabs Inc., Redmond, Washington, USA) and applanation tonometry Sphygmocor device respectively. The findings revealed that central blood pressure and ambulatory blood pressure are more predictive of cardiovascular events among people of African ancestry. Our findings are pointers to cardiovascular risk in the study population. Additionally, this study provides new insights to the role of obesity in the perturbation of left ventricular geometry of people of African ancestry with metabolic syndrome; using quantitative and comprehensive evaluation of biochemical and echocardiographic profile. Aldosterone produced locally in adipose tissue, heart, kidney and vasculature increase the expression of cytokines and other fibrotic factors. Thus, role of the local renin angiotensin aldosterone system (RAAS) in the pathophysiology of atherosclerosis and cardio-renal fibrosis was evaluated in animal study. With high prevalence of metabolic syndrome and obesity in Africans, elevated aldosterone from diet may likely predispose African community to diastolic dysfunction; this may be a pointer to increased incidence of heart failure in groups of African ancestry. Hence, this study lends insights into the potential role of TRPM7; a novel non selective cation channel and chanzyme in aldosterone-induced cardiovascular fibrosis. This study concluded that modified NCEP-ATPIII has suitable components for the diagnosis of MS in people of African ancestry. Metabolic syndrome in people of African ancestry is strongly associated with factors such as sex, smoking and alcohol. Consequently, MS and other risk factors such as obesity, aldosterone and insulin resistance may lead to left diastolic dysfunction among individuals with MS. Experimentally, aldosterone-salt induced cardio-renal fibrosis, aggravated by TRPM7 might be the underlying pathogenesis of MS and its cardiovascular complications in Africans; thus suggests TRMP7 inhibitors has potential anti-fibrotic agents.
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    The association between adult attachment style and pain perception in a South African cohort
    (University of the Witwatersrand, Johannesburg, 2024) Stamp, Gabriella Elisabeth
    Our response to threats, including pain, is believed to be learnt during our early interpersonal connections and experiences. Interpersonal relationships can be measured through four adult attachment style classifications: Secure, Dismissing, Preoccupied and Fearful, with the latter three being collectively classified as Insecure attachment styles. Preliminary epidemiological evidence suggests that Insecure attachment styles are more prevalent in those with chronic pain, while experimental studies investigating the association between adult attachment and pain are inconclusive. In two separate investigations, the aims of my research were (i) to determine the association between adult attachment style and chronic pain prevalence and burden in a South African population, and (ii) to determine the association between the different adult attachment styles and measures of experimental pain as a way of assessing a potential mechanism for possible differences in pain perception between the attachment styles. In the first study, a nationwide online survey of a general South African population assessed adult attachment style (using The Experience in Close Relationships - Relationship Structures (ECR-RS) Questionnaire), prevalence of chronic pain and psychological factors that are typically associated with pain, including depression, anxiety and pain catastrophising. In participants who reported experiencing chronic pain, the association with attachment style and pain burden (pain sites, severity and interference, using the Brief Pain Inventory) was further investigated. A total of 2371 participants completed the survey, with the cohort being generally young in age (median age 23 years; IQR 20-28), well-educated and primarily female (74%), with predominantly a middle-to-high socioeconomic status. In this cohort, I found a higher-than-expected prevalence of chronic pain (27%); previously reported prevalence data in a South African population found the prevalence to be 18%. All three Insecure attachment styles were associated with increased chronic pain prevalence when compared to the Secure attachment style (Dismissing: 31%, Odds ratio [95%CI] = 1.38 [1.02-1.85], p=0.037; Preoccupied: 42%, Odds ratio [95%CI] = 2.26 [1.62-3.13], p<0.001; Fearful: 49%, Odds ratio [95%CI] = 2.95 [2.03-4.29], p<0.001). In participants with chronic pain, adult attachment style was not directly associated with the overall burden of chronic pain. Rather, my study found that pain catastrophising was the mediating factor between Insecure adult attachment styles and an increased burden of chronic pain. Female volunteers who had completed the survey were invited to participate in the second study, which involved in-person experimental procedures to evaluate the experience of thermal pain and mechanisms of pain analgesia using the Conditioned Pain Modulation (CPM) paradigm. In the 103 young (median age 21 years; IQR 20- 23) and well-educated (all completed at least secondary education) sample, no significant relationship was found between attachment style and heat pain threshold (t(54) = -0.45, p = 0.654), heat pain tolerance (t(47) = -1.16, p = 0.250), and intensity of heat pain (Estimate [95%CI] = -0.11 [-0.34-0.11], p-value = 0.330). Similarly, descending pain inhibition (assessed using CPM) was not associated with adult attachment style (t(59) = -0.97, p = 0.338). In these South African cohorts, adult attachment style directly associated with chronic pain prevalence, with remarkably more than double the chronic pain prevalence in Fearfully, compared to Securely, attached individuals. A possible mechanism underlying the association between insecure attachment style and high chronic pain prevalence may be differences in pain modulatory pathways, which was investigated through the CPM test paradigm in Part 2 of my research. Pain catastrophising mediated the relationships between attachment style and burden of pain, highlighting the role and impact of cognitive factors and the perception of threat on both attachment style and pain. Adult attachment style did not associate with perception of experimental pain, nor did it associate with mechanisms of pain inhibition. The data of the two research components of my thesis highlight the differences between chronic clinical pain and the once-off experience of experimental pain in a controlled and safe environment. The negative data in the experimental study may be explained by three main limitations: (i) The experimental protocol was not threatening enough and was unlikely to consistently activate the adult attachment system; (ii) individuals with high attachment anxiety and attachment avoidance dimension scores did not participate in the experimental study, which means the sample was biased and may not have shown any differences even if the protocol was threatening enough to activate the attachment system; (iii) the experimental pain protocol likely does not capture the threatening nature of chronic pain due to complex interactions of psychosocial factors that accompany chronic pain. These limitations are informative for future experimental pain studies, and I believe that CPM cannot, at this point, be ruled out as a mechanism for the increased chronic pain prevalence in insecurely compared to securely attached individuals. Moreover, pain catastrophising as a potential mechanism underlying the association between adult attachment style and the prevalence of chronic pain may also be a potential avenue for future studies to pursue.
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    The potential of zingerone to protect against ethanol-induced liver disease
    (2024) Asiedu, Bernice
    Alcohol can cross the placental blood-barrier and can also be secreted into breast milk. This can affect developing foetuses and/or nursing neonates negatively, thus impacting on metabolic health in early or later life. Zingerone (ZO) has anti-oxidant, anti-diabetic, anti-inflammatory, hypolipidaemic and hepato-protective properties. I hypothesised that neonatal oral administration of ZO could programme for protection against alcohol-induced metabolic derangements in suckling Sprague-Dawley (SD) rat pups mimicking human neonates that indirectly consume alcohol through their mother’s breast milk. The first experiment evaluated ZO’s potential to protect suckling rat pups against alcohol-induced metabolic derangements. Seventy 10-day old SD rat pups (males = 35; females = 35) were randomly assigned to four groups and administered treatments daily from postnatal (PND) 12-21: group 1-nutritive milk (NM), group 2-1 g/kg body mass ethanol (Eth), group 3- 40 mg/kg body mass ZO and group 4 - NM+Eth+ZO. Terminal body mass, blood glucose concentration, lipid profile and hepatic antioxidant status were determined. Zingerone and ethanol had no effect on pups’ growth performance, blood glucose, total cholesterol, HDL- and LDL-cholesterol and hepatic thiobarbituric acid (TBARs), superoxide dismutase and catalase concentrations (p > 0.05). Ethanol decreased plasma triglyceride concentration in female rat pups (p = 0.04) but increased hepatic cytochrome P450E21 (CYP2E1) and decreased total glutathione (tGSH) concentration in male rat pups (p < 0.05). Zingerone increased tGSH in male rat pups (p = 0.003). A combination of ZO and ethanol increased (p = 0.047) hepatic CP2E1 concentration in male rat pups compared to control but had no effect (p = 0.717) on tGSH concentration. Neonatal orally administered ethanol induced hepatic oxidative stress which ZO, administered during the suckling period, failed to protect against In experiment II, 123 SD rat pups (males = 60; females = 63) were administered the same neonatal interventions as in experiment I but from PDN22 they were grown to adolescence (PND45) with ad libitum access to normal rat chow and tap water. From PND 46-100, rats from each of the four neonatal groups were divided into two subgroups: subgroup I had tap water and subgroup II had ethanol solution as drinking fluids, for eight weeks. Body mass, feed, fluid and caloric intake were measured. Blood glucose concentration, plasma alanine transaminase and aspartate transaminase (ALT and AST) activities, adiponectin (ADP), leptin (LEP) and insulin (INS), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cytochrome P4502E1 (CYP2E1) concentrations were measured. HOMA-IR was computed. Visceral fat mass, hepatic fat content and histomorphometry were assessed. Hepatic TBARs and mRNA expressions of peroxisome proliferator activator receptor-alpha (PPAR-α), sterol regulatory element binding protein 1c (SREBP1c), nuclear factor kappa beta (NF-Kβ) and TNF-α were measured. Ethanol consumption in adulthood decreased feed and fluid intake but increased calorie intake and plasma CYP2E1 concentration (p < 0.05 vs control). It decreased blood glucose concentration of male rats (p = 0.026). A late single- and a double-alcohol hit had no effect on body and visceral fat mass of the rats (p > 0.05). Neonatal orally administered zingerone and ethanol and consumption of ethanol in adulthood had no effect on body mass, plasma lipid profile, adiponectin, leptin and insulin concentrations, HOMA-IR, AST and ALT activities, IL-6, TNF-α and hepatic TBARS and mRNA expression of NF-KB and TNF-α (p > 0.05). A late single hit with ethanol increased hepatic fat content of male rats only (p = 0.014). A double and or late single ethanol hit increased liver fat content in female rats (p < 0.05). Both a late single and double ethanol hit downregulated PPAR-α but upregulated SREBP1c expression in male and female rats (p < 0.05) and it caused the development of large droplet macrosteatosis. A combination of neonatal orally administered ZO and a late single ethanol hit decreased visceral fat mass of female rats (p = 0.045 vs control) but it did not affect the blood glucose concentration of male rats (p > 0.05). Neonatal orally administered ZO with either a late single- or a double-ethanol hit caused hepatic macrosteatosis, but it had no effect on mRNA expression of PPAR-α of the rats (p > 0.05). However, neonatal orally administered ZO in combination with a late single ethanol hit did not affect SREBP1c expression of the rats but a combination of neonatal orally aministered ZO with a double ethanol hit increased SREBP1c expression of female rats (p = 0.005). The responses of the rats to interventions showed sexual dimorphism: ethanol consumption in adulthood decreased blood glucose concentration of male rats only and an early single ethanol hit caused microsteatosis only in female rats. Zingerone protected male rats against ethanol-induced hepatic fat accumulation. It attenuated the ethanol-induced upregulation of hepatic SREPB1c expression in males but not in females. Ethanol (late single and/or double hit) downregulated the hepatic PPAR-α expression in the rats which was mitigated by ZO. Neonatal orally administered ZO attenuated the late single- and double-hit ethanol-induced macrosteatosis in the rats. Thus, neonatal orally administered ZO can potentially be used as a prophylactic agent against ethanolinduced hepatic lipid accumulation in males and steatosis in both males and females.