Faculty of Health Sciences (ETDs)
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Item The potential of zingerone to protect against alcohol-induced liver disease(University of the Witwatersrand, Johannesburg, 2023-05) Asiedu, Bernice; Chivandi, Eliton; Nyakudya, Trevor; Lembede, BusisaniAlcohol 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 administered 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 ethanol-induced hepatic lipid accumulation in males and steatosis in both males and females.Item Avascular necrosis (AVN) of the hip in patients operated in the Orthopaedic Arthroplasty Unit at Chris Hani Baragwanath Academic Hospital(University of the Witwatersrand, Johannesburg, 2023-08) Mwoyofiri, Jephta; Magobotha, S.K.; Frey, C.; Jingo, M.Background: Avascular necrosis (AVN) of the femoral head is a progressive structural damage of the head of the femur because of interruption of blood supply to the subchondral bone resulting in the collapse of the head of the femur and secondary arthritis. Moreover, this chronic debilitating disease of the hip causes an immense contribution to the need for total hip arthroplasty (THA) and is common in young persons between the third and fifth decades of life. The aim of the study was to describe the causes of osteonecrosis of the femoral head (ONFH) in patients operated at Chris Hani Baragwanath Academic Hospital (CHBAH) Arthroplasty unit from 2017 to 2022. Methods: A retrospective review of all patients operated between the above-mentioned period, was conducted through collecting the patients’ demographic data, risk factors and treatment given. Results: The study had 285 participants with AVN from a total of 838 patients who had hip surgery. There were 149 (52%) females and 136 (48%) males. The mean age was 51.7 years with a SD 11.4 years. Majority of the patients were in the age group: 50 ‒ 59 years. The main risk factor of AVN was human immunodeficiency virus (HIV) with 117 (41%) patients. Those on highly active anti-retroviral therapy (HAART) were 115 (98%) patients. The median cluster of differentiation 4 (CD4) count was 584 (IQR 470 ‒ 711) and the viral load was undetected in 29 of the 32 (91%) patients with recorded viral load results. Ficat/Arlet stage 4 had 199 (70%) patients and all our patients had total hip replacement. Conclusion: ONFH contributes significantly to the burden of total joint arthroplasty in young patients. As our study has shown, there are several risk factors such as HIV, alcohol use and steroids being among the commonest. Our study draws attention to the significant burden that HIV has on hip pathology. HIV was the commonest cause of AVN at our local health institution and may be in the Sub-Saharan region. However, in our study we could not isolate HAART as a cause of AVN due to inadequate patient records. Majority of patients usually present with advanced stages of ONFH requiring a femoral head sacrificing operation due to late referral and long waiting list before surgery.Item Effects of binge alcohol consumption on the development of the femur of adolescent Sprague Dawley rats(University of the Witwatersrand, Johannesburg, 2024) Mngoma, Ndabenzinhle Ronald; Bhika, AkaashniExcessive alcohol consumption adversely affects bone metabolism, thus resulting in reduced bone length, density, and strength. While excessive alcohol consumption is an established risk factor for osteoporotic fractures, there remains a dearth of information in literature regarding bone effects of binge alcohol consumption in adolescents. Therefore, our study aimed to examine the effects of binge alcohol consumption in an acute and chronic binge model, on the development and growth of the adolescent femur. Forty-eight Sprague Dawley rats (24 male and 24 female) aged 7 weeks were randomly allocated to one of the 4 treatment groups (n= 12/group) receiving binge alcohol (3g/kg of 20% alcohol) or caloric equivalent of maltose dextrin (pair-fed control), via oral gavage. The treatment groups were; A1, receiving alcohol on 3 alternating days for one week, C1, receiving the caloric equivalent of maltose dextrin in the same manner as A1 (acute), A4 and C4 received treatments in the same manner as A1 and C1 for four consecutive weeks (chronic). Trabecular morphometry in both the proximal and distal epiphysis, and cortical dimensions were assessed by using three-dimensional Micro- Focus X-ray Computed Tomography (3D-μCT) and Volume Graphics Studio® software. The morphology of the epiphyseal growth plate was examined by Haematoxylin and Eosin staining, whereas Ki-67 immunostaining was employed to quantify the proliferation of chondrocytes in the proliferative zone of the growth plate. A three-point bending test was employed to examine the effects of alcohol on bone strength. Results showed that binge alcohol consumption causes thinner trabeculae that are more widely spaced and with a smaller bone to volume ratio (BV/TV). However, the tensile strength was similar in the alcohol exposed rats and paired fed groups in male rats, whereas it appeared improved in female rats exposed to alcohol. A binge model also affected the number of chondrocytes in the proliferative zone negatively. All the adverse changes observed in the osseous tissue in the current study were shown in the male rats. Our study found alcohol to have no adverse effects on female rats, which could be due to hormonal differences.”Item Conjoint tobacco and alcohol use, and depressive symptoms among hiv positive patients in Sedibeng District, Gauteng(2024) Akahilem, Kenneth E.Background: Psychosocial challenges among HIV positive patients may promote substance use disorders. In this study, we explored the relationship between conjoint tobacco and alcohol use and depression symptoms among HIV positive patients in Sedibeng district, South Africa. Methods: In a cross-sectional study of 404 participants, a questionnaire collected information on socio-demography, tobacco and alcohol use, and depression symptoms. Outcome measures included the prevalence of conjoint tobacco and alcohol use, and its association with depression. Results: The mean participant age was 43.2 years. Most completed secondary school 62.9% (253/402), were black 99.0% (400/404), female 65.8% (266/404), unemployed 53.6% (216/403) and on ART for >1 year 97.8% (393/402). Current tobacco use was reported by 23.3% (94/404) participants with most smoking cigarette (73.7%) and having low nicotine dependence (75.5%). Current alcohol use was reported by 43.6% (176/404) participants, and 36.9% were categorised as harmful users. Only 7.7% (31/404) participants screened positive for depression; most of these (83.3%) previously undiagnosed. The prevalence of conjoint tobacco and alcohol use was 19.6% (79/404) and this was not associated with depression (p=0.438). Harmful alcohol users were more than five times likely to report conjoint tobacco and alcohol use (p=0.000) but women were less likely to report it (p=0.000).Item Evaluation of the neuroprotective effects of simvastatin against alcohol-induced damage to the sciatic nerve and the somatosensory barrels in adolescent C57BL/6J mice(2024) Efuntayo, Alice AdetokunboAlcohol is a commonly used and abused drug among adolescents which has an adverse effect on the body’s overall health, especially on the developing brain. It causes neurodevelopmental, neurobehavioral, neurocognitive, and social problems because alcohol exerts its neurodegenerative effects by up-regulating oxidative stress which is responsible for neuronal death. The rising prevalence of alcohol-related diseases and disabilities and the cost to the government necessitates investigation into interventions that could protect the neurons against the damaging effects of alcohol. One drug with antioxidant properties is Simvastatin, a U.S. Food and Drug Administration (FDA) approved drug for lowering blood cholesterol levels. The neuroprotective effects of Simvastatin against alcohol neurotoxicity were evaluated on the sciatic nerves and the somatosensory barrel cortices of adolescent mice. 40 four–week old C57BL/6J male and female mice were administered 20% alcohol (i.p.), 5 or 10 mg/kg Simvastatin orally followed by 20% alcohol (i.p.) or the controls (i.e. 5 mg/kg Simvastatin only or non-treated) consecutively for 28 days. The axonal density, myelin thickness and g-ratio of the sciatic nerves were assessed as well as the sizes of the Posteromedial barrel subfield (PMBSF) barrels. The results confirmed alcohol neurotoxicity on the axonal density and myelination in both sexes. At the same time, Simvastatin was effective against the onset of alcohol nerve damage. For the somatosensory barrels, alcohol did not significantly reduce the mean areas of (I) the PMBSF barrels, (II) the enclosure, or (III) the septal portion in both sexes. However, the barrel-to-barrel comparison revealed alcohol toxicity on specific barrels in specific rows and arcs of the PMBSF barrels. Both concentrations of Simvastatin were also effective against alcohol–induced damage on those specific barrels. These may explain the reasons for the sensory-motor delays that are often seen in alcoholics due to possible delays in the relaying of sensory input and the processing and interpreting of information from the somatosensory cortex. Simvastatin seems to have the ability to protect against the damaging effect of alcohol on the peripheral nerves and the somatosensory cortex and this may be beneficial in reducing the prevalence of alcohol-related diseases or disabilities, especially in adolescents that are prone to abusing alcohol.