Faculty of Health Sciences (ETDs)

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    Understanding the in vitro effect of TNF-α and hyperglycaemia on endothelial activation
    (University of the Witwatersrand, Johannesburg, 2023) Amoni, Joel Ikechukwu; Millen, A; Gunter, S
    Background. Inflammation is one of the main underlying mechanisms in the development of cardiovascular disease (CVD). Indeed, in diseases characterised by high-grade systemicinflammation and in comorbid conditions, such as diabetes mellitus, it has been suggested that inflammation, at least in part, contribute to the increased risk of CVD. One of the earliest signs of inflammation-induced CVD is endothelial dysfunction. However, whether inflammation promotes endothelial dysfunction via the same signalling pathways in different pathological conditions characterised by systemic inflammation is not well understood. Inflammation- induced aberrant expression of microRNA (miRNA), small non-coding RNAs that function to regulate gene expression post-transcriptionally, have been linked to impaired endothelial function. However, the mechanisms whereby miRNAs may mediate endothelial activation requires further investigation. Therefore, the aim of this study was to investigate the molecular mechanisms involved in the regulation of endothelial function in different models of inflammation. Methods. EA.hy926 immortalized endothelial cells were cultured in Dulbecco’s modified eagle’s medium (DMEM) + HAM’s F12 nutrient mix supplemented with 10% foetal bovine serum (FBS). EA.hy926 cells were exposed to tumour necrosis factor-alpha (TNF-α) at a concentration of 10ng/ml for 24 hours to induce an inflammatory response while the controls were cells exposed to plain media for 24 hours. EA.hy926 cells were also exposed to either 5mM or 30mM glucose for 72 hours, as a model of glycemia-induced inflammation, while the control cells were exposed to plain media for 72 hours. Total RNA was extracted from the cell pellets and subsequently reverse transcribed to miRNA cDNA and mRNA cDNA. Quantitative real time PCR was used to determine the relative expression of interleukin-6 (IL-6), vascular cell adhesion molecule 1 (VCAM-1), miRNA-155-5p, endothelial nitric oxide synthase (eNOS) and superoxide dismutase 2 (SOD-2). Additionally, an ELISA assay was used to determine the ratio of phosphorylated p65/total p65 in cells exposed to TNF-α (10ng/ml for 24 hours), glucose (30mM for 72 hours) and plain media controls. Results. Compared to control cells, the relative mRNA expression of the inflammatory marker IL-6 was significantly increased in the cells exposed to TNF-α (p=0.002) and 5mM (p=0.002) and 30mM (p = 0.0001) glucose, respectively. In addition, the relative mRNA expression of VCAM-1 was increased in the cells exposed to TNF-α (p <0.0001) and 30mM glucose (p =0.03) when compared to their respective controls. Interestingly, miRNA-155-5p expression was also increased in the cells exposed to TNF-α (p= 0.04), 5 mM glucose (p = 0.007) and 30 mM glucose (p = 0.02). Exposure to TNF-α, and 5 mM and 30 mM glucose resulted in increased eNOS expression compared to the control cells (p = 0.04, p=0.002 and p = 0.0002, respectively). The ratio of phosphorylated-to-total NF-κB p65 were not different in either the TNF-α exposed or glucose exposed cells compared to control cells (all p>0.05). Conclusion. These findings suggest that TNF-α and hyperglycaemia exposure resulted in endothelial dysfunction. However, hyperglycaemia caused much greater oxidative stress (increased eNOS) most likely due to glucose scavenging of nitric oxide (NO). This suggests that the underlying mechanisms of endothelial dysfunction occurring due to hyperglycaemia and inflammation may be driven by different mechanisms. This study highlights the need for further investigation into the mechanisms whereby miRNA-155-5p regulate endothelial dysfunction
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    Preoperative fasting practices and incidence of hypoglycaemia in patients presenting for caesarean section at a central hospital
    (University of the Witwatersrand, Johannesburg, 2023) Prinsloo, Nathalie
    Background Prolonged preoperative fasting times have a negative impact on parturients and may have a negative impact on the neonate. This study aimed to describe the preoperative fasting practices and incidence of hypoglycaemia in obstetric patients undergoing caesarean section, as well as the incidence of neonatal hypoglycaemia at Chris Hani Baragwanath Academic Hospital. Methods This prospective, cross-sectional study was conducted in 2021 over six months at Chris Hani Baragwanath Academic Hospital, a tertiary referral hospital in Johannesburg, South Africa. The sample consisted of 213 adult parturients who presented for emergency or elective caesarean section and excluded those who could not provide a history of fasting practices. Maternal blood glucose levels were measured prior to anaesthesia and neonatal blood glucose levels were measured immediately after delivery. Results Mean (SD) fasting times to solids and fluids were 18 h, 19 min (12 h, 4 min) and 13 h, 2 min (8 h, 31 min), respectively. Maternal hypoglycaemia occurred in 24.4% of the parturients and was associated with longer periods of fasting to solids (P=0.049). The incidence of neonatal hypoglycaemia was 1.8% and maternal blood glucose level was significantly positively correlated with neonatal blood glucose level (r=0.59, P<0.001). Conclusion Preoperative starvation times were excessive and should be addressed to avoid maternal hypoglycaemia. The impact of maternal hypoglycaemia on the neonate is less clear and further research is required before a protocol can be developed. It may be prudent to check the blood glucose levels of all parturients prior to caesarean section.
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    Assessment of the management of inpatient hyperglycaemia by physicians and intensivists in South African hospitals
    (2024) Hewson, Peter Llewellyn Blanshard
    Background Hyperglycaemia is highly prevalent in patients admitted to hospital and is associated with prolonged hospital stay, increased costs, morbidity and mortality. As there is currently limited local data on the management of hyperglycaemia, this study aimed to investigate physician practices in the management of inpatient hyperglycaemia in South African hospitals Methods: A survey investigated the practices of 154 physicians in general medical wards and intensive care units (ICUs) in the state and private sectors. To validate these responses, an audit of 100 general medical and 111 ICU patient files was performed at three major Johannesburg academic hospitals. Patients with inpatient hyperglycaemia related to diabetes mellitus (DM) or hospital-associated factors were included, while patients admitted with diabetic emergencies were excluded. Results: In the general medical wards, oral hypoglycaemic agents (OHAs) were used in the majority of survey respondents (94.5%) and audited files (64%). In the ICU, OHAs were used by 34.9% of survey respondents and 14.4% of audited patient files. Of the OHAs, metformin use was most frequently reported (93.8% in the survey) and used (64% in the audit) agent in the general medical wards, followed by sulfonylureas (SUs) (75.8% in the survey and 5% in the audit). In the critical care setting, the survey demonstrated frequent use of metformin followed by dipeptidyl peptidase-4 inhibitors (DPP4-i), while the audit showed that metformin and SU use was 14.4% and 0.9% respectively. Surveyed clinicians in general medical wards report most frequently using the basal insulin plus sliding scale insulin (SSI) regimen (36.6%), while the audit showed that SSI alone (36%) or premix insulin-based regimens (34%) are used most often. In the critical care setting, more surveyed clinicians reported using an insulin infusion (34.9%) compared to other insulin regimens, while the audit demonstrated that the majority of patients (59.5%) were managed with SSI alone. Four-to-six hourly glycaemic monitoring was noted as the standard of care in both surveys and audits. While the majority of clinicians reported daily review of their glycaemic management (91.7% and 87.3% of participants in the general medical wards and ICU, respectively), the audit revealed that this was noted in just 34% and 3.6% of participants in the general medical wards and ICU, respectively. Conclusion: Both the survey and audit demonstrated significant discrepancies from current clinical guidelines. This highlights a significant impact on patient care, in particular, as OHAs have not been recommended for use in the ICU setting, one in every three critical care patients may be exposed to potential complications as a result of the use of such agents. The findings of this study suggest further investigations regarding inpatient hyperglycaemia practices as well as implementation of education and in-hospital protocols are needed in the South Africa healthcare context in order to improve clinical outcomes.