ResearchSpace
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The effects of chronic administration of Cannabidiol and Cannabidiol-Selexipag combination on haematological parameters, oxidative stress, BNP, and TNF-α in a rat model of Pulmonary Arterial Hypertension.
(2024) Gunpath, Chayil.; Nadar, Anand.
Background: Pulmonary arterial hypertension (PAH) is a severe condition characterized by elevated pulmonary artery pressure, leading to progressive cardiovascular impairment and high mortality rates. Current therapies often fall short of providing adequate symptom relief and disease management. This study evaluates the combined therapeutic potential of Cannabidiol (CBD) and Selexipag, assessing their effects on key biomarkers and haematological parameters associated with PAH.
Methods: In a preclinical model, PAH was induced in rats using monocrotaline (MCT), followed by treatment with CBD, Selexipag, or their combination. Biomarkers including B-type natriuretic peptide (BNP), total antioxidant capacity (T-AOC), and tumour necrosis factor-alpha (TNF-α) were measured to evaluate cardiovascular and inflammatory responses. Additionally, haematological parameters such as platelet count, and haemoglobin levels were assessed. Statistical analysis was conducted using Welch’s ANOVA and unpaired Welch’s T-Tests to determine the significance of treatment effects.
Results: The combination therapy of CBD and Selexipag was found to be significantly more effective in normalizing BNP and T-AOC levels compared to the individual treatments. This suggests that adjunctive therapy might enhance cardiovascular function and reduce oxidative stress. Despite CBD’s established anti-inflammatory properties, elevated TNF-α levels in the MCT-CBD group indicated a potential exacerbation of inflammation. This finding is at odds with previous literature on CBD’s effects, which may be influenced by specific experimental conditions or dosages. Haematological analysis revealed elevated platelet counts and haemoglobin levels, with increased platelet activation noted, which correlates with findings linking these parameters to PAH progression.
Discussion: The study underscores the potential of combining CBD with Selexipag as a promising approach for PAH management, showing improved biomarker profiles indicative of better cardiovascular function and oxidative stress mitigation. However, the unexpected rise in TNF-α levels with CBD treatment highlights the complexity of its anti-inflammatory effects and suggests that its therapeutic benefits may vary based on the disease context. Furthermore, changes in haematological parameters support existing literature linking elevated haemoglobin and platelet activation to PAH, emphasizing the need for careful monitoring of these parameters in clinical settings.
Conclusion: The combination of CBD and Selexipag demonstrates enhanced therapeutic potential for PAH compared to monotherapy, with promising improvements in key biomarkers. Nevertheless, the paradoxical increase in TNF-α and associated haematological changes necessitate further research to elucidate the mechanisms behind CBD’s effects and optimize therapeutic strategies for PAH. Future studies should focus on understanding these complex interactions and exploring the full therapeutic potential of CBD and Selexipag in cardiovascular disease management.
Keywords: Pulmonary Arterial Hypertension, Cannabidiol, Selexipag, Brain Natriuretic Peptide, Total antioxidant capacity, Tumour Necrosis Factor Alpha, Monocrotaline, Platelet count, Haemoglobin levels
Carbapenem-resistant enterobacterales at a quaternary public hospital in Durban, KwaZulu-Natal: Ascertaining the clinical and molecular paradigm shift following COVID-19.
(2025) Brijlal, Nitesh.; Swe Swe-Han, Khine.; Maphumulo, Sandra Lihle.
Extensive carbapenem use has resulted in an increasing occurrence of difficult-to-treat resistant gram-negative bacteria (DTR-GNB), such as carbapenem-resistant Enterobacterales (CREs). The international antimicrobial resistance (AMR) landscape was profoundly impacted due to varying antibiotic prescribing practices following coronavirus disease 2019 (COVID-19). The resultant evolution in multidrug-resistant organism (MDRO) trends underscored this novel study’s aim in establishing the COVID-19 pandemic’s influence on the prevalence, molecular characterisation, and clinical outcome of CRE infections at a South African quaternary public hospital.
Methods
Demographics, microorganism identification, antibiograms, and patient outcomes with associated factors were extracted retrospectively from electronic records at Inkosi Albert Luthuli Central Hospital (IALCH). Carbapenemase-encoding genes from CRE isolates were prospectively identified by conventional multiplex polymerase chain reaction. Comparisons between the pre-COVID-19 (01 January 2018 to 05 March 2020) and post-COVID-19 (06 March 2020 to 31 May 2023) periods were conducted.
Results
A total of 1481 (n) CRE samples were analysed from 985 patients, with an age range of 2 days to 91-years-old. The post-COVID-19 CRE prevalence (13.58%) was more than double the prepandemic prevalence (6.72%). Klebsiella pneumoniae (85.7%; 1269/1481) was the predominant microbial species, followed by Enterobacter cloacae (6.4%; 95/1481), both of which exhibited in vitro resistance to majority of antibiotic classes. Of the 357 molecularlytested isolates, 322 (90.2%) were carbapenemase-producers, with an upsurge in blaOXA-48 (20.8%; 15/72 versus 61.2%; 137/224, p < 0.001) and decrease in blaNDM (69.4%; 50/72 versus 17.9%; 40/245, p < 0.001) in Klebsiella pneumoniae relative to the COVID-19 periods. Overall, majority of deaths (42.2%; 57/135) occurred within 7 days of CRE isolation, while linear regression analysis showed that intensive/high-care unit admission and sterile site infection were significantly associated Conclusion
There is a rising CRE burden and shift in carbapenemase-encoding gene prevalence within this referral healthcare institution following COVID-19. This study highlights the need for ongoing epidemiological surveillance and suggests conducting routine carbapenemase testing for CRE infections amongst selected patients. Multisectoral collaborative approaches streamlining accessibility to the newer β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations, such as ceftazidime-avibactam, including agents like aztreonam and cefiderocol, are urgently required to provide directed therapy, thereby potentially improving patient clinical outcomes. ith increased all-cause mortality.
Investigating the biomarker potential of circulating small extracellular vesicles in patients presenting with sepsis.
(2024) Bhagwan-Valjee, Roushka.; Mackraj, Irene.
Sepsis is defined as an inflammatory disorder caused by a dysregulated immune response to infection, affecting approximately 48.9 million people globally. The complex and multifaceted pathophysiology of sepsis complicates clinical diagnosis, management and treatment. Without a validated gold standard for diagnosis, definitive biomarkers are critical. Recently, small extracellular vesicles (sEVs) and exosomes1 have emerged as promising biomarkers of disease, owing to their role in intercellular communication. Therefore, the present study has evaluated the use of sEVs as possible biomarkers for sepsis. The approach included providing a theoretical framework surrounding sEVs, their role in sepsis pathophysiology and the potential these sEVs have as diagnostic, prognostic and therapeutic tools for sepsis. This led to the evaluation of commonly used surface markers for identifying extracellular vesicles using a multi-level, automated and precise platform. We identified an abundance of CD63, CD81 and CD9 positive particles in sepsis patients. Interestingly, the data provided distinct colocalization patterns which are abundant in sepsis patients. Our study highlighted that the CD63/CD9 colocalization may be of increasing interest in exploring the potential of these vesicles as biomarkers for sepsis. Furthermore, developing biomarkers for sepsis has become increasingly difficult due to the presence of co-morbidities. These co-morbidities further complicate the pathophysiology of sepsis, increasing the mortality rate and the risk of developing organ failure. Additionally, previous studies confirm a vast array of surface markers on the membrane of sEVs. These markers have roles in protein-protein interactions and target cell signalling. We then, further investigated the surface marker profiles in 4 cohorts (viz. healthy controls, hypertension, sepsis patients with no pre-existing co-morbidities and sepsis patients with previously diagnosed hypertension). In doing so, we identified specific surface marker profiles of sepsis and hypertension when compared to healthy controls or the other pathological states. These surface marker profiles could aid in the further understanding of sepsis pathophysiology and the role sEVs play therein. This study highlights that sEVs and the identified surface marker profiles could be exploited in the interest of biomarker development for sepsis.
Immune-mediated disorders of the peripheral nervous system in HIV with special focus on the following: myasthenia gravis, motor neuron syndrome, chronic inflammatory demyelinating polyneuropathy, pure motor lumbosacral polyradiculopathy, autoimmune nodopathies, combined central peripheral demyelinating a novel case of CCPD in 2 siblings: genetic or immune mediated.
(2023) Moodley, Kaminie.; Patel, Vinod Bhagu.; Rinaldi, Simon.; Moodley , Anandan Angamuthu.
Background:
Literature regarding the prevalence, clinical features, CSF changes, laboratory investigations, response to therapy, and pathophysiology of autoimmune disease in HIV-associated lower motor neuron syndromes is limited. The above topic is broad and for the purpose of this thesis, has been restricted to chronic immune mediated polyradiculoneuropathies (chronic inflammatory demyelinating polyneuropathy (CIDP), autoimmune nodopathies, pure motor lumbosacral polyradiculopathy (PM LSP)),motor neuron syndrome (MNS),and myasthenia gravis(MG) as these are the commonest HIV-immune mediated lower motor neuron syndromes seen at our neuromuscular unit. Neuropathies due to HIV vasculitis and diffuse infiltrative lymphocytosis (DILS) were excluded as they are rare. Muscle disorders forms part of planned prospective work.
Objective:
To describe the differences in clinical presentation, electro-diagnostic findings, cerebrospinal fluid (CSF) changes, radiology (where applicable), treatment outcomes and pathophysiology of disease in HIV-infected immune mediated polyradiculoneuropathies, MNS and MG and to compare the above to the HIV-uninfected category. Additionally, we tested for nodal/paranodal and ganglioside antibodies in patients with HIV-associated chronic immune mediated radiculoneuropathies and MNS and explored their pathogenetic potential. We also explored genetic and immune factors that are potentially implicated in CCPD in two siblings, one HIV infected. Nodal/paranodal antibodies have not previously been described in an HIV-infected cohort of patients or in the African population in general and similarly genetic testing for acquired demyelination, has not been performed in South Africa.
Methods:
An insight into the virology, epidemiology, clinical aspects and immunology of HIV is essential in understanding the complexities of immune mediated neurological conditions which occur in people living with HIV infection and is discussed in chapter 1. Chapter 1 also provides background literature of the various neurological syndromes in the HIV-uninfected population, equipping the reader with the necessary tools to understand the clinicopathological correlates in the context of HIV. Available worldwide literature is discussed and analysed in chapter 2, which is a scoping review of the above topic. A retrospective analysis of medical records of all patients meeting the diagnostic criteria for chronic immune mediated radiculoneuropathies (CIDP,DRG,PM LSP), MNS/D, and MG from our neuromuscular unit in Durban, Kwa-Zulu Natal (KZN) between 2003 and 2020 was performed (see individual manuscripts).Clinical, demographic, laboratory, electrophysiological and treatment outcome data were extracted and compared in the 2 arms of the study, namely the HIV-infected and HIV-uninfected cohorts. In addition, HIV-infected patients who met the inclusion criteria for chronic immune-mediated radiculo-neuropathies (IMRN) and MNS were prospectively screened for IgG antibodies directed against nodal (neurofascin (NF)186) and paranodal (NF155, contactin1 (CNTN1) and contactin-associated protein-1, (Caspr1) cell adhesion molecules, using a live, cell-based assay. This has not been previously done in South Africa and is therefore novel. Further testing was performed to determine pathogenicity of the antibodies using myelin co-culture screens and addition of complement. Other novel antibody detection methods included myelin co-culture screens, immunoprecipitation experiments and mass spectrometry. Whole exome sequencing for a potential novel mutation, and genetics for known inherited disorders such as CMT, mitochondrial disease and leukodystrophy was performed in the surviving sibling with CCPD.
Results:
Manuscript 1: A comparison of clinical, electro-diagnostic, laboratory and treatment outcome differences in a cohort of HIV-infected and HIV-uninfected patients with Myasthenia Gravis: One hundred and seventy-eight (178) patients fulfilled the clinical criteria for MG. Twenty-four (13.4%) were HIV-infected and 154 (86.5%) were HIV-uninfected. There were 116 (65%) females, median 45 years, (IQR 40-62), 90 (50.5%) black African, 66 (37%) Indian, 20 (11.2%) white and two (1.1%) of mixed ancestry. In the HIV-infected cohort, 20 (87%) had generalised MG, 12 (50%) bulbar and 14 (60.9%) respiratory onset MG, 12 (50%) presented with MG Foundation of America (MGFA) class 5 disease at diagnosis, 6 (25%) presented with MG crisis during the 5-year follow up. Thirteen (54%) of the HIV-infected group required rescue therapy using (plasma exchange or IV immunoglobulin) combined with pulse cyclophosphamide compared to 17 (11%) in the HIVuninfected cohort respectively. At five years, eight (33%) of the HIV-infected group remained refractory to treatment compared to 10 (6.5%) HIV-uninfected cohort respectively. No adverse events were documented in HIV-infected patients receiving combination rescue therapy (PLEX or IVIG combined with IV cyclophosphamide). In conclusion HIV-infected MG patients are more likely to require combination rescue therapy with PE/IVIG and IV cyclophosphamide compared to those who were HIV-uninfected. No side effects were documented in the HIV-infected group receiving the above therapy.
Manuscript 2: A comparative study of HIV-infected and HIV un-infected patients with motor neuron syndrome: One hundred and thirty-six patients were included in the study, 101 (76%) were HIV-uninfected and 35 (26%) were HIV-infected. Ninety four percent of the HIV-infected cohort were under 50 years, median 41, IQR (33-45), p<0.001, had median ALS functional rating scale revised score (ALSFRSRS)of 28, IQR (24-30) and 40% of these patients on anti-retroviral therapy (ART) survived longer than 10 years. Ninety one percent of the HIV-uninfected cohort were over 50 years, median 66 years, IQR (57-74), p<0.001, had median ALSFRS-RS score of 44 (IQR 42-45) and 93% died within 5 years of their illness.
Manuscript 3: A comparative study of HIV-infected and HIV un-infected patients with CIDP: Eighty-four patients were included in the study. Amongst HIV-infected patients 61% were female, median age was 37 years (IQR 30-42), 87.2% presented with a monophasic progressive illness, median CSF lymphocyte count was 5.75 (IQR 0-7.2), 86% were corticosteroid (CST) responsive and 76% were in remission within 6- 12 months requiring no further treatment. HIV- uninfected patients were predominantly male (64%), older (median age was 53years (IQR 29-66)), 53% had a relapsing remitting course, median CSF lymphocyte count was 0 (IQR 0-2), 22% were corticosteroid responsive, 95% required combination therapy and 33% were not in remission by 18 months followup.
Manuscript 4: Motor lumbosacral radiculopathy in HIV-infected patients: Eleven black African patients met the inclusion criteria. There were 6 females. The median age was 29 years, interquartile range (IQR), 23-41 years, median duration of symptom progression was 6.5 IQR (3-7.5) months. The median CD4 count of 327 cells/μL, IQR (146-457). The CSF median polymorphocyte count was 0 cells/μL, IQR 0-2, lymphocyte count was 16 cells/μL IQR 1-18 cells/μL, glucose was 3.1 mmol/L, IQR 2.8-3.4 mmol/L and protein was 1.02g/dl, IQR 0.98-3.4 g/dl. All patients tested negative for nodal (neurofascin (NF)186) and paranodal (NF155, contactin1 (CNTN1) and contactin-associated protein, Caspr1) cell adhesion molecules, using a live, cell-based assay and ganglioside antibodies, using ELISA. All patients were treated with corticosteroid therapy. Ninety one percent (91%) recovered fully within 6 months of treatment, median time for recovery was 3.4 months, IQR (1.8- 5.6). There were no relapses during the 18-month follow up period.
Manuscript 5 : Nodal-paranodal antibodies in HIV-immune mediated radiculo-neuropathies: Clinical phenotypes and relevance: Twenty-four HIV-infected patients with IMRN were included in the study, 15 met the EFNS/PNS clinical and diagnostic criteria for CIDP, 4 had ventral root radiculopathies (PM LSP) and 5 had dorsal root ganglionopathies (DRG). Five patients with CIDP had combined central and peripheral demyelination. Three patients (12.7 %) tested positive for Neurofascin IgG1 antibodies in the following categories: 1 patient with PM LSP was NF186 positive and 2 patients were NF155 positive with DRG and mixed sensory motor CIDP with optic neuritis respectively.
Manuscript 6: Case report of CCPD in siblings: Despite the above cases being fully worked up, they remain cryptic as various immune and genetic tests performed in this study have been inconclusive.
Conclusion
The 1st study shows that MG patients present with more severe bulbo-respiratory signs requiring supportive care in ICU. The study also suggests that immunosuppressive drugs, including IV cyclophosphamide may be safe and efficacious in HIV-infected patients. In the 2nd study, HIVinfected MNS patients were younger, had more severe disease at presentation and survived longer if treated with ART with possible reversal of the disease process, compared to patients with MND which is likely neurodegenerative. The findings of the 3rd study are that HIV-infected CIDP patients were younger, female predominant, had a CSF lymphocytosis, displayed slowly progressive disease, were highly steroid responsive and went into remission within 6-12 months of CST initiation compared to HIV-uninfected patients. This may argue for a different disease pathogenesis in this cohort. In the 4th study HIV-infected patients with PM LSP, had a pure motor presentation and responded to CST with no relapses during the 18 month follow up period. This cohort tested negative for NF186 and GM1 antibodies which are usually implicated in pure motor syndromes. The 5th study highlights the fact that nodal-paranodal antibodies occur at a similar frequency in HIV-infected and HIV-uninfected IMRN. However, interpretation of results in the context of HIV infection, especially with IgG1 subtypes and low antibody titres is challenging as many antibodies occur as an epiphenomenon in HIV and may therefore be non-specific and non-pathogenetic. Pathogenicity was not established using myelin co-cultures or complement assays. The 6th manuscript describes a rare and cryptic entity of CCPD in siblings and serves as a platform for future genetic, epigenetic and immune studies. The above retrospective and prospective studies add valuable new background information to the medical literature as they describe our clinical experience in complex and rare HIV- related patientconditions where international experience in managing such patients is scant. In addition our work, provides a crude but invaluable direction for future clinical management and basic science research protocols.
Utilization of automated eye tracking as an ancillary diagnostic test in neurological disorders.
(2024) Karimi, Hadi.; Moodley, Anandan Angamuthu.
Modern eye-tracking technology, a non-invasive modality that records eye movements in response to visual stimuli, has shown significant promise as a diagnostic tool for neurological disorders. Its capacity to detect subtle abnormalities in ocular motor function, often linked to underlying neural circuitry dysfunction, provides a distinct advantage over traditional bedside examinations, which may overlook these nuances and typically require more advanced or invasive diagnostic modalities. Moreover, these advanced methods are not always readily available in routine clinical practice and may not capture the valuable insights that eye-tracking can provide. Despite its potential, the application of eye-tracking has largely remained confined to research settings, often restricted by a narrow focus on specific neurological conditions and a reliance on individualized data analysis. This has impeded its broader adoption in clinical neurology, where standardized, scalable, and automated diagnostic tools are essential. In this project, we aimed to bridge this gap by developing a comprehensive and automated Diagnostic Eye-Tracking Study (DETS) tailored for routine clinical practice. We established standardized protocols incorporating relevant visual stimuli and tasks, and defined biometrics that are both informative and practical for clinical neurology. Additionally, we developed an advanced analytical software platform capable of generating both quantitative and qualitative results, ensuring robust and clinically relevant interpretations. To validate our approach, we conducted a pilot study that demonstrated the efficacy and feasibility of the protocols, as well as the validity and reliability of our automated analytical software. The study confirmed that our approach offers a valuable ancillary tool to enhance diagnostic accuracy across a range of neurological disorders. By integrating this tool into standard neurological assessments, we anticipate a significant improvement in patient outcomes.