School of Health Sciences

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Comparative study of covalent & non-covalent drug inhibitory mechanism investigation: targeting HSP72 protein in cancer therapy using molecular modelling techniques.
(2021) Aljoundi, Aimen Khalefa Misbah.; Soliman, Mahmoud Elsayed Soliman.
Cancer is the most complicated and diverse disease that has been menacing human beings worldwide. Up to date, important advancement has been done to improve the existing therapeutic interventions in the treatment and management of cancer. However, the side effect of these drugs that are mostly associated with the “off-target” effects is a perpetual failure in cancer drug development. Therefore, efficient regimen with minimal toxicities and high drug target selectivity should be achieved. Covalent inhibition is an emerging field in drug discovery and a very distinct category of therapeutics that reduces adverse side effects and possible interactions that lead to drug resistance due to its attainable reactivity and high selectivity. The Heat shock proteins (HSPs) play a crucial role in the clearance of damaged proteins by encouraging proteotoxicity and proteins acclamation. This process occurs by avoiding unsuitable stress-induced protein aggregation, ensure suitable refolding of denatured proteins, and promoting their degradation; thus, the involvement of this enzyme in many human diseases, including cancer. In this study, we delve into the structural features of one of the most crucial enzymatic targets of the stress proteins, the Heat shock proteins72. In drug development, the integration of computational techniques including molecular dynamic simulations, docking and molecular modelling has allowed drug developers to screen and syntheses millions of compounds and thus screen out possible lead drugs. Computer-Aided Drug Design has been validated as a cost-effective strategy to fast trace the drug discovery process due to these in silico methods. One of the characteristics of the HSP72 is its ability to be targeted either covalently or non-covalently through small drug molecules. Therefore, the above-mentioned methods, amongst several other computational tools were employed out in this study to provide insights into conformational changes that explain potential covalent and non-covalent inhibitory mechanisms, binding sites assessment features leading to promising small molecule inhibitor candidates. These combinatorial computational studies offer an inclusive in silico perspective to fill the gap in drug design studies about targeting protein degradation, thus providing insights toward the structural characteristics of the pivotal target and describing promising drug developments.
Integrating knowledge-to-practice for occupational therapists working with high-risk infants in the KwaZulu-Natal public health sector: a qualitative explorative inquiry.
(2020) Dawood, Ayesha.; Naidoo, Pragashnie.; Ogunlana, Michael Opeoluwa.; Rencken, Gina.
Introduction: Neonates are an at-risk population due to their increased susceptibility of mortality and morbidity. Occupational therapists have an important role in Early Childhood Intervention (ECI) and implementing Neurodevelopmental Supportive Care (NDSC) for high-risk infants whilst they are admitted in the Neonatal Intensive Care Unit (NICU). To the best knowledge of the author there is a paucity of literature available within the South African context in the use of evidence-based practices (EBP), and the integration of knowledge translation (KT) amongst occupational therapists who provide therapeutic management to high-risk infants and their families. Aim: This study aims to explore the knowledge to practice gaps experienced by occupational therapists who support high-risk infants in different levels of care in the public health sector of KwaZulu-Natal South Africa. Methods: A qualitative exploratory research design was used for this study. A nonprobability sampling technique was used. Seventeen occupational therapists who have more than two years of experience and are employed on a full-time basis in the public health sector of KZN participated in this study via online focus group discussions. Data were analysed using thematic analysis with inductive deductive reasoning, guided by a combined theoretical framework using the Appreciative Inquiry (AI) approach and KT process as a methodological orientation to the study. Research Ethics: Principles of confidentiality, autonomy, informed consent, beneficence, non-maleficence, and justice were adhered to. Participants were not of a vulnerable population and therefore support was not offered upon completion of the research discussions. Results: Five themes emerged in this study, namely, occupational therapy (OT) and neonatal care in the public health sector, Knowledge Acquisition and Knowledge Synthesis, Knowledge Translation/Utilization, Contextual barriers/adaptation, and the ideal OT in the ideal neonatal setting. Therapists outlined the facilitators, inhibitors, referral pathways and their personal interests in OT neonatal care. Supportive management and multidisciplinary teams (MDT) were highlighted as facilitators in the hospital environment whilst OT staff shortages, insufficient undergraduate training in the field and a lack of funding for courses for postgraduate OT training were regarded as inhibitors to practice. OTs source and synthesise knowledge from multiple sources to integrate, utilise and translate into neonatal practice. Contextual barriers are identified in various levelled facilities with acquired neonatal knowledge being adapted by therapists for low resourced settings. Participants envision the dream of the ideal day and therapist to intervene with neonates in the public health sector of KZN. Conclusion: Findings have identified several knowledge-to-practice gaps for OTs who support neonates in low resourced settings. Therapeutic resources and funding for postgraduate training, an improvement in the undergraduate curriculum, and policy development appear to be necessary to inform a standard of care across the province.
Nanoencapsulation of novel pyrazolone-based compounds to enhance solubility and biological activity.
(2022) Igbokwe, Nkeiruka Nkeonyere.; Faya, Andile Kennedy Mbuso.; Karpoormath, Rajshekhar.
The biological activity of pyrazolone-based derivatives has been thoroughly documented; nonetheless, low stability and water solubility are their main drawbacks, preventing effective translation to clinical application. Based on this, two previously reported weakly soluble pyrazolone-based compounds, PBC-301 and PBC-302, were encapsulated using PLGA: poloxamer complex to improve their solubility and further examine the influence of solubility augmentation on their biological activities. We first developed and validated a simple, accurate RP HPLC-PDA method for detecting, measuring, and standardising the compounds in nanoformulations to achieve this wide goal. Efficient separation and quantification were carried out using Shim-pack GIST C18 (5 𝜇m 150 × 4.6 mm) column, maintained at 25 ℃ with isocratic elution using acetonitrile and acidified water (0.1% Trifluoracetic acid) (75:25 v/v) at 0.5 mL/min flow rate. The injection volume was 20 𝜇L, and eluents were detected at 333 nm at a retention time of 4.82 mins. Method validation was done following ICH guidelines. Results demonstrated that the method is specific, precise, and accurate within the recommended limits. The method showed good linearity with a 0.9994 correlation coefficient over a concentration range of 2.5-50 𝜇g/ml. The method efficiently detected and quantified the novel pyrazolone compound in the nanosuspension. The obtained nanoformulations PBC-PLGA 301 and PBC-PLGA 302 were characterised using various in vitro techniques. Size, PDI and ZP of the optimised nanoformulations were 166.6 ± 7.12 nm, 0.129 ± 0.042, -14.14 ± 2.90 mV for PBC-PLGA 301 and 192.5 ± 1.08 nm, 0.132 ± 0.025, -10.77 ± 1.515 mV for PBC-PLGA 302 with the encapsulation efficiency being 84.20 ± 0.930 and 81.5 ± 2.051, respectively. The compound release from the nanovesicles followed a sustained release pattern, with PBC-PLGA 301 and PBC-PLGA 302 attaining a cumulative release of approximately 37% and 53% in 48 hours. The biological activity assays showed a better-enhanced activity with the nanoformulations compared to the non-encapsulated PBC 301 and PBC-302. In vitro antibacterial activity revealed that the compound-loaded nanovesicles have better activity against the two gram-positive bacteria S. aureus and Methicillin-resistant S. aureus compared to the standard drug vancomycin and the non-encapsulated compound. On the other, the cell penetration assay further revealed that the compound-loaded nanovesicles achieved greater than 90% propidium iodide penetration (translating to cell death) at the reported MIC well for S. aureus while showing 86% and 89% cell penetration for Methicillin-resistant S. aureus. Also, the nanoformulations showed improved radical scavenging activity in a concentration-dependent manner, with PBC-PLGA 301 exhibiting the best antioxidant activity against DPPH, FRAP and nitric oxide compared to the standard antioxidant-gallic acid and the non-encapsulated compounds. In conclusion, the aqueous solubility of the two pyrazolone compounds, PBC-301 and PBC-302, was greatly enhanced by their encapsulation into a nanosystem, resulting in improved biological activities. Therefore, the nanoformulations of the pyrazolone-based derivatives can be exploited as potential pharmaceutical agents to fight bacterial infections and other diseases triggered by oxidative stress, cancer, and hepatic and vascular diseases. The data from this study has resulted in two first-authored research publications.
Operationalizing family quality of life: occupational therapy outcome measurement for South African forensic psychiatric rehabilitation.
(2020) dHangest dYvoy, Margaux Louise.; Fewster, Deborah Leigh.
Background: Families of forensic mental health care users (MHCUs) experience a great burden of disease. Families of forensic MHCUs in KwaZulu-Natal, South Africa, are identified as the primary community based support system. Relevant psycho-social rehabilitation and support services are required to empower the family as the primary community based support structures, for successful community reintegration and role re-acquisition of young adult forensic MHCUs to be achieved. Occupational therapists (OTs) have had a limited role in forensic “family work” in achieving family-centred health outcomes. Health outcomes have not been developed for occupational therapy practice to direct strategic family-centred rehabilitation. Family Quality of Life (FQOL) has been identified as a strengths-based family outcome which could be used in forensic mental health care. Operationalization of a unique occupation-based FQOL construct was required to inform outcome measurement tool development ensuring family-centred effective and efficient service delivery in the future. Research aim: This study aimed to identify and operationally define FQOL in the development of a FQOL outcome measurement tool that could direct family centred OT services for MHCUs and their families within a forensic psychiatric facility setting in KwaZulu-Natal, South Africa. Method: A qualitative research strategy was used to establish the meaning of FQOL, particularly, an interpretivist qualitative research design. Focus groups of experts (mental health care professionals, forensic MHCUs, and family members) attributed meaning to the existing FQOL construct. A hybrid of inductive and deductive data analysis was necessary to operationalize this construct for application to forensic mental health outcome measurement tool development. Results: An operational definition of the occupation-based FQOL construct using an occupational lens for evidence-based forensic mental health OT practice, was developed. FQOL operational definition(s) of the construct, themes, sub-themes, domains, and sub-domains were formulated and presented in a meaning map of meaning attributed by expert participants. This novel construct consists of two (2) themes (family unit factors, and individual member factors), their related sub-themes (e.g. family unit factors’ sub-themes: family characteristics, family dynamics, and external family unit support) and domains addressing pertinent areas of family life contributing to a collective FQOL experience of forensic MHCUs and their family members. Findings merged FQOL and OT frameworks for application to forensic mental health as compared to previous disability fields of inquiry. A diagrammatic presentation of the novel FQOL construct using an ecological perspective iv displays pertinent areas of family life requiring support by OTs rendering psycho-social rehabilitation. Conclusion: OTs practicing within the specialist forensic mental health facility in KwaZuluNatal, South Africa, are hereby presented with an operationalized FQOL health outcome which could direct evidence-based, family-centred, strengths-based, and support-orientated service delivery, strategically positioning the profession in community-based rehabilitation.
Zulu cultural perspectives and experiences of mental health and occupational therapy in KwaZulu Natal, South Africa.
(2022) Moonsamy, Ashira.; Lingah, Thanalutchmy.; Gurayah, Thavanesi.
Background: Healthcare systems are formulated utilising worldviews, specifically in mental health, where norms are created dictating what is normal versus abnormal. The era of coloniality promoted western dogma over collectivist cultures. Occupational therapy practice must consider the client’s context during assessment and intervention for the process to be client centred. Methods: A qualitative descriptive design was utilised. Purposive sampling was used to recruit 10 participants. Data was collected through semi-structured interviews. Analysis was guided by utilising Braun and Clark’s six phases of thematic analysis. Findings: Three themes emerged from the data, personal perceptions, cultural perceptions, and health-seeking behaviour. Sub-themes accompanied each. Personal perceptions explored how Zulu people made sense of mental illness or related behaviours through a modern or traditional lens. It also explored the importance of the strength of the Zulu individual. A dissonance occurs when faced with cultural norms and personal needs. Finally, their perspectives were altered through their experience with mental illness. Cultural perceptions were that problems were solved internally in families or communities, and progress was promoted as necessary for the Zulu individual. It also explored spiritual beliefs regarding mental illness, which could range between God, Ancestors or both and could be causal factors or healing mechanisms. Suicidality is seen as a weakness in the culture, and stigma was attached to mental illness. The final theme concerns the experience of the Zulu mental health care user dealing with their mental illness. Cognitive dissonance is prevalent in all three aspects not merely due to the difference between westernised mental health treatment and traditional healing systems but also due to the value found in each. The method of sharing vulnerability or issues with an individual outside the family contradicts cultural norms. However, participants expressed that being understood in group discussions and sharing vulnerability significantly improved their healing. Conclusion: Zulu individuals create their sense of self in an interdependent manner. The family and community are intertwined in their participation, reputation, and healing. There is an emphasis on strength and the following of norms in the Zulu culture, perpetuated by the importance of consulting elders or close family when faced with conflict. Disregarding these norms can outcast the Zulu individual who thrives on being included in the community. The study was conducted with a limited sample size and in an urban area. Further research within rural communities and diverse facilities would be beneficial. Occupational therapists working in communities such as KwaZulu Natal should understand the causal factors of mental illness for the Zulu mental health care user and their personal beliefs around healing when designing an intervention.

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