MSUIR Collection:

Towards the development of an indigenous psychological trauma model for war veterans in Zimbabwe

2022-06-27T13:49:07Z

Title: Towards the development of an indigenous psychological trauma model for war veterans in Zimbabwe Authors: Mutambara, Julia Abstract: Literature has shown that war has negative psychological consequences and long-term effects on war veterans that can be passed on from generation to generation. Little is known about Zimbabwe war veterans` conceptualisation of trauma. The study was aimed at developing a culturally appropriate psychological model for Zimbabwean war veterans. The research objectives were; 1)To explore the Zimbabwean war veterans’ conceptualisation of complex trauma. 2)To establish how Zimbabwean war veterans cope with complex trauma in their lives. 3) To develop a culturally relevant psychological trauma model for war veterans in Zimbabwe. The study was qualitative and the phenomelogical research approach was adopted. The research was informed by the Afrocentric paradigm. Criterion sampling was used to select twenty-six participants. Sixteen individual interviews and two focus group discussions were conducted. Data were analysed using thematic content analysis. The research revealed five major themes covering the experiences of complex trauma among war veterans in Zimbabwe. These themes are social, economic, spiritual, political and personal trauma. Research findings also identified cultural notions of trauma. The participants` had their own way of conceptualising trauma in their local language. The following broad themes that described the participants` coping strategies were identified; appraisal coping, social coping, problem focused coping, emotion focused coping and spiritual coping. Their coping strategies were informed by their culture, experiences and social context. From these themes a cultural model of trauma was developed. The model is unique as it acknowledges the importance of the cultural context in the conceptualisation of trauma and the need to be knowledgeable about local constructs, meanings and languages that inform world views. The model validates propositions by the Afrocentric paradigm that trauma in African contexts is multifaceted. The study recommends the need to be culturally sensitive to understand an individual`s behaviour, explanations of distress, symptom presentation and coping strategies. The study recommends a holistic and contextual approach when intervening among war veterans in Zimbabwe.

Mechanistic modulation of a bifunctional GC-linked receptor kinase, PSKR1

2022-06-27T13:49:07Z

Title: Mechanistic modulation of a bifunctional GC-linked receptor kinase, PSKR1 Authors: Muleya, Victor Abstract: Receptor kinases possessing intrinsic guanylate cyclase (GC) activity constitute a family of catalytically active membrane-bound proteins that play crucial roles in a myriad of signal transduction processes. Currently known GC-linked receptor kinases have an extracellular ligand-binding domain and an intracellular portion that is composed of an inactive kinase homology domain and a functional GC catalytic centre. A novel class of GC-linked receptor kinases was unearthed using homologyguided bioinformatic data mining tools designed from annotated amino acid residues in the GC catalytic centres of lower eukaryotes. The GC catalytic centre in this new class of receptor kinases is encapsulated within an active kinase domain, thereby conferring a dual catalytic function to this class of proteins. This is contrary to currently known classical GC-linked receptor kinases, which are mono-functional. There are currently four members of this novel class of receptor kinases which have been demonstrated to possess intrinsic GC and kinase activity. However, there is a paucity of information as to how this dual catalysis is physiologically regulated. In an attempt to uncover the modulatory mechanisms regulating the dual catalysis of novel GC-linked receptor kinases, this thesis examines the elements influencing the dual catalysis of the phytosulfokine receptor, PSKR1. Most specifically, this study focuses on how receptor dimerisation, phosphorylation, and the effect of intracellular signalling molecules like calcium and ATP influence PSKR1’s intrinsic dual catalysis. Analytical ultracentrifugation and size exclusion chromatography have demonstrated that the recombinantly expressed cytoplasmic domain of PSKR1 is reversibly dimeric in solution. This observation probably represents a catalytically competent iv physiological arrangement of the receptor that may be a pre-requisite for PSKR1- mediated nucleotide cyclase and phospho-transferase activity. Mapping out of the phosphorylation pattern in the cytoplasmic domain of PSKR1 using tandem mass spectroscopy identified 14 phosphorylation sites; eight phosphoserines, three phosphothreonines and three phosphotyrosines. Further in vitro studies revealed that PSKR1 is capable of self-phosphorylating and that phosphorylation is essential for PSKR1-mediated dual catalysis. Apart from its obvious role in phosphorylation, ATP seemed to potentiate the nucleotide cyclase activity of PSKR1, possibly through allosteric modulation. Intriguingly, calcium had a direct influence in regulating PSKR1-mediated dual catalysis without the aid of calcium sensor proteins such as calmodulin. At physiologically high calcium concentrations, PSKR1’s nucleotide cyclase activity was enhanced while on the other hand the phospho-transferase activity of PSKR1 was significantly suppressed. This observation points to calcium acting as a molecular switch regulating the dual catalysis of PSKR1. Taken together, the findings obtained in this study informs a proposed model of how all these regulatory elements modulate PSKR1-mediated dual catalysis. In summation, the presence of catalytically relevant motifs within functional protein domains allows signalling proteins to self-regulate and fine-tune their signal output in concert with their immediate cellular environment. This necessitates the need for prospective studies to carry out similar bioinformatics search strategies in order to uncover hidden regulatory elements that facilitate the self-regulation of proteins.

Left ventricular hypertrophy and its detection in an African community

2022-06-27T13:49:07Z

Title: Left ventricular hypertrophy and its detection in an African community Authors: Maunganidze, Fabian Abstract: Left ventricular hypertrophy (LVH), the detection of which is recommended for routine risk prediction by all guidelines, is more prevalent in groups of African ancestry. This is in-part attributed to higher prevalence rates of obesity. The ability to detect LVH using electrocardiographic (ECG) criteria may be modified in groups of African ancestry. The impact of co-existent obesity on the ability to detect ECG-LVH in this ethnic group has not been determined. Moreover, whether estimated glomerular filtration rate (eGFR) or serum C-reactive protein (CRP concentrations are independently associated with LV mass index (LVMI) and can therefore be used to complement ECG criteria for LVH detection is uncertain. ECG voltage criteria for the detection of echocardiographic LVH were evaluated in 661 participants from a community sample of African ancestry (43% obese). Body mass index (BMI) was inversely associated with Sokolow-Lyon (SL) voltages (partial r=-0.27, p<0.0001) and no BMI-Cornell voltage relations were noted (p=0.21). BMI was associated with voltage criteria that incorporate only limb lead recordings (r=0.17-0.23), but these relationships were weaker than BMI-LVMI relations (r=0.36, p<0.01-p<0.0001 for comparisons of r values). All ECG criteria were as strongly related to blood pressure (BP) as LVMI. Sokolow-Lyon voltage-LVMI relations were noted only after adjustments for BMI (p<0.02) and SL voltages showed no performance for LVH detection. Cornell voltages showed significant performance in the non-obese (area under the receiver operating curve [AUC]=0.67±0.04, p<0.0005), but not the obese (AUC=0.56±0.04, p=0.08). ECG criteria which employ limb-lead recordings only (e.g. RaVL) showed better performance in non-obese than obese (AUC=0.75±0.04 and 0.59±0.04 respectively, p<0.005 for comparison) and markedly reduced specificity for LVH detection in obese (76%) than non-obese (92%, p<0.0001) despite similar sensitivities (32 vs 29%). Thus, in groups of African ancestry, obesity contributes toward a poor validity and performance of all voltage criteria for the detection of LVH. None of the current criteria are recommended for use in obesity in groups of African descent. Alternative approaches are required for LVH detection in these groups.In 621 randomly selected participants from the community sample [332 were normotensive (NT)], eGFR was associated with LVMI and LVM in excess of that predicted from stroke work (inappropriate LVM, LVMinappr) in all participants (LVMI: partial r=-0.18, p<0.0001; LVMinappr: partial r=-0.17, p<0.0001) and NT (LVMI: partial r=-0.23,p<0.0001; LVMinappr: partial r=-0.22, p<0.0001) separate from hypertensives. When replacing clinic BP with either aortic systolic BP (applanation tonometry and SphygmoCor software), 24-hour BP, aortic pulse wave velocity (PWV) (applanation tonometry and SphygmoCor software), stroke work (for LVMI), LV end diastolic diameter (LVEDD), or circumferential wall stress in the regression models, eGFR retained strong associations with LVMI (p=0.01 to <0.0001) and LVMinappr (p<0.005 to <0.0001). Thus, strong relationships between eGFR and LVM occur at a community level irrespective of the presence of hypertension and independent of 24-hour and aortic BP, PWV, LVEDD,stroke work and wall stress. The independent relationships between eGFR and LVMI, support the notion that eGFR may be evaluated for LVH detection. In 361 randomly selected participants from a community with a high prevalence of CRP concentrations considered to be high-risk (54.0%), but without cardiovascular or renal disease, serum CRP concentrations were correlated with both LVMI and LVMinappr (p<0.0001). With adjustments for a number of potential confounders including age, systolic BP, waist circumference (or BMI), and glucose control (glycated haemoglobin), the relationships between serum CRP concentrations and both LVMI and LVMinappr (partial r=0.11, p<0.05 for both) persisted. The independent relationship between CRP and LVMI or LVMinappr translated into a higher multivariate-adjusted LVMI and LVMinappr values in the highest as compared to the lowest quartile of CRP (LVMI; highest quartile CRP=48.8±10.7, lowest quartile CRP=45.0±11, p<0.05; LVMinappr; highest quartile CRP=137±24, lowest quartile CRP=127±24, p<0.05). The independent relationships between CRP and LVMI, support the notion that CRP may also be evaluated for LVH detection. In 358 participants from a randomly selected community sample with a high prevalence of obesity (41%), a combination of CRP concentrations and eGFR above or below the median for the sample respectively showed significant performance (AUC=0.61±0.03, p<0.0005), but a low specificity for LVH detection (77%). When eGFR and CRP concentrations were employed to complement RaVL, although the overall performance did not improve (AUC=0.71±0.03, p<0.0005, RaVL alone: AUC=0.70±0.03), the specificity increased (93%) whilst sensitivity (25%) was in-line with previously reported sensitivities for LVH detection using ECG criteria in alternative population samples. Without changing overall performance, eGFR together with RaVL increased the specificity to 88% and CRP concentrations when considered together with RaVL increased the specificity to 87%. Thus, in a community sample where the specificity and performance of ECG criteria for LVH detection are poor, the use of eGFR and/or CRP concentrations to complement ECG criteria increase the specificity without altering the overall performance. In conclusion, the present thesis provides evidence to indicate that current ECG criteria for the detection of LVH are invalid in obese individuals of African ancestry, but that clinical markers of renal dysfunction and systemic inflammation, which are associated with LVMI independent of haemodynamic factors and co-morbidities may be employed to complement ECG criteria to improve the specificity for LVH detection.