Medicine

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Conditions associated with levels of allergens and fungal aerosols in selected homes of selected primary school children in Durban.
(2007) Jafta, Nkosana.
This indoor environment study formed part of the South Durban Health Study (SDHS) that investigated the health effects of exposure to ambient air pollution. Homes of children from seven communities corresponding schools were recruited to participate. This study was designed to determine characteristics in the homes that are associated with higher or lower levels of allergens and fungal aerosols. Homes were inspected using a field tested walkthrough checklist to collect data on home characteristics associated to adverse health effects. The characteristics include dampness, visible mould, type of flooring, type of bedding, type of heating systems, and building type and age. Dust samples for allergen analysis were collected from the bedding and the floor of the sleep area used by the children. Air samples from all rooms in the house were collected on malt extract agar, the media used for identifying and quantifying airborne fungal aerosols. More than 70% of the homes were single units standing on their own, 20% were attached houses (flats or apartments) and the rest (10%) were informal houses. Construction material of the homes comprised of bricks (93%), wood (5%) and other material (2%) such as corrugated iron of which 94% were formally constructed. Dampness signs were observed in 51% of the homes and visible mould growth 13% of them. In all them, at least one characteristic that is hypothetically associated to elevated house dust mite allergens was found. Levels of mould (Asp f 1) allergen and house dust mite (Der p 1 and Der f 1) allergen were comparable to levels found in other parts of the world. Asp f 1 allergen levels ranged between 0.32-1.379g/g and Der p 1 and Der f 1 allergen levels ranged from undetectable to 49.61 and from undetectable to 39.319g/g of dust respectively. Some home characteristics from walkthrough checklist were associated with Asp f 1, Der p1 and Der f 1 allergen levels when simple regression analysis was performed. Asp f 1 was significantly associated with single family home [OR= 0.004 (95%CI 0.004–0.35)] and polyester filled pillows [OR= 0.07 (95%CI 0.01– 0.61)] in logistic regression models. Der p 1 allergen was associated with observed extent of roof dampness [OR= 0.33 (95%CI 0.13–0.81)]. Fungal aerosol mixture consisted of Cladosporium spp. as the predominant genus together with other genera such as Aspergillus, Penicillium and Fusarium were, to a lesser extent, identified in the samples from the homes. Mean concentration of total indoor fungal aerosol of indoor and outdoor were 1108 CFU/m3 and 1298 CFU/m3 respectively. Individual genera of fungi in the childrens sleep area had mean levels of 783 CFU/ m3, 30CFU/ m3, 64CFU/ m3, 48CFU/ m3 and 43 CFU m3 for Cladosporium spp., Aspergillus spp., Penicillium, spp., Fusarium spp. and Rhizopus spp. respectively. Simple regression showed some conditions in the homes to be predictors of higher levels of total fungal aerosols. In a linear regression models, total outdoor fungal levels were a protective effect on total indoor fungal levels [C= 0.542 (95%CI 0.437–0.647)] whilst homes with hard floors had about 25 CFU/m3 [C= 5.235 (95%CI 0.557–9.913)] in the homes were significantly associated. This study showed the need to adapt observational instrument/ checklist/ questionnaire to suit the environment or the study area of interest. As other studies and findings indicated, the best way to assess exposure to biological pollutants indoors needs a combination of two or more methods, i.e. direct and indirect methods.
The clinical natural history of snakebite victims in Southern Africa.
(2000) Blaylock, Roger.; Robbs, John Vivian.
The author wrote a dissertation for the Mmed Sc degree entitled The Clinical Natural History of Snakebite in Southern Africa, which dealt with the epidemiology of snakebite and the clinico-pathological events in snakebite victims. This thesis is a sequel on the management of snakebite victims. Publications on the overall management of snakebite in the Southern African region that include original scientific research are those of F.W. Fitzsimons (1912), F.W. Fitzsimons (1929) (assisted by V.F.M. Fitzsimons), P.A. Christensen (1955, 1966, 1969) and Christensen & Anderson (1967). Subsequent books, pamphlets and journal articles have rehashed this knowledge or advocated methods of treatment developed in other countries. An example of the latter is the pressure immobilisation prehospital measure advocated for snakebites in Australia (Sutherland et aL, 1979, 1981, 1995), which I regard as benefiting less than 1% of snakebite victims here and being deleterious in most cases. In view of the paucity of research done in Southern African in recent years, many questions remain unanswered, and some strongly held views are without logical or scientific foundation. Most of these questions arose prior to the writing of this thesis, and others arose when the data were analysed. The following are some questions on the management of snakebite that have still have to be addressed. Is vaccination against snakebite possible and practical? Are folk and traditional remedies advantageous or deleterious? How commonly are they used? Immobilisation of the bitten part and the patient is an internationally recognised aid measure, but is this relevant to the Southern African situation? Tourniquet use in the case of necrotising venoms is considered to aggravate or precipitate necrosis. Does immediate active movement following a bite ameliorate or prevent necrosis without increasing mortality? The majority of clinicians recommend antibiotic prophylaxis, but is this necessary for all snakebites, against which bacteria should antibiotics be administered, and what is the source of these bacteria? Should antivenom be administered to all snakebite victims: for species-specific bites, only if envenomation is present, for severe envenomation, or not at all? Acute adverse reactions to South African manufactured snakebite antivenom has been variously recorded as less than 1% (Visser & Chapman 1978) up to 76% (Moran et al., 1998). What is the truth? Is syndromic management of snakebite efficacious or is it essential to identify the particular snake species? Is the present liberal use of fasciotomy necessary? Is there an optimum time to debride necrotic areas and is surgery necessary at all? Is paresis or paralysis due to neurotoxic envenomation always the result of a post-synaptic block? Would such a block respond to neostigmine or prostigmine in a similar way to post-synaptic anaesthetic muscle relaxants? Is heparin of value when procoagulant toxins induce a consumption coagulopathy? Do fibrinstabilising agents or fibrinolytics have a role? Does the management of pregnant snakebite patients differ from that of non-pregnant patients? Is snake venom teratogenic? Does snake venom ophthalmia frequently lead to blindness? Are steroids, NSAIDs and antihistaminics, which are commonly used in the management of snakebite, of proven value? This thesis attempts to answer these questions and more, and comprises six sections. The first section deals with pre-hospital management, the second with infection which may occur at the bite site wound, the third with SAIMR snakebite antivenom, the fourth with the three envenomation syndromes, the fifth with snakebite in pregnancy, venom ophthalmia and other treatment modalities, and the sixth section includes a summary, appendix and references. Unless otherwise stated, the materials and methods of each chapter are based on 336 snakebite victims admitted to Eshowe Hospital, KwaZulu-Natal, from January 1990 - July 1993 and other victims treated by the author, the data of which have been prospectively maintained. This has been an ongoing process up to the present time.
Human T cell lymphotropic virus 1 associated infective dermatitis in KwaZulu-Natal, South Africa.
(2008) Hlela, Carol.; Mosam, Anisa.
Background Human T cell Lymphotropic Virus Type I (HTLV-I) associated infective dermatitis, first described by Sweet in Jamaican children, is a pattern of eczema characterized by exudation, crusting around the nostrils, ears and scalp with eventual appearance of a generalized fine papular rash. More recently LeGranade and co-workers have proposed major and minor criteria in establishing the diagnosis of HTLV-I associated infective dermatitis (HAID). HTLV-I has been aetiologically linked to Adult T cell leukaemia/lymphoma (ATLL) and tropical spastic paraparesis (TSP). HAID is not only a marker of childhood infection with HTLV-I but may be a harbinger of more serious HTLV-I associated diseases later on in life such as ATLL or TSP. The pathogenesis of HAID is poorly understood so are the histopathological features of this entity. The effects of co-infection with human immunodeficiency virus- 1 (HIV-1) are inconclusive. HAID is described in Sub Saharan Africa, Senegal but no data is published on this entity in Southern Africa, characterizing the clinical, laboratory features and the histopathology of this entity. Aims and Objectives 1) To describe the clinical and histological features of HTLV-I associated infective dermatitis in KZN, South Africa 2) To determine the virological characteristics of HTLV-I in KZN, South Africa 3) To assess for HTLV-I / HIV co-infection Methods This was a prospective study of all patients with HAID who presented to King Edward VIII hospital (KEH), outpatient department over a period of 42 months. These were patients who fulfilled the clinical criteria of HAID. Enrolled patients were subjected to a confirmatory HTLV-I serology testing. Demographic data was obtained from all HTLV-I seropositive patients. Their clinical examination included dermatological, neurological and pathological examination. A blood count, immunoglobulin levels, serum protein electrophoresis measuring albumin levels and globulin fractions were measured. For bacteriological assessment skin swabs were taken from the affected sites with stool samples examined for parasites, ova and cysts. The HIV-1 status together with HIV-1 viral load were determined on those enrolled. The CD4 count, CD8 counts and CD4/CD8 ratio were also calculated. Skin biopsies were taken for histological examination. PCR for HTLV subtyping was performed on a subset of the cohort. Results Demography Of the 60 patients recruited, 33 fulfilled criteria for HAID. The majority of patients fell between age categories of 6 to lOyears. The male to female ratio was 1:1. There were more females in the adult group than there were within the childhood group. All of the patients in our cohort were African. Clinical features The lesions were erythematous, scaly, exudative, and crusted in all cases. The distribution of lesions was as follows: scalp (77.4%), retroauricular areas (71%), the axilla (65%) and paranasal areas (58%) were the sites more commonly affected. Nasal crusting was not a significant feature in this series. Bacteriology Culture was positive for Staphylococcus aureus (S. aureus) in 90%, with streptococcal group of organisms found in 68% of the skin swabs taken from the lesional skin. Haematological Our patients were mildly anaemic as has been shown in previous studies. They had a mean Hb of 11.5g/dl. In 12 of the 14 patients tested, the erythrocyte sedimentation rate (ESR) was elevated. Serum protein electrophoresis and levels of Immunoglobulin A, G and M were raised. The mean CD4 count in the entire group was elevated at 1730 cells/fil, CD8 was 1299 cells/ul Histopathology The major histological findings were as follows: 38% demonstrated a superficial and deep perivascular inflammatory infiltrate, 28% had a superficial and deep perivascular inflammatory infiltrate together with a lichenoid dermatitis, 12.9% had features of superficial and deep inflammatory infiltrate with an interface dermatitis, 6.4% revealed features of seborrhoeic dermatitis. Genotyping Our patients were infected with the strains belonging to the Cosmopolitan, A Subtype (HTLV-Ia). Complications Complications were low in this series with the commonest being scabies in 6(18.1%), corneal opacities in 3(8.6%), 2(6 %) with HAM/TSP. No parasitic worm infestations were isolated. HIV/HTLV-I co-infection Of the 33 patients, 9 (30 %) were co-infected with HIV. The mean viral load in this group was 52 000 copies/ml. Their mean CD4 count was also elevated at 1505cells/^il with a CD8 of 1704 cells/Mi and a CD4/CD8 ratio of 1.15. Discussion Thirty three of the 60 patients enrolled met the diagnosis for HAID according to the established criteria. The mean age in this series was 17 years (range: 8 months-46 years)however; almost a third (30.3%) were children under 12 years, reinforcing the entity as a childhood infective condition. There was an equal male female distribution in the childhood group and a female predominance in the adult group. Clinically patients presented with infected erythematous, scaly lesions mainly on the scalp, neck and post- auricular area. The clinical features were in keeping with other series worldwide. The complication rate was low in our cohort. S. aureus was the predominant organism in both anterior nares and lesional skin. The most common histological pattern was superficial and deep perivascular inflammatory infiltrate. The subtype in our series was the Cosmopolitan Subtype A (HTLV-Ia) as opposed to subtype B in Japan. We share with Brazil a common subtype. A subset of our patients (30%) was co-infected with HIV. The CD4 cell count in this subgroup was lower than the entire group but this was not statistically significant. The histological patterns found in this subgroup infected with HIV were similar to the rest of the group except for a more intense eosinophilic infiltrate in these skin biopsy specimens. Conclusion HTLV-I associated infective dermatitis is distinct entity which affects the African population of KwaZulu Natal, South Africa. It is predominantly a disease of childhood with an equal female to male ratio in children. The clinical features are an exudative, erythematous scaly rash most commonly found involving the scalp, axillae, paranasal and retroauricular areas. HTLV-I positivity is essential for the diagnosis; the Cosmopolitan Subtype A is commonest in South Africa. The commonest histological pattern is a superficial and deep perivascular infiltrate in 38%. A subset, 30%, was co-infected with HIV.
Impaired glucose tolerance (IGT) : a study in South African Indians in Durban.
(1990) Motala, Ayesha Ahmed.
No abstract available.
Isolation, identification, immunolocalisation and elucidation of the role of plasma kallikrein in human tissues.
(2000) Cerf, Marlon Eugene.; Raidoo, Deshandra Munsamy.
Introduction: Plasma kallikrein (PK) is a cofactor in blood coagulation and modulates inflammation through the release of bradykinin (BK). Previously it was believed that plasma prekallikrein (PPK), the precursor of PK and a member of the serine protease superfamily, was synthesised exclusively by hepatocytes and secreted into circulation. However, recent studies show that various human tissues contain PPK mRNA. In this study we sought to determine in which human tissues PK is expressed. Methods: Following approval by the Ethics Committee at the University of Natal, tissue samples from the spinal cord, 13 different regions of the brain, 7 different blood vessels and various other organs were collected at autopsy within 24h of death (n =10). Sections were probed using polyclonal antibodies specific for PK. PK concentrations in extracts of these tissues were measured by competitive EllSA. Results: A Western blot analysis demonstrated the monospecificity of the antibody for the PK protein. The presence of immunoreactive PK in cells of the pancreatic islets of Langerhans served as a positive control for each immunolabeling experiment. The hepatocytes, renal distal convoluted tubules and epithelial cells lining the bronchiole and pulmonary alveoli labeled positively for PK. In the gastrointestinal tract tissue, immunoreactive PK was visualised in the acinar cells of the salivary gland, in stromal and glandular duct cells of the oesophagus, and in some chief and glandular cells in the stomach. Some of the above-mentioned tissues contained a few inflammatory cells which stained intensely for PK. Immunoreactive PK was visualised in the endothelial cells and smooth muscle cells of the all the blood vessels examined, except the renal vein. Increased immunolabeling for PK in the endothelial cells, foam cells and macrophages was observed in arteries with atheromatous plaques. In neural tissue immunoreactive PK was observed in neurons, ependymal cells, fibre tracts, and in secretory cells of the anterior pituitary gland. Immunolabeling for PK was visualised in some neurons of the spinal cord and in different brain regions viz. hypothalamus, cerebral cortex, thalamus, brain stem and hippocampus. In sections of the hypothalamus and spinal cord, we observed immunolabeling for PK in ependymal cells lining the third ventricle and central canal respectively. Positive labeling for PK was evident in fibre tracts of the pons, medulla and hippocampus. No immunoreactive PK was visualised in the choroid plexus or cerebellum. High amounts of PK were measured by competitive ELlSA in extracts of the pancreas (12.94 ± 2.04 /-lg/ml), the pons (1.67 ± 1.46 /-lg/ml) and aorta (0.44 ± 0.14 /-lg/ml). The basilar artery (0.09 ± 0.07 /-lg/ml) and spinal cord (0.09 ± 0.04 /-lg/ml) had the least PK concentrations. Discussion and Conclusions: We have shown that the PPK mRNA demonstrated in various human tissues is most likely translated into protein by the immunolocalisation of PK within specific cells in the different tissues examined. The actions of PK within these tissues may be two fold, firstly by its kininogenase activity it may release BK from high molecular weight kininogen, or alternatively, PK may act as a proteolytic enzyme on other proteins. With respect to the latter) PK may be involved in the processing of protein precursors, for example precursors of the digestive enzymes found in saliva and in gastric secretion, insulin precursors in the pancreas, and hormonal precursors in the pituitary gland. The localisation of PK and B1 and B2 kinin receptors in the kidney, lung, stomach, blood vessels and brain suggests that the effects of PK in these tissues are mediated by BK-receptor interaction. These may include the regulation of glucose uptake in the pancreas, water and ion transport in the kidney, and local and systemic blood pressure in the cardiovascular system. The presence of immunoreactive PK in neurons suggests that BK-receptor mediated interaction may regulate neurophysiological processes such as synaptic transmission. Immunolabeling for PK in polymorphonuclear leukocytes observed in some of these tissue sections suggests the potential to mediate the inflammatory process.
Community acquired pneumonia in HIV and non-HIV infected patients presenting to a teaching hospital in KwaZulu-Natal : aetiology, distribution, and determinants of morbidity and mortality.
(2004) Nyamande, Kennedy.; Lalloo, Umesh Gangaram.
No abstract available.
An immunocytochemical study of the kallikrein-kinin system on the circulating neutrophil.
(1996) Naidoo, Yugenthree.; Bhoola, Keshavlal Daya Narotam.
Inflammation is the normal biological response to tissue injury, and is characterised by the interactive activation of multiple mediators and cell types. One response to tissue injury is the production of pain, not only by direct trauma to sensory fibres, but also through the release of mediators from sensory nerve terminals. One such mediator is kinin which is a vasoactive peptide considered to play a primary role in inflammation by causing constriction of venules, dilation of arterioles, increasing permeability of the capillary membrane, and interacting with sensory nerve terminal transmitters to evoke pain. The kinin forming enzymes (kallikreins) reach inflammation sites either on the surface of migrating neutrophils or by transudation from plasma. The kininogen molecule which contains the kinin moiety, has been localised on the external surface of the neutrophil, and provides the substrate from which kinins can be cleaved through enzymatic action. The cellular actions of kinins are mediated through B2 receptors, which are also located on the external surface of the neutrophils. In addition, the induced effects of kinins are regulated by B1 receptors. The formation of nitric oxide (NO) from arginine released from the kinin C terminus, and receptor membrane signal transduction by nitric oxide following kinin receptor activation is discussed. A molecular response to cell injury is the formation of chemotactic mediators that attract neutrophils to sites of inflammation. The question whether neutrophils contribute to circulating levels of kinins was examined in infections and inflammatory disorders. This novel hypothesis was tested using circulating neutrophils harvested from patients with tuberculosis meningitis and pneumonia. These neutrophils showed a distinct loss of only the kinin moiety from the kininogen molecule located on the external surface. The confocal images of fixed, permeabilised neutrophils provided multi-dimensional constructs, and the intensity of fluorescence reflected the relative amounts of the molecule present in both neutrophils harvested from healthy volunteers as well as patient blood. The immunocytochemical labelling experiments using colloidal gold as markers, confirmed, at the ultrastructural level, the presence or disappearance of the kinin moiety from the kininogen molecule on the neutrophil surface. The cell component of synovial fluid in rheumatoid athritis (RA) consists mainly of neutrophils. This study demonstrates the absence of the kinin moiety from circulating and synovial fluid neutrophils from patients with RA, as well as an increased signal from immunolabelled B2 receptors in synovial fluid neutrophils. These findings support the hypothesis that in RA, kinins are released during the inflammatory response in the joints, and suggests that there is an upregulation of the B2 receptor at the site of inflammation. Neutrophils chemotactically drawn to the site of inflammation become activated to release kinin from the kininogen molecule, and thereafter re-enter the circulation where they were harvested systemically. B2 receptors may be upregulated following activation by kinins or by other mediators present in the inflammatory milieu. Interleukin-1 has been shown to upregulate kinin receptors on human synovial cells. Anti-peptide antibodies to the loops of cloned B1 and B2 receptors have provided powerful probes for the cellular identification of the two kinin receptor families. Mapping of the B2 receptors showed upregulation on the neutrophils gathered from inflamed joints. However, no activation of the Br receptors was observed in normal blood neutrophils as well as those obtained from the different disease states.
A study of urinary and intracellular sodium and potassium, renin, aldosterone and hypertension in Africans and Indians in Natal.
(1987) Hoosen, Sakina.; Seedat, Yakoob K.
No abstract available.
Respiratory health survey in an Indian South African community : distribution and determinants of symptoms, diseases and lung function.
(1992) Lalloo, Umesh Gangaram.; Seedat, Yakoob K.; Becklake, Margaret.
A cross-sectional epidemiologic survey of the respiratory health status was conducted in the adult (15 years and older) Indian South African population resident in Lenasia, Johannesburg to study the distribution and determinants of respiratory symptoms, disease and lung function level. A slightly modified self-administered version of a standardised respiratory health questionnaire and a wedge spirometer was used. There were a high proportion of current smokers among men. Although women smoked less than men in other communities they nevertheless smoked on average more heavily than other Indian South African women. Indian men and women who smoked had a high prevalence of respiratory symptoms. The women also demonstrated an increased susceptibility to the effects of cigarette smoking when compared with women in other communities. Indians in this study had spirometric lung function levels that were lower than that recorded in recent studies in Blacks and Whites in South Africa. Respiratory symptoms, disease and lung function level were examined in a multiple logistic regression model which contained all the potential determinants recorded in the present study. Voluntary tobacco smoking, recent chest illnesses and any kind of heart trouble was associated with a significant risk for having most of the respiratory symptoms and diseases in men and women. In addition exposure to dust in the work environment, little or no exercise,>Std. 8 education a history of any kind of chest trouble and respiratory trouble before the age of 16 years was associated with an increased risk for having respiratory symptoms in men in this model. An increased risk for respiratory symptoms was demonstrated in women only with age. Age and standing height were the most important determinants of lung function level in men and women in the regression model. Dust exposure in the work environment was associated with a significantly lower lung function level in men. Alcohol consumption and a history of whooping cough was also independently associated with a lower lung function level in men but were of borderline significance. In women involuntary /passive tobacco smoke exposure and respiratory trouble before the age of 16 years were associated with a lower lung function level. Women who spent most of their lives in a rural area and those who had a university education had a higher lung function level. The deleterious effects of smoking on lung function were minimal in this study possibly because lung function was performed only in subjects in the 18-45 year age category. A "healthy smoker" effect was demonstrated in men. Men who ever smoked and were without cardiorespiratory symptoms had significantly higher lung function levels compared to men who never smoked and were without symptoms.
Regulation of tumour-angiogenesis by protease inhibitors and receptor antagonists.
(2012) Naidu, Naressa.; Naidoo, Strinivasen.; Botha, Julia Hilary.
Introduction Angiogenesis, the growth of new blood vessels from the pre-existing vasculature, is a pre-requisite for tumour growth and metastasis. Tumour-angiogenesis is regulated by various pro- and anti-angiogenic factors released by both endothelial and tumour cells, as well as by the micro-environment. Numerous studies have implicated various systems in the acquisition of the angiogenic phenotype. The present study sought to investigate the role of the kallikrein-kinin system (KKS) in tumour-angiogenesis. The kallikreins consist of two serine proteases, plasma and tissue kallikrein (TK), involved in the release of kinin peptides by enzymatic cleavage of kininogens. Stimulation of the cognate bradykinin receptors (BKR), B1R and B2R, mediates the mitogenic and vasoactive properties of kinins. In addition, TK activates matrix metallo-proteinases (MMPs) involved in extracellular matrix (ECM) degradation. The expression profiles of TK and kinins have been found to be dys-regulated in numerous human cancers, and several studies have demonstrated the involvement of the KKS in growth and metastasis of prostate tumours. Further, previous in vitro models in our laboratory have established an association between the KKS and prostate tumour-angiogenesis. In those studies it was postulated that the up-regulated TK (produced by endothelial and tumour cells) stimulated endothelial cell proliferation. Thus, the aim of the present study was to define the effects of the KKS and seek a direct correlation with angiogenesis using in vitro models with tumour conditioned medium (CM), kinin receptor agonists and antagonists. Methods Ethical approval for this project was granted by the Biomedical Research Ethics Committee, University of KwaZulu-Natal (reference number BE152/08). Micro-vascular endothelial cells represent a suitable in vitro angiogenic model and dermal micro-vascular endothelial cells (dMVECs) were obtained commercially for this purpose. The tumour model used in this study was an immortalised prostate cancer (DU145) cell line. The CM model involves the treatment of one cell line with the metabolites of another. In the angiogenic model, dMVECs were exposed to increasing concentrations of DU145 CM. Stimulation was further augmented with BKR agonists. Specific BKR antagonists were used to test the specificity of stimulation. In addition, vascular endothelial growth factor (VEGF) was tested as a positive proliferation control. The potential of these agents to induce proliferation and migration was determined using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and a modified Boyden chamber assay, respectively. Previous studies investigating the pro-angiogenic effects of CM differed, in many respects, in terms of their models and methodologies. In an attempt to fully explore the pro-mitogenic effects of CM on endothelial cells, various modifications, as well as alternate endothelial and tumour cell types, were employed in the present study. The mitogenic and migratory effect of BKR agonists and antagonists on DU145 cells was also assessed. Further, the tumour model was expanded to investigate the autocrine potential of the KKS, by investigating the effect of DU145 CM on DU145 migration. Results In the angiogenic model, although the addition of DU145 CM elicited a statistically significant increase in micro-vascular endothelial cell proliferation, this increase was very small (<10%) and not dose-dependent. Pre-incubation of dMVECs with a B1R or B2R antagonist did not influence this small effect of CM on proliferation. In addition, neither B1R nor B2R agonists, at any concentration, produced any significant proliferative effect on endothelial cells. In contrast to these findings VEGF, a well-known mitogen, was able to stimulate proliferation of dMVECs. Migration assays revealed that DU145 CM failed to stimulate endothelial cell motility. Further, neither BKR agonist displayed any chemo-attractant potential in those assays. The most important finding was in the tumour model, where stimulation with a B1R agonist significantly enhanced proliferation and especially migration of DU145 cells. In addition, pre-treatment with a B1R antagonist abolished both these effects. B2R agonists could not produce the same positive effect as the B1R agonist on growth and migration of prostate tumour cells. DU145 CM did not prove to be a migratory stimulus for DU145 cells at any concentration. Discussion Previous studies in our laboratory have shown prostate-tumour CM to promote proliferation of endothelial cells and have postulated that TK up-regulation may be the reason for this. However, the present study could not reproduce this effect of CM. Further, BKR antagonists had no notable or consistent effect on the minimal promotion of proliferation that had been produced by DU145 CM. In addition, selective BKR agonists failed to induce proliferation or migration of endothelial cells, key events in the angiogenic cascade. Although in contrast to some studies, the present study was unable to implicate the KKS in angiogenesis, tumour neo-vascularisation is a consequence of several angiogenic factors functioning together as opposed to a single, isolated factor. For example, we were able to demonstrate a positive mitogenic effect of VEGF on endothelial cells and it may be this as well as other factors in the CM that are responsible for the small proliferation we observed. Up-regulation of kallikreins and kinins in tumours may enhance fundamental events in tumourigenesis in an autocrine manner, and bradykinin (BK) has previously been shown to promote tumour growth in mouse models. Our study supported the involvement of the KKS in tumourigenesis. Although CM from DU145 cells did not self-stimulate the migration of these cells, a B1R agonist enhanced both proliferation and migration, an effect that was also abrogated by the relevant antagonist, indicating a role for kinins. In contrast to the findings of another study, stimulation of the B2R failed to significantly promote tumour growth or motility. However, this is not an unexpected finding because it is thought that the ubiquitous B2R mediates physiological effects in the prostate while the inducible B1R plays a role in prostate cancer pathology. In summary, this study lends support to the ongoing exploration of BKR antagonists as possible candidates in the development of alternate approaches to cancer therapy. This may be particularly beneficial to hormone-independent tumours, such as those of the prostate, for which there exists few effective treatment options.
The effect of self-generated hypoxia on the expression of target genes coding for electron transport related products in mycobacterium tuberculosis.
(2010) Ramchandra, Prathna Harrikaran.; Sturm, Adriaan Willem.
The work presented here aims at identifying whether the genes identified in the genome of Mycobacterium tuberculosis that code for products involved in anaerobic metabolism are active or inactivated genes. The study consists of three distinct parts. In part one, serial dilutions of sputum of patients with pulmonary tuberculosis (PTB) were grown on agar surface and in high columns of un-agitated broth. The highest dilution from which mycobacteria was grown was for all patients significantly higher in the broth cultures than on the plates suggesting the presence of anaerobically metabolizing mycobacteria in the lungs of patients with PTB. Part two of the study identified gene expression by measuring the concentration of transcripts for 5 genes involved in aerobic or anaerobic pathways. This was done over a period of 15 weeks using un-agitated broth cultures (the Wayne method). Undulating patterns of gene expression were found with the genes coding for anaerobic metabolic pathway components expressed at higher levels than those coding for aerobic pathway components while the cultures grew older. Part three aimed at measuring transcription products of the same set of genes directly in sputum specimens. Although quantitation at bacterial cell level in the sputum could not be achieved, expression of all genes was established with on average larger quantities of transcripts of genes coding for the anaerobic pathway components.
Characterization of CD4+ and CD8+ T cell responses in HIV-1 C-Clade infection.
(2011) Ramduth, Dhanwanthie.; Kiepiela, Photini.; Ndung'u, Peter Thumbi.; Walker, Bruce D.
HIV-1 specific CD4+ T cell activity in clade C infected subjects has not been studied. CD4+ T cells play a vital role in controlling infectious diseases and there is a need to augment our knowledge of HIV immunology to aid vaccine design. We therefore embarked on a study to characterize HIV-1 specific CD4+ T cell activity in both adults and infants; assess the relationship between CD4+ and CD8+ immune responses; and the relationship between CD4+ T cell activity and markers of disease progression (viral loads and CD4 counts). Our study revealed that the magnitude of CD8+ T cell responses correlated significantly with CD4+ T cell responses, but that the percentage of CD8+ T cells directed against HIV-1 was always greater than that of CD4+ T cells. Gag was the frequently targeted HIV-1 protein by CD4+ T cells and had the highest density of epitopes targeted by CD4+ T cells. Patients with either a dominant CD4 or CD8 T cell response against Gag had significantly lower viral loads than patients in whom non-Gag proteins were the main target (p< 0.0001 for CD4 activity and p= 0.007 for CD8 responses). Single IFN- producing CD4+ T cells were present in significantly higher numbers than cells producing both IFN- and IL-2 simultaneously (p=0.009). Gag also dominated the CD4+ T cell response in acutely infected infants with IFN- production detected more frequently than IL-2 or TNF- . Longitudinal analysis of infants receiving early ARV treatment and then ceasing after 12 months revealed that early treatment conferred no protection against increasing viremia and disease progression. CD4+ T cell responses were detected sporadically in untreated infants indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia. Taken together, the data reveal that a vaccine inducing Gag specific CD4+ T cell responses has the potential to confer some degree of protection, but other immunological parameters need to be investigated especially in infants.
Assessment of the immune response in kidney transplant patients.
(2009) Omarjee, Saleha.; Assounga, Alain Guy Honore.
Background: Management of a transplant recipient involves the use of multiple immunosuppressant drugs. Currently there is no test that reflects the overall immune status of the patient. This results in under or over suppression of the immune system and consequently increases in morbidity and mortality rates. Evaluation of the proliferative response of PBMC's to a mitogen PHA by measurement of intracellular ATP was evaluated as a tool to assess the immune response in kidney transplant patients. Method: PBMC's were separated from the blood samples of healthy controls and kidney transplant patients on cyclosporine, sirolimus, and tacrolimus based regimens by density gradient centrifugation, cells were counted and incubated overnight with and without PHA. The luciferin-Iuciferase enzyme reaction which induces bioluminescence and the Turner Biosystem luminometer were used to measure intracellular ATP levels in relative light units (RLU). An A TP standard curve was generated for each test. Results: The ATP (nglml) levels measured in the transplant recipients were lower and statistically significantly different (p< 0.0001) than the healthy controls. No statistically significant difference was measured between the cycIosporine and sirolimus drug groups. Patients on tacrolimus gave a statistically significant (p501 nglml ATP). Conclusion: Future studies to determine the predictive value of the A TP assay in directing immunosuppressive therapy are required. The assay described in this study is simple, sensitive and rapid and has possible application in immunological monitoring in a variety of conditions that affects the immune system. Keywords: kidney transplantation, immunosuppression, bioluminescence, lymphocyte, Adenosine Triphosphate (A TP), Phytohemmagglutinin (PHA)
Abnormal IgA1 O-glycosylation in a multi-ethnic population of IgA nephropathy patients in KwaZulu-Natal, South Africa.
(2013) Nansook, Prishani.; Assounga, Alain Guy Honore.
Background: The pathogenesis of IgA Nephropathy (IgAN) is poorly understood globally and curative therapy currently does not exist. Variable presentation among IgAN patients globally may be indicative of various underlying pathogenic mechanisms. Pathogenetic data on IgAN in Africa is scarce to nil. The current study provides the first O-glycosylation data for IgAN in South Africa or Africa. Methods: An enzyme-linked immunosorbent assay-type lectin binding assay was used to compare the serum IgA1 O-galactosylation in 19 IgAN patients and 20 controls. During 2007, 2009, and 2011, blood was extracted from consenting biopsy-diagnosed South African IgAN patients of African, Caucasian, Indian (predominantly) and mixed-race descent in KwaZulu Natal. The mean absorbance value corresponding to the degree of degalactosylation for the IgAN group was compared to that of the normal control group for each test. A non-parametric Wilcoxon matched-pairs test was used accordingly. The two-tailed p-value was used to assess for statistical significance between the groups. The low number of attending and consenting IgAN patients precluded IgA1 O-galactosylation analyses between race, gender, and disease stage. Results: The average means of the experiments for the IgAN group is 0.3678 ± 0.0790 (SEM) and is statistically significantly greater than the normal control group which is 0.2969 ± 0.0586 (SEM); (p = 0.0076). Conclusion: Thus, IgAN patients exhibited abnormal IgA1 O-glycosylation with a greater level of terminal degalactosylation of IgA1 in comparison to controls. Such a finding is consistent with other studies in Caucasian and Asian populations globally. Future specific therapeutic strategies that target the formation of abnormal glycosylation in IgA1 may be potentially beneficial in the study population.
Metabolic complications of antiretroviral therapy (ART) in a South African black population..
(2014) Magula, Nombulelo Princess.; Lalloo, Umesh Gangaram.; Motala, Ayesha Ahmed.
Aims To determine the prevalence and incidence of lipodystrophy (fat distribution [lipoatrophy and lipohypertrophy] and metabolic complications [insulin resistance-dysglycaemia and dyslipidemia]) in HIV-1 infected adult subjects of second generation Zulu descent at baseline and during 24 months of follow-up on antiretroviral therapy (ART). Methods The total study group included three groups: HIV infected ART naive patients eligible for ART (HIV-ART, n=150), age, gender and ethnically matched HIV infected not eligible for ART (HIV-no ART, n=88) and HIV negative (control, n=88) subjects. All participants had demographic, anthropometric, biochemical and radiological assessments at baseline; in addition, the HIV-ART group had follow-up assessments for 24 months on ART (tenofovir, lamivudine and nevirapine or efavirenz). Fat distribution was assessed using FRAM questionnaires, computerized tomography (CT) scans and dual energy absorptiometry X-ray (DXA). Disorders of glycaemia (diabetes mellitus (DM), impaired glucose tolerance and impaired fasting glucose) were defined using WHO criteria. Total, LDL, HDL cholesterol and triglycerides were measured for each group; CD4 cell count and HIV RNA for group 2 and 3, at baseline, 3, 6, 12, 18 and 24 months. Poisson approximations estimated incidence of disorders of glycaemia. Results At baseline, when compared with the control group, the mean BMI (kg/m2) was significantly lower in the HIV-ART and HIV-no ART subjects (26.4 vs. 28.6 vs. 29.1; p =0.01). Prevalence of lipoatrophy as measured by participant and physician examination questionnaires was similar in the three groups. Visceral and subcutaneous fat area by CT scan were similar between the groups but limb and trunk fat mass by DXA scan was significantly lower in the HIV-ART compared to control subjects. In the HIV-ART group, at the 24 month follow-up, there was a significant mean reduction in HIV RNA (p<0.0001) and increase in CD4 cell count (p<0.0001). The mean BMI increased to 29.4 kg/m2 and no lipoatrophy developed; DXA scan showed a 33.6% increase in trunk fat mass (mean difference 4.2 kg, p <0.0001) and 30.8% increase in total fat mass (mean difference 9.4 kg, p < 0.0001); visceral (p 0.005) and subcutaneous (p 0.0002) fat area also increased. At baseline, the prevalence of DM was 0% in HIV-ART and HIV-no ART and 4.9% in control subjects (p 0.005); the prevalence of “any dysglycaemia” was 3.7% in HIV-ART and HIV-no ART compared to 8.6% in control subjects. When compared with group 1, mean values in group 3 were lower for the following serum lipids: total cholesterol (p<0.0001), LDL (p=0.0007) and HDL (p<0.0001). There was no difference in mean total triglycerides in the three groups (p=0.3). During follow-up, in the HIV-ART group, using glucose-based WHO criteria, the incidence of diabetes mellitus was 2.3 per 100 person year follow-up (PYFU) and of “any dysglycaemia” 7.6 per 100 PYFU. The only independent predictor of DM was visceral: subcutaneous fat ratio measured by CT scan (HR 2.95 [95% CI 1.25-6.98], p 0.01). Significant predictors for development of “any dysglycaemia” included systolic blood pressure (HR 1.04 [95%CI 1.02-1.07], p=0.0006), serum albumin (HR 0.85 [95% CI 0.76-0.94], p=0.002), CD4 cell count (HR 0.988 [95%CI 0.978-0.997], p=0.01) and efavirenz (HR 6.27 [95%CI 1.65-23.80], p=0.01) Serum total (p<0.0001), LDL (p<0.0001) and HDL-cholesterol (p<0.0001) increased significantly during follow-up. Conclusion: In this cohort of South Africans with HIV-1 infection, at baseline (prior to ART) there was no significant fat redistribution or lipoatrophy and an absent to low prevalence of dysglycaemia. In the follow-up study, ART use was not associated with lipoatrophy although there was significant increase in BMI and in limb and trunk fat mass by DXA scan. ART was associated with increased incidence of dysglycaemia. These findings underscore the importance of clinical monitoring on ART. The association of efavirenz with dysglycaemia warrants further evaluation.
Quantitative susceptibility testing of chlamydia trachomatis against clinically relevant drugs.
(2017) Matadin, Riona.; Joubert, Bronwyn C.; Sturm, Adriaan Willem.
Abstract available in PDF file.
“Sowing the seeds” the use of feedback in postgraduate medical education : a key factor in developing and enhancing clinical competence.
(2016) Bagwandeen, Chauntelle Ingrid.; Singaram, Veena S.
Background: The importance of feedback in enhancing clinical competency in the postgraduate medical education arena is well documented. Many definitions of, and models and frameworks for delivering feedback exist. Trainee specialists must learn how to use the feedback that they receive to hone their knowledge, skills and professional performance. Clinical supervisors must be equally effective in delivering the best feedback possible in all spheres of the training platform so as to impact positively on performance. However, while many studies have explored how feedback is given and received in postgraduate medical education, these studies have been conducted in homogenous settings. Aim: This study set out to examine how contextual and demographic factors affect the provision of feedback in a clinical training environment with heterogeneous demographics. This study aimed to investigate the perceptions of the registrars, consultants and Clinical Training Heads regarding the quality and factors that influence the process of giving and receiving feedback, so as to make recommendations for improvement and to develop policy guidelines for the enhancement of postgraduate clinical speciality training in diverse clinical training environments. Methods: A mixed methods approach was adopted for this study. Qualitative and quantitative analysis was done regarding the perceptions of the quality of the current delivery of feedback across six disciplines at a teaching hospital. Consultants and registrars consented to complete a questionnaire consisting of open- and close-ended questions to determine the quality, quantity, type and timing of feedback. Responses were coded on a five-point Likert Scale and combined to give an overall positive or negative response. The relationship between demographic factors such as age, race, gender, home language and discipline of study were also evaluated, with responses to open-ended questions used to extend and enrich the quantitative data. Descriptive statistics were used to analyse the data. Differences between groups were calculated using Pearson’s Chi Square test for independent variables, with a p–value of < 0.05 regarded as being statistically significant. Semi-structured interviews were conducted with the Clinical Training Heads to explore their feedback regarding the feedback received about feedback from the consultants and registrars. The Walt and Gilson (1994) triangular framework for policy analysis was used to explore the perceptions of current practice of the Clinical Training Heads of six major disciplines. A thematic analysis was conducted of their perceptions of how feedback was currently given and received by consultants and registers, with a view to developing policy guidelines to improve the practise of giving and receiving feedback. Results: The results revealed a disparity in the perceptions of consultants and registrars regarding current practise. Although consultants believed that they provided adequate feedback, registrars disagreed, citing an overall dissatisfaction with the process. Registrars believed that consultants lacked training in how to give feedback , and that important elements such as prior provision of the standards to be obtained, as well as feedback being based on directly observed performance were missing. Consultants concurred that they lacked capacity in how to give adequate feedback, but felt that heavy workloads, fear of negative reactions and the apathy of registrars as well as their failure to act on feedback when given, hampered the process. Male consultants and registrars both reported better experiences of giving and receiving feedback overall. Registrars who were English second language speakers had statistically significantly more favourable outcomes with feedback compared to English first language speakers. The Clinical Training Heads reported that lack of appropriate institutional support and an overall guiding framework, combined with multiple administrative bodies of registrars as well as language barriers, were challenges to be overcome. They identified areas for future improvement, including standardisation of the process, more effective use of logbooks and better monitoring and evaluation. Conclusion: Registrars and consultants agreed that feedback was essential to ensuring that clinical competencies were achieved. However, ongoing in-service education and training of consultants and registrars was necessary to ensure that consultants were fully capacitated to provide constant, high quality feedback and that registrars were able to recognise feedback when it was given. Feedback needs to be an integral part of the culture of the university teaching and learning ethos. To this end, policy guidelines incorporating elements of identified ‘Best Practices’ on how to give feedback were developed and recommended for implementation under the auspices of an overarching Postgraduate Committee for Teaching and Learning.
The prevalence of bacterial vaginosis in KwaZulu-Natal and its association with the vaginal immune response and shedding of HIV and HSV-2.
(2017) Naido, Kavitha.; Sturm, Adriaan Willem.
Introduction: South Africa has a high burden of sexually transmitted infections (STIs) and HIV. The role of Gardnerella vaginalis in the development of BV has been disputed after the recovery of G. vaginalis from healthy patients and the discovery of new bacteria using molecular identification. Infection with HSV has been associated with increased vaginal HIV RNA copies and bacterial vaginosis has been implicated as a risk factor for the transmission of HIV. Methodology: Consenting patients of > 18 years were recruited from two different primary health clinics. Microscopy was used to diagnose BV and serology for HIV, HSV-2 and syphilis testing. Chlamydia trachomatis and Neisseria gonorrhoeae were detected by BD Probetec, and conventional PCR was used for the diagnosis of Trichomonas vaginalis and recognised ulcer pathogens. Quantitative bacteriology and HIV viral loads were done using the Applied biosystems ABI 7500 Real Time instrument. Immune cells from vaginal tampon specimens were analysed using flow cytometry. Results: In both clinics, of the discharge pathogens T. vaginalis had the highest prevalence. The prevalence of both T. vaginalis and N. gonorrhoeae was significantly higher in Boomstreet clinic (p<0.05). The Umlazi D clinic had significantly more patients with BV (p<0.0001) and HSV-2 (p<0.05). Of the patients with ulcers, HSV-2 was detected in a one third of the specimens in each of the clinics. One patient was diagnosed with lymphogranuloma venereum (LGV). The Nugent score group 0-3 was dominated by Lactobacillus spp. while the Nugent score group 7-10 was dominated by Gardnerella vaginalis. The group with Nugent score 7-10 was shown to have significantly higher levels of immune cells that are proposed HIV targets. Lactobacillus spp. was associated with the group that was HIV antibody negative and Prevotella spp. with the HIV antibody positive group (p < 0.05). Prevotella spp. was not associated with shedding of HIV. The number of bacterial copies of G. vaginalis was significantly higher in patients shedding HIV (p < 0.05). In those shedding HSV-2 the number of copies of G. vaginalis was also higher but this did not reach statistical significance. Conclusion: The trend in STI prevalence was similar to that described previously. We report circulating LGV and there is a possible increase in gonorrhoeae which needs to be confirmed. The potential pathogenic role of G. vaginalis in BV as well as the increased risk of HIV transmission is emphasized.
A cross-sectional survey of patients attitude to vaginal examination and chaperone at King Edward V111 hospital.
(2012) Amaechina, Okezie Ubaka.; Ramnarain, Harry.
Abstract available in PDF file.
An assessment of DSP pharmacy medication delivery for HIV treatment in a family practice in KwaZulu-Natal.
(2014) Reddy, Vinothan Vadival.; Mahomed, Ozayr Haroon.
Abstract available in PDF file.

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