Digitized using a Konica Minolta 211 PCL Scanner. 300dpi (OCR). / Thesis (MA (Psychology))--University of Stellenbosch, 2006. / AFRIKAANSE OPSOMMING: Hierdie studie ondersoek die uitvoerbaarheid van die implementering van 'n benadering genaamd Kort Motiverende Onderhoud (KMO) in die konteks van die behandeling van tuberkulose (TB) in Suid-Afrika. TB is 'n ernstige bedreiging vir wereldwye gesondheid en is nog nie onder beheer gebring nie, ten spyte van die feit dat dit geneesbaar is. Sedert die beskikbaarheid van effektiewe medisyne-middels, is die oorsaak vir die voortdurende verspreiding van die siekte gesien as 'n probleem van gebrekkige deurvoerbaarheid van die behandeling. Hierdie eng begrip van die epidemie is deur die psigologiese en sosiale wetenskappe, asook andere, verbreed. Daar is baie debatering oor en om die onderwerp van deurvoerbaarheid en die internasionale TB beheer beleid, bekend as Direkte Observerings-Behandeling, Kortkursus (DOBK). Sekere deskundiges argumenteer dat DOBK 'n onvoldoende respons is tot die uitdaging van die verbetering van deurvoerbaarheid en die kontrolering van TB. Dit skyn asof die meelewende aspekte van die TB behandeling nagelaat word in die TB beleide en protokol en sommige beweer dat hierdie faktor sowel as gebrekkige aandag aan ander sistemiese faktore verantwoordelik is vir swak programuitvoering. Suid-Afrika is 'n voorbeeld hiervan, waar die kommunikasie tussen verpleegsters en TB pasiente beskryf word as outoriter, verpleegstergesentreerd en taakgeorienteerd. 'n Pasientgesentreerde benadering (PGB) is 'n wyse waarop die pasientversorger kommunikasie en die bevredigingsvlak van die pasient bevorder word en sommige promoveer dit as a wyse om die behandelingsdeurvoerbaarheid en genesingsuitkomste te verbeter. Die uitdaging is egter dat die konsep van 'pasientgesentreerdheid' op verskeidenheid van wyses geinterpreteer en geimplimenteer kan word. KMO is 'n PGB tot kommunikasie wat bestem is om 'n gees van samewerking te bevorder en om mense se gemengde gevoelens oor gedragsverandering by te le. KMO as 'n aanpassing van Motiverende Onderhoudvoering, is 'n spyskaart van konkrete vaardighede of middels wat gesondheidsvoorsieners in onderhoude rakende geneeskundige gedragsverandering kan gebruik. KMO is gebaseer op teoriee oor gedragsverandering en word gebruik in 'n wye verskeidenheid van genesingsbehandeling, insluitende deurvoerbaarheidsbehandeling. Alhoewel dit selde in minder ontwikkelende lande toegepas is en nog nooit in TB, is KMO suksesvol toegepas in ander besige kontekste vir gesondheidsvoorsiening. Die ontwerp van die huidige studie oor die lewensvatbaarheid van KMO in die konteks van TB behandeling in Suid-Afrika het ontstaan uit die ontwerp van 'n groter studie wat ander intervensies vir 'n PGB ingesluit het. Die doelstellinge van die huidige studie was om die konteks te beskrywe en wat gebeur het gedurende die intervensietydperk en om die uitvoerbaarheid van KMO te verduidelik. / ENGLISH ABSTRACT: This thesis explores the feasibility of implementing an approach called Brief Motivational Interviewing (BMI) in the context of tuberculosis (TB) treatment in South Africa. TB is a serious threat to global health and has not been controlled despite the fact that it is curable. Ever since effective drugs became available, continued spread of the disease has been understood as a problem of poor adherence to treatment. This narrow understanding of the epidemic has been broadened by psychological and social science perspectives among others. There has been much debate around the topic of adherence and the international TB control policy known as Directly Observed Treatment, Short-course (DOTS), as some suggest that it is an incomplete response to the challenge of improving adherence and controlling TB. The caring aspects of TB treatment seem to be neglected in TB policies and protocols, and some argue that this and the lack of attention to other systemic factors are responsible for poor programme performance. South Africa is an example of this, where the communication between nurses and TB patients has been described as authoritarian, nursecentred and task-oriented. A patient-centred approach (PCA) is a way of improving patient-provider communication and patient satisfaction, and some promote it as a way of improving treatment adherence and health outcomes. The challenge, however, is that the concept of 'patient-centredness' can be interpreted and implemented in a variety of ways. BMI is a PCA to communication that is designed to promote a spirit of collaboration and resolve people's mixed feelings about behaviour change. An adaptation of Motivational Interviewing, BMI is a menu of concrete skills or tools that health providers can use in consultations about health behaviour change. BMI is based on theories about behaviour change and has been used to address a wide variety of health behaviours, including treatment adherence. Although seldom applied in less developed country settings and never before applied in TB, BMI has been successfully applied in other busy health care settings. The design of the present study of the feasibility of BMI in the context of TB treatment in South Africa evolved within the design of a larger study that included other interventions designed for a PeA. The present study aims were to describe the context and what happened during the intervention period and to describe BMI's feasibility. Using elements of participatory action research, BMI communication training was developed and implemented with TB staff based in four urban primary health care facilities. A grounded theory approach was used to describe the dynamics of the implementation process and generate a theory about what made BMI more or less feasible in this context. A multidisciplinary team contributed to the study design. Data were gathered largely through participant observation, focus groups and key informant interviews and generated volumes of diverse materials including field notes, training materials, video and audio-taped interactions. The data were analysed using the inductive approach to grounded theory analysis promoted by Glaser (1992) and relied on theoretical sampling and constant comparative analysis. The quality and trustworthiness of the data were ensured through an emphasis on researcher reflexivity and triangulation of the perspectives of different materials, participants and health facilities. The study was implemented as a pilot BMI training process at one facility in Port Elizabeth (Eastern Cape Province) followed by expanded training targeting TB staff of three facilities in Cape Town (Western Cape Province). Data analysis resulted in a categorised description of the research settings, the interactions and relationships among patients, providers, managers and researchers, the training interventions and the way participants responded to it during each phase of the process. Although seemingly similar at the outset, analysis began to show that dynamics of implementation at each facility were complex and multidimensional. The categories that were generated during each cycle of implementation were used to shape the categories selected for the next. Examining the categories across the four health facilities yielded a grounded theory with seven core categories regarding the role of: (1) the personal qualities of the TB staff involved, (2) the way staff moved in and out of the TB service, (3) the leadership, hierarchy and staff dynamics in the health facilities, (4) the pressurised working conditions of TB staff, (5) the poverty of patients, (6) mismatches between the TB programme's protocols and BMI, and (7) the capacity of staff to innovate and improve care. These findings are discussed in terms of the way they respond to the study's research questions and the way the grounded theory categories relate to each other. Their significance is understood from a social constructivist perspective as bound within the context of the study. The findings are also compared to the theoretical perspectives included in the study design and new literature on the diffusion of innovations in service organisations. Recommendations are made for future context-focused research and adherence related intervention development. If interventions like BMI are to be implemented successfully in contexts such as those included in this thesis, policy-makers and managers need to consider the ways in which working conditions, policies and protocols and patient poverty may be counter-productive, and focus on the innovative potential of health staff and teams for delivering patient-centred care.

Thesis (MScMedSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: The current anti-TB drugs have had success in decreasing the number of deaths caused by TB, however, this success is limited by the emergence of drug resistant TB strains. Therefore, a novel TB therapy that limits the development of resistance has become necessary in an attempt to effectively control TB. The anti-TB drugs directly target mycobacterial enzymes, and potentiate the development of this resistance, and have therefore provided the rationale for this study. The aim was therefore to identify host macrophage genes that affect M. tb intracellular survival. The proposed alternative anti-TB therapy potentially involves the application of RNA interference (RNAi) and RNA activation (RNAa) biological processes that will target host genes, thereby inducing an indirect bactericidal effect. We hypothesized that macrophage genes that are differentially expressed by pathogenic and non-pathogenic mycobacterial species may be important in the regulation of M. tb intracellular survival. The lipid-rich mycobacterial cell wall is implicated in the excessive clumping of the mycobacterial cells in liquid culture. In order to minimize this, Tween 80 detergent was supplemented (mycobacteriaT). However, due to substantial evidence emphasising the detrimental effects of Tween 80 on the mycobacterial cell wall, mycobacteria were also cultured without Tween 80 (mycobacteriaNT), in order to investigate if the perturbed mycobacterial cell wall induced by Tween 80 affects the transcriptional response of macrophages. We endeavoured to develop a new method to culture mycobacteria without Tween 80 that will still generate single cells. We further hypothesized that the macrophage gene expression profile induced by mycobateriaNT differs from the response induced by mycobacteriaT. Differentiated THP-1 (dTHP-1) cells were infected with pathogenic and non-pathogenic mycobacteria (for 3 h, 24 h and 48 h with M. tb and M. bovis BCG, and 3 h and 8 h with M. smegmatis) cultured in the presence or absence of Tween 80. The expression of 12 macrophage genes, selected based on their involvement in the phagocytic pathway and autophagy, as well as their general involvement in the immune response, was determined by qRT-PCR and further analysed on the REST programme. The expression of each target gene was normalised relative to the expression of the reference gene (Beta actin). We observed that out of the 12 genes, TLR7 and VAMP7 were consistently downregulated in dTHP-1 cells infected with M. tbNT and upregulated in dTHP-1 cells infected with M. smegmatisNT. Their response to M. bovis BCG was inconsistent and not significantly different, and therefore could not be interpreted. Furthermore, CCL1 was upregulated by all the mycobacterial species. However, its expression was more pronounced in response to mycobacteriaNT, when compared to mycobacteriaT. Differential gene expression of TLR7 and VAMP7 in response to pathogenic and non-pathogenic mycobacteriaNT suggests that these 2 genes may be potential targets for RNAa-based anti-TB therapy, even though we could not conclude whether their response was specific to macrophages. In addition, the observed difference in the expression of CCL1 induced by mycobacteriaNT, compared to mycobacteriaT suggests that the perturbation caused by Tween 80 on the mycobacterial cell wall most likely affected the response of macrophages to infection with mycobacteria. Furthermore, this study has demonstrated a feasible method by filtration to generate single cells from mycobacteriaNT, which should be considered for future mycobacterial infection studies. / AFRIKAANSE OPSOMMING: Die huidige anti-tuberkulose middels se sukses lê daarin dat dit die aantal sterftes verminder maar hierdie sukses word weer beperk met die ontstaan van middel-weerstandige M.tb stamme. Daarom is nuwe middels nodig wat die ontwikkeling van middel-weerstandigheid beperk in ʼn poging om effektiewe TB behandeling te bewerkstellig. Anti-tuberkulose middels teiken hoofsaaklik mycobakteriële ensiemsisteme en ontlok sodoende weerstandigheid in M.tb stamme en dit vorm die rasionale vir hierdie studie. Die doel was om gasheer makrofaag gene te identifiseer wat M.tb oorlewing intrasellulêr bewerkstellig. Die voorgestelde alternatiewe anti-TB behandeling sal dan behels die toepassing van RNA intervensie (RNAi) en RNA aktivering (RNAa) tegnologie wat gasheer selgene teiken (inaktiveer) en sodoende ʼn bakterisidiese respons induseer. Die kanse is skraal dat mycobakterieë weerstandigheid sal kan ontwikkel onder hierdie omstandighede. Ons hipotetiseer dus dat makrofaag gene wat differensieel uitgedruk word deur patogeniese en nie-patologiese mycobakteriële spesies belangrik mag wees vir die oorlewing van M.tb intrasellulêr. Die lipiedryke selwand van mycobakterieë word geïmpliseer in die oormatige sameklomping van die bakterieë in vloeistofkulture. Om hierdie effek te minimaliseer word Tween 80 normaalweg tot die medium gevoeg (mycobakterieëT). Maar weens genoegsame bewyse dat Tween-80 die selwand van bakterieë nadelig beïnvloed, is mycobakterieë ook in die afwesigheid van Tween 80 gekultureer (mycobakterieëNT) om te bepaal of die nadelige effek van Tween 80 op die selwand die transkripsionele respons in makrofage beïnvloed post-infeksie. Dit was daarom ook ons doelstelling om ʼn nuwe tegniek te ontwikkel om mycobakterieë te kultureer in die afwesigheid van Tween 80 wat ook enkelselle sal genereer vir beter gekontroleerde makrofaag infeksie. Ons hipotetiseer ook verder dat makrofaag geenuitdrukking-profiele verskil afhangende of infeksie gedoen is met mycobakterieë wat in die afwesigheid of teenwoordigheid van Tween 80 gekultureer is. Gedifferensieerde THP-1 (dTHP-1) was geïnfekteer met patogeniese en nie-patogeniese mycobakterieë (vir 3 h, 24 h en 48 h met M.tb en M.bovis BCG, en 3 h en 8 h met M.smegmatis) gekultureer in die teenwoordigheid en afwesigheid van Tween 80. Die uitdrukking van 12 makrofaag gene, geselekteer op grond van hul betrokkenheid in die fagositose meganisme en in outofagie asook hul betrokkenheid in die immuunrespons, is gekwantifiseer met qRT-PCR en daaropvolgens geanaliseer met die REST-program. Die uitdrukking van elke geen is genormaliseer relatief tot die uitdrukking van die verwysingsgeen (Beta actin). Daar is bevind dat van die 12 gene, TLR7 en VAMP7 deurlopend afgereguleer was in dTHP-1 selle geïnfekteer met M.tbNT en opgereguleer was in dTHP selle geïnfekteer met M.smegmatisNT. Selrespons met M.bovis BCG was onbeduidend en derhalwe kon geen gevolgtrekking hier gemaak word nie. Ook, CCL1 was opgereguleer met infeksie deur enige van die mycobakteriële spesies, maar CCL1 se uitdrukking was groter in respons tot mycobakterieëNT wanneer vergelyk word met respons tot mycobakterieëT. Differensiële geenuitdrukking van TLR7 en VAMP7 in respons tot patogeniese en nie-patogeniese mycobakterieëNT impliseer dat hierdie twee gene potensiële teikens kan wees vir RNAa-gebaseerde anti-TB behandeling, alhoewel ons nie kon beslis of hierdie respons spesifiek vir makrofage was nie. Ook, die verskille waargeneem in die uitdrukking van CCL1 geïnduseer deur mycobakterieëNT, vergeleke met mycobakterieëT, impliseer dat die steuring in die selwand veroorsaak deur Tween 80, heelwaarskynlik die respons van die makrofaag beïnvloed het. Hierdie studie beskryf ook ʼn filtrasiemetode om enkele mycobakteriële selle te genereer wat oorweeg moet word by toekomstige mycobakteriële infeksiestudies.

Thesis (MSc in Medical Science)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Para-aminosalicylic acid (PAS) is one of the first effective anti-tuberculosis agents and has become one of the principal second-line drugs to treat patients with an extended resistance spectrum. Despite being one of the oldest anti-tuberculosis drugs, little data is available regarding its pharmacokinetics, drug interactions, genetic factors and dosing regimens, especially for the relative new granular slow release PAS (GSR-PAS) preparation. Objectives The aim of the study was to investigate the pharmacokinetics, tolerability and safety of a single 8 g once- or 4 g twice-daily GSR-PAS dose in a multidrug- or extensively drug resistant tuberculosis (M/XDR-TB) population, in which some subjects were also co-infected with the human immunodeficiency virus (HIV). An additional objective was to investigate the potential covariates (i.e. genetic factors and drug interactions) that can alter the pharmacokinetics of PAS. Study design and methodology A randomised, two-period, open-label cross-over study was conducted in 32 adults (≥18 years old) with M/XDR-TB admitted at Brooklyn Chest Hospital, Cape Town, South Africa and treated for drug resistant tuberculosis with a multidrug regimen containing GSR-PAS. The subjects were randomised to follow a single 8 g once-daily GSR-PAS regimen or a 4 g twice-daily GSR-PAS regimen for 8 days. On the eighth day blood samples were obtained at 0, 1, 2, 3, 4, 6, 8, 12 and 24 hours. After the 24-hour sample (Day 9) the regimens were crossed-over. The tolerability and safety of the two regimens were determined using Visual Analogue Scales and interviews. PAS plasma concentrations were determined by a developed HPLC-MS/MS method. N-acetyltransferase (NAT1 and NAT2) genotyping was performed. The data of this study together with unpublished data of a previous study in a very similar population were used in a pharmacometric analysis to determine the PK parameters and any subject covariates. Results and Discussion In comparison to the 4 g twice-daily GSR-PAS dose, the single 8 g once-daily GSR-PAS dose generated a pharmacokinetic profile with a significantly higher maximum concentration (Cmax), concentration at 12 hours (C12) and area under the curve 0 to 12 hours (AUC12). The concentrations of all subjects on the twice-daily regimen were maintained above a minimum inhibitory concentration (MIC) throughout a 12-hour interval, while the single 8 g dose was able to sustain the PAS plasma concentrations above the MIC in 18 out of 29 subjects (62.1%) for the entire 24-hour dosing interval. Both regimens were reasonably well tolerated but most subjects preferred the twice-daily dosing. The clearance of PAS was increased by 45% in HIV positive subjects prescribed antiretroviral treatment (ART), possibly due to interaction with efavirenz (EFV). No significant associations were found for any of the individual NAT1 or NAT2 genotypes, but a difference between mean concentrations of the different genotypic groups was reported. Conclusions The 8 g once-daily dose has the potential to be included in future regimens. The higher peak concentrations achieved can be expected to increase the bactericidal effect of GSR-PAS without significant loss of bacteriostatic effect, i.e. time over MIC. The 8 g once-daily dose has a reasonable tolerability and is potentially easier to supervise in an outpatient setting. Since antiretrovirals (ARVs) increase PAS clearance and decrease PAS exposure in HIV co-infected subjects on ART, the 8 g once-daily dose will be less suitable for maintaining bacteriostasis in these patients (inadequate PAS exposure). Therefore, PAS and ARV interactions need to be clarified before the 8 g once-daily dose can be recommended for the HIV co-infected patients on ART. / AFRIKAANSE OPSOMMING: Agtergrond Para-aminosalisielsuur (PAS) is een van die eerste effektiewe anti-tuberkulose middels en het een van die hoof tweede-lyn middels geword om pasiënte met 'n uitgebreide weerstand spektrum te behandel. Ondanks die feit dat PAS die oudste anti-tuberkulose middel is, is daar baie min data beskikbaar met betrekking tot die farmakokinetika, middel interaksies, genetiese faktore en dosering, veral in die geval van die relatiewe nuwe granulêre stadige vrystelbare PAS voorbereiding (GSV-PAS). Doel Die doel van die studie was om navorsing te doen oor die farmakokinetika, verdraagsaamheid en veiligheid van ʼn enkele 8 g een keer daaglikse en 4 g twee keer daaglikse GSV-PAS dosering in ʼn multi- of uitgebreide weerstandige tuberkulose (M/XDR-TB) populasie, waar sommige proefpersone ook met die Menslike Immuniteitsgebreksvirus (MIV) geko-infekteer is. ʼn Verdere doel van die studie was om te bepaal of potensiële kovariate soos genetika en medisyne interaksies die farmakokinetika van PAS verander. Metodes ʼn Onwillekeurige, twee-periode, oop-etiket oorkruisingstudie was op 32 M/XDR-TB volwassenes (≥ 18 jaar oud) uitgevoer terwyl hulle vir middel weerstandige tuberkulose in Brooklyn Chest hospitaal (Kaapstad, Suid-Afrika) behandel is. Die deelnemers was onwillekeurig ingedeel om ʼn 8 g eenkeer daaglikse GSV-PAS dosering of ʼn 4 g twee keer daaglikse GSV-PAS dosering vir agt dae te volg. Op die agste dag was bloedmonsters op die volgende ure 0, 1, 2, 3, 4, 6, 8, 12, en 24 geneem. Na die 24-uur monster (Dag 9) was die doserings omgekeer. Die verdraagsaamheid en veiligheid van die twee doserings is bepaal deur gebruik te maak van Visueel Analogiese Skale en onderhoude. PAS plasma konsentrasies is bepaal deur 'n ontwikkelde HPLC-MS/MS metode. N-asetieltransferase (NAT1 en NAT2) genotipering is uitgevoer. Die data van hierdie studie saam met ongepubliseerde data van 'n vorige studie is gebruik in farmakometriese analise om die farmakokinetiese parameters en enige kovariate te bepaal. Resultate en Bespreking In vergelyking met die 4 g GSV-PAS twee keer daaglikse dosis, het die enkele 8 g daaglikse dosis, ‘n pharmakokinetiese profiel met ‘n beduidende hoër maksimum konsentrasie (Cmax), 12-uur konsentrasie (C12) en area onder die kurwe van 0 tot 12 uur (AUC12), gegenereer. Die PAS plasma konsentrasies van alle proefpersone, wat op die twee keer daaglikse dosis was, was tydens die 12-uur interval bo die die minimum inhiberende konsentrasie (MIK) gehou. Terwyl die enkele 8 g dosis die PAS plasma konsentrasies vir die duur van die 24 uur interval bo die MIK in 18 van 29 (62%) proefpersone gehandhaaf het. Die meeste proefpersone het die twee-daaglikse dosering verkies, maar beide doserings was redelik goed verdra. Die verwydering van PAS het met 45% toegeneem in HIV positiewe proefpersone wat antiretrovirale behandeling ontvang het, moontlik weens interaksies met efavirenz. Geen beduidende assosiasies vir enige van die individuele NAT1 of NAT2 genotiepes was gevind nie, maar ‘n verskil tussen die gemiddelde konsentrasies van die verskillende genotiepes is gerapporteer. Gevolgtrekking Die 8 g een keer daaglikse dosis het die potensiaal om in toekomstige doserings ingesluit te word. Die hoër piek konsentrasies van die 8 g daaglikse dosis, kan moontlik die bakterisidiese (kiem-dodende) effek van GSV-PAS verhoog, sonder om die beduidende bakteriostatiese (kiem-inhiberende) effek (o.a. tyd oor MIK), te verloor. Die 8 g een keer daaglikse dosis is redelik verdraagsaam en kan potensieël makliker gekontrolleer word in die geval van buite-pasiënte. Serdert antiretrovirale middels (ARVs) PAS verwydering verhoog en gevolglik die PAS plasma konsentrasies verlaag in die MIV ko-infekteerde proefpersone wat op ARVs is, sal die 8 g een keer daaglikse dosis minder geskik wees vir die handhawing van bakteriostasis in hierdie pasiënte (onvoldoende PAS blootstelling). Dus moet daar klarigheid verkry word oor PAS en ARV interaksies voordat die 8 g een keer daaglikse dosis vir MIV ko-infekteerde pasiënte op ARVs aanbeveel kan word.

Thesis (DMed (Medicine. Internal Medicine))-University of Stellenbosch, 2005. / Mycobacterium tuberculosis (M. tuberculosis) accounts for more adult deaths than any other infectious agents. The present study included 162 patients with tuberculous pericarditis; 50% of the tuberculous pericarditis patients studied were human immunodeficiency virus (HIV) positive, compared to only 4.2% of patients who presented with non-tuberculous pericardial effusions. A steady year-to-year rise in HIV prevalence was observed in this 6-year study. Although the prognosis of pericardial tuberculosis (TB) is excellent with appropriate medical treatment, untreated pericardial TB has a mortality of 80-85%. It is thus important to diagnose tuberculous pericarditis efficiently. Traditionally, the diagnosis of pericardial TB is established by positive mycobacterial culture and/or histological evidence of necrotising granulomatous inflammation of the pericardium. Our study confirmed the insensitivity of pericardial fluid culture and pericardial biopsy in the diagnosis of pericardial TB, and at the time of clinical decision-making, results were usually not available. To overcome these difficulties, we explored various alternative strategies and this resulted in two diagnostic tools, namely a diagnostic rule and a diagnostic algorithm or classification tree. By means of classification and regression tree analysis, we allocated a weighted diagnostic index to each of five independently predictive features (fever, night sweats, weight loss, serum globulin >40 g/L and peripheral blood leukocyte count <10x109/L). A total diagnostic index of 6 or more corresponded to 82-86% sensitivity and 76-87% specificity for a diagnosis of tuberculous pericarditis. When possible, pericardial fluid should be aspirated to determine adenosine deaminase (ADA) levels and pericardial differential leukocyte counts. Fluid should also be sent for Gram stain and culture. The proposed diagnostic classification tree utilises the independently predictive attributes of pericardial adenosine deaminase levels, pericardial fluid lymphocyte/neutrophil ratios, peripheral leukocyte counts and the HIV status. Applying this prediction model to our entire data set of 233 patients resulted in 96% sensitivity and 97% specificity for the correct diagnosis of tuberculous pericarditis. Generally, patients were critically ill at the time of enrolment; 90% of tuberculous pericarditis presented with echocardiographic features of cardiac tamponade. Echoguided percutaneous pericardiocentesis with an indwelling catheter and intermittent daily aspiration was highly effective and safe. It is likely that the combination of this drainage technique and the early initiation of anti-tuberculous chemotherapy contributed to the almost complete absence of constriction in the patients studied, and our data do not support the routine use of adjunctive corticosteroids in patients with tuberculous pericarditis. Tuberculous exudates result from a Th1 mediated immune response characterised by lymphocyte dominance, significantly elevated levels of gamma-interferon (IFN-γ) and undetectable levels of interleukin-4 (IL-4). IFN-γ levels were not influenced by HIV status in spite of the severely diminished pericardial CD4+ lymphocyte counts observed in this study. It is thus likely that in HIV positive patients IFN-γ production is partly maintained by activated CD8+ T cells, which were significantly elevated in HIV positive patients compared to HIV negative tuberculous pericarditis patients. This finding underlines the importance of IFN-γ in the human immune response against M. tuberculosis. We also demonstrated that the presence of ADA in pericardial fluids reflects the activity of the cellular immune response. Both IFN-γ and ADA can be utilised as sensitive and specific diagnostic tools for pericardial TB.

Submitted in fulfillment of the requirements for the Degree in Masters of Technology in Nursing, Durban University of Technology, Durban, South Africa, 2015. / Introduction Tuberculosis is still a leading cause of deaths in low and middle income countries especially those of Sub-Saharan Africa. The successful implementation of strategies to improve TB outcomes remains critical for South Africa as the country is faced with the burden of many TB related deaths. South Africa has included TB management as a priority programme for the country in its strategies to the achieve millennium development goals. The National Department of Health introduced the CCG programme to assist professional health workers in the control and management of various health conditions including TB. The competent management of the CCGs is central to meeting service delivery objectives. Aim of the study The aim of the study was to explore and describe the experiences of community care givers caring for TB clients. Methodology A qualitative, exploratory, descriptive design was used to conduct the study. Purposive sampling was used to recruit 24 community care givers that were employed by Department of Health receiving a stipend and had been working as community care givers for at least two years. Data was collected using semi structured interviews and was subsequently analysed using Tesch’s method of data analysis Results The themes that emerged from the interviews included: accessibility of kits and protective clothing to the CCGs, their safety and security, training and development, ii including financing of the CCG programme. The following sub-themes emerged as part of the themes: Insufficient supply of kits, alternative means of making kits available to the CCG’s, promotion and supply of uniforms for the CCGs, procurement and supply of protective clothing, alternative ways of getting protective clothes, vaccination against communicable diseases, safety allowance, transparency on criteria for further training and development, age limits regarding the selection of the CCGs, lack of career pathing, stipend received by the CCGs and employment benefits for the CCGs. Recommendations Recommendations were made with regards to institutional management and practice, policy development and implementation, and further research. These included establishing processes for: supply of kits, protective clothes and vaccines, pre and periodical medicals, criteria for further training and development, and issuing of stipend. A broader study involving all the CCGs affiliated to all PHC clinics in eThekwini district on the required support and supervision was also recommended. / M

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2016-03-07T14:37:51Z No. of bitstreams: 2 license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) PDF - Rayrla Cristina de Abreu Temoteo.pdf: 1166188 bytes, checksum: f66fa12dcea2f0be3aa103dcf669e42c (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2016-06-13T20:35:46Z (GMT) No. of bitstreams: 2 PDF - Rayrla Cristina de Abreu Temoteo.pdf: 1166188 bytes, checksum: f66fa12dcea2f0be3aa103dcf669e42c (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2016-06-13T20:37:58Z (GMT). No. of bitstreams: 2 PDF - Rayrla Cristina de Abreu Temoteo.pdf: 1166188 bytes, checksum: f66fa12dcea2f0be3aa103dcf669e42c (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2015-07-14 / The Directly Observed Treatment objective of strengthening TB treatment adherence, reducing cases of abandonment and increasing the likelihood of cure. The individual and social vulnerability elements can interfere with adherence to this treatment, contextualized in the environment in which the patient is inserted. OBJECTIVE: Analyze the adhesion potential to tuberculosis treatment related to aspects of individual and social vulnerability, in Campina Grande - Paraíba. MATERIAL AND METHOD: Descriptive and analytical study with cross-cut with a quantitative approach. Held in Campina Grande, Paraiba, 2015. They were included as research participants tuberculosis cases treated, diagnosed from September 2014 to February 2015. Performed descriptive analyzes (absolute frequencies, relative rather boxplot graphics), to view the dispersion of data and factor analysis of multiple correspondence, to highlight similarities between data. RESULTS: The lower potential for adherence to tuberculosis treatment evidenced by unfavorable answers to questions such as: impact of tuberculosis on work, conception of causality of health-disease and work process (employment status). Established diagnosis in more than 30 days lack of support treatment at work (or unemployment), negative reaction to the diagnosis, negative impact on the life and lack of family support, were also aspects which have worsened the vulnerability to non-adherence to treatment tuberculosis. CONCLUSIONS: The success of this treatment is conditional on the complexity of each case, considering the family, professional and social (individual and social vulnerabilities). The intersectoral actions aimed at finding facilities in the resolution of this problem. / Elementos de vulnerabilidade individual e social podem interferir na adesão ao tratamento da tuberculose (TB), contextualizados no ambiente o qual o doente está inserido. Os marcadores de adesão, por sua vez, detectam precocemente vulnerabilidades na adesão ao tratamento de doentes com TB, por meio de escores, apresentando forte potencialidade para o monitoramento dessa adesão no âmbito da Atenção Primária à Saúde (APS), aprimorando a vigilância de pessoas com TB. OBJETIVO: Verificar aspectos de vulnerabilidade individual e social relacionados ao diagnóstico e a potencialidade de adesão ao tratamento da tuberculose, em Campina Grande – Paraíba. MATERIAL E MÉTODO: Estudo descritivo, com recorte transversal, de abordagem quantitativa realizado com 39 doentes com tuberculose, em tratamento há no mínimo 30 dias, no município de Campina Grande, no ano de 2015. Foram incluídos como participantes da pesquisa casos de tuberculose em tratamento, diagnosticados no período de setembro de 2014 a fevereiro de 2015. Realizadas análises descritivas (frequências absolutas, relativas, e gráficos boxplot), para visualizar a dispersão dos dados e análise fatorial de correspondência múltipla, para evidenciar similaridades entre os dados. RESULTADOS: O menor potencial para adesão ao tratamento da tuberculose foi evidenciado por respostas desfavoráveis a quesitos como: impacto da tuberculose sobre o trabalho, concepção sobre a causalidade do processo saúdedoença e trabalho (condição empregatícia). Diagnóstico estabelecido em período superior a 30 dias, falta de apoio ao tratamento no trabalho (ou desemprego), reação negativa diante do diagnóstico, impacto negativo sobre a vida e falta de apoio familiar, foram também aspectos que podem potencializar a vulnerabilidade a não adesão ao tratamento da tuberculose. CONCLUSÃO: O sucesso do tratamento está condicionado à complexidade de cada caso, considerando o ambiente familiar, profissional e social (vulnerabilidades individual e social). A intersetorialidade das ações visa encontrar facilidades na resolução dessa problemática. A utilização do instrumento foi importante para evidenciar marcadores em baixo potencial de vulnerabilidade à adesão ao tratamento da tuberculose, evidenciando quais deles necessitam de intervenção, recomendando-se sua utilização na APS para o monitoramento da adesão ao tratamento da TB.

Thesis (Ph. D. (Microbiology)) --University of Limpopo, 2019 / Tuberculosis (TB) is one of the top ten diseases that causes morbidity and mortality worldwide. Although TB is curable, the main problem currently with TB is development resistance to the current chemotherapy. Medicinal plants, as a source of drugs, have been found to cause less or no resistance. Medicinal plants are studied and considered for their efficacy and safety because they possess bioactive compounds with various biological activities. The aim of the study was to isolate and characterise bioactive compounds from selected seven plant species [A. dimidiata (LNBG 1969/46), A. afra (LNBG 2010/27), Z. capense (LNBG 1969/100), C. herorense (LNBG 1977/71), L. javanica (LNBG 1969/460), E. camaldulensis and C. lemon (UNIN 12330)] with activity against Mycobacterium smegmatis, Multi- drug resistant tuberculosis starain and H37Rv Mycobacterium tuberculosis strain. It was also imperative to determine whether crude extracts, sub- fractions of the extracts and the isolated bioactive compounds are cytotoxic or not. Leaves of the seven selected plants were collected from South African National Botanical Institute (SANBI) at Nelspruit, Mpumalanga Province, South Africa. The leaves were dried and milled to fine powder. The leaves of each plant were extracted using solvents of varying polarity (i.e. hexane, dichloromethane, acetone and methanol). Phytochemical screening was done using Thin Layer Chromatography (TLC) developed in three mobile phases varying in polarity and then sprayed with vanillin sulphuric acid in methanol heated at 110oC for optimal colour development. Qualitative antioxidant activity was determined by using 1,2- diphenylpicryl hydrazyl (DPPH) assay on TLC plates. Antimycobacterial activity for all the plant extracts was done using bioautography assay in qualitative analysis of the active compounds and for quantitative analysis, the microplate dilution assay was used. The plants which showed better activity (C. lemon, C. hereroense and A. dimidiata) with the microplate dilution assay and bioautography were further subjected to solvent- solvent fractionation as the first step towards isolation of bioactive compounds. Synergistic, additive, indifferent and antagonistic effects of the crude extracts combinations of the three selected plants was determined. The combinations where A. dimdiata was also part of the combinations frequently showed synergistic effect. On the other hand, with the combinations of C. hereroense and A. dimdidata (CH-AD) there was no antagonistic effect observed. The combinations of crude extracts of C. lemon and A. dimidiata all showed synergistic effect, except for only three combinations. Based on the synergistic effect observed and the bioactivity on the bioautography and microplate dilution assay of the sub- fractions, A. dimidiata was chosen for further analysis for antimycobacterial activity using the MDR- TB strain and M. tuberculosis H37Rv strain. The sub- fractions of A. dimidiata with the most activity were hexane and butanol. Hexane and butanol fractions both showed good MIC activity against the TB isolated M. tuberculosis field strain and H37Rv strain of 0.47 and 031 mg/ml, respectively. Butanol fraction was further taken for isolation using open colum chromatography doing bioassay guided isolation. The isolated compounds, together with the crude were tested for their biological activity using MTT assay to determine their cytotoxicity and antimycobacterial activity assay to confirm their activity against M. smegmatis and M. tuberculosis. Cytotoxicity assay showed that the crude extracts of A. dimidiate were toxic against the Vero kidney cells and the subfractions (i.e. butanol and hexane) became moderate to non-toxic and one compound (oleanolic acid) from the butanol sub-fraction was non- cytotoxic. This indicates that the isolation of the crude extracts tends to become non- toxic to the cells. The study suggests the use of pure compounds to fight against TB as compared to crude extracts since they are both bioactive and non- cytotoxic. Crude extracts combinations were effective in killing Mycobacterium as compared to single crude extracts. The present study recommends the use of A. dimidiata plant leaves crude extracts combinations as they mostly exhibit synergistic effect. Furthermore, Mycobacterium and also contain non- cytotoxic antimycobacterial compound (oleanolic acid). The study serves as a scientific proof for the use of this plant in traditional medicine for TB treatment.

Thesis (MPH.) -- University of Limpopo, 2012 / Tuberculosis (TB) is the cause of 1, 8 million deaths annually, 99% of the deaths occurs in the developing countries and among the poorest people of these countries. Studies between high and low income countries demonstrate that rates of TB are significantly higher in poorer populations. World Health Organization introduced DOTS as global strategy for providing TB services which was expected to be delivered primarily by government run public health services (Malmborg, Mann, Thomson, & Squire, 2006). AIM Investigate factors that influence compliance and non-compliance to treatment among patients on tuberculosis drug treatment. STUDY SITE This study was conducted in Shiluvane local area in Greater Tzaneen Municipality under Mopani District in Limpopo Province, South Africa. One district hospital, one health centre and five clinics were selected for this study: Dr CN Phatudi hospital, Shiluvane Health Centre, Moime, Lenyenye, Mogoboya, Maake and Lephepane Clinics. (v) STUDY DESIGN This is a quantitative and qualitative study as mixed methods were used to get a comprehensive research report. SAMPLING The sample size used 150 of a given population using Morgan and Krejcie table (1994). The case register was used to select respondents. The respondents were selected according to particular interval; each second name on the list was selected. Questionnaire and structured interview was selected for data collection. Questionnaires were distributed among clients who are able to read and write for them to complete, the researcher and the assistant helped to fill questionnaires for those who cannot read or write. The study was conducted at identified hospital, health center and clinics. RESULTS Education Level, the findings of this study displays that only 3,7% of participants hold tertiary qualifications, and 50% secondary education and 37,3% of primary education. Occupation, 76.4% of participants are unemployed. Income, 52,6% of participants earn between R1000-R2999 and 17,5% does not have income. (vi) CONCLUSION In conclusion based on the results and objectives of this study compliance with drug treatment among patients with tuberculosis in Shiluvane local Area, Mopani District, Limpopo province is 90.9%.

The study seeks to identify factors affecting compliance to TB treatment and determine those that make some patients complete TB treatment in Andara district, Kavango region in Namibia. The self-efficacy model by Shortridge-Baggett and Van der Bijl (1996) was the conceptual framework which guided this study. A quantitative, cross-sectional, descriptive and comparative study design was used. Data was collected using a structured questionnaire administered by a registered nurse. A total of 49 respondents were interviewed: (23 compliant and 26 non-compliant). Informed consent was obtained from each respondent prior to data collection. SPSS and MS Excel were used to analyse data and describe differences between the two groups. Respondents (N=26) gave „feeling better‟ 7 (27%), „distance‟ 8 (31%), „lack of family support‟ 4 (15%), no food 2 (8%), side effects 2 (8%), other reasons 2 (8%) and medicines not working 1 (4%), as their reasons for not completing treatment. However, long waiting times at the clinic, non availability of food and lack of knowledge of TB or treatment are the significant factors contributing to non-compliance. / Health Studies / M.A. (Public Health)

Submitted in fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry, Durban University of Technology, Durban, South Africa, 2017. / In drug discovery and development of anti-tubercular therapeutics, it is necessary to study the physiology and genetics of the molecular mechanisms present in the Mycobacterium tuberculosis. The virulence of M. tuberculosis is attributed to its unique genome, which contains a high frequency of glycine-rich proteins and genes involved in the metabolism of the fatty acids. Consequently, the presence of a diversity of the pathogenic pathways such as acid tolerance and drug resistance mechanisms in M. tuberculosis makes the treatment of Tuberculosis (TB) challenging. However, the molecular basis of the virulence factors involved in the pathogenesis is not fully understood. Accordingly, the current study focuses on better understanding of the pathogenic proteins present in this bacterium using available computational techniques. In South Africa, there is an alarming increase in the drug-resistant TB in HIV co-infected patients, which is one of the biggest challenges to the current anti-tubercular therapies. An extensive literature search showed that the mutations in the virulent proteins of M. tuberculosis resulted in the development of drug tolerance in the pathogen. The molecular and genetic studies identified frequently occurring point mutations associated with the drug resistance in proteins of M. tuberculosis. Despite the efforts, TB infection is still increasing because different pathogenic pathways in the bacterial system are still undiscovered. Therefore, this study involves an in silico approach aimed at the identification of novel drug resistance implicated point mutations. The site- directed mutations leading to the development of resistance against four first-line drugs (Ethambutol, Isoniazid, Rifampicin, and Streptomycin) were studied extensively. In the primary investigation, pathogenic mutational landscapes were classified in the sequences of the studied proteins. The effects of these mutations on the stability of the proteins were studied using diverse computational techniques. The structural basis of the point mutations with the highest destabilizing effects was analyzed using the principles of the Density Functional Theory (DFT), molecular docking and molecular dynamics (MD) simulation studies. The varied conformational behavior resulted from these predicted substitutions were compared with the experimentally derived mutations reported in the literature. The outcome of this study enabled the identification of the novel drug resistance-associated point mutations which were not previously reported. Furthermore, a detailed understanding of the conformational behavior of diverse virulent proteins present in M. tuberculosis was also generated in this study. Literature study showed that inside the host’s macrophage cells, the virulent proteins such as isocitrate lyase, lipase lipF, magnesium transporter MgtC, porin protein OmpATb, a protein of two component systems PhoP, Rv2136c and Rv3671c have an established role in the development of the acid tolerance. On the other hand, information regarding their role in the acid resistance is scarce. Accordingly, the structural basis of their role in acid resistance was analyzed using constant pH based MD simulations. In the studied proteins, the lipF and PhoP showed highest structural stability in highly acidic conditions throughout the course of MD simulations. Therefore, these proteins may play a primary role in the process of resistance. In addition to these pathogenic proteins, there is a need to identify new undiscovered virulent proteins in the genome of M. tuberculosis, which increases the efficiency of the current therapy. The knowledge generated by the analyses of the proteins involved in resistance and pathogenic mechanisms of M. tuberculosis forms the basis for the identification of new virulence factors. Therefore, an in silico protocol was used for the functional annotations and analyses of the virulence characteristics. M. tuberculosis contains 1000 Hypothetical Proteins (HPs), which are functionally uncharacterized proteins and their existence was not validated at the biochemical level. In this study, the sequences of the HPs were extensively analyzed and the functions of 662 HPs were successfully predicted. Furthermore, 483 HPs were classified in the category of the enzymes, 141 HPs were predicted to be involved in the diverse cellular mechanisms and 38 HPs may function as transporters and carriers proteins. The 307 HPs among this group of proteins were less precisely predicted because of the unavailability of the reliable functional homologs. An assessment of the virulence characteristics associated with the 1000 HPs enabled the classification of 28 virulent HPs. The structure of six HPs with highest predicted virulence score was analyzed using molecular modelling techniques. Amongst the predicted virulent HPs, the clone for Rv3906c purchased from the DNASU repository because of the ease of its availability. The gene of Rv3906c was isolated and cloned into a pET-21c expression vector. The analyses of the nucleotide sequence showed that Rv3906c gene (500 bp) encodes a 169 amino acid protein of molecular weight 17.80 kDa (~18.0 kDa). The sequence analyses of Rv3906c showed that the HPs showed high similarities with pullulanase, a thermophilic enzyme. The stability profile at different temperatures for Rv3906c generated using MD simulations showed that Rv3906c maintained its structural identity at higher temperatures. It is expected that this study will result in the design of better therapeutic against the infection of M. tuberculosis, as novel undiscovered virulence factors were classified and analyzed in addition to the conformational profiles of the virulent proteins involved in the resistance mechanisms. / M