Thesis (Doctoral)--Westfälischen Wilhelms-Universität zu Münster i Westf., 1934.

Made available in DSpace on 2014-06-11T19:32:53Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-11-29Bitstream added on 2014-06-13T19:22:40Z : No. of bitstreams: 1 miyata_m_dr_arafcf.pdf: 1125608 bytes, checksum: 1f8f6a7c62d2f6a383319def72bb3a51 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / De acordo com a Organização Mundial de Saúde em 2009, 9,27 milhões de novos casos de tuberculose ocorreram em 2007. Destes novos casos, 4,9% eram multidroga resistentes. Muitas pesquisas são realizadas na procura de novas drogas com atividade contra o bacilo da tuberculose, havendo então a necessidade de se entender os mecanismos de ação destes novos compostos. Este projeto objetivou propiciar ferramentas para compreender um pouco mais sobre os mecanismos de ação de novas drogas. Isolados clínicos de M. tuberculosis foram caracterizados quanto ao seu perfil de susceptibilidade aos fármacos do esquema terapêutico e foram determinadas as mutações responsáveis por estas resistências. Com os isolados caracterizados, foi construído um painel de M. tuberculosis. Pelo REMA, os isolados foram analisados quanto ao seu perfil de susceptibilidade aos fármacos (INH, RMP, STR e ETB) e avaliados quanto à presença de mutações nos genes de resistência (inhA, katG, ahpC, rpoβ, rpsL, rrs e embB) empregando a PCR-SSCP. Pelo REMA foram avaliados 80 isolados clínicos, sendo observada a resistência a INH em 74,7%, a RMP em 51,2%, a STR em 53,7% e ao ETB em 58,7%. Nos isolados resistentes, a porcentagem de mutações encontradas nos genes foi de 20,6% para inhA, 50% para katG, 6,3% para ahpC, 60% para rpoβ, 20% para rpsL e 0% para rrs e embB. Um painel com 12 isolados foi testado frente a três novos compostos, dois derivados de INH (Cu-INH1 e Cu-INH2) e um de RMP (Cu-RMP). Verificou-se que os isolados resistentes a INH foram também resistentes a Cu-INH1 e Cu-INH2. A mesma situação foi verificada em relação à RMP, com o composto Cu-RMP. Provavelmente, estes novos compostos têm os mesmos mecanismos de ação da INH e da RMP, que são os fármacos que lhes deram origem / According to World Health Organization in 2009, 9.27 million new TB cases occurred in 2007. Among these new cases, 4.9% were multidrug resistant. Many surveys are conducted in the search for new drugs with activity against the tuberculosis bacillus, therefore there is a need to understand the action mechanism of these new compounds. This project aimed to provide tools to understand about the action mechanisms of new drugs. M. tuberculosis clinical isolates were analyzed for their susceptibility profile to drugs, mutations responsible for resistance and a panel of these characterized isolates. The isolates were analyzed for susceptibility profile to drugs (INH, RIF, STR and ETB) and evaluated for presence of mutations in the resistance genes (inhA, katG, ahpC, rpoβ, rpsL, rrs and embB) applying the PCR-SSCP. REMA evaluated 85 clinical isolates and the resistance was observed in 74.7% to INH, 51.5% to RIF, 53.7% to STR and 58.7% to ETB. In the resistant isolates, percentage of mutations found in the genes was 20.6% for inhA, 50% for katG, 6.3% for ahpC, 60% for rpoβ, 20% for rpsL and 0% for rrs and embB. A panel of 12 isolates was tested against three new compounds, two INH-derivatives (Cu-INH1 and Cu-INH2) and one RMP-derivative (Cu-RMP). The isolates resistant to INH were also resistant to Cu-INH1 and Cu-INH2 compounds. The same situation was verified in relation to the RMP with the Cu-RMP compound, indicating that probably these three new compounds have the same action mechanism of INH and RMP drugs

Thesis (MTech (Biomedical Technology))--Cape Peninsula University of Technology, 2010 / The World Health Organisation estimates that nine million people are infected with tuberculosis (TB) every year of which ninety-five percent live in developing countries. Africa has one of the highest incidences of TB in the world. but few of its countries are equipped to diagnose drug-resistant TB. This study aimed to develop a robust. yet simple and cost-effective assay. which would require minimal sophisticated instrumentation and specialised personnel that would make drug sensitivity screening for multi-drug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) accessible to resource-poor high-burden settings. A four-quadrant colorimetric agar plate method was developed which showed good specificity (97.3%-100%) and sensitivity (77.8%-100%) compared to the polymerase chain reaction (PCR) method used as gold standard. Agreement between the methods. using Simple Kappa Coefficients. ranged between very good and excellent. all with high statistical significance (P < 0.0001). The currently used BACTEC MGIT SIREN sensitivity assay coupled with the E-test® strip method. as routinely used in the TB reference laboratory. was compared and showed excellent comparison with the newlydeveloped plate method. for each antibiotic tested. as well as the resultant monoresistant, MDR- or XDR-TB diagnoses. Moreover. the new method was found to be extremely cost-effective. priced at half the cost of a peR assay. These four quadrant plates. with a colorimetric indicator and selected antibiotics. can be considered as an economic altemative or a complimentary method for laboratories wishing to reduce the cost and complexity for TB drug sensitivity testing. Routine diagnostic testing would thus be made more accessible and affordable to laboratories that are not presently diagnosing drug resistant TB. therefore enhancing case detection and treatment in the resource-poor settings hardest hit by this curable disease.

Thesis (MTech (Radiography (Nuclear Medicine)))--Cape Peninsula University of Technology, 2010 / Radioactively labelled red blood cells (RBC) are used in various nuclear medicine studies. In order to obtain accurate results when performing these studies, it is of paramount importance that a good binding of the radioactivity (Tc-99m) with the red blood cells is ensured. The literature indicates that certain drugs can influence red cell membrane properties and biochemistry. These drugs can potentially influence the binding of radionuclides to cells. Antibiotics may possibly alter the labelling efficiency of Tc-99m RBC. Due to the high incidence of tuberculosis (TB) in South Africa, many patients receive anti-TB medication, and therefore the influence of these drugs on the labelling efficiencies of Tc-99m RBC was studied.

M.Cur. / Tuberculosis is regarded as a global health problem as accelerated by the impact of the HIV/AIDS epidemic. In South Africa it is regarded as a top national health priority. Taking treatment regularly prevents multi-drug resistance TB. The introduction of Directly Observed Treatment Short-course (DOTS) ensures that treatment supporters observe TB patients swallow tablets under direct supervision. In the area of research, treatment supporters are trained by South African National Tuberculosis Association trainers to supervise treatment. It happened on a regular basis that patients complain about various aspects of the observational progress, resulting in change of treatment supporters, some preferred to be supervised from the clinic. The researcher developed interest to find out about the shortcomings in the observation of TB patients by treatment supporters, so as to address those shortcomings. A qualitative, exploratory, descriptive and contextual research study was conducted to identify the experience of treatment supporters in observing tuberculosis patients on TB treatment and also, the experience of TB patients as observed by treatment supporters. Permission was obtained from both treatment supporters and TB patients. A pilot phenomenological interview was conducted from one TB patient and one treatment supporter supervising TB treatment, who met the selection criteria. The phenomenological interviews were conducted in Northern Sotho (Pedi), Shangaan, Tswana, Xhosa, Zulu, Southern Sotho and Northern Sotho (Tlokwa) from both treatment supporters and TB patients. The samples comprises of 14 TB patients and 14 treatment supporters supervising those TB patients. Steps were taken to ensure trustworthiness. Tesch’s method of data-analysis was followed to analyze the data. Results indicated that there are interfering factors relating to the working relationship between the TB patients and the treatment supporter. From the findings, facilitative factors are used as proposals to promote the observation of TB patients by treatment supporters. Strategies are described from the rationale, which explain how the proposal can be reached. The strategies were based on the study findings and the literature reviewed.

The tuberculosis epidemic is escalating in South Africa as well as globally. This escalation is exacerbated by the increasing prevalence of multidrug-resistant tuberculosis (MDRTB), which is defined by the World Health Organisation (WHO) as resistance of Mycobacteria to at least isoniazid and rifampicin. Multi-drug resistant tuberculosis is estimated to occur in 1-2% of newly diagnosed tuberculosis (TB) patients and in 4-8% of previously treated patients. MDRTB is both difficult and expensive to treat, costing up to 126 times that of drug-sensitive TB. Resource constrained countries such as South Africa often lack both the money and the infrastructure to treat this disease. The aim of this project was to determine whether the performance of a systematic review with subsequent economic modelling could influence the decision making process for policy makers. Data was gathered and an economic evaluation of MDRTB treatment was performed from the perspective of the South African Department of Health. Three treatment alternatives were identified: a protocol regimen of second line anti-tuberculosis agents, as recommended in the South African guidelines for MDRTB, an appropriate regimen designed for each patient according to the results of culture and drug susceptibility tests, and non-drug management. A decision-analysis model using DATA 3.0 by Treeage® was developed to estimate the costs of each alternative. Outcomes were measured in terms of cost alone as well as the ‘number of cases cured’ and the number of ‘years of life saved’ for patients dying, being cured or failing treatment. Drug, hospital and laboratory costs incurred using each alternative were included in the analysis. A sensitivity analysis was performed on all variables in order to identify threshold values that would change the outcome of the evaluation. Results of the decision analysis indicate that the individualised regimen was both the cheaper and more cost-effective regimen of the two active treatment options, and was estimated to cost R50 661 per case cured and R2 070 per year of life saved. The protocol regimen was estimated to cost R73 609 per case cured and R2 741 per year of life saved. The outcome of the decision analysis was sensitive to changes in some of the variables used to model the disease, particularly the daily cost of drugs, the length of time spent in hospital and the length of treatment received by those patients dying or failing treatment. This modelling exercise highlighted significant deficiencies in the quality of evidence on MDRTB management available to policy makers. Pragmatic choices based on operational and other logistic concerns may need to be reviewed when further information becomes available. A case can be made for the establishment of a national database of costing and efficacy information to guide future policy revisions of the South African MDRTB treatment programme, which is resource intensive and of only moderate efficacy. However, due to the widely disparate range of studies on which this evaluation was based, the outcome of the study may not be credible. In this case, the use of a systematic review with subsequent economic modelling could not validly influence policy-makers to change the decision that they made on the basis of drug availability.

This study examines the psycho-social aspects of tuberculosis in a low income group in an urban setting. The locale chosen was Social Area Three of the City of Vancouver. Part of this area known as the "Strathcona District" was surveyed in 1947 by a University of British Columbia team, of which the writer was a member, as part of a demonstration slum clearance project. This group was specially selected to give clearer focus to the important "residual area" problem in tuberculosis control, namely, that large group of the tuberculous in whom the interaction of the emotional aspects of illness and defects in their material environment combine to make them the hard core of the tuberculosis problem and of many other social problems in the community. A general perspective for the study is drawn from tuberculosis and social work literature from North America, Britain and Scandinavia. The details of the study are based on the case records of seventy-nine people aged eighteen to fifty who were almost one hundred per cent of the diagnosed cases of active tuberculosis in the white races living in Social Area Three of Vancouver in August, 1948. The case list was compiled from the files of the public health .nurses of the Metropolitan Health Committee. The Social Service Exchange registrations of patients and their families were followed up and a total of one hundred and eighty seven case records were read. Information from home interviews with selected patients was also utilized. In terms of social characteristics the sample includes; (a) patients in family settings and, (b) unattached men living alone, who numbered one quarter of the group. The group as a whole were near the border-line income brackets, but might never have Become social liabilities but for their tuberculosis. The problems presented by the disease to the patient as an individual, to his family and to the community are then discussed. The importance of the personality of the patient as a factor in illness is stressed, and the role of the medical social worker in diagnosis and treatment is outlined. Illustrative case material is utilized. The study indicates that the three most important factors determining the successful management of tuberculosis are: (a) the existence of facilities for finding, treating and rehabilitating cases, (b) adequate ancillary social services for the treatment of the social aspects of the disease, (c) the degree of cooperation of the patient and his family in the treatment plan, which cooperation is largely determined by their degree of emotional maturity. The problem of patient non-cooperation is found to stem mainly from lack of sufficient services to meet primary human needs. Because of this lack the life experiences of most people in the group in their formative years had not been conducive to the development of the requisite emotional maturity for dealing constructively with the problems of chronic illness. There is evidence that the weakness of the rehabilitation services in British Columbia vitiates much of the excellence of other treatment facilities. The principle conclusion drawn from the evidence is that the prevention and control of tuberculosis are inextricably interwoven with many other social problems, including poverty, bad housing and family insecurity, which must be attacked in their entirety if advances in tuberculosis control are to be continued. Poverty, in particular, shows up its paramount importance in the perpetuation of tuberculosis as a major health and welfare problem. Specific recommendations are made regarding changes in legislation, medical services, medical social work, social assistance, rehabilitation services and voluntary social agencies services. Many of these recommendations would have valid application in the treatment of other chronic illnesses. / Arts, Faculty of / Social Work, School of / Graduate

This anthropological research began with curiosity about human relationships with microbes. Inside the contained environment of a Biosafety Level 3 laboratory at a South African university-based tuberculosis research division, the fieldwork focused on the relationships between scientists and Mycobacterium tuberculosis − the pathogenic bacterium that causes the disease tuberculosis (TB). These deadly bacteria were cared for and nurtured by women scientists. This care extended to the cells and various species with which they worked. Moreover, this care moved beyond the scope of their immediate scientific research projects and well beyond the laboratory. Care was also central to how the participants conducted their scientific research and themselves in the world. This long-term, qualitative ethnographic research weaves together many layers of care in biomedical scientific research, highlighting that scientific research is a deeply personal, caring and subjective practice. The natural and the social are not − and can never be − mutually exclusive. Boundaries between mind/body, subject/object, human/nonhuman, researcher/researched, subjectivity/objectivity and science/society are porous. Acutely aware of the socio-political moment in which this research was embedded, these findings are put into conversation with South African student calls to decolonise science that emerged alongside the #RhodesMustFall student movement. In particular, the focus is on a 2016 meeting about decolonising science at the University of Cape Town where students argued for connection between the university and the community, science and society and the world of academia and the world of Africans. Implicit was the need for science to be relevant to Africans and deeply complex African social formations and problems. The care by women scientists that was observed inside the laboratory and beyond it speaks volumes to cultivating a more caring science and caring institutions of science that connect the laboratory to the world in which it exists in meaningful, relevant and impactful ways. I demonstrate how the participants embodied a decolonised science, and that what they cared about and how they acted upon those cares could serve as important guides for decolonising science and scientific institutions. This research provides important contributions to the field of science and technology studies (STS), to anthropological research on TB and to the conversation on decolonising science in South Africa.

Study objectives: To examine the utilization of chemoprophylaxis for tuberculosis in certain high-risk groups, ie, infected contacts 50 years and older, and to study the safety of isoniazid (INH) preventive therapy in such persons. Design: From 1987 to 1992, two-part questionnaires were sent to each of the regional health offices within the 95 counties of Tennessee to document cases of purified protein derivative skin test conversion or reaction among close contacts of new patients with active tuberculosis. Infected contacts 50 years and older were included in the study. Methods: Data collected from these questionnaires were grouped according to age, sex, race, liver functions test (LFT), and whether chemotherapy was completed. Reasons for early discontinuation were also recorded. High values of LFTs were classified in the various groups as either twofold elevation or greater than threefold elevation. Results: Of the 829 responses for persons fitting the criteria for INH chemoprophylaxis, 415 began treatment; 249 (60%) of those completed the full course (9 months) and 166 stopped prematurely. Of the 414 persons (50%) who did not start preventive therapy, 233 (56.5%) respondents listed age as the reason. No patients started on a regimen of therapy developed hepatitis. Of those completing therapy, 6.9% had a rise in liver enzyme values but remained asymptomatic for hepatitis. Liver enzyme level elevation was significantly higher among patients who discontinued therapy, particularly white women, than those who completed the full course. Asymptomatic liver enzyme level elevation (≥3 times normal value), private practitioners' preferences, and patients arbitrarily stopping therapy were the leading reasons for incomplete INH preventive therapy. Conclusion: We conclude that 30% of tuberculosis-infected contacts deserving chemoprophylaxis were actually provided the full benefit of INH preventive therapy, indicating underutilization of this prevention strategy, particularly in contacts older than 50 years.

Transmission between hosts is crucial for the success and survival of the obligate human pathogen and aetiological agent of tuberculosis (TB), Mycobacterium tuberculosis (Mtb). Despite this, little is known about how and when Mtb is aerosolized nor the key metabolic and morphological determinants driving successful transmission. To address these knowledge gaps, my doctoral research sought to develop a microscopic method for the detection of aerosolized Mtb following liquidcapture within the respiratory aerosol sampling chamber (RASC). This was achieved through the combination of the mycobacterial cell wall probe, 4-N,Ndimethylamino-1,8-naphthalimide-trehalose (DMN-tre), with the arraying of bioaerosol samples on bespoke nanowell devices amenable to fluorescence microscopy. With this method, a median of 14 live Mtb bacilli (range 0-36) were detected in 90% of confirmed TB patients following 60 minutes of bioaerosol sampling. Three distinct DMN-tre staining patterns were identified among aerosolized Mtb, strongly suggestive of metabolic heterogeneity. Moreover, a low proportion of patients produced Mtb in small clumps. These observations highlight the advantages of using microscopy over conventional culture- or molecular-based techniques for probing the metabolic and morphological characteristics of aerosolized Mtb. Applying this method in a second study, we sought to understand how and when Mtb is aerosolized. To this end, we aimed to compare the aerosolization of Mtb and total particulate matter from patients with TB during three respiratory manoeuvres: tidal breathing (TiBr), forced vital capacity (FVC), and cough. Although total particle counts were 4.8-fold greater in cough samples than either TiBr or FVC, all three manoeuvres returned similar rates of positivity for Mtb. No correlation was observed between total particle production and Mtb count. Instead, for total Mtb counts, the variability between individuals was greater than the variability between sampling manoeuvres. Finally, when modelled using 24-hour breath and cough frequencies, our data indicate that TiBr might contribute more than 90% of the daily aerosolized Mtb among symptomatic TB patients. Assuming the number of viable Mtb organisms detected provides a proxy measure of patient infectiousness, this method suggests that TiBr is a significant contributor to TB transmission. In developing a novel platform for the detection of aerosolized Mtb, this work has suggested the need to re-examine old assumptions about Mtb transmission.