Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 309-336). Also available in electronic version. Access restricted to campus users.

Thesis (M. Phil.)--University of Hong Kong, 1998. / Includes bibliographical references.

Thesis--Columbia University.

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2005. / Includes bibliographical references. Also available in electronic version.

No description available.

Background The World Health Organisation currently recommends the use of artemisinin-based combination drugs for treatment of uncomplicated malaria in high malaria endemic regions. However, comprehensive understanding of factors affecting treatment of malaria with antimalarials is lacking in many rural communities in Africa. This study seeks to test the following hypothesise: 1. That socio-economic and demographic factors at the household level affect treatment of self reported malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania 2. Distance of a household to a health facility affects treatment of malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Methods: Secondary data analysis of a cross- sectional household survey on antimalarials carried out in 2005 in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Georeferenced health facilities and households’ datasets from the Rufiji and Ifakara demographic surveillance systems sites were also used to estimate distance variables. Results: Out of a total of 1433 participants who reported malaria/fever, 32% (95% CI: 29.29, 34.89) obtained treatment with antimalarials. Among them, 36% obtained treatment with Sulfadoxine Pyreminthamine (SP) as a monotherapy and 44% treated malaria/fever with SP and Artesunate as a combination therapy.8% used quinine while 11 % used Amodiaquine and Artesunate. The remaining 1% used chloroquine. After adjusting for all confounding variables in a multivariate survey logistic regression model, age group, education level of the household head and district of residence were found, with statistical evidence, to be associated with treatment of reported malaria/fever with antimalarials. Background The World Health Organisation currently recommends the use of artemisinin-based combination drugs for treatment of uncomplicated malaria in high malaria endemic regions. However, comprehensive understanding of factors affecting treatment of malaria with antimalarials is lacking in many rural communities in Africa. This study seeks to test the following hypothesise: 1. That socio-economic and demographic factors at the household level affect treatment of self reported malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania 2. Distance of a household to a health facility affects treatment of malaria/fever with antimalarials in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Methods: Secondary data analysis of a cross- sectional household survey on antimalarials carried out in 2005 in the Kilombero/Ulanga and Rufiji valleys in Tanzania. Georeferenced health facilities and households’ datasets from the Rufiji and Ifakara demographic surveillance systems sites were also used to estimate distance variables. Results: Out of a total of 1433 participants who reported malaria/fever, 32% (95% CI: 29.29, 34.89) obtained treatment with antimalarials. Among them, 36% obtained treatment with Sulfadoxine Pyreminthamine (SP) as a monotherapy and 44% treated malaria/fever with SP and Artesunate as a combination therapy.8% used quinine while 11 % used Amodiaquine and Artesunate. The remaining 1% used chloroquine. After adjusting for all confounding variables in a multivariate survey logistic regression model, age group, education level of the household head and district of residence were found, with statistical evidence, to be associated with treatment of reported malaria/fever with antimalarials. Conclusion: The results suggest that participant’s age, education level of household head and location of district are important predictors of treatment of malaria with antimalarials in rural Tanzania. The implementation of any antimalarials policy in Tanzania would therefore, require a careful consideration of these factors.

Chan Ping Kei. / Thesis submitted in: December 2001. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 135-143). / Abstracts in English and Chinese. / ACKNOWLEGEMENTS --- p.i / ABSTRACT --- p.ii / TABLE OF CONTECTS --- p.v / LIST OF FIGURE --- p.viii / LIST OF ABBREVIATIONS --- p.xii / CHAPTER / Chapter 1 --- INTRODUCTION / Chapter 1.1 --- Epidemilogy --- p.1 / Chapter 1.2 --- Malaria disease --- p.1 / Chapter 1.3 --- Life cycle of Malaria --- p.1 / Chapter 1.4 --- Current measure to control Malaria --- p.6 / Chapter 1.5 --- Anti-malaria vaccine candidate --- p.7 / Chapter 1.6 --- Anti-erythrocytic malaria vaccine MSP-1 --- p.10 / Chapter 1.7 --- Baculovirus Expression System --- p.20 / Chapter 1.8 --- hexa-histidine tagged fusion protein --- p.25 / Chapter 1.9 --- IMAC --- p.26 / Chapter 1.10 --- Aim of study --- p.26 / Chapter 2 --- MATERIALS AND METHODS / Chapter 2.1 --- Materials --- p.29 / Chapter 2.2 --- Methods --- p.40 / Chapter 3 --- CONSTRUCTION AND CHARACTERIZATION OF RECOMBINANT BmNPV CARRYING PfMSP-l42 / Chapter 3.1 --- Cloning of C-HisPfMSP-l42 into pBM030 --- p.71 / Chapter 3.2 --- Construction of Recombinant BmNPV Carrying PfMSP-l42 --- p.72 / Chapter 3.3 --- Purification of Recombinant BmNPVs --- p.78 / Chapter 3.4 --- In vitro expression of Recombinant --- p.80 / Chapter 3.5 --- In Vivo Expression of Recombinant PfMSP-l42 Protein --- p.80 / Chapter 4 --- PURIFICATION OF BmNPV-EXPRESSED RECOMBINANT C- TERMIAL HEXA-HIS-TAGGED PfMSP-l42 PROTEIN / Chapter 4.1 --- Nickel ion charged Chelating Sepharose Fast Flow (immobilized metal affinity chromatography) --- p.88 / Chapter 4.2 --- POROS HS/M (Strong Cation Exchanger) --- p.105 / Chapter 4.3 --- Combination of chromatographic separations --- p.107 / Chapter 5 --- CHARACTERIZATION OF RECOMBINANT C-HISPfMSP-l42 PROTEIN / Chapter 5.1 --- Proper formation of disulphide bridges in epidermal growth factor (EGF) like domains --- p.115 / Chapter 5.2 --- Characterization of the integrity of hexa-histidines residue on recombinant PfMSP-142 protein --- p.117 / Chapter 5.3 --- Immunogenicity of Recombinant C-HisPfMSP-l42 Protein --- p.117 / Chapter 6 --- DISCUSSION / Chapter 6.1 --- Construction of recombinant BmNPV carrying HisPfMSP-l42 --- p.122 / Chapter 6.2 --- Expression of recombinant HisPfMSP-l42 proteins --- p.123 / Chapter 6.3 --- Purification of recombinant C-HisPfMSP-l42 protein --- p.125 / Chapter 6.4 --- Characterization of recombinant C-HisPfMSP-l42 protein --- p.128 / Chapter 6.5 --- Future prospects --- p.130 / REFERENCE --- p.135 / APPENDICES / Chapter 1. --- Appearance of Mulberry leaves / Chapter 2. --- Biomark 2000 (Beckman) program for sandwich ELISA protocol / Chapter 3. --- Nucleotide Sequence of PfMSP-l42 3D7 Isolate / Chapter 4. --- Nucleotide sequence of PfMSP-l42 FVO isolate / Chapter 5. --- Efficiency of the mAb5.2 immunoaffinity column in purifying the recombinant PfMSP-l42 protein

Thesis (Ph. D.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains viii, 146 p. : ill. (some col.). Includes abstract. Includes bibliographical references (p. 125-142).

The development of Plasmodium falciparum malarial resistance to the current armoury of anti-malarial drugs requires the development of new treatments to help combat this disease. The marine environment is a well established source of potential pharmaceuticals. Of interest to us are isonitrile, isocyanate and isothiocyanate compounds isolated from marine sponges and molluscs which have exhibited nano-molar anti-plasmodial activities. Through quantitative structure-activity relation studies (QSAR), a literature precedent exists for a pseudoreceptor model from which a pharmacophore for the design of novel anti-malarial agents was proposed. The current theory suggests that these marine compounds exert their inhibitory action through interfering with the heme detoxification pathway in P. falciparum. We propose that the computational methods used to draw detailed conclusions about the mode of action of these marine compounds were inadequate. This thesis addresses this problem using contemporary computational methodologies and seeks to propose a more robust method for the rational design of new anti-malarial drug compounds that inhibit heme polymerization to hemozoin. In order to investigate the interactions of the marine compounds with their heme targets, a series of modern computational procedures were formulated, validated and then applied to theoretical systems. The validations of these algorithms, before their application to the marine compound-heme systems, were achieved through two case studies. The first was used to investigate the applicability of the statistical docking algorithm AutoDock to be used for the exploration of conformational space around the heme target. A theoretical P. falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) enzyme model, constructed by the Biochemistry Department at Rhodes University, provided the ideal model to validate the AutoDock program. The protein model was accordingly subjected to rigorous docking simulations with over 30 different ligand molecules using the AutoDock algorithm which allowed for the docking algorithm’s limitations to be ascertained and improved upon. This investigation facilitated the successful validation of the protein model, which can now be used for the rational design of new PfDXR-inhibiting anti-plasmodial compounds, as well as enabling us to propose an improvement of the docking algorithm for application to the heme systems. The second case study was used to investigate the applicability of an ab initio molecular dynamics algorithm for simulation of bond breaking/forming events between the marine compounds and their heme target. This validation involved the exploration of intermolecular interactions in a naturally occurring nonoligomeric zipper using the Car-Parrinello Molecular Dynamics (CPMD) method. This study allowed us to propose a model for the intermolecular forces responsible for zipper self-assembly and showcased the CPMD method’s abilities to simulate and predict bond forming/breaking events. Data from the computational analyses suggested that the interactions between marine isonitriles, isocyanates and isothiocyanates occur through bond-less electrostatic attractions rather than through formal intermolecular bonds as had been previously suggested. Accordingly, a simple bicyclic tertiary isonitrile (5.14) was synthesized using Kitano et al’s relatively underutilized isonitrile synthetic method for the conversion of tertiary alcohols to their corresponding isonitriles. This compound’s potential for heme detoxification inhibition was then explored in vitro via the pyridine-hemochrome assay. The assay data suggested that the synthesized isonitrile was capable of inhibiting heme polymerization in a similar fashion to the known inhibitor chloroquine. Attempts to synthesize tricyclic analogues of 5.14 were unsuccessful and highlighted the limitation of Kitano et al’s isonitrile synthetic methodology.

No description available.