No description available.

No description available.

No description available.

No description available.

Human travel affects important processes in public health and infectious disease dynamics. Refined spatial and temporal data are needed to accurately model how the dynamics of human travel contribute to epidemiological patterns of disease as well as access to healthcare resources. Here, I address a number of key issues related to modeling human mobility patterns and applications for understanding the spatial spread of infectious diseases and geographic access to public health resources. Using large sources of behavioral data anonymously collected from mobile phones within two African countries, I first analyze the utility of these data to quantify human mobility patterns as well as the usefulness of common modeling frameworks. Then I compare these data to two more common sources of human travel data: the national census and a comprehensive travel survey. Next, I use these data to assess the impact of human travel on the movement of malaria parasites. The final component of my thesis focuses on the utility of this data source to generally understand the role of geographic isolation on travel patterns to better understand the disparity between areas with various levels of access to public resources and the uptake of preventative healthcare such as immunizations and antenatal care.

Malaria, a preventable disease caused by a mosquito-transmitted parasitic infection, continues to be a prominent public health problem today. Progress has been made in the last decade demonstrated by malaria mortality reductions primarily attributed to current vector control strategies. However, the continuing threat of resistance, both resistance of mosquitoes to insecticides and parasites to antimalarial medicines, requires the development of new and improved strategies to supplement those already in place. Housing improvements such as screening doors and windows, closing eaves, patching cracks in walls, and installing ceilings are one such intervention that help stop contact between malaria vectors and humans, and therefore, help stop malaria transmission. Historically considered successful in helping fight malaria, housing improvements are being looked to again today.

Background: The distribution of malaria in sub-Saharan Africa is determined largely by climatic influences on the development and survival of P. falciparum and its Anopheline vectors. This inter-relationship has been exploited in developing a limited number of predictive maps of malaria's distribution but these climate maps have limitations. Climate alone does not fully describe the complex dynamics of transmission and, in particular, human influences such as urbanization and the use of widespread anti-malarial interventions. The improved accuracy and validation of solely climatedriven maps relies on the availability of robust malariometric training data. To date, such data have been scarce. This study redresses several deficiencies of existing malaria maps for Africa through the collation of an extensive database of empirical P. falciparum prevalence data, the investigation of the relationship between prevalence and a widely-used climate-driven map, an assessment of the influence of urbanization on prevalence and finally, through the use of empirical training data to develop an improved malaria map for Kenya, Tanzania and Uganda. Methods: An extensive published and grey-literature search was conducted between 1996 and 2004 and identified 2003 P. falciparum prevalence surveys conducted among childhood populations across East Africa between 1927 and 2003. Stringent criteria were applied to select the best sample data; only randomly sampled community-based surveys, surveys with samples >=50 children, surveys conducted between 1980-2004 and children aged 0-14 years, and surveys which were spatially and temporally unique. The selected data were used to investigate the association between P. falciparum prevalence and a fuzzy logic climatic suitability (PCS) map of malaria transmission, the effect of urbanization on prevalence and to train Fourier-processed multi-temporal climate surrogate data derived from meteorological satellites in order to predict prevalence for un-sampled areas. Using discriminant analysis, the top ten climatic predictor variables that distinguished best between 4 categories of malaria prevalence (0-<5, 5-<25%, 25-<75% and >=75%) were selected and these used to develop a predictive transmission map.

Of the four Plasmodium species which cause malaria in humans, P. falciparum is responsible for the majority of the morbidity and mortality associated with this disease. The surface expression of parasite-derived proteins in the middle of the asexual cycle coincides with two important modifications of the host erythrocyte. First, a protective immune response is directed against a family of variant antigens, known as P. falciparum Erythrocyte Membrane Protein-1 (PfEMPl). Second, ligands are detected at the surface which mediate the specific cytoadherence of infected erythrocytes to vascular endothelium, such that infected cells are sequestered away from the peripheral circulation in deep vascular beds. The potentially fatal syndrome known as cerebral malaria can ensue when infected cells sequester at high density in the brain. Indirect studies have shown that the antigenic and adhesive phenotypes at the surface are linked to the expression of PfEMPl. However, there is a paucity of biochemical data which relate to PfEMPl, and this problem is addressed in this thesis. This study has confirmed, at the biochemical level, inferences from serology that clonal antigenic variation occurred rapidly. Variation produced a number of novel antigenic and adhesive phenotypes which were associated with unique forms of PfEMPl. Further insights into the mechanism of sequestration were possible because of the finding that single infected erythrocytes had the capacity to bind to at least three putative endothelial cell receptors; CD36, Intercellular Adhesion Molecule-1 (ICAM1), and Thrombospondin (TSP). It was demonstrated for the first time that PfEMPl was responsible for cytoadherence to CD36 and ICAM1, but was probably not involved in adhesion to TSP. Extensive analysis with sequence-specific proteases proved that adhesive interactions with each receptor were separable properties of the surface, and facilitated the proposal of a domain model for PfEMPl. Detailed analysis of the antigenic and adhesive phenotypes of a series of clonally-derived parasites demonstrated that infected cells expressing all variant antigenic types could adhere to CD36 whereas adhesion to ICAM1 was seen in a restricted subset. This may be clinically relevant if, as current data suggests, adhesion of infected cells to ICAM1 is important in the development of cerebral malaria. Identification of all ICAM1 binding phenotypes could lead to the design of novel therapeutic strategies for this life-threatening condition.

No description available.

Today, malaria remains the biggest killer of the third world, killing over a million people every year, despite intensive research efforts. Carbamoyl phosphate synthetase II (CPSII) is the first and rate-limiting enzyme in pyrimidine biosynthesis of Plasmodium falciparum, the causative agent of malaria. PfCPSII is a unique target for DNAzyme therapy due to the presence of two unique insertion sequences of 700bp and 1800bp that exist within the mature mRNA transcript. Previous studies have demonstrated that exogenous delivery of nucleic acids such as ribozymes and DNAzymes targeting PfCPSII insertion II effectively inhibited the growth of P. falciparum cultures at sub-micromolar levels. The objective of this study was to investigate the insertion sequences within CPSII from rodent malaria species P. berghei, P. chabaudi and P. yoelii in order to further validate the insertions as DNAzyme targets in vivo. In addition, the insertions were isolated from another human malaria parasite, P. vivax. All Plasmodium CPSII genes investigated encoded two highly hydrophilic insertion sequences of similar size and nature, in the precise position seen in PfCPSII. Although these insertions are poorly conserved, border and internal regions of high homology are present. Thirty-one new DNAzymes were designed to target the P. berghei CPSII insertion II region, seventeen of which demonstrated the ability to cleave the target RNA. Of these, four showed significant cleavage activity, with the DNAzyme MD14 cleaving greater than half the target RNA within five minutes. These DNAzymes were then further characterised for kinetic behaviour. Again, MD14 displayed favourable kinetics of cleavage and was chosen as a suitable candidate in an in vivo rodent malaria trial. Analysis of parasitaemia from the MD14 treated mice indicated the administration of MD14 effected a highly statistically significant reduction of parasitaemia, although this reduction was low (6.3%). More efficient DNAzyme delivery methods were investigated in order to improve DNAzyme efficacy and included the novel use of porphyrin conjugated DNAzymes. The porphyrin-conjugated DNAzymes improved uptake into parasitised red blood cells and significantly reduced parasite growth in vitro at nanomolar levels.