Mahidol University

About: Mahidol University is a education organization based out in Bangkok, Nakhon Pathom, Thailand. It is known for research contribution in the topics: Population & Malaria. The organization has 23758 authors who have published 39761 publications receiving 878781 citations.

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

Abstract: Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.

Meta-Analysis of Molecular Association Studies: Vitamin D Receptor Gene Polymorphisms and BMD as a Case Study

Abstract: With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of the vitamin D receptor (VDR) gene polymorphisms and BMD. We also highlight methodological issues that need to be resolved. Introduction: With the rise of molecular and genetic epidemiology, molecular association studies are increasingly common; however, meta-analysis of these studies has been a neglected area. This study performed a meta-analysis of the association of vitamin D receptor (VDR) gene polymorphisms and BMD/osteoporosis and highlights methodological issues. Materials and Methods: Studies published from 1994 to 2001 were identified through Medline using PubMed software. The reference lists of the articles retrieved were also reviewed. Where eligible papers had insufficient information, we contacted authors by mail (up to three mailings) for additional information. Any observational study, which tested the association between VDR BsmI genotypes and either BMD or osteoporosis at the femoral neck or spine in adult women, was included in the review. Data were extracted independently by two reviewers (AT and JA) using a standardized data extraction form. Results: The B allele was significantly associated with BMD at the spine; it seemed to follow a recessive model, with the BB genotype having lower BMD than Bb/bb genotypes at baseline, which led to greater bone mineral loss over time. Highlighted methodological lessons included the need to check Hardy-Weinberg equilibrium and the importance of exploring heterogeneity, pooling data in a manner that is sensitive to genetic models, and avoiding multiple comparisons. Conclusion: With the proliferation of molecular association studies, there will be an increased need to quantify the magnitude of the risk associated with genetic polymorphisms. This will likely entail meta-analytic methods, and this meta-analysis highlights some of the methodological issues that will need to be resolved.

Eco-bio-social determinants of dengue vector breeding: a multicountry study in urban and periurban Asia.

Abstract: OBJECTIVE: To study dengue vector breeding patterns under a variety of conditions in public and private spaces; to explore the ecological, biological and social (eco-bio-social) factors involved in vector breeding and viral transmission, and to define the main implications for vector control. METHODS: In each of six Asian cities or periurban areas, a team randomly selected urban clusters for conducting standardized household surveys, neighbourhood background surveys and entomological surveys. They collected information on vector breeding sites, people's knowledge, attitudes and practices surrounding dengue, and the characteristics of the study areas. All premises were inspected; larval indices were used to quantify vector breeding sites, and pupal counts were used to identify productive water container types and as a proxy measure for adult vector abundance. FINDINGS: The most productive vector breeding sites were outdoor water containers, particularly if uncovered, beneath shrubbery and unused for at least one week. Peridomestic and intradomestic areas were much more important for pupal production than commercial and public spaces other than schools and religious facilities. A complex but non-significant association was found between water supply and pupal counts, and lack of waste disposal services was associated with higher vector abundance in only one site. Greater knowledge about dengue and its transmission was associated with lower mosquito breeding and production. Vector control measures (mainly larviciding in one site) substantially reduced larval and pupal counts and "pushed" mosquito breeding to alternative containers. CONCLUSION: Vector breeding and the production of adult Aedes aegypti are influenced by a complex interplay of factors. Thus, to achieve effective vector management, a public health response beyond routine larviciding or focal spraying is essential.