Spatio-temporal patterns of dengue risk in Malaysia were studied both at the address and the sub-district level in the province of Selangor and the Federal Territory of Kuala Lumpur. We geocoded laboratory-confirmed dengue cases from the years 2008 to 2010 at the address level and further aggregated the cases in proportion to the population at risk at the sub-district level. Kulldorff's spatial scan statistic was applied for the investigation that identified changing spatial patterns of dengue cases at both levels. At the address level, spatio-temporal clusters of dengue cases were concentrated at the central and south-eastern part of the study area in the early part of the years studied. Analyses at the sub-district level revealed a consistent spatial clustering of a high number of cases proportional to the population at risk. Linking both levels assisted in the identification of differences and confirmed the presence of areas at high risk for dengue infection. Our results suggest that the observed dengue cases had both a spatial and a temporal epidemiological component, which needs to be acknowledged and addressed to develop efficient control measures, including spatially explicit vector control. Our findings highlight the importance of detailed geographical analysis of disease cases in heterogeneous environments with a focus on clustered populations at different spatial and temporal scales. We conclude that bringing together information on the spatio-temporal distribution of dengue cases with a deeper insight of linkages between dengue risk, climate factors and land use constitutes an important step towards the development of an effective risk management strategy.
Griseofulvin (1) is an important antifungal agent that has recently received attention due to its antiproliferative activity in mammalian cancer cells. Comprehensive SAR studies have led to the identification of 2'-benzyloxy griseofulvin 2, a more potent analogue with low micromolar anticancer potency in vitro. Analogue 2 was also shown to retard tumor growth through inhibition of centrosomal clustering in murine xenograft models of colon cancer and multiple myeloma. However, similar to griseofulvin, compound 2 exhibited poor metabolic stability and aqueous solubility. In order to improve the poor pharmacokinetic properties, 11 griseofulvin analogues were synthesized and evaluated for biological activity and physiological stabilities including SGF, plasma, and metabolic stability. Finally, the most promising compounds were investigated in respect to thermodynamic solubility and formulation studies. The 2'-benzylamine analogue 10 proved to be the most promising compound with low μM in vitro anticancer potency, a 200-fold increase in PBS solubility over compound 2, and with improved metabolic stability. Furthermore, this analogue proved compatible with formulations suitable for both oral and intravenous administration. Finally, 2'-benzylamine analogue 10 was confirmed to induce G2/M cell cycle arrest in vitro.