Triazolopyrimidine herbicides are potent inhibitors of Aspergillus fumigatus acetohydroxyacid synthase and potential antifungal drug leads.

Aspergillus fumigatus is a fungal pathogen whose effects can be debilitating and potentially fatal in immunocompromised patients. Current drug treatment options for this infectious disease are limited to just a few choices (e.g. voriconazole and amphotericin B) and these themselves have limitations due to potentially adverse side effects. Furthermore, the likelihood of the development of resistance to these current drugs is ever present. Thus, new treatment options are needed for this infection. A new potential antifungal drug target is acetohydroxyacid synthase (AHAS; EC 2.2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway, and a target for many commercial herbicides. In this study, we have expressed, purified and characterised the catalytic subunit of AHAS from A. fumigatus and determined the inhibition constants for several known herbicides. The most potent of these, penoxsulam and metosulam, have Ki values of 1.8 ± 0.9 nM and 1.4 ± 0.2 nM, respectively. Molecular modelling shows that these compounds are likely to bind into the herbicide binding pocket in a mode similar to Candida albicans AHAS. We have also shown that these two compounds inhibit A. fumigatus growth at a concentration of 25 µg/mL. Thus, AHAS inhibitors are promising leads for the development of new anti-aspergillosis therapeutics.

Factors that influence the choice of seeking treatment at polyclinics.

INTRODUCTION: Patients in Singapore can choose their primary care provider on a per-episode basis and pay out-of-pocket for services rendered. The infrastructure of subsidised and private primary care sector facilities differs. Onsite ancillary services are available in subsidised facilities, allowing for convenience of routine investigations, while private clinics are usually standalone practices. This study sought to examine the factors influencing patients' choice of polyclinic. METHODS: This was a cross-sectional survey of a convenient sample of 484 random patients who sought treatment at a polyclinic located in a new housing estate from 24-27 June 2008. RESULTS: The response rate was 85.4% (n = 409). 38.1% of the patients were male. Mean age was 36.2 years. Only 13.8% had a regular private family physician, while 37.3% were followed up at polyclinics. Patients on regular polyclinic follow-up were more likely to be older (p < 0.001), unemployed, retirees or housewives (p < 0.001) and were seeking treatment for chronic diseases (p < 0.001). Geographical convenience (p = 0.002), low cost of consultation (p = 0.024), and onsite laboratory (p = 0.001) and imaging services (p = 0.018) significantly influenced those on regular polyclinic follow-up to attend the polyclinic. CONCLUSION: Affordability, convenience of travel and onsite laboratory facilities influence patients' choice of seeking treatment at polyclinics. Further research examining whether the overall convenience of onsite ancillary services influences patients' choice of primary care provider would be useful in redesigning private primary care infrastructure to enhance patient convenience and encourage more patients to have a regular private family physician.

Chronic exposure to schistosome eggs reduces serum cholesterol but has no effect on atherosclerotic lesion development.

Previous studies have shown that people infected with schistosomiasis have lower levels of serum cholesterol than uninfected controls. To better understand the impact of this parasitic infection on serum cholesterol levels and on atherosclerotic lesion development induced by hypercholesterolemia, apolipoprotein E (ApoE)-deficient mice were chronically exposed to the eggs of Schistosoma mansoni over a period of 16 weeks. Total serum cholesterol and low-density lipoprotein (LDL) were reduced in egg-exposed ApoE-deficient mice fed a diet high in cholesterol compared to unexposed controls. However, exposure to eggs had no effect on atherosclerotic lesion size or progression in ApoE-deficient mice. Macrophages isolated from egg-exposed mice had an enhanced ability to take up LDL but not acetylated LDL (acLDL). This study suggests that schistosome eggs alone may alter serum lipid profiles through enhancing LDL uptake by macrophages, but these changes do not ultimately affect atherosclerotic lesion development.