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Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil's action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function. Here we demonstrate that proguanil, and cyclization-blocked analogue tBuPG, have potent, but slow-acting, in vitro anti-plasmodial activity. Activity is folate-metabolism and isoprenoid biosynthesis-independent. In yeast dihydroorotate dehydrogenase-expressing parasites, proguanil and tBuPG slow-action remains, while bc1-inhibitor activity switches from comparatively fast to slow-acting. Like proguanil, tBuPG has activity against P. berghei liver-stage parasites. Both analogues act synergistically with bc1-inhibitors against blood-stages in vitro, however cycloguanil antagonizes activity. Together, these data suggest that proguanil is a potent slow-acting anti-plasmodial agent, that bc1 is essential to parasite survival independent of dihydroorotate dehydrogenase-activity, that Malarone® is a triple-drug combination that includes antagonistic partners and that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors in vivo., Competing Interests: The authors declare no competing interests. more...

To assist in nuclear forensic investigations, new techniques are required to evaluate radioactive materials that may be discovered outside of regulatory control. Using a recently developed pressure digestion method for iridium powder, assessments have been made of this techniques suitability for undertaking iridium target material evaluations. In addition to determining the reaction conditions necessary for total dissolution, these investigations have provided an insight into the elemental impurities that are present within unirradiated iridium targets that are used in QSA Global radiography sources, and established the speciation of the iridium solutions that are formed during this process. more...

Nuclear hormone receptors, such as the ecdysone receptor, often display a large amount of induced fit to ligands. The size and shape of the binding pocket in the EcR subunit changes markedly on ligand binding, making modelling methods such as docking extremely challenging. It is, however, possible to generate excellent 3D QSAR models for a given type of ligand, suggesting that the receptor adopts a relatively restricted number of binding site configurations or 'attractors'. We describe the synthesis, in vitro binding and selected in vivo toxicity data for gamma-methylene gamma-lactams, a new class of high-affinity ligands for ecdysone receptors from Bovicola ovis (Phthiraptera) and Lucilia cuprina (Diptera). The results of a 3D QSAR study of the binding of methylene lactams to recombinant ecdysone receptor protein suggest that this class of ligands is indeed recognised by a single conformation of the EcR binding pocket., (Crown Copyright (c) 2010. Published by Elsevier Ltd. All rights reserved.) more...

Laser ablation inductively coupled plasma-mass spectrometry (LA-ICP-MS) has been used to examine the spatial distribution of metals in particulate matter on ambient air filters. The implications of the inhomogeneous distribution observed for the sub-sampling of such filters for multiple analyses have been discussed. It has been shown that large biases in measured values may occur unless the position and size of the sub-sample are chosen judiciously. Additionally, LA-ICP-MS has been compared against acid digestion ICP-MS as an alternative method for the determination of metals in particulate matter. It has been shown that the majority of variation in the LA-ICP-MS sensitivity accrues from small differences in the positioning of samples. more...

The transfer of radioactive caesium from soils to plants has been well researched. In contrast there is limited knowledge on natural stable 133Cs and its potential role as a predictor for radiocaesium behaviour. In a pot experiment with Agrostis capillaris close correlations were found between plant 137Cs and plant 133Cs concentrations (R2 90-96%). Season and leaf age had significant effects with concentrations increasing 10-30-fold between June and December. Simultaneously the plant concentrations of K, the nutrient analogue of Cs, decreased to around one third. In the soil the exchangeable fractions of K and 137Cs declined. No clear relationships were found between 137+133Cs in the plant and exchangeable K in the soil. However, at the end of the experiment the K content of the above-ground biomass was higher than the exchangeable pool in the soil, suggesting that depletion of soil K could be a key factor in the observed increase of plant 137+133Cs over time. more...

The distribution of platinum, rhodium, and palladium (platinum-group elements; PGEs) adjacent to two major U.K. roads shows a rapid decrease (more than 1 order of magnitude) away from the road and reflects patterns shown by other traffic-derived trace elements such as Pb and Zn. However, ratios of Pt:Rh remain relatively constant from 0 to 10 m distance, suggesting that at least some of the PGEs are transported away from the source. A temporal study over a 12-month period, of road dust and surface samples, reveals elevated concentrations above background levels, with maximum values of Pt >500 ng g(-1), Rh 70 ng g(-1), and Pd 70 ng g(-1). Concentrations vary considerably throughout the year and show some tentative correlation with rainfall. Element speciation, an essential control on mobility and hence distribution, was investigated, and the results of solubility experiments show that up to 30% of the Pd present dissolves in acid solutions. This indicates that at least some of the Pd is present in a soluble form and is therefore potentially highly mobile. more...

Boron is present at low levels in groundwater and rainfall in the UK, ranging between 2 and 200 ng ml-1. A sensitive technique has been developed using inductively coupled plasma mass spectrometry (ICP-MS) to measure boron isotope ratios at low concentrations with a precision (Sr) of between 0.1 and 0.2%. Samples were evaporated to increase elemental boron concentrations to 200 ng ml-1 and interfering matrix elements were removed by an adapted cation-exchange separation procedure. The validity of measuring boron isotopic ratios by ICP-MS at this concentration level is discussed in relation the theoretical instrument precision attainable based on counting statistics. Using the developed procedure it is possible to use ICP-MS to establish a reliable database documenting the natural variation in boron isotope compositions in aquifers and rain water in the UK. Preliminary results demonstrate a trend in boron isotopic compositions with increasing boron concentration. The method may be used to evaluate possible levels of boron pollution from anthropogenic inputs into natural aqueous systems. more...

A multidisciplinary audit of care delivered to diabetic patients was completed at the Royal Victoria Hospital, in Montreal. The audit of inpatient care was implemented using Criteria Mapping. A Criteria Map is based on decision-making logic and allows use of criteria relevant to individual patients. The Map includes 23 criteria: 18 medical, three dietetic, and one nursing. The charts of 17 patients discharged with a diagnosis of diabetes mellitus were reviewed. A score above 75% indicated that each discipline rendered adequate care. The medical compliance was 78.46%, dietetic 79.17%, and nursing 85.71%. Mean dossier score was 80.62%. The Criteria Map was highly satisfactory as an audit method; the results of the audit illustrated a need for more complete documentation of services, especially in the area of patient education. more...