Post-emergence selectivity of metribuzin to carrot.

The objective of this study was to evaluate the selectivity of the herbicide metribuzin to carrot plants as a function of genotype, dose, and plant growth stage at the time of application. Two experiments were carried out, one in a greenhouse and another in the field

The effect of different dosing regimens of motesanib on the gallbladder: a randomized phase 1b study in patients with advanced solid tumors

Extent: 11 p.BACKGROUND: Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. METHODS: Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). RESULTS: Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. CONCLUSION: Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration: ClinicalTrials.gov NCT00448786Lee S. Rosen, Lara Lipton, Timothy J. Price, Neil D. Belman, Ralph V. Boccia, Herbert I. Hurwitz, Joe J. Stephenson Jr., Lori J. Wirth, Sheryl McCoy, Yong-jiang Hei, Cheng-Pang Hsu and Niall C. Tebbut

Triple Co-Administration of Ivermectin, Albendazole and Praziquantel in Zanzibar: A Safety Study

This paper describes how the use of three drugs which are used separately in mass drug distribution programmes when given together appear safe for use in large populations which have been previously treated with the same drugs separately (Mectizan [ivermectin], albendazole and praziquantel). The target diseases—lymphatic filariasis, soil-transmitted worms and schistosomiasis—were prevalent in Zanzibar up to 2000 but have been largely controlled by mass drug administration. The Ministry of Health and Social Welfare, with the support of WHO, initiated a small scale trial in a population of triple therapy in over 5,000 people initially in two sites, and having found there were no severe adverse events associated with the combined treatment then upscaled to treat the whole of the eligible population of over 700,000. Similarly, there were no severe adverse events. This is the first time the three drugs have been used together at the same time at scale in Africa and provide a basis for expansion of integrated preventive chemotherapy of helminths (worms). The next steps need to be initiated in populations which have heavier worm loads and such interventions need to be subject to close monitoring and ethical review

Identification of Candidate Genes for Dyslexia Susceptibility on Chromosome 18

Background: Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.Publisher PDFPeer reviewe

Schistosoma haematobium Treatment in 1–5 Year Old Children: Safety and Efficacy of the Antihelminthic Drug Praziquantel

Urogenital schistosomiasis is an important, but neglected, infectious disease affecting over 100 million people, mainly in Africa. Children carry the heaviest burden of infection with children as young as 1 year old showing signs of infection. Children aged 5 years and below are currently excluded from schistosome control programmes for several reasons, including operational difficulties associated with accessing preschool children, misconceptions about their level of exposure to infective water and lack of safety data on the drug of choice for schistosome control, praziquantel, in children aged 5 years and below. This study was one of a small number of studies recently funded by the World Health Organization to investigate the need for praziquantel treatment in preschool children (aged 1–5 years) and to subsequently assess the safety and efficacy of the drug praziquantel in this age group. This study confirmed that preschool children carry significant levels of schistosome infection, exceeding those carried by their parents/guardians, highlighting the urgent need for their immediate inclusion in schistosome control programmes. The study also showed that praziquantel treatment is as safe and efficacious in children aged 1–5 years as it is in older children aged 6–10 years who are currently the target for mass drug administration

Global Pyrogeography: the Current and Future Distribution of Wildfire

Climate change is expected to alter the geographic distribution of wildfire, a complex abiotic process that responds to a variety of spatial and environmental gradients. How future climate change may alter global wildfire activity, however, is still largely unknown. As a first step to quantifying potential change in global wildfire, we present a multivariate quantification of environmental drivers for the observed, current distribution of vegetation fires using statistical models of the relationship between fire activity and resources to burn, climate conditions, human influence, and lightning flash rates at a coarse spatiotemporal resolution (100 km, over one decade). We then demonstrate how these statistical models can be used to project future changes in global fire patterns, highlighting regional hotspots of change in fire probabilities under future climate conditions as simulated by a global climate model. Based on current conditions, our results illustrate how the availability of resources to burn and climate conditions conducive to combustion jointly determine why some parts of the world are fire-prone and others are fire-free. In contrast to any expectation that global warming should necessarily result in more fire, we find that regional increases in fire probabilities may be counter-balanced by decreases at other locations, due to the interplay of temperature and precipitation variables. Despite this net balance, our models predict substantial invasion and retreat of fire across large portions of the globe. These changes could have important effects on terrestrial ecosystems since alteration in fire activity may occur quite rapidly, generating ever more complex environmental challenges for species dispersing and adjusting to new climate conditions. Our findings highlight the potential for widespread impacts of climate change on wildfire, suggesting severely altered fire regimes and the need for more explicit inclusion of fire in research on global vegetation-climate change dynamics and conservation planning

Alzheimer's Aβ Peptides with Disease-Associated N-Terminal Modifications: Influence of Isomerisation, Truncation and Mutation on Cu2+ Coordination

coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression. coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus. coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species