A Detailed Urinary Excretion Time Course Study of Captan and Folpet Biomarkers in Workers for the Estimation of Dose, Main Route-of-Entry and Most Appropriate Sampling and Analysis Strategies

Captan and folpet are two fungicides largely used in agriculture, but biomonitoring data are mostly limited to measurements of captan metabolite concentrations in spot urine samples of workers, which complicate interpretation of results in terms of internal dose estimation, daily variations according to tasks performed, and most plausible routes of exposure. This study aimed at performing repeated biological measurements of exposure to captan and folpet in field workers (i) to better assess internal dose along with main routes-of-entry according to tasks and (ii) to establish most appropriate sampling and analysis strategies. The detailed urinary excretion time courses of specific and non-specific biomarkers of exposure to captan and folpet were established in tree farmers (n = 2) and grape growers (n = 3) over a typical workweek (seven consecutive days), including spraying and harvest activities. The impact of the expression of urinary measurements [excretion rate values adjusted or not for creatinine or cumulative amounts over given time periods (8, 12, and 24 h)] was evaluated. Absorbed doses and main routes-of-entry were then estimated from the 24-h cumulative urinary amounts through the use of a kinetic model. The time courses showed that exposure levels were higher during spraying than harvest activities. Model simulations also suggest a limited absorption in the studied workers and an exposure mostly through the dermal route. It further pointed out the advantage of expressing biomarker values in terms of body weight-adjusted amounts in repeated 24-h urine collections as compared to concentrations or excretion rates in spot samples, without the necessity for creatinine correction

Structure-based optimization of potent, selective, and orally bioavailable CDK8 inhibitors discovered by high-throughput screening

The mediator complex-associated cyclin dependent kinase CDK8 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies

Behavioural responses of humpback whales to food-related chemical stimuli

Publisher's version (útgefin grein)Baleen whales face the challenge of finding patchily distributed food in the open ocean. Their relatively well-developed olfactory structures suggest that they could identify the specific odours given off by planktonic prey such as krill aggregations. Like other marine predators, they may also detect dimethyl sulfide (DMS), a chemical released in areas of high marine productivity. However, dedicated behavioural studies still have to be conducted in baleen whales in order to confirm the involvement of chemoreception in their feeding ecology. We implemented 56 behavioural response experiments in humpback whales using two food-related chemical stimuli, krill extract and DMS, as well as their respective controls (orange clay and vegetable oil) in their breeding (Madagascar) and feeding grounds (Iceland and Antarctic Peninsula). The whales approached the stimulus area and stayed longer in the trial zone during krill extract trials compared to control trials, suggesting that they were attracted to the chemical source and spent time exploring its surroundings, probably in search of prey. This response was observed in Iceland, and to a lesser extend in Madagascar, but not in Antarctica. Surface behaviours indicative of sensory exploration, such as diving under the stimulus area and stopping navigation, were also observed more often during krill extract trials than during control trials. Exposure to DMS did not elicit such exploration behaviours in any of the study areas. However, acoustic analyses suggest that DMS and krill extract both modified the whales’ acoustic activity in Madagascar. Altogether, these results provide the first behavioural evidence that baleen whales actually perceive prey-derived chemical cues over distances of several hundred metres. Chemoreception, especially olfaction, could thus be used for locating prey aggregations and for navigation at sea, as it has been shown in other marine predators including seabirds.This research was funded by the Fondation Total (www.fondation.total.com), grant #144903 to A.C., and the Ministère de l'Enseignement Supérieur et de la Recherche (www.enseignementsup-recherche.gouv.fr) to B.B., Bourse doctorale. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer Reviewe

EuReCa ONE—27 Nations, ONE Europe, ONE Registry A prospective one month analysis of out-of-hospital cardiac arrest outcomes in 27 countries in Europe

AbstractIntroductionThe aim of the EuReCa ONE study was to determine the incidence, process, and outcome for out of hospital cardiac arrest (OHCA) throughout Europe.MethodsThis was an international, prospective, multi-centre one-month study. Patients who suffered an OHCA during October 2014 who were attended and/or treated by an Emergency Medical Service (EMS) were eligible for inclusion in the study. Data were extracted from national, regional or local registries.ResultsData on 10,682 confirmed OHCAs from 248 regions in 27 countries, covering an estimated population of 174 million. In 7146 (66%) cases, CPR was started by a bystander or by the EMS. The incidence of CPR attempts ranged from 19.0 to 104.0 per 100,000 population per year. 1735 had ROSC on arrival at hospital (25.2%), Overall, 662/6414 (10.3%) in all cases with CPR attempted survived for at least 30 days or to hospital discharge.ConclusionThe results of EuReCa ONE highlight that OHCA is still a major public health problem accounting for a substantial number of deaths in Europe.EuReCa ONE very clearly demonstrates marked differences in the processes for data collection and reported outcomes following OHCA all over Europe. Using these data and analyses, different countries, regions, systems, and concepts can benchmark themselves and may learn from each other to further improve survival following one of our major health care events

Native diversity buffers against severity of non-native tree invasions

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species$^{1,2}$. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies$^{3,4}$. Here, leveraging global tree databases$^{5,6,7}$, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions