The FFAG R&D and medical application project RACCAM

JACoW web site http://accelconf.web.cern.ch/AccelConf/e06/Pre-Press/WEPCH161.pdf WEPCH161International audienceThe RACCAM project (Recherche en ACCelerateurs et Applications Medicales) has recently obtained fundings, extending over three years (2006-2008), from the French National Research Agency (ANR). RACCAM is a tripartite collaboration, involving (i) the CNRS Laboratory IN2P3/LPSC, (ii) the French magnet industrial SIGMAPHI, and (iii) the nuclear medecine Departement of Grenoble Hospital. The project concerns fixed field alternating gradient accelerator (FFAG) research on the one hand, and on the other hand their application as hadrontherapy and biology research machines. RACCAM's goal is three-fold, (i) participate to the on-going international collaborations in the field of FFAGs and recent concepts of "non-scaling" FFAGs, with frames for instance, the Neutrino Factory (NuFact) and the EMMA project of an electron model of a muon FFAG accelerator, (ii) design, build and experiment a prototype of an FFAG magnet proper to fulfil the requirements of rapid cycling acceleration, (iii) develop the concepts, and show the feasibility, of the application of such FFAG beams to hadrontherapy and to biology research

Cardiovascular and Gastrointestinal Safety of NSAIDs: a Systematic Review of Meta-Analyses of Randomized Clinical Trials.

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3.5 The homing flight ring test: method for the assessment of sublethal doses of plant protection products on the honey bee in field conditions

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Singularities and Topology of Meromorphic Functions

We present several aspects of the "topology of meromorphic functions", which we conceive as a general theory which includes the topology of holomorphic functions, the topology of pencils on quasi-projective spaces and the topology of polynomial functions.Comment: 21 pages, 1 figur

Seasonal and interannual variability of the pelagic ecosystem and of the organic carbon budget in the Rhodes Gyre (eastern Mediterranean): influence of winter mixing

The Rhodes Gyre is a cyclonic persistent feature of the general circulation of the Levantine Basin in the eastern Mediterranean Sea. Although it is located in the most oligotrophic basin of the Mediterranean Sea, it is a relatively high primary production area due to strong winter nutrient supply associated with the formation of Levantine Intermediate Water. In this study, a 3D coupled hydrodynamic–biogeochemical model (SYMPHONIE/Eco3M-S) was used to characterize the seasonal and interannual variability of the Rhodes Gyre's ecosystem and to estimate an annual organic carbon budget over the 2013–2020 period. Comparisons of model outputs with satellite data and compiled in situ data from cruises and Biogeochemical-Argo floats revealed the ability of the model to reconstruct the main seasonal and spatial biogeochemical dynamics of the Levantine Basin. The model results indicated that during the winter mixing period, phytoplankton first progressively grow sustained by nutrient supply. Then, short episodes of convection driven by heat loss and wind events, favoring nutrient injections, organic carbon export, and inducing light limitation on primary production, alternate with short episodes of phytoplankton growth. The estimate of the annual organic carbon budget indicated that the Rhodes Gyre is an autotrophic area, with a positive net community production in the upper layer (0–150 m) amounting to 31.2 ± 6.9 gCm-2yr-1. Net community production in the upper layer is almost balanced over the 7-year period by physical transfers, (1) via downward export (16.8 ± 6.2 gCm-2yr-1) and (2) through lateral transport towards the surrounding regions (14.1 ± 2.1 gCm-2yr-1). The intermediate layer (150–400 m) also appears to be a source of organic carbon for the surrounding Levantine Sea (7.5 ± 2.8 gCm-2yr-1) mostly through the subduction of Levantine Intermediate Water following winter mixing. The Rhodes Gyre shows high interannual variability with enhanced primary production, net community production, and exports during years marked by intense heat losses and deep mixed layers. However, annual primary production appears to be only partially driven by winter vertical mixing. Based on our results, we can speculate that future increase of temperature and stratification could strongly impact the carbon fluxes in this region.</p

Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases.

International audienceBACKGROUND: Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times-to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naïve approach) on parametric maximum likelihood estimation of time-to-onset distribution. METHODS: Both approaches, naïve or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF-¿ treatment from the French pharmacovigilance is presented. RESULTS: The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1. CONCLUSIONS: It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases

Knowledge and perceptions of the risks of non-steroidal anti-inflammatory drugs among orthopaedic patients in Thailand

Background There is a high incidence of adverse effects from non-steroidal antiinflammatory drugs (NSAIDs) in Thailand, but patients’ perceptions and knowledge of NSAID risks is unknown. Objective This study aims to assess patients’ perceptions and knowledge of NSAID risks and factors affecting them. Setting University hospital in North-East of Thailand. Method A Cross-sectional study conducted over 4 months, using a self-administered questionnaire. Patients prescribed NSAIDs for at least one month duration from orthopaedic clinic were recruited using systematic random sampling. Main outcome measure Patients’ perceptions on NSAID risks, knowledge on risk factors, and their associated factors. Results A total of 474 questionnaires were assessed. Overall perceptions of risks was low (scoring below five on a 0–10 visual analogue scale), with risks associated with the renal system scoring highest. Perceived risk of gastrointestinal problems differed between patients using non-selective and selective NSAIDs (3.47 ± 2.75 vs 2.06 ± 2.98; P < 0.001). Receiving side effect information from a health professional was associated with higher risk perception. Most patients (80 %) identified high doses, renal disease and gastrointestinal ulcer increased risks of NSAIDs, but fewer than half recognized that use in the elderly, multiple NSAID use, drinking, hypertension and cardiovascular disease also increased risk of adverse events. Having underlying diseases and receiving side effect information were associated with 1.6–2.0 fold increased knowledge of NSAID risks. Conclusion Perceptions and knowledge concerning NSAID risks was generally low in Thai patients, but higher in those who had received side effect information. Risk-related information should be widely provided, especially in high-risk patients

Accurate prediction of protein secondary structure and solvent accessibility by consensus combiners of sequence and structure information

Background : Structural properties of proteins such as secondary structure and solvent accessibility contribute to three-dimensional structure prediction, not only in the ab initio case but also when homology information to known structures is available. Structural properties are also routinely used in protein analysis even when homology is available, largely because homology modelling is lower throughput than, say, secondary structure prediction. Nonetheless, predictors of secondary structure and solvent accessibility are virtually always ab initio. Results: Here we develop high-throughput machine learning systems for the prediction of protein secondary structure and solvent accessibility that exploit homology to proteins of known structure, where available, in the form of simple structural frequency profiles extracted from sets of PDB templates. We compare these systems to their state-of-the-art ab initio counterparts, and with a number of baselines in which secondary structures and solvent accessibilities are extracted directly from the templates. We show that structural information from templates greatly improves secondary structure and solvent accessibility prediction quality, and that, on average, the systems significantly enrich the information contained in the templates. For sequence similarity exceeding 30%, secondary structure prediction quality is approximately 90%, close to its theoretical maximum, and 2-class solvent accessibility roughly 85%. Gains are robust with respect to template selection noise, and significant for marginal sequence similarity and for short alignments, supporting the claim that these improved predictions may prove beneficial beyond the case in which clear homology is available. Conclusion: The predictive system are publicly available at the address http://distill.ucd.ieScience Foundation IrelandIrish Research Council for Science, Engineering and TechnologyHealth Research BoardUCD President's Award 2004au, da, ke, ab, sp - kpw30/11/1

Human MLH1 Protein Participates in Genomic Damage Checkpoint Signaling in Response to DNA Interstrand Crosslinks, while MSH2 Functions in DNA Repair

DNA interstrand crosslinks (ICLs) are among the most toxic types of damage to a cell. For this reason, many ICL-inducing agents are effective therapeutic agents. For example, cisplatin and nitrogen mustards are used for treating cancer and psoralen plus UVA (PUVA) is useful for treating psoriasis. However, repair mechanisms for ICLs in the human genome are not clearly defined. Previously, we have shown that MSH2, the common subunit of the human MutSα and MutSβ mismatch recognition complexes, plays a role in the error-free repair of psoralen ICLs. We hypothesized that MLH1, the common subunit of human MutL complexes, is also involved in the cellular response to psoralen ICLs. Surprisingly, we instead found that MLH1-deficient human cells are more resistant to psoralen ICLs, in contrast to the sensitivity to these lesions displayed by MSH2-deficient cells. Apoptosis was not as efficiently induced by psoralen ICLs in MLH1-deficient cells as in MLH1-proficient cells as determined by caspase-3/7 activity and binding of annexin V. Strikingly, CHK2 phosphorylation was undetectable in MLH1-deficient cells, and phosphorylation of CHK1 was reduced after PUVA treatment, indicating that MLH1 is involved in signaling psoralen ICL-induced checkpoint activation. Psoralen ICLs can result in mutations near the crosslinked sites; however, MLH1 function was not required for the mutagenic repair of these lesions, and so its signaling function appears to have a role in maintaining genomic stability following exposure to ICL-induced DNA damage. Distinguishing the genetic status of MMR-deficient tumors as MSH2-deficient or MLH1-deficient is thus potentially important in predicting the efficacy of treatment with psoralen and perhaps with other ICL-inducing agents