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Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

Les sources de micropolluants au sein d’un territoire peuvent etre tres variees et la tres grande diversite de ces micropolluants rend leur suivi et leur gestion tres complexe. Cette etude presente la mise en place d’outils innovants pour une premiere etape dans la cartographie des micropolluants metalliques et organiques au sein d’un reseau d’assainissement et leur utilisation dans le cadre de l’etude de ces micropolluants au sein du systeme d’assainissement du bassin d’Arcachon. La combinaison d’un outil simple de prelevement passif pour identifier les principales sources de contribution de contaminants metalliques et d’un outil dit de screening pour une caracterisation des micropolluants organiques constitue une premiere etape dans la gestion des micropolluants. Ces premieres briques du diagnostic des micropolluants permettent une hierarchisation des actions a mener en vue de leur reduction.

Resume Les risques psycho-sociaux (RPS) sont divers (stress, harcelement, violences internes ou externes…) et frequents en milieu de travail. Les medecins du travail et plus largement les services de sante au travail sont frequemment sollicites pour aider a les diminuer ou a traiter les consequences. La prise en charge des RPS allie des competences medicales et organisationnelles avec une double approche : individuelle et collective. Bien connaitre leurs definitions permet de poser un diagnostic, cadrer la thematique, attirer l’attention sur des situations potentiellement dangereuses et reperer des signes de gravite. Le medecin du travail a un role de soutien psychologique et d’orientation dans un contexte de protection du salarie. Il a un devoir d’alerte en particulier en cas d’atteinte au droit des personnes. Il doit contextualiser les problemes au travail, faire le lien avec les divers intervenants et l’entreprise dans le respect du secret medical des elements qui lui sont confies et dans le respect d’une impartialite stricte. La prise en charge des RPS necessite une action pluridisciplinaire impliquant le service de sante au travail mais egalement de nombreux autres interlocuteurs internes et externes a l’entreprise. Le medecin du travail coordonne la mise en place de procedures appropriees permettant d’identifier, comprendre et traiter des differents signalements de RPS.

BACKGROUND Recent global economic difficulties have widened social inequalities, but their impact on pregnant workers is not known. AIMS To investigate the association between deprivation, exposure to occupational hazards and adverse perinatal outcomes in pregnant workers. METHODS A cross-sectional study performed in 2014 in French occupational health services. Eligible workers were women who had worked during their pregnancy and had a medical visit by occupational health physicians (OHPs) after delivery and at the time of returning to work. Deprivation was measured using the EPICES scale (Evaluation of Precariousness and Inequalities in Health Examination Centres). Information on birth outcomes was self-reported. Occupational risks for pregnancy were assessed by OHPs. Jobs were coded by the occupational health team using standardized French nomenclature. The groups (deprivation/no deprivation) were compared using univariate (chi-squared test) and multivariate Poisson regression analyses. RESULTS Of 1402 pregnant workers, 293 (21%) were classed as deprived. This group more frequently encountered occupational hazards, particularly for physical exposures (P < 0.001), and had a higher risk of cumulated occupational hazards of three or more for pregnancy [adjusted relative risk (RRa) = 4.2; 95% confidence interval (CI) 2.2-7.9]. Our findings suggest that deprivation and exposure to three or more occupational hazards during pregnancy cumulatively increased the risk of pre-term birth (RRa = 3.9; 95% CI 1.2-12.4). CONCLUSIONS Our data suggest that deprived pregnant workers are an occupationally vulnerable group.

Resume L’Agence nationale de securite sanitaire de l’alimentation, de l’environnement et du travail (ANSES) assure des missions de veille, d’expertise, de recherche et de reference sur un large champ couvrant la sante humaine, la sante et le bien-etre animal, et la sante vegetale. Elle a ete creee le 1er juillet 2010 par la fusion de deux agences sanitaires francaises : l’Agence francaise de securite sanitaire des aliments (AFSSA) et l’Agence francaise de securite sanitaire de l’environnement et du travail (AFSSET). L’ANSES intervient dans les domaines du travail, de l’environnement, de l’alimentation, de la sante et du bien-etre des animaux, de la sante des vegetaux avec un objectif prioritaire : contribuer a assurer la securite des travailleurs et des consommateurs. Pour elaborer des recommandations de sante publique credibles et efficaces, l’ANSES met en œuvre une expertise scientifique independante, pluridisciplinaire, collective et contradictoire. Elle s’appuie sur un ensemble de comites et de groupes d’experts specialises et developpe l’apport des sciences humaines et sociales a son expertise scientifique. L’evaluation des risques est le cœur des missions de l’ANSES. Les grandes etapes du dispositif sont : la saisine ; la realisation de l’evaluation par le(s) comite(s) d’experts specialise(s) concerne(s) par la thematique ; la remise du rapport d’expertise signe de ses rapporteurs ; la publication de l’avis et des recommandations de l’Agence signes par son directeur general. Sous reserve du respect des secrets proteges par la loi, et notamment des informations couvertes par le secret industriel et commercial, les avis et recommandations de l’Agence sont rendus publics sur le site internet de l’ANSES. Une selection d’avis ou de rapports publies par l’ANSES en 2012 est presentee.

Resume Parce qu’elles quantifient les relations entre l’exposition a une substance chimique et l’effet sur la sante, les valeurs toxicologiques de reference (VTR) sont des parametres determinants pour les resultats des calculs des evaluations des risques sanitaires. De nombreux organismes proposent des VTR dans des bases de donnees accessibles sur Internet. La France s’est engagee depuis 2004 dans la construction de ses propres VTR. La recherche et le choix des VTR sont complexes et chronophages. L’Institut de veille sanitaire (InVS) a developpe un moteur de recherche Furetox (faciliter l’usage des ressources toxicologiques) accessible par Internet. Furetox vise a elargir le champ de la recherche sur Internet et en raccourcir les delais. En particulier, pour une substance chimique donnee, Furetox permet d’acceder rapidement aux VTR, de faciliter l’acces aux documents detaillant leur construction et d’acceder a la classification de la cancerogenicite. Furetox encourage aussi l’expertise critique, en donnant quelques reperes (des fiches de lecture pour chacune des bases) sur les methodes de construction de ces valeurs.

Resume Objectifs Face a de nombreux evenements depuis 20 ans, la forte pression des citoyens, de la presse et des tribunaux, les pouvoirs politiques ont profondement remodele l’approche de l’environnement, notamment de son impact sur la sante. De nombreux organismes publics ont ete crees ou ont vu leurs missions reorientees. Cet article decrit les principaux organismes publics intervenant dans le champ sante et environnement afin de permettre a chacun de reperer qui fait quoi dans ce domaine en France et ou trouver information et aide. Methode Les differents organismes publics intervenant dans le domaine de l’environnement, sous l’angle notamment de son impact sur la sante sont presentes. Leurs principales missions, leurs actions dans le champ sante-environnement sont resumees. La majorite des informations sur ces organismes sont issues de leurs sites Internet. Seuls les organismes publics ou parapublics sont decrits. Resultats Les activites des 19 organismes publics intervenant dans ce domaine (InVS, IRSN, ADEME, Ineris, Inserm, EHESP, INPES…) sont presentes, ainsi que certains Conseils nationaux, commissions ou observatoires. Leurs principales competences sont relatees, permettant ainsi aux lecteurs de reperer qui fait quoi en France pour etudier l’impact de l’environnement sur la sante et ou trouver l’information. Conclusion Du fait du nombre important des structures et de la diversite des themes englobes dans ce domaine, cette presentation n’est pas exhaustive et est centree sur les structures dont l’activite principale concerne l’environnement et la sante ou dont l’activite peut en priorite interesser les acteurs de la prevention notamment des services de sante au travail.

Resume Objectif L’objectif de cet article est de presenter le deuxieme plan national sante–environnement qui vient d’etre publie pour les annees 2009–2013. Methode Le Plan national sante–environnement (PNSE 2), qui decrit le plan d’action de l’Etat dans ce domaine pendant ces cinq annees, vient d’etre publie. La publication de ce plan tous les cinq ans est prevue dans le Code de la sante. Il s’agit du deuxieme plan publie dans ce cadre. Resultats Ce plan decline les engagements du Grenelle de l’environnement en matiere de sante–environnement. Il a ete redige par un groupe de travail reunissant divers experts. Il aborde conjointement : environnement domestique, exterieur, mais aussi environnement professionnel. Deux axes prioritaires sont retenus : reduire les expositions responsables de pathologies a fort impact sur la sante ; reduire les inegalites environnementales. Ce PNSE est decompose en 16 fiches qui comprennent au total 58 actions. Il comprend egalement 12 mesures phares. Conclusion Ce deuxieme plan confirme que le premier PNSE n’etait qu’une premiere demarche pour mieux prendre en compte l’impact de l’environnement sur la sante. Il represente une veritable chance pour la sante publique a condition que chacun sache s’en emparer pour ameliorer la qualite de la vie.

European regulations (transcribed into French law) aimed at protecting employees from chemicals toxic to reproduction enable classification and labelling of such substances, if they are liable to cause an alteration of male or female reproductive functions or capacity, or to induce non-hereditary harmful effects on their offspring. Three categories can be used to classify these substances in two areas, namely their impairment of fertility and their effects on development. This classification is rarely based on epidemiological study results, but most often on those of experimental toxicological studies conducted by substance manufacturers. These reproduction toxicological studies are only compulsory above a certain tonnage placed on the market. The high level of this tonnage means that these tests are effectively only conducted on rare occasions. It is reckoned that there is no reproduction experimental data for over 95% of substances newly placed on the market. These products therefore appear to be reproduction non-toxic only because they have not been tested. This is a major fault in the current labelling system, which does not allow non-toxic products to be differentiated from non-tested products. The future EU regulatory framework for Registration, Evaluation and Authorisation of CHemicals (REACH) will only slightly enhance information in this area. It can be estimated that over 80% of chemical products will not be exhaustively tested for reproduction and nearly 75% will not be tested to any degree.

A new actively cooled advanced launcher is being built for Tore Supra LHCD to inject 4 MW during 1000 s at 3.7 GHz, at a power density of 25 MW/m 2 (a conservative value observed in Tore Supra experiments). It is made from an array of 6×48 active and 6×9 passive waveguides. The design uses technologies which are relevant for a next step machine such that it can: (i) withstand a plasma radiated flux of 0.15 MW/m 2 ; (ii) radiate power with spectra having peak N// values of 2.02±0.35; (iii) withstand a total torque of 8.6 10 4 N m during disruptions; (iv) allow an antenna 20 cm radial stroke adjustable in real time, (v) withstand a convected power flux of 10 MW/m 2 on its guard limiter made of CFC tiles. A prototype of each new component of this antenna has been tested successfully at the nominal power with a pulse length of 1000 s.

Objectif Decrire les situations de precarite (SP) chez les femmes enceintes au travail en mesurant leur prevalence, les expositions professionnelles a risque, les mesures de prevention et les relations avec la prematurite. Methode Il a ete conduit une etude transversale en services interentreprises de sante au travail en 2014. Les salariees recues apres leur accouchement par le medecin du travail (MT) repondaient a un auto-questionnaire. L’exposition a des risques professionnels pour la grossesse etait evaluee par le MT (physiques, chimiques, biologiques, organisationnels). La SP etait mesuree a partir de l’echelle EPICES. Utilisant la nomenclature des categories socioprofessionnelles de l’Insee (version 2003), le codage des emplois etait realise par les equipes de MT et controle par un codeur experimente. L’information sur la prematurite etait recueillie aupres des salariees. Les deux groupes (precarite/non-precarite) ont ete compares en utilisant des analyses unifactorielles (tests du χ2) et multifactorielles basees sur une regression de Poisson. Resultats Parmi 1402 salariees enceintes recrutees par 83 MT, 293 salariees (21 %) etaient classees en SP. Les SP concernaient plus particulierement les employees et les ouvrieres mais egalement certaines professions intermediaires. Il emergeait une association significative (p Conclusion Ces resultats soulignent l’interet de reperer les SP des femmes enceintes au travail d’autant plus qu’elles sont plus souvent exposees a des risques professionnels pour la grossesse. L’impact sur la prematurite doit etre confirme par d’autres etudes.

International audience

European regulations (transcribed into French law) aimed at protecting employees from chemicals toxic to reproduction enable classification and labelling of such substances, if they are liable to cause an alteration of male or female reproductive functions or capacity, or to induce non-hereditary harmful effects on their offspring. Three categories can be used to classify these substances in two areas, namely their impairment of fertility and their effects on development. This classification is rarely based on epidemiological study results, but most often on those of experimental toxicological studies conducted by substance manufacturers. These reproduction toxicological studies are only compulsory above a certain tonnage placed on the market. The high level of this tonnage means that these tests are effectively only conducted on rare occasions. It is reckoned that there is no reproduction experimental data for over 95% of substances newly placed on the market. These products therefore appear to be reproduction non-toxic only because they have not been tested. This is a major fault in the current labelling system, which does not allow non-toxic products to be differentiated from non-tested products. The future EU regulatory framework for Registration, Evaluation and Authorisation of CHemicals (REACH) will only slightly enhance information in this area. It can be estimated that over 80% of chemical products will not be exhaustively tested for reproduction and nearly 75% will not be tested to any degree.

Seven superconducting focusing magnets have been constructed for vertical gyrotrons devoted to the plasma heating of the tokomak Tore Supra. The performances in magnetic field strength, profile and homogeneity are spread over a large range so as to suit gyrotrons of microwave frequencies extending from 110 GHz to 150 GHz. The cryostats have a low consumption in cryogenic fluids which insure a one week autonomy. >

Introduction Cowden disease belongs to the PTEN hamartoma tumor syndrome (PHTS) group, defined by germline PTEN heterozygous inactivation. Describing the PTEN germline mutation in Cowden disease patients is of particular importance for their breast cancer and thyroid carcinoma predisposition evaluation. Material & methods Targeted resequencing was done on germline DNA of 22 index cases patients with a Cowden disease clinically well established since they do not demonstrate any PTEN mutation analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). The 565 exons of 34 genes of interest together with the entire genomic locus of PTEN were captured using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Suredesign, Ensembl human genome v70 and a UCSC repeat masker least stringent were used to create the capture design. This gave us 28405 unique 120-mers oligonucleotide probes which were duplicated 1 to 16 times depending on the GC content or the size of the targeted regions (maximum boosting performance criteria). For each gene of interest, an exon of the surrounding gene was also captured in order to define the extent of gross gene rearrangement. Samples were prepared according the manufacturer's recommendations. Results Each of the 22 Cowden disease patients demonstrates a mean rate of 70 intronic mutations in the entire genomic locus of PTEN. All of those for which the minor allelic frequency is unknown, were subjected to splicing site bioinformatic prediction. For one patient, the prediction reveals the apparition of a splicing site in a deep intronic mutation of the large intron 1 of PTEN. Furthermore, next generation sequencing (NGS) seems to be more sensitive than our current screening method since for two patients, a germline mosaic exonic heterozygous inactivating mutation of PTEN was detected and confirmed by Sanger sequencing on different biological samples. The level of mosaicism was evaluated by NGS at 3 to 12% depending on the sample and confirmed by pyrosequencing. In addition, some mutations were identified in exons of genes encoding proteins of the PI3Kinase pathway, which could be involved in disease belonging to the PHTS group. With an increasing sensitivity, NGS is a powerful tool to detect low frequency variant. This could used to explain at a molecular level Cowden disease with no initially detectable PTEN mutation. Clinical and biological rationale, bioinformatics workflow and comprehensive results will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-04.

Archives des Maladies Professionnelles et de l'Environnement - Vol. 69 - N° 5-6 - p. 758-759

Introduction: Next-generation sequencing (NGS) appears to be an accurate tool adapted for molecular oncogenetics. In contrast to certain somatic mutations, a lack of germline mutation hotspots in genes involved in cancer predisposition syndromes, especially hereditary breast and ovarian cancer (HBOC), force the molecular biologist to screen the entire coding sequence. Material & methods: In order to screen a panel of genes predominantly involved in HBOC & Cowden disease in a molecular diagnostic setting, we captured 408 exons (and their surrounding intronic sequences) of 25 genes using the SureSelect oligonucleotide library capture (Agilent technologies). The bioinformatics resources Earray (Agilent technologies), Ensembl human genome v62 and UCSC repeat masker were used to create the capture design. This gave us 2899 unique 120-mers oligonucleotide probes which were duplicated 19 to 38 times depending on the GC content or the size of the targeted regions. Germline DNA of 190 patients (40 with previously identified mutations and 150 without previous molecular genetic analysis) was sequenced using a MiSeq bench top next-generation sequencer (Illumina) and in parallel was analyzed using our current screening method (EMMA, Enhanced Mismatch Mutation Analysis, similar to high resolution melting). Samples were prepared according the manufacturer's recommendations (Agilent technologies). Results: All previously identified mutations along with 33 mutations in previously unscreened patients were detected. In addition, more than five hundred variants described as polymorphisms were identified. NGS seems to be more sensitive than our current screening method due to its detection and identification of homozygous variants. In order to limit the interpretation time, we restricted sequence analysis to the exon, −50 bp (including the acceptor splice site of the upstream intron) and +50 bp (including the donor splice site of the downstream intron). We have validated NGS as a technique adapted for germline mutation screening in oncogenetics. From the beginning of 2013, all germline DNA samples will be screened by NGS for oncogenetic molecular diagnostics. Sample preparation, technical organization, bioinformatics workflow and comprehensive results will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD05-04.

Abstract #1102 Background : Recent studies showed that large genetic rearrangements (duplication or deletion of one or several exons) are of great importance in genetic diseases. Only few methods such as QMPSF and MLPA fit a routine use for these large deletions and duplications. They have to be performed additionally to a point mutation detection method (usually sequencing or dHPLC), which is labor intensive, time consuming and expensive. We present here a method called Enhanced Mismatch Mutation Analysis (EMMA) based on heteroduplex analysis that offers great sensitivity for point mutation detection and simultaneously detection of gross gene rearrangement by capillary electrophoresis. Material and Methods : EMMA is able to detect point mutations in PCR fragment ranging from 200 bp to 550 bp. It is thus possible to perform size multiplexing and analyze up to 6 fragments in the same run. PCR multiplex fragments of different sizes are prepared by semi-quantitative PCR. Separations are performed in multi-capillary electrophoresis. Poly(acrylamide-g-poly(dimethylacrylamide)) is used as a self coating sieving matrix; this separation matrix contains also additives like free nucleotides for a better sensitivity. One of the fragment is chosen as a reference for peak area normalization. Results : A series of 30 patients has been screened for BRCA1 and BRCA2 genes simultaneously by EMMA and the classical package dHPLC-QMPSF. All mutations and polymorphism detected by dHPLC have been detected by EMMA and new polymorphisms have been characterized for those genes. Furthermore, we will present the whole results of the positive mutation controls of BRCA1 and BRCA2 of the Institut Bergonie molecular genetic lab database screened by EMMA. Discussion : Using a unique condition of capillary electrophoresis separation for a lower number of PCR reaction for each gene (9 for BRCA1 and 15 for BRCA2), EMMA demonstrates a 5 times saving of lab time for technician, and displays a large easiness to use it in a routine way for molecular diagnosis. Finally this technology will benefit of a grant of French Ministry of Industry to be spread in molecular lab of Comprehensive Cancer Centers. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1102.

Infectious embolic retinopathy occurring secondary to a bacterial endocarditis is described in a 38-year-old woman with known aortic disease. The infectious organism was a haemophilus parainfluenzae confirmed by serial blood cultures and characterized by an embolic power equal to fungal infection. After four-weeks period of appropriate and intensive antibiotic therapy, blood cultures became negative but new emboli were observed in the fundus. This report describes ocular lesions rarely observed in endogenous bacterial retinitis. The delay between the bacterial endocarditis and the occurrence of the retinitis emphasizes the need for a long-term follow-up. Ophthalmologic examination can be acline for changing the heart valve.

Intravenous glucagon has been advocated as a useful adjunct to intraoperative cholangiography. Thirty patients scheduled for elective cholecystectomy were entered into a prospective, randomized, double-blind study to test the effects of glucagon on intraoperative cholangiography. All patients randomly received either glucagon or normal saline (control group) and had two cholangiograms taken at one and five minutes after injection during the course of the cholecystectomy. The films were scored in a blinded fashion by both radiologists and the operating surgeon, and scores were compared between the control subjects and the study group. There was no significant statistical improvement in cholangiograms obtained after glucagon injection (alpha = .05).