Search

International audience; The anti-Müllerian hormone (AMH) is a heterodimeric glycoprotein belonging to the TGFb superfamily implicated in human embryonic development. This hormone was first described as allowing regression of the epithelial embryonic Müllerian structures in males, which would otherwise differentiate into the uterus and fallopian tubes. It activates a signaling pathway mediated by two transmembrane receptors. Binding of AMH to its receptor induces morphological changes leading to the degeneration of Müllerian ducts. Recently, new data has shown the role played by this hormone on structures other than the genital tract. If testicular AMH expression decreases in humans over the course of a lifetime, synthesis may persist in other tissues in adulthood. The mechanisms underlying its production have been unveiled. The aim of this review is to describe the different pathways in which AMH has been identified and plays a pivotal role.

International audience; The oocyte microenvironment constituted by the follicular fluid (FF) is a key for the optimal development of female gametes. Its composition reflects the physiological state of the ovarian follicle. The particularity of FF is to contain a huge diversity of extracellular vesicles specific to women, in the same way as seminal plasma in men. Here, we described and compared morphological aspects of broad subcategories of human FF-related Extracellular Vesicles (EVs). EVs participate in physiological and pathological processes and have potential applications in diagnostics or therapeutics. EVs isolated from FF are involved in different biological functions related to follicular growth, oocyte maturation, and embryo development. However, knowledge on the morphology of FF-derived EVs is limited, mainly due to their sub-micrometer size and to intrinsic limitations in methods applied for their characterization. The aim of this study was to provide a comprehensive morphological description of EVs from FF of healthy subjects and quantification. EVs separation was realized by centrifugation, with comparison of the EV yield obtained from differential centrifugation and one-step ultracentrifugation. Cryo-Transmission Electron Microscopy was used to reveal the morphology, size, and phenotype of EVs. Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) were used to quantify and analyze the size distribution for each centrifugation step. We performed a comprehensive inventory of human follicular fluid EVs. We show that human FF contains a huge diversity of EVs. This study brings novel insights on EVs from normal FF and provides a reference for further studies of EVs in ovarian diseases.

Background Stratifying risk of postoperative pulmonary complications after major abdominal surgery allows clinicians to modify risk through targeted interventions and enhanced monitoring. In this study, we aimed to identify and validate prognostic models against a new consensus definition of postoperative pulmonary complications. Methods We did a systematic review and international external validation cohort study. The systematic review was done in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched MEDLINE and Embase on March 1, 2020, for articles published in English that reported on risk prediction models for postoperative pulmonary complications following abdominal surgery. External validation of existing models was done within a prospective international cohort study of adult patients (≥18 years) undergoing major abdominal surgery. Data were collected between Jan 1, 2019, and April 30, 2019, in the UK, Ireland, and Australia. Discriminative ability and prognostic accuracy summary statistics were compared between models for the 30-day postoperative pulmonary complication rate as defined by the Standardised Endpoints in Perioperative Medicine Core Outcome Measures in Perioperative and Anaesthetic Care (StEP-COMPAC). Model performance was compared using the area under the receiver operating characteristic curve (AUROCC). Findings In total, we identified 2903 records from our literature search; of which, 2514 (86·6%) unique records were screened, 121 (4·8%) of 2514 full texts were assessed for eligibility, and 29 unique prognostic models were identified. Nine (31·0%) of 29 models had score development reported only, 19 (65·5%) had undergone internal validation, and only four (13·8%) had been externally validated. Data to validate six eligible models were collected in the international external validation cohort study. Data from 11 591 patients were available, with an overall postoperative pulmonary complication rate of 7·8% (n=903). None of the six models showed good discrimination (defined as AUROCC ≥0·70) for identifying postoperative pulmonary complications, with the Assess Respiratory Risk in Surgical Patients in Catalonia score showing the best discrimination (AUROCC 0·700 [95% CI 0·683–0·717]). Interpretation In the pre-COVID-19 pandemic data, variability in the risk of pulmonary complications (StEP-COMPAC definition) following major abdominal surgery was poorly described by existing prognostication tools. To improve surgical safety during the COVID-19 pandemic recovery and beyond, novel risk stratification tools are required. Funding British Journal of Surgery Society.

Background Skeletal muscle wasting is a devastating consequence of cancer that affects up to 80% of cancer patients and associates with reduced survival. Herein, we investigated the biological significance of Forkhead box P1 (FoxP1), a transcriptional repressor that we demonstrate is up‐regulated in skeletal muscle in multiple models of cancer cachexia and in cachectic cancer patients. Methods Inducible, skeletal muscle‐specific FoxP1 over‐expressing (FoxP1iSkmTg/Tg) mice were generated through crossing conditional Foxp1a transgenic mice with HSA‐MCM mice that express tamoxifen‐inducible Cre recombinase under control of the skeletal muscle actin promoter. To determine the requirement of FoxP1 for cancer‐induced skeletal muscle wasting, FoxP1‐shRNA was packaged and targeted to muscles using AAV9 delivery prior to inoculation of mice with Colon‐26 Adenocarcinoma (C26) cells. Results Up‐regulation of FoxP1 in adult skeletal muscle was sufficient to induce features of cachexia, including 15% reduction in body mass (P

© The Author(s), under exclusive licence to Springer Nature Limited 2021, corrected publication 2022, The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world., This project was supported by funds from: the Amazon Web Services (AWS) Imagine Grant (to E.M.B.); the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (JSPS KAKENHI; 16h03079, 17h00875, 18k12015, and 20h04581 to Y.Y.); the research programme Dipartimenti di Eccellenza from the Ministry of Education University and Research (MIUR to N. Cellini and G.M. and the Department of General Psychology of the University of Padua); statutory funds of the University of Wroclaw (to A. Sorokowska); the Charles University Research Programme PROGRES (Q18 to M. Vranka); the Knut and Alice Wallenberg Foundation (2016:0229 to J.K.O.); the Rubicon Grant (019.183sg.007 to K.v.S.) from the Netherlands Organisation for Scientific Research; the Australian Research Council (dp180102384 to R.M.R.); the US National Institutes of Health (NIMH111640 to M.N.-D.), the Huo Family Foundation to N.J.; the NSF Directorate for Social, Behavioral and Economic Sciences, Division of Social and Economic Sciences (1559511 to J.S.L.); the US National Institutes of Health (RO1-CA-224545 to J.S.L.); Eesti Teadusagentuur–Estonian Research Council (PSG525 to A. Uusberg); the J. William Fulbright Program (to F. Azevedo); the HSE Basic Research Program (to D. Dubrov); Dominican University (a Faculty Development Grant to A. Krafnick); and the French National Research Agency Investissements d’avenir supporting PSF (ANR-15-IDEX-02 to H.I.); the Slovak Research and Development Agency (project no. APVV-20-0319 to M. Adamkovič); the programme FUTURE LEADER of Lorraine Université d’Excellence within the French National Research Agency Investissements d’avenir (ANR-15-IDEX-04-LUE to S.M.). Computation for this research was assisted by: the Harvard Business School compute cluster (HBSGrid); and the Open Science Grid. The Open Science Grid is supported by the National Science Foundation award 1148698 and the US Department of Energy’s Office of Science, as well as by the compute resources and assistance of the UW-Madison Center For High Throughput Computing (CHTC) in the Department of Computer Sciences. The CHTC is supported by UW-Madison, the Advanced Computing Initiative, the Wisconsin Alumni Research Foundation, the Wisconsin Institutes for Discovery, and the National Science Foundation, and is an active member of the Open Science Grid, which is supported by the National Science Foundation and the U.S. Department of Energy’s Office of Science.

International audience; Mutations leading to haploinsufficiency in SCN5A, the gene encoding the cardiac sodium channel Na v 1.5 α-subunit, are involved in life-threatening cardiac disorders. Using CRISPR/Cas9-mediated genome edition, we generated here a human induced-pluripotent stem cell (hiPSC) line carrying a heterozygous mutation in exon 2 of SCN5A, which leads to apparition of a premature stop codon. SCN5A-clone 5 line maintained normal karyotype, morphology and pluripotency and differentiated into three germ layers. Cardiomyocytes derived from these hiPSCs would be a useful model for investigating channelopathies related to SCN5A heterozygous deficiency.

Pathogenic variants inThe present study sought to examine whether Nav1.5 channels can cooperate, or transcomplement each other, to rescue the Na+ current (INa). Such a mechanism could contribute to explain the genotype-phenotype discordance often observed in family members carrying Na+-channel pathogenic variants.Patch-clamp and immunocytochemistry analysis were used to investigate biophysical properties and cellular localization in HEK293 cells and rat neonatal cardiomyocytes transfected respectively with WT and 3 mutant channels chosen for their particular trafficking and/or gating properties.As previously reported, the mutant channels G1743R and R878C expressed alone in HEK293 cells both abolished INa, G1743R through a trafficking deficiency and R878C through a gating deficiency. Here, we showed that coexpression of both G1743R and R878C nonfunctioning channels resulted in a partial rescue of INa, demonstrating a cooperative trafficking of Nav1.5 α-subunits. Surprisingly, we also showed a cooperation mechanism whereby the R878C gating-deficient channel was able to rescue the slowed inactivation kinetics of the C-terminal truncated R1860X (ΔCter) variant, suggesting coupled gating.Altogether, our results add to the evidence that Nav channels are able to interact and regulate each other's trafficking and gating, a feature that likely contributes to explain the genotype-phenotype discordance often observed between members of a kindred carrying a Na+-channel pathogenic variant.

Discrepant results have been reported regarding an intramuscular mechanism underlying the ergogenic effect of caffeine on neuromuscular function in humans. Here, we reevaluated the effect of caffeine on muscular force production in humans and combined this with measurements of the caffeine dose-response relationship on force and cytosolic free [Ca2+] ([Ca2+]i) in isolated mouse muscle fibers. Twenty-one healthy and physically active men (29 ± 9 yr, 178 ± 6 cm, 73 ± 10 kg, mean ± SD) took part in the present study. Nine participants were involved in two experimental sessions during which supramaximal single and paired electrical stimulations (at 10 and 100 Hz) were applied to the femoral nerve to record evoked forces. Evoked forces were recorded before and 1 h after ingestion of 1) 6 mg caffeine/kg body mass or 2) placebo. Caffeine plasma concentration was measured in 12 participants. In addition, submaximal tetanic force and [Ca2+]iwere measured in single mouse flexor digitorum brevis (FDB) muscle fibers exposed to 100 nM up to 5 mM caffeine. Six milligrams of caffeine per kilogram body mass (plasma concentration ~40 µM) did not increase electrically evoked forces in humans. In superfused FDB single fibers, millimolar caffeine concentrations (i.e., 15- to 35-fold above usual concentrations observed in humans) were required to increase tetanic force and [Ca2+]i. Our results suggest that toxic doses of caffeine are required to increase muscle contractility, questioning the purported intramuscular ergogenic effect of caffeine in humans.

The effectiveness of neuromuscular electrical stimulation (NMES) for rehabilitation is proportional to the evoked torque. The progressive increase in torque (extra torque) that may develop in response to low intensity wide-pulse high-frequency (WPHF) NMES holds great promise for rehabilitation as it overcomes the main limitation of NMES, namely discomfort. WPHF NMES extra torque is thought to result from reflexively recruited motor units at the spinal level. However, whether WPHF NMES evoked force can be modulated is unknown. Therefore, we examined the effect of two interventions known to change the state of spinal circuitry in opposite ways on evoked torque and motor unit recruitment by WPHF NMES. The interventions were high-frequency transcutaneous electrical nerve stimulation (TENS) and anodal transcutaneous spinal direct current stimulation (tsDCS). We show that TENS performed before a bout of WPHF NMES results in lower evoked torque (median change in torque time-integral: − 56%) indicating that WPHF NMES-evoked torque might be modulated. In contrast, the anodal tsDCS protocol used had no effect on any measured parameter. Our results demonstrate that WPHF NMES extra torque can be modulated and although the TENS intervention blunted extra torque production, the finding that central contribution to WPHF NMES-evoked torques can be modulated opens new avenues for designing interventions to enhance WPHF NMES.

Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. in this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution., Vienna Science and Technology Fund [WWTF VRG13-007]; ERCEuropean Research Council (ERC)European Commission [647910]; CONICET, ArgentinaConsejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET); European Social Fund (Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pecs) [EFOP-3.6.1.-16-2016-00004]; Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission [PZ00P1_154911]; Social Sciences and Humanities Research Council of Canada (SSHRC)Social Sciences and Humanities Research Council of Canada (SSHRC)CGIAR; Comunidad de MadridComunidad de Madrid [2016-T1/SOC-1395]; AEI/FEDER UE [PSI2017-85159-P]; National Science Centre, PolandNational Science Centre, Poland [2015/19/D/HS6/00641]; Joep Lange Institute; Slovak Research and Development AgencySlovak Research and Development Agency [APVV-17-0418]; French National Research Agency 'Investissements d'Avenir' programme grantFrench National Research Agency (ANR) [ANR-15-IDEX-02]; Australian Government Research Training Program ScholarshipAustralian GovernmentDepartment of Industry, Innovation and Science; University Grants Commission, New Delhi, IndiaUniversity Grants Commission, India; Department of Psychology, University of Gothenburg; Beijing Natural Science FoundationBeijing Natural Science Foundation [5184035]; CAS Key Laboratory of Behavioral Science, Institute of Psychology; National Science Foundation Graduate Research FellowshipNational Science Foundation (NSF) [R010138018], C.L. was supported by the Vienna Science and Technology Fund (WWTF VRG13-007); L.M.D. was supported by ERC 647910 (KINSHIP); D.I.B. and N.I. received funding from CONICET, Argentina; L.K., F.K. and A. Putz were supported by the European Social Fund (EFOP-3.6.1.-16-2016-00004; `Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pecs'). K.U. and E. Vergauwe were supported by a grant from the Swiss National Science Foundation (PZ00P1_154911 to E. Vergauwe). T.G. is supported by the Social Sciences and Humanities Research Council of Canada (SSHRC). M.A.V. was supported by grants 2016-T1/SOC-1395 (Comunidad de Madrid) and PSI2017-85159-P (AEI/FEDER UE). K.B. was supported by a grant from the National Science Centre, Poland (number 2015/19/D/HS6/00641). J. Bonick and J.W.L. were supported by the Joep Lange Institute. G.B. was supported by the Slovak Research and Development Agency (APVV-17-0418). H.I.J. and E.S. were supported by a French National Research Agency 'Investissements d'Avenir' programme grant (ANR-15-IDEX-02). T.D.G. was supported by an Australian Government Research Training Program Scholarship. The Raipur Group is thankful to: (1) the University Grants Commission, New Delhi, India for the research grants received through its SAP-DRS (Phase-III) scheme sanctioned to the School of Studies in Life Science; and (2) the Center for Translational Chronobiology at the School of Studies in Life Science, PRSU, Raipur, India for providing logistical support. K. Ask was supported by a small grant from the Department of Psychology, University of Gothenburg. Y.Q. was supported by grants from the Beijing Natural Science Foundation (5184035) and CAS Key Laboratory of Behavioral Science, Institute of Psychology. N.A.C. was supported by the National Science Foundation Graduate Research Fellowship (R010138018). We acknowledge the following research assistants: J. Muriithi and J. Ngugi (United States International University Africa); E. Adamo, D. Cafaro, V. Ciambrone, F. Dolce and E. Tolomeo (Magna Graecia University of Catanzaro); E. De Stefano (University of Padova); S. A. Escobar Abadia (University of Lincoln); L. E. Grimstad (Norwegian School of Economics (NHH)); L. C. Zamora (Franklin and Marshall College); R. E. Liang and R. C. Lo (Universiti Tunku Abdul Rahman); A. Short and L. Allen (Massey University, New Zealand), A. Ates, E. Gunes and S. Can Ozdemir (Bogazici University); I. Pedersen and T. Roos (Abo Akademi University); N. Paetz (Escuela de Comunicacion Monica Herrera); J. Green (University of Gothenburg); M. Krainz (University of Vienna, Austria); and B. Todorova (University of Vienna, Austria). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Maintenance of cell proteostasis relies on two degradation pathways: proteasome and autophagy. Here we describe a new proteostasis pathway avoiding degradation of abnormal proteins yet carrying them outside the cell using nanovesicles called myelinosomes. These myelinosomes are produced in pathological or stress situations in relation with genetic or environmental factors. Myelinosome vesicles are nano-sized multi-stacked membrane structures, resembling myelin sheath. It has recently been shown in two models of genetic diseases (Huntington's disease and cystic fibrosis) that myelinosomes are important for eliminating mutant proteins in an unusual secretory process, thus preventing their accumulation and aggregation in cells.Les myélinosomes : une nouvelle voie du contrôle de qualité des protéines.Deux voies de dégradation des protéines mal repliées sont classiquement décrites : la voie du protéasome et la voie de l’autophagie. Nous décrivons ici une nouvelle voie de protéostase cellulaire ne dégradant pas la protéine anormale mais l’expulsant hors de la cellule grâce à des nanovésicules appelées myélinosomes. Ces myélinosomes sont produits par la cellule dans des situations pathologiques ou de stress en lien avec des facteurs génétiques ou environnementaux. Sur le plan morphologique, les myélinosomes sont caractérisés par des membranes osmiophiles denses aux électrons dont l’arrangement empilé est semblable à celui de la myéline et présente jusqu’à 30 feuillets selon le type de cellule. Dans deux modèles, au moins, de maladies génétiques (la maladie de Huntington et la mucoviscidose), les myélinosomes sont importants pour éliminer les protéines mutées par un processus sécrétoire inhabituel, évitant ainsi leur agrégation dans les cellules.

Background: Genetic variants in voltage-gated sodium channels (Nav) encoded by SCNXA genes, responsible for INa, and Kv4.3 channels encoded by KCND3, responsible for the transient outward current (Ito), contribute to the manifestation of both Brugada syndrome (BrS) and spinocerebellar ataxia (SCA19/22). We examined the hypothesis that Kv4.3 and Nav variants regulate each other’s function, thus modulating INa/Ito balance in cardiomyocytes and INa/I(A) balance in neurons. Methods: Bicistronic and other constructs were used to express WT or variant Nav1.5 and Kv4.3 channels in HEK293 cells. INa and Ito were recorded. Results: SCN5A variants associated with BrS reduced INa, but increased Ito. Moreover, BrS and SCA19/22 KCND3 variants associated with a gain of function of Ito, significantly reduced INa, whereas the SCA19/22 KCND3 variants associated with a loss of function (LOF) of Ito significantly increased INa. Auxiliary subunits Navβ1, MiRP3 and KChIP2 also modulated INa/Ito balance. Co-immunoprecipitation and Duolink studies suggested that the two channels interact within the intracellular compartments and biotinylation showed that LOF SCN5A variants can increase Kv4.3 cell-surface expression. Conclusion: Nav and Kv4.3 channels modulate each other’s function via trafficking and gating mechanisms, which have important implications for improved understanding of these allelic cardiac and neuronal syndromes.

National audience; Development of genetic testing direct-to-consumer (DTC) for recreational purposes, although prohibited in France, is a real challenge to the current practice of gamete donation. Indeed, anonymity is a fundamental principle contributing to the ethics of donation. This principle is weakened due to the availability to the general public of these tests on the Internet. Several thousands of people are conceived by gamete donation worldwide, some of whom do not know how they were conceived. Gamete donors should be informed that their anonymity is no longer guaranteed, as they can be found by homologies of their DNA, or that of a parent or a child, potentially available in databases. Thus, adults conceived by gamete donation but not informed by their parents can discover their way of conception. Recipients of gamete donation should also be informed that their child's DNA will establish the biological discrepancy and they should be encouraged to disclose the conception to their child. Several countries now allow children conceived by donation to obtain donor's identity. In France, the Bioethics Law is currently being finalized and will now allow access to donor's identity for people conceived by gamete donation.

International audience; Seminal plasma is particularly rich in extracellular vesicles. Myelinosomes are membranous organelles described throughout the seminiferous epithelium of the testis but never reported in semen. Our aim was to determine the presence of myelinosomes in human seminal plasma. Transmission electron microscopy and cryo electron microscopy analysis of standard myelinosome preparation from TM4 Sertoli cells and human seminal plasma samples. We have specified by cryo-EM the morphological aspect of "standard" myelinosomes isolated from the culture media of TM4 Sertoli cells. Vesicles with the same morphological appearance were revealed in human seminal plasma samples. Human seminal plasma contains a population of large EV (average diameter 200 nm) whose morphological appearance resemble those of myelinosomes. Defining the specific biomarkers and functionalities of myelinosome in human seminal plasma are the concerns to be addressed in our further research.

International audience; Recently, four SCN5A mutations have been associated with Multifocal Ectopic Purkinje-related Premature Contractions (MEPPC), a rare cardiac syndrome combining polymorphic ventricular arrhythmia with dilated cardiomyopathy (DCM). Here, we identified a novel heterozygous mutation in SCN5A (c.611C>A, pAla204Glu) in a young woman presenting with polymorphic premature ventricular contractions (PVCs) and DCM. After failure of antiarrhythmic drugs and an attempt of radiofrequency catheter ablation showing three exit-sites of PVCs, all with presystolic Purkinje potentials, a treatment by hydroquinidine was tried, leading to an immediate and spectacular disappearance of all PVCs and normalization of cardiac function. Electrophysiological studies showed that Nav 1.5-A204E mutant channels exhibited a significant leftward shift of 8 mV of the activation curve, leading to a larger hyperpolarized window current when compared to wild-type. Action potential modeling using Purkinje fiber and ventricular cell models predicted an arrhythmogenic effect predominant in Purkinje fibers for the A204E mutation. Comparison with other MEPPC-associated Nav 1.5 mutations revealed a common electrophysiological pattern of abnormal voltage-dependence of activation leading to a larger hyperpolarized window current as a shared biophysical mechanism of this syndrome. These features of the mutant sodium channels are likely to be responsible for the hyperexcitability of the fascicular-Purkinje system observed in patients with MEPPC.

Infertility, a global problem affecting up to 15% of couples, can have varied causes ranging from natural ageing to the pathological development or function of the reproductive organs. One form of female infertility is premature ovarian insufficiency (POI), affecting up to 1 in 100 women and characterised by amenorrhoea and elevated FSH before the age of 40. POI can have a genetic basis, with over 50 causative genes identified. Non-obstructive azoospermia (NOA), a form of male infertility characterised by the absence of sperm in semen, has an incidence of 1% and is similarly heterogeneous. The genetic basis of male and female infertility is poorly understood with the majority of cases having no known cause. Here, we study a case of familial infertility including a proband with POI and her brother with NOA. We performed whole-exome sequencing (WES) and identified a homozygous STAG3 missense variant that segregated with infertility. STAG3 encodes a component of the meiosis cohesin complex required for sister chromatid separation. We report the first pathogenic homozygous missense variant in STAG3 and the first STAG3 variant associated with both male and female infertility. We also demonstrate limitations of WES for the analysis of homologous DNA sequences, with this variant being ambiguous or missed by independent WES protocols and its homozygosity only being established via long-range nested PCR.

Spermiogenesis, the ultimate stage of spermatogenesis, is a process involving autophagy. At this stage, the acrosome is generated by vesicular fusion and most of the cytoplasm disappears. Autophagy, literally "eating oneself", allowing the elimination and replacement of proteins and nonfunctional organelles, ensures the recycling of cellular constituents and is a highly conserved cellular mechanism within eukaryotic cells. The machinery of autophagy is present in the spermatozoon, regulating the vitality and mobility of the cells. The environmental and behavioral impact on autophagy and the consequences on spermatogenesis are beginning to be studied. The purpose of this review is to synthesize current knowledge about autophagy in the mature male gamete.Autophagie et spermatozoïde.La spermiogenèse, étape ultime de la spermatogenèse, est un processus qui fait intervenir des acteurs qui participe à l’autophagie. C’est en effet lors de cette étape que se forme l’acrosome par fusion vésiculaire et que disparaît la majeure partie du cytoplasme du spermatozoïde. L’autophagie (littéralement « se manger soi-même »), en permettant l’élimination et le remplacement continuel des protéines et des organites non fonctionnels, assure le recyclage des constituants de la cellule. C’est un mécanisme cellulaire très conservé au sein des cellules eucaryotes. La machinerie de l’autophagie est également présente dans les spermatozoïdes. Elle régule la vitalité de ces cellules et leur mobilité. Les conséquences environnementales et comportementales sur l’autophagie et sur la spermatogenèse commencent à être étudiées. Le but de cette revue est de synthétiser les connaissances actuelles concernant les processus d’autophagie dans le gamète mâle mature.

Purpose: To evaluate the etiology and extent of neuromuscular fatigue induced by 50 squat jumps performed with and without neuromuscular electrical stimulation (NMES) of the knee extensors. Methods: Nine healthy, recreationally active men (24 ± 2 y) took part in 2 experiments. These consisted of 50 squat jumps performed with stimulation (NMES) or without (CON). Maximal voluntary contraction (MVC) force, maximal voluntary activation level (VAL), and forces evoked by single and double (10 and 100 Hz) stimulations were recorded before and after the 50 jumps. NMES was delivered at the maximal tolerated intensity. Results: Despite average jump height being ∼16% lower in the NMES than in the CON session, a reduction over time in jump height was only found in the NMES condition (−6%). After the 50 jumps, MVC force was reduced to a greater extent in NMES than in CON (−25% ± 11% vs −11% ± 12%). Similarly, forces evoked by single stimulations, as well as by 10-Hz and 100-Hz paired stimulations, were reduced to a greater extent in NMES (−33% ± 12%, −42% ± 15%, and −25% ± 13%) than in CON (−21% ± 6%, −30% ± 9%, and −14% ± 11%). VAL was not significantly altered by either condition. Conclusion: Performing repeated squat jumps with concomitant NMES induced a greater fatigue than squat jumps performed alone and might potentially represent a stronger training stimulus.

International audience; Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies (related to the Y chromosome or to the autosomes) are validated genetic factors leading to spermatogenic quantitative defects with a frequency depending on the severity of the phenotype. The most frequent structural chromosomal rearrangements of autosomes are translocations and inversions, whereas dicentric chromosomes involving autosomes are rare. We report a man bearing a pseudodicentric chromosome (9;21) and presenting with oligozoospermia. Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome and to discount the presence of interstitial telomeric sequences. Defects in spermatogenesis and abnormal segregation at meiosis for existing spermatozoa are proposed and are the likely cause of the reproductive phenotype of the patient.

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. Significance: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.

STUDY QUESTION Do human granulosa cells (GCs) ingest and destroy apoptotic oocytes? SUMMARY ANSWER Somatic GCs ingest and destroy apoptotic oocytes and other apoptotic substrates through unconventional autophagy-assisted phagocytosis. WHAT IS KNOWN ALREADY Most (99%) ovarian germ cells undergo apoptosis through follicular atresia. The mode of cleaning of atretic follicles from the ovary is unclear. Ovarian GCs share striking similarities with testicular Sertoli cells with respect to their origin and function. Somatic Sertoli cells are responsible for the elimination of apoptotic spermatogenic cells through unconventional autophagy-assisted phagocytosis. STUDY DESIGN, SIZE, DURATION Human GCs were tested for the ability to ingest and destroy the apoptotic oocytes and other apoptotic substrates. A systemic study of the main phagocytosis steps has been performed at different time points after loading of apoptotic substrates into the GC. PARTICIPANTS/MATERIALS, SETTING, METHODS Primary cultures of GC retrieved following controlled ovarian stimulation of five women for IVF/ICSI and a human granulosa KGN cell line were incubated with different apoptotic substrates: oocytes which underwent spontaneous apoptosis during the cultivation of immature germ cells for IVF/ICSI; apoptotic KGN cells; and apoptotic membranes from rat retinas. Cultured GC were analyzed for the presence of specific molecular markers characteristic of different steps of phagocytic and autophagy machineries by immunocytochemistry, confocal microscopy, transmission electron microscopy and western blotting, before and after loading with apoptotic substrates. MAIN RESULTS AND THE ROLE OF CHANCE Incubation of human GC with apoptotic substrates resulted in their translocation in cell cytoplasm, concomitant with activation of the phagocytosis receptor c-mer proto-oncogene tyrosine kinase MERTK (P LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION The number of patients described here is limited. Also the dependence of phagocytosis on reproductive hormone status of patients should be analyzed. WIDER IMPLICATIONS OF THE FINDINGS Removal of apoptotic oocytes by surrounding GC seems likely to be a physiological mechanism involved in follicular atresia. Proper functioning of this mechanism may be a new strategy for the treatment of ovarian dysfunctions associated with an imbalance in content of germ cells in the ovaries, such as premature ovarian failure and polycystic ovary syndrome. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by Rennes Metropole (AIS 2015) and Agence de BioMédecine. This work was supported by funding from Université de Rennes1, Institut National de la Santé et de la Recherche Médicale (INSERM) and CHU de Rennes. A.B. is funded in part by the program Actions Concertées Interpasteuriennes (ACIP) and a research grant from the European Society of Pediatric Endocrinology. This work is supported by the Agence Nationale de la Recherche Grants ANR-17-CE14-0038 and ANR-10-LABX-73. The authors declare no competing interests.

Mechanisms underlying the efficacy of sprint interval training (SIT) remain to be understood. We previously reported that an acute bout of SIT disrupts the integrity of the sarcoplasmic reticulum (SR) CaEight recreationally active males participated in a 3-week SIT program consisting of nine sessions of four-six 30-s all-out cycling bouts with 4 min of rest between bouts.Total work performed during a SIT session and maximal power (WThree weeks of SIT improves exercise performance and provides some protection against RyR1 modification, whereas it does not accelerate recovery of contractile function.

A recent study reported an increased risk of contralateral estrogen-negative breast cancer after a first primary estrogen-negative breast cancer. Our study aims to confirm this result and to evaluate how the risk of second breast cancer occurrence is affected by family history of breast cancer and anti-estrogen treatment. We included all 4,152 women diagnosed with breast cancer between 1995 and 2007, using data from the population-based Geneva Cancer Registry. We compared the incidence of second breast cancer among patients according to estrogen receptor (ER) status with that expected in the general population by age-period Standardized Incidence Ratios (SIRs). Among the cohort, 63 women developed second breast cancer. Patients with ER-positive first tumors had a decreased risk of second breast cancer occurrence (SIR: 0.67, 95% CI: 0.48-0.90), whereas patients with ER-negative primary tumors had an increased risk (SIR: 1.98, 95% CI: 1.19-3.09) limited to ER-negative second tumors (SIR: 7.94, 95% CI: 3.81-14.60). Patients with positive family history had a tenfold (SIR: 9.74, 95% CI: 3.57-21.12) higher risk of ER-negative second tumor which increased to nearly 50-fold (SIR: 46.18, 95% CI: 12.58-118.22) when the first tumor was ER-negative. Treatment with anti-estrogen decreased the risk of second ER-positive tumors but not ER-negative tumors. The risk of second ER-negative breast cancer is very high after a first ER-negative tumor, in particular among women with strong family history. Surveillance and prevention of second cancer occurrence should consider both ER status of the first tumor and family history.

Hormone replacement therapy (HRT) use declined sharply after mid-2002, when the Women's Health Initiative trial reported an association between breast cancer occurrence and HRT. Hypothesized mechanism behind this association is that HRT promotes growth of pre-existing small tumors, leading to earlier tumor detection. We evaluated the impact of the sudden decline in HRT use on age distribution of breast cancer in Geneva. We included all incident breast cancer cases recorded from 1975 to 2006 at the Geneva cancer registry. We calculated mean annual incidence rates per 100,000 for 2 year periods for three age groups and assessed temporal changes by joinpoint regression. We compared age-specific incidence curves for different periods, reflecting different prevalence rates of HRT use. After increasing constantly between 1986 and 2002 among women aged 50-69 years [annual percent change (APC): +4.4, P < 0.0001], rates declined sharply after 2003 (APC: -6.0; P = 0.0264). Age-specific breast cancer rates changed dramatically with changes in prevalence of HRT use. During low HRT prevalence, breast cancer incidence increased progressively with age, when HRT prevalence was reaching its maximum (1995-2002), higher rates were seen in 60- to 64-year-old women, with a concomitant decrease in risk among elderly. After the sudden decline in HRT use, the incidence peak diminished significantly and incidence increased again with age. Following the abrupt decline in HRT use in Geneva, breast cancer incidence rates among post-menopausal women decreased considerably with striking changes in age-specific incidence rates before, during and after the peak in HRT prevalence.

Objective To study the impact of subtypes and comorbidities on breast cancer (BC) relapse and survival in the heterogeneous patients of the real world. Methods We identified patients diagnosed with BC between January 2003 and December 2005 from six population-based Swiss cancer registries. Clinicopathologic data was completed with information on locoregional and distant relapse and date and cause of death for over 10-years. We approximated BC subtypes using grade and the immunohistochemical panel for oestrogen, progesterone and human epidermal growth factor 2 (HER2) receptor status. We studied factors affecting relapse and survival. Results Luminal A-like subtype represented 46% of all newly diagnosed BC (N = 1831), followed by luminal B-like (N = 1504, 38%), triple negative (N = 436, 11%) and HER2 enriched (N = 204, 5%). We observed regional disparities in subtype prevalence that contribute to explain regional differences in survival formerly described. Disease relapse and BC specific mortality differed by subtype and were lower for luminal A like tumours than for other subtypes for any stage at diagnosis. After a median follow-up of 10.9 years, 1311 (33%) had died, half of them 647 (16%) due to another disease, showing the importance of comorbidities. Omission of systemic therapies in selected patients was not associated with poorer BC specific survival, BC subtype and life expectancy playing a role. Conclusions Information on tumour subtype is necessary for an adequate interpretation of population-based BC studies. Measures of comorbidity or frailty help in the evaluation of quality of care in the highly heterogeneous patients of the real world.

As it might lead to less discomfort, magnetic nerve stimulation (MNS) is increasingly used as an alternative to electrical stimulation methods. Yet, MNS and electrical nerve stimulation (ENS) and electrical muscle stimulation (EMS) have not been formally compared for the evaluation of plantar flexor neuromuscular function. We quantified plantar flexor neuromuscular function with ENS, EMS and MNS in 10 volunteers in fresh and fatigued muscles. Central alterations were assessed through changes in voluntary activation level (VAL) and peripheral function through changes in M-wave, twitch and doublet (PS100) amplitudes. Discomfort associated with 100-Hz paired stimuli delivered with each method was evaluated on a 10-cm visual analog scale. VAL, agonist and antagonist M-wave amplitudes and PS100 were similar between the different methods in both fresh and fatigued states. Potentiated peak twitch was lower in EMS compared to ENS, whereas no difference was found between ENS and MNS for any parameter. Discomfort associated with MNS (1.5 ± 1.4 cm) was significantly less compared to ENS (5.5 ± 1.9 cm) and EMS (4.2 ± 2.6 cm) (p

Whether viewed from the desk of a police chief, a city mayor, or a citizen in a deprived, high-crime community, maintaining the balance between police effectiveness and fair policing is complicated and difficult to achieve, let alone to sustain over the long term. However, it is at the heart of good policing, for when policing goes out of that balance—as happened in Brixton, London in the 1970s (1) and more recently in Ferguson, Missouri (2)—the outcome can be a major breakdown in law and order, with wider, rippling consequences for our societies, The author is supported by the Jerry Lee Centre for Experimental Criminology at the Institute of Criminology, University of Cambridge.

Introduction: We aimed to compare forces evoked by wide-pulse high-frequency (WPHF) neuromuscular electrical stimulation (NMES) delivered to a nerve trunk vs. muscle belly and to assess their test-retest intra- and inter-individual reliability. Methods: Forces evoked during two sessions with WPHF NMES delivered over the tibial nerve trunk and two over the triceps surae muscle belly were compared. Ten individuals participated in four sessions involving ten 20-s WPHF NMES contractions interspaced by 40 s recovery. Mean evoked force and force time integral of each contraction were quantified. Results: For both nerve trunk and muscle belly stimulation, intra-individual test-retest reliability was good (intra-class correlation coefficient > 0.9) while inter-individual variability was large (coefficient of variation between 140 and 180%). Nerve trunk and muscle belly stimulation resulted in similar evoked forces. Discussion: WPHF NMES locations might be chosen by individual preference, as intra-individual reliability was relatively good for both locations. This article is protected by copyright. All rights reserved.

Triple‐negative breast cancer (TNBC) is associated with a poor prognosis. Surgery, radiotherapy, chemotherapy, and referral for genetic counseling are the standard of care. We assessed TNBC prevalence, management, and outcome using data from the population‐based Geneva cancer registry. 2591 women had a first invasive stage I‐III breast cancer diagnosed between 2003 and 2011. We compared TNBC to other breast cancers (OBC) by χ 2‐test and logistic regression. Kaplan–Meier survival curves, up to 31‐12‐2014, were compared using log‐rank test. TNBC risk of mortality overall (OS) and for breast cancer (BCSS) was evaluated through Cox models. Linkage with the Oncogenetics and Cancer Prevention Unit (OCPU) database of the Geneva University Hospitals provided genetic counseling information. TNBC patients (n = 192, 7.4%) were younger, more often born in Africa or Central‐South America than OBC, had larger and more advanced tumors. 18% of TNBC patients did not receive chemotherapy. Thirty‐one (17%) TNBC women consulted the OCPU, 39% among those aged

Patients with cerebral palsy develop an important muscle weakness which might affect the aetiology and extent of exercise-induced neuromuscular fatigue.This study evaluated the aetiology and extent of plantar flexor neuromuscular fatigue in patients with cerebral palsy.Ten patients with cerebral palsy and 10 age- and sex-matched healthy individuals (∼20 years old, 6 females) performed four 30-s maximal isometric plantar flexions interspaced by a resting period of 2-3s to elicit a resting twitch. Maximal voluntary contraction force, voluntary activation level and peak twitch were quantified before and immediately after the fatiguing task.Before fatigue, patients with cerebral palsy were weaker than healthy individuals (341±134N vs. 858±151N, p0.05) and presented lower voluntary activation (73±19% vs. 90±9%, p0.05) and peak twitch (100±28N vs. 199±33N, p0.05). Maximal voluntary contraction force was not significantly reduced in patients with cerebral palsy following the fatiguing task (-10±23%, p0.05), whereas it decreased by 30±12% (p0.05) in healthy individuals.Plantar flexor muscles of patients with cerebral palsy were weaker than their healthy peers but showed greater fatigue resistance.Cerebral palsy is a widely defined pathology that is known to result in muscle weakness. The extent and origin of muscle weakness were the topic of several previous investigations; however some discrepant results were reported in the literature regarding how it might affect the development of exercise-induced neuromuscular fatigue. Importantly, most of the studies interested in the assessment of fatigue in patients with cerebral palsy did so with general questionnaires and reported increased levels of fatigue. Yet, exercise-induced neuromuscular fatigue was quantified in just a few studies and it was found that young patients with cerebral palsy might be more fatigue resistant that their peers. Thus, it appears that (i) conflicting results exist regarding objectively-evaluated fatigue in patients with cerebral palsy and (ii) the mechanisms underlying this muscle fatigue - in comparison to those of healthy peers - remain poorly understood. The present study adds important knowledge to the field as it shows that when young adults with cerebral palsy perform sustained maximal isometric plantar flexions, they appear less fatigable than healthy peers. This difference can be ascribed to a better preservation of the neural drive to the muscle. We suggest that the inability to drive their muscles maximally accounts for the lower extent of exercise-induced neuromuscular fatigue in patients with cerebral palsy.

The extent and characteristics of muscle fatigue of different muscle groups when subjected to a similar fatiguing task may differ. Thirteen healthy young men performed sustained contractions at 50% maximal voluntary contraction (MVC) force until task failure, with four different muscle groups, over two sessions. Per session, one upper limb and one lower limb muscle group were tested (knee extensors and thumb adductor, or plantar and elbow flexors). Changes in voluntary activation level and contractile properties were derived from doublet responses evoked during and after MVCs before and after exercise. Time to task failure differed ( P < 0.05) between muscle groups (220 ± 64 s for plantar flexors, 114 ± 27 s for thumb adductor, 77 ± 25 s for knee extensors, and 72 ± 14 s for elbow flexors). MVC force loss immediately after voluntary task failure was similar (−30 ± 11% for plantar flexors, −37 ± 13% for thumb adductor, −34 ± 15% for knee extensors, and −40 ± 12% for elbow flexors, P > 0.05). Voluntary activation was decreased for plantar flexors only (from 95 ± 5% to 82 ± 9%, P < 0.05). Potentiated evoked doublet amplitude was more depressed for upper limb muscles (−59.3 ± 14.7% for elbow flexors and −60.1 ± 24.1% for thumb adductor, P < 0.05) than for knee extensors (−28 ± 15%, P < 0.05); no reduction was found in plantar flexors (−7 ± 12%, P > 0.05). In conclusion, despite different times to task failure when sustaining an isometric contraction at 50% MVC force for as long as possible, diverse muscle groups present similar loss of MVC force after task failure. Thus the extent of muscle fatigue is not affected by time to task failure, whereas this latter determines the etiology of fatigue.

Prognosis of colon cancer (CC) has steadily improved during the past three decades. This trend, however, may vary according to proximal (right) or distal (left) tumor location. We studied if improvement in survival was greater for left than for right CC.We included all CC recorded at the Geneva population-based registry between 1980 and 2006. We compared patients, tumor and treatment characteristics between left and right CC by logistic regression and compared CC specific survival by Cox models taking into account putative confounders. We also compared changes in survival between CC location in early and late years of observation.Among the 3396 CC patients, 1334 (39%) had right-sided and 2062 (61%) left-sided tumors. In the early 1980s, 5-year specific survival was identical for right and left CCs (49% vs. 48%). During the study period, a dramatic improvement in survival was observed for patients with left-sided cancers (Hazard ratio [HR]: 0.42, 95% confidence interval [CI]: 0.29-0.62, p 0.001) but not for right CC patients (HR: 0.76, 95% CI: 0.50-1.14, p = 0.69). As a consequence, patients with distal CC have a better outcome than patients with proximal CC (HR for left vs. right CC: 0.81, 95% CI: 0.72-0.90, p 0.001).Our data indicate that, contrary to left CC, survival of patients with right CC did not improve since 1980. Of all colon cancer patients, those with right-sided lesions have by far the worse prognosis. Change of strategic management in this subgroup is warranted.

Background Using data from the population-based Geneva Cancer Registry we evaluated the risk of invasive cervical cancer following carcinoma in situ (CIS) or cervical intraepithelial neoplasia (CIN) III according to type of treatment. Methods Included in the study were all women diagnosed with CIS/CIN III in Geneva (Switzerland) between 1970 to 2002 (n = 2658) and followed for invasive cervical cancer occurrence until 31st December 2008. We calculated age and period standardised incidence ratios (SIR) and multiadjusted hazard ratios (HR) of invasive cervical cancer by treatment groups. Results During follow-up, 17 women developed invasive cervical cancer, conferring a SIR of 5.1 (95% confidence intervals [CI] 3.0–8.1). The risk of cervical cancer was significantly increased until 10 years after diagnosis. The risk was highest for women ⩾50 years (SIR = 7.3, 95% CI: 2.7–15.8) and for women who did not undergo excisional treatment (SIR = 25, 95% CI: 12.0–46.0). The multiadjusted HR of invasive cervical cancer for women who did not undergo surgical excisional treatment was 9.4 (95% CI: 2.8–32.2) compared with women who did. Conclusion Women diagnosed with CIS/CIN III are at increased risk of developing invasive cervical cancer. This risk is particularly high for women who did not have excision of cervical lesions.

Population-based studies have shown a concordance of breast cancer survival among first-degree relatives (FDRs), suggesting a heritable component. Reasons for such heritability remain to be elucidated. We aimed to determine whether association of breast cancer survival among FDRs is linked to shared patient and tumor characteristics or type of treatment. At the population-based Geneva Breast Cancer Registry, we identified 162 FDR pairs diagnosed with breast cancer. We categorized FDRs into poor, medium and good familial survival risk groups according to breast cancer-specific survival of their proband (mother or sister). We compared patient, tumor and treatment characteristics between categories and calculated standardized mortality ratios (SMRs) and adjusted disease-specific mortality for each group. Breast cancer patients in the poor familial survival risk group were more likely to be diagnosed at later stages than those in the good familial survival risk group. Similarly, they had higher SMRs than those in the medium and good survival risk groups (18.7, 95% confidence interval [CI]: 9.4-33.5 vs. 16.5, 95% CI: 7.5-31.3 and 9.4, 95% CI: 3.4-20.4, respectively). After adjustment for patient and tumor characteristics and type of treatment, women in the poor familial survival risk group were almost five times more likely to die of breast cancer than those in the good familial survival risk group (adjusted hazard ratio 4.8, 95% CI: 1.4-16.4). Our study shows that breast cancer prognosis clusters within families and suggests that the hereditary component is independent of patient and tumor characteristics and type of treatment.

OBJECTIVES: To assess the characteristics of young women with endometrial carcinoma, and evaluate those potentially eligible for conservative therapy. METHODS: We identified women diagnosed with endometrial cancer between 1970 and 2005 at the population-based Geneva Cancer Registry (n=1365). We classified patients into two age groups (< or =45 and >45 years old). Differences in demographic, tumor, diagnostic and treatment characteristics were tested with chi square. Kaplan-Meier analysis was used to calculate survival from endometrial cancer and the log-rank test to analyze differences in survival between the two groups. RESULTS: The young group comprised 44 (3.2%) women and the old group 1321 (96.8%) women. Synchronous ovarian malignancies were found in six patients (14%) in the young group, compared with 23 (2%) in the old group (P

In this population-based study, we evaluated the impact of obesity on presentation, diagnosis and treatment of breast cancer. Among all women diagnosed with invasive breast cancer in the canton Geneva (Switzerland) between 2003 and 2005, we identified those with information on body mass index (BMI) and categorized them into normal/underweight (BMI or =- or =30 kg/m(2)) women. Using multivariate logistic regression, we compared tumour, diagnosis and treatment characteristics between groups. Obese women presented significantly more often with stage III-IV disease (adjusted odds ratio [OR(adj)]: 1.8, 95% CI: 1.0-3.3). Tumours > or =1 cm and pN2-N3 lymph nodes were significantly more often impalpable in obese than in normal/underweight patients (OR(adj) 2.4, [1.1-5.3] and OR(adj) 5.1, [1.0-25.4], respectively). Obese women were less likely to have undergone ultrasound (OR(adj) 0.5, [0.3-0.9]) and MRI (OR(adj) 0.3, [0.1-0.6]) and were at increased risk of prolonged hospital stay (OR(adj) 4.7, [2.0-10.9]). This study finds important diagnostic and therapeutic differences between obese and lean women, which may impair survival of obese women with breast cancer. Specific strategies are needed to optimize the care of obese women with or at risk of breast cancer.

Purpose In the current pTNM classification system, nodal status of breast cancer is based on the number of involved lymph nodes and does not account for the total number of lymph nodes removed. In this study, we assessed the prognostic value of the lymph node ratio (LNR; ie, ratio of positive over excised lymph nodes) as compared with pN staging and determined its optimal cutoff points. Patients and Methods From the Geneva Cancer Registry, we identified all women diagnosed with node-positive breast cancer between 1980 and 2004 (n = 1,829). The prognostic value of LNRs was calculated for values ranging from 0.05 to 0.95 by Cox regression analysis and validated by bootstrapping. Based on maximum likelihood, we identified cutoff points classifying women into low-, intermediate-, and high-risk LNR groups. Results Optimal cutoff points classified patients into low- (≤ 0.20), intermediate- (> 0.20 and ≤ 0.65), and high-risk (> 0.65) LNR groups, corresponding to 10-year disease-specific survival rates of 75%, 63%, and 40%, and adjusted mortality risks of 1 (reference), 1.78 (95% CI, 1.46 to 2.18), and 3.21 (95% CI, 2.54 to 4.06), respectively. In contrast to LNR risk categories, survival curves of pN2 and pN3 crossed after 15 years, and their adjusted mortality risks showed overlapping CIs: 2.07 (95% CI, 1.69 to 2.53) and 2.84 (95% CI, 2.23 to 3.61), respectively. Conclusion LNR predicts survival after breast cancer more accurately than pN classification and should be considered as an alternative to pN staging.

The effect of age on breast cancer survival is still a matter of controversy. Breast cancer in young women is thought to be more aggressive and to have worse prognosis but results from clinical research have been neither consistent nor definitive. In this study, we have assessed the impact of young age at diagnosis on tumor characteristics, treatment and survival of breast cancer. The study included 82 very young (or = 35 years), 790 young (36-49), and 2125 older (50-69) women recorded between 1990 and 2001 at the Geneva Cancer Registry. Very young and young patients had more often stage II cancers (P = 0.009), poorly differentiated (P0.001) and estrogen receptor negative (P0.001) tumors. They were also more likely to receive chemotherapy (P0.001) and less likely to receive hormonal therapy (P0.001). Specific five-year survival was not different in the three groups (91%, 90%, and 89% for very young, young and older, respectively). When adjusting for all prognostic variables, age was not significantly related to mortality from breast cancer with a hazard ratio of 0.8 (95% CI: 0.3-2.0) for very young and 1.1 (95% CI: 0.8-1.4) for young patients compared to older women. Tumor stage, differentiation, estrogen receptor status, surgery, and radiotherapy were all independent determinants of breast cancer prognosis. We conclude that age is not an independent prognostic factor when accounting for breast tumor characteristics and treatment.

This study was undertaken to assess the incidence of 1) metachronous colorectal cancer and 2) subsequent extracolonic cancers, in relation to the location (proximal or distal to the splenic flexure) of the first primary colorectal tumor. In this population-based study, a cancer registry database was used to identify patients diagnosed with colorectal adenocarcinoma between 1970 and 1999. Patients with familial adenomatous polyposis and those with hereditary nonpolyposis colorectal cancer syndrome were excluded from the study, as were patients with nonepithelial tumors. Location of the first tumor was established according to International Classification of Diseases-Oncology-02 classification. The registry covers a population of 500,000 residents. A total of 5,006 patients had sporadic adenocarcinoma of the colon or rectum during this period of time, with 1,703 first primary tumors (34 percent) being located proximal to the splenic flexure. One hundred twenty occurrences of second primary colorectal cancer were observed in this population (2.39 percent). The risk for developing a second incidence of primary colorectal cancer was higher in patients whose initial tumor was located in the proximal colon (3.4 percent vs. 1.8 percent; odds ratio, 1.92; 95 percent confidence interval, 1.33–2.77; P < 0.001). The risk for each segment of the large bowel was as follows: cecum, 3.4 percent; right colon, 3 percent; transverse colon, 3.8 percent; left colon, 2.8 percent; sigmoid colon, 1.7 percent; and rectum, 1.8 percent. By contrast, the risk for developing a second, extracolonic tumor did not differ between patients with proximal and distal tumors (13.7 percent vs. 13.4 percent, P = 0.73). Patients with a first tumor located within the proximal colon are at twice the risk for developing metachronous colorectal cancer. From an epidemiologic standpoint, these data are in accordance with 1) the increasing incidence and 2) the better prognosis of proximal colon cancer in various populations. Our results confirm that proximal colon cancer is a distinct entity, which justifies the reporting of cases of colon cancer according to their location proximal or distal to the splenic flexure.

Background: The objective of this population-based study was to assess patient, physician and tumour determinants associated with positive surgical margins after prostatectomy, and to assess the effects of positive surgical margins on prostate cancer-specific survival. Methods: We included 1’254 prostate cancer patients recorded at the Geneva Cancer Registry who had radical prostatectomy during 1990–2008. To assess factors associated with positive margins, we used logistic regression. We assessed the effects of positive margins on prostate cancer-specific survival by Cox proportional hazard models accounting for numerous other prognostics factors including prostate and tumour volume, the total percentage of tumour, radiotherapy, surgical approach and surgeon’s caseload. Results: Among men undergoing prostatectomy, 479 (38%) had positive margins. In the multivariate logistic regression analysis, period, clinical- and pathological T stage, Prostate Specific Antigen (PSA) level, Gleason score and percentage of tumour in the prostate were significantly associated to positive margins. Ten-year prostate cancer-specific survival was 96.6% for the negative margins group and 92.0% for the positive margins group (log rank p = 0.008). In the Cox survival analysis adjusted for tumour characteristics, surgical margin status per se was not an independent prognostic factor while age, pathological T, PSA level and Gleason score remained associated with prostate cancer-specific survival. Conclusions: More aggressive tumour characteristics were strong determinants for positive margins. Furthermore, surgical margin status per se was not an independent prognostic factor for prostate cancer-specific survival after adjusting by the gravity of the disease in the multivariate analysis.

Spectral frequencies of the surface electromyogram (sEMG) increase with contraction force, but debate still exists on whether this increase is affected by various methodological and anatomical factors. This study aimed to investigate the influence of inter-electrode distance (IED) and contraction modality (step-wise vs. ramp) on the changes in spectral frequencies with increasing contraction strength for the vastus lateralis (VL) and vastus medialis (VM) muscles. Twenty healthy male volunteers were assessed for isometric sEMG activity of the VM and VL, with the knee at 90° flexion. Subjects performed isometric ramp contractions in knee extension (6-s duration) with the force gradually increasing from 0 to 80 % MVC. Also, subjects performed 4-s step-wise isometric contractions at 10, 20, 30, 40, 50, 60, 70, and 80 % MVC. Interference sEMG signals were recorded simultaneously at different IEDs: 10, 20, 30, and 50 mm. The mean (F mean) and median (F median) frequencies and root mean square (RMS) of sEMG signals were calculated. For all IEDs, contraction modalities, and muscles tested, spectral frequencies increased significantly with increasing level of force up to 50–60 % MVC force. Spectral indexes increased systematically as IED was decreased. The sensitivity of spectral frequencies to changes in contraction force was independent of IED. The behaviour of spectral indexes with increasing contraction force was similar for step-wise and ramp contractions. In the VL and VM muscles, it is highly unlikely that a particular inter-electrode distance or contraction modality could have prevented the observation of the full extent of the increase in spectral frequencies with increasing force level.

Background Mutations in the SCN5A gene, encoding the α subunit of the cardiac Na + channel, Na v 1.5, can result in several life-threatening arrhythmias. Objective To characterize a distal truncating SCN5A mutation, R1860Gfs*12, identified in a family with different phenotypes including sick sinus syndrome, atrial fibrillation (AF), atrial flutter, and atrioventricular block. Methods Patch-clamp and biochemical analyses were performed in human embryonic kidney 293 cells transfected with wild-type (WT) and/or mutant channels. Results The mutant channel expressed alone caused a 70% reduction in inward sodium current (I Na ) density compared to WT currents, which was consistent with its partial proteasomal degradation. It also led to a negative shift of steady-state inactivation and to a persistent current. When mimicking the heterozygous state of the patients by coexpressing WT and R1860Gfs*12 channels, the biophysical properties of I Na were still altered and the mutant channel α subunits still interacted with the WT channels. Since the proband developed paroxysmal AF at a young age, we screened 17 polymorphisms associated with AF risk in this family and showed that the proband carries at-risk polymorphisms upstream of PITX2 , a gene widely associated with AF development. In addition, when mimicking the difference in resting membrane potentials between cardiac atria and ventricles in human embryonic kidney 293 cells or when using computer model simulations, R1860Gfs*12 induced a more drastic decrease in I Na at the atrial potential. Conclusion We have identified a distal truncated SCN5A mutant associated with gain- and loss-of-function effects, leading to sick sinus syndrome and atrial arrhythmias. A constitutively higher susceptibility to arrhythmias of atrial tissues and genetic variability could explain the complex phenotype observed in this family.

We compared the extent and origin of muscle fatigue induced by short-pulse-low-frequency [conventional (CONV)] and wide-pulse-high-frequency (WPHF) neuromuscular electrical stimulation. We expected CONV contractions to mainly originate from depolarization of axonal terminal branches (spatially determined muscle fiber recruitment) and WPHF contractions to be partly produced via a central pathway (motor unit recruitment according to size principle). Greater neuromuscular fatigue was, therefore, expected following CONV compared with WPHF. Fourteen healthy subjects underwent 20 WPHF (1 ms-100 Hz) and CONV (50 μs-25 Hz) evoked isometric triceps surae contractions (work/rest periods 20:40 s) at an initial target of 10% of maximal voluntary contraction (MVC) force. Force-time integral of the 20 evoked contractions (FTI) was used as main index of muscle fatigue; MVC force loss was also quantified. Central and peripheral fatigue were assessed by voluntary activation level and paired stimulation amplitudes, respectively. FTI in WPHF was significantly lower than in CONV (21,717 ± 11,541 vs. 37,958 ± 9,898 N·s P 0.05). Overall, our results showed a different motor unit recruitment pattern between the two neuromuscular electrical stimulation modalities with a lower FTI indicating greater muscle fatigue for WPHF, possibly limiting the presumed benefits for rehabilitation programs.

PURPOSE: The present study was designed to determine the stimulation intensity necessary for an adequate assessment of central and peripheral components of neuromuscular fatigue of the knee extensors. METHODS: Three different stimulation intensities (100, 120 and 150 % of the lowest intensity evoking a plateau in M-waves and twitch amplitudes, optimal stimulation intensity, OSI) were used to assess voluntary activation level (VAL) as well as M-wave, twitch and doublet amplitudes before, during and after an incremental isometric exercise performed by 14 (8 men) healthy and physically active volunteers. A visual analog scale was used to evaluate the associated discomfort. RESULTS: There was no difference (p > 0.05) in VAL between the three intensities before and after exercise. However, we found that stimulating at 100 % OSI may overestimate the extent of peripheral fatigue during exercise, whereas 150 % OSI stimulations led to greater discomfort associated with doublet stimulations as well as to an increased antagonist co-activation compared to 100 % OSI. CONCLUSION: We recommend using 120 % OSI, as it constitutes a good trade-off between discomfort and reliable measurements.

In 1990, an international consensus was reached on the efficacy of adjuvant chemotherapy for lymph node positive (stage III) colon carcinoma (CC). This study evaluates the use and benefit of such therapy in routine health care practice. The study includes all patients with stage III CC treated by putative curative surgery (n= 182) recorded at the Geneva cancer registry between 1990 and 1996. Factors modifying chemotherapy use were determined by logistic regression, considering patients with chemotherapy as cases (n= 55) and others as controls (n= 127). The effect of chemotherapy on the 5-year survival was evaluated by the Cox model. Analyses were adjusted for possible confounders. The use of chemotherapy increased over the period (Ptrend < 0.001). Age strongly modulated chemotherapy use. In 1996, 54% of eligible patients received chemotherapy, this proportion fell to 13% after age 70. Decisions to use chemotherapy significantly depended on stage, grade and cancer site. The chance to be treated was non-significantly lower among individuals of low social class, widowed and foreigners. Chemotherapy significantly decreased mortality rates (Hazard ratio: 0.35, 95%CI: 0.18–0.68), independently of the prognostic factors and with similar benefit regardless of stage and age group. Strong beneficial effect of adjuvant chemotherapy on stage III CC can be achieved in routine practice. However, this study shows that it is probably not optimally utilised in Switzerland, particularly among the elderly. © 2001 Cancer Research Campaign

Background —The 2 genes KCNQ1 (LQT1) and HERG (LQT2), encoding cardiac potassium channels, are the most common cause of the dominant long-QT syndrome (LQTS). In addition to QT-interval prolongation, notched T waves have been proposed as a phenotypic marker of LQTS patients. Methods and Results —The T-wave morphology of carriers of mutations in KCNQ1 (n=133) or HERG (n=57) and of 100 control subjects was analyzed from Holter ECG recordings. Averaged T-wave templates were obtained at different cycle lengths, and potential notched T waves were classified as grade 1 (G1) in case of a bulge at or below the horizontal, whatever the amplitude, and as grade 2 (G2) in case of a protuberance above the horizontal. The highest grade obtained from a template defined the notch category of the subject. T-wave morphology was normal in the majority of LQT1 and control subjects compared with LQT2 (92%, 96%, and 19%, respectively, P P HERG . Conclusions —This study provides novel evidence that Holter recording analysis is superior to the 12-lead ECG in detecting G1 and G2 T-wave notches. These repolarization abnormalities are more indicative of LQT2 versus LQT1, with G2 notches being most specific and often reflecting HERG core domain missense mutations.

The long QT syndrome is mainly defined by QT interval prolongation (QTc0.44s). However, data obtained in genotyped patients showed that resting QTc measurement alone may be inaccurate for ascertaining the phenotype. The aim of this study was to evaluate the diagnostic performance of QT interval rate-dependence in untreated chromosome 11-linked patients.The study population consisted of 25 untreated long QT patients linked to chromosome 11 and 25 age- and gender-matched controls. QTc intervals were measured on 12-lead resting ECG recordings. From 24-h Holter recordings, the slope of the relationship between ventricular repolarization and heart rate was studied separately day and night to assess neural modulation. Mean heart rates and rate-dependences of QT and Q-maximum of T (QTm) intervals were compared between long QT patients and controls for both time periods.In both groups, the rate-dependences were modulated by day-night influences. When compared to controls, long QT patients showed a significant increase at night in QT/RR slopes (0.158 +/- 0.05 vs 0.117 +/- 0.03, P = 0.002) and QTm/RR slopes (0.163 +/- 0.05 vs 0.116 +/- 0.04, P = 0.0006). Multivariate analysis, adjusting QTc interval on age and gender, discriminated between long QT patients and controls with a 76% sensitivity and a 84% specificity. A 96% sensitivity and a 96% specificity were reached by taking into account the QTm/RR slope at night, the QTc interval and the mean heart rate during the day.QT interval variables obtained from 24-h ECG recordings improve long QT syndrome diagnosis by showing an increased nocturnal ventricular repolarization rate-dependence in genotyped chromosome 11-linked patients.

Background In this population-based study, we investigated the degree of concordance between Gleason scores obtained from prostate biopsies and those obtained from prostatectomy specimens, as well as the determinants of biopsy understaging. Methods We considered for this study all 371 prostate cancer patients recorded at the Geneva Cancer Registry diagnosed from 2004 to 2006 who underwent a radical prostatectomy. We used the kappa statistic to evaluate the Gleason score concordance from biopsy and prostatectomy specimens. Logistic regression was used to determine the parameters that predict the undergrading of the Gleason score in prostate biopsies. Results The kappa statistic between biopsy and prostatectomy Gleason score was 0.42 (p