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Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (β-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell–cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.

Dandy-Walker malformation (DWM) and Cerebellar vermis hypoplasia (CVH) are commonly recognized human cerebellar malformations diagnosed following ultrasound and antenatal or postnatal MRI. Specific radiological criteria are used to distinguish them, yet little is known about their differential developmental disease mechanisms. We acquired prenatal cases diagnosed as DWM and CVH and studied cerebellar morphobiometry followed by histological and immunohistochemical analyses. This was supplemented by laser capture microdissection and RNA-sequencing of the cerebellar rhombic lip, a transient progenitor zone, to assess the altered transcriptome of DWM vs control samples. Our radiological findings confirm that the cases studied fall within the accepted biometric range of DWM. Our histopathological analysis points to reduced foliation and inferior vermian hypoplasia as common features in all examined DWM cases. We also find that the rhombic lip, a dorsal stem cell zone that drives the growth and maintenance of the posterior vermis is specifically disrupted in DWM, with reduced proliferation and self-renewal of the progenitor pool, and altered vasculature, all confirmed by transcriptomics analysis. We propose a unified model for the developmental pathogenesis of DWM. We hypothesize that rhombic lip development is disrupted through either aberrant vascularization and/or direct insult which causes reduced proliferation and failed expansion of the rhombic lip progenitor pool leading to disproportionate hypoplasia and dysplasia of the inferior vermis. Timing of insult to the developing rhombic lip (before or after 14 PCW) dictates the extent of hypoplasia and distinguishes DWM from CVH.

Resume Objectif Ce travail presente la strategie utilisee pour construire un programme d’education therapeutique des patients (ETP) sur la douleur liee au cancer, sa mise en œuvre en region et l’identification des freins et des leviers concernant son deploiement. Methodologie 10 binomes medecin-infirmiere des Structures « Douleur Chronique » de l’ex-Basse-Normandie, apres formation a l’ETP, ont concu et construit le programme EFFADOL (Ensemble Faire Face A la DOuLeur). Ils ont collaborativement elabore les outils d’apprentissage, d’evaluation et de communication mis en œuvre. Resultats Suite au diagnostic educatif, 3 seances sont proposees au patient pour lui permettre d’acquerir des competences selon les objectifs suivants (1) Comprendre les differents types de douleur (2) Comprendre les traitements antalgiques et mieux gerer leurs effets indesirables (3) S’adapter au mieux a la douleur au quotidien. Le patient peut associer un proche pour participer aux ateliers et en choisir le format (individuel et/ou collectif). La mise en œuvre du programme et l’importance accordee a la communication avec les oncologues hospitaliers mais aussi avec les professionnels de sante liberaux sont presentees. Discussion et conclusion Le programme, accessible aux patients a proximite de leur domicile, est en adequation avec les besoins educatifs, evalues en amont par une enquete regionale. Les freins a l’inclusion des patients et les strategies pour les pallier sont identifies. Les difficultes sont d’ordre organisationnel, structurel et communicationnel. Le defi essentiel est le remaniement des pratiques de soins et la modification de posture des soignants dans l’objectif d’autonomisation du patient.

Summary Chronic granulomatous disease (CGD) is a rare inherited disorder in which phagocytes lack nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. The most common form is the X-linked CGD (X91-CGD), caused by mutations in the CYBB gene. Clinical, functional and genetic characterizations of 16 CGD cases of male patients and their relatives were performed. We classified them as suffering from different variants of CGD (X910, X91− or X91+), according to NADPH oxidase 2 (NOX2) expression and NADPH oxidase activity in neutrophils. Eleven mutations were novel (nine X910-CGD and two X91−-CGD). One X910-CGD was due to a new and extremely rare double missense mutation Thr208Arg-Thr503Ile. We investigated the pathological impact of each single mutation using stable transfection of each mutated cDNA in the NOX2 knock-out PLB-985 cell line. Both mutations leading to X91−-CGD were also novel; one deletion, c.-67delT, was localized in the promoter region of CYBB; the second c.253-1879A>G mutation activates a splicing donor site, which unveils a cryptic acceptor site leading to the inclusion of a 124-nucleotide pseudo-exon between exons 3 and 4 and responsible for the partial loss of NOX2 expression. Both X91−-CGD mutations were characterized by a low cytochrome b558 expression and a faint NADPH oxidase activity. The functional impact of new missense mutations is discussed in the context of a new three-dimensional model of the dehydrogenase domain of NOX2. Our study demonstrates that low NADPH oxidase activity found in both X91−-CGD patients correlates with mild clinical forms of CGD, whereas X910-CGD and X91+-CGD cases remain the most clinically severe forms.

The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss-of-function variants of the THOC6 gene were identified in the Beaulieu-Boycott-Innes syndrome (BBIS- OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano-genital and renal congenital malformations.In the present study, we report on a new family with two affected sibs. The 6-year-old female had severe intellectual disability with autistic features, feeding difficulties, growth delay, facial dysmorphic, and congenital malformations (hand, skeletal and cardiac anomalies). The male fetus presented antenatally with a cystic hygroma associated with severe aortic and left ventricular hypoplasia. Autopsy, after termination of pregnancy at 15 weeks of gestation, showed facial dysmorphic, short right thumb and hypospadias.Exome sequencing detected in both sibs compound heterozygous variants of the THOC6 gene (NM_024339.3, GRCh37): the already reported c.[298TA;700GT;824GA] haplotype and a novel variant c.977TG, p.(Val326Gly).We made a review of the literature of 17 BBIS reported patients including our two siblings. Severe to moderate ID and congenital malformations were constant. Prenatal and postnatal failure to thrive were frequent. Brain MRI were not specific. Prenatal findings were reported in 40% of cases but we described the first case of cystic hygroma. The present study reports extends the prenatal delineation of the phenotypic features observed in association with the presence of THOC6 variants. In addition, it underscores the intrafamilial phenotypic variability observed in BBIS.

Riassunto L’ipertermia maligna (IM) dell’anestesia e una patologia farmacogenetica che si manifesta in modo incostante con uno stato di ipermetabolismo del muscolo scheletrico in seguito all’esposizione a un agente anestetico volatile scatenante. I numerosi progressi nella fisiopatologia dell’IM hanno permesso di evidenziare il gene RYR1 principalmente implicato e l’implementazione di procedure di screening mediante test genetici o biologici. Tuttavia, forme di crisi di IM fruste o interrotte con il miglioramento del monitoraggio anestesiologico o ancora dei decessi perioperatori inspiegabili possono portare a sottovalutare l’incidenza delle manifestazioni di IM durante un’anestesia. Benche siano stati compiuti notevoli progressi negli strumenti di genetica molecolare nell’esplorazione dettagliata dei genomi degli individui, essi si accompagnano talvolta a maggiori difficolta nella diagnosi poiche mancano ancora le correlazioni genotipo-fenotipo che consentirebbero una diagnosi di certezza. Oggi, un’organizzazione nazionale ed europea relativa all’IM ha permesso l’implementazione di raccomandazioni in tutti i settori della patologia: procedura terapeutica urgente e uso del dantrolene in caso di crisi di IM, screening e valutazione del rischio di IM in un soggetto in visita anestesiologica, rischio di IM nei parenti, precauzioni anestetiche in pazienti con un’IM o considerati a rischio e procedura per diagnosticare la suscettibilita all’IM in un paziente in corso di valutazione o nei suoi parenti.

Resumen La hipertermia maligna (HM) de la anestesia es una enfermedad farmacogenetica que se manifiesta de manera inconstante por un estado de hipermetabolismo del musculo esqueletico durante la exposicion a un agente anestesico volatil desencadenante. Los numerosos avances referentes a la fisiopatologia de la HM han permitido evidenciar el gen RYR1, mayoritariamente implicado, y la instauracion de procedimientos de deteccion por genetica o prueba biologica. Sin embargo, formas de episodios de HM incompletas o abortadas por la mejoria de la monitorizacion anestesica o, tambien, fallecimientos perioperatorios inexplicados pueden conducir a una infravaloracion de la incidencia de manifestaciones de HM durante la anestesia. Aunque se hayan realizado progresos considerables en las herramientas de genetica molecular para la exploracion detallada de los genomas de individuos, a veces se acompanan de dificultades mayores en el diagnostico, porque las correlaciones genotipo-fenotipo que permitirian un diagnostico de certeza todavia no existen. Actualmente, una organizacion nacional y europea dedicada a la HM ha permitido el establecimiento de recomendaciones en todos los ambitos de la enfermedad: procedimiento terapeutico de urgencia y utilizacion del dantroleno en caso de episodios de HM, deteccion y evaluacion del riesgo de HM en un individuo en la consulta de anestesia, riesgo de HM en los parientes, precauciones anestesicas en pacientes con una HM o considerados de riesgo y procedimiento de diagnostico de la sensibilidad a la HM en un probando o sus parientes.

Resume Objectif Le pronostic des nouveau-nes porteurs d’une omphalocele depend de nombreux facteurs, en particulier de l’existence d’anomalies associees. Les syndromes de Wiedemann–Beckwith sont reputes presenter de petites omphaloceles. Cependant, aucun critere echographique ne permet de predire les autres anomalies associees. L’objectif de ce travail etait donc de decrire les issues globales des omphaloceles de diagnostic prenatal, et de rechercher une correlation eventuelle entre le contenu de l’omphalocele precocement evaluee et les anomalies associees constatees en postnatal. Methode Etude retrospective realisee a l’hopital Necker-Enfants Malades entre 2008 et 2018. Les issues de grossesses et le diagnostic post natal ont ete recueillis, et analyses en fonction du contenu de l’omphalocele au premier trimestre. Resultats Cent quatre-vingt-onze femmes avec diagnostic antenatal d’omphalocele ont ete incluses. Vingt-huit pour cent des cas etaient isoles a la naissance, 32 % presentaient un syndrome polymalformatif associe a une anomalie chromosomique, 13 % de syndrome polymalformatif sans cause genetique retrouvee, 9 % de syndrome de Wiedemann Beckwith, 7 % d’association a une cardiopathie, 6 % de sequence du cordon court, 3 % de sequence OEIS et une pentalogie de Cantrell. La presence du foie au 1er trimestre a ete un facteur predictif de cardiopathie (85,7 % vs 48,6 % p = 0,01). La presence des anses digestives au premier trimestre a ete un facteur predictif d’anomalies chromosomiques (69,6 % vs 37,2 % p Conclusion L’analyse en echographie au premier trimestre du contenu exhaustif de l’omphalocele est une aide precieuse pour l’evaluation du risque d’anomalies associees et donc le conseil prenatal.

Purpose: Patient education constitutes a relevant strategy to improve pain management. In the field of therapeutic patient education (TPE), we aimed 1) to assess pain impact in cancer patients, 2) to identify patients' educative needs in pain management, and 3) to refine research criteria for its future evaluation. Patients and methods: Pain intensity, relief and interference were assessed in 75 cancer patients with unbalanced background pain. Self-assessment questionnaire evaluated i) patients' pain management and ii) their knowledge and needs in TPE. Results: Most patients experienced pain for more than 6 months and 41.6% reported adequate pain relief. Understanding pain and pain management were major patients' preferences (>58%). Most patients declared they knew their pain treatments, but fewer than half of them were able to name them. However, education concerning pain treatment was considered as essential in

Background In early terminations of pregnancy for fetal anomaly (TOPFA) without identified cytogenetic abnormality, a fetal autopsy is recommended for diagnostic purposes, to guide genetic counseling. Medical induction, which allows analysis of a complete fetus, is generally preferred over surgical vacuum aspiration. Our objective was to assess the diagnostic value of fetal autopsies in these early terminations, relative to the first-trimester ultrasound, overall and by termination method. Materials For this retrospective study at the Port Royal Maternity Hospital, we identified all TOPFA performed from 11 weeks to 16 weeks diagnosed at the first-trimester ultrasound in cases with a normal karyotype. The principal endpoint was the additional value of the autopsy over /compared to the ultrasound and its impact on genetic counseling, globally and by termination method. The secondary objective was to compare the complication rate by method of termination. Results The study included 79 women during period of 2013–2017: 42 with terminations by medical induction and 37 by aspiration. Fetal autopsy found additional abnormalities in 54.4% of cases, more frequently after medical induction (77.5%) than after aspiration (21.4%, p < .01). Genetic counseling was modified in 20.6% of cases, more often after induction (32.5% vs 3.6%, p < .01). The length of stay was significantly longer and a secondary aspiration was required in 16,7% of case in the medical induction group (p < .01). Conclusion Medically induced vaginal expulsion appears preferable and can change genetic counseling for subsequent pregnancies.

Giant omphalocele often represents a major surgical challenge and is reported with high mortality and morbidity rates. The aim of this study was to assess the outcome of neonates with giant omphalocele managed with early operative surgical treatment, and subsequently to identify possible factors that could alter the prognosis.We reviewed the medical records of 29 consecutive newborns with prenatally diagnosed giant omphalocele. In these cases one of two procedures had been performed: either staged closure after silo, or immediate closure with a synthetic patch. The cases were separated into 2 groups: Isolated giant omphalocele (IO group) and giant omphalocele associated with malformation (NIO group).Infants in the IO group had a lower size of the omphalocele (p0,001), a shorter hospital stay (95 days [45-915] vs. 41.5 days [10-110] p= 0, 02), and a shorter median ventilation length (10 days [1-33] vs. 27, 5 [6-65] p = 0, 05). In the NIO group, 5 cases displayed a significantly more difficult course than the others. They were compared to the remaining cases for prenatal and anatomic features. Four factors associated with greater morbidity were identified: CONCLUSIONS: Isolated omphalocele, even containing the whole liver, has a very good prognosis with early surgical treatment. Without associated anomalies, 95% of giant omphaloceles can be discharged with a median of 41.5 days in hospital. However, associated anomalies (especially cardiopathies) may burden the prognosis and should be both carefully assessed during pregnancy and taken into account in parental information.Retrospective Study LEVEL OF EVIDENCE: Level I.

International audience; In the field of cancer pain, therapeutic patient education (TPE) allows patients to develop skills to better manage their pain. In the Lower Normandy region of France, the management of pain is based on networking, thus allowing proximity and accessibility for all concerned. We have thus designed and initiated a broad five-stage research program that includes the following: (1) training for caregivers in TPE; (2) identifying the educational expectations of patients and their relatives with regard to cancer pain; (3) the design of a TPE program; (4) the evaluation of its quality; and (5) the evaluation of its effectiveness by comparative randomization. This article presents this approach and more particularly the research phases (stages 2, 4, 5) for which the objectives, the methodology, and the expected results are justified. Among the key points, particular attention is paid to the evaluation of the educational dimension that provides patients with self-efficacy to participate actively in the management of their pain, their perception of changes in relation to it and its impact. The choice of a specific assessment criterion (subscale 9 of the Brief Pain Inventory) and of the step-wedge design are thus argued. This approach, which is based on a partnership between health care professionals and researchers, aims to demonstrate the benefits provided by TPE to patients in order to enable them to better manage their pain on a daily basis.

This study aims to assess the feasibility and the effectiveness of a fetoscopic myelomeningocele (MMC) coverage using a sealed inert patch through a two-port access, in the sheep model. Forty-four fetuses underwent surgical creation of a MMC defect at day 75 and were divided into four groups according to the MMC repair technique, performed at day 90. Group 1 remained untreated. Group 2 had an open surgery using suture of the defect. Groups 3 and 4 underwent defect coverage using a Gore®-polytetrafluoroethylene patch secured with surgical adhesive (Bioglue®), with an open approach (group 3) and a fetoscopic one (group 4). Lambs were killed at term, and histological examinations were performed. Fetoscopic patch coverage was achieved in all the lambs of group 4. All the fetuses of group 2 had a complete closure of the defect whereas only 38% in group 3 and 14% in group 4. Fetal loss rate seems to be lower in group 4 than in groups 2 and 3. Fetoscopic coverage of MMC defect can be performed using a sealed patch through a two-port access, but the patch and glue correction may not be the ideal technique to repair fetal MMC.

To estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity after trial of labor after cesarean (TOLAC).Retrospective observational cases-controls study conducted at a level 3 maternity units between 2006 and 2016. Included women were patient with trial of labor after one previous cesarean section, alive singleton fetus in cephalic presentation ≥ 37WG. Two groups were compared according to pelvic mesures at pelvimetry: pelvic dimension considered as abnormal, defined by Conjugate Diameter10.5cm and/or Transverse Diameter12cm and pelvic dimension considered as normal for other women. The primary outcome was a composite criterion of neonatal morbidity and mortality. A logistic multivariate regression model was use to estimate the association between an abnormal pelvic dimension at pelvimetry and the occurrence of severe neonatal morbidity.2474 women were included. 863 (34.8 %) have a normal pelvic dimension and 1611 (65.2 %) an abnormal. Characteristics of labor were similar in two groups. Success of TOLAC was 84.7 % in normal pelvic group and 64.6 % in abnormal dimension of pelvic group. Neonatal morbidity was similar between two groups (1.7 % in normal pelvic dimension group versus 2.3 % in abnormal pelvic dimension group, p=0.26; crude OR: 1.39 (0.77-2.49) ; adjusted OR : 0.93 (0.51-1.68)).There were no association between pelvic dimension at pelvimetry and neonatal morbidity. In case of abnormal pelvic dimension, a combination of more prudence, and stringent user practices, achieve a high rate of vaginal delivery and a neonatal morbidity comparable to the normal pelvic dimension group.

Left ventricular noncompaction cardiomyopathy (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. A NGS workflow, based on a panel of 95 genes developed for sequencing most prevalent sudden cardiac death-causing genes, was used to make a rapid and costless molecular diagnosis in two siblings with a severe noncompaction cardiomyopathy starting prenatally and leading to rapid cardiac failure. For the first time, a total homozygous PKP2 deletion was identified. This molecular defect was further confirmed by MLPA and array-comparative genomic hybridization (CGH). Heterozygous PKP2 mutations are usually reported in a significant proportion of Arrhythmogenic Right Ventricular Cardiomyopathy cases. Our results show, for the first time, the involvement of PKP2 in severe cardiomyopathy with ventricular non compaction.

Triadin knockout syndrome (TKOS) is a rare, inherited arrhythmia syndrome caused by recessive null mutations in TRDN-encoded cardiac triadin. Based previously on 5 triadin null patients, TKOS has been characterized by extensive T-wave inversions, transient QT prolongation, and severe disease expression of exercise-induced cardiac arrest in early childhood refractory to conventional therapy.We have established the International Triadin Knockout Syndrome Registry to include patients who have genetically proven homozygous/compound heterozygous TRDN null mutations. Clinical/genetic data were collected using an online survey generated through REDCap.Currently, the International Triadin Knockout Syndrome Registry includes 21 patients (11 males, average age of 18 years) from 16 families. Twenty patients (95%) presented with either cardiac arrest (15, 71%) or syncope (5, 24%) at an average age of 3 years. Mild skeletal myopathy/proximal muscle weakness was noted in 6 (29%) patients. Of the 19 surviving patients, 16 (84%) exhibit T-wave inversions, and 10 (53%) have transient QT prolongation480 ms. Eight of 9 patients had ventricular ectopy on exercise stress testing. Thirteen (68%) patients have received implantable defibrillators. Despite various treatment strategies, 14 (74%) patients have had recurrent breakthrough cardiac events.TKOS is a potentially lethal disease characterized by T-wave inversions in the precordial leads, transient QT prolongation in some, and recurrent ventricular arrhythmias at a young age despite aggressive treatment. Patients displaying this phenotype should undergo TRDN genetic testing as TKOS may be a cause for otherwise unexplained cardiac arrest in young children. As gene therapy advances, enrollment into the International Triadin Knockout Syndrome Registry is encouraged to better understand TKOS and to ready a well-characterized cohort for future TRDN gene therapy trials.

Introduction Hereditary heart diseases (cardiomyopathy & channelopathies) are most often characterized by autosomal dominant inheritance and delayed cardiac expression. The risk of complications of these diseases are sudden cardiac death and heart failure. Medical management allow to reduce significantly, but does not cancel, the risk of complications. If the causal mutation is known, couples with a pregnancy project may discuss the use of prenatal genetic diagnosis (PND) or preimplantation genetic diagnosis (PGD). The use of PND or PGD in these diseases is controversial and the medical, ethical and psychological issues are particularly complex. Purpose The aim of this study was (i) to collect at national level the procedures of PNDs and PGDs in the context of “isolated” hereditary heart disease; (ii) obtain the opinion of patients about this issue. Methods and Results The data collected with help of the French Biomedicine Agency show that 18 PND were carried out in France between 2009 and 2017 and 13 PGD between 2013 and 2017. So, number of PND and PGD for hereditary heart disease is rare in comparison of the relatively high prevalence of these diseases. The opinion of 20 patients (95% with cardiomyopathy), followed at Pitie-Salpetriere referral center for hereditary heart diseases, was prospectively collected via auto-questionnaires. Their answers show that few know the options (PND, PGD, gamete donation, adoption): only 25% are aware of all the alternatives. Despite this, 45% of patients mentioned that they did not want more information about these procreation options. Moreover, 45% consider the use of a PND to be fully acceptable or acceptable and 75% for the use of PGD, although they would not ask for themselves. Conclusions We report the first data about procreation procedures in France, and wishes of patients, in non-syndromic hereditary heart diseases. This may help to better manage these complex issues in clinical practice.

Sudden Death Linked to the Triadin Gene We describe a new family with cathecholaminergic polymorphic ventricular tachycardia (CPVT) linked to the Triadin gene. This is the second report of such a CPVT of autosomal recessive inheritance. Using an NGS panel including 42 genes involved in cardiac sudden death, 2 heterozygous pathogenic mutations (c.613C> T/p.Gln205* and c.22 + 29 A>G) were identified in the Triadin gene in 2 sibs who experienced early severe arrhythmias without evidence of CPVT diagnosis at first cardiac evaluation. However, significant arrhythmias occurred after catecholaminergic stimulation. Each of the TRDN mutations was inherited from a healthy parent. In this family, genetic studies permit confirmation of the CPVT diagnosis in the 2 affected sibs and permit the early diagnosis of the third asymptomatic child. It also helped guide the therapeutic strategy in this family.

Vertical specialization generated by the international fragmentation of production within global networks is driven not only by comparative advantage, but also by the locational decisions of lead firms which determine the role and bargaining power of local producers in their value chain. This study examines the consequences of such specialization in textiles and clothing for 26 labour-abundant countries from 1990 to 2007. Fixed effects regressions based on panel data reveal that the industry does not always reap the benefits of the resulting international trade integration. Rather, the authors observe a negative relationship between vertical specialization and relative real wages in the textile and clothing industry.

Resume La fragmentation de la production au sein de reseaux mondiaux n'obeit pas seulement a l'avantage comparatif, mais aussi aux decisions de localisation des entreprises dominantes en fonction de la capacite de negociation des producteurs locaux et du role qu'elles leur assignent dans la chaine de production. Les auteurs examinent les consequences de cette specialisation dans le textile et l'habillement, pour vingt-six pays ou l'offre de main-d'œuvre est abondante, sur la periode 1990–2007. L'etude econometrique montre que le secteur ne tire pas toujours benefice de l'integration commerciale: on observe plutot une association negative entre specialisation verticale et salaires reels.

La especializacion vertical generada por la fragmentacion de la produccion en redes mundiales no solo esta motivada por la ventaja comparativa, sino tambien por las estrategias de deslocalizacion de las empresas lideres, que determinan el papel y el poder negociador de los productores locales. Este estudio examina las consecuencias de tal especializacion en los textiles y el vestido en 26 paises con abundante mano de obra de 1990 a 2007. Las regresiones de efectos fijos con datos de panel revelan que el sector no siempre gana con la integracion comercial internacional: se observa una correlacion negativa entre la especializacion vertical y los salarios reales relativos.

Objectives Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. Material & methods We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. Results Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. Conclusion Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.

Objective: The aim of this study was to assess the feasibility and the effectiveness of a fetoscopic myelomeningocele (MMC) repair with a running single suture using a 2-port access in the sheep model. Methods: Eighteen fetuses underwent surgical creation of a MMC defect at day 75. Fetuses were then randomized into 3 groups. Four fetuses remained untreated (control group). In the other 14 fetuses, a prenatal repair was performed at day 90: 7 fetuses had an open repair (oMMC), and 7 fetuses had a fetoscopic repair (fMMC) using a single-layer running suture through a 2-port access. Lambs were sacrificed at term, and histological examinations were performed. Results: Hindbrain herniation was observed in all live lambs in the control group. A complete closure of the defect was achieved in all the lambs of the fMMC group. A complete healing of the defect and no hindbrain herniation were observed in all live lambs of the oMMC and fMMC groups. The durations of surgeries were not statistically different between the oMMC and the fMMC groups (60 vs. 53 min, p = 0.40), as was the risk of fetal loss (fMMC: 1/7, oMMC: 3/7, p = 0.56). Discussion: Fetoscopic repair of MMC can be performed using a single-layer running suture through a 2-port access and may be promising to reduce the risk of premature rupture of membranes.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2.We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population.We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations.We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available.In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.

To assess the extent to which the distribution of crown-rump length (CRL) values may be correlated with different criteria for the quality of the CRL images.This is a retrospective analysis of a series of 977 CRL images, by two independent observers, for the presence or the absence of 14 quality hallmarks. Inter-observer agreement for the hallmarks was assessed by the proportion of agreement and Cohen's kappa. The association between the quantiles of the CRL distribution and the presence or absence of the 14 quality hallmarks was modeled using quantile regression.The overall inter-observer agreement across the 14 hallmarks was 91.7%, kappa=0.81, 95% CI [0.80-0.82]. Distribution of CRL measurements varied considerably as a function of image quality: when the fetus was in extension, the mean CRL was +5.7mm (vs. not in extension, p0.001), when the fetus was in flexion (vs. not), the mean CRL was -4.7mm (p0.001) and when the image magnification was65% (vs.65%), the mean CRL was -4.2mm (p0.001). There was a global trend to over-estimate the CRL for the higher deciles and to under-estimate the CRL for the lower deciles when the sagittal quality hallmarks were absent. No significant impact on CRL distribution was observed in association with the precise placement of the calipers nor with the horizontal orientation of the fetus.Distribution of CRL measurements was influenced by the quality of CRL images. In particular, inadequate position of the fetus (flexion/extension) and insufficient image magnification were associated with systematic changes in the values of CRL. Our results show that as the quality of CRL images decreases, the associated variations in the distribution of CRL can have an impact on the chromosomal risk assessment and may lead to inappropriate obstetrical decisions.

This article shows first that, despite significant trade gains expected from the Euro-Mediterranean Agreements, especially the Barcelona Agreement, actual gains are positive but small. The reasons for such small effects are investigated. They include delays in the implementation of the tariff schedule, the lack of European Union (EU) market access for agricultural products, the persistence of non-tariff barriers, the lack of regional integration in terms of services and Foreign Direct Investment (FDI), the role of rules of origins, the impact of inappropriate specialization, etc. This appraisal makes it possible to suggest several policy options which are necessary to optimize the effects of the Euromed partnership. In this regard, the Arab Spring creates new opportunities to reinforce trade integration in this area.

Plus de dix ans apres la mise en place des accords de Barcelone, le constat des effets de l’ouverture des Pays mediterraneens est decevant quant a leur impact sur la croissance et la dynamique d’emploi. Il s’agit dans ce papier d’identifier les secteurs dynamiques d’emploi et de richesse au Maroc et d’apprecier si les choix de specialisation permettent une croissance de longue periode qui absorberait l’excedent de main-d’œuvre. Dans un premier temps, nous analysons les potentiels d’emploi des secteurs economiques avec une attention plus particuliere a l’industrie manufacturiere entre 1985-2001, et dans un deuxieme temps, nous evaluons l’impact de l’ouverture et des specialisations sur la creation nette d’emploi a la fois a partir d’une etude empirique et d’une approche econometrique. Nos resultats nuancent les conclusions traditionnelles, qui donnent le plus souvent un impact positif de l’ouverture sur l’emploi.

Le secteur textile-habillement est l’un des secteurs industriels les plus touches par les phenomenes de delocalisation. Cependant, les producteurs des pays europeens reagissent face aux defis de la concurrence asiatique en se recentrant sur leur cœur de metier et en se repositionnant sur le marche du fast-fashion qui exige de miser sur la flexibilite, la reactivite et un controle strict de la qualite. Ces strategies offensives permettent aux firmes europeennes de degager de nouvelles sources de competitivite, car elles reposent sur une reorganisation de la production en chaines de valeur, sur la mise en coherence des complementarites des competences requises a chaque niveau de la chaine de valeur et sur le developpement de l’innovation. Cet article defend l’idee que les avantages tires des delocalisations en termes de couts de production peuvent etre neutralises par des couts d’organisation du reseau, et que, en revanche, l’excellence organisationnelle peut compenser les differentiels de couts de main d’œuvre.

We describe a new family with cathecholaminergic polymorphic ventricular tachycardia (CPVT) linked to the Triadin gene. This is the second report of such a CPVT of autosomal recessive inheritance. Using an NGS panel including 42 genes involved in cardiac sudden death, 2 heterozygous pathogenic mutations (c.613CT/p.Gln205* and c.22 + 29 AG) were identified in the Triadin gene in 2 sibs who experienced early severe arrhythmias without evidence of CPVT diagnosis at first cardiac evaluation. However, significant arrhythmias occurred after catecholaminergic stimulation. Each of the TRDN mutations was inherited from a healthy parent. In this family, genetic studies permit confirmation of the CPVT diagnosis in the 2 affected sibs and permit the early diagnosis of the third asymptomatic child. It also helped guide the therapeutic strategy in this family.

Distribution and behavior of many trace elements in the aquatic environment has been well characterized, but little is known about silver (Ag) concentrations in coastal waters, even though this element ranks among the most toxic to marine invertebrates (Calabrese et al., 1977 ; Fisher and Hook, 1997 ; Webb and Wood, 1998). Studies conducted by Flegal et al. (1995), River-Duarte et al. (1999), and Ndung'u et al. (2001), provided the first valuable data on Ag distribution in the oceanic environment, indicating that this element is found in very low concentrations in the dissolved phase. However, although silver concentrations in coastal waters do not reach the nanomolar range (Smith and Flegal, 1993 ; Squire et al., 2002), formation of a stable chloro complex enhances bioavailability and toxicity to biota (Luoma et al., 1995). Experimental studies have shown that Ag is toxic to some living organisms at environmentally realistic levels (Bryan and Langston, 1992). Silver found in the aquatic environment mainly originates in effluents from sewage treatment plants (Rozan and Hunter, 2001). Silver can therefore be used as a tracer of wastewater discharges in coastal waters (Martin et al., 1988 ; Sañudo-Wilhelmy and Flegal, 1992), for instance through the use of sentinel organisms, which concentrate bioavailable contaminants in their tissues (Stephenson and Leonard, 1994 ; Jiann and Presley, 1997 ; Riedel et al., 1998 ; Muñoz-Barbosa et al., 2000). This study concerns biological monitoring as a means of providing a synoptic view of silver contamination in French coastal waters. The National Network for the Observation of Marine Environment Quality (RNO, the French Mussel-Watch) which has been regularly measuring concentrations of various chemical contaminants in oyster and mussel tissues for 25 years (Claisse, 1989), has been monitoring silver levels since 2003. This valuable database including data collected at 80 sampling sites distributed along the French coasts (Fig. 1), is used as a reference to provide the spatial distribution of a given contaminant (Chiffoleau and Bonneau, 1994), identify trends of contamination/decontamination (Chiffoleau et al., 2001), and detect peak concentrations due to accidental events (Chiffoleau et al., 2004). Mussels (Mytilus edulis and Mytilus galloprovincialis) and oysters (Crassostrea gigas) are collected twice a year in February and November. Sample collection (size of samples, size of animals) and treatment (cleaning, depuration, removal of soft parts from the shells, draining, homogenization, and freeze-drying) are performed according to the OSPAR Convention guidelines and the method described by Claisse (1989).

International audience; We identified a heterozygous p.Arg2401His mutation of RYR2 by sequencing the DNA of a 7-year-old girl who was referred for catecholaminergic polymorphic ventricular tachycardia (CPVT). Using high-resolution melting assay, we have demonstrated a mosaicism for this mutation in her asymptomatic mother which illustrates the benefit of extensive genetic analysis in CPVT, in particular regarding genetic counselling.

International audience; Central core disease is a myopathy often arising from mutations in the type 1 ryanodine receptor (RYR1) gene, encoding the sarcoplasmic reticulum calcium release channel RyR1. No treatment is currently available for this disease. We studied the pathological situation of a severely affected child with two recessive mutations, which resulted in a massive reduction in the amount of RyR1. The paternal mutation induced the inclusion of a new in-frame pseudo-exon in RyR1 mRNA that resulted in the insertion of additional amino acids leading to the instability of the protein. We hypothesized that skipping this additional exon would be sufficient to restore RyR1 expression and to normalize calcium releases. We therefore developed U7-AON lentiviral vectors to force exon skipping on affected primary muscle cells. The efficiency of the exon skipping was evaluated at the mRNA level, at the protein level, and at the functional level using calcium imaging. In these affected cells, we observed a decreased inclusion of the pseudo-exon, an increased RyR1 protein expression, and a restoration of calcium releases of normal amplitude either upon direct RyR1 stimulation or in response to membrane depolarization. This study is the first demonstration of the potential of exon-skipping strategy for the therapy of central core disease, from the molecular to the functional level.

With production activity tending rapidly towards international fragmentation, this study examines the consequences for labour countries of the forms of specialisation brought about by fragmentation processes. It further addresses the risk that fragmented sectors may become excluded from greater developments within the manufacturing industry as a whole. An empirical analysis using panel data reveals that, contrary to expectation, the textile and clothing sector in labour countries does not always reap the positive benefits of this form of international trade integration. Rather, we observe a phenomenon of immiserising specialisation, due to a drop in relative wages within this sector.

Deux phénomènes marquants apparaissent dans les débats sur la globalisation : d’une part, l’ouverture économique des pays accélère les échanges et les possibilités de financement, et d’autre part, on constate un développement des phénomènes de fragmentation qui segmentent le processus de production en plusieurs étapes. La fragmentation d’abord intra-muros se développe ensuite entre les nations à travers l’amélioration permanente des télécommunications notamment. Hummels, Ishii et Yi (2001) es...

Cardiac contraction is triggered when a membrane depolarisation induces a massive increase in intracellular calcium concentration. This process called “excitation-contraction (E-C) coupling” relies on a multimolecular protein complex, the calcium release complex (CRC) organized around the sarcoplasmic reticulum calcium channel, the ryanodine receptor (RyR2). Among the proteins involved in the efficient function of the CRC, calsequestrin, triadin and junctin are sarcoplasmic reticulum proteins able to interact with RyR2 and regulate calcium release.Mutations in RyR2 and calsequestrin are associated to a rare but fatal cardiac arrhythmia: catecholaminergic polymorphic ventricular tachycardia (CPVT). Nevertheless, variations in these two genes (RYR2 and CASQ2) account so far for only 50 to 70% of the cases, suggesting that other genes are most probably involved. To reveal new genes involved in CPVT, we have based a candidate gene approach on the hypothesis that the pathology could be considered as a disease of the calcium release complex. We therefore searched for variations in the genes encoding proteins of the CRC in a large French cohort of CPVT patients with no detected mutations in RYR2 or CASQ2. We have identified for the first time mutations in the human triadin gene TRDN, and studied the functional consequences of a missense mutation both in a cell model and in vivo after expression in triadin KO mice. Our results confirmed the hypothesis that CPVT can be more generally considered as a defect in the CRC.

Recurrent rhabdomyolysis episodes in adults are commonly caused by glycogenosis or fatty-acid oxidation disorders. However, in many cases the etiology remains unknown, and recently mutations in RYR1 appeared as a possible cause of exercise induced rhabdomyolysis. We studied 14 adults who presented acute rhabdomyolysis (CK above 10,000 UI/l) triggered by exercise or fever, in whom McArdle disease, fatty acid oxidation disorders, and LPIN1 mutations were excluded. All patients underwent muscle biopsy in order to screen RYR1 mutation on cDNA. Potentially pathogenic mutations in RYR1 gene were detected in 5 unrelated patients. Mutations were the following: p.Val4847Leu, p.G593R, p R3539H, Gly2434Arg, p.Gln3461Pro, p.A1352T, p.A933T and p.Ser1342Gly. Two patients presented each 2 and 3 heterozygous variants. Baseline CK levels were elevated in all cases but one (400–700 UI/l). None of them complained of myalgia or exercise intolerance. Rhabdomyolysis were triggered by weight-training in two patients, viral infection in two cases, and retinoic acid treatment in the last case. Higher recorded CK levels were between 28,000 and 94,000 UI/l, without renal failure. Three patients had a unique episode, whereas two other had several rhabdomyolysis episodes. Muscle biopsies were either normal, or showed moderate structure disorganization. Two siblings of a patient, the father of another patient, and the brother of a third patient, also presented mutations in the RYR1 gene and high baseline CK level. Per-anesthetic malignant hyperthermia was noticed in a grand-mother of one patient. Mutations in RYR1 gene should be systematically searched in patients with exercise or fever induced rhabdomyolysis episodes, after having excluded common metabolic disorders. This diagnostic implies major consequences for genetic counselling in the families, due to the potential risk of anesthetic malignant for the patients and their relatives.

Introduction: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is predominantly caused by desmosomal gene mutations, that account for only ∼50% of ARVC/D cases. RYR2 gene mutations usually cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) but have been associated with atypical phenotype of ARVC/D. In addition RYR2 is a large gene, therefore usually not analysed in routine. We aim to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population. Methods and results: We analyzed the whole RyR2 coding sequence (105 exons and related splice sites) in a population of 64 ARVC/D probands without desmosomal gene mutations. We identified six heterozygous putative missense mutations in six unrelated probands. Two (p.Pro1583Ser and p.Leu4670Val) were considered as disease-causing mutations and four (p.Ala2213Ser, p.Gly2367Arg, p.Tyr2932His, p.Val3219Me) were considered as genetic variants of unknown significance (GVUS). Phenotype associated with RYR2 variants was unremarkable, associating typical ECG abnormalities, frequent monomorphic ventricular tachycardia with only a minority developing polymorphic ventricular arrhythmias. All displayed typical right ventricular (RV) abnormalities associating RV dilatation and wall motion abnormalities. Fibro-fatty replacement was demonstrated when tissue available for analysis. Conclusion: In this first systematic screening of the whole RyR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we observed that (i) putative mutations were not infrequent (9% of ARVC/D probands) and (i) were predominantly associated with a conventional phenotype of ARVC/D, not overlapping with CPVT, in contrast with previous findings. Therefore, we propose that RYR2 gene should be added to the panel of genes analysed in patients with ARVC/D.