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The prediction of (un)binding rates and free energies is of great significance to the drug design process. Although many enhanced sampling algorithms and approaches have been developed, there is not yet a reliable workflow to predict these quantities. Previously we have shown that free energies and transition rates can be calculated by directly simulating the binding and unbinding processes with our variant of the WE algorithm "Resampling of Ensembles by Variation Optimization", or "REVO". Here, we calculate binding free energies retrospectively for three SAMPL6 host-guest systems and prospectively for a SAMPL9 system to test a modification of REVO that restricts its cloning behavior in quasi-unbound states. Specifically, trajectories cannot clone if they meet a physical requirement that represents a high likelihood of unbinding, which in the case of this work is a center-of-mass to center-of-mass distance. The overall effect of this change was difficult to predict, as it results in fewer unbinding events each of which with a much higher statistical weight. For all four systems tested, this new strategy produced either more accurate unbinding free energies or more consistent results between simulations than the standard REVO algorithm. This approach is highly flexible, and any feature of interest for a system can be used to determine cloning eligibility. These findings thus constitute an important improvement in the calculation of transition rates and binding free energies with the weighted ensemble method.

Resume Le depistage neonatal (DNN) de la mucoviscidose, grâce a une prise en charge multidisciplinaire tres precoce des nourrissons, est optimal en termes de pronostic pour les patients. Depuis 20 ans, il a connu une expansion internationale spectaculaire. Les performances du DNN national francais realise depuis 2002 sont en accord avec les standards europeens pour la valeur predictive positive (0,31 pour un minimum de 0,30) et la specificite (0,95 pour un minimum de 0,95) ; nous soulignons le nombre tres faible de cas non conclus, un pourcentage tres eleve de test de la sueur realises (95,5 %) et d’identification des mutations (96,6 %), un ratio de cas de mucoviscidose par rapport aux cas de diagnostic incertain de 6,3:1, ainsi qu’une strategie efficace pour reperer les faux negatifs. Une nouvelle organisation du DNN francais vient de se mettre en place, il est capital de maintenir l’efficacite du processus, du nouveau-ne en maternite jusqu’au diagnostic dans des centres de reference ou de competences de la mucoviscidose avec un recueil exhaustif des donnees et leur validation. Par ailleurs, une proposition de changement d’algorithme introduisant le dosage du polypeptide d’activation pancreatique est soumise aux nouvelles instances du DNN. L’annonce d’un diagnostic positif reste difficile et peu standardisee, si bien qu’une plateforme de simulation est en cours de mise en place. Nous detaillons ici les bonnes pratiques et les difficultes de realisation du test de la sueur, avec les seuils de chlorures recemment redefinis, ainsi que les modalites du conseil genetique.

The free energy of transitions between stable states is the key thermodynamic quantity that governs the relative probabilities of the forward and reverse reactions and the ratio of state probabilities at equilibrium. The binding free energy of a drug and its receptor is of particular interest, as it serves as an optimization function for drug design. Over the years, many computational methods have been developed to calculate binding free energies, and while many of these methods have a long history, issues such as convergence of free energy estimates and the projection of a binding process onto order parameters remain. Over 20 years ago, the Jarzynski equality was derived with the promise to calculate equilibrium free energies by measuring the work applied to short nonequilibrium trajectories. However, these calculations were found to be dominated by trajectories with low applied work that occur with extremely low probability. Here, we examine the combination of weighted ensemble algorithms with the Jarzynski equality. In this combined method, an ensemble of nonequilibrium trajectories are run in parallel, and cloning and merging operations are used to preferentially sample low-work trajectories that dominate the free energy calculations. Two additional methods are also examined: (i) a novel weighted ensemble resampler that samples trajectories directly according to their importance to the work of work and (ii) the diffusion Monte Carlo method using the applied work as the selection potential. We thoroughly examine both the accuracy and efficiency of unbinding free energy calculations for a series of model Lennard-Jones atom pairs with interaction strengths ranging from 2 kcal/mol to 20 kcal/mol. We find that weighted ensemble calculations can more efficiently determine accurate binding free energies, especially for deeper Lennard-Jones well depths.

Rod and cone photoreceptor outer segment (OS) structural integrity is essential for normal vision; disruptions contribute to a broad variety of retinal ciliopathies. OSs possess many hundreds of stacked membranous disks, which capture photons and scaffold the phototransduction cascade. Although the molecular basis of OS structure remains unresolved, recent studies suggest that the photoreceptor-specific tetraspanin, peripherin-2/rds (P/rds), may contribute to the highly curved rim domains at disk edges. Here, we demonstrate that tetrameric P/rds self-assembly is required for generating high-curvature membranes in cellulo, implicating the noncovalent tetramer as a minimal unit of function. P/rds activity was promoted by disulfide-mediated tetramer polymerization, which transformed localized regions of curvature into high-curvature tubules of extended lengths. Transmission electron microscopy visualization of P/rds purified from OS membranes revealed disulfide-linked tetramer chains up to 100 nm long, suggesting that chains maintain membrane curvature continuity over extended distances. We tested this idea in Xenopus laevis photoreceptors, and found that transgenic expression of nonchain-forming P/rds generated abundant high-curvature OS membranes, which were improperly but specifically organized as ectopic incisures and disk rims. These striking phenotypes demonstrate the importance of P/rds tetramer chain formation for the continuity of rim formation during disk morphogenesis. Overall, this study advances understanding of the normal structure and function of P/rds for OS architecture and biogenesis, and clarifies how pathogenic loss-of-function mutations in P/rds cause photoreceptor structural defects to trigger progressive retinal degenerations. It also introduces the possibility that other tetraspanins may generate or sense membrane curvature in support of diverse biological functions.

Conventional molecular dynamics simulations are incapable of sampling many important interactions in biomolecular systems due to their high dimensionality and rough energy landscapes. To observe rare events and calculate transition rates in these systems, enhanced sampling is a necessity. In particular, the study of ligand-protein interactions necessitates a diverse ensemble of protein conformations and transition states, and for many systems, this occurs on prohibitively long time scales. Previous strategies such as WExplore that can be used to determine these types of ensembles are hindered by problems related to the regioning of conformational space. Here, we propose a novel, regionless, enhanced sampling method that is based on the weighted ensemble framework. In this method, a value referred to as "trajectory variation" is optimized after each cycle through cloning and merging operations. This method allows for a more consistent measurement of observables and broader sampling resulting in the efficient exploration of previously unexplored conformations. We demonstrate the performance of this algorithm with the N-dimensional random walk and the unbinding of the trypsin-benzamidine system. The system is analyzed using conformation space networks, the residence time of benzamidine is confirmed, and a new unbinding pathway for the trypsin-benzamidine system is found. We expect that resampling of ensembles by variation optimization will be a useful general tool to broadly explore free energy landscapes.

Objectives To provide an overview of non-specific modifications on whole-body post-mortem computed tomography (PMCT) images of infants and children. Materials and methods 69 infants and children underwent a whole-body PMCT scan at our institution following sudden unexpected death. Two paediatric radiologists reviewed the PMCT images, specifically focusing on non-specific postmortem modifications unrelated to the presumed cause of death. Results Iatrogenic post-mortem modifications included focal infiltration of the legs ( n =15) and hemopericardium ( n =2). Vascular postmortem modifications included hypostasis (density in the posterior sagittal sinus was correlated with density in the dependent portion of the heart ( p n =56, 75.3%), hyperattenuating aortic wall and reduced abdominal aortic diameter ( n =69, 100%). Intravascular gas was detected in 40 subjects (57.9%). Ligamentum arteriosum calcification was seen in 42 children and was not correlated with age ( p =0.68). Umbilical artery calcification was found in 30 children and was correlated with age ( p n =45, 65.2%) and bowels ( n =44, 63.7%) was a frequent finding. Mean liver density was 49.6±7.5HU and mean spleen density was 43.2±5.9HU. Ground-glass opacity was observed in 63 cases (91.3%) and mild bilateral consolidation in 16 cases (23.1%). Conclusion Non-specific post-mortem signs are rare and new to clinical paediatric radiologists. They should be aware of these signs when interpreting whole-body PMCT images in cases of sudden unexpected death in infancy or childhood in order to avoid pitfalls that may have a critical impact.

Deprivation-related pathology can take the form of faltering growth, medical neglect, psychomotor delay, and/or behavioral problems, in various combinations.

Every year in France, nearly 50 infants live in a prison nursery with their mother. According to French law, infants can live with their mother in the prison nursery until they reach 18 months of age. The international community is concerned about the lack of validated social, medical and legal data on these infants living in prison. This was a retrospective and descriptive study. Medical and paramedical files of the General Council of Île-et-Vilaine, France, were studied. Every infant born between 1998 and 2013 while their mother was in prison were included. Fifty-four files were collected. The average length of stay was 6.2 months (n=54). The type of the mother's prison sentence was property damage in 40 % of cases, personal injury in 51.1 % of cases and both in 8.9 % of cases (n=45). The length of the mother's imprisonment was on average 45 months, ranging from 3 to 216 months (n=34). After prison, 42.9 % of the infants were placed in foster care and 57.1 % resided with their family (n=42). This child-mother incarceration could be an opportunity for positive intergenerational paramedical, medical and social services. The lack of data and problems collecting data restrict our knowledge of these families. This should motivate a national follow-up for these children.

Neonatal screening for cystic fibrosis (CF) may detect infants with elevated immunoreactive trypsinogen (IRT) levels but with inconclusive sweat tests and/or DNA results. This includes cases associating (1) either the presence of at most one CF-causing mutation and sweat chloride values between 30 and 59mmol/L or (2) two CFTR mutations with at least one of unknown pathogenicity and a sweat chloride below 60mmol/L. This encompasses different clinical situations whose progression cannot be predicted. These cases require redoing the sweat test at 12 months and if possible at 6 and 24 months of life. This must be associated with extended genotyping. CFTR functional explorations can also help by investigating CFTR dysfunction. These infants must be initially evaluated in dedicated CF centers including bacteriological sputum analysis, chest radiology and fecal elastase dosage. A home practitioner must be informed of the specificity of follow-up. These infants will be reviewed in the CF center at 3, 6 and 12 months and every year. Any CF-related symptom requires reevaluation of the diagnosis. These guidelines were established by the "neonatal screening and difficult diagnoses" working group of the French CF Society. They aim to standardize management of infants with unclear diagnosis in French CF centers.

Resume La semiologie du syndrome du « bebe secoue », en tant qu’entite nosologique, est aujourd’hui bien connue. Son expression clinique neurologique fait reposer l’etablissement du diagnostic, en premiere intention, sur la realisation d’une tomodensitometrie (TDM) cerebrale, qui offre les avantages d’accessibilite, de rapidite d’acquisition et de facilite d’interpretation. L’imagerie par resonance magnetique (IRM), si elle demeure moins accessible, offre en revanche une semiologie radio-anatomique plus riche. Mais, l’action ou l’intervention violente d’un tiers, sous-entendue des lors que l’on evoque le « bebe secoue », constitue une infraction penale qui interesse le magistrat. Il incombe au medecin legiste de repondre en termes de constat des lesions et de compatibilite avec les mecanismes lesionnels retenus par les investigations judiciaires. La compatibilite peut se deduire d’une date supposee des faits. Or la notion de delai entre le fait (objet de l’enquete) et la lesion n’interesse pas au premier chef le therapeute et n’oriente donc pas la strategie des examens complementaires. Elle interesse en revanche le magistrat et donc le medecin legiste. Des lors, sur quels elements cliniques ou radiocliniques le medecin legiste peut-il s’appuyer pour dater les lesions neurologiques constatees chez ces enfants ? Avec quelle fiabilite ? Des strategies d’investigations concertees, servant le double interet diagnostique et medicolegal sont-elles envisageables ?

Dans le contexte actuel de la discussion sur l’opportunite d’un depistage neonatal generalise, six questions servent de fil conducteur.La surdite permanente de l’enfant est-elle un probleme de sante publique ? Si le degre de surdite concerne et sa prevalence paraissent consensuels, la reponse au critere de gravite necessite tact et respect. Les questions sur l’identification a un stade latent, l’existence d’un test de depistage simple, fiable et bien accepte et le benefice en termes d’âge diagnostique sont, comparativement, plus simples, le depistage neonatal faisant doubler la proportion d’enfants sourds identifies avant l’âge de 6 mois.Le meilleur developpement des enfants sourds sous l’effet d’une prise en charge precoce a mis du temps a etre demontre. Parmi les enfants sourds profonds congenitaux ayant recu un implant cochleaire, le developpement du langage oral est plus rapide chez ceux implantes entre 12 et 24 mois. Si on prend en compte l’ensemble des degres de surdite, l’instauration precoce (avant 9 mois) de la prise en charge conduit, a l’âge de 8 ans, a un langage receptif (fonde sur tous les moyens de communication) significativement plus eleve.Les faux-positifs du depistage neonatal ont-ils un inconvenient a long terme ? D’apres une etude comparative recente sur des familles dont les enfants avaient eu un depistage faussement positif et d’autres chez lesquels le depistage avait permis de conclure d’emblee a une audition normale, l’anxiete parentale est similaire a l’âge de 6 mois. Mais dans le groupe des faux-positifs, 60 % des parents reconnaissent verifier souvent que leur enfant entend bien.Prat Organ Soins 2009;40(3):207-212

Summary In 2002 France implemented a nationwide newborn screening program for cystic fibrosis (CF). The strategy combined immunoreactive trypsinogen and, in case of a value over the cut-off level, DNA analysis in dried blood samples at day 3. Data were centralized and periodically analyzed thus maintaining the percentage of samples requiring mutation analysis (0.6%), limiting the number of false-positive cases (0.1%) without increasing the number of false-negative cases (3.2%). 3.527.353 infants were screened between 2002 and 2006. The overall cystic fibrosis incidence was 1/ 4136 with a wide range of regional variations. Dilemma case presentation occurred for 14 % of the patients; an European working group is actively working on this topic, attempting to establish a consensus on the adequate procedures. Cystic fibrosis newborn screening is feasible all over a nation but needs a strong organization from maternity wards to CF care centers.

Resume Cela fait plus de 40 ans que le depistage de la mucoviscidose en periode neonatale a debute. Apres la possibilite d'un test de depistage par dosage de l'albumine meconiale, le dosage de la trypsine immunoreactive sanguine sur papier buvard couple a la recherche des principales mutations du gene CFTR est utilise de facon courante avec une bonne sensibilite et specificite du test. Ce depistage a longtemps fait l'objet de controverses, mais ses avantages au moins a moyen terme et notamment sur le plan nutritionnel, sont bien demontres. L'interet d'un tel depistage est rappele au vu des experiences francaises et etrangeres. Ces resultats sont etroitement lies avec la qualite du suivi de l'enfant depiste dans des centres specialises. Des lors, ce depistage neonatal n'a de sens que s'il est assorti de ce type de suivi. C'est la raison pour laquelle la generalisation du depistage neonatal sur l'ensemble de la France en 2002 s'est accompagnee de recommandations de suivi de l'enfant depiste dans des centres de soins que les autorites de sante ont officialise et denomme centres de ressources et de competences de la mucoviscidose. La France est ainsi devenue le premier pays au monde a effectuer ce depistage sur l'ensemble de son territoire, dont l'organisation a ete confiee a l'Association francaise de depistage et de prevention des handicaps de l'enfant. Depuis le debut du programme, 621 nouveau-nes ont ete ainsi reperes, soit une incidence de 1/4376, avec de fortes variabilites regionales. Le probleme actuel, qui se produit dans 14 % des cas, est celui de la revelation de formes cliniques ou paucisymptomatiques avec des tests de la sueur intermediaires ou normaux et au moins une mutation dite moderee et dont on ignore le pronostic. Neanmoins, en evaluant les benefices et les risques d'un tel depistage, le CDC estime maintenant que ce depistage est justifie.

Los examenes sistematicos forman parte de la actividad basica de la asistencia sanitaria infantil, tanto en el ejercicio privado como en el servicio de Proteccion Materna e Infantil (PMI) o en la asistencia medica escolar. La deteccion precoz y la correccion de una enfermedad se orientan a permitir una relacion normal del nino con el mundo exterior, para lograr un desarrollo psicomotor e intelectual optimo. En los ultimos anos han tenido lugar varias conferencias de consenso de la maxima autoridad sanitaria francesa (HAS) y reuniones colectivas del Instituto Nacional de Salud e Investigacion Medica (INSERM) para proponer los examenes mas adecuados en funcion de la edad del nino. Estos examenes sistematicos se concentran sobre todo durante los 6 primeros anos de vida, con la realizacion de 20 examenes por parte de la Seguridad Social, que registran los datos esenciales sobre el crecimiento, las etapas del desarrollo psicomotor e intelectual, la exploracion fisica y sensorial, asi como las vacunaciones. Estas informaciones deben anotarse en el documento de salud infantil, que constituye una util herramienta de comunicacion. Tambien contiene numerosas indicaciones para los medicos, al senalar los puntos esenciales que han de buscarse y las distintas pruebas que se deben emplear segun las edades, asi como mensajes de prevencion: deteccion precoz de los trastornos sensoriales o de la relacion, prevencion de la obesidad y de las alergias alimentarias, proteccion del sueno y de los ritmos de vida del nino, prevencion de los accidentes ambientales y del riesgo de maltrato. Para cada edad, figuran consejos de educacion sanitaria, destinados a los padres y despues a los propios adolescentes. Tambien se contempla el tratamiento global de los ninos (psicoconductual, sensorial y ambiental). Por desgracia, no todos los ninos se benefician de la totalidad de estos examenes y tres de ellos, realizados a edades clave (8.° dia, 9 meses y 24 meses) se ponen de relieve mediante el establecimiento de certificados medicos obligatorios. Despues, se debe profundizar en el examen de los 3 anos, porque es una edad adecuada para detectar los trastornos conductuales y del aprendizaje. Despues de los 3 anos, el nino esta escolarizado y los examenes sistematicos pueden realizarse por el servicio de PMI y la medicina escolar. Esto no excluye la deteccion individual realizada de forma periodica por el medico de cabecera e incluye, ademas de trastornos por deficit de atencion con hiperactividad, alteraciones visuales y auditivas, trastornos del aprendizaje y del lenguaje, anomalias del desarrollo puberal, trastornos de la conducta alimentaria y obesidad, escoliosis, asma y rinoconjuntivitis alergica, riesgos relacionados con la sexualidad, trastornos de la conducta y trastornos por conflictividad, conductas de riesgo, consumo de sustancias, trastornos por ansiedad, conductas suicidas y, por ultimo, depresion.

On 5 March 2007 the law concerning the child protection system was reformed. Since this date, child protection services are responsible for child abuse and neglect. Child protection services are now attempting to determine the rightful place for parents. Asking for child protection is now easier for the general practitioner (GP), who can submit a "preoccupying information (PI)" form. The aim of this study was to review GPs' knowledge on this issue 6 years after the passage of this new law.Prospective postal investigation between 04/01/2013 and 06/01/2013.A total of 298 (113 women) of the 899 GPs of the Ille-et-Vilaine area in Brittany answered a few questions about their activity and their knowledge on child abuse and neglect. The sample's mean age, sex, and practice was representative of the GPs in this area. Only 25.5% of the GPs had any knowledge of this new law. The term "preoccupying information" was unfamiliar to 70.1% of the GPs and what to do with the PI was unknown to 77.2%. The GPs did not know which type of letter to send nor where to send it between legal child protection and social protection services. Only 5% of the GPs had child protection training on PI. The main problem informing the child protection services was the lack of training. Consequently, 91.9% of the GPs would like training.The GPs in the Ille-et-Vilaine area in Brittany are unfamiliar with the child protection updates and need special training.

Initiated in 1978 by a Colombian team, then largely adapted in industrialized countries as well as in poor developed countries, the kangaroo mother care (KMC) are known to ensure for low birth weight newborn, a thermoregulation, a good physiological stability and a better relational comfort with their parents. The goal of this work is to make a bibliographical review on current concepts, interests and limits of this method. We re-examined impact of the KMC on the basal metabolism, thermoregulation, growth and evolution of these children. They are helpful in the developing countries but medical safety should not be forgotten. In these countries where there's high frequentation of the services, they are able to regulate body temperature and metabolic adaptation of the newborn. In developed countries, KMC contribute to decrease anxiety of parents and improve the relations with their child. However, it is difficult to recommend their use in current practice. Rigorous randomised studies are necessary to argue their establishment in full safety, to know the neuropsychological development and the real somatic growth on the long term of the children and to known their true economic cost.

We propose here an application to sensing of annular aperture arrays (AAA). We theoretically investigate the optical properties of the reflective AAA device when illuminated in plane. The cavity presents almost perfect absorption due to the waveguide mode resonance with strong field localization in the aperture. Additionally the reflective cavity is modeled to be available for on chip sensing with a theoretically expected sensitivity of 764 nm/RIU (refractive index unit).

Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. While the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is restricted to the biliary epithelium in the liver, recent findings indicate that CFTR modulates reduced glutathione (GSH) transport and that CFTR dysfunction creates an imbalance in the antioxidant defense. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. Because oxidative injury contributes to the development of liver disease, we hypothesized that 2 members of the GST superfamily, GSTM1 and GSTP1, which are expressed in the biliary epithelium, could influence the hepatic status in patients with CF. The potential impact of GSTM1 and GSTP1 gene polymorphisms was assessed in 106 children with CF (mean age, 11.5 years). Based on polymerase chain reaction/restriction fragment length polymorphism analysis, we found that the frequency of GSTP1-Ile105/Ile105 genotype was significantly higher in patients with CF with liver disease than in those without (P < .03). Among the youngest patients, aged 6 years, GSTP1-Ile105/Ile105 genotype was associated with a 8-fold increase in the risk of liver disease compared with other GSTP1 genotypes (P = .002). No association between the GSTM1 genotype and liver status was documented. In conclusion, GSTP1-Ile105-encoding allele contributes to hepatic dysfunction in CF. Identification of this polymorphism may have prognostic value and prompt early treatment in patients with CF with an increased risk of liver disease. (HEPATOLOGY 2002;36:913-917.)

The sources of exposure during diseases due to Aspergillus fungi in cystic fibrosis patients are still poorly explored. We assessed home fungal exposure in patients suffering from cystic fibrosis and analysed its impact on the presence of Aspergillus biological markers, the colonisation of airways, as well as the sensitization and Aspergillus serology. Between March 2012 and August 2012, 34 patients benefited from a visit performed by a home environment medical adviser including sampling for mycological analysis. The number of colonies of Aspergillus was not significantly different in the various sampling sites (P=0.251), but the number of non-Aspergillus colonies was much higher in the kitchen (P=0.0045). Subsequently, home fungal exposure was compared between the groups "absence of Aspergillus-related markers" and "presence of Aspergillus-related markers". Home exposure to Aspergillus (P=0.453) and non-Aspergillus (P=0.972) flora was not significant between the 2 groups. Within this series of 34 patients that should be expanded, we note an absence of clear relationship between home exposure and the Aspergillus-linked markers in patients suffering from cystic fibrosis. This result should be taken into account regarding too restrictive hygiene advices provided to families, given the fact that fungal exposure can also results from activities performed away from home.

These guidelines aim to standardize the care of infants diagnosed with a typical form of cystic fibrosis (CF) at neonatal screening. They have been implemented by the National Working Group for Neonatal Screening of the French Federation for CF and have been validated using the Delphi methodology by a large group of clinicians involved in the care of CF infants. These guidelines encompass management and organization of care at diagnosis and describe nutritional, digestive, and respiratory monitoring and treatment during the first 2 years of life.

Resume Le depistage neonatal de la mucoviscidose repose sur le dosage d'une enzyme pancreatique, la trypsine immunoreactive, dans le sang des nouveau-nes. La decouverte du gene CFTR en 1989 a permis d'incorporer la recherche directe des mutations dans le protocole. Nous tracons ici le bilan de l'apport de la biologie moleculaire au depistage neonatal en nous focalisant sur notre experience menee en Bretagne depuis six annees. La trypsine est mesuree par radio-immunoanalyse; trois exons du gene (7, 10, 11) sont analyses systematiquement en cas d'hypertrypsinemie. Parmi les 204 202 nouveau-nes depistes, 66 enfants porteurs de deux mutations ont ete detectes conduisant a une incidence de 1/3 093. Toutes les anomalies moleculaires ont ete identifiees: 27 mutations differentes resultant en 28 genotypes. L'introduction de l'analyse moleculaire a permis d'augmenter la sensibilite du test qui est actuellement de 100 % mais surtout d'augmenter la specificite en reduisant le taux de rappel ce qui permet de poser plus rapidement le diagnostic. Les techniques de biologie moleculaire permettent de determiner le genotype et donc de predire le phenotype et l'evolution de la maladie, et d'activer le depistage en cascade et le diagnostic prenatal dans les familles.

Resume L'utilisation d'un milieu selectif pour l'isolement de Burkholderia (Pseudomonas) cepacia a conduit a la mise en evidence de la bacterie dans les secretions respiratoires de 4 patients suivis en 1993 par la Consultation Multidisciplinaire de Mucoviscidose du CHRU de Rennes. Une transmission inter-humaine etant suspectee, ces 4 souches ont ete ribotypees et comparees, entre elles, et avec 9 autres souches isolees dans 2 autres centres de surveillance et de traitement de la meme region. Onze ribotypes ont ete retrouves parmi les 13 souches etudiees. Les 4 souches isolees a Rennes avaient des profils differents, ce qui excluait une origine commune de la contamination.

Congenital adrenal hyperplasia neonatal screening has been introduced in France since 1995. A recent survey has questioned its relevance in premature infants because of a high number of false positives and a low positive predictive value of 17-hydroxyprogesterone dosage. A workgroup at the French screening association (Association française de dépistage et de prévention des handicaps de l'enfant) collected all the epidemiological, clinical and biological data of premature children presenting with adrenal hyperplasia from the national cohort. Their results were compared with those of healthy premature children. All the data showed that the screening in children born before 32 weeks of gestational age is irrelevant, but that it is efficient after this term. A pilot study has been implemented in population to evaluate the opportunity to discontinue this screening in extreme preterm neonates.

Shaken baby syndrome (SBS) is defined by the association of intracranial hemorrhage and retinal hemorrhage in infants under 2 years of age, with no obvious external trauma. This syndrome leads to frequent neurological sequelae. Therefore, these infants can claim compensation for damage if sequelae are directly and irrefutably linked to the trauma. Data on the judicial treatment are for the most part inexistent in the medical literature, the reason for which this study was conducted.We conducted a retrospective study over a period of 10 years. We included all cases of SBS reported to the High Courts of the Ille-et-Vilaine department (Rennes and St Malo). The cases were listed from the archives of the Department of Medical Information, the Specialized Unit for Abused Children and Forensic Department at the Rennes University Hospital. We were able to look the judicial cases up after receiving agreement from the prosecutors of the two courts.Of the 34 cases included, 12 could not be used (lost, ongoing, destroyed, transferred to another court), 16 led to an order of dismissal or to no further action because of an unknown perpetrator, insufficiently described offense, or insufficient evidence. Six authors were sentenced. It was the father (n=5) or the childminder (n=1). All perpetrators had confessed to part or all of the charges brought against them. Five children received compensation: three by the civil court and two by the commission of compensation for victims of an offense.Most cases led to no conviction and no compensation. The identification by the physician of the person responsible for the lesions in SBS does not mean that the perpetrator will be convicted because of the strict application of criminal law. The nomination of an administrator representing the infant could resolve the lack of compensation.

International audience; To investigate the contribution of whole-body post-mortem computed tomography (PMCT) in sudden unexpected death in infants and children.METHODS:Forty-seven cases of sudden unexpected death in children investigated with radiographic skeletal survey, whole-body PMCT and autopsy were enrolled. For imaging interpretation, non-specific post-mortem modifications and abnormal findings related to the presumed cause of death were considered separately. All findings were correlated with autopsy findings.RESULTS:There were 31 boys and 16 girls. Of these, 44 children (93.6 %) were younger than 2 years. The cause of death was found at autopsy in 18 cases (38.3 %), with 4 confirmed as child abuse, 12 as infectious diseases, 1 as metabolic disease and 1 as bowel volvulus. PMCT results were in accordance with autopsy in all but three of these 18 cases. Death remains unexplained in 29 cases (61.7 %) and was correlated with no abnormal findings on PMCT in 27 cases. Major discrepancies between PMCT and autopsy findings concerned pulmonary analysis.CONCLUSIONS:Whole-body PMCT may detect relevant findings that can help to explain sudden unexpected death and is essential for detecting non-accidental injuries. We found broad concordance between autopsy and PMCT, except in a few cases of pneumonia. It is a non-invasive technique acceptable to relatives.KEY POINTS:• Whole-body post-mortem computed tomography (PMCT) is an effective non-invasive method. • Whole-body PMCT is essential for detecting child abuse in unexpected death. • There is concordance on cause of death between PMCT and autopsy. • Whole-body PMCT could improve autopsy through dissection and sampling guidance. • PMCT shows findings that may be relevant when parents reject autopsy.

Newborn screening (NBS) enables detection of pre-symptomatic cystic fibrosis (CF) patients. A major issue confronting the multidisciplinary team is that of implementing adequate follow-up care, thereby preventing nutritional and pulmonary complications. NBS may also identify newborns who do not fulfil the CF diagnosis criteria; the clinician and family are faced with the diagnostic and prognostic dilemma of atypical CF. Published recommendations are mainly a consensus of expert opinions on follow-up modalities and treatment to help families and primary care physicians, thus harmonizing current practices among CF care specialists. Well-designed clinical trials for these young children focusing on nutritional and pulmonary function are of crucial importance. Indeed, evaluation of pulmonary function is hampered by the absence of accurate, sensitive, reproducible outcome parameters. The European Cystic Fibrosis Society Clinical Trials Network is actively stimulating clinical research on these very young patients.

These guidelines aim to standardize the standard operating procedures for the sweat test in newborn cystic fibrosis (CF) screening. They have been implemented by the national Neonatal Screening working group of the French Federation for Cystic Fibrosis. It is recommended that the sweat test be performed when the infant weighs more than 3 kg and is at least 3 weeks of age. Sweat gland secretion is stimulated by transdermal administration of pilocarpine by iontophoresis. Sweat is preferentially collected in a Macroduct coil. Diagnosis of CF is based on the sweat chloride level. A sweat chloride level below 30 mmol/l very probably rules out CF; 60 mmol/l or higher supports the diagnosis of CF. Values between 30 and 60 mmol/l are considered abnormal.

Sudden infant death syndrome (SIDS) is a huge hardship for parents, but also for health professionals. In 2007, 210 cases occurred in France, corresponding to a crude rate of 31.8 for 100,000 births. Between 1994 and 2007, 140 children of less than 2 years old were examined in the reference centre for SIDS in Rennes, France. We included in our study the children who were aged more than 28 days at death date, did not have a known lethal disease and were autopsied. A total of 80 children fulfilled those criteria. Post-mortem investigation included an autopsy, clinical and paraclinical exams (blood test, radiography, CT-scan...), and investigation of the circumstances of the death. Most of the cases were boys and were 2- to 5-month old. Ventral decubitus and gastrointestinal symptoms were often present. Autopsy gave elements about the causes of death in 23 cases and the other exams performed frequently showed an infectious viral context. Thanks to prevention and information campaigns about childcare done in the 1990s, SIDS incidence has largely decreased in France, but it is still too frequent. In our opinion, advice needs to be given again and again, especially concerning safe sleep practices, in order to increase adherence to these recommendations. Moreover, research should be continued to better understand this unexplained syndrome.

Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p R117H), on either intron 8 T5 or T7 background, and F508del (p F508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p F508del was 1.06%, p R117H;T7 0.27% and p R117H;T5 ,0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes .

Infections by Nocardia species are uncommon and generally affect immunocompromised patients. This bacteria has rarely been isolated from cystic fibrosis patients (CF), especially those who are not taking oral corticosteroids. We report a case of a patient with CF harbouring Nocardia farcinica. An 18-year-old male diagnosed with CF at the age of eight (F508 del/G85E) had been treated for allergic bronchopulmonary aspergillosis in 1998 with itraconazole, and a first colonization with Pseudomonas aeruginosa was eradicated in 2003. From May 2006, he presented with recurrent left- and right-sided pneumothorax. In June 2006, he presented with dyspnoea, fever, and nodular eruption on his ankles. Chest X-ray and CT scan revealed a right pneumothorax, severe bronchiectasis and bilateral alveolar consolidation. N. farcinica was idolated from his sputum without any other pathogens. Treatment with intravenous cotrimoxazole associated with imipenem and amikacin was initiated for three weeks followed by oral cotrimoxazole for a further nine months. The patient's symptoms and alveolar consolidation on CT scan improved. During 2007, his respiratory condition worsened and his FEV(1) declined from 50 to 26 % predicted. His pneumothorax recurred. He had chronic colonization with P. aeruginosa and was on the list for lung transplantation. Nocardia, a Gram positive bacillus, causes mainly pulmonary infection, usually in the context of immune suppression. The most frequent species is N. asteroides. In CF, very few cases have been reported; almost always N. asteroides, but exceptionally N. farcinica. In CF patients with worsening pulmonary condition, Nocardia should be considered, as well as other unusual pathogens.

The photonic and phononic band gap properties of lithium niobate are investigated both theoretically and experimentally. The computed photonic band structures are used to discuss the appearance of band gaps and of slow light modes. Actual lithium niobate photonic crystals are presented and a striking phenomenon of enhanced electro-optic coefficient for slow light is emphasized. Phononic crystals fabricated in lithium niobate are then discussed theoretically and experimentally, with an emphasis on phononic band gap properties for surface acoustic waves, i.e. for phonons that are confined close to the surface. Some perspectives for future work are given, including the development of thin layer devices and of phoXonic crystals, artificial crystals that possess simultaneous photonic and phononic band gaps.

In 2002 France implemented a nationwide newborn screening program for cystic fibrosis (CF). The strategy combined immunoreactive trypsinogen and, in case of a value over the cut-off level, DNA analysis in dried blood samples at day 3. Data were centralized and periodically analyzed thus maintaining the percentage of samples requiring mutation analysis (0.6%), limiting the number of false-positive cases (0.1%) without increasing the number of false-negative cases (3.2%). 3.527.353 infants were screened between 2002 and 2006. The overall cystic fibrosis incidence was 1/ 4136 with a wide range of regional variations. Dilemma case presentation occurred for 14 % of the patients; an European working group is actively working on this topic, attempting to establish a consensus on the adequate procedures. Cystic fibrosis newborn screening is feasible all over a nation but needs a strong organization from maternity wards to CF care centers.