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International audience; Objective: To investigate cerebral anomalies other than Chiari type 2 malformation in fetuses with myelomeningocele (MMC).Design: A retrospective cohort study in a single tertiary centre.Setting: A review of associated cerebral anomalies in cases with prenatal diagnosis of myelomeningocele.Population: Seventy cases of fetal myelomeningocele.Methods: Ultrasound and MRI images were blindly reviewed. Postnatal imaging and results of the postmortem results were also reviewed. The association between cerebral anomalies and the following ultrasound findings was measured: level of the defect, ventriculomegaly, microcephaly and fetal talipes.Main outcome measures: A microcephaly was observed in 32/70 cases (46%) and a ventriculomegaly was observed in 39/70 cases (56%). Other cerebral anomalies were diagnosed in 47/70 (67%).Results: Other cerebral anomalies were represented by 42/70 cases with abnormal CC (60%), 8/70 cases with perinodular heterotopia (PNH; 11%), 2/70 cases with abnormal gyration (3%). MRI performed only in fetal surgery cases confirmed the ulltrasound findings in all cases and provided additional findings in two cases (PNH). Risk ratios of fetal cerebral anomalies associated with MMC did not reach significance for microcephaly, ventriculomegaly, talipes or the level of the defect There was an overall good correlation between pre- and postnatal findings with a Kappa value of 0.79 [95% CI 0.57-1] and 82% agreement.Conclusion: Fetal brain anomalies other than Chiari type 2 malformation are frequently observed in fetuses with myelomeningocele, predominantly represented by CC anomalies. Whether these associated cerebral anomalies have an impact on selecting cases eligible for fetal surgery needs further evaluation.Tweetable abstract: Fetal cerebral anomalies other than Chiari type 2 malformation, microcephaly, and ventriculomegaly may be associated with MMC in up to 67% of the cases.

International audience; Fetal akinesia has multiple clinical subtypes with over 160 gene associations, but the genetic etiology is not yet completely understood.Methods: In this study, 51 patients from 47 unrelated families were analyzed using next-generation sequencing (NGS) techniques aiming to decipher the genomic landscape of fetal akinesia (FA).Results: We have identified likely pathogenic gene variants in 37 cases and report 41 novel variants. Additionally, we report putative pathogenic variants in eight cases including nine novel variants. Our work identified 14 novel disease-gene associations for fetal akinesia: ADSSL1, ASAH1, ASPM, ATP2B3, EARS2, FBLN1, PRG4, PRICKLE1, ROR2, SETBP1, SCN5A, SCN8A, and ZEB2. Furthermore, a sibling pair harbored a homozygous copy-number variant in TNNT1, an ultrarare congenital myopathy gene that has been linked to arthrogryposis via Gene Ontology analysis.Conclusion: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate genes. By combining NGS with deep clinical phenotyping, we achieved a 73% success rate of solved cases.

International audience; BACKGROUND:The risk of congenital neurologic defects related to Zika virus (ZIKV) infection has ranged from 6 to 42% in various reports. The aim of this study was to estimate this risk among pregnant women with symptomatic ZIKV infection in French territories in the Americas.METHODS:From March 2016 through November 2016, we enrolled in this prospective cohort study pregnant women with symptomatic ZIKV infection that was confirmed by polymerase-chain-reaction (PCR) assay. The analysis included all data collected up to April 27, 2017, the date of the last delivery in the cohort.RESULTS:Among the 555 fetuses and infants in the 546 pregnancies included in the analysis, 28 (5.0%) were not carried to term or were stillborn, and 527 were born alive. Neurologic and ocular defects possibly associated with ZIKV infection were seen in 39 fetuses and infants (7.0%; 95% confidence interval, 5.0 to 9.5); of these, 10 were not carried to term because of termination of pregnancy for medical reasons, 1 was stillborn, and 28 were live-born. Microcephaly (defined as head circumference more than 2 SD below the mean for sex and gestational age) was detected in 32 fetuses and infants (5.8%), of whom 9 (1.6%) had severe microcephaly (more than 3 SD below the mean). Neurologic and ocular defects were more common when ZIKV infection occurred during the first trimester (24 of 189 fetuses and infants [12.7%]) than when it occurred during the second trimester (9 of 252 [3.6%]) or third trimester (6 of 114 [5.3%]) (P=0.001).CONCLUSIONS:Among pregnant women with symptomatic, PCR-confirmed ZIKV infection, birth defects possibly associated with ZIKV infection were present in 7% of fetuses and infants. Defects occurred more frequently in fetuses and infants whose mothers had been infected early in pregnancy. Longer-term follow-up of infants is required to assess any manifestations not detected at birth. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT02916732 .).

International audience; PURPOSE: Jejunoileal atresia represents about 40% of intestinal atresia. After surgical repair, intestinal motility disorders are burdened with the postoperative outcome, and the origin of these troubles remains unclear. To specify the physiopathologic feature of jejunoileal atresia, we developed an experimental surgical model in fetal rat. METHODS: Time-dated pregnant rats were operated on at 18 days of gestational age. Hysterotomy was performed, followed by fetal wall incision. The exteriorization of the bowel loop was obtained by saline injection; the intestine was ligated and returned to the abdominal cavity before incisions were closed. Fetal intestine was excised at day 21, after cesarean delivery. RESULTS: Twenty-one pregnant rats underwent operation with 90% maternal survival rate. Among the 56 fetuses successfully operated on, 49 survived (87%). In fetuses with atresia, the mean birth weight (4.5 +/- 0.6 g) and the mean intestinal length (12.8 +/- 1.3 cm) were significantly lower compared to sham fetuses and controls. CONCLUSION: The rat model offers the advantage of a low-expense mammal model with a wide panel of probes and reagents available for the study of the gut. This model of jejunoileal atresia could be used to study the consequences of prenatal intestinal obstruction on fetal gut.

International audience; Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very difficult. Hepatocyte nuclear factor-1beta that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between -2 and +2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.

International audience; BACKGROUND: Clinical manifestations of human herpesvirus-6 (HHV-6) have not been clearly defined, and the role of HHV-6 in human disease remains to be fully elucidated. OBJECTIVE: To determine the frequency of HHV-6 infections at Rennes Teaching Hospital and to describe all possible symptoms of such infections. STUDY DESIGN: We systematically analyzed in a retrospective study all the samples between May 2003 and December 2004 from patients with HHV-6 by polymerase chain reaction (PCR). Clinical records of patients with positive HHV-6 PCR were recorded. Diagnosis of HHV-6 infection was accepted if all other possible diagnoses had been eliminated. RESULTS: Over the study period, 1591 PCRs were performed from various tissues, including blood, cerebrospinal fluid, ascitis and tissue biopsies. Forty-three samples from 25 patients tested positive (3%). We describe three groups of clinical manifestations of HHV-6 infection. The first group consisted of neurological complications (32% of patients), including convulsions, encephalitis and chronic psychiatric disorders in immunocompetent patients. The second group consisted of clinical problems relating to gastrointestinal tract, which was found in 9 of our patients (36%). All of these patients were immunocompromised. Four of them presented colitis, and one of them died one month after liver transplantation because of this colitis. The last group of clinical symptoms was associated with maternal-fetal infection leading to abortion following HHV-6 seroconversion during pregnancy. CONCLUSION: Three clinical types of HHV-6 infections are described: neurological manifestations including encephalitis in non-immunocompromised patients, digestive problems in immunosuppressed patients and severe maternal-fetal infection.

International audience; OBJECTIVE: To evaluate prenatal management and to define the criteria of gravity for accurate assessment of the renal and overall prognosis of fetuses presenting malformations of the urinary tract. METHODS: We carried out a retrospective study of 127 cases of urinary tract malformation. We carried out descriptive statistical and univariate analyses as a function of severity criteria and the outcome of pregnancy. RESULTS: One-third of fetuses presented associated extrarenal malformations and 10% of the karyotypes were abnormal. There were more abortions in case of decrease in amniotic fluid volume (p < 0.001), extent of renal damage (p < 0.05), presence of associated extrarenal malformations (p < 0.05), early diagnosis of the malformation (p < 0.001) and presence of chromosomal syndrome (p = 0.01). In our study, there was an excellent correlation between prenatal data and pathological findings for the fetus following abortions for medical reasons or obtained during the surveillance of live-born children. Fetal biochemistry made very little contribution. CONCLUSION: In cases of urinary tract malformation, this work confirms the need for regular and frequent ultrasound scans, checking for the echographic factors indicative of gravity and for adapted karyotyping. It also demonstrates that pluridisciplinary management is necessary for the prenatal evaluation of renal and overall fetal prognosis.

International audience; PURPOSE: Although intestinal motility disorders often complicate the postoperative surgical management of newborns with congenital intestinal atresia, their pathogenesis remains unclear. Animal models of prenatal intestinal obstruction have been mainly developed in the lamb and the chicken. Despite new insights brought by these models, they have one or more limitations, such as high fetal mortality rates, high costs, long gestation periods, and an insufficient number of fetuses per litter. Moreover, some species are phylogenetically distant from mammals. METHODS: We developed a reproducible model of prenatal intestinal obstruction in the rat to study the histologic changes induced by the obstruction. We report, the technical devices and the first assessment of this atresia model in a didactic way to allow other researchers to easily reproduce the model. RESULTS: Prenatal intestinal obstructions in this study fulfilled all the macroscopic and histologic criteria usually listed by other models of prenatal intestinal obstruction that have been developed in other species. Furthermore with our model, we obtained a high success rate at a low cost. CONCLUSIONS: We presented in this study a reproducible model of prenatal intestinal obstruction in the rat with the macroscopical and histologic features of prenatal intestinal obstruction.

International audience; During pregnancy both mother and foetus are at increased risk of being infected with either pandemic or seasonal influenza viruses, and it is thus legitimate to implement enhanced surveillance for infection particularly with the A/H1N1v and discuss priority vaccine administration. We will review the alterations in immunologic parameters which lead to some degree of cellular immunodeficiency, but also in anatomic changes and pulmonary restrictions which contribute to this suceptibility of pregnant women to severe complications of an influenza infection. We also provide an update on the epidemiological data available for the A/H1N1v infection in this population, and discuss the benefit/risk ratio of treatment with the antiviral medications.; Les femmes enceintes constituent classiquement un terrain fragile et à haut risque de complications sévères au cours de processus infectieux et notamment au cours de la grippe, expliquant la vigilance actuelle des autorités de santé envers cette population à risque de contracter le virus A/H1N1v. Se pose également le problème de l’attitude thérapeutique et de lévaluation des bénéfices et des risques pour le foetus et la mère lors de la prescription non seulement du vaccin, mais aussi des antiviraux. Dans cet article nous faisons le point des données épidémiologiques et de morbi-mortalité disponibles pour la population de femmes enceintes en ce qui concerne la pandémie actuelle A/H1N1v mais en se référant également aux pandémies antérieures et aux infections grippales saisonnières ; nous rappelons les modifications d’ordre immunologique, hémodynamique, et anatomique ventilatoire liées à la grossesse qui entraînent une susceptibilité particulière vis-à-vis d’agents infectieux dont le virus grippal.

International audience; During pregnancy both mother and foetus are at increased risk of being infected with either pandemic or seasonal influenza viruses, and it is thus legitimate to implement enhanced surveillance for infection particularly with the A/H1N1v and discuss priority vaccine administration. We will review the alterations in immunologic parameters which lead to some degree of cellular immunodeficiency, but also in anatomic changes and pulmonary restrictions which contribute to this suceptibility of pregnant women to severe complications of an influenza infection. We also provide an update on the epidemiological data available for the A/H1N1v infection in this population, and discuss the benefit/risk ratio of treatment with the antiviral medications.; Les femmes enceintes constituent classiquement un terrain fragile et à haut risque de complications sévères au cours de processus infectieux et notamment au cours de la grippe, expliquant la vigilance actuelle des autorités de santé envers cette population à risque de contracter le virus A/H1N1v. Se pose également le problème de l’attitude thérapeutique et de lévaluation des bénéfices et des risques pour le foetus et la mère lors de la prescription non seulement du vaccin, mais aussi des antiviraux. Dans cet article nous faisons le point des données épidémiologiques et de morbi-mortalité disponibles pour la population de femmes enceintes en ce qui concerne la pandémie actuelle A/H1N1v mais en se référant également aux pandémies antérieures et aux infections grippales saisonnières ; nous rappelons les modifications d’ordre immunologique, hémodynamique, et anatomique ventilatoire liées à la grossesse qui entraînent une susceptibilité particulière vis-à-vis d’agents infectieux dont le virus grippal.

International audience; The enteric nervous system maturation occurs during embryonic life and continues after birth. Some prenatal events on the digestive tract such as intestinal atresia have been shown to dramatically alter this maturation. Thus, we developed a fetal rat model of intestinal atresia by surgically obstructing the small bowel at embryonic day E18. Fetuses were removed at day E21, and small bowels sections were examined by immuno-histochemistry. Synaptophysin and smooth muscle actin staining was used to define the cellular aspect. Labeling revealed marked alterations of the myenteric plexus in the lower extremity of the occluded small bowel. At day E21, the myenteric plexus of the lower part and the 2 muscle layers surrounding it, retained the staining pattern observed at day E17. This cellular pattern was classified as: immature (aspect at day E17) vs. mature (aspect of day E21) by 3 pathologists not familiar with the study. The number of samples with an immature cellular pattern at the lower end of the occluded bowel was different from that observed for the upper end (Mac Nemar test, p

International audience; Fetomaternal alloimmunization with antenatal glomerulopathies (FMAIG) is a recently described alloimmune disorder, which results from the production of maternal antibodies that cross the placenta, bind to fetal glomerular podocytes, and mediate renal disease. The pathogenic antibodies are directed against CD10/neutral endopeptidase (NEP). The infant's mother is NEP-deficient and thus she becomes immunized during the first pregnancy against CD10/NEP expressed by placental cells. Because future pregnancies in CD10/NEP-immunized mothers are at high risk for the fetus, detection of anti-NEP antibodies in pregnant mothers and antigen-driven therapies including induction of tolerance, are urgently needed. This ideally requires identification of the pathogenic epitopes born by the antigen and specifically recognized by B- and T-cells. We have recently characterized such epitopes that will be used in diagnostic tests (ELISA) and for new therapeutic approaches based on peptide-specific immune intervention. For this purpose, we have developed an experimental model by crossing NEP/CD10-deficient female mice to wild-type males. The females develop an alloimmune reaction against NEP, which is a prerequisite for tolerance induction experiments. Although NEP/CD10 does not seem to be involved in common idiopathic forms of membranous nephropathy in the adult, alloimmune antibodies may be implicated in de novo membranous nephropathy that develop in the kidney graft and after alloimmune bone marrow transplantation.

International audience; Human embryonic stem cells (hESC) are obtained from the inner cell mass from the early embryo at blastocyste stage. Derived in cell lines for the first time in 1998, they can be maintained in culture in an undifferentiated state indefinitely under certain conditions. Two essential properties characterize hESC: pluripotency and self-renewal. Pluripotency is convey by the expression of specific transcription factors such as OCT4 and NANOG, and is under the control of growth factors such as IGF2 and FGFb. Markers used to characterize these cells include surface antigens, notably SSEA-3 and SSEA-4, and nuclear markers such as OCT4. HESC can differentiate into different cell types in vitro. They represent a unique and essential model for early human development research and for regenerative medicine. By their self-renewal capacity and their potential to differentiate into several cell types, hESC are an unlimited source of cells enabling to replace or restore lost or damaged cells in numerous diseases. Even if it is not conceivable today to use them in clinical practice for ethic and scientific reasons, it seems essential to explore the numerous potentialities of these cells. This knowledge might be relevant to handle adult stem cells in vitro and will be mandatory for a therapeutic use of hESC in the future.

Blood platelets play a crucial part in the blood clotting process by forming the platelet plug. Recent evidence indicates that they are likely to play a key role in the inflammatory reaction via CD154/CD40 interactions. CD40 was known to be widely expressed, for instance on cells of the vasculature including endothelial cells, smooth muscle cells and macrophages. It was also known that the triggering of CD40 on these cells led to the acquisition of an activated pro-inflammatory and pro-coagulant phenotype. It was subsequently shown that platelets express CD154 which is cryptic in unstimulated platelets but is expressed at the platelet surface upon platelet activation. When expressed at the platelet surface and exposed to CD40-expressing vascular cells, the platelet-associated CD154 triggers a variety of pro-inflammatory and pro-coagulant responses including induction of adhesion receptors, release of cytokines and chemokines, induction of tissue factor and of metalloproteinases. Platelet-associated CD154 is also involved in platelet/platelet interactions during platelet aggregation. Furthermore, in vivo models have emphasized the critical role of the platelet-associated CD154 in the progression of atherosclerotic disease and in the stabilization of arterial thrombi. Recent data show that CD40-bearing cells involved in fibrosis such as hepatic stellate cells and glomerular mesangial cells also respond to platelet-associated CD154, thus suggesting a new mechanism by which platelets may be instrumental in the inflammatory diseases of the liver or the kidney. Finally, platelet-associated CD154 has been shown to have immune competence both in vitro and in vivo, observations that open new fields of research on the potential implications of platelets in the immune response and auto-immune diseases.

Background: Airway inflammation and infection are early events in cystic fibrosis (CF) pathogenesis. The existence of an imbalance in the immune cell population of the CF fetal airway before infection remains completely unknown. Objective: The aim of this study was to determine whether early signs of inflammation are observed in CF airways during human fetal development. Methods: Tracheas and lungs were collected from 21 CF and 16 non-CF fetuses. In tissue sections, the numbers of neutrophils, mast cells, macrophages, and B and T lymphocytes were quantitatively analyzed by means of image cytometry. The presence of IL-4, IL-6, IL-8, IL-10, RANTES, IFN-γ, TNF-α, and NFκB and its inhibitor IκB-α was qualitatively evaluated by immunofluorescent staining. Results: During fetal airway development, epithelial and glandular differentiation, as well as the distribution of inflammatory markers, was similar in CF and non-CF tissues. Significant differences between CF and non-CF fetal airways were observed only in the numbers of mast cells and macrophages. In the CF trachea, the mast cell number increased slowly but continuously, whereas in the non-CF trachea this number rapidly reached a plateau. In the CF lung, the macrophage number increased with time, whereas in the non-CF lung it decreased. Conclusion: Although no intrinsic inflammation was demonstrated, we observed a distinct appearance of mast cells and macrophages in CF airways in comparison with non-CF airways during fetal development. These 2 cell populations were greater in CF airways at a late stage of fetal development, suggesting their possible involvement in the early onset of inflammation in CF infants. (J Allergy Clin Immunol 2001;108:524-9.)