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Le recueil des indications des spécialités pharmaceutiques inscrites sur la liste en sus a été rendu obligatoire à partir de mars 2018. A partir de septembre 2018 les indications devaient être renseignées pour être remboursées. Notre objectif est de décrire l’impact de ces obligations règlementaires sur les informations transmises via le programme de médicalisation des systèmes d’information (PMSI).

Follicle histogenesis, in which follicles arise from fragmenting ovigerous cords, is a poorly understood mechanism that is strictly dependent upon the presence of germ cells. Our previous studies have shown that severely germ cell-depleted rat ovaries after fetal gamma-irradiation display modifications of follicular endowment and dynamics during the immature period. The primordial follicle stock was absent and the follicles with primary appearance remained quiescent longer than in control ovaries during the neonatal period. The aim of the present work was to analyze the initial steps of follicle histogenesis, and to investigate the etiology of the alterations observed in the development of irradiated ovaries. Just after birth, we observed, in addition to sterile ovigerous cords, the emergence of the first follicles which exhibited several abnormal features as compared to those of control ovaries. Most of the follicles appeared as primary follicles, as they were composed of a layer of cuboidal-shaped granulosa cells surrounding an enlarged oocyte. Interestingly, the granulosa cells of these primary-like follicles did not proliferate and did not express the genes for anti-Müllerian hormone (Amh)or bone morphogenetic protein receptor type II (Bmpr2), both of which are normally expressed from the primary stage onwards. In contrast, the oocytes strongly expressed the gene for growth and differentiation factor 9 (Gdf9), which is normally upregulated from the primary follicle stage onwards, which suggests an uncoupling of granulosa cell development from oocyte development. In addition, irradiated ovaries displayed a higher frequency of follicles that contained 2 or 3 oocytes, which are also referred to as multi-oocyte follicles (MOFs). Examination at the time of follicle histogenesis indicated that MOFs arise from incomplete ovigerous cord breakdown. Taken together, the results of this study indicate that severe perturbations of follicular histogenesis take place following irradiation and massive germ cell depletion during fetal life. In addition to the classically described sterile cords, we have pointed out the differentiation of MOFs and primary-like quiescent follicles, which finally evolve into growing follicles and participate in ovarian function. We propose that these phenotypes are closely correlated to the proportion of granulosa cells to oocytes at the time of neonatal follicle histogenesis.

This article addresses the issue of the uses of the multidivisional form in the French context at the end of the 1960s and the beginning of the 1970s. Comparing two case studies, Danone and Hachette, it sheds light on specific experiences in two different industries, the food and the book industry, respectively, in order to contribute to the debate over the Chandlerian paradigm. These two cases show that the implementation of the M-form in European companies can neither be reduced to the necessary diffusion of a universal structure nor to managerial fashion. At first a matter of redistributing the power between the shareholders and the management, the M-form led to hybrid organizations with characteristics heavily dependent on intensive internal negotiations. These findings emphasize the potential diversity of the implementation of the M-form and of the relations between management and shareholders. Far from being linear, company trajectories then heavily depend on partial compromises.

The role of fibroblast growth factor (FGF) 2 and FGF9 as mediators of cell–cell interactions between Sertoli cells (SCs) and peritubular cells (PCs) was investigated. Using RT-PCR, we demonstrated that SCs and PCs recovered from 20-day-old rats expressed several of the seven FGF receptors (FGFRs), and more specifically the FGFR1 IIIc. FGF2 and FGF9 did not elicit any morphological changes in primary cultures of SCs, nor did they alter the number of SCs in culture. By contrast, changes in shape were observed in FGF2- and FGF9-treated PCs. In addition, FGF2 but not FGF9 enhanced significantly and dose-dependently the number of PCs in culture, indicating that FGF2 was a survival factor for these cells. It was also mitogenic because it enhanced the [3H]thymidine labeling index in PCs. We next examined the effects of FGF2 and FGF9 in a coculture system using 20-day-old rat SCs and PCs, and in an organotypic culture system using XY rat embryonic gonads. In both models, FGF2 and FGF9 were found to promote cellular interactions as evidenced by the extent of cellular reorganization in the coculture system, and cord morphogenesis and growth in the organotypic culture system. A key feature in SC–PC interactions is the synthesis and remodeling of the basement membrane which is co-elaborated by the two cell types. Since basement membrane homeostasis depends upon the coordinated activity of proteinases and inhibitors, the proteinases and inhibitors produced by PCs and SCs degrading or opposing degradation of the major components of the basement membrane were further studied. Specifically, we monitored the metalloproteinases (MMP)- 2 and -9 and the tissue inhibitors -1, -2 and -3, the plasminogen activators (PAs) and the PA inhibitor-1, using zymography for the proteinases and Western blots for the cognate inhibitors. Cocultures received FGF or an analog of cAMP in order to prevent cellular reorganization. We found that FGF2 was unique in inducing MMP-9 in coculture. Also, the enhanced levels of the PA inhibitor-1 and the 30 kDa band glycosylated form of tissue inhibitor-3 correlated with the enhanced SC–PC reorganization. It was concluded that FGF2 and FGF9 are morphogens for the formation of testicular cords.

In mammals, anti-Müllerian hormone (AMH) is produced by Sertoli cells from the onset of testicular differentiation and by granulosa cells after birth. In birds, AMH starts to be expressed in indifferent gonads of both sexes at a similar level and is later up-regulated in males. We previously demonstrated that, unlike in mammals, the onset of AMH expression occurs in chick embryo in the absence of SOX9. We looked for potential factors that might be involved in regulating AMH expression at different stages of chick gonad differentiation by comparing its expression pattern in embryos and young chicken with that of DMRT1, SF-1, WT1, GATA-4, Wnt-4, and Lhx9, by in situ hybridization. The results allowed us to distinguish different phases. (1) In indifferent gonads of both sexes, AMH is expressed in dispersed medullar cells. SF-1, WT1, GATA-4, Wnt-4, and DMRT1 are transcribed in the same region of the gonads, but none of these factors has an expression strictly coincident with that of AMH. Lhx9 is present only in the cortical area. (2) After this period, AMH is up-regulated in male gonads. The up-regulation is concomitant with the beginning of SOX9 expression and a sex dimorphic level of DMRT1 transcripts. It is followed by the aggregation of the AMH-positive cells (Sertoli cells) into testicular cords in which AMH is coexpressed with DMRT1, SF-1, WT1, GATA-4, and SOX9. (3) In the females, the low level of dispersed medullar AMH expression is conserved. With development of the cortex in the left ovary, cells expressing AMH accumulate in the juxtacortical part of the medulla, whereas they remain dispersed in the right ovary. At this stage, AMH expression is not strictly correlated with any of the studied factors. (4) After hatching, the organization of left ovarian cortex is characterized by the formation of follicles. Follicular cells express AMH in conjunction with SF-1, WT1, and GATA-4 and in the absence of SOX9, as in mammals. In addition, they express Lhx9 and Wnt-4, the latter being also found in the oocytes. (5) Moreover, unlike in mammals, the chicken ovary retains a dispersed AMH expression in cortical interstitial cells between the follicles, with no obvious correlation with any of the factors studied. Thus, the dispersed type of AMH expression in indifferent and female gonads appears to be bird-specific and not controlled by the same factors as testicular or follicular AMH transcription. © 2002 Wiley-Liss, Inc.

Several factors have led to intensified public scrutiny of the human food supply chain. Consumer concerns for food safety, animal welfare, and the environmental and ecological impact of food production and agro-processing have become increasingly important. These concerns have been exacerbated by several factors, including the trend towards further globalization of the food supply chain, the incidence of new and emerging safety hazards such as the human form of BSE (mad cow disease), and illnesses and deaths resulting from contamination of fresh and processed food. As a consequence of these growing concerns, consumers and other stakeholders in agroindustry now demand transparency in the way food is grown and handled throughout the supply chain, resulting in the emergence of 'traceability' as an important policy issue in food quality and safety. This paper provides a global overview of 'traceability' as a quality index in food trade, and discusses some of the drivers in both developed and developing countries. Policy changes are necessary specifically to incorporate traceability into existing food safety regulations and trade agreements. This will require further investments in information technology for data capture, storage and retrieval. Small-scale farmers in many developing regions moving towards market orientation face considerable technical and financial challenges in implementing appropriate food traceability systems in order to meet marketing compliance requirements.

Six relative palaeointensity records from the north Atlantic Ocean were stacked together to produce a new record for the last 75 kyr (NAPIS–75). Five of these records have been previously correlated at millennial scale and placed on the GISP2 age scale, the sixth record was tied to the others using magnetic susceptibility. From 75 ka the field strength exhibits some oscillations, with a first minimum ca.65 ka, followed by a progressive increase to a broad maximum centred at ca.48 ka. There is then a well–marked low at 40 ka, corresponding to the directional anomaly of the Laschamp event. Another intensity low, observed at ca.34 ka, corresponds in age to the Mono Lake event. After a high at 33 ka and two lows at 30 and 24 ka with a broad maximum between, the field strength seems to slowly increase to the upper limit of the studied interval. In the 10–20 kyr interval some differences exist between individual records, and fine–scale details are not always resolved. In the 20–75 kyr interval, on the other hand, well–resolved millennial–scale features are superimposed to the broader trends. The duration of the Laschamp event, which is recorded directionally in five cores, appears to be about 1500 years, consistent with a recent suggestion on the origin of geomagnetic excursions.

Little is still known about the origin of somatic progenitor cells of human fetal gonads, their molecular identity and the transcriptional programs controlling their differentiation towards multiple fates. In this study, we performed single-cell RNA-sequencing to characterize cell lineage progression during gonad differentiation and to build the first atlas of human fetal gonads at single cell resolution.

Recent records of normalised intensity of natural remanent magnetization (NRM) obtained from deep-sea sediments document an asymmetrical saw-tooth pattern, associated with geomagnetic reversals. This observation may reflect a fundamental aspect of the geodynamo time evolution or, alternatively, delay in acquisition of the NRM. It is demonstrated here that a simple model, in which a large fraction of the magnetic grains acquire NRM at deposition time while remaining grains reorientate or acquire magnetization after deposition, is able to produce a ‘saw-tooth’ profile strikingly similar to that observed. Interestingly, this mechanism of NRM acquisition does not damp out high frequency oscillations of the field, such as those observed in the deep-sea records exhibiting the saw-tooth profile. It provides an accurate record of field directions, except for periods of very low field intensity.

SDS‐PAGE and N‐tenninal sequence analysis of hydrolysis products from 3 substrates containing a unique sensitive bond usually recognized by chymosin (k‐casein, a synthetic hexapeptide and a recombinant tripartite protein) revealed that a 45 kDa endoprotease of Myxococcus xanthusDK101 cleaved the same characteristic Phe‐Met bond with high specificity. Such an enzyme, easy to obtain from culture supernatant and to use in acidic conditions, could be a new tool for protein engineering.

We have used a new sedimentary record of geomagnetic field intensity, combined with published volcanic data, to examine the extent to which geomagnetic changes have affected 14C production in the past. The production record was then converted into an atmospheric Δ14C signal using a 4‐box model of past oceanic circulation. The results indicate that changes in geomagnetic field intensity account for at least 80% of the Δ14C shift documented by published U‐Th data, which are of the order of 500 per mil with respect to a constant production hypothesis. Model simulations show that changes in past oceanic circulation account for only ±100 per mil of Δ14C variation, which is within the uncertainty of the geomagnetic correction. In terms of dating, these results show that the radiocarbon ages have to be shifted by 2 to 3.5 kyr towards older ages during the 20–40 ka interval.

Le nombre de revues systématique (RS) et méta-analyses (MA) publiées est en constante augmentation. Des outils permettent d’évaluer leur rigueur méthodologique (AMSTAR 2) et spécifient les items devant être rapportés (PRISMA). Notre objectif était d’évaluer la méthodologie et l’exhaustivité des données rapportées des RS/MA en dermatologie.

Plusieurs essais contrôlés ont montré l’efficacité du dupilumab dans la dermatite atopique (DA) modérée à sévère de l’adulte. Son utilisation est pour le moment limitée aux adultes (phase III chez l’enfant non publiée). Nous présentons la première série de cas française en pratique courante décrivant:

Local translation is a conserved mechanism conferring cells the ability to quickly respond to local stimuli. In the brain, it has been recently reported in astrocytes, whose fine processes contact blood vessels and synapses. Yet the specificity and regulation of astrocyte local translation remain unknown. We study hippocampal perisynaptic astrocytic processes (PAPs) and show that they contain the machinery for translation. Using a refined immunoprecipitation technique, we characterize the entire pool of ribosome-bound mRNAs in PAPs and compare it with the one expressed in the whole astrocyte. We find that a specific pool of mRNAs is highly polarized at the synaptic interface. These transcripts encode an unexpected molecular repertoire, composed of proteins involved in iron homeostasis, translation, cell cycle, and cytoskeleton. Remarkably, we observe alterations in global RNA distribution and ribosome-bound status of some PAP-enriched transcripts after fear conditioning, indicating the role of astrocytic local translation in memory and learning.

(Abstracted from Hum Reprod2018;33(3):482–493)Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used over-the-counter medications for treatment of pain, inflammation, and fever. In 2013, up to 28.3% of pregnant women reported the use of ibuprofen at some stage during their pregnancy.

The statistical properties of the magnetic polarity time scale have been examined recently1,2for several time scales. For some of these scales the time evolution of the frequency of reversals as seen through an 8-Myr moving rectangular window have been determined. In particular, over the past 100 Myr, the mean reversal frequency appears to be dominated by a linearly increasing trend on which is superimposed a rhythmic fluctuation. We have attempted to analyse the mathematical structure of the reversal frequency curve in detail and to determine whether the rhythmic fluctuation was indeed periodic. By modelling the time evolution of the reversal frequency, we find a dominant frequency corresponding to a period of ∼15 Myr. This result represents one of the most persistent long-term periodicities ever reported for a geophysical phenomenon.

Le virus lymphotropique T de type 1 (HTLV-1) est un rétrovirus humain oncogène responsable d’une lymphoprolifération rare, la leucémie/lymphome T de l’adulte (ATLL), entraînant une immunosuppression sévère. Il existe différents sous-types, les formes indolentes (chroniques et « smoldering ») avec une médiane de survie de 54 et 33 mois respectivement et les formes agressives (aiguës et lymphomateuses) avec une médiane de survie qui n’excède pas un an malgré les traitements intensifs. La maladie de Kaposi (MK) est une prolifération tumorale de cellules dérivées de l’endothélium viro-induite par l’herpes virus humain de type 8 (HHV8), favorisée par l’immunodépression (VIH, néoplasie). Nous rapportons le cas exceptionnel d’un patient présentant une MK sévère révélatrice d’un ATLL « smoldering ».

Le patient obèse présente un risque majoré de désaturation à l’induction de l’anesthésie. La ventilation spontanée avec aide inspiratoire et pression positive de fin d’expiration (VSAI-PEP) a montré son efficacité pour optimiser la préoxygénation du sujet sain [1], obèse morbide [2]et du patient hypoxémique de réanimation. Une étude chez le patient obèse, réalisée avec des niveaux d’AI et de PEP à 4cm d’H2O et un positionnement en décubitus dorsal strict, n’a montré qu’un bénéfice modeste [3]. L’objectif de cette étude observationnelle était d’évaluer l’intérêt de la VSAI-PEP après optimisation du positionnement et des niveaux d’AI et de PEP, pour la préoxygénation du patient ayant un IMC compris entre 27 et 40kg/m2.

Les patients présentant une surface cutanée brûlée (SCB) supérieure à 50 % sont rares mais leur prise en charge constitue un défi pour les centres de traitement des brûlés. La survie et la durée de séjour de tels patients sont des marqueurs simples de la qualité des soins. Nous avons donc étudié la morbi-mortalité des patients sévèrement brûlés de notre service, ainsi que la pertinence des scores pronostiques utilisés au quotidien.

Le méthotrexate (MTX) est largement prescrit à doses immunomodulatrices, en dermatologie comme dans d’autres domaines (polyarthrite rhumatoïde, maladie de Crohn…). De façon étonnante, très peu de données sont disponibles concernant le risque relatif d’effets indésirables chez les patients traités par MTX.

Le syndrome des nævus éruptifs (SNE) est un phénomène rare caractérisé par l’apparition rapide simultanée de multiples nævus. Il a été décrit dans différents contextes : utilisation d’immunomodulateurs, épidermolyses bulleuses ou stimulation mélanocytaire chimique (mélanotane). Nous rapportons les 2 premiers cas de SNE après traitement par anti-TNF alpha en monothérapie pour une spondylarthropathie (SpA).

Transcription factor GATA4 is required for the development and function of the mammalian gonads. We first reported that the GATA4gene in both human and rodents is expressed as two major alternative transcripts that differ solely in their first untranslated exon (exon 1a vs. exon 1b). We had also showed by quantitative PCR that in mouse tissues, both Gata4exon 1a- and 1b-containing transcripts are present in all sites that are normally positive for GATA4 protein. In adult tissues, exon 1a-containing transcripts generally predominate. A notable exception, however, is the testis where the Gata4exon 1a and 1b transcripts exhibit a similar level of expression. We now confirm by in situ hybridization analysis that each transcript is also strongly expressed during gonad differentiation in both sexes in the rat. To gain further insights into how Gata4gene expression is controlled, we characterized the mouse Gata4promoter sequence located upstream of exon 1b. In vitro studies revealed that the Gata41b promoter is less active than the 1a promoter in several gonadal cell lines tested. Whereas we have previously shown that endogenous Gata4transcription driven by the 1a promoter is dependent on a proximally located Ebox motif, we now show using complementary in vitro and in vivo approaches that Gata4promoter 1b-directed expression is regulated by GATA4 itself. Thus, Gata4transcription in the gonads and other tissues is ensured by distinct promoters that are regulated differentially and independently.

GATA4 is an essential transcription factor required for the development and function of multiple tissues derived from both mesoderm and endoderm. Among these tissues, GATA4 is highly expressed in the somatic cell lineages of the gonads in both sexes throughout development. Various knockout models in mice have demonstrated that GATA4 is essential for the onset of normal gonadal morphogenesis and is later recruited as a key regulator of numerous genes (e.g., Star, Cyp19a1, Inha) in response to hormonal cell signaling. Very recent evidence in the literature also supports a role for GATA4 in human gonadal development, at least in the male. In spite of its essential biological functions, the factors and mechanisms that control GATA4 expression have yet to be fully understood. We have shown that humans and rodents express the GATA4 gene as multiple transcript variants that differ solely in their untranslated first exons. The most frequently used first exons are exon 1a, which is closest to the ATG and driven by the proximal 1a promoter, and exon 1b whose usage is controlled by an alternative distal promoter (named 1b) that is approximately 30 kb further upstream. Since all GATA4 transcript variants produce the same GATA4 protein, our hypothesis is that differential promoter usage is an important mechanism for regulating spatiotemporal GATA4 expression in the gonads and possibly other tissues. Our previous work demonstrated that a conserved E-box motif in the proximal 1a promoter is essential for its activity both in vitro and in vivo. Using in situ hybridization, we now show that the Gata4 1b transcripts are also present in the somatic cell lineages of the developing testis and ovary. We also show, using quantitative real-time PCR (qPCR) that the Gata4 1b transcript is present in several gonadal cell lines (MSC-1, TM3, TM4, MA-10, DC3), albeit less abundant than the Gata4 1a transcript. Consistent with this observation, transient transfection studies revealed that the Gata4 1b regulatory region was less active than the Gata4 1a promoter in all cell lines tested. Progressive 5' deletion analysis of the Gata4 1b promoter showed that regulatory elements required for its activity are located in the first 171 bp. This region contains two conserved binding motifs for GATA family members (conserved at least in mouse, rat and human). Both motifs actively bind GATA4 protein as revealed by electrophoretic mobility shift assay (EMSA). The -171 bp Gata4 1b promoter was stimulated 3 to 7-fold by GATA4 in homologous and heterologous cells, respectively. Site-directed mutagenesis of both GATA motifs abolished GATA4-dependent activation of the 1b promoter. Finally, knockdown of GATA4expression in MA-10 cells by siRNA also led to a marked drop in Gata4 1b promoter activity. Therefore, unlike the Gata4 1a promoter, which is regulated by ubiquitous factors binding to an E-box element, our present data suggest that GATA4 can also autoregulate its expression at the level of its distal 1b promoter. This represents a potentially key mechanism for regulating GATA4expression in different cell types and at different timepoints during development. This research was supported by CIHR grant MOP-14796 to RSV.(poster)