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La crise sanitaire de la Covid-19 du printemps 2020 a peu touché les enfants avec peu d’hospitalisations dans les hôpitaux pédiatriques. Le défi a été d’apporter une aide aux hôpitaux adultes avec un personnel principalement formé à la pédiatrie tout en maintenant la permanence des soins urgents pour les enfants atteints ou non de la Covid-19. À l’hôpital universitaire Armand-Trousseau, nous avons créé des unités dédiées pour les enfants atteints de la Covid-19, identifié les spécificités des enfants atteints de la Covid-19 et notamment les formes de Kawasaki like ou PIMS (paediatric multisystem inflammatory syndrome), créé une unité de réanimation adulte au pic de l’épidémie pour augmenter les capacités en lits de réanimation dans notre région, mutualisé notre centre de dépistage pour le personnel d’hôpitaux adultes. Enfin, nous avons envoyé plus de 140 personnels médicaux et paramédicaux dans les hôpitaux adultes de notre groupe hospitalier. Cette aide a pu être organisée grâce aux liens étroits établis par des cellules de crises communes avec les hôpitaux adultes de notre groupe hospitalier. Nous rapportons ainsi un retour d’expérience d’un hôpital pédiatrique au cours de la crise de la Covid-19 en Île-de-France.

Resume En 2005, le Groupe francophone de reanimation et d’urgences pediatriques (GFRUP) publiait des recommandations concernant les limitations et arrets des traitements (LAT) en reanimation pediatrique. Depuis cette date, le Code de sante publique (CSP), modifie par les lois de 2005 et 2016 et leurs decrets d’application, est venu encadrer ces pratiques. Quinze ans apres leur parution, ces recommandations necessitaient d’etre actualisees pour tenir compte de l’experience acquise par les equipes, des nouvelles questions soulevees par des etudes de pratique, des recommandations parues dans l’intervalle, ainsi que des evolutions legislatives et des rares jurisprudences. Ce texte a pour objectif d’aider les equipes de reanimation pediatrique a conjuguer l’ethique de la prise en charge de l’enfant, de sa famille et le respect des dispositions reglementaires actuelles.

International audience; In 2005, the French-speaking task force on pediatric critical and emergency care [Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP)] issued recommendations on withholding and withdrawing treatments in pediatric critical care. Since then, the French Public Health Code, modified by the laws passed in 2005 and 2016 and by their enactment decrees, has established a legal framework for practice. Now, 15 years later, an update of these recommendations was needed to factor in the experience acquired by healthcare teams, new questions raised by practice surveys, the recommendations issued in the interval, the changes in legislation, and a few legal precedents. The objective of this article is to help pediatric critical care teams find the closest possible compromise between the ethical principles guiding the care offered to the child and the family and compliance with current regulations and laws.

Cet ouvrage vise a offrir a un large public un panorama simple de la sismologie en ce debut de XXIe siecle, sans aucune formule mathematique mais sans occulter la complexite des problematiques traitees.

International audience

International audience; Seismological detection methods are traditionally based on picking techniques. These methods cannot be used to analyse emergent signals where the arrivals cannot be picked. Here, we detect and locate seismic events by applying a beamforming method that combines multiple body-wave phases to USArray data. This method explores the consistency and characteristic behaviour of teleseismic body waves that are recorded by a large-scale, still dense, seismic network. We perform time-slowness analysis of the signals and correlate this with the time-slowness equivalent of the different body-wave phases predicted by a global traveltime calculator, to determine the occurrence of an event with no a priori information about it. We apply this method continuously to one year of data to analyse the different events that generate signals reaching the USArray network. In particular, we analyse in detail a low-frequency secondary microseismic event that occurred on 2010 February 1. This event, that lasted 1 d, has a narrow frequency band around 0.1 Hz, and it occurred at a distance of 150° to the USArray network, South of Australia. We show that the most energetic phase observed is the PKPab phase. Direct amplitude analysis of regional seismograms confirms the occurrence of this event. We compare the seismic observations with models of the spectral density of the pressure field generated by the interferences between oceanic waves. We attribute the observed signals to a storm-generated microseismic event that occurred along the South East Indian Ridge.

We design an earthquake detection and location algorithm that explores coherence and characteristic behavior of teleseismic waves recorded by a large-scale seismic network. The procedure consists of three steps. First, for every tested source location we construct a time-distance gather by computing great-circle distances to all stations of the network and aligning the signals respectively. Second, we use the constructed gather to compute a Tau-P transform. For waves emitted by teleseismic sources, the amplitude of this transform has a very characteristic behavior with maxima corresponding to different seismic phases. Relative location of these maxima on the time-slowness plane strongly depends on the distance to the earthquake. To explore this dependence, in a third step, we convolve the Tau-P amplitude with a time-slowness filter whose maxima are computed based on prediction of a global travel-time calculator. As a result of this three-step procedure, we obtain a function that characterizes a likelihood of occurrence of a seismic event at a given position in space and time. We test the developed algorithm by applying it to vertical-component records of USArray to locate a set of earthquakes distributed around the Globe with magnitudes between 6.1 and 7.2.

We investigate the possibility to estimate the depths of earthquakes of moderate magnitude (3.5>M m b 3.6 Ardeche earthquake (France, 3 August 2011). In the case of the Po Plain earthquake (Italy, 27 January 2012), this provides another example of the great interest in teleseismic analysis, where the detection of the Moho reflected phase ( pmP ) shows without doubt an upper‐mantle event. Finally, the Murcia event (Spain, 11 May 2011) shows the limits of these methods for very shallow events (

Intrauterine growth restriction (IUGR) is a common complication of pregnancy whereby the fetus fails to achieve its genetic growth potential. Malformation of the placental vasculature is observed in IUGR and may be due to the development of the placenta in a chronically hypoxic environment. Recently, we identified that the predominant stromal cells in the angiogenic zones of the placenta are fibrocyte-like cells. The conditioned medium from fibrocyte-like cells (FcCM) has been shown to stimulate angiogenesis in vitro . Thus, we hypothesized that FcCM from IUGR cells would have a reduced ability to stimulate angiogenesis and that chronic hypoxia would decrease the ability of both normal and IUGR fibrocyte-like cells to stimulate angiogenesis. IUGR FcCM had a reduced ability to stimulate endothelial tubule-like structure formation and an increased ability to stimulate endothelial migration compared with normal FcCM. However, normal and IUGR FcCM produced in chronic hypoxia did not alter endothelial proliferation, migration, or tubule-like structure formation. IUGR FcCM was found to have reduced levels of the pro-angiogenic cytokine IL-8 and increased levels of the anti-angiogenic factors activin-A and pigment epithelium-derived growth factor. Thus, alterations in the ability of IUGR fibrocyte-like cells to stimulate angiogenesis may contribute to the development of vascular malformation in IUGR, but in vitro these changes cannot be attributed to a chronically hypoxic environment.

Bronchopulmonary dysplasia (BPD) of very preterm infants is a multifactorial chronic lung disease and its incidence has not decreased despite improvements in neonatal intensive care, including lung protective strategies. Pulmonary hypertension (PH) can complicate the course of BPD. Mortality in infants with BPD-associated PH is thought to be very high, but its incidence is unknown and a standard diagnostic and therapeutic strategy has not been well defined. In this article, we will first describe the current knowledge on the BPD-associated PH and the current treatments available for this pathology. We will then present the HTP-DBP Study, carried out in Paris (France) starting in 2012. The diagnosis of PH is suspected on echocardiographic criteria, but cardiac catheterization is considered the gold standard for diagnosis and evaluation of the severity of PH. Moreover, pulmonary vasoreactivity testing is used to guide the management of patients with PH. The pathogenesis of BPD-associated PH is poorly understood and even less is known about appropriate therapy. Today, optimizing ventilation and reducing the pulmonary vascular tone with specific pulmonary vasodilatator drugs are the main goals in treating HTP-associated DBP. Animal studies and a few clinical studies suggest that medications targeting the nitric oxide (NO) signaling pathway (NO inhalation, oral sildenafil citrate) could be effective treatments for BPD-associated PH, but they have not been approved for this indication. The HTP-DBP study is a French multicenter prospective observational study. The objective is to evaluate the frequency of BPD-associated PH, to describe its physiopathology, its severity (morbidity and mortality), and the effectiveness of current treatments.

The seismicity of the Mediterranean, compiled by the Euro-Mediterranean Seismological Centre (EMSC), is presented for the period 1998–2010. The data set contains earthquakes recorded by more than 3000 stations operated by 78 networks. The Euro-Med Bulletin (EMB) provides parametric information for 273,000 tectonic events. The location resolution is characterised by a constant improvement over the years made possible by gathering steadily increasing data contribution. Dedicated collaboration with the network operators through regular discussion and interaction allow proper review of input and output information. In addition to natural events, seismic networks report data related to nontectonic activity. Discrimination is a crucial step in the production of seismicity catalogues to provide accurate information used for seismic hazard assessment. Over 13 years, 62,000 artificial events are characterised, mostly located in the vicinity of the largest mine and quarry areas of the region. While a large amount of man-related seismic activity is properly described, we show that through statistical analysis, discrimination in the EMB can still be improved. This is especially useful to scan past data, when routine discrimination was usually not performed by local networks. Seismicity catalogues are also useful for integrated access data portal to diverse and distributed seismological products as multi-disciplinary approaches of seismology is necessary. It leads us to propose and develop an e-Bulletin where the scientists could access all type of seismological and engineering products (from strong motion or broad band waveforms to macroseismic analysis) by simply connecting to a single event dedicated web page.

Objective: We compared two polymethylpentene oxygenators being used in our unit: the Maquet Quadrox-iD paediatric® and the Medos Hilite 800LT®. Study design: A mono-centric, prospective pilot study was conducted on ten consecutive newborn patients who had been admitted to our hospital service for extracorporeal circulation (EC) treatment. We examined the rate of oxygen transfer, the CO2 removal capacity and the average sweep gas flow required to produce this result. We also assessed the disturbances of haemostasis, the need for labile blood products and the membrane oxygenator lifetime and cost of use. Conclusions: According to our study, it seems to us that Medos Hilite 800LT® membrane oxygenators demonstrate greater oxygen transfer and CO2 removal capacity than Maquet Quadrox-iD paediatric® membrane oxygenators, at a similar cost. These results lead us to conclude that it is reasonable to continue using Medos Hilite 800LT® membrane oxygenators. A broader comparison study would be necessary in order to support these initial results.

SUMMARY To understand the mechanisms of intraplate earthquakes, well-documented seismological and geodynamical studies are needed, to provide information for adequate mechanical modelling. This paper describes a detailed analysis of the earthquake sequence associated with the Rambervillers (France) M ∼ 5.4 earthquake (2003 February 22), which occurred in the western Vosges massif (France), some tens of kilometres to the north of the sites of the Epinal (1973–1974) and Remiremont (1984–1985) earthquake sequences. We computed the location of the mainshock and focal mechanism, together with the double-difference locations of 419 aftershocks of the subsequent earthquake sequence, which included 195 well-recorded similar events (earthquakes with similar waveforms). We combined pP phases recorded by remote dense seismic networks with waveform modelling, to accurately determine the mainshock depth (12.5 ± 1.5 km). Computations of focal mechanisms from regional waveform inversions showed a normal fault plane with a N315 ◦ ± 10 ◦ strike and a 45 ◦ ± 15 ◦ dip. A detailed space–time analysis allowed two earthquake sequences to be identified: a classic mainshock–aftershock sequence and a secondary sequence that began 250 days after the mainshock. More events were recorded during the secondary sequence than during the main sequence. Very few similar events were recorded during the first 2 days after the mainshock, although data were recorded continuously. Double-difference locations from traveltime differences show that these immediate, non-similar aftershocks occurred in a 4 km × 2k m subhorizontal area at a depth of about 12 km. Similar events were far more numerous during the secondary earthquake sequence. Double-difference relocation of these similar events revealed a N315 ◦ striking, 65 ◦ dipping fault plane that is compatible with the mainshock source mechanism. During this later sequence, seismicity oscillated over a vertical range of 2–3 km around a mean depth of approximately 12 km. This observation strongly suggests fluid migration. Normal faulting, subhorizontal faulting and fluid transfer at about 12 km depth can be interpreted in terms of the crust’s response (mainshock and post-seismic relaxation) to flexural stresses induced by the alpine compression. This relaxation involves weakening and collapse of the crust, and fluid transfer.

Acute osteomyelitis, although a rare complication in neonates, is a diagnostic and therapeutic challenge. Successful treatment to avoid functional sequelae depends on early recognition of infection and rapid initiation of therapy. Although Staphylococcus aureus is the most common causative agent, coagulase-negative Staphylococcus (CONS), well known for bloodstream infection, can be involved in neonatal osteomyelitis. Risk factors of osteomyelitis include prematurity and invasive procedures, such as long-term central venous catheterization. We report on 3 cases of acute CONS osteomyelitis in preterm infants presenting with prolonged CONS bacteremia. Bacteremia persisted despite antibiotic treatment in accordance with antibiograms and despite removal of the intravascular device. All catheter cultures were negative and osteomyelitis was not located on the limb where the central catheter had been inserted in all cases. Osteomyelitis diagnosis may be difficult in neonates because of the paucity of clinical signs. In our observations, (99m)Tc scintigraphy was the key investigation for diagnosis and detection of multiple sites of bone infection. The place of this investigation is discussed in relation to other imaging techniques. These observations suggest that in the context of persisting CONS bacteremia, a secondary bone infection should be considered. Scintigraphy is a discriminating diagnostic tool.

Problem Methods for monocyte purification are common but few work with umbilical cord monocytes that do not activate the cell for subsequent culture analysis. Methods of study The collection procedure avoids use of needles and procedures that variably activate blood clotting and uses a purification procedure that involves diluted Ficoll, autologous serum to remove platelets and 42% and 51% Percoll step gradients for the final purification. The resulting monocytes were stimulated with bacterial lipopolysaccharide and formalin-treated bacteria Escherichia coli and group B streptococci (GBS) to secrete TNF-α and IL-1β, measured by ELISA. Results The purification procedure results in non-active but stimulation-competent monocytes with high yields (2.3–9 × 107 cells) and purity (from 70% to 98%). Conclusion We describe a procedure that is easy, uses common reagents and provides a uniformly high yield and purity of non-activated fetal monocytes for studies of innate defense responses.

Placentae from newborns with congenital human cytomegalovirus (HCMV) infection often display shallow implantation, chronic villitis and disruptions of the syncytiotrophoblast. Little is known about how HCMV infection induces inflammation in the placenta and loss of the trophoblast. We propose that the inflammation is initiated with innate defense responses of mature syncytiotrophoblast (ST) to virus. Previously we have shown that ultraviolet irradiation-inactivated (UV-) HCMV interacts with toll-like receptor 2 (TLR2) on primary placental cytotrophoblasts (CT) differentiated into ST-like cells thereby stimulating the release of tumor necrosis factor alpha (TNFalpha) and inducing apoptosis of neighboring cells (Chan et al, J. Pathol. 210: 111, 2006). We now determine whether known co-factors of the interaction of HCMV and TLR2 (TLR1 and CD14) bind to UV-HCMV to stimulate expression of TNFalpha and apoptosis in ST-like cells but not CT. We show that CT both fail to express detectable TLR1 and express much less CD14 than ST and that ST express CD14 but not TLR1 both in vivo and in cultured cells. The interaction of UV-HCMV and HCMV with CD14 on the surface of ST-like cells increases TNFalpha expression and induces apoptosis in the population. Antibody to CD14 also inhibits infectious HCMV induction of HCMV immediate early (HCMV IE) expressing ST-like cells. We conclude that primary villous CT express low levels of CD14 and no TLR1 but that ST strongly expresses CD14 which acts upstream of TLR2 to collect even transcriptionally inactive virus particles to stimulate TNFalpha expression and villous trophoblast damage.

An earthquake that occurred with a local magnitude of 4.3 and at a depth of 3 km beneath the coastal town of Folkestone, United Kingdom, generated atmospheric acoustic waves in the 2–5 Hz bandwidth (infrasound). These were recorded at the FLERS microbarometer array in France at a range of 284 km. Earthquake-generated infrasound is often associated with large earthquakes close to large mountain ranges; the shaking of prominent topographic points act as infrasound sources, coupling seismic energy into the atmosphere. In this example there is little prominent topography in the source region apart from the coastal cliffs, which have an average height of 75 m. We explore the possibility that the seismic-to-infrasound coupling occurs at the cliffs by modelling a 23 km length of coast as a series of 305 pistons independently generating acoustic waves. Synthetic seismograms modelling the motion of the cliffs are constrained using recordings from a three-component accelerometer located 4 km from the epicenter. Meteorological data, combined with array processing of the microbarometer records, suggest that the acoustic energy propagated to FLERS within the troposphere. The synthetic microbarograms show close agreement with the observations; the modelled arrival time is 5 sec earlier than that observed, and the peak-to-peak amplitude and signal duration are within a factor of 2 of those recorded. This study shows that moderately sized, shallow seismic disturbances can generate observable infrasound if the topographic conditions close to the epicenter are favorable.

In adult mammals, hemopoiesis takes place primarily in the bone marrow. The steady-state production of blood cells depends to a large extent on the interaction between hemopoietic stem/progenitor cells (HPC) and the different components of the microenvironment present in the medullary cavity. During the last three decades, in vivo and in vitro studies have allowed significant advances in understanding of the biology of such a hemopoietic microenvironment. Although not evident in histological sections, it is well known that the hemopoietic microenvironment is a highly organized structure that regulates the location and physiology of HPC. The hemopoietic microenvironment is composed of stromal cells (fibroblasts, macrophages, endothelial cells, adipocytes), accessory cells (T lymphocytes, monocytes), and their products (extracellular matrix and cytokines). Microenvironmental cells can regulate hemopoiesis by interacting directly (cell-to-cell contact) with HPC and/or by secreting regulatory molecules that influence, in a positive or negative manner, HPC growth. Recent in vitro studies suggest that functional abnormalities of the hemopoietic microenvironment may be implicated in the manifestation of certain hematological disorders such as aplastic anemia, and acute and chronic myelogenous leukemia. Thus, the characterization of the structure and function of the human hemopoietic microenvironment may have relevance in understanding and treating different hematological disorders.

S'il reste illusoire d'esperer disposer rapidement d'une methode fiable de prevision de l'occurrence imminente d'un seisme, l'evaluation du risque de sa survenue realise de reels progres auxquels contribue le pole alea sismique du CEA.

Highly purified (>99.99%) primary villous cytotrophoblasts from uncomplicated pregnancies and pregnancies complicated with intrauterine growth restriction (IUGR) alone, IUGR with pre-eclampsia (IUGR-PE) and PE alone were cultured for 5 days and the extent of differentiation into syncytiotrophoblasts measured in terms of syncytialisation and secretion of chorionic gonadotropin (hCG) and placental lactogen (hPL). Three separate phenotypes were observed: (1) normal and IUGR-PE cells showed low syncytialisation and secretion of hCG and hPL, (2) IUGR cells showed the highest levels of syncytialisation and secretion and (3) PE cells showed high syncytialisation but low secretion. These results strongly suggest IUGR, IUGR-PE and PE to be distinct conditions in which villous cytotrophoblasts are either exposed to different environments or are genetically different.

Puberty is the phenomenon that conducts once to reproductive maturation. Delayed puberty (DP) is defined by the absence of testicular development in boys beyond 14 years old (or a testicular volume lower than 4 ml) and by the absence of breast development in girls beyond 13 years old. DP occurs in approximatively 3% of cases. Most cases are functional DP, with a large amount of constitutional delay of puberty. Others etiologies are hypogonadotrophic hypogonadism like Kallmann syndrome, or hypergonadotrophic hypogonadism. Turner syndrome is a diagnostic one should not forget by its frequency. Treatment is hormonal replacement therapy and of the etiology. During the last decade, many genes have been identified and elucidated the etiological diagnosis of some hypogonadotrophic hypogonadism syndrome. Further studies are required in collaboration with molecular biologists to better understand the mechanism of hypothalamic pituitary gonadal axis abnormalities and of the neuroendocrine physiology of the onset of puberty.

Extracorporeal membrane oxygenation is used as a last resort during neonatal and pediatric resuscitation in case of refractory circulatory or respiratory failure under maximum conventional therapies. Different types of ECMO can be used depending on the initial failure. The main indications for ECMO are refractory respiratory failure (acute respiratory distress syndrome, status asthmaticus, severe pneumonia, meconium aspiration syndrome, pulmonary hypertension) and refractory circulatory failure (cardiogenic shock, septic shock, refractory cardiac arrest). The main contraindications are a gestational age under 34 weeks or birth weight under 2kg, severe underlying pulmonary disease, severe immune deficiency, a neurodegenerative disease and hereditary disease of hemostasis. Neurological impairment can occur during ECMO (cranial hemorrhage, seizure or stroke). Nosocomial infections and acute kidney injury are also frequent complications of ECMO. The overall survival rate of ECMO is about 60 %. This survival rate can change depending on the initial disease: from 80 % for meconium aspiration syndrome to less than 10 % for out-of-hospital refractory cardiac arrest. Recently, mobile ECMO units have been created. These units are able to perform ECMO out of a referral center for untransportable critically ill patients.

The aim of the SI-Hex project (acronym for « Sismicité Instrumentale de l’Hexagone ») is to provide a catalogue of seismicity for metropolitan France and the French marine economic zone for the period 1962–2009 by taking into account the contributions of the various seismological networks and observatories from France and its neighbouring countries. The project has been launched jointly by the Bureau Central Sismologique Français (CNRS-University/BCSF) and the Laboratoire de Détection et de Géophysique (CEA-DAM/LDG). One of the main motivations of the project is to provide the end user with the best possible information on location and magnitude of each earthquake. So far, due to the various procedures in use in the observatories, the different locations and magnitudes of earthquakes located in the SI-Hex zone were presenting large discrepancies. In the 2014 version of the catalogue, 1D localizations of hypocentres performed with a unique computational scheme and covering the whole 1962–2009 period constitute the backbone of the catalogue (SI-Hex solutions). When available, they are replaced by more precise localizations made at LDG or, for recent times, by the regional observatories within: 1) the French Alps, 2) the southernmost Alps and the Mediterranean domain including Corsica, 3) the Pyrenees, and 4) the Armorican massif. Moment magnitudes Mw are systematically reported in the SI-Hex catalogue. They are computed from coda-wave analysis of the LDG records for most Mw>3.4 events, and are converted from local magnitudes ML for smaller magnitude events. Finally, special attention is paid to the question of discrimination between natural and artificial seismic events in order to produce a catalogue for direct use in seismic hazard analysis and seismotectonic investigations. The SI-Hex catalogue is accessible on the web site www.franceseisme.fr and contains 38,027 earthquake hypocentres, together with their seismic moment magnitudes Mw.

SUMMARY On 2005 June 13, a major earthquake (M7.8) occurred in the Tarapaca region (North Chile), within the region of high mountains. At large distances from the epicentre, this event produced coherent infrasonic waves detected by three infrasound stations that are part of the International Monitoring System. The observed azimuth variations and the long signal durations suggest that wide regions in the Andes Mountains radiated infrasonic waves. From these observations, the main sources' regions are reconstructed. Such an event recorded by multiple stations offers an unique opportunity to evaluate the relative contributions of the different source mechanisms involved in large earthquakes as well as to improve our understanding of the amplification of ground displacement caused by the topography. With a review of infrasound signals from past earthquakes, extended empirical scaling relations are derived. We show that beyond the seismic magnitude, both seismic source and topographic features also play a predominant role in the generation of infrasound.

The Euro-Mediterranean Seismological Center (EMSC) is in charge of collecting parametric data to operate a real-time information and alert system for potentially damaging earthquakes and to publish a comprehensive seismological bulletin for the Euro-Mediterranean region. The region is a seismically active area associated with a complex tectonic structure (Dercourt et al. 1986) but monitored by numerous local or national seismological networks. To obtain a coherent image of the seismicity, it is important to gather and merge data from all countries. The Euro-Mediterranean bulletin computed at the EMSC therefore provides a coherent source of information for the scientific community, for seismic hazard studies, or for tomographic and tectonophysic studies. At the global scale, the three main seismological bulletins are produced by the International Seismological Centre (ISC), the International Data Center (IDC), and the National Earthquake Information Center of the United States (NEIC). The ISC produces a worldwide and exhaustive bulletin with a two-year delay and is considered the most comprehensive database (Willemann et al. 2001). The ISC is a nongovernmental and nonprofit organization mostly funded by academic institutions; it works closely with the International Association of Seismology and Physics of the Earth's Interior (IASPEI). Until 2001, the ISC bulletin location had been solely based on P arrivals. After 2001, all phases have been included in the location. The magnitude completeness varies among regions, but the ISC aims to report all events as well as review and relocate those recorded by more than one network. In addition to known earthquake location determination, the ISC searches for events unidentified by the local networks by associating groups of phases from different agencies. The other global bulletin available is provided by the NEIC, which provides three bulletin publications: the Quick Epicenter Determinations (QED), produced daily; and the Preliminary Determination of Epicenters (PDE), produced both weekly …

Excessive fetal exposure to glucocorticoids has been implicated in the etiology of adult metabolic and cardiovascular disease. Placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) may protect the fetus from excessive glucocorticoid exposure. Maternal stress may be accompanied by elevated levels of cortisol and increased proinflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)]. We hypothesize that proinflammatory cytokines inhibit human placental 11β-HSD activity. We incubated explant cultures of term human placental villi in the presence or absence of 10 ng/ml IL-1β, IL-6, or TNF-α, with or without agonists or antagonists of intracellular Ca2+ and adenylyl cyclase. Activity for 11β-HSD2 was estimated using a radioisotope assay, and mRNA was measured using quantitative RT-PCR. All cytokines significantly ( P ≤ 0.05) reduced 11β-HSD2 activity (>75% suppression); maximal inhibition occurred within 2 h and was maintained for at least 24 h. The IL-1β-induced inhibitory activity was attenuated using a Ca2+ channel blocker (nifedipine), an intracellular Ca2+ antagonist [8-( N, N-diethylamino)octyl-3,4,5-trimethoxybenzoate], or the adenylyl cyclase stimulant forskolin. Conversely, 11β-HSD2 activity was diminished in the presence of the Ca2+ ionophore A-23187 or the adenylyl cyclase inhibitor SQ-22536. mRNA levels for 11β-HSD2 were not changed by any of the treatments. Proinflammatory cytokines inhibit human placental 11β-HSD2 activity through a mechanism that involves increased intracellular Ca2+ and inhibition of adenylyl cyclase. This could result in excessive fetal exposure to maternal cortisol. This mechanism might mediate part of the increased risk of metabolic and cardiovascular disease in adult offspring.

The mammalian placenta consists of different trophoblast cell types that assist in the variety of functions required for the maintenance of pregnancy. In rodents, labyrinthine trophoblasts of the placenta are especially important, because they are capable of differentiating into fused labyrinthine cells, which form the feto-maternal exchange surface. Even though the molecular signals triggering labyrinthine trophoblast differentiation are poorly understood, transforming growth factor-beta (TGF-beta) has been shown to be present in the placental environment and alter trophoblast development. In this study, we investigated the effects of TGF-beta on the differentiation of the labyrinthine trophoblast stem cell lines SM10 and HRP-1. RT-PCR analyses demonstrated that while the molecular expression of labyrinthine-specific lineage markers (Esx1, Tfeb, and Tec) was maintained in TGF-beta-treated SM10 and HRP-1 cells, TGF-beta induced the down-regulation of trophoblast stem cell markers Id2 and Cdx2. In contrast, TGF-beta induced the expression of a marker of differentiated labyrinthine trophoblasts, Gcm1, only in the SM10 cell line. Furthermore, we demonstrated an increased glucose uptake in the TGF-beta-treated SM10 cells, indicative of functional differentiation. Finally, cell fusion in TGF-beta-treated SM10 and HRP-1 cells was investigated by western blotting analysis of placental alkaline phosphatase and cadherin-11 and by microscopic analyses of cell morphology using green fluorescent protein (GFP) and rhodamine phalloidin staining. The western blotting and morphological analyses indicate TGF-beta-induced cell fusion and morphological differentiation in the SM10 cell line. The SM10 cell line will provide a new and unique model for detailed analysis of TGF-beta-induced molecular events associated with labyrinthine trophoblast differentiation and function.

The failure of placental trophoblasts to differentiate properly is thought to play an important role in the cause of pregnancy disorders such as preeclampsia. We looked at the effects of the bioactive lipid sphingosine-1-phosphate (S1P) on the differentiation of primary human cytotrophoblasts (CTs) into syncytiotrophoblasts (STs) in culture. We found that S1P inhibited CT differentiation measured by human chorionic gonadotropin (hCG) secretion and the expression of placental alkaline phosphatase but had no effect on their fusion into multinucleated syncytialized cells. G-protein-linked S1P receptors 1, 2, and 3 were found in CTs by reverse transcriptase-polymerase chain reaction, and receptor 1 was found by Western blot analysis. Disruption of G(i) signaling with pertussis toxin reversed the inhibitory effects of S1P. S1P reduced intracellular cAMP, and the addition of 8-bromo-cAMP reversed S1P inhibition of hCG secretion. Therefore, we suggest that S1P inhibits the differentiation of CTs into STs through G(i)-coupled S1P receptor interaction(s), leading to the inhibition of adenylate cyclase and reduced production of intracellular cAMP. This is the first reported effect of S1P on placental trophoblast function.

Epidermal growth factor (EGF) reduces apoptosis in primary cytotrophoblast (CT) in culture through two separate pathways: the extracellular signal related kinase (ERK) 1/2 and phosphatidyl inositol 3-kinase (PI-3 kinase) paths. Whether other pathways are involved in survival signalling is unknown. We here show that the c-Jun NH2 terminal kinase (JNK) and the mitogen activated kinase (MAPK) p38 are also activated by EGF as seen by increases in JNK and p38 phosphorylation. However, inhibition of JNK phosphorylation with the specific inhibitor SP600125 increases apoptosis in a manner refractory to the addition of EGF but inhibition of p38 phosphorylation with its specific inhibitor SB 203580 does not increase apoptosis. EGF also activates sphingosine kinase-1 (SPHK-1), which converts sphingosine to sphingosine-1-phosphate, and its inhibition with dimethyl sphingosine (DMS) increased trophoblast death. Inhibition of SPHK-1 also did not affect EGF stimulated phosphorylation of PI-3 kinase, Akt, ERK1/2 or p38 but inhibition of PI-3 kinase with a specific inhibitor LY294002 partly (40%) inhibited the EGF-stimulated increase in SPHK-1 activity. We conclude that, in addition to the PI-3 kinase and ERK1/2 pathways, EGF acts through its receptor to stimulate JNK, p38 and SPHK-1 pathways, but that the JNK and SPHK-1, and not the p38, pathways are involved in suppressing apoptosis. This information provides evidence that EGF stimulates survival along multiple pathways that differ in trophoblast and other cell types.

PL74, a novel member of the TGFbeta superfamily that has highest expression in placenta, is a multifunctional peptide that can induce differentiation, inhibit inflammatory stimulation of TNFalpha, and execute apoptosis after p53 overexpression and cytotoxic injury. To study its expression and function in placenta and preeclampsia, we first determined mRNA expression in nine normal and 10 preeclamptic placentas. PL74 mRNA was overexpressed by 57.3% in preeclampsia. Transfection of PL74 into term cytotrophoblasts resulted in increased apoptosis by terminal uridine deoxynucleotidyl nick end labeling labeling (control, 2.8 +/- 0.5%; PL74, 19.1 +/- 0.2%; P < 0.005). Addition of PL74 protein to HTR8/SVneo extravillous cytotrophoblast cells showed a dose-response (0-100 ng/ml) inhibition of [3H]thymidine uptake and increase in apoptosis shown by terminal uridine deoxynucleotidyl nick end labeling and histone-associated DNA fragment ELISA (control, 0.11 +/- 0.01 absorbance units; PL74, 0.21 +/- 0.01; P < 0.01). PL74 did not alter cytotrophoblast invasion using a Matrigel in vitro invasion assay. Cytokine regulation of PL74 mRNA expression in term cytotrophoblasts showed that epidermal growth factor and IFNgamma increased PL74 expression, but TGFbeta and TNFalpha had no effect. Transfection of antisense PL74 into term cytotrophoblast cells resulted in an inhibition of spontaneous differentiation at 2 and 24 h of culture (control vector, 30.8 +/- 3.1% and 26.4 +/- 1.2%; antisense PL74, 17.6 +/- 1.8%and 12.6 +/- 1.4% syncytial units, at 2 and 24 h respectively; P < 0.01). We conclude that PL74 is overexpressed in preeclampsia and may thus promote apoptosis of cytotrophoblasts at the expense of differentiation. PL74 secretion is induced by IFNgamma and may play a role in abnormal placental responses in preeclampsia.

SUMMARY Refinement of the seismicity distribution (4574 events) in western and central France, has been done by synthesis of seismological bulletins. Earthquakes have then been relocated by joint hypocentre and velocity structure inversion. The new hypocentre distribution indicates that the seismicity of those regions is much less diffuse than previously thought, mainly with regard to the depth distribution. The hypocentre improvement allows us to compute 44 new focal mechanisms and to revise bibliographic focal mechanism solutions. Then, the regional stress field was determined from 119 available focal mechanisms. It is characterized by a regionally significant strike-slip regime with NW-trending σ 1. However, the refinement in location and increasing available focal mechanism solutions allow us to show that this strike-slip regime is overprinted by local extensional perturbations in three distinct areas. In the Massif Central, the Sillon Houiller, a ancient vertical shear zone, appears to be acting as a passive boundary between a western unit and an eastern unit that is uplifted by the ascension of a hot mantle plume at the base of the lithosphere. Extension is unexpectedly observed in the southern Armorican Massif (SAM), as well as in northwestern Massif Central. One can observe a good relation between the observed perturbed zones and lateral variation of Pn anisotropy in the mantle. This correlation and the scale of these areas are arguments in favour of a lithospheric process as the origin for the stress characteristics. We believe these extensional perturbations could be related to the anticlockwise rotation of the Iberian microplate and/or incipient subduction in the Bay of Biscay.

There is evidence of impaired placental development in intrauterine growth restriction (IUGR). Matrix metalloproteinases (MMPs) are extracellular matrix-degrading enzymes that are released by placental cells during tissue remodeling processes. We hypothesized 1) that release of MMP-2 and -9 is decreased and/or release of tissue inhibitors of metalloproteinases (TIMPs) is increased from placental explants in pregnancies complicated by IUGR and 2) that oxygen levels affect such release.Placental villous explants from normal (n = 7) and IUGR (n = 7) pregnancies were cultured at high (20%) and low (3%) oxygen levels for 24 hours. Supernatants were analyzed for MMP-2 and MMP-9 by zymography and for TIMP-1 and -2 by western blot analysis.: At 20% oxygen there was significantly reduced MMP-2 (P.05) and TIMP-1 (P.01) release and a trend for decreased MMP-9 release (P = .07) in explants from IUGR pregnancies compared with normal pregnancies; however, there were no differences at 3% oxygen. TIMP-2 was below detectable levels in all samples. Although MMP-2 and TIMP-1 release was significantly reduced at 3% compared with 20% oxygen in explants from both normal (P.001; P.05) and IUGR (P.05) pregnancies, MMP-2 release changed less in IUGR compared with normal explant cultures. There were no significant effects of oxygen on MMP-9 release.Placental explants from IUGR pregnancies demonstrated reduced MMP-2, MMP-9, and TIMP-1 release compared with explants from normal pregnancies at high (20%) but not low (3%) oxygen.

There is evidence of altered vascular endothelial function in women with preeclampsia as well as in the endothelial cells from umbilical vessels of preeclamptic pregnancies. Matrix metalloproteinase (MMP)-2 is elevated in the plasma of preeclamptic women and is a mediator of vascular reactivity; however, whether MMP-2 release is altered in preeclamptic endothelial cells is unknown. We hypothesize that MMP-2 release is enhanced in endothelial cells from preeclamptic compared with uncomplicated pregnancies and that this phenomenon may be mediated by an oxygen-dependent mechanism. Our specific hypothesis is that cells from normal pregnancies will demonstrate enhanced MMP-2 release at low oxygen (0.5%, 2%) compared to high oxygen (20%), thus mimicking the behavior of preeclamptic cells.Human umbilical vein endothelial cells (HUVECs) from preeclamptic pregnancies (n = 4) and normal pregnancies (n = 4) were incubated for 12 hr in standard culture conditions (20% oxygen). In a separate series of experiments, HUVECs from normal pregnancies (n = 6) were incubated for 12 hr at0.5%, 2%, and 20% oxygen. Supernatants were analyzed for MMP-2 and tissue inhibitors of metalloproteinases (TIMP)-1 and -2.The HUVECs from women with preeclampsia demonstrated significantly enhanced release of MMP-2 (p0.05), TIMP-1 (p0.001), and TIMP-2 (p = 0.01) compared to normal cells. MMP-2 release from HUVECs from uncomplicated pregnancies was significantly elevated at 2% oxygen compared to0.5% and 20% oxygen (p0.05). TIMP-1 and -2 secretion was not altered with varying oxygen.Preeclamptic endothelial cells demonstrate significantly enhanced MMP-2, TIMP-1 and TIMP-2 release compared to normal cells. Our data show that there are significant effects of oxygen tension on MMP-2 release from normal cells; however, the magnitude of the enhanced release is small when compared to the differences in MMP-2 release in cells from preeclamptic and normal pregnancies. Furthermore, TIMP-1 and -2 release is not affected by changes in oxygen. It is unlikely that oxygen is a key mediator of the enhanced MMP-2, TIMP-1 and TIMP-2 release observed in preeclamptic cells.

Villous trophoblasts undergo increased apoptosis and experience a wider gradient of oxygen tensions (pO(2)) in pregnancies complicated by intrauterine growth restriction. We hypothesize that pO(2)affects trophoblast apoptosis by altering survival signalling through the phosphatidylinositol-3 (PI-3)-kinase and mitogen activated protein kinase (MAPK) pathways. Cytotrophoblasts were cultured at pO(2)from

Infection of the fetal epithelium (trophoblast) lining the villous placenta by human cytomegalovirus (HCMV) accompanies placental inflammations and fetal intrauterine growth restriction. However, the consequences of infection on the villous trophoblast have not been explored. We show that HCMV infection of primary immature (cytotrophoblast-like) or mature (syncytiotrophoblast-like) cultures results in loss of half of the cells within 24 hours of virus challenge. Two-color immunofluorescence of HCMV immediate early (IE) gene expression and apoptosis (terminal dUTP nick-end labeling) revealed apoptosis only in uninfected cells. Antibody to tumor necrosis factor (TNF)-alpha completely inhibited infection-induced trophoblast apoptosis and cell loss, as did co-incubation with epidermal growth factor, known to inhibit trophoblast apoptosis. Transfection with HCMV immediate early- (IE)1-72 and IE2-86, but not IE2-55, expression plasmids induced paracrine trophoblast apoptosis inhibitable by epidermal growth factor or antibody to TNF-alpha. These results show that HCMV infection of villous trophoblasts leads to rapid loss of neighboring cells mediated by viral IE protein-induced TNF-alpha secretion. We propose that HCMV infection damages the placental trophoblast barrier by accelerating trophoblast turnover and decreasing its capacity for renewal.

Human cytomegalovirus (HCMV) is a ubiquitous infectious pathogen that, when transmitted to the fetus in utero, can result in numerous sequelae, including late-onset sensorineural damage. The villous trophoblast, the cellular barrier between maternal blood and fetal tissue in the human placenta, is infected by HCMV in vivo. Primary trophoblasts cultured on impermeable surfaces can be infected by HCMV, but release of progeny virus is delayed and minimal. It is not known whether these epithelial cells when fully polarized can release HCMV and, if so, if release is from the basal membrane surface toward the fetus. We therefore ask whether, and in which direction, progeny virus release occurs from HCMV-infected trophoblasts cultured on semipermeable (3.0-m-pore-size) membranes that allow functional polarization. We show that infectious HCMV readily diffuses across cell-free 3.0-m-pore-size membranes and that apical infection of confluent and multilayered trophoblasts cultured on these membranes reaches cells at the membrane surface. Using two different infection and culture protocols, we found that up to 20% of progeny virus is released but that

Introduction . Apoptosis can be induced in cytotrophoblasts and syncytiotrophoblast in culture by a combination of TNF-α and IFN-γ (Yui et al., 1994a; Garcia-Lloret et al., 1996). This apoptotic action of TNF-α and IFN-γ can be inhibited/‘rescued’ by EGF (Garcia-Lloret et al., 1996). Additional ‘survival’ factors have been sought which might protect cells against apoptosis induced by TNF-α/IFN-γ. The survival factors investigated were bFGF, IGF-1, PDGF-AA, VEGF and PLGF. These cytokines were chosen specifically because in common with EGF, the receptors for these molecules are all direct protein tyrosine kinases. Materials and Methods . All the experiments were carried out using a standard cell culture protocol (Yui et al., 1994a, b; Garcia-Lloret et al., 1996). Apoptosis was induced using TNF-α/IFN-γ, and rescue was attempted using the various cytokines. Apoptosis was identified using the TUNEL technique and quantified by counting 3000 cells in each experimental well. Results . As in previous studies EGF produced a complete inhibition of the apoptotic action of TNF-α/IFN-γ. bFGF, IGF-1, and PDGF-AA produced a partial but significant inhibition of the apoptotic action of TNF-α/IFN-γ. VEGF and PLGF in these experiments had no protective effects against TNF-α/IFN-γ induced apoptosis. Discussion . Previous studies relating to EGF have been confirmed. bFGF, IGF-1, and PDGF have all been shown to provide partial protection against TNF-α/IFN-γ induced apoptosis. VEGF and PLGF did not protect against apoptosis, and the mechanisms of action remain unclear.

Teleseismic tomography across the Chinese Tien Shan shows that seismic wave speeds in the lithosphere beneath central Tien Shan are high and therefore the lithosphere is not weaker than that beneath the adjacent undeformed Tarim and Junggar basins. There is evidence for significant velocity contrasts within the lithosphere that are presumably inherited from the Palaeozoic collision history. The high-velocity, thick Yili block observed underneath the northern Tien Shan is a clue for shortening by a intracontinental subduction. The observed geometry is consistent with a simple model of intracontinental subduction and suggests that, during orogeny, the lithosphere has remained heterogeneous and has deformed along existing planes of weakness rather than by homogeneous thickening of a particularly weak lithosphere.

Evidence for HIV-1 infection of trophoblasts is discordant. Utilizing highly purified full-term trophoblasts, we demonstrate that full-term trophoblasts express CXCR4 but are negative for CCR5 and ...

International audience; S U M M A R Y We present an analysis of the M w = 5.3 earthquake that occurred in the Southeast Indian Ridge on 2010 February 11 using USArray data. The epicentre of this event is antipodal to the USArray, providing us with an opportunity to observe in details the antipodal focusing of seismic waves in space and time. We compare the observed signals with synthetic seismograms computed for a spherically symmetric earth model (PREM). A beamforming analysis is performed over the different seismic phases detected at antipodal distances. Direct spatial snapshots of the signals and the beamforming results show that the focusing is well predicted for the first P-wave phases such as PKP or PP. However, converted phases (SKSP, PPS) show a deviation of the energy focusing to the south, likely caused by the Earth's heterogeneity. Focusing of multiple S-wave phases strongly deteriorates and is barely observable.

The activity of CVT-E002, an aqueous extract containing mainly oligosaccharides and polysaccharides from North American ginseng (Panax quinquefolium), as an immunobooster on murine spleen cells and peritoneal macrophages, was studied in-vitro. CVT-E002 stimulated the proliferation of normal mouse spleen cells, of which the major responding subpopulation was identified as B lymphocytes. CVT-E002 also activated peritoneal exudate macrophages leading to enhanced interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and nitric oxide (NO) production. In addition, CVT-E002 stimulated in-vivo immunoglobulin G (IgG) production in treated mice. These results identify some of the immunomodulating activities of CVT-E002 and suggest its use clinically for the modulation of immune responses.

Placental inflammations (villitis) are accompanied by loss of the syncytiotrophoblast, which is the cellular barrier separating maternal blood from fetal tissue in the villous placenta. We propose that syncytiotrophoblast loss is mediated by adhesion of activated maternal monocytes. This hypothesis was tested with a co-culture model of peripheral blood monocytes and placental syncytiotrophoblasts. We find that LPS-activated monocytes adhere to interferon-γ (IFN-γ)-treated syncytiotrophoblasts via monocyte LFA-1 for >48 h, during which time the monocytes induce trophoblast apoptosis and subsequent damage of the trophoblast layer. Optimal monocyte-mediated syncytiotrophoblast death requires both lipopolysaccharide (LPS) and IFN-γ and is inhibited by either anti-tumor necrosis factor (TNF) antibody or epidermal growth factor. Syncytiotrophoblast damage is largely limited to culture surfaces in the vicinity of bound monocytes. These results show that activated maternal monocytes bound to the placental barrier can induce focal damage mediated by the inflammatory cytokine TNF-α and suggest a route for maternal leukocyte infiltration into the fetal stroma.

The large increase in placental surface area and fetal villous vascular development in the third trimester of pregnancy requires degradation and reformation of the placental basal lamina. Degradation is carried out by matrix metalloproteinases (MMPs) secreted by adjacent cells. Although the gelatinases, MMP-2 and MMP-9, which are released by extravillous cytotrophoblasts (CTs) are believed to play crucial roles in early placental expansion, neither has been reported in third trimester villous trophoblasts nor has appropriate (basolateral) release of any MMP by the highly polarized syncytiotrophoblast (ST) been demonstrated. We demonstrated villous trophoblast expression of both MMP-2 and MMP-9 by in situ immunohistochemistry and by Western blot analysis and zymography of lysates and culture supernatants of highly purified villous CTs. We also found that epidermal growth factor (EGF)-stimulated CT differentiation into ST and stimulation by the phorbol diester, PMA, both increase MMP-9 secretion. The direction of MMP release was determined with confluent cultures of ST on porous membranes. We found that >90% of MMP-2 and MMP-9 were released from the basolateral surface. We conclude that villous STs express and release gelatinases from their basolateral surfaces in a regulated manner and suggest that such polarized release may be important to villous tissue remodeling.

The activation of sphingomyelinase and the subsequent generation of ceramide are emerging as important components of signaling pathways leading to apoptosis. The combination of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) induces apoptosis of primary placental trophoblasts in vitro. This apoptosis is inhibited completely by cotreatment with epidermal growth factor (EGF). We therefore examined the role of sphingomyelinase and ceramide in trophoblast apoptosis and how this may be influenced by EGF. Exogenous C16-ceramide (20 microM) and acid sphingomyelinase induced trophoblast apoptosis, an effect abrogated completely by cotreatment with 10 ng/ml EGF. Neutral sphingomyelinase also increased ceramide levels but did not induce apoptosis. Treatment with EGF alone decreased cellular ceramide levels. This decrease could be blocked by cotreatment with the acid ceramidase inhibitor N-oleoylethanolamine (OE). OE alone increased ceramide levels and induced apoptosis that could not be blocked by cotreatment with EGF. In contrast, the alkaline ceramidase inhibitor D-MAPP, although it also increased ceramide levels, did not induce apoptosis nor did it affect TNF-alpha/IFN-alpha-induced cell death. These results implicate sphingolipids as important mediators in trophoblast apoptosis and suggest that the antiapoptotic properties of EGF can in part be explained by its control of ceramide concentrations in trophoblasts.