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Le Touquet – Paris-Plage, France

Martinerie L.,French Institute of Health and Medical Research | Martinerie L.,University Paris - Sud | Pussard E.,French Institute of Health and Medical Research | Pussard E.,University Paris - Sud | And 6 more authors.

Background: Glucocorticoid hormones play a major role in fetal organ maturation. Yet, excessive glucocorticoid exposure in utero can result in a variety of detrimental effects, such as growth retardation and increased susceptibility to the development of hypertension. To protect the fetus, maternal glucocorticoids are metabolized into inactive compounds by placental 11beta-hydroxysteroid dehydrogenase type2 (11βHSD2). This enzyme is also expressed in the kidney, where it prevents illicit occupation of the mineralocorticoid receptor by glucocorticoids. We investigated the role of renal 11βHSD2 in the control of neonatal glucocorticoid metabolism in the human and mouse. Methods: Cortisol (F) and cortisone (E) concentrations were measured in maternal plasma, umbilical cord blood and human newborn urine using HPLC. 11βHSD2 activity was indirectly assessed by comparing the F/E ratio between maternal and neonatal plasma (placental activity) and between plasma and urine in newborns (renal activity). Direct measurement of renal 11βHSD2 activity was subsequently evaluated in mice at various developmental stages. Renal 11βHSD2 mRNA and protein expression were analyzed by quantitative RT-PCR and immunohistochemistry during the perinatal period in both species. Results: We demonstrate that, at variance with placental 11βHSD2 activity, renal 11βHSD2 activity is weak in newborn human and mouse and correlates with low renal mRNA levels and absence of detectable 11βHSD2 protein. Conclusions: We provide evidence for a weak or absent expression of neonatal renal 11βHSD2 that is conserved among species. This temporal and tissue-specific 11βHSD2 expression could represent a physiological window for glucocorticoid action yet may constitute an important predictive factor for adverse outcomes of glucocorticoid excess through fetal programming. © 2012 Martinerie et al. Source

Martinerie L.,French Institute of Health and Medical Research | Martinerie L.,University Paris Diderot | Pussard E.,French Institute of Health and Medical Research | Pussard E.,University Paris - Sud | And 10 more authors.
Journal of Clinical Endocrinology and Metabolism

Context: The neonatal period, notably in preterm infants, is characterized by high sodium wasting, implying that aldosterone, the main hormone regulating sodium reabsorption, is unable to maintain sodium homeostasis. Objective: This study sought to assess aldosterone secretion and action in neonates according to gestational age (GA). DesignandSetting: Thiswasamulticenter prospective study(NCT01176162)conductedbetween2011and 2014 at five neonatology departments in France. Infants were followed during their first 3 months. Participants: The 155 newborns included were classified into three groups: Group 1 (n = 46 patients), <33 gestational weeks (GW); Group 2 (n = 67 patients), 33-36 GW; and Group 3 (n = 42 patients), ≥37 GW. Main Outcome Measures: Plasma aldosterone was measured in umbilical cord blood. Urinary aldosterone (UAldo)wasassessed at day 0, day 3,month1,andmonth3 postnatal.ThecorrelationbetweenUAldoand the urinary Na/K ratio was determined as an index of renal aldosterone sensitivity. Results: UAldo significantly increased with GA: from 8.8 ± 7.5 μg/mmol of creatinine (Group 1) to 21.1 ± 21.0 (Group 3) in correlation with plasma aldosterone levels in all groups (P < .001), demonstrating its reliability. The aldosterone/renin ratio significantly increased with GA, suggesting an aldosterone secretion defect in preterm infants. UAldo and urinary Na/K were correlated in very preterm but not in term neonates, consistent with very preterm neonates being renal-aldosterone sensitive and term neonates being aldosterone resistant. Conclusions: Very preterm infants have a previously unrecognized defective aldosterone secretion but conserved renal aldosterone sensitivity in the neonatal period, which modifies the current view of sodium balance in these infants and suggests alternative management approaches. Copyright © 2015 by the Endocrine Society. Source

Charriaut-Marlangue C.,University Paris Diderot | Bonnin P.,University Paris Diderot | Pham H.,University Paris Diderot | Loron G.,University Paris Diderot | And 6 more authors.
Annals of Neurology

Nitric oxide (NO) is a powerful vasodilator, involved in both physiological functions and pathophysiological alterations of various regulatory processes, for example, the maintenance of vascular tone and inflammation. The recently demonstrated impact of exogenous NO on the central nervous system extends its role under normal and pathological conditions. At times neuroprotective, at times neurotoxic, NO is capable of different effects depending upon the extent of cerebral damage, the cellular redox state, and the spatiotemporal coordinates and concentration at which it is synthesized. This review provides new insights into the short- and long-term effects of endogenous and exogenous NO in brain injury. © 2013 American Neurological Association. Source

Morel O.,University of Lorraine | Morel O.,French Institute of Health and Medical Research | Grange G.,PremUp Foundation | Grange G.,Royal University | And 9 more authors.
Journal of Maternal-Fetal and Neonatal Medicine

Objective. To assess the feasibility of placental and myometrial vascularization quantification using 3D power Doppler ultrasonography. Methods. 3D standardized acquisition was performed in the mid part of the utero-placental unit, once, in 38 patients undergoing normal pregnancies between 15 and 39 weeks. Vascularization parameters (VI, FI, and VFI) of placentae and myometrium were measured. Intra and inter-observer, as well as inter-acquisition reproducibility were evaluated. Results. Intra-class Correlation Coefficient of vascularization measurements were at least 0.94 for intra-observer, 0.92 for inter-observer, and 0.56 for inter-acquisition reproducibility. There was no significant difference for placental measurements for VI, FI and VFI between the second trimester and the third trimester pregnancies. Concerning the myometrium, we observed no significant difference between second and third trimester for FI. However, VI (28.090 vs. 19.374) and VFI (17.691 vs. 11.336) was significantly lower in the third trimester (p<0.01). Conclusion. 3D quantification of placental and myometrial vascular parameters is feasible with a high intra and inter-observer reproducibility. Evaluating a potential myometrial vascular impairment appears to be as relevant as studying the placenta alone and might be of great clinical interest. We believe that this technique should therefore be evaluated in clinical observational studies. © 2011 Informa UK, Ltd. Source

Jovelet C.,Translational Research Laboratory | Seck A.,Gustave Roussy | Mir O.,University Paris - Sud | Simasotchi C.,PremUp Foundation | And 7 more authors.
Annals of Oncology

Background: The use of tyrosine kinase inhibitors (TKis) during pregnancy in humans remains rare, and little data are available on their transplacental passage. Erlotinib and gefitinib are the first-line targeted therapy in case of stage IV nonsmall- cell lung cancer with an EGFR-activating mutation. There are no data available regarding the comparative use of these TKis in pregnant patients. We aimed to compare the transplacental transfer of gefitinib, imatinib and erlotinib, using the ex vivo method of human perfused cotyledon, and to determine the placental accumulation of TKis. Materials and methods: Term placentas were perfused after delivery with gefitinib, imatinib and erlotinib at targeted maternal concentrations around the steady-state plasma trough concentration (i.e. 500, 1000 and 1500 ng/ml, respectively). Samples from fetal and maternal circulations were collected in order to monitor TKis concentrations. Main transfer parameters such as fetal transfer rate (FTR), clearance index (CI) and placental uptake were assessed. Results: Mean FTR of gefitinib, imatinib and erlotinib were 16.8%, 10.6% and 31.4%, respectively. Mean CI of gefitinib, imatinib and erlotinib were 0.59, 0.48 and 0.93, respectively. Placental uptake in cotyledon was 0.030% %, 0.010% and 0.003% for gefitinib, imatinib and erlotinib, respectively, corresponding to a mean mass of 27.7 μg for gefitinib, 15.7 μg for imatinib and 6.8 μg for erlotinib. Conclusion: The results suggest that TKis cross the placenta at therapeutic level. Particularly, erlotinib crosses the placenta at a higher rate than gefitinib or imatinib. All of them have a very low placental uptake. These data may suggest that gefitinib should be preferred to erlotinib for the treatment of pregnant woman with lung cancer harboring an EGFRactivating mutation, during the second and third trimesters of pregnancy. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

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