The Intensity of IUGR-Induced Transcriptome Deregulations Is Inversely Correlated with the Onset of Organ Function in a Rat Model

A low-protein diet applied during pregnancy in the rat results in intrauterine growth restricted (IUGR) fetuses. In humans, IUGR is associated with increased perinatal morbidity, higher incidence of neuro-developmental defects and increased risk of adult metabolic anomalies, such as diabetes and cardiovascular disease. Development and function of many organs are affected by environmental conditions such as those inducing fetal and early postnatal growth restriction. This phenomenon, termed “fetal programming” has been studied unconnectedly in some organs, but very few studies (if any) have investigated at the same time several organs, on a more comparative basis. However, it is quite probable that IUGR affects differentially most organ systems, with possible persistent changes in gene expression. In this study we address transcriptional alterations induced by IUGR in a multi-organ perspective, by systematic analysis of 20-days rat fetuses. We show that (1) expressional alterations are apparently stronger in organs functioning late in foetal or postnatal life than in organs that are functioning early (2) hierarchical classification of the deregulations put together kidney and placenta in one cluster, liver, lungs and heart in another; (3) the epigenetic machinery is set up especially in the placenta, while its alterations are rather mild in other organs; (4) the genes appear deregulated in chromosome clusters; (5) the altered expression cascades varies from organ to organ, with noticeably a very significant modification of the complement and coagulation cascades in the kidney; (6) we found a significant increase in TF binding site for HNF4 proteins specifically for liver genes that are down-regulated in IUGR, suggesting that this decrease is achieved through the action of HNF transcription factors, that are themselves transcriptionnally induced in the liver by IUGR (x 1.84 fold). Altogether, our study suggests that a combination of tissue-specific mechanisms contributes to bring about tissue-driven modifications of gene cascades. The question of these cascades being activated to adapt the organ to harsh environmental condition, or as an endpoint consequence is still raised

Clinical research in newborn infants: difficulties and specificity

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Extrême prématurité (prise en charge périnatale, devenir neonatal et à l'âge de deux ans, étude rétrospective descriptive réalisée au CHU de Grenoble entre 2000 et 2004)

Les avancées médicales périnatales de ces vingt dernières années ont permis une meilleure prise en charge d enfants naissant à un âge gestationnel de plus en plus bas, aux limites de viabilité. Malgré une augmentation du taux de survie, le taux de séquelles plus ou moins sévères augmente quand l âge gestationnel diminue. Une étude locale rétrospective a été menée pour apporter des données concrètes et aider à mieux informer les parents et les soignants sur le devenir des enfants nés avant 28 SA. Nos résultats semblent similaires aux données de la littérature: le taux de survie de ces enfants augmente proportionnellement à l âge gestationnel, il dépasse 50% à 25 SA pour atteindre 70% à 27 SA. L hémorragie cérébrale reste la cause principale des décès, surtout aux limites de viabilité. En terme de morbidité, la dysplasie broncho-pulmonaire est très fréquente et les pathologies de la substance blanche telle que la leucomalacie périventriculaire touchent 5% des enfants survivants. Le suivi à deux ans montre que 80% des enfants ont un développement moteur normal. Le nombre croissant de perdus de vue et l apparition tardive des troubles cognitifs et comportementaux, mettent en évidence la nécessité d un suivi prolongé de ces enfants. Face au risque de séquelles lourdes et irréversibles responsables de handicap sévère, une réflexion éthique sur le sens et la pertinence de la prise en charge active et de la poursuite ou non des soins se pose aux équipes soignantes. Cette réflexion doit débuter si possible en anténatal en collaboration étroite avec l équipe obstétricale. Il semble important que ces décisions soient prises au cas par cas en prenant en compte l opinion des parents.GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Case Report: Clostridium neonatale Bacteremia in a Preterm Neonate With Necrotizing Enterocolitis

International audienceNecrotizing enterocolitis is a life-threatening acquired gastrointestinal disorder among preterm neonates and is associated with a high mortality rate and long-term neurodevelopmental morbidity. No etiologic agent has been definitively established; nonetheless, the most implicated bacteria include members of the Clostridium genus. We reported here on a case of Clostridium neonatale bacteremia in a preterm neonate with necrotizing enterocolitis, providing more information regarding the potential role of this bacterium in pathogenesis of necrotizing enterocolitis. We emphasized the sporulating form of C. neonatale that confers resistance to disinfectants usually applied for the hospital environmental cleaning. Further works are needed to establish the causal relationship between the occurrence of NEC and the isolation of C. neonatale , with promising perspectives in terms of diagnostic and therapeutic management

Altered angiogenesis in low birth weight individuals: a role for anti-angiogenic circulating factors

International audienceObjective: Low birth weight (LBW) is a risk factor for hypertension at adulthood. Endothelial progenitor cells (EPCs) dysfunction has been characterized in LBW neonates. We hypothesized that changes in soluble, plasma pro-or anti-angiogenic factors are associated with EPCs dysfunction and impaired angiogenesis in LBW neonates. Method: Venous umbilical cord blood was collected from 42 normal, term neonates and 75 LBW neonates. Cord blood endothelial colony forming cells (ECFC) from control patients were cultured in the presence of 10% of serum obtained from both groups. Results: The proliferation and the migration of ECFC were significantly reduced when cultured with 10% of serum of LBW neonates compared to serum of control neonates. Matrigel invasion assay was not significantly altered. Umbilical vein plasma VEGF concentration was significantly reduced in LBW neonates while that of sVEGFR and PF4 were significantly higher. Addition of VEGF corrected the inhibitory effect of LBW serum on normal ECFC proliferation. Conclusions: Serum obtained from LBW babies contains factors that exhibit an antiangiogenic effect on ECFC proliferation and migration. VEGF/sVEGF/PF4 pathway seems to be involved in the EPCs dysfunction in LBW neonates

Effect of two models of intrauterine growth restriction on alveolarization in rat lungs: morphometric and gene expression analysis.

Intrauterine growth restriction (IUGR) in preterm infants increases the risk of bronchopulmonary dysplasia, characterized by arrested alveolarization. We evaluated the impact of two different rat models (nitric oxide synthase inhibition or protein deprivation) of IUGR on alveolarization, before, during, and at the end of this postnatal process. We studied IUGR rat pups of dams fed either a low protein (LPD) or a normal diet throughout gestation and pups of dams treated by continuous infusion of Nω-nitro-L-arginine methyl ester (L-NAME) or its diluent on the last four days of gestation. Morphometric parameters, alveolar surface (Svap), mean linear intercept (MLI) and radial alveolar count (RAC) and transcriptomic analysis were determined with special focus on genes involved in alveolarization. IUGR pups regained normal weight at day 21 in the two treated groups. In the LPD group, Svap, MLI and RAC were not different from those of controls at day 4, but were significantly decreased at day 21, indicating alveolarization arrest. In the L-NAME group, Svap and RAC were significantly decreased and MLI was increased at day 4 with complete correction at day 21. In the L-NAME model, several factors involved in alveolarization, VEGF, VEGF-R1 and -R2, MMP14, MMP16, FGFR3 and 4, FGF18 and 7, were significantly decreased at day 4 and/or day 10, while the various factors studied were not modified in the LPD group. These results demonstrate that only maternal protein deprivation leads to sustained impairment of alveolarization in rat pups, whereas L-NAME impairs lung development before alveolarization. Known growth factors involved in lung development do not seem to be involved in LPD-induced alveolarization disorders, raising the question of a possible programming of altered alveolarization

Weight gain: at P4, P10 and P21 of rat pups in L-NAME-induced intrauterine growth restriction group and control.

<p>The significance for each bar is indicated by *p<0.05, control vs. L-NAME; two-tailed Mann-Whitney test. Values are expressed as mean ± SEM. n = 5–10 rat pups per group.</p

Morphometric analysis in control and low protein diet rat pups.

<p>Sv(a,p), Mean Linear Intercept (MLI) and Radial alveolar count (RAC) at P4, P10, and P21 were expressed as percentage of mean control value. Significance for each bar is indicated by p values, Control vs. LPD; two-tailed Mann-Whitney test (p<0.05). N = 5 animals per group.</p