Programme Hospitalier Recherche Clinique, Institut Pasteur, Inserm, French Public Health Agency.

This study confirms that the currently recommended dose regimen (10-5-5 mg/kg) of IBU is associated with a high closure rate (80%) and few adverse effects in premature infants with a PMA of 27-29 weeks. The failure rate was much higher below 27 weeks. A higher dose regimen (20-10-10 mg/kg) might achieve a higher closure rate. However, tolerability and safety of this dose regimen should be assessed in a larger population before considering the use of these doses for ductus arteriosus closure.

The prognosis of antenatally diagnosed CDH was improved by systematic HFOV on admission, no systematic transfer, and delayed surgery. This improvement is associated with modification of postnatal outcome.

No abstract

Dendritic growth is pivotal in the neurogenesis of cortical neurons. The sodium pump, or Na,K-ATPase, is an evolutionarily conserved protein that, in addition to its central role in establishing the electrochemical gradient, has recently been reported to function as a receptor and signaling mediator. Although a large body of evidence points toward a dual function for the Na,K-ATPase, few biological implications of this signaling pathway have been described. Here we report that Na,K-ATPase signal transduction triggers dendritic growth as well as a transcriptional program dependent on cAMP response element binding protein (CREB) and cAMP response element (CRE)-mediated gene expression, primarily regulated via Ca 2+ /calmodulin-dependent protein (CaM) kinases. The signaling cascade mediating dendritic arbor growth also involves intracellular Ca 2+ oscillations and sustained phosphorylation of mitogen-activated protein (MAP) kinases. Thus, our results suggest a novel role for the Na,K-ATPase as a modulator of dendritic growth in developing neurons.

Endotracheal tubes (ETTs) constitute a resistive extra load for intubated patients. The ETT pressure drop (DeltaP(ETT)) is usually described by empirical equations that are specific to one ETT only. Our laboratory previously showed that, in adult ETTs, DeltaP(ETT) is given by the Blasius formula (F. Lofaso, B. Louis, L. Brochard, A. Harf, and D. Isabey. Am. Rev. Respir. Dis. 146: 974-979, 1992). Here, we also propose a general formulation for neonatal and pediatric ETTs on the basis of adimensional analysis of the pressure-flow relationship. Pressure and flow were directly measured in seven ETTs (internal diameter: 2.5-7.0 mm). The measured pressure drop was compared with the predicted drop given by general laws for a curved tube. In neonatal ETTs (2.5-3.5 mm) the flow regime is laminar. The DeltaP(ETT) can be estimated by the Ito formula, which replaces Poiseuille's law for curved tubes. For pediatric ETTs (4.0-7.0 mm), DeltaP(ETT) depends on the following flow regime: for laminar flow, it must be calculated by the Ito formula, and for turbulent flow, by the Blasius formula. Both formulas allow for ETT geometry and gas properties.

The aim of this pharmacokinetic analysis was to develop and validate a population pharmacokinetic model for R- and S-ibuprofen from samples obtained after 3 successive administrations of ibuprofen (10-5-5 mg/kg) at 24-hour intervals to preterm newborn infants aged from <6 hours to 8 days of life. A model including unilateral bioconversion of R-ibuprofen into S-ibuprofen was developed using the software NONMEM. R- and S-ibuprofen plasma concentrations were adequately fitted by this model. Estimated clearance and volume of distribution were 3.5 mL/h/kg and 173 mL/kg, respectively, with a calculated half-life (t((1/2))) of 34.3 hours for S-ibuprofen. Estimated clearance at birth and volume of distribution were 25.5 mL/h/kg and 306 mL/kg with a t((1/2)) at birth of 8.3 hours for R-ibuprofen. R-ibuprofen elimination increased during the first week of life, whereas S-ibuprofen pharmacokinetics were weakly modified. Therefore, because the activity of the 2 enantiomers differs, it is important that subsequent studies consider R- and S-enantiomers separately. Mean simulated ibuprofen concentrations at various dose regimens were in agreement with observed concentrations. The present analysis allows a more accurate estimation of the ibuprofen pharmacokinetics as parameters could be estimated separately for each enantiomer and the effect of postnatal age on the elimination of R-ibuprofen was elicited.

Background:Cellular quiescence is a state of reversible proliferation arrest that is induced by anti-mitogenic signals. The endogenous cardiac glycoside ouabain is a specific ligand of the ubiquitous sodium pump, Na,K-ATPase, also known to regulate cell growth through unknown signalling pathways.Methods:To investigate the role of ouabain/Na,K-ATPase in uncontrolled neuroblastoma growth we used xenografts, flow cytometry, immunostaining, comet assay, real-time PCR, and electrophysiology after various treatment strategies.Results:The ouabain/Na,K-ATPase complex induced quiescence in malignant neuroblastoma. Tumour growth was reduced by >50% when neuroblastoma cells were xenografted into immune-deficient mice that were fed with ouabain. Ouabain-induced S-G2 phase arrest, activated the DNA-damage response (DDR) pathway marker γH2AX, increased the cell cycle regulator p21Waf1/Cip1 and upregulated the quiescence-specific transcription factor hairy and enhancer of split1 (HES1), causing neuroblastoma cells to ultimately enter G0. Cells re-entered the cell cycle and resumed proliferation, without showing DNA damage, when ouabain was removed.Conclusion:These findings demonstrate a novel action of ouabain/Na,K-ATPase as a regulator of quiescence in neuroblastoma, suggesting that ouabain can be used in chemotherapies to suppress tumour growth and/or arrest cells to increase the therapeutic index in combination therapies.