Persistent Müllerian duct syndrome associated with genetic defects in the regulatory subunit of myosin phosphatase.

STUDY QUESTION: Can mutations of genes other than AMH or AMHR2, namely PPP1R12A coding myosin phosphatase, lead to persistent Müllerian duct syndrome (PMDS)? SUMMARY ANSWER: The detection of PPP1R12A truncation mutations in five cases of PMDS suggests that myosin phosphatase is involved in Müllerian regression, independently of the anti-Müllerian hormone (AMH) signaling cascade. WHAT IS KNOWN ALREADY: Mutations of AMH and AMHR2 are detectable in an overwhelming majority of PMDS patients but in 10% of cases, both genes are apparently normal, suggesting that other genes may be involved. STUDY DESIGN, SIZE, DURATION: DNA samples from 39 PMDS patients collected from 1990 to present, in which Sanger sequencing had failed to detect biallelic AMH or AMHR2 mutations, were screened by massive parallel sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS: To rule out the possibility that AMH or AMHR2 mutations could have been missed, all DNA samples of good quality were analyzed by targeted next-generation sequencing. Twenty-four samples in which the absence of AMH or AMHR2 biallelic mutations was confirmed were subjected to whole-exome sequencing with the aim of detecting variants of other genes potentially involved in PMDS. MAIN RESULTS AND THE ROLE OF CHANCE: Five patients out of 24 (21%) harbored deleterious truncation mutations of PP1R12A, the gene coding for the regulatory subunit of myosin phosphatase, were detected. In addition to PMDS, three of these patients presented with ileal and one with esophageal atresia. The congenital abnormalities associated with PMDS in our patients are consistent with those described in the literature for PPP1R12A variants and have never been described in cases of AMH or AMHR2 mutations. The role of chance is therefore extremely unlikely. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is the lack of experimental validation of the role of PPP1R12A in Müllerian regression. Only circumstantial evidence is available, myosin phosphatase is required for cell mobility, which plays a major role in Müllerian regression. Alternatively, PPP1R12A mutations could affect the AMH transduction pathway. WIDER IMPLICATIONS OF THE FINDINGS: The study supports the conclusion that failure of Müllerian regression in males is not necessarily associated with a defect in AMH signaling. Extending the scope of molecular analysis should shed light upon the mechanism of the initial steps of male sex differentiation. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by la Fondation Maladies Rares, GenOmics 2021_0404 and la Fondation pour la Recherche Médicale, grant EQU201903007868. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Shielding Parenteral Nutrition Solutions From Light: A Randomized Controlled Trial.

INTRODUCTION: Oxidant stress is implicated in the pathogenesis of bronchopulmonary dysplasia (BPD). Light induces peroxide generation in parenteral nutrition (PN) solutions, creating an oxidant stress. Shielding PN from light decreases its peroxide content, which has nutrition and biochemical benefits in animals and humans. This study aims at determining whether full light protection of PN decreases the rate of bronchopulmonary dysplasia and/or death in very low-birth-weight infants. METHODS: Multicenter randomized controlled trial of photoprotection, using amber bags and tubing initiated during compounding of PN and maintained throughout infusion in the light-protected (LP) group. The control group (light exposed [LE]) received PN exposed to ambient light. Depending on centers, lipids were infused either separately or as all-in-one PN. RESULTS: In total, 590 infants born <30 weeks gestational age were included. At randomization, LE and LP groups did not differ clinically except for maximal FiO2 before 12 hours. The rate of BPD/death was not different between groups at 28 days (77% LP vs 72% LE, P = .16) or at 36 weeks corrected age (30% LP vs 27% LE, P = .55). Multivariate analysis showed no significant effect of photoprotection on BPD and/or death. The rate of BPD/death was significantly lower (odds ratio, 0.54; 95% confidence interval, 0.32-0.93; P = .02) in infants receiving all-in-one PN vs those who received lipids separately. CONCLUSION: This study did not show significant beneficial effects of photoprotection. Since the decreased rate of BPD/death found with all-in-one PN relates to a center-dependent variable, this warrants further investigation.

A multicenter, randomized, placebo-controlled trial of prophylactic recombinant granulocyte-colony stimulating factor in preterm neonates with neutropenia.

OBJECTIVE: To test the hypothesis that prophylactic treatment of neutropenic premature neonates with recombinant granulocyte-colony stimulating factor (rG-CSF) would reduce the incidence of nosocomial infections (NIs). STUDY DESIGN: A total of 25 neonatal intensive care units participated in this multicenter, randomized, double-blind, placebo-controlled trial. Premature infants of gestational age (GA)

Hypotension in preterm infants with significant patent ductus arteriosus: effects of dopamine.

OBJECTIVE: To study the effects of dopamine on systemic arterial pressure (SAP) and systemic blood flow (SBF) (estimated with the superior vena cava [SVC] flow) in preterm infants with hypotension and patent ductus arteriosus (PDA). STUDY DESIGN: Clinical and echocardiographic variables were measured before and 2 hours after starting dopamine in premature infants <32 weeks gestational age with PDA and systemic hypotension. RESULTS: Seventeen premature infants were included (gestational age, 28+/-2 weeks; birth weight, 1030 +/- 400 g). A mean rate of 8 +/- 2 microg/kg/min of dopamine raised SAP from 30 +/- 3 to 41 +/- 5 mm Hg (P < .05), and the pulmonary artery pressures from 25 +/- 5 to 32 +/- 8 mm Hg (P < .05). The SVC flow increased by 30% (from 130 +/- 40 to 170 +/- 44 mL/kg/min; P < .05). The left ventricular output and the end-diastolic and mean left pulmonary artery blood flow velocities did not change despite the increase in pulmonary artery pressure. CONCLUSION: In preterm infants with hypotension and PDA, dopamine (<10 microg/kg/min) increases the systemic blood pressure and the systemic blood flow. Our results suggest that dopamine decreases left-to-right shunting across ductus arteriosus, caused by a rise in pulmonary vascular resistances.

Influence of three nasal continuous positive airway pressure devices on breathing pattern in preterm infants.

The pattern of breathing was studied in 13 premature newborns treated by variable-flow Nasal Continuous Positive Airway Pressure (NCPAP), conventional NCPAP, and nasal cannulae. Compared to constant-flow NCPAP and nasal cannulae, the variable-flow NCPAP increases tidal volume and improves thoraco-abdominal synchrony, suggesting that variable-flow NCPAP provides more effective ventilatory support than conventional NCPAP or nasal cannulae.

Role of the alpha2-adrenoceptors on the pulmonary circulation in the ovine fetus.

Recent in vitro studies reported that nitric oxide release and pulmonary vasorelaxation can be mediated by endothelial alpha2-adrenoceptor activation. As norepinephrine (alpha1-,alpha2-, and beta1-adrenoceptor agonist) was found to induce pulmonary vasodilation in the ovine fetus, we hypothesized that alpha2-adrenoceptors may modulate basal pulmonary vascular tone and mediate the vascular effect of norepinephrine during fetal life. To determine the role of alpha2-adrenoceptors and the mechanisms of norepinephrine-mediated vasodilation in the fetal pulmonary circulation, we tested, in chronically prepared late-gestation fetal lambs, the hemodynamic response to 1). yohimbine (alpha2 antagonist); 2). UK 14304 (alpha2 agonist) with and without l-nitro-arginine (nitric oxide synthase inhibitor); and 3). norepinephrine infusion with and without yohimbine. We found that yohimbine increased mean pulmonary artery pressure by 15% (p < 0.05), decreased pulmonary flow by 22% (p < 0.01), and increased pulmonary vascular resistance by 51% (p < 0.01). UK 14304 increased pulmonary flow by 145% (p < 0.01) and decreased pulmonary vascular resistance by 58% (p < 0.01). l-Nitro-arginine abolished the UK 14304-mediated pulmonary vasodilation. Norepinephrine (0.5 microg x kg(-1)x min(-1) increased both pulmonary flow by 61% (p < 0.01) and pulmonary arterial pressure by 13% (p < 0.01) and decreased pulmonary vascular resistance by 33% (p < 0.01). Yohimbine abolished the norepinephrine-induced pulmonary vasodilation. This study suggests that 1). a basal alpha2-adrenoceptor activation-induced pulmonary vasodilation exists during fetal life; 2). the pulmonary vascular effects of alpha2-adrenoceptor activation are related at least in part to nitric oxide production; and 3). the norepinephrine-mediated pulmonary vasodilation involves alpha2-adrenoceptor activation. As a surge of norepinephrine exists at birth, we speculate that norepinephrine and endothelial alpha2-adrenoceptor activation may play a significant role in pulmonary vasodilation at birth.