Rfx6 directs islet formation and insulin production in mice and humans.

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

Pilot Study to Evaluate a New Method for Endotracheal Administration of Surfactant in Neonatal Respiratory Distress Syndrome: Fiberscope Assisted Surfactant Therapy (FAST).

INTRODUCTION: Currently, INSURE (Intubation-Surfactant-Extubation) and LISA (Less Invasive Surfactant Administration) are two recommended techniques for surfactant delivery to newborns with respiratory distress syndrome. The aim of this study was to evaluate the feasibility, safety, tolerability of a new technique of surfactant administration in newborns without anesthesia or laryngoscopy: Fiberscope Assisted Surfactant Therapy (FAST). METHODS: This monocentric, prospective, nonrandomized, pilot feasibility study was conducted from January to December 2021. Spontaneously breathing infants born ≥28 weeks gestational age with respiratory distress syndrome received surfactant by a 1.5 French catheter inserted in the trachea using a flexible endoscope without anesthesia, while maintaining a continuous positive expiratory pressure. The learning curve of this new technique by caregivers was studied during training sessions on high fidelity mannequins. RESULTS: Eight infants born ≥28 weeks of gestation with a birth weight of 1,000 g-2,685 g were included in the study. FAST was successfully performed in each case without anesthesia, second dose of surfactant or mechanical ventilation. One hour after FAST, a decrease of FiO2 and PCO2 and an increase of arterial pressure and pH were recorded with medians of individual differences of -0.9, -4 mm Hg, 6.5 mm Hg, and 0.06, respectively. The learning curves of 13 physicians showed a rapid mastery of FAST from the third attempt onwards (mean duration of 113, 66, and 50 s for 1st, 2nd, and 3rd attempts, respectively, 29-37 s for further attempts). CONCLUSION: FAST may be considered as a possible new minimally invasive surfactant therapy technique for neonates ≥28 weeks with mild respiratory distress syndrome.

Neonatal euthanasia: A claim for an immoral law.

Active ending of the life of a newborn baby is a crime. Yet its clandestine practise is a reality in several European countries. In this paper, we defend the necessity to institute a proper legal frame for what we define as active neonatal euthanasia. The only legal attempt so far, the Dutch Groningen protocol, is not satisfactory. We critically analyse this protocol, as well as several other clinical practises and philosophical stances. Furthermore, we have tried to integrate our opinions as clinicians into a law project, with the purpose of pinpointing several issues, specific of perinatality that should be addressed by such a law. In conclusion, we argue that the legalisation of neonatal euthanasia under exceptional circumstances is the only way to avoid all the "well-intentioned" malpractices associated with ending life at the very dawn of it.

Neonatal hemochromatosis and Martinez-Frias syndrome of intestinal atresia and diabetes mellitus in a consanguineous newborn.

Neonatal hemochromatosis is a heterogeneous disorder of iron metabolism characterized by hepatic failure and marked iron accumulation in liver and extrahepatic tissues. Autosomal recessive transmission is found in most cases. Neonatal hemochromatosis shares cellular features with the adult disease but is clinically and genetically distinct, the causal gene(s) being presently unknown. We report on a newborn from consanguineous parents who presented with multiple congenital anomalies and neonatal hemochromatosis. The syndrome consisted of intra-uterine growth retardation, intestinal atresia, gallbladder aplasia and diabetes mellitus, and fitted with the diagnosis of Martinez-Frias syndrome, a very rare autosomal recessive phenotype, the gene of which remains to be identified. We suggest that neonatal hemochromatosis may be part of the Martinez-Frias syndrome. Molecular analyses in this and other reported patients with the Martinez-Frias syndrome should shed light on gut development and iron metabolism.

Preferential production of the IL-12(p40)/IL-23(p19) heterodimer by dendritic cells from human newborns.

Human newborns present impaired T helper type 1 cell responses, associated with a defect in the synthesis of IL-12 by dendritic cells (DC). IL-23 is a heterodimeric cytokine structurally related to IL-12, implicated in protective and autoimmune responses. We recently showed that upon activation neonatal T cells up-regulate a functional IL-23 receptor and that this cytokine polarizes the differentiation of naive T cells. We therefore investigated the capacity of neonatal DC to secrete IL-23. Lipopolysaccharide (LPS) stimulation induced the transcription of IL-23(p19) mRNA in both adult and neonatal DC, in sharp contrast to the repressed IL-12(p35) gene expression observed in neonatal cells. In comparison to adult DC, neonatal DC produced similar levels of IL-23 protein, in reponse to Toll-like receptor (TLR)-2- and TLR-3 ligands, and higher levels in response to TLR-4- or TLR-8 ligands. The same profile was observed in neonatal mononuclear cells. The supernatant of LPS-stimulated DC induced the secretion of IL-17 by polyclonally activated neonatal CD8(+) T cells, confirming the IL-23 bioactivity. Altogether, these observations strongly suggest that IL-23 could play a role in the immune system of human newborns. In particular, a functional IL-23/IL-17 axis might compensate a suboptimal IL-12/IFN-gamma pathway in early life.

IL-23 up-regulates IL-10 and induces IL-17 synthesis by polyclonally activated naive T cells in human.

Interleukin (IL)-23 is a heterodimeric cytokine of the IL-12 family. Human IL-23 is known to induce interferon (IFN)-gamma production and proliferation in T cells, preferentially in the CD45RO+ memory subset. Yet, its role in the differentiation of human naive T cells remains largely unknown. We investigated the effect of recombinant human (rh)IL-23 on cord blood CD4+ and CD8+ T cells during polyclonal activation. The IL-23 receptor complex was not detectable in resting naive T cells. Nevertheless, both IL-23 receptor subunits, IL-12Rbeta1 and IL-23R, were rapidly induced after activation in both naive CD4+ and CD8+ T cells. In both cell types, rhIL-23 enhanced IFN-gamma production. This effect was demonstrable as early as 2 days after activation, illustrating that a functional IL-23 receptor is rapidly induced in naive T cells upon activation. In naive CD8+ T cells, rhIL-23 specifically induced the secretion of IL-17, a pro-inflammatory cytokine. Moreover, rhIL-23 significantly increased the production of IL-10 in both naive CD4+ and CD8+ T cells. IL-17 and IL-10 levels were not affected by the addition of rhIL-12. We conclude that IL-23 induces a specific cytokine profile, remarkably distinct from IL-12, in activated human naive T cells.