Characterization of RAGE and CK2 Expressions in Human Fetal Membranes.

At the feto-maternal interface, fetal membranes (FM) play a crucial role throughout pregnancy. FM rupture at term implicates different sterile inflammation mechanisms including pathways activated by the transmembrane glycoprotein receptor for advanced glycation end-products (RAGE) belonging to the immunoglobulin superfamily. As the protein kinase CK2 is also implicated in the inflammation process, we aimed to characterize the expressions of RAGE and the protein kinase CK2 as a candidate regulator of RAGE expression. The amnion and choriodecidua were collected from FM explants and/or primary amniotic epithelial cells throughout pregnancy and at term in spontaneous labor (TIL) or term without labor (TNL). The mRNA and protein expressions of RAGE and the CK2α, CK2α', and CK2ß subunits were investigated using reverse transcription quantitative polymerase chain reaction and Western blot assays. Their cellular localizations were determined with microscopic analyses, and the CK2 activity level was measured. RAGE and the CK2α, CK2α', and CK2ß subunits were expressed in both FM layers throughout pregnancy. At term, RAGE was overexpressed in the amnion from the TNL samples, whereas the CK2 subunits were expressed at the same level in the different groups (amnion/choriodecidua/amniocytes, TIL/TNL), without modification of the CK2 activity level and immunolocalization. This work paves the way for future experiments regarding the regulation of RAGE expression by CK2 phosphorylation.

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.

Systematic review of high-flow nasal cannula versus continuous positive airway pressure for primary support in preterm infants.

INTRODUCTION: We conducted a meta-analysis of trials that compared efficacy and safety of high-flow nasal cannula (HFNC) with continuous positive airway pressure (CPAP) as primary respiratory support in preterm infants and a study of the impact of clinical relevant parameters. METHODS: Databases were searched for randomised controlled trials comparing HFNC with CPAP as primary respiratory support in preterm infants. Treatment failure was considered as primary outcome and adverse events as secondary outcomes. We calculated risk ratios (RRs) in intention-to-treat analysis and random-effects meta-analyses of risks were conducted. RESULTS: We included 10 studies for a total of 1830 patients. Meta-analysis demonstrated an RR of treatment failure multiplied by 1.34 using HFNC compared with CPAP (RR=1.34, 95% CI 1.01 to 1.68, I2=16.2%). Secondary outcome meta-analysis showed no difference in intubation rates (RR=0.90, 95% CI 0.66 to 1.15) and a lower rate of nasal trauma using HFNC compared with CPAP (RR=0.48, 95% CI 0.31 to 0.65, I²=0.0%). Meta-regressions did not show any influence of gestational age and weight at birth, HFNC flow rate, type of CPAP generator or use of surfactant. CONCLUSIONS: Despite a higher risk of treatment failure, considering no difference in intubation rates and a lower rate of nasal trauma using HFNC compared with CPAP, we suggest that HFNC should be used as primary respiratory support in preterm infants.