Maternally acquired genotoxic Escherichia coli alters offspring’s intestinal homeostasis

The neonatal gut is rapidly colonized by a newly dominant group of commensal Escherichia coli strains among which a large proportion produces a genotoxin called colibactin. In order to analyze the short- and long-term effects resulting from such evolution, we developed a rat model mimicking the natural transmission of E. coli from mothers to neonates. Genotoxic and non-genotoxic E. coli strains were equally transmitted to the offspring and stably colonized the gut across generations. DNA damage was only detected in neonates colonized with genotoxic E. coli strains. Signs of genotoxic stress such as anaphase bridges, higher occurrence of crypt fission and accelerated renewal of the mature epithelium were detected at adulthood. In addition, we observed alterations of secretory cell populations and gut epithelial barrier. Our findings illustrate how critical is the genotype of E. coli strains acquired at birth for gut homeostasis at adulthood.     

Sphincter pharyngoplasty as a treatment of velopharyngeal incompetence in young people: a prospective evaluation of effects on sleep structure and sleep respiratory disturbances

BACKGROUND: Sphincter pharyngoplasty (SP) appears to be the more "physiologic" surgical technique to treat velopharyngeal incompetence (VPI). This procedure creates a dynamic sphincter of variable diameter and keeps the flexibility of the soft palate. SP also induces velopharyngeal size reduction, mainly in the transverse diameter, which may cause upper airway (UA) occlusions during sleep. AIM: To prospectively evaluate the effects of SP by a modified Orticochea procedure on sleep structure and sleep respiratory disturbances. METHODS: Polysomnographic studies before and after surgery in 17 consecutive patients treated by a modified Orticochea procedure SP for VPI. RESULTS: For the whole group, SP did not induce significant impairment of apnea-hypopnea index or nocturnal oxygen saturation. Slow-wave sleep (SWS) was significantly reduced after surgery (25 +/- 9% of total sleep time [TST] vs 28 +/- 9% of TST before SP [p = 0.04]). Following surgery, there was a trend for an increase in the microarousal index) (p = 0.09) and more specifically in respiratory-related microarousals. CONCLUSION: SP, although creating a clinically obvious reduction of velopharyngeal diameter, generally did not lead to the occurrence of an obstructive sleep apnea syndrome. However, we found a significant reduction of SWS quantity and a trend toward an increase in the number of cortical microarousals. These findings suggest that the reduction of UA diameter associated with the surgical technique leads to increases in respiratory effort sufficient to induce sleep fragmentation and SWS reduction, even in the absence of apneas or hypopneas.     

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α₂δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.     

The effect of hydroxychloroquine on platelet activation in model experiments

Journal of Thrombosis and Thrombolysis - Hydroxychloroquine (HCQ) is an antimalarial agent with pleiotropic effects and now represents a cornerstone in the management of patients with autoimmune...     

The Notch ligand Delta1 is sequentially cleaved by an ADAM protease and gamma-secretase

Notch signaling is involved in numerous cell fate decisions in invertebrates and vertebrates. The Notch receptor is a type I transmembrane (TM) protein that undergoes two proteolytic steps after ligand binding, first by an ADAM (a distintegrin and metalloprotease) in the extracellular region, followed by gamma-secretase-mediated cleavage inside the TM domain. We demonstrate here that the murine ligand Delta1 (Dll1) undergoes the same sequence of cleavages, in an apparently signal-independent manner. Identification of the ADAM-mediated shedding site localized 10 aa N-terminal to the TM domain has enabled us to generate a noncleavable mutant. Kuzbanian/ADAM10 is involved in this processing event, but other proteases can probably substitute for it. We then show that Dll1 is part of a high-molecular-weight complex containing presenilin1 and undergoes further cleavage by a gamma-secretase-like activity, therefore releasing the intracellular domain that localizes in part to the nucleus. Using the shedding-resistant mutant, we demonstrate that this gamma-secretase cleavage depends on prior ectodomain shedding. Therefore Dll1 is a substrate for regulated intramembrane proteolysis, and its intracellular region possibly fulfills a specific function in the nucleus.     

Diagnosing Autism Spectrum Disorder in Toddlers Born Very Preterm: Estimated Prevalence and Usefulness of Screeners and the Autism Diagnostic Observation Schedule (ADOS)

This study estimated ASD prevalence in a cohort of 3-year-old very preterm children (N?=?55) and investigated the usefulness of parent-reported ASD screeners and the ADOS-2. 12.7% received an ASD diagnosis by clinical judgment based on DSM-5 criteria. An additional 14.5% were classified as having a broader-autism-phenotype outcome. Sensitivity values for the screeners were poor, whereas specificity values ranged from poor to excellent. The ADOS-2 identified all children with ASD and had a fair specificity. These findings confirm the elevated ASD prevalence made by previous studies with preterm children but also highlight the challenges of successfully identifying ASD in this at-risk group. Caution is warranted when interpreting results of ASD instruments with the currently available cut-off scores and algorithms, especially when developmental challenges are present.