Immune-endocrine status and coeliac disease in children with Down’s syndrome: relationships with zinc and cognitive efficiency

Immune defects, thyroid abnormalities, plasma zinc levels, and the presence of gastrointestinal disease were investigated in 43 children with Down’s syndrome (DS). Peripheral T lymphocytes with the phenotype of helper cells or cluster of differentiation 4 (CD4) were decreased. Circulating activated T cells (CD3/HLA-DR-positive cells) and large granular lymphocytes (CD16/CD56 positive cells) were increased. Plasma levels of interleukin-6 were higher in DS children than in controls. Serum levels of thyroid-stimulating hormone were increased in DS. Coeliac disease was over-represented in the group of DS children and many of these children also showed increased serum levels of immunoglobulin-G (IgG) specific for gliadin antigen. The increment of serum interleukin-6 was age-related and correlated with anti-gliadin IgG levels in DS. Plasma zinc levels were lower in DS children with coeliac disease and in those with anti-gliadin IgG than in DS without detectable anti-gliadin IgG. Dietary antigens may represent a continuous stimulus for the immune system in this syndrome and interfere with normal immune responses. Altered intestinal absorption of nutrients may in turn affect endocrine functions, brain development, and cognitive performances.     

TLR4 elimination prevents synaptic and myelin alterations and long-term cognitive dysfunctions in adolescent mice with intermittent ethanol treatment

The adolescent brain undergoes important dynamic and plastic cell changes, including overproduction of axons and synapses, followed by rapid pruning along with ongoing axon myelination. These developmental changes make the adolescent brain particularly vulnerable to neurotoxic and behavioral effects of alcohol. Although the mechanisms of these effects are largely unknown, we demonstrated that ethanol by activating innate immune receptors toll-like receptor 4 (TLR4), induces neuroinflammation and brain damage in adult mice. The present study aims to evaluate whether intermittent ethanol treatment in adolescence promotes TLR4-dependent pro-inflammatory processes, leading to myelin and synaptic dysfunctions, and long-term cognitive impairments. Using wild-type (WT) and TLR4-deficient (TLR4-KO) adolescent mice treated intermittently with ethanol (3.0 g/kg) for 2 weeks, we show that binge-like ethanol treatment activates TLR4 signaling pathways (MAPK, NFκB) leading to the up-regulation of cytokines and pro-inflammatory mediators (COX-2, iNOS, HMGB1), impairing synaptic and myelin protein levels and causing ultrastructural alterations. These changes were associated with long-lasting cognitive dysfunctions in young adult mice, as demonstrated with the object recognition, passive avoidance and olfactory behavior tests. Notably, elimination of TLR4 receptors prevented neuroinflammation along with synaptic and myelin derangements, as well as long-term cognitive alterations. These results support the role of the neuroimmune response and TLR4 signaling in the neurotoxic and behavioral effects of ethanol in adolescence.     

Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma

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