Being macrosomic at birth is an independent predictor of overweight in children: results from the IDEFICS study

Fetal macrosomia is a risk factor for the development of obesity late in childhood. We retrospectively evaluated the relationship between maternal conditions associated with fetal macrosomia and actual overweight/obesity in the European cohort of children participating in the IDEFICS study. Anthropometric variables, blood pressure and plasma lipids and glucose were measured. Socio-demographic data, medical history and perinatal factors, familiar and gestational history, maternal and/or gestational diabetes were assessed by a questionnaire. Variables of interest were reported for 10,468 children (M/F = 5,294/5,174; age 6.0 +/- A 1.8 years, M +/- A SD). The sample was divided in four groups according to child birth weight (BW) and maternal diabetes: (1) adequate for gestational age offspring (BW between the 10th and 90th percentiles for gestational age) of mothers without diabetes (AGA-ND); (2) adequate for gestational age offspring of mothers with diabetes (AGA-D); (3) macrosomic offspring (BW > 90th percentile for gestational age) of mothers without diabetes (Macro-ND); (4) macrosomic offspring of mothers with diabetes (Macro-D). Children macrosomic at birth showed significantly higher actual values of body mass index, waist circumference, and sum of skinfold thickness. In both boys and girls, Macro-ND was an independent determinant of overweight/obesity, after the adjustment for confounders [Boys: OR = 1.7 95 % CI (1.3;2.2); Girls: OR = 1.6 95 % CI (1.3;2.0)], while Macro-D showed a significant association only in girls [OR = 2.6 95 % CI (1.1;6.4)]. Fetal macrosomia, also in the absence of maternal/gestational diabetes, is independently associated with the development of overweight/obesity during childhood. Improving the understanding of fetal programming will contribute to the early prevention of childhood overweight/obesity

Sleep duration and blood pressure in children: Analysis of the pan-European IDEFICS cohort

The present study aims to examine the cross-sectional and longitudinal association between self-reported nocturnal sleep duration, blood pressure, and hypertension in European children, aged 2-9.9 years, participating in the IDEFICS project. Blood pressure (BP) and the main anthropometric indices were measured according to standardized procedures. Childhood elevated BP and hypertension were defined according to the European Society of Hypertension Guidelines for children and adolescents. Parents reported lifestyle and socio-demographic data. Nocturnal sleep duration was assessed as part of a parental 24-h recall and categorized as follows: (a) <= 9 hours/night; (b) >9 hours to <= 10 hours/night; (c) >10 hours to <= 11 hours/night; and (d) >11 hours/night. A complete set of variables included in the present analysis was provided by 7974 participants (boys/girls = 4049/3925) at the baseline survey (T0). Of them, 5656 were re-examined 2 years later at follow-up (T1). Children reporting shorter sleep duration at T0 had significantly higher BP values (P for trend < 0.001) compared to those who slept more. Prospective analyses showed that shorter sleep duration at baseline predicted, over the 2-year follow-up, higher increases in systolic blood pressure and diastolic blood pressure, after adjustment for age, sex, country of origin, BMI z-score, parental education, physical activity, screen time, and T0 value of the examined outcome variables (P for trend < 0.001). Our findings reveal that shorter sleep duration is associated with higher BP in childhood, suggesting that sleep may be a potential risk factor for hypertension later in life

Azathioprine therapy induces selective NK cell depletion and IFN-γ deficiency predisposing to herpesvirus reactivation

BACKGROUND: Azathioprine is a widely prescribed drug for patients with chronic inflammatory diseases such as myasthenia gravis or organ transplant recipients. Azathioprine exerts immunosuppressive effects by inhibiting intracellular purine synthesis and reducing the numbers of circulating B and T lymphocytes. Case reports indicate increased risk for serious infections that can occur despite regular measurements of lymphocyte counts during azathioprine therapy. OBJECTIVE: We sought to comprehensively investigate therapy-associated patient risks and the underlying immune dysfunction of azathioprine use. METHODS: Peripheral blood leukocytes were analyzed using single-cell mass and spectral flow cytometry to detect specific effects of azathioprine use on the systemic immune signature. Therapy-associated clinical features were analyzed in 2 independent cohorts of myasthenia gravis patients. RESULTS: Azathioprine therapy selectively induced pronounced CD56$^{dim}$CD16$^{+}$ natural killer cell depletion and concomitant IFN-γ deficiency. Cytokine profiling revealed a specific contraction of classical T$_{H}$1 cells during azathioprine treatment. We further observed an increased occurrence of reactivation of endogenous latent herpesviruses in the azathioprine-treated group versus in patients with myasthenia gravis who were not receiving immunomodulatory treatment; this increased occurrence was validated in an independent cohort. CONCLUSION: Our study highlights the risk of development of adverse events during azathioprine therapy and suggests that natural killer cell monitoring could be valuable in clinical practice

Embryonic and neonatal waves generate distinct populations of hepatic ILC1s

Group 1 innate lymphoid cells (ILCs) comprising circulating natural killer (cNK) cells and tissue-resident ILC1s are critical for host defense against pathogens and tumors. Despite a growing understanding of their role in homeostasis and disease, the ontogeny of group 1 ILCs remains largely unknown. Here, we used fate mapping and single-cell transcriptomics to comprehensively investigate the origin and turnover of murine group 1 ILCs. Whereas cNK cells are continuously replaced throughout life, we uncovered tissue-dependent development and turnover of ILC1s. A first wave of ILC1s emerges during embryogenesis in the liver and transiently colonizes fetal tissues. After birth, a second wave quickly replaces ILC1s in most tissues apart from the liver, where they layer with embryonic ILC1s, persist until adulthood, and undergo a specific developmental program. Whereas embryonically derived ILC1s give rise to a cytotoxic subset, the neonatal wave establishes the full spectrum of ILC1s. Our findings uncover key ontogenic features of murine group 1 ILCs and their association with cellular identities and functions

Single-cell profiling of immune system alterations in lymphoid, barrier and solid tissues in aged mice

Aging exerts profound and paradoxical effects on the immune system, at once impairing proliferation, cytotoxicity and phagocytosis, and inducing chronic inflammation. Previous studies have focused on individual tissues or cell types, while a comprehensive multisystem study of tissue-resident and circulating immune populations during aging is lacking. Here we reveal an atlas of age-related changes in the abundance and phenotype of immune cell populations across 12 mouse tissues. Using cytometry-based high parametric analysis of 37 mass-cytometry and 55 spectral flow-cytometry parameters, mapping samples from young and aged animals revealed conserved and tissue-type-specific patterns of both immune atrophy and expansion. We uncovered clear phenotypic changes in both lymphoid and myeloid lineages in aged mice, and in particular a contraction in natural killer cells and plasmacytoid dendritic cells. These changes correlated with a skewing towards myelopoiesis at the expense of early lymphocyte genesis in aged mice. Taken together, this atlas represents a comprehensive, systematic and thorough resource of the age-dependent alterations of the mammalian immune system in lymphoid, barrier and solid tissues

NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis.

Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLDassociated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A+ γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD

NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis

Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A$^{+}$ γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD