Impact of infant protein supply and other early life factors on plasma metabolome at 5.5 and 8 years of age: a randomized trial.

OBJECTIVES: A high dairy protein intake in infancy, maternal pre-pregnancy BMI, and delivery mode are documented early programming factors that modulate the later risk of obesity and other health outcomes, but the mechanisms of action are not understood. METHODS: The Childhood Obesity Project is a European multicenter, double-blind, randomized clinical trial that enrolled healthy infants. Participating infants were either breastfed (BF) or randomized to receive higher (HP) or lower protein (LP) content formula in the first year of life. At the ages 5.5 years (n = 276) and 8 years (n = 232), we determined plasma metabolites by liquid chromatography tandem-mass-spectrometry of which 226 and 185 passed quality control at 5.5 years and 8 years, respectively. We assessed the effects of infant feeding, maternal pre-pregnancy BMI, smoking in pregnancy, delivery mode, parity, birth weight and length, and weight gain (0-24 months) on the metabolome at 5.5 and 8 years. RESULTS: At 5.5 years, plasma alpha-ketoglutarate and the acylcarnitine/BCAA ratios tended to be higher in the HP than in the LP group, but no metabolite reached statistical significance (Pbonferroni>0.09). There were no group differences at 8 years. Quantification of the impact of early programming factors revealed that the intervention group explained 0.6% of metabolome variance at both time points. Except for country of residence that explained 16% and 12% at 5.5 years and 8 years, respectively, none of the other factors explained considerably more variance than expected by chance. CONCLUSIONS: Plasma metabolome was largely unaffected by feeding choice and other early programming factors and we could not prove the existence of a long term programming effect of the plasma metabolome.

Correction to: longitudinal analysis of physical activity, sedentary behaviour and anthropometric measures from ages 6 to 11 years.

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Are All Breast-fed Infants Equal? Clustering Metabolomics Data to Identify Predictive Risk Clusters for Childhood Obesity.

OBJECTIVES: Fetal and early life represent a period of developmental plasticity during which metabolic pathways are modified by environmental and nutritional cues. Little is known on the pathways underlying this multifactorial complex. We explored whether 6 months old breast-fed infants could be clustered into metabolically similar groups and that those metabotypes could be used to predict later obesity risk. METHODS: Plasma samples were obtained from 183 breast-fed infants aged 6 months participating in the European multicenter Childhood Obesity Project study. We measured amino acids along with polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, sphingomyelins). We determined the metabotypes using a Bayesian agglomerative clustering method and investigated the properties of these clusters with respect to clinical, programming, and metabolic factors up to 6 years of age. RESULTS: We identified 20 metabolite clusters comprising 1 to 39 children. Phosphatidylcholines predominantly influenced the clustering process. In the largest clusters (n ≥ 14), large differences existed for birth length (unadjusted P < 0.0001) and length and weight at 6 months (unadjusted P < 0.0001 and P = 0.012, respectively). Infants tended to cluster together by country (unadjusted P < 0.001). The body mass index (BMI) z score at 6 years of age tended to differ (unadjusted P = 0.07). CONCLUSIONS: Our exploratory study provided evidence that breast-fed infants are not metabolically homogeneous and that variation in metabolic profiles among infants may provide insight into later development and health. This work highlights the potential of metabotypes for identifying inter-individual differences that may form the basis for developing personalized early preventive strategies.

Longitudinal analysis of physical activity, sedentary behaviour and anthropometric measures from ages 6 to 11 years.

BACKGROUND/OBJECTIVES: The aim of this study was to examine the effect of physical activity (PA) and sedentary behaviour (SB) on body mass index (BMI) and fat mass index (FMI) in children over the course of five years and identify potential bi-directional associations. SUBJECTS/METHODS: Data were drawn from the EU Childhood Obesity Project (CHOP). PA and SB were measured with the SenseWear Armband 2 at the ages of 6 (T1), 8 (T2) and 11 (T3) years. Height and weight were measured and BMI was calculated at each time point, resulting in 1254 complete observations from 600 children. Bio impedance analysis was used to measure body fat mass and eventually calculate FMI. To examine the longitudinal association between PA/SB and BMI/FMI as well as to account for repeated measure on these children, mixed model analysis was employed. RESULTS: Higher levels of total PA and moderate-to-vigorous PA (MVPA) were associated with lower BMI and FMI and higher SB with higher BMI and FMI over the five year period. When looking at the age dependent effects, negative associations of MVPA (ßMVPA x age: - 0.05, 95% confidence interval (CI): - 0.09 - -0.01, p = 0.007) and positive associations of SB (ßSB x age: 0.04, 95% CI: 0.02-0.06, p < 0.001) increased with each year of age. In a model combining these two effects, only SB x age interaction remained significant (ßSB x age: 0.04, 95% CI: 0.03-0.06, p = 0.01). No significant interaction between MVPA and SB could be discerned. Light Physical activity showed no significant associations with BMI or FMI. When reversing outcome and predictor; higher BMI or FMI showed a negative association with MVPA and a positive association with SB, but no age dependency. CONCLUSIONS: More time per day in SB was associated with a higher BMI over the course of five years, whereas higher MVPA had an inverse effect. In a combined model, only effects of higher SB remained significant, emphasizing the importance of SB in obesity prevention. Present bidirectional associations, where lower body size was associated with higher PA and lower SB, indicated the need for an integrated approach of activity and weight control for obesity prevention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00338689 . Registered: June 19, 2006 (retrospectively registered).

BMI and recommended levels of physical activity in school children.

BACKGROUND: Physical activity (PA) and its health benefits are a continuous point of discussion. Recommendations for children's daily PA vary between guidelines. To better define the amount of PA necessary to prevent overweight and obesity in children, further research is needed. The present study investigates children's compliance to physical activity guidelines (PAGs) and the association between objectively measured PA and body mass index (BMI). METHODS: Participating children were 11 years old (n = 419) and part of the European CHOP trial, which was conducted in Germany, Belgium, Poland, Spain, Italy. At least 2 days of PA measurements were collected from each child using a SenseWear™ armband. BMI was calculated from children's height and weight. Thresholds of min·day-1 in PA needed to differentiate between normal and excess weight (overweight/obesity) were determined with Receiver Operator Characteristics (ROC) analysis. Additionally, adjusted linear and logistic regressions models were calculated for group differences and effects of a 5, 15 and 60 min·day-1 increases in PA on BMI. RESULTS: Median time spent in total PA was 462 min·day-1 (25th percentile; 75th percentile: 389; 534) and 75 min·day-1 (41; 115) in moderate to vigorous PA (MVPA). Girls spent 36 min·day-1 less in MVPA than boys and overweight/obese children 24 min·day-1 less than normal weight children (linear regression, p < 0.001). 63.2% of the children met PAGs of 60 min·day-1 in MVPA. The optimal threshold for min·day-1 in MVPA determined with ROC analysis was 46 min·day-1. Comparing 5, 15 and 60 min·day-1 increases in PA revealed that an additional 15 min·day-1 of vigorous PA had the same effect as 60 min·day-1 of MVPA. Sedentary time and light PA showed contrary associations to one another, with light PA being negatively and sedentary time being positively associated with excessive weight. CONCLUSIONS: Current PAGs are met by 2/3 of children and seem appropriate to prevent excess weight in children. An official recommendation of daily 15-20 min of vigorous PA and further reduction of sedentary time could help to fight youth overweight and thus be of potential public health importance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00338689 . Registered: June 19, 2006 (retrospectively registered).

Serum salicylic acid and fruit and vegetable consumption in obese and normal-weight children: a pilot-study.

Salicylic acid (SA), a phenolic compound produced by plants, may play a beneficial role on health. This pilot study evaluated whether there might be an association between serum SA and fruit and vegetable (FV) consumption in obese and normal-weight children. Thirty-four obese children (17 boys and 17 girls) and 34 normal-weight children were recruited. Dietary intake was evaluated by the 7-day dietary record. Serum SA was measured using gas chromatography-mass spectrometry method. FV intake in obese and normal-weight children was not different between groups (175.00 (97.66) g versus 192.29 (90.54) g, p = .455). Obese children had lower serum SA than normal-weight children [mean difference, -0.025; 95% CI (-0.044; -0.006) µmol/L]. Serum SA was not associated with daily intake of FV in obese (p = .111) and normal-weight (p = .092) children. Further studies are needed to evaluate the role of FV on serum SA, taking into account also the quantity and the type.

Prenatal experience with language shapes the brain.

Human infants acquire language with notable ease compared to adults, but the neural basis of their remarkable brain plasticity for language remains little understood. Applying a scaling analysis of neural oscillations to address this question, we show that newborns' electrophysiological activity exhibits increased long-range temporal correlations after stimulation with speech, particularly in the prenatally heard language, indicating the early emergence of brain specialization for the native language.

Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome.

OBJECTIVE: A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader-Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low-Dose Tetracosactrin Stimulation Test (LDTST), 1 µg] or standard-dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. DESIGN: Cross-sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. PATIENTS: Eighty-four children with PWS. MEASUREMENTS: Assessment of adrenal response by morning cortisol and ACTH dosage, and 1-µg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm; below this threshold, patients were submitted to a second test. Responses were correlated with the patients' clinical and molecular characteristics to assess genotype-phenotype correlation. RESULTS: Pathological cortisol peak responses to the LDTST were registered in 12 patients (14.3%) who had reduced basal (169.4 ± 83.3 nm) and stimulated (428.1 ± 69.6 nm) cortisol levels compared to patients with normal responses (367.1 ± 170.6 and 775.9 ± 191.3 nm, P < 0.001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0.001), and the patients' ages (P < 0.001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0.030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r(2) = 0.353, P < 0.001). Standard-dose (250 µg) tetracosactrin test confirmed CAI in 4/12 patients (4.8% of the cohort). CONCLUSIONS: Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood.

Disentangling the critical signatures of neural activity.

The critical brain hypothesis has emerged as an attractive framework to understand neuronal activity, but it is still widely debated. In this work, we analyze data from a multi-electrodes array in the rat's cortex and we find that power-law neuronal avalanches satisfying the crackling-noise relation coexist with spatial correlations that display typical features of critical systems. In order to shed a light on the underlying mechanisms at the origin of these signatures of criticality, we introduce a paradigmatic framework with a common stochastic modulation and pairwise linear interactions inferred from our data. We show that in such models power-law avalanches that satisfy the crackling-noise relation emerge as a consequence of the extrinsic modulation, whereas scale-free correlations are solely determined by internal interactions. Moreover, this disentangling is fully captured by the mutual information in the system. Finally, we show that analogous power-law avalanches are found in more realistic models of neural activity as well, suggesting that extrinsic modulation might be a broad mechanism for their generation.

Neuronal Avalanches Across the Rat Somatosensory Barrel Cortex and the Effect of Single Whisker Stimulation.

Since its first experimental signatures, the so called "critical brain hypothesis" has been extensively studied. Yet, its actual foundations remain elusive. According to a widely accepted teleological reasoning, the brain would be poised to a critical state to optimize the mapping of the noisy and ever changing real-world inputs, thus suggesting that primary sensory cortical areas should be critical. We investigated whether a single barrel column of the somatosensory cortex of the anesthetized rat displays a critical behavior. Neuronal avalanches were recorded across all cortical layers in terms of both multi-unit activities and population local field potentials, and their behavior during spontaneous activity compared to the one evoked by a controlled single whisker deflection. By applying a maximum likelihood statistical method based on timeseries undersampling to fit the avalanches distributions, we show that neuronal avalanches are power law distributed for both multi-unit activities and local field potentials during spontaneous activity, with exponents that are spread along a scaling line. Instead, after the tactile stimulus, activity switches to a transient across-layers synchronization mode that appears to dominate the cortical representation of the single sensory input.

Physical Activity and Sedentary Behavior From 6 to 11 Years.

: media-1vid110.1542/5849572910001PEDS-VA_2018-0994Video Abstract OBJECTIVES: Physical activity (PA) is presumed to decline during childhood and adolescence, but only few long-term studies about PA development during this period of life exist. We assessed PA and sedentary behavior (SB) over a 5-year period to gain a better understanding of the extent of change in activity and potential influencing factors. METHODS: PA and SB of 600 children from the Childhood Obesity Project were objectively measured with the SenseWear Armband 2 at the ages of 6, 8, and 11 years, resulting in 1254 observations. Longitudinal changes of total PA, moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), and SB were modeled with mixed-effects models. RESULTS: Total PA revealed a significant quadratic decline with age (P < .001), resulting in a change of total PA by -75.3 minutes per day from 6 to 11 years. LPA linearly declined (P < .001) by 44.6 minutes per day, MVPA quadratically declined (P < .001) by an overall 30.7 minutes, whereas SB increased significantly (+107 minutes; P = .001). Boys showed a steeper decline in LPA (P = .003) and MVPA (P < .001) than did girls. Higher fat mass index and BMI z scores were associated with lower levels of total PA and MVPA and higher levels of SB (all P < .001). CONCLUSIONS: We showed that PA decreased, and SB increased in earlier years than previously thought. MVPA remained relatively stable until 8 years, but revealed a drop-off at 11 years, identifying this period as a crucial time for intervention.

An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children.

Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10-23) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10-16), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children.

Genetic analysis of Italian patients with congenital hyperinsulinism of infancy.

BACKGROUND/AIMS: Congenital hyperinsulinism of infancy is a rare disease that needs prompt treatment to avoid brain damage. There are currently no data regarding the clinical and molecular features of Italian patients. METHODS: Thirty-three patients with HI and their parents were included. Consanguinity was reported in six patients. Half of patients were macrosomic at birth. None had raised 3-hydroxybutyrylcarnitine or hyperammonemia. Molecular analysis of ABCC8 and KCNJ11 genes was performed in all patients, and subjects with no mutation underwent analysis of HNF4A and GCK. GLUD1 and HADH genes were analyzed in a patient with leucine sensitivity. RESULTS: Mutations in the ABCC8 and KCNJ11 genes were found in 45% of the patients (6 novel). No mutations in HNF4A, GLUD1 and GCK genes were found. Recessive mode of inheritance was found in 21% of patients. A single heterozygous mutation was identified in 24% of probands. 72% of the patients were responsive to medical treatment, and 44% of the 17 patients with no identified mutation achieved spontaneous remission. Nine children, unresponsive to medical therapy, underwent pancreatectomy. CONCLUSION: This is the first report on hyperinsulinism of infancy in Italy, confirming the complexity of the clinical forms and the heterogeneity of the genetic causes of the disease.