Maternal Smoking during Pregnancy and DNA-Methylation in Children at Age 5.5 Years: Epigenome-Wide-Analysis in the European Childhood Obesity Project (CHOP)-Study.

Mounting evidence links prenatal exposure to maternal tobacco smoking with disruption of DNA methylation (DNAm) profile in the blood of infants. However, data on the postnatal stability of such DNAm signatures in childhood, as assessed by Epigenome Wide Association Studies (EWAS), are scarce. Objectives of this study were to investigate DNAm signatures associated with in utero tobacco smoke exposure beyond the 12th week of gestation in whole blood of children at age 5.5 years, to replicate previous findings in young European and American children and to assess their biological role by exploring databases and enrichment analysis. DNA methylation was measured in blood of 366 children of the multicentre European Childhood Obesity Project Study using the Illumina Infinium HM450 Beadchip (HM450K). An EWAS was conducted using linear regression of methylation values at each CpG site against in utero smoke exposure, adjusted for study characteristics, biological and technical effects. Methylation levels at five HM450K probes in MYO1G (cg12803068, cg22132788, cg19089201), CNTNAP2 (cg25949550), and FRMD4A (cg11813497) showed differential methylation that reached epigenome-wide significance according to the false-discovery-rate (FDR) criteria (q-value<0.05). Whereas cg25949550 showed decreased methylation (-2% DNAm ß-value), increased methylation was observed for the other probes (9%: cg12803068; 5%: cg22132788; 4%: cg19089201 and 4%: cg11813497) in exposed relative to non-exposed subjects. This study thus replicates previous findings in children ages 3 to 5, 7 and 17 and confirms the postnatal stability of MYO1G, CNTNAP2 and FRMD4A differential methylation. The role of this differential methylation in mediating childhood phenotypes, previously associated with maternal smoking, requires further investigation.

Leptin and Adiponectin Serum Levels from Infancy to School Age: Factors Influencing Tracking.

BACKGROUND: Early adiponectin and leptin in children correlate with those measured at a later age. Prenatal and early life factors may influence the pattern of leptin and adiponectin longitudinal changes. We aimed to identify subgroups of children with distinct trajectories of leptin and adiponectin over the first eight years of life, and to explore determinants predisposing an individual to be included in a specific trajectory class. METHODS: The analysis was based on data obtained from the EU Childhood Obesity Project (CHOP) cohort. The current study involved 459 children with adiponectin and leptin measured at 6 months, 5½ and 8 years of age. RESULTS: Three groups of leptin trajectories were identified: low-decreasing, medium-stable, and high-increasing, and two trajectory groups for adiponectin: lower and higher. The risk to be classified in the high-increasing group was higher than in the low-decreasing group for female gender (OR 10.67; 95% CI 4.94-23.05; p < 0.001); formula feeding (OR 3.34; 95% CI 1.11-10.09; p < 0.05); maternal overweight (OR 4.43; 95% CI 2.20-8.94; p < 0.001); and smoking in pregnancy (OR 4.14; 95% CI 2.07-8.29; p < 0.001). No predictors for being in the higher vs. lower adiponectin group were discovered. CONCLUSIONS: Mothers' smoking during pregnancy, maternal overweight, and formula feeding distinguished different courses of leptin trajectories; but the effect may be associated with changes in adiposity.

Prebiotic effect of an infant formula supplemented with galacto-oligosaccharides: randomized multicenter trial.

OBJECTIVE: The objective of the study was to investigate the effects of a galacto-oligosaccharides (GOS)-supplemented formula on the intestinal microbiota in healthy term infants, with a specific consideration for gastrointestinal symptoms as colic, stool frequency and consistency, regurgitation. METHODS: This was a randomized, double-blind, controlled, parallel-group clinical trial performed simultaneously by 6 centers in Italy. Three groups were considered: breastfed, formula-fed, and GOS-supplemented formula-fed infants. Formula-fed infants were randomized to receive either the control or the study formula and consume the assigned formula exclusively until the introduction of complementary feeding. The nutritional composition of the 2 formulas were identical, apart from the supplemented GOS (0.4 g/100 mL) in the study formula. Four different types of bacteria were evaluated in order to assess the efficacy of GOS-supplemented formula on infants: Bifidobacterium, Lactobacillus, and Clostridium, Escherichia coli. RESULTS: A total of 199 breastfed infants and 163 formula-fed infants were recruited. When considering stool frequency and consistency, GOS-supplemented formula presented normal and soft stools in the majority of episodes (89%). In the supplemented group the incidence of colic was lower with respect to the control group. A significantly lower count of Clostridium and a higher count of Bifidobacterium were found when comparing study formula and control formula in infants with colic. In children with colic the ratio between Clostridium count and Bifidobacterium and Lactobacillus count was in favor of the latter two when considering the GOS-supplemented formula group with respect to the control one. CONCLUSIONS: The prebiotic-supplemented formula mimicked the effect of human milk in promoting Bifidobacterium and Lactobacillus growth and in inhibiting Clostridium growth, resulting in a significantly lower presence of colic.

Epigenetic effects of human breast milk.

A current aim of nutrigenetics is to personalize nutritional practices according to genetic variations that influence the way of digestion and metabolism of nutrients introduced with the diet. Nutritional epigenetics concerns knowledge about the effects of nutrients on gene expression. Nutrition in early life or in critical periods of development, may have a role in modulating gene expression, and, therefore, have later effects on health. Human breast milk is well-known for its ability in preventing several acute and chronic diseases. Indeed, breastfed children may have lower risk of neonatal necrotizing enterocolitis, infectious diseases, and also of non-communicable diseases, such as obesity and related-disorders. Beneficial effects of human breast milk on health may be associated in part with its peculiar components, possible also via epigenetic processes. This paper discusses about presumed epigenetic effects of human breast milk and components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are still unclear. Studies have to be conducted to clarify the actual role of human breast milk on genetic expression, in particular when linked to the risk of non-communicable diseases, to potentially benefit the infant's health and his later life.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

Electrolyte abnormalities in cystic fibrosis: systematic review of the literature.

BACKGROUND: Cystic fibrosis per se can sometimes lead to hyponatremia, hypokalemia, hypochloremia or hyperbicarbonatemia. This tendency was first documented 60 years ago and has subsequently been confirmed in single case reports or small case series, most of which were retrospective. However, this issue has not been addressed analytically. We have therefore systematically reviewed and analyzed the available literature on this subject. METHODS: This was a systematic review of the literature. RESULTS: The reports included in this review cover 172 subacute and 90 chronic cases of electrolyte imbalances in patients with cystic fibrosis. The male:female ratio was 1.57. Electrolyte abnormalities were mostly associated with clinically inapparent fluid volume depletion, mainly affected patients aged ≤2.5 years, frequently tended to recur and often were found before the diagnosis of cystic fibrosis was established. Subacute presentation often included an history of heat exposure, vomiting, excessive sweating and pulmonary infection. History of chronic presentation, in contrast, was often inconspicuous. The tendency to hypochloremia, hypokalemia and metabolic alkalosis was similar between subacute and chronic patients, with hyponatremia being more pronounced (P < 0.02) in subacute compared to chronic presentations. Subacute cases were treated parenterally; chronic ones were usually managed with oral salt supplementation. Retention of urea and creatinine was documented in 38 % of subacute cases. CONCLUSIONS: The findings of our review suggest that physicians should be aware that electrolyte abnormalities can occur both as a presenting and a recurring feature of cystic fibrosis.

Benefits of breastfeeding in cystic fibrosis: a single-centre follow-up survey.

AIM: To study the effect of breastfeeding (BF) on growth, lung function and number of infections during the first 3 years of life in children with cystic fibrosis (CF). MATERIAL AND METHODS: One hundred forty-six CF patients, 5-18 years old, were recruited at their annual care visit. Information about infant feeding, psychosocial and socioeconomic conditions and smoking exposure was obtained by interviews. Anthropometric parameters at 1 year of age and the number of infections and hospitalisations during the first 3 years of life were obtained from clinical charts. Anthropometrics and pulmonary function parameters were obtained at enrollment. RESULTS: In CF patients, particularly those with pancreatic insufficiency, the prevalence of BF was lower than the general Italian population. After multivariate analysis patients with prolonged BF showed higher values of CED expiratory volume in 1 sec (FEV-1) (p = 0.001) and a lower number of infections during the first 3 years of life (p = 0.098). CONCLUSION: Prolonged BF is beneficial in children with CF and may protect them against decline of pulmonary function. Particular attention should be paid to promote BF in infants with CF.

Dietary and circulating polyunsaturated fatty acids in cystic fibrosis: are they related to clinical outcomes?

OBJECTIVE: To assess the relationship between dietary intakes, plasma phospholipid (PL) fatty acid profile and clinical parameters in children with cystic fibrosis (CF) in comparison to healthy controls. PATIENTS AND METHODS: A cross-sectional survey including 37 patients with CF (ages 8.0 +/- 2.9 yrs) and a reference group of 68 healthy children (ages 8.0 +/- 0.7 yrs) was carried out by means of a food-frequency questionnaire. At enrollment, all subjects underwent blood sampling for plasma PL fatty acids (FA). In CF patients, pulmonary function tests (forced expiratory volume in 1 second and forced vital capacity), anthropometric measurements and the Shwachman score were also determined. RESULTS: In CF patients, mean z score for weight and height (-0.35 +/- 1.16 and -0.28 +/- 0.99) were lower than controls (0.83 +/- 1.73 and 0.55 +/- 1.11, respectively). Patients with CF showed higher energy intakes (110 +/- 43 kcal/d) compared with controls (75 +/- 22 kcal/d; P < 0.0001), with higher intake of total (saturated and monounsaturated) fats and lower intake of polyunsaturated FA (3.9 +/- 1.0% of total macronutrient intake vs 4.3 +/- 1.2%, P = 0.05). In CF patients, plasma and PL levels of linoleic and docosahexaenoic acids were lower, whereas those of arachidonic acid were similar compared with controls. The Shwachman score showed significant positive associations with plasma PL levels of arachidonic acid and total n-6 long-chain FA (r = 0.32, P = 0.05, and r = 0.35, P = 0.03, respectively). CONCLUSIONS: The data give suggestions that fat intake and CF-associated biomechanisms are bound in a vicious circle, concurring to create the clinical and biochemical picture of CF. The quantity and quality of fat supplementation in CF need careful attention to balance the fat supply with polyunsaturated FA.

Double-blind, placebo-controlled trial comparing effects of supplementation with two different combinations of micronutrients delivered as sprinkles on growth, anemia, and iron deficiency in cambodian infants.

OBJECTIVES: To assess and compare efficacy of two micronutrient sprinkle supplementation on growth, anemia, and iron deficiency in Cambodian infants. METHODS: A total of 204 infants aged 6 months and living in Kompong Chhnang Province, Cambodia were randomly assigned to receive daily supplements of either iron (12.5 mg) plus folic acid (150 mug) plus zinc (5 mg) (MMN, n = 68), or iron (12.5 mg) plus folic acid (150 microg) alone (FFA, n = 68), or placebo (n = 68) for a 12 month period in powder form as sprinkles. Anthropometrics was evaluated bimonthly. Biochemical assessment was performed at baseline and at the end of intervention period. RESULTS: At baseline, the overall mean (SD) of hemoglobin concentration was 101 g/L. No difference among groups was found for growth pattern. Significant decline was observed for weight-for-age and height-for-age z-scores in any group (P < 0.0001). The rate of recovery from anemia was significant (P < 0.001) and comparable between MMN (54%) and FFA (53%) groups and higher than in the placebo group (22%, P < 0.0001). Through the study period, no significant change in the rate of iron deficiency was found in MMN and FFA groups, whereas it increased in the placebo group (31%, baseline vs. 52%, end of study; P < 0.0001). CONCLUSION: Both MMN and FFA supplements were effective for preventing or treating anemia in Cambodian infants and stabilizing plasma levels of ferritin. Use of micronutrients in a controlled home setting, as sprinkled daily supplements, may be promising in preventing and treating anemia in developing countries.

Reduced docosahexaenoic acid synthesis may contribute to growth restriction in infants born to mothers who smoke.

In newborn infants, progressive decrease in anthropometric values and impairment of the docosahexaenoic acid (DHA) status was associated with maternal smoking during pregnancy, with a parallel increase of the metabolic precursor of DHA, alpha-linolenic acid. Maternal smoking may impair DHA synthesis which may contribute to reduced fetal growth.

Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature.

UNLABELLED: We studied the genotype/phenotype correlation in a cohort of glycogen storage disease type (GSD) 1b patients. A total of 25 GSD1b patients, 13 females and 12 males, age range: 4.3-28.4 years, mean:14.6+/-6.8 years; median: 15 years, representing the entire case load of Italian GSD1b patients, were enrolled in the study. Molecular analysis of the glucose 6-phosphate translocase (G6PT1) gene was performed in all patients. We analysed the presence of a correlation among both the clinical features associated with GSD1b (neutropenia, frequency of admission to the hospital for severe infections) and the presence of systemic complications (liver adenomas, nephropathy, bone mineral density defect, polycystic ovaries, short stature, inflammatory bowel disease) and the mutations detected in each patient. Nine patients were homozygous or compound heterozygous for mutations causing stop codons. In particular, three patients were homozygous for the same mutation (400X); of these patients, one showed chronic neutropenia with severe and frequent infections and severe inflammatory bowel disease, another patient cyclic neutropenia associated with rare bacterial infections and mild bowel involvement and the last one normal neutrophil count. Two patients were homozygous for the mutation 128X; one of these patients did not show neutropenia, whereas the other one had severe neutropenia needing frequent hospital admission and was under granulocyte-colony stimulating factor treatment. In three patients no mutations were detected. CONCLUSION: No correlation was found between individual mutations and the presence of neutropenia, bacterial infections and systemic complications. These results suggest that different genes and proteins modulate neutrophil differentiation, maturation and apoptosis and thus the severity and frequency of infections. The absence of detectable mutations in three patients could suggest that a second protein plays a role in microsomal phosphate transport.