Gene-environment interaction in the association of residential greenness and 25(OH) vitamin D.

There is increasing awareness for beneficial health effects of green space surrounding the home, but the underlying mechanisms are not yet fully understood and challenging to study given the correlation with other exposures. Here, the association of residential greenness and vitamin D including a gene-environment interaction is investigated. 25-hydroxyvitamin D (25(OH)D) was measured by electrochemiluminescence at ages 10 and 15 years in participants of two German birth cohorts GINIplus and LISA. Greenness was measured using the Landsat-derived Normalized Difference Vegetation Index (NDVI) in a 500 m buffer surrounding the home. Linear and logistic regression models were applied at both time points adjusted for several covariates (N10Y = 2,504, N15Y = 2,613). In additional analyses vitamin D-related genes, physical activity, time spent outdoors, supplements, and measurement season were investigated as potential confounders or effect modifiers. A 1.5-SD increase in NDVI was significantly associated with increased 25(OH)D values at ages 10 and 15 years (ß10y = 2.41 nmol/l, p=<0.01; ß15y = 2.03 nmol/l, p = 0.02). In stratified analyses, the associations were not seen in participants spending more than 5 h/day outside in summer, having a high physical activity level, taking supplements, or being examined during the winter season. In a subset (n = 1,732) with genetic data, a significant gene-environment interaction of NDVI with CYP2R1, an upstream gene in 25(OH)D synthesis, was observed at age 10 years. When investigating 25(OH)D sufficiency, defined as values above 50 nmol/l, a 1.5-SD increase in NDVI was associated with significantly higher odds of having sufficient 25 (OH)D levels at age 10 years (OR = 1.48, 1.19-1.83). In conclusion, robust associations between residential greenness and 25 (OH)D levels were observed in children and adolescents independent of other confounders and additionally supported by the presence of a gene-environment interaction. Effects of NDVI were stronger in those having lower vitamin D levels at age 10 years due to their covariate profile or genetically lower 25(OH)D synthesis.

Partially Hydrolysed Whey-Based Infant Formula Improves Skin Barrier Function.

Specific partially hydrolysed whey-based infant formulas (pHF-W) have been shown to decrease the risk of atopic dermatitis (AD) in infants. Historically, AD has been associated primarily with milk allergy; however, defective skin barrier function can be a primary cause of AD. We aimed to ascertain whether oral supplementation with pHF-W can improve skin barrier function. The effect of pHF-W was assessed on transepidermal water loss (TEWL) and antibody productions in mice epicutaneously exposed to Aspergillus fumigatus. Human primary keratinocytes were stimulated in vitro, and the expression of genes related to skin barrier function was measured. Supplementation with pHF-W in neonatal mice led to a significant decrease in TEWL and total IgE, but not in allergen-specific antibody levels. The whey hydrolysate was sufficient to decrease both TEWL and total IgE. Aquaporin-3 gene expression, linked with skin hydration, was modulated in the skin of mice and human primary keratinocytes following protein hydrolysate exposure. Skin barrier improvement may be an additional mechanism by which pHF-W may potentially reduce the risk of AD development in infants. Further human studies are warranted to confirm the clinical efficacy of these observations.

Association of early life and acute pollen exposure with lung function and exhaled nitric oxide (FeNO). A prospective study up to adolescence in the GINIplus and LISA cohort.

BACKGROUND: Pollen exposure has both acute and chronic detrimental effects on allergic asthma, but little is known about its wider effects on respiratory health. This is increasingly important knowledge as ambient pollen levels are changing with the changing global climate. OBJECTIVE: To assess associations of pollen exposure with lung function and fractional exhaled nitric oxide (FeNO) at age 15 in two prospective German birth cohorts, GINIplus and LISA. METHODS: Background city-specific pollen exposure was measured in infancy (during the first three months of life), and contemporary (on the day of and 7 days prior to lung function measurement). Greenness levels within circular buffers (100-3000 m) around the birth and 15-year home addresses were calculated using the satellite-derived Normalized Difference Vegetation Index. Regression models were used to assess the associations of grass and birch pollen with lung function and FeNO, and the modifying effects of residential greenness were explored. RESULTS: Cumulative early life exposure to grass pollen was associated with reduced lung function in adolescence (FEV1: -4.9 mL 95%CI: -9.2, -0.6 and FVC: -5.2 mL 95%CI: -9.8, -0.5 per doubling of pollen count). Acute grass pollen exposure was associated with increased airway inflammation in all children, with higher FeNO increases in children living in green areas. In contrast acute birch pollen exposure was associated with reduced lung function only in children sensitised to birch allergens. CONCLUSION: This study provides suggestive evidence that early pollen exposure has a negative effect on later lung function, which is in turn influenced by acute pollen exposures.

Differences in Outcomes Over Time With Exclusive Enteral Nutrition Compared With Steroids in Children With Mild to Moderate Crohn's Disease: Results From the GROWTH CD Study.

BACKGROUND: Exclusive enteral nutrition [EEN] and corticosteroids [CS] induce similar rates of remission in mild to moderate paediatric Crohn's disease [CD], but differ with regard to mucosal healing. Our goal was to evaluate if EEN at diagnosis was superior to CS for improving long-term outcomes. METHODS: We prospectively followed newly diagnosed children aged < 17 years, with mild to moderate CD at baseline, for 2 years in the GROWTH CD study. Patients were evaluated at baseline and at 8, 12, 78, and 104 weeks. Remission, relapses, complications [fibrostenotic disease, penetrating disease, and active perianal disease] and growth were recorded throughout the study. A propensity score analysis was performed. RESULTS: A total of 147 children [mean age 12.9 ± 3.2 years], treated by EEN [n = 60] or CS [n = 87] were included. New complications developed in 13.7% of CS [12/87] versus 11.6% of EEN [7/60], p = 0.29. Remission was achieved in 41/87 [47%] in CS and 38/60 [63%] EEN, p = 0.036. Median time to relapse did not differ [14.4 ± 1 months with CS, 16.05 ± 1.1 EEN, p = 0.28]. Mean height Z scores decreased from Week 0 to Week 78 with CS [-0.34 ± 1.1 to -0.51 ± 1.2, p = 0.01], but not with EEN [-0.32 ± 1.1 to -0.22 ± 0.9, p = 0.56]. In a propensity score analysis, EEN was superior to CS for inducing remission [p = 0.05] and trended to superiority for height Z score [p = 0.055]. CONCLUSIONS: Use of EEN was associated with higher remission rates and a trend toward better growth but with similar relapse and complication rates in new-onset mild to moderate paediatric CD.

Urban upbringing and childhood respiratory and allergic conditions: A multi-country holistic study.

OBJECTIVE: We integratively assessed the effect of different indoor and outdoor environmental exposures early in life on respiratory and allergic health conditions among children from (sub-) urban areas. METHODS: This study included children participating in four ongoing European birth cohorts located in three different geographical regions: INMA (Spain), LISAplus (Germany), GINIplus (Germany) and BAMSE (Sweden). Wheezing, bronchitis, asthma and allergic rhinitis throughout childhood were assessed using parental-completed questionnaires. We designed "environmental scores" corresponding to different indoor, green- and grey-related exposures (main analysis, a-priori-approach). Cohort-specific associations between these environmental scores and the respiratory health outcomes were assessed using random-effects meta-analyses. In addition, a factor analysis was performed based on the same exposure information used to develop the environmental scores (confirmatory analysis, data-driven-approach). RESULTS: A higher early exposure to the indoor environmental score increased the risk for wheezing and bronchitis within the first year of life (combined adjusted odds ratio: 1.20 [95% confidence interval: 1.13-1.27] and 1.28 [1.18-1.39], respectively). In contrast, there was an inverse association with allergic rhinitis between 6 and 8 years (0.85 [0.79-0.92]). There were no statistically significant associations for the outdoor related environmental scores in relation to any of the health outcomes tested. The factor analysis conducted confirmed these trends. CONCLUSION: Although a higher exposure to indoor related exposure through occupants was associated with an increased risk for wheezing and bronchitis within the 1st year, it might serve as a preventive mechanism against later childhood allergic respiratory outcomes in urbanized environments through enhanced shared contact with microbial agents.

Surgical Management of Crohn Disease in Children: Guidelines From the Paediatric IBD Porto Group of ESPGHAN.

The incidence of Crohn disease (CD) has been increasing and surgery needs to be contemplated in a substantial number of cases. The relevant advent of biological treatment has changed but not eliminated the need for surgery in many patients. Despite previous publications on the indications for surgery in CD, there was a need for a comprehensive review of existing evidence on the role of elective surgery and options in pediatric patients affected with CD. We present an expert opinion and critical review of the literature to provide evidence-based guidance to manage these patients. Indications, surgical options, risk factors, and medications in pre- and perioperative period are reviewed in the light of available evidence. Risks and benefits of surgical options are addressed. An algorithm is proposed for the management of postsurgery monitoring, timing for follow-up endoscopy, and treatment options.

Timing and diversity of complementary food introduction for prevention of allergic diseases. How early and how much?

The timing of the introduction of complementary foods appears crucial to the development of allergic diseases later in life. The results from recent observational studies might be misinterpreted to suggest that introducing complementary food prior to the age of four months might have a beneficial effect on the induction of immune tolerance. Since these two recently published papers cannot completely account for reverse causation, as is the case for all observational studies, we recommend that the current ESPGHAN and American Academy of Pediatrics recommendations be maintained as long as new evidence from large randomized controlled intervention trials do not suggest otherwise. That is, complementary foods should be first introduced between the age of 17 to 26 weeks.

Influence of exclusive enteral nutrition therapy on bone density and geometry in newly diagnosed pediatric Crohn's disease patients.

BACKGROUND AND AIMS: Exclusive enteral nutrition (EEN) induces remission in patients with Crohn's disease (CD). We investigated the short-term impact of EEN on bone quality and muscle mass in children with CD. METHODS: Ten newly diagnosed CD patients (7 male, 10.6-17.7 years of age) were assessed by peripheral quantitative computed tomography (pQCT) at the forearm before starting an 8-weeks treatment with EEN, and after 12 and 52 weeks. No steroids or biologicals were applied. Trabecular and cortical bone mineral density, total bone, and muscle cross-sectional area (CSA) were measured by pQCT and expressed as age- and sex-specific z-scores; size-dependent CSAs were corrected for low height for age. Wilcoxon rank sum test was applied. RESULTS: Remission at week 12 was achieved in 8 patients; 2 still had mild disease. Initially low trabecular density z-scores improved (+0.3; p = 0.006) at week 12; simultaneously, the increased cortical density z-scores normalized (-0.4; p = 0.027). The low z-score for muscle CSA corrected for height (median -2.5, range -3.49 to -0.97) increased within 12 weeks (+1.0; p = 0.002) with no further improvement thereafter. CONCLUSIONS: The results indicate disturbed bone remodeling and severely impaired muscle mass in newly diagnosed CD children. Bone metabolism and muscle mass improved within 3 months after starting EEN with no further normalization thereafter.

Utilization and costs of conventional and alternative pharmaceuticals in children: results from the German GINIplus and LISAplus birth cohort studies.

PURPOSE: The socioeconomic determinants for drug utilization, especially in children, have not been investigated sufficiently so far. The study's aim was the estimation of prevalences and determinants of conventional, homeopathic and phytotherapeutic drugs and expenditures. METHODS: Population-based data on drug utilization of 3,642 children in two German birth cohorts (GINIplus and LISAplus, 10-year follow-up) were collected using a self-administered questionnaire. For analysis, the reported drugs (use within the last four weeks) were classified into the therapeutic categories of 'conventional medicine', 'homeopathy', 'phytotherapy' and 'others'. Drug costs were estimated using pharmaceutical identification numbers. RESULTS: In all, 42.3% of the children reported drug use; 24.1% of the drugs were homeopathic and 11.5% were phytotherapeutic. The proportion of children who took at least one homeopathic remedy was 14.3%. Drugs prescribed by physicians were dominated by conventional medicine (76.5%), whereas in non-prescribed drugs, both homeopathy and conventional medicine accounted for 37% each. Boys (OR = 0.78) used less homeopathy than girls. Income showed only a weak influence. Education had a strong effect on the use of phytotherapy such that children of mothers with higher school education (>10 years vs. <10 years) used more phytotherapy (OR = 2.01). If out-of-pocket payments arose (n = 613), the mean was €20. On average, total drug expenditures summed up to €39 in 4 weeks for drug users if only clearly identifiable prices for drugs were considered (58% of all data). CONCLUSIONS: Utilization of homeopathy is common in children from the analyzed cohort. User profiles of homeopathy and phytotherapy differ from each other and should be analyzed separately.

Early diet and the risk of allergy: what can we learn from the prospective birth cohort studies GINIplus and LISAplus?

Recently, the American Academy of Pediatrics and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published new guidelines on early nutrition and allergy prevention in infants and children. This article reviews epidemiologic evidence from 2 prospective German birth cohort studies, the GINIplus and the LISAplus, regarding maternal diet during pregnancy and feeding patterns in early life and the risk of allergy in light of the new recommendations. The 2 cohorts include a total of 9088 infants who were recruited within different regions of Germany between 1995 and 1999. A subgroup of 2252 infants with a hereditary risk of atopy was enrolled in a double-blind, randomized trial to investigate the effect of feeding regimen in infancy on the development of allergy with the strict recommendation that allergenic solid food be introduced late in the study. The results of the GINIplus and LISAplus studies mainly support the new finding regarding allergy prevention that a delayed introduction of solid foods or the avoidance of highly allergenic foods during the first year does not seem to be beneficial for allergy prevention. A very early introduction of solid foods and a high diversity before week 17 of age may increase the risk of later allergy. We showed that a high intake of margarine, vegetable oils, and some allergenic fruit and vegetables during pregnancy was associated with an increased risk of allergies, especially eczema. Because maternal diet during pregnancy is not reflected in the current recommendations, it should be the focus of future studies.

Regional and socio-economic differences in food, nutrient and supplement intake in school-age children in Germany: results from the GINIplus and the LISAplus studies.

OBJECTIVE: To describe regional differences between eastern and western Germany with regard to food, nutrient and supplement intake in 9-12-year-old children, and analyse its association with parental education and equivalent income. DESIGN: Data were obtained from the 10-year follow-up of the two prospective birth cohort studies - GINIplus and LISAplus. Data on food consumption and supplement intake were collected using an FFQ, which had been designed for the specific study population. Information on parental educational level and equivalent income was derived from questionnaires. Logistic regression modelling was used to analyse the effect of parental education, equivalent income and region on food intake, after adjusting for potential confounders. SETTING: Germany. SUBJECTS: A total of 3435 children aged 9-12 years. RESULTS: Substantial regional differences in food intake were observed between eastern and western Germany. Intakes of bread, butter, eggs, pasta, vegetables/salad and fruit showed a significant direct relationship with the level of parental education after adjusting for potential confounders, whereas intakes of margarine, meat products, pizza, desserts and soft drinks were inversely associated with parental education. Equivalent income had a weaker influence on the child's food intake. CONCLUSIONS: Nutritional education programmes for school-age children should therefore account for regional differences and parental education.

Growth of infants fed formula rich in canola oil (low erucic acid rapeseed oil).

BACKGROUND & AIMS: Canola oil is a variety of rapeseed oil low in erucic acid (<2%). For many years, canola oil has been widely used as an ingredient in infant formula in Europe, but not in North America due to safety concerns. A number of studies have used variable canola content of infant formulas to investigate the effects of linoleic acid: α-linolenic acid ratio on visual function of infants. However, little published data is available to compare the safety of canola versus non-canola containing infant formula. The aim of this study is to investigate whether infant formulas containing canola oil support normal growth in infants as assessed by weight and length gain. METHODS: Re-analyses of data on infant weight and length gain from a prospective randomized double-blind trial in full-term infants in the German Infant Nutritional Intervention study (GINI). This analysis compared growth in infants receiving infant formulas with or without canola oil from week 4 to month 7. Absolute weight and length, weight and length gain in gram or cm per day and standardized weight and length measurements were analyzed by analyses of variance and a longitudinal random effects model. Standardization was conducted according to the new WHO 2006 age- and sex-specific child growth standards. RESULTS: Absolute and standardized weight and length measures did not differ between the formula groups with or without canola oil. This was true for both, analyses within each of the three anthropometric measurement periods (4-6 weeks, 3-4 months, 6-7 months) and for the longitudinal analyses over the whole period from 4 weeks to 7 months of life. Power analyses confirmed that sample size was sufficient to detect a difference of 3 g per day between 14 and 120 days between the two formula groups. CONCLUSIONS: Infant formula containing canola oil supports normal infant growth as assessed by weight and length gain.

Esomeprazole-based 1-week triple therapy directed by susceptibility testing for eradication of Helicobacter pylori infection in children.

BACKGROUND: Poor compliance to therapy and antibiotic resistance are the main causes for failure of anti-Helicobacter pylori therapy. OBJECTIVE: To evaluate the effectiveness of esomeprazole-based triple therapy directed by susceptibility testing. METHODS: Symptomatic children with H. pylori infection, who underwent successful susceptibility testing and were colonized by no double-resistant strain, received 1-week triple therapy with esomeprazole, amoxicillin and either clarithromycin or metronidazole. Success of eradication was investigated by C-urea breath test. RESULTS: Fifty-eight children (median age, 11.4 years; range, 2.2-17.7 years; 81% immigrants) were included. Helicobacter pylori was resistant to clarithromycin in 5 (9%) and to metronidazole in 9 children (16%). Eradication was successful in 49 (92%) of 53 children receiving esomeprazole, amoxicillin and clarithromycin and in all 5 children treated with metronidazole instead of clarithromycin, resulting in an eradication rate of 93% (95% confidence interval, 83%-98%, intention-to-treat analysis). All 4 treatment failures occurred in immigrants with language problems; 2 of them were obviously noncompliant. CONCLUSION: Esomeprazole-based 1-week triple therapy directed by susceptibility testing is highly effective for eradication of H. pylori infection in children.