Analysis of DNA methylation at birth and in childhood reveals changes associated with season of birth and latitude.

BACKGROUND: Seasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear. METHODS: We carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points. RESULTS: We identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N). CONCLUSIONS: In this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Meta-analysis of epigenome-wide association studies in newborns and children show widespread sex differences in blood DNA methylation.

BACKGROUND: Among children, sex-specific differences in disease prevalence, age of onset, and susceptibility have been observed in health conditions including asthma, immune response, metabolic health, some pediatric and adult cancers, and psychiatric disorders. Epigenetic modifications such as DNA methylation may play a role in the sexual differences observed in diseases and other physiological traits. METHODS: We performed a meta-analysis of the association of sex and cord blood DNA methylation at over 450,000 CpG sites in 8438 newborns from 17 cohorts participating in the Pregnancy And Childhood Epigenetics (PACE) Consortium. We also examined associations of child sex with DNA methylation in older children ages 5.5-10 years from 8 cohorts (n = 4268). RESULTS: In newborn blood, sex was associated at Bonferroni level significance with differences in DNA methylation at 46,979 autosomal CpG sites (p < 1.3 × 10-7) after adjusting for white blood cell proportions and batch. Most of those sites had lower methylation levels in males than in females. Of the differentially methylated CpG sites identified in newborn blood, 68% (31,727) met look-up level significance (p < 1.1 × 10-6) in older children and had methylation differences in the same direction. CONCLUSIONS: This is a large-scale meta-analysis examining sex differences in DNA methylation in newborns and older children. Expanding upon previous studies, we replicated previous findings and identified additional autosomal sites with sex-specific differences in DNA methylation. Differentially methylated sites were enriched in genes involved in cancer, psychiatric disorders, and cardiovascular phenotypes.

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.

Body mass index trajectory classes and incident asthma in childhood: results from 8 European Birth Cohorts--a Global Allergy and Asthma European Network initiative.

BACKGROUND: The causal link between body mass index (BMI) or obesity and asthma in children is still being debated. Analyses of large longitudinal studies with a sufficient number of incident cases and in which the time-dependent processes of both excess weight and asthma development can be validly analyzed are lacking. OBJECTIVE: We sought to investigate whether the course of BMI predicts incident asthma in childhood. METHODS: Data from 12,050 subjects of 8 European birth cohorts on asthma and allergies were combined. BMI and doctor-diagnosed asthma were modeled during the first 6 years of life with latent growth mixture modeling and discrete time hazard models. Subpopulations of children were identified with similar standardized BMI trajectories according to age- and sex-specific "World Health Organization (WHO) child growth standards" and "WHO growth standards for school aged children and adolescents" for children up to age 5 years and older than 5 years, respectively (BMI-SDS). These types of growth profiles were analyzed as predictors for incident asthma. RESULTS: Children with a rapid BMI-SDS gain in the first 2 years of life had a higher risk for incident asthma up to age 6 years than children with a less pronounced weight gain slope in early childhood. The hazard ratio was 1.3 (95% CI, 1.1-1.5) after adjustment for birth weight, weight-for-length at birth, gestational age, sex, maternal smoking in pregnancy, breast-feeding, and family history of asthma or allergies. A rapid BMI gain at 2 to 6 years of age in addition to rapid gain in the first 2 years of life did not significantly enhance the risk of asthma. CONCLUSION: Rapid growth in BMI during the first 2 years of life increases the risk of asthma up to age 6 years.

Long-term exposure to NO2 and PM10 and all-cause and cause-specific mortality in a prospective cohort of women.

We assessed whether long-term exposure to air pollution is associated with all-cause and cause-specific mortality during a period of declining particulate matter concentrations. Approximately 4800 women aged 55 years from North Rhine-Westphalia, Germany, were followed for up to 18 years. Exposure to air pollution was assessed in two ways: (1) using the distance between the residential address and the nearest major road, as calculated from Geographic Information System data and (2) calculating 1-year average particulate matter concentrations below 10 µm (PM(10)) and nitrogen dioxide (NO(2)) levels using data from the nearest air-monitoring station data to the subjects' residences. Ninety-two per cent of all subjects lived in the same community during the entire follow-up period. Associations between mortality and exposure were assessed using Cox's proportional hazards models, including confounder adjustment. Sixteen per cent of women passed away during the follow-up period. An increase of 7 µg/m(3) PM(10) (IQR) was associated with an increased HR for all-cause (HR 1.15, 95% CI (1.04 to 1.27)), cardiopulmonary (HR 1.39, 95% CI (1.17 to 1.64)), and lung cancer mortality (HR 1.84, 95% CI (1.23 to 2.74)). An increase of 16 µg/m(3) (IQR) NO(2) exposure was associated with all-cause (HR 1.18, 95% CI (1.07 to 1.30)) and cardiopulmonary mortality (HR 1.55, 95% CI (1.30 to 1.84)). The association between cardiopulmonary mortality and PM(10) was reduced for the extended follow-up period, during which PM(10) concentrations (but not NO(2) concentrations) were lower. Living close to a major road was associated with an increased relative risk for all-cause, cardiopulmonary and respiratory mortality. These associations were temporally stable. Long-term exposure to ambient PM(10) and NO(2) was associated with increased mortality rates.

Gestational weight gain and body mass index in children: results from three german cohort studies.

INTRODUCTION: Previous studies suggested potential priming effects of gestational weight gain (GWG) on offspring's body composition in later life. However, consistency of these effects in normal weight, overweight and obese mothers is less clear. METHODS: We combined the individual data of three German cohorts and assessed associations of total and excessive GWG (as defined by criteria of the Institute of Medicine) with offspring's mean body mass index (BMI) standard deviation scores (SDS) and overweight at the age of 5-6 years (total: n = 6,254). Quantile regression was used to examine potentially different effects on different parts of the BMI SDS distribution. All models were adjusted for birth weight, maternal age and maternal smoking during pregnancy and stratified by maternal pre-pregnancy weight status. RESULTS: In adjusted models, positive associations of total and excessive GWG with mean BMI SDS and overweight were observed only in children of non- overweight mothers. For example, excessive GWG was associated with a mean increase of 0.08 (95% CI: 0.01, 0.15) units of BMI SDS (0.13 (0.02, 0.24) kg/m(2) of 'real' BMI) in children of normal-weight mothers. The effects of total and excessive GWG on BMI SDS increased for higher- BMI children of normal-weight mothers. DISCUSSION: Increased GWG is likely to be associated with overweight in offspring of non-overweight mothers.

Temporal changes in total serum immunoglobulin E levels in East German children and the effect of potential predictors.

BACKGROUND: Elevated total serum immunoglobulin E (IgE) levels are a prominent feature of allergic and parasitic diseases. An epidemiologic study was conducted in East German children to describe trends in the development of total serum IgE levels and analyze the impact of potential determinants. METHODS: The study consisted of three cross-sectional surveys in 1992-1993, 1995-1996 and 1998-1999 and was conducted in three areas of the former German Democratic Republic. In total, 8,051 questionnaires were completed by the parents of children aged 5-14 years, supplying information on allergic symptoms and potential risk factors. A total of 5,918 measurements of total serum IgE and specific IgE to 5 common aeroallergens were available from 4,353 schoolchildren. Generalized estimating equations were applied to data from all children and stratified for atopic and nonatopic children to identify trends and estimate the effect of potential determinants on total IgE. RESULTS: Total serum IgE levels decreased significantly with a linear trend in East German schoolchildren between 1992 and 1999, the effect being stronger in nonatopic children. The following factors were associated with lower total serum IgE levels: female gender, living in a household with fewer than 4 people, no history of helminth infestation, younger age group (5-7 years), no parental allergy and high socioeconomic status. No association was seen for 'smoking at home' and close contact to pets. CONCLUSION: Total serum IgE declined parallel to helminth infestation; however, the latter explained the decrease only in part. Furthermore, total IgE developed in an opposite direction to specific IgE, indicating that it has determinants other than allergic sensitization.

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.

Childhood onset inflammatory bowel disease: predictors of delayed diagnosis from the CEDATA German-language pediatric inflammatory bowel disease registry.

OBJECTIVES: To examine predictors of delayed diagnosis of inflammatory bowel disease in children and adolescents. STUDY DESIGN: A total of 2,436 patients (age 0-18 years) with Crohn's disease, ulcerative colitis, or unclassified colitis were included from 53 pediatric gastroenterologists. Predictors were examined with the proportional hazards model, presented as hazard ratios (HR) with 95% confidence intervals. HR < 1.0 represent factors associated with late diagnosis. RESULTS: Median time to diagnosis was 4 (2-8) months. Crohn's disease (HR 0.62; 0.56-0.68), and within Crohn's disease, ileal disease (HR 0.77, 95% confidence interval 0.67 to 0.89) were associated with delayed diagnosis. Chances for early diagnosis increased with increasing age (HR 1.07 per year of age; 1.06 to 1.08). There was also an effect by center (HR 0.63, 0.52 to 0.67), but not by sex or country (Austria vs Germany). Growth failure was more common in those cases with delayed diagnosis. CONCLUSIONS: There is still concern about delays in the diagnosis of inflammatory bowel disease in the very young and in children with small bowel disease. Inequalities of care by region require further investigation.

Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups.

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.

Prenatal and postnatal tobacco exposure and behavioral problems in 10-year-old children: results from the GINI-plus prospective birth cohort study.

BACKGROUND: Prenatal and postnatal tobacco exposure have been reported to be associated with behavioral problems. However, the magnitude of the association with tobacco exposure at specific periods of exposure is unclear. OBJECTIVE: We assessed the relative risk of behavioral problems in children who had been exposed to tobacco smoke in utero and postnatally. METHODS: We analyzed data from a prospective birth cohort study in two cities in Germany: the German Infant Nutrition Intervention. Our sample included 5,991 children born between 1995 and 1998 as well as their parents. We measured behavioral problems using the Strength and Difficulties Questionnaire (SDQ) at follow-up 10 years after birth. According to prespecified SDQ cutoff values, children were classified as "normal," "borderline," or "abnormal" according to the subscales "emotional symptoms," "conduct problems," "hyperactivity/inattention," "peer-relationship problems," and a total difficulties score. Smoke exposure and further covariates were assessed using parent questionnaires. RESULTS: Compared with children not exposed to tobacco smoke, children exposed both pre- and postnatally to tobacco smoke had twice the estimated risk [95% confidence interval (CI), 1.4-3.1] of being classified as abnormal according to the total difficulties score of the SDQ at 10 years of age. Children who were only prenatally exposed had a 90% higher relative risk (95% CI, 0.9-4.0), whereas children who were only postnatally exposed had a 30% higher relative risk (95% CI, 0.9-1.9). These results could not be explained by confounding by parental education, father's employment, child's time spent in front of computer or television screen, being a single father or mother, or mother's age. CONCLUSIONS: Prenatal exposure to tobacco smoke is associated with behavioral problems in school-age children. Although our findings do not preclude the influence of postnatal exposure, prenatal exposure seems to be more important.

A new FFQ designed to measure the intake of fatty acids and antioxidants in children.

OBJECTIVE: The present paper describes the systematic development of an FFQ to assess the intake of fatty acids and antioxidants in school-aged children. In addition, a validation study applying 24 h dietary recalls was performed. DESIGN: Using the variance-based Max_r method, a list of eighty-two foods was compiled from data obtained by 3 d weighed dietary records. The foods were used to design an FFQ, the comprehensibility of which was evaluated in a feasibility study. In addition, the FFQ was validated in a subset of 101 children from the German Infant Nutritional Intervention Study (GINI PLUS) against one 24 h dietary recall. RESULTS: The feasibility study attested a good acceptance of the FFQ. Mean intake of foods compared well between the FFQ and the 24 h dietary recall, although intake data generated from the FFQ tended to be higher. This difference became less apparent at the nutrient level, although the estimated average consumption of arachidonic acid and EPA using the FFQ still exceeded values recorded with the 24 h recall method by 45 % and 29 %, respectively. CONCLUSIONS: On the basis of the systematic selection process of the food list, the established practicability of the FFQ and the overall plausibility of the results, the use of this FFQ is justified in future epidemiological studies.

Period-specific growth, overweight and modification by breastfeeding in the GINI and LISA birth cohorts up to age 6 years.

Children's weight/growth development is age-specific and may be influenced by breastfeeding. We therefore assessed velocities of weight, length, body-mass-index and overweight/obesity development from birth up to age 6 years overall and in relation to breastfeeding. The method of this study is based on pooled data of the birth-cohorts GINI-plus and LISA-plus and follows 7,643 healthy full-term neonates in four study-centers in Germany. Up to nine anthropometric measurements are available. Overweight/obesity is percentile-defined according to WHO-Child-Growth-Standards. Fully-breastfed is defined as breastfed for at least 4 months. Piecewise-linear-random-coefficient-models were applied to assess growth trajectories and velocities between 0-3, 3-6, 6-12, 12-24 and beyond 24th months. Velocities for weight-, length- and BMI-development are highest in the first 3 months after birth and diminish, with differing pace, in the periods that follow. For overweight and obesity, peak-velocities are estimated in periods 6-12 and 3-6 months. The difference in the velocity of weight gain for breastfed vs. other children is -18 g/month in the first 3 month, -93 g/month between month 3 and 6, -14 g/month between month 6 and 12 and -3 g/month beyond the 24th month. Velocities in length are not different between breastfed and non-breastfed children. Over time, a slightly lower risk (difference < 2%) of being overweight was estimated for breastfed children, after adjustment for study-center, socio-economic-status and maternal smoking in pregnancy. Infants fully-breastfed gain less weight, but grow equally in length in the first 12 months of life versus mixed or formula-fed children. The protective effect of breastfeeding on becoming overweight is related to its weight-velocity-modifying-effect in early infancy.

Decreased cord blood IL-4, IL-13, and CCR4 and increased TGF-beta levels after fish oil supplementation of pregnant women.

BACKGROUND: Altered intakes of n-3 and n-6 polyunsaturated fatty acids were suggested to modulate allergic disease, but intervention trials yielded inconclusive results. Because allergies are primed in early infancy and in utero, the fetus might be more accessible to nutritional intervention strategies. OBJECTIVE: We sought to investigate how supplementation of pregnant women with a fish oil (FO) preparation modulates allergy-related immune parameters in mothers and offspring. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled trial. Three hundred eleven pregnant women received daily either FO with 0.5 g of docosahexaenoic acid and 0.15 g of eicosapentaenoic acid, 400 mug of methyl-tetra-hydrofolic acid, both, or placebo from the 22nd gestational week. T(H)1/T(H)2-related molecules were quantified in 197 maternal and 195 cord blood samples by using real-time RT-PCR. Data are given as geometric means [95% CIs]. RESULTS: FO supplementation was associated with increased TGF-beta mRNA in maternal (0.85 [0.8-0.89]; placebo: 0.68 [0.64-0.72]) and cord blood (0.85 [0.81-0.9]; placebo: 0.75 [0.71-0.79]). IL-1 (0.69 [0.66-0.73]; placebo: 0.83 [0.79-0.88]) and IFN-gamma (0.54 [0.51-0.57]; placebo: 0.65 [0.61-0.69]) were decreased in mothers only (P < .001). Cord blood mRNA levels of IL-4 (0.54 [0.52-0.57]; placebo: 0.64 [0.61-0.68]), IL-13 (0.61 [0.58-0.65]; placebo: 0.85 [0.80-0.89]), CCR4 (0.70 [0.67-0.73]; placebo: 0.88 [0.84-0.92]; all P < .001), and natural killer (P < .001) and CCR3+CD8+ T cells (P < .04) were decreased in the FO group. CONCLUSION: Supplementation with FO during pregnancy is associated with decreased mRNA levels of T(H)2-related molecules in the fetus and decreased maternal inflammatory cytokines. We speculate that both effects are mediated by TGF-beta.

Weight change, weight cycling and mortality in the ERFORT Male Cohort Study.

OBJECTIVE: To investigate the effect of weight change and weight fluctuations on all-cause-mortality in men. METHODS: Within a prospective population-based cohort of 1,160 men aged 40-59 years at recruitment, complete weight change patterns from baseline and three follow-up examinations during a period of 15 years of follow-up was used to categorize the 505 men into stable obese, stable non-obese, weight gain, weight loss and weight fluctuation groups. For these men (age range: 55-74 years at start time of survival analysis) further survival was analyzed during the subsequent 15 years. RESULTS: Overall, 183 deaths were observed among the 505 men. Only weight fluctuations had a clear significant impact on all-cause mortality. Adjusted hazard rate ratio (HRR (95%-CI)) was 1.86 (1.31-2.66) after adjustment for age group, pre-existing cardiovascular disease or diabetes mellitus, smoking and socio-economic status. The risk rate due to weight loss was borderline significant (HRR = 1.81 (0.99-3.31)). Risk of death due to weight gain (HRR = 1.15 (0.70-1.88)) or stable obesity (HRR = 1.16 (0.69-1.94)), however, were not significantly increased compared to men staying non-obese for the first 15 years after cohort recruitment. CONCLUSION: Weight fluctuations are a major risk factor for all-cause mortality in middle aged men. Moreover, stable obesity does not increase further mortality in men aged 55-74 years in long-term follow-up.

Health-related quality of life measurement in long-term survivors and outcome following radical radiotherapy for localized prostate cancer.

PURPOSE: To report long-term outcomes in terms of health-related quality of life (HRQoL) and survival of a dose-escalating radiotherapy protocol and to validate a new disease-specific HRQoL instrument. PATIENTS AND METHODS: 189 consecutive men with prostate cancer were analyzed; 127 patients had T1-2 (1% T1, 66% T2) and 62 patients (33%) T3 tumors. The pelvic lymphatics were treated to a dose of 50 Gy by external-beam irradiation. The prostate dose was limited to 40 Gy using compensators. The prostate was treated to the total nominal dose of 70 Gy using high-dose-rate (HDR) brachytherapy. The fraction dose was 15 Gy in the McNeal zone (planning target volume [PTV] 1), while 8-9 Gy were applied in the entire prostate (PTV 2). The HRQoL of the 145 long-term survivors was assessed using the EORTC QLQ-C30 and a new prostate-specific instrument (PSM-G 1.0). The reliability of the instruments used and HRQoL scale scores were calculated. Uni-/multivariate analyses of variance were performed. RESULTS: At a mean follow-up of 6.5 years 86.3% of the patients were disease-free, and 78% were biochemically controlled. The mean Cronbach's alpha-values were 0.81 for the QLQ-C30, and 0.74 for the prostate-specific module. Univariate analyses of variance by T-stage, grading, prostata-specific antigen (PSA) status after therapy and adjuvant androgen suppression (AS) revealed that PSA elevation after irradiation and AS were associated with significantly diminished HRQoL. In multivariate analyses AS significantly lowered the HRQoL without survival benefit. CONCLUSION: The described radiotherapy regimen represents a curative and well-tolerated treatment for localized prostate cancer. The HRQoL assessment with both instruments used was reliable. Adjuvant AS and PSA elevation were associated with diminished HRQoL.

Predictors of health care utilization of children with asthma in the community.

The aim of this study was to assess the pattern of use of health care services among children with asthma symptoms within the community, and assess groups at increased risk of emergency department (ED) visits or hospital admissions (HA). Using International Study of Asthma and Allergies in Childhood phase II protocol, information about asthma management and utilization of health care services was collected by parental questionnaire in a community-based random sample of 5-7- and 9-11-year-old children (n = 11,094) in Dresden and Munich. Only 11.2% of children with current wheeze did not utilize any health care facility or consultation for their asthma symptoms in the 12 months prior to survey, while 86.2%, 12.3%, and 3.6% had at least one asthma related physician's consultation, ED visits, or HA, respectively. Predictors of ED visits and HA among current wheezers were: younger age, male gender, speech-limiting wheeze, level of exposure to environmental tobacco smoke. In addition, children of low socioeconomic status were more likely to have ED visits because of their asthma. Childhood asthma is a major public health problem in Germany leading to substantial morbidity and utilization of health care services. Exposure to tobacco smoke comes out as the major modifiable risk factor related to asthma morbidity in children.

Quality of life and nutritional state in patients on home enteral tube feeding.

OBJECTIVE: We assessed quality of life (QOL) in patients on home enteral tube feeding (HETF). The data should contribute to ethically justified decision making. METHODS: We used a prospective cross-sectional study (study 1) in 155 consecutive patients and a prospective longitudinal study (study 2) with a follow-up of 4 mo in 56 patients. QOL was assessed by proxy rating (Karnofsky and Spitzer indices) and self-rating (European Organization for Research and Treatment of Cancer [EORTC] QLQ C30) extended by a specific module. RESULTS: In study 1, weight losses 3 mo before HETF were 10.5 +/- 8.4% and 7.9 +/- 6.3% in competent (P < 0.05) and non-competent (P < 0,05) patients, respectively. The prevalences of severe malnutrition and weight loss were 50% and 73%, respectively. When compared with EORTC reference data for a general population, QOL was lower in HETF patients. The lowest QOL was seen in non-competent patients. Nutrition status explained up to 13% of the variance in QOL. In study 2, nutrition status stabilized or increased slightly in response to HETF. This was true for competent and non-competent patients and for patients with malignant and benign diseases. Concomitantly, physical functioning improved, whereas fatigue decreased. QOL increased in response to HETF in competent and non-competent patients, and 50% of the non-competent patients became competent CONCLUSIONS: . Measures of QOL research can be used in HETF patients. QOL is reduced in patients on HETF. Part of this effect is explained by malnutrition. HETF can prevent further weight loss and improve some aspects of QOL, thus allowing physicians to focus on patients.

Smoking among adolescents in Muenster, Germany: increase in prevalence (1995-2000) and relation to tobacco advertising.

BACKGROUND: Understanding patterns and trends of smoking among youths is of major importance for the assessment of the burden of smoking in the society and efforts to decrease it. OBJECTIVE: The aims were to determine the prevalence and trends of smoking among adolescents in Muenster, Germany, and to assess its relation to youths' awareness of tobacco advertisement. DESIGN: Information on smoking habits was collected during two school-based surveys (1994/1995 and 1999/2000) of 12- to 15-year-old adolescents (3934 students in 1994/5 and 4028 students in 1999/2000) in Muenster, Germany. In addition, in 1994/1995 information about youths' awareness and appreciation of tobacco advertisement was collected. RESULTS: During the 5-year period, the prevalence of current smoking increased from 21.3 to 28.3%, and daily smoking increased from 10.0 to 14.2%. Among girls, daily smoking increased by 62% during this period. Almost all participants (94%) in 1994/1995 knew a tobacco brand, and appreciation of tobacco advertisement was strongly associated with the frequency of smoking. CONCLUSION: Smoking is increasing among adolescents in Germany especially among girls. These data are a cause of concern and call for efforts to reverse these trends, which should include a ban on tobacco advertisement in Germany.