The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood.

Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (IGF2) and H19, are involved in fetal growth and each is regulated by DNA methylation. This study aimed to determine the association between maternal mental well-being during pregnancy and differentially methylated regions (DMRs) of IGF2 (DMR0) and the IGF2/H19 imprinting control region (ICR) in newborn offspring. Maternal depression, anxiety and perceived stress were assessed at 28 weeks of pregnancy in the Barwon Infant Study (n=576). DNA methylation was measured in purified cord blood mononuclear cells using the Sequenom MassArray Platform. Maternal anxiety was associated with a decrease in average ICR methylation (Δ=-2.23%; 95% CI=-3.68 to -0.77%), and across all six of the individual CpG units in anxious compared with non-anxious groups. Birth weight and sex modified the association between prenatal anxiety and infant methylation. When stratified into lower (⩽3530 g) and higher (>3530 g) birth weight groups using the median birth weight, there was a stronger association between anxiety and ICR methylation in the lower birth weight group (Δ=-3.89%; 95% CI=-6.06 to -1.72%), with no association in the higher birth weight group. When stratified by infant sex, there was a stronger association in female infants (Δ=-3.70%; 95% CI=-5.90 to -1.51%) and no association in males. All the linear regression models were adjusted for maternal age, smoking and folate intake. These findings show that maternal anxiety in pregnancy is associated with decreased IGF2/H19 ICR DNA methylation in progeny at birth, particularly in female, low birth weight neonates. ICR methylation may help link poor maternal mental health and adverse birth outcomes, but further investigation is needed.

Stress-related maternal factors during pregnancy in relation to childhood eczema: results from the LISA Study.

BACKGROUND: Stress has been suggested to impact the onset and exacerbation of eczema and other atopic disorders. Whether early exposure to stress-related factors might exert long-term effects remains to be clarified. OBJECTIVE: The objective of this study was to investigate whether stress-related maternal factors during pregnancy are associated with childhood eczema during the first 6 years of life. METHODS: Data from 3004 children from a prospective German birth cohort study (LISA) were analyzed. Information from maternity certificates and questionnaire information on unwanted pregnancy were used to evaluate stress-related maternal factors during pregnancy. Prevalence data for physician-diagnosed eczema were available up to the age of 6 years. RESULTS: Maternal factors during pregnancy were positively associated with childhood eczema in terms of cumulative prevalence up to the age of 2 years (adjusted odds ratio, 1.48; 95% confidence interval, 0.95-2.30) after adjusting for potential confounders. Beyond the second year no increased risk was observed. CONCLUSIONS: The results of this study suggest that stress-related maternal factors during pregnancy are associated with an increased risk of childhood eczema during the first 2 years of life. The impact of postnatal stress such as parental divorce or separation on this association could not be clarified. Future studies should therefore further elucidate how prenatal and postnatal stress interact and whether prenatal stress might have a programming effect. If future studies confirm the findings of this study, reducing maternal stress during pregnancy might be a possible target in the primary prevention of eczema during childhood.

International variation in prevalence of rhinitis and its relationship with sensitisation to perennial and seasonal allergens.

The relative importance of atopy in the aetiology of rhinitis is largely unknown. The present study investigated the geographical variations in rhinitis in relation to atopy. The cross-sectional study involved 54,178 children (aged 8-12 yrs) from 30 study centres in 22 countries worldwide. Symptoms of rhinoconjunctivitis and rhinitis without conjunctivitis in the last 12 months were reported in parental questionnaires and children were skin-prick tested. The prevalence of rhinoconjunctivitis and rhinitis without conjunctivitis varied widely (1.5-24.5% and 1.4-45.2%, respectively). For rhinoconjunctivitis, the population attributable fraction (PAF) varied 0-71% for a positive skin-prick test to one or more seasonal allergens and 0-41% for perennial allergens. The PAF for sensitisation to seasonal and perennial allergens was higher in affluent countries (36 and 25%, respectively) than nonaffluent countries (1.3 and 12.6%, respectively). For rhinitis without conjunctivitis, the PAF for perennial allergens was 8 and 4% for affluent and nonaffluent countries, respectively. No significant PAF was found for seasonal allergens. Overall, atopy explained only a limited proportion of rhinitis symptoms, suggesting that the importance of other environmental factors has been under emphasised, particularly in less affluent countries. Atopy seems to be only marginally relevant for rhinitis without conjunctivitis, which seems mainly to reflect nonatopic rhinitis.

Development of relative weight, overweight and obesity from childhood to young adulthood. A longitudinal analysis of individual change of height and weight.

BACKGROUND: To investigate individual longitudinal change of relative weight, overweight and obesity from age 5 to 25 years by gender. METHODS: A cohort was imbedded in four surveys conducted 1992/1993, 1995/1996, 1998/1999 and 2004/2005 in three areas in Germany. Twelve-year-follow-up of 2183 children initially aged 5-13 years at baseline. Main measurements are body mass index (BMI) and international obesity task force (IOTF)-cut point defined overweight and obesity. A special longitudinal random effects model for cohort data was applied, which uses age as meta-meter of follow-up time and takes age at study entry into account. RESULTS: BMI, overweight and obesity increases with linear and squared age. Girls have a significant higher growth rate than boys in BMI (BMI: 0.89 vs. 0.75 kg/m(2) per 1 year age increment), whereas there is no statistical significant gender difference for overweight [odds ratio (OR) = 1.08 per 1 year] or obesity (OR = 1.11 per 1 year). Longitudinal change rates of BMI vary substantially between individuals [95% reference range (beta +/- 1.96 x SD) for linear change per 1 year is -0.14 to 1.98 in females and -0.29 to 1.83 in males; the 95% range of quadratic change rates are -0.09 to 0.04 in females and -0.08 to 0.05 in males]. Moreover, a steeper increase in BMI over time is observed for children with a higher baseline relative weight. CONCLUSION: Increases in BMI and the propensity of overweight and obesity follow a quadratic growth curve with the steepest increase before and during puberty. However, the substantial variability of relative weight gain within individuals indicate, that more research in individual change patterns is needed.

Influence of physical inactivity on the prevalence of hay fever.

BACKGROUND: Atopic diseases constitute a major public health problem, increasing constantly in frequency and severity. While treatments are improving, the main cause for an increasing trend of hay fever and its definite triggers remain unclear. The aim of our study was to assess whether physical inactivity could be a risk factor for hay fever. METHODS: We analysed data of a cohort of children aged 5-14 years at baseline (1992-1993) who were followed up until 2003-2005. Parental-reported information on physical activity (being active, doing sports) was obtained for 2429 children participating at the baseline survey (active: n = 1923; semi-active: n = 364; inactive: n = 142). A total of 1703 children (70.1%) were reapproached at least once during follow-up. Logistic regression models were applied to study associations between hay fever, allergic sensitization and physical activity, adjusted for potentially relevant confounders such as age, gender, study site, parental education, breastfeeding, crowding, daycare, dampness or visible moulds, contact to cats, current or prior environmental tobacco smoke exposure and parental atopy. RESULTS: Significantly higher rates of hay fever were seen for inactive children [aOR 2.39 (95% CI 1.31-4.36) for baseline survey 1992-1993 and aOR 1.76 (95% CI 1.14-2.71) for the follow-up-period until 2005]. In addition, the relative risk of incident cases of hay fever increased depending on inactivity [aRR 1.50 (95% CI 1.05-2.13)]. No association was found between physical inactivity and allergic sensitization assessed by radioallergosorbent test determinations. CONCLUSIONS: Although the underlying biological mechanisms could not be clarified, increasing physical activity in childhood is suggested to prevent hay fever.

Smoking and the incidence of asthma during adolescence: results of a large cohort study in Germany.

BACKGROUND: The association between smoking and asthma or wheeze has been extensively studied in cross sectional studies, but evidence from large prospective cohort studies on the incidence of asthma during adolescence is scarce. METHODS: We report data from a cohort study in two German cities, Dresden and Munich. The study population (n = 2936) was first studied in 1995/6 at age 9-11 years as part of phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II) and followed up in 2002/3. At baseline the parents completed a questionnaire and children underwent clinical examination and blood sampling. At follow up the young adults completed questionnaires on respiratory health, living, and exposure conditions. Incidence risk ratios (IRR) were calculated and adjusted for potential confounders using a modified Poisson regression approach. RESULTS: The adjusted IRR for incident wheeze for active smokers compared with non-smokers was 2.30 (95% confidence interval (CI) 1.88 to 2.82). The adjusted IRR was slightly higher for incident wheeze without a cold (2.76, 95% CI 1.99 to 3.84) and the incidence of diagnosed asthma (2.56, 95% CI 1.55 to 4.21). Analysis of duration and intensity of active smoking indicated dose dependent associations. Stratified analyses showed that the risk of incident wheeze without a cold in atopic smokers increased with decreasing plasma alpha(1)-antitrypsin levels at baseline (1.64, 95% CI 1.22 to 2.20 per interquartile range). CONCLUSIONS: Active smoking is an important risk factor for the incidence of asthma during adolescence. Relatively lower plasma levels of alpha(1)-antitrypsin, although well above currently accepted thresholds, may increase susceptibility to respiratory disease among atopic smokers.

Symptoms of asthma and the home environment. The ISAAC I and III cross-sectional surveys in Münster, Germany.

BACKGROUND: The indoor home environment has been shown to be associated with the presence of respiratory symptoms and atopic disease. METHODS: Two cross-sectional surveys (1995-2000) were conducted, using data from the ISAAC phase I and III surveys, collected in Münster, Germany (n = 6,996, response 81.8%). We analyzed the prevalence ratio (PR) for several indoor exposures and asthma-related outcomes in 6- to 7-year-old children, adjusting for potential confounders. RESULTS: Positive associations were observed regarding exposure to molds, environmental tobacco smoke, cooking with gas and space heating with fossil fuels, but most associations were not statistically significant. Surprisingly, presence of a carpet was negatively associated with most respiratory conditions. When restricting the analysis to participants without avoidance of a carpet due to a history of atopic disease, the protective associations disappeared. Mostly, present pet ownership did not show positive associations with respiratory symptoms. However, ownership at different times in life revealed positive associations, particularly in regard to birds owned in the first year of life (PR 1.51, 95% CI 1.11-2.06, for sleep disturbance due to wheeze and PR 1.28, 95% CI 1.01-1.63, for wheeze during the last 12 months, respectively). CONCLUSIONS: Only few indoor factors were positively associated with the studied outcomes. The change of associations in participants that reported allergy-related avoidance of carpets suggests that the observed effects are a result of asthmatics' changed behavior. The effect of allergy-related change in behavior and the results observed concerning the ownership of pets at different ages underline the need of establishing a precise temporal relationship between disease and exposure.

Climate and the prevalence of symptoms of asthma, allergic rhinitis, and atopic eczema in children.

AIMS: To investigate the association between climate and atopic diseases using worldwide data from 146 centres of the International Study of Asthma and Allergies in Childhood (ISAAC). METHODS: Between 1992 and 1996, each centre studied random samples of children aged 13-14 and 6-7 years (approx. 3000 per age group and centre) using standardised written and video questionnaires on symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema during the past 12 months. Data on long term climatic conditions in the centres were abstracted from one standardised source, and mixed linear regression models calculated to take the clustering of centres within countries into account. RESULTS: In Western Europe (57 centres in 12 countries), the prevalence of asthma symptoms, assessed by written questionnaire, increased by 2.7% (95% CI 1.0% to 4.5%) with an increase in the estimated annual mean of indoor relative humidity of 10%. Similar associations were seen for the video questionnaire and the younger age group. Altitude and the annual variation of temperature and relative humidity outdoors were negatively associated with asthma symptoms. The prevalence of eczema symptoms correlated with latitude (positively) and mean annual outdoor temperature (negatively). CONCLUSIONS: Results suggest that climate may affect the prevalence of asthma and atopic eczema in children.

Are asthma and allergies in children and adolescents increasing? Results from ISAAC phase I and phase III surveys in Münster, Germany.

OBJECTIVE: To assess time trends in symptoms of asthma, allergic rhinitis, and atopic eczema among children in Münster, Germany. METHODS: Two cross-sectional surveys 5-years apart (1994/1995, 1999/2000) using ISAAC core written and video questionnaires and applying the ISAAC protocol. Two main age groups (6-7 and 13-14 year olds) were designated with information collected by parental and self-report for both age groups, respectively. A school-based sample of 7744 participants in the 1994/1995 survey and 7962 participants in the 1999/2000 survey was recruited. In the first and second surveys, response rates for the 6-7 year olds were 81 and 82%, respectively, while for the 13-14 year olds response rates were 94% in both. Analyses focus on the change in 12-month prevalence of symptoms of asthma, rhinitis, and eczema. RESULTS: There is a tendency towards an increase in current symptoms for all three conditions and in both age groups, but more so among girls. Indices of diagnosis either remained the same or increased in parallel to the increase in symptoms. Indices of severity also showed a homogenous increase in the 5-year study period. CONCLUSIONS: Our study shows that symptoms of asthma, rhinitis, and eczema are increasing, reflecting a change in the morbidity of these conditions in our population.

[High dosage brachytherapy and external irradiation of localized prostate carcinoma--results at the Kiel University Clinic]. / High-dose-rate Brachytherapie und externe Bestrahlung beim lokalisierten Prostatakarzinom--Ergebnisse der Kieler Universitätsklinik.

To evaluate a new therapy protocol for local dose escalation by high dose rate (HDR) brachytherapy for survival, morbidity and prognostic variables in men with localized prostate cancer. The prospectively recorded files of 189 men aged in median 69 years with a mean follow-up of 6 years (12-143 months) receiving curatively intended combined high dose rate (HDR) 192-iridium-brachytherapy (BT) and external beam radiation (EBR) for locally confined prostate cancer were analyzed. Mean age was 68.2 (range 44-84 years). Hundred and twenty-seven patients had T1-2 tumors, and 62 patients had T3-tumors. The total planned dose applied by external beam radiation was 50 Gy in the pelvis, and 40 Gy in the prostate by in-field-dose modification. The HDR-brachytherapy was delivered in two fractions. The dose per fraction amounted 15 Gy. Mean survival was 6 years (range 12-143 months), 76.7% of the patients survived and 86.3% were disease-free. The biochemical non-evidence of disease rate (BNED) was 78%. Univariate survival analysis revealed that low stage (T1-2), low grade (G1-2), normal PSA status after radiation therapy, and no adjuvant hormonal treatment were associated with long survival. However, the stratification for adjuvant hormonal treatment was not according to random. In multivariate analyses PSA status was an independent prognostic factor. The six year results confirm that local dose escalation by HDR-brachytherapy and external beam radiation is curative in men with locally confined prostate cancer. The results are especially in high risk patients encouraging.