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BACKGROUND: An important window of opportunity for early-life exposures has been proposed for the development of atopic eczema and asthma.OBJECTIVE: However, it is unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life.METHODS: In the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.5 years and classified by repeated measure latent class analyses (n [ 769). Fecal samples at ages 2 and 12 months were sequenced by 16S rRNA. Hay fever was defined by parent -reported symptoms and/or physician's diagnosis of hay fever in the last 12 months using questionnaires at 10.5 years.RESULTS: Farm children had half the risk of hay fever at 10.5 years (adjusted odds ratio [aOR] 0.50; 95% CI 0.31-0.79) than that of nonfarm children. Whereas early life events such as gut microbiome richness at 12 months (aOR 0.66; 95% CI 0.46-0.96) and exposure to animal sheds in the first 3 years of life (aOR 0.26; 95% CI 0.06-1.15) were determinants of hay fever, the continuous consumption of farm milk from infancy up to school age was necessary to exert the protective effect (aOR 0.35; 95% CI 0.17-0.72).CONCLUSIONS: While early life events determine the risk of subsequent hay fever, continuous exposure is necessary to achieve protection. These findings argue against the notion that only early life exposures set long-lasting trajectories. (c) 2022 The Authors. Published by Elsevier Inc

Parental exposures prior to conception might influence asthma and allergy risk in offspring. As occupational exposures are established risk factors for asthma and allergies, we investigated if parental occupational exposures prior to conception cause wheeze and eczema in offspring during the first year of life.We analysed data of 436 families from an offspring cohort based on a follow-up study of German participants of the International Study of Asthma and Allergies in Childhood (ISAAC). Offspring cohort data was collected between 2009 and 2019. Occupational exposures were based on participants' work histories and measured by a Job-Exposure-Matrix. We used Bayesian logistic regression models for analysis. Inference and confounder selection were based on directed acyclic graphs.In mothers, for both allergic and irritative occupational exposures prior to conception suggestive effects on offspring eczema during the first year of life were found (allergens: odds ratio (OR) 1.22, 95% compatibility interval (CI) 0.92-1.57; irritants: OR 1.36, 95% CI 0.99-1.77), while no relation with wheeze was suggested.Our results suggest that reduction of asthma-related occupational exposures might not only reduce the burden of disease for occupationally induced or aggravated asthma and allergies in employees but also in their children.

Background: Childhood wheeze represents a first symptom of asthma. Early identification of children at risk for wheeze related to 17q12-21 variants and their underlying immunological mechanisms remain unknown. We aimed to assess the influence of 17q12-21 variants and mRNA expression at birth on the development of wheeze. Methods: Children were classified as multitrigger/viral/no wheeze until six years of age. The PAULINA/PAULCHEN birth cohorts were genotyped (n = 216; GSA-chip). mRNA expression of 17q21 and innate/adaptive genes was measured (qRT-PCR) in cord blood mononuclear cells. Expression quantitative trait loci (eQTL) and mediation analyses were performed. Genetic variation of 17q12-21 asthma-single nucleotide polymorphisms (SNPs) was summarized as the first principal component (PC1) and used to classify single SNP effects on gene expression as (locus)-dependent/independent eQTL SNPs. Results: Core region risk variants (IKZF3, ZPBP2, GSDMB, ORMDL3) were associated with multitrigger wheeze (OR: 3.05–5.43) and were locus-dependent eQTL SNPs with higher GSDMA, TLR2, TLR5, and lower TGFB1 expression. Increased risk of multitrigger wheeze with rs9303277 was in part mediated by TLR2 expression. Risk variants distal to the core region were mainly locus-independent eQTL SNPs with decreased CD209, CD86, TRAF6, RORA, and IL-9 expression. Distinct immune signatures in cord blood were associated either with multitrigger wheeze (increased innate genes, e.g., TLR2, IPS1, LY75) or viral wheeze (decreased NF-κB genes, e.g., TNFAIP3 and TNIP2). Conclusion: Locus-dependent eQTL SNPs (core region) associated with increased inflammatory genes (primarily TLR2) at birth and subsequent multitrigger wheeze indicate that early priming and imbalance may be crucial for asthma pathophysiology. Locus-independent eQTL SNPs (mainly distal region, rs1007654) may be involved in the initiation of dendritic cell activation/maturation (TRAF6) and interaction with T cells (CD209, CD86). Identifying potential mechanistic pathways at birth may point to critical key points during early immune development predisposing to asthma.

Allergic diseases, including atopic dermatitis (AD), food allergy (FA), asthma and allergic rhinitis/rhinoconjunctivitis (AR) are the most prevalent chronic childhood diseases affecting one in four children in the Western world (1). This global health problem imposes a significant burden on patient's quality of life (2), family, health care and society. The current state of knowledge assumes that complex interactions between genetic and environmental factors influence a child´s immune maturation prior to the development of allergic diseases (3). To date, no reliable predictions of allergy development exists. Current scores, including clinical features and laboratory data, have only reached limited specificity and/or sensitivity (4).

Background: Allergic diseases are the most prevalent chronic childhood diseases resulting in a massive societal and economic burden for the community and a significant reduction of health-related quality of life (HRQoL) for affected families. The project CHAMP (CHildhood Allergy and tolerance: bioMarkers and Predictors) was funded in 2017 by the German Federal Ministry for Education and Research. Methods: CHAMP investigates the determinants of different allergic diseases from birth to adolescence to identify clinically relevant biomarkers predicting onset, progression, remission and severity. Data on HRQoL and patient’s needs and requirements were collected, supported by the German Asthma and Allergy Association (DAAB). Using validated questionnaires and outpatient visits, eight subprojects analysed allergic diseases in epidemiological or clinical cohorts (more than 2500 children/adolescents), sampling numerous biomaterials to assess omics on several levels. Murine models disentangled underlying mechanisms of early tolerance, translating findings from the cohorts to models and vice versa. Results: The DAAB survey, including 851 participants, showed that 83% were interested in prediction of the course of different current allergic diseases and future manifestation. 86% of participants considered doctor’s specialized training and their education as highly important, over 70% chose research for allergy understanding and prevention as critical. CHAMP addresses these needs. Common SOPs have been established and recruitment is ongoing. Conclusion: The DAAB patient survey confirmed the critical need for translational allergy research. CHAMP envisions to predict onset, tolerance and remission of allergic diseases and to identify disease sub-phenotypes for future development of preventive strategies and novel avenues for therapeutic options.

The frequency of consultations and the waiting times in pediatric hospital outpatient clinics are steadily increasing. The aim of this study was to compare the occurrence of patients in a large pediatric group practice and a hospital-based general pediatric outpatient clinic. Primary parameters were the most common reasons for consultation, the waiting times and the reasons for selecting a certain institution. Most frequent diagnoses in the pediatric practice were upper respiratory tract infections (22.7% ( n = 141/621)), otitis media (5.2% ( n = 32/621)), and viral pharyngitis (3.9% ( n = 24/621)). Most common reasons for consultation in the hospital outpatient clinic were upper respiratory tract infections (18.4% ( n = 121/658)) and bacterial pharyngitis (17.9% ( n = 118/658)). In the pediatric practice, bacterial pharyngitis was only diagnosed in 3.1% ( n = 19/621) of the cases. Only slight differences exist between the two institutions regarding the observed entities, which mainly comprise mild to moderate acute illnesses. It can be concluded from this that the majority of patients might as well be treated in the nonhospital setting. Facilitating the communication and coordination between practices and hospitals might allow a better utilization of capacities. Thereby, waiting times, unnecessary reexaminations, and costs in the health-care system could be reduced.

Streszczenie Wstep Astma wieku dzieciecego dzieli sie na astme alergiczną (AA) i astme niealergiczną (NA), jednak leczenie w obu przypadkach jest identyczne i tylko cześciowo skuteczne. Cel Identyfikacja nowych immunofenotypow w przypadku AA i NA u dzieci. Metody Badaniem Stowarzyszenia Badan Klinicznych nad Astmą objeto 275 niemieckich dzieci w wieku od 4 do 15 lat, ktore do tej pory nie otrzymywaly sterydow (grupa kontrolna dzieci zdrowych [HC], pacjenci z AA, pacjenci z NA). Wśrod komorek jednojądrzastych krwi obwodowej (PBMC) wykonano analize ilościową i funkcjonalną limfocytow T regulatorowych (Treg) i Th17 (cytometria przeplywowa/supresja komorek Treg) przed i po stymulacji przeciwcialami anty-CD3/CD28, lipidem A i peptydoglikanem. Wykonano analize regresji dla cytokin i ekspresji genow, ocenianych w analizatorze Luminex lub przy uzyciu transkryptomiki/ ilościowego PCR w czasie rzeczywistym. Do zroznicowania fenotypow uzyto liniowej analizy dyskryminacyjnej. Wyniki Za pomocą mikromacierzy i analizy bialek przy uzyciu liniowej analizy dyskryminacyjnej wyrozniono 3 fenotypy immunologiczne. U pacjentow z AA obserwowano wyzsze stezenie komorek Treg w porownaniu z grupą HC, ale nie z grupą NA. Komorki Treg w przypadku pacjentow z AA, ale nie w przypadku pacjentow z NA, istotnie hamowaly wydzielanie IL-5, IL-13 oraz IFN-γ. U pacjentow z AA obnizona byla ekspresja wewnątrzkomorkowego kanalu chlorkowego 4 (CLIC4) i stwardnienia guzowatego 1 (TSC1), waznych regulatorow odporności wrodzonej. U pacjentow z NA podwyzszony byl poziom prozapalnej IL-1β i liczba neutrofili, a odpornośc przesunieta byla w kierunku IL-17. Jednocześnie u pacjentow z NA wzmozona byla ekspresja przeciwzapalnej IL-37, bialka PSTPIP2 (bialko oddzialujące na fosfataze prolino-serynowo-treoninową 2) i związanych z neutrofilami genow CD93, receptora wyzwalającego komorek mieloidalnych 1 (TREM1) i bialka regulującego przekazywanie sygnalu przez bialko G 13 (RGS13). W przypadku obu fenotypow astmy obserwowano ograniczoną odpornośc Th2. Wnioski Zidentyfikowane nowe mechanizmy immunoregulacyjne w przypadku astmy u dzieci charakteryzowaly sie podwyzszonym poziomem komorek Treg u pacjentow z AA w porownaniu z grupą HC, ale nie w porownaniu z NA, oraz obnizonym poziomem genow wrodzonej odporności u pacjentow z AA. Pierwsza z tych cech potencjalnie wskazuje na przeciwregulacyjny mechanizm hamujący cytokiny, niewystarczający jednak do kontroli alergicznej reakcji zapalnej. U pacjentow z NA obserwowano bardzo wyraźne przesuniecie odporności w kierunku prozapalnej IL-17, promującej zapalenie neutrofilowe i obnizenie funkcjonalności komorek Treg. Identyfikacja tych unikatowych ściezek stanowi podstawe do tworzenia dalszych zindywidualizowanych strategii rozwoju astmy, przebiegu choroby i jej zapobiegania.

BACKGROUND: Associations between childhood asthma phenotypes and genetic, immunological and environmental factors have been previously established. Yet, strategies to integrate high-dimensional risk factors from multiple distinct data sets, and thereby increase the statistical power of analyses, have been hampered by a preponderance of missing data and lack of methods to accommodate them. METHODS: We assembled questionnaire, diagnostic, genotype, microarray, RT-qPCR, flow cytometry and cytokine data (referred to as data modalities) to use as input factors for a classifier that could distinguish healthy children, mild-to-moderate allergic asthmatics and non-allergic asthmatics. Based on data from 260 German children aged 4-14 from our university outpatient clinic, we built a novel multi-level prediction approach for asthma outcome which could deal with a present complex missing data structure. RESULTS: The optimal learning method was boosting based on all data sets, achieving an area-underneath-the-receiver-operating-characteristic curve (AUC) for three classes of phenotypes of 0.81 (95%-confidence interval (CI): 0.65-0.94) using leave-one-out cross-validation. Besides improving the AUC, our integrative multi-level learning approach led to tighter CIs than using smaller complete predictor data sets (AUC=0.82[0.66-0.94] for boosting). The most important variables for classifying childhood asthma phenotypes comprised novel identified genes, namely PKN2 (protein kinase N2), PTK2 (protein tyrosine kinase 2), and ALPP (alkaline phosphatase, placental). CONCLUSION: Our combination of several data modalities using a novel strategy improved classification of childhood asthma phenotypes but requires validation in external populations. The generic approach is applicable to other multi-level data-based risk prediction settings, which typically suffer from incomplete data. This article is protected by copyright. All rights reserved.

Introduction Our aim was to examine the internet health seeking behaviour of parents attending a general paediatric outpatient clinic. For this purpose, the proportion of parents going online to obtain child health information, the most commonly used online resources, and factors having an influence on internet usage were identified. Methods This cross-sectional observational study was conducted at a general paediatric outpatient clinic in Vienna, Austria. Data collection was done by means of an anonymous questionnaire containing 14 items. A total number of 500 questionnaires were collected. Results Among parents visiting the outpatient clinic, 94.4% use the internet to obtain child health information in general and 21% to be informed about the reason for consultation. Most commonly used online resources are Google (91.4%), websites run by doctors (84.8%), Wikipedia (84.7%), health portals (76.4%), the outpatient clinic's homepage (76.4%), as well as health forums and communities (61.9%). Younger parents ( p = 0.022) and parents of younger children ( p Discussion Important reasons for high internet use might be the inexperience of young parents regarding child health as well as the frequent infections, vaccinations, and preventive check-ups which are associated with young age of children. In contrast to former findings relating to health seekers in general, internet usage of parents is independent of their sex and educational level.

Background: Tregs have been shown to be functionally modulated in allergic asthma (Hartl et al., JACI, 2007; Raedler et al., JACI, 2015). Recently, we observed that microRNA (miR)-17, and miR-21 are increased in murine experimental asthma and transfection of primary murine CD4+ T cells with both miRNAs reduced Treg differentiation and function in vitro. Thus, we aimed to investigate if miR-17 and miR-21 are involved in Treg function in paediatric allergic asthma. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from 7 healthy control children (HC), 7 with allergic asthma (AA), and 7 with non-allergic asthma (NA) (Clinical Asthma Research Association cohort study (Raedler et al., JACI, 2015)) and stimulated with lipid A (LpA), anti-CD3/CD28 or none. Frequencies of Treg in blood were quantified via flow cytometry. microRNA were assessed by qRT-PCR. Results: miR-17 and miR-21 levels were significantly increased in PBMCs after stimulation with anti-CD3/CD28, but did not differ significantly among HCs, NA or AA overall. We observed a positive correlation of PBMC miR-17 (r=-0.519, p=0.023), and miR-21 (r=-0.519, p=0.023) expression with percentages of CD4+CD25+Foxp3+CD49d- T cells, while they were negatively correlated with CD4+IL17+ T cells (miR-17: r=0.555, p=0.014; miR-21: r=0.621, p= 0.005). miR-21 also negatively correlated with IL10 levels in AA (r=0.886, p=0.033). Conclusion: miRNA levels in PBMCs seem to be influenced by different stimulations and their expression correlates with distinct cell types and cytokines in the blood. A dysregulation of miRNAs during the development of allergic asthma may thus contribute to the development of chronic airway inflammation.

Process-orientated, unmanaged forest remnants are not sufficient for halting the loss of forest biodiversity. Thus, integrated biodiversity-promoting management for forest inhabitants is needed. Microhabitats, such as tree cavities or bark pockets, are essential for the preservation of saproxylic species and of critical importance for endangered ones. This study investigates (1) which factors trigger the formation of microhabitats at both the individual tree and aggregated plot level, and (2) whether the co-occurrence of microhabitats differs between managed (=logged) and unmanaged forests. Relationships between the occurrence of 17 microhabitat types and individual tree features (e.g. light availability, and tree vitality) and plot characteristics (e.g. stand density index and stand age) in 398 plots dominated by Fagus sylvatica or Pseudotsuga menziesii in Germany and the USA were studied using random-effects logistic and normal regression modelling. Separate analyses were performed for German beech forests, German Douglas-fir forests, and the US Douglas-fir forests. Our results show that (1) tree diameter in breast height (DBH), tree vitality and branchiness or epicormic branches are highly related with the occurrence of one or more microhabitats on individual trees in managed and unmanaged beech and US Douglas-fir forests. In managed German Douglas-fir forests, vitality is not a predictor for the occurrence of microhabitats on a tree, but tree density and the maximum age of trees in a stand in addition to DBH and branchiness have an effect. Time since last management is not a statistically significant predictor for the presence of microhabitats at the tree level, but it is for German beech at the plot level. In Douglas-fir-dominated forests both in Germany and in the USA, the stand density index was the only common predictor at the plot level. (2) Unmanaged German beech and Douglas-fir forests exhibit more statistically significant and positive correlations with microhabitat groups than managed stands, implying that the presence of one microhabitat group on a tree is associated with the presence of other microhabitat groups. We finally conclude that measures for supporting microhabitat inhabitants in managed forests are scale and species dependent (tree versus plot level; beech versus Douglas-fir-dominated forests). Trees that carry microhabitats seem to have similar features independently of forest management. At the plot level, density management may trigger the accumulation of microhabitats. Our results indicate that in forest management, it is possible to consider the factors influencing the formation of microhabitats and implement adequate forest practices to advance their formation.

Background: Childhood asthma prevalence is significantly greater in urban areas compared with rural/farm environments. Murine studies have shown that TNF-alpha-induced protein 3 (TNFAIP3; A20), an anti-inflammatory regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling, mediates environmentally induced asthma protection. Objective: We aimed to determine the role of TNFAIP3 for asthma development in childhood and the immunomodulatory effects of environmental factors. Methods: In a representative selection of 250 of 2168 children from 2 prospective birth cohorts and 2 cross-sectional studies, we analyzed blood cells of healthy and asthmatic children from urban and rural/farm environments from Europe and China. PBMCs were stimulated ex vivo with dust from "asthma-protective'' farms or LPS. NF-kappa B signaling-related gene and protein expression was assessed in PBMCs and multiplex gene expression assays (NanoString Technologies) in isolated dendritic cells of schoolchildren and in cord blood mononuclear cells from newborns. Results: Anti-inflammatory TNFAIP3 gene and protein expression was consistently decreased, whereas proinflammatory Toll-like receptor 4 expression was increased in urban asthmatic patients (P

In a long-term settling test with loose-fill cellulose insulation under three different types of climatic and mechanical exposure (standard climate, outdoor climate and dynamic vibration) the influence of different impacts on the settlement behavior was compared. Strongest settling was observed in outdoor climate, followed by dynamic vibration at a clearly lower level while least settling occurred under constant standard climatic conditions. A correlation between the progress of settling in outdoor climate and the climate data showed a tendency to accelerated settling, especially when the material is drying.

As a preliminary test regarding the expected influence of wall friction on the settling behavior of loose-fill cellulose insulation (LFCI), a settling test was performed according to the draft ISO CD 18393, B. Two test boxes with different cavity depth were used with acrylic glass and soft board as two plank materials of different surface roughness. The wall elements were filled with LFCI and strained by drop off impacts. After 13 and 20 impacts, settling was measured and documented. Results of all four test variations show a clearly lower settling on the rougher surface consisting of soft board compared with the smooth acrylic glass. Concerning the different cavity depth, no obvious influence on wall friction is visible. Based on these results, a wall friction test with LFCI according to the Jenike test method was performed on three types of wood based panels with different roughness and acrylic glass as reference. Results show only little difference between the two rough surfaces. Under low normal stress, the three wood based surfaces are almost similar. Only acrylic glass as the smoothest surface of the test differs significantly from the others. On acrylic glass and oriented strand board, the coefficient of wall friction is rising with decreasing normal stress.

The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Here we show that, within this network, two interferon regulatory factors (IRF), IRF1 and IRF4, display opposing effects on Th9 differentiation. IRF4 dose-dependently promotes, whereas IRF1 inhibits, IL-9 production. Likewise, IRF1 inhibits IL-9 production by human Th9 cells. IRF1 counteracts IRF4-driven Il9 promoter activity, and IRF1 and IRF4 have opposing function on activating histone modifications, thus modulating RNA polymerase II recruitment. IRF1 occupancy correlates with decreased IRF4 abundance, suggesting an IRF1-IRF4-binding competition at the Il9 locus. Furthermore, IRF1 shapes Th9 cells with an interferon/Th1 gene signature. Consistently, IRF1 restricts the IL-9-dependent pathogenicity of Th9 cells in a mouse model of allergic asthma. Thus our study reveals that the molecular ratio between IRF4 and IRF1 balances Th9 fate, thus providing new possibilities for manipulation of Th9 differentiation., IFN-γ signalling inhibits production of IL-9, the defining cytokine of the Th9 cell subset. Here the authors show that IFN-γ does this by driving IRF1 to compete with IRF4 for Il9 promoter binding and skewing these cells towards a Th1 phenotype, an effect that reduces asthmatic inflammation in mice.

Background Before seeing a pediatrician, parents often look online to obtain child health information. We aimed to determine the influence of IUC (internet use regarding the reason for consultation) on their subjective information level, their assessment of acute diseases and the change in this assessment. Secondary objectives were to identify the most commonly used online resources and factors with an influence on IUC. Methods This cross-sectional observational study was conducted at a general pediatric outpatient clinic located in Vienna, Austria. An anonymous, voluntary and 14-items-containing questionnaire served to gather all data. A total number of 500 questionnaires were collected. Results Of the parents attending the outpatient clinic, 21 % use the internet before the appointment (= IUC). Most common online resources utilized for this purpose are websites run by doctors (61.3 %), the outpatient clinic’s homepage (56.3 %), Google (40 %), Wikipedia (32.5 %), health advisory services provided by doctors (28.7 %), health portals (21.3 %) and health forums and communities (18.8 %). The information level in terms of the reason for consultation is rated as good by 50.6 %, as average by 46.7 % and as insufficient by 2.7 % (internet users: 42.7 %, 55.3 %, 1.9 %). Acute diseases of the children are estimated to be mild by 58.4 %, to be moderate by 41.1 % and to be severe by 0.5 % (internet users: 54.9 %, 45.1 %, 0 %). After having used any source of information, this assessment is unchanged in 82.8 %, acute diseases are rated as more severe in 13.8 % and as less severe in 3.4 % (internet users: 79.2 %, 16.7 %, 4.2 %). Internet users and non-users do not differ with respect to their information level (p = 0.178), the assessment of acute diseases (p = 0.691) and the change in this assessment (p = 0.999). A higher education level of parents (mothers: p = 0.025, fathers: p = 0.037), a young age of their children (p = 0.012) and acute diseases of their children (p = 0.046) predispose to IUC. Conclusions Against the common perception that online health information might fuel panic-mongering, we could not determine a link between IUC and the assessment of acute diseases. The information level of internet users and non-users does not differ either. Further research is needed to clarify causes for high and low IUC.

Background: IL-33 polymorphisms influence the susceptibility to asthma. IL-33 indirectly induces Th2-immune responses via dendritic cell activation, being important for development of atopic diseases. Furthermore, IL-33 upregulates regulatory T cells (Tregs), which are critical for healthy immune homeostasis. This study investigates associations between IL-33 polymorphisms during the development of childhood atopic diseases and underlying mechanisms including immune regulation of Tregs. Methods: Genotyping of IL-33-polymorphisms (rs928413, rs1342326) was performed by MALDI-TOF-MS in 880 of 1133 PASTURE/EFRAIM children. In 4.5-year-old German PASTURE/EFRAIM children (n = 99), CD4(+) CD25(high)FOXP3(+) Tregs were assessed by flow cytometry following 24-h incubation of PBMCs with PMA/ionomycin, LPS or without stimuli (U). SOCS3, IL1RL1, TLR4 mRNA expression and sST2 protein levels ex vivo were measured in PASTURE/EFRAIM children by real-time PCR or ELISA, respectively. Health outcomes (hay fever, asthma) were assessed by questionnaires at the age of 6 years. Results: rs928413 and rs1342326 were positively associated with hay fever (OR = 1.77, 95% CI = 1.02-3.08;OR = 1.79, 95% CI = 1.04-3.11) and CD4(+) CD25(high)FOXP3(+) Tregs (%) decreased in minor allele homozygotes/heterozygotes compared to major allele homozygotes (p(U) = 0.004;p(LPS) = 0.005;p(U) = 0.001;p(LPS) = 0.012). SOCS3 mRNA expression increased in minor allele homozygotes and heterozygotes compared with major allele homozygotes for both IL-33-polymorphisms (p (rs928413) = 0.032, p(rs1342326) = 0.019) and negatively correlated to Tregs. Conclusions: IL-33-polymorphisms rs928413 and rs1342326 may account for an increased risk of hay fever with the age of 6 years. Lower Tregs and increased SOCS3 in combined heterozygotes and minor allele homozygotes may be relevant for hay fever development, pointing towards dysbalanced immune regulation and insufficient control of allergic inflammation.

Increasing risk of pollinosis (hay fever) is one of the most anticipated consequences of climate change on human health. Wind-pollinated plants are representative of allergenic species because they include species with the highest capability of causing allergy-related diseases in humans. Therefore, changes in wind-pollinated species may reflect impacts of climate change on allergenic plants. In particular, flowering is one of the developmental stages most affected by climate change. This report specifically addresses changes in flowering dates that have occurred during the three decades 1971–2000 as a function of pollination mode and woodiness. The assessment is made using a phenological data set comprising trends of flowering dates of 29 species in 983 locations in Europe. Linear mixed models assessing the statistical significance of trends while adjusting for spatial correlation are used. The main results indicate for the first time that the onset of flowering of wind-pollinated plants advanced more than for insect-pollinated plants, while full flowering phases tended to advance less. These novel findings are contrary to the results of Fitter and Fitter (2002) for Oxfordshire, who reported larger advances of insect-pollinated plants. Onset of flowering and full flowering of insect-pollinated species are more likely to advance for seasons early in the year; instead, wind-pollinated plants showed no dependence of trends on the season (first flowering) or a decreased advance of phases that are early in the year (full flowering). The effect of woodiness could not be unambiguously defined, but seems to be of minor importance. The presented findings suggest a lengthening of the flowering period in general, which might lead to an increasing time of exposure to airborne pollen of allergic subjects, with consequent likely increment in severity and incidence of allergic symptoms.

Tree diameter and height are commonly measured forest structural variables, and indicators based on them are candidates for assessing forest diversity. We conducted our study on the uncertainty of estimates for mostly large geographic scales for four indicators of forest structural gamma diversity: mean tree diameter, mean tree height, and standard deviations of tree diameter and tree height. We had three objectives: to estimate the number of national forest inventory (NFI) plots whose data must be aggregated to obtain precise estimates of the indicators of gamma forest structural diversity; to assess differences in structural associations with respect to different forest categories; and to assess the effects of geographic distance on estimates of indicators of forest structural diversity. Uncertainty assessments were conducted using a bootstrap resampling approach and a geospatial approach to assess the effects of geographic distances. Our study relied on a database populated with NFI plot data (12,536 plots and 256,513 trees) from 13 European countries and three ecoprovinces of the United States. The results were threefold. First, data from approximately 150 NFI plots randomly selected from a large database are generally sufficient to estimate standard deviations (SDs) of diameter and height as indicators of structural forest diversity at large scales with acceptable precision. Second, the uncertainties of the estimates were generally greater for forest categories in Europe than in the United States with the exception of Douglas fir forests in the Pacific Northwest of the United States. Third, diameter and height gamma diversities expressed by the means and SDs of distributions of tree diameter and tree height were more similar for geographic areas separated by smaller distances.

Background: Previous studies have reported an increased frequency of restless legs syndrome (RLS) in adult migraine patients. Until now, the frequency of RLS in pediatric patients has not been investigated. We set out to assess the frequency of RLS in children and adolescents with migraine compared to headache-free controls. Methods: We investigated 111 consecutive patients with a sole diagnosis of migraine with or without aura presenting to the Headache Unit at the Department of Child and Adolescent Psychiatry and 73 headache-free controls for the presence of RLS using a semistructured interview. In addition, we assessed the level of daytime sleepiness by means of the Epworth sleepiness scale (ESS). A second group of headache-free controls was screened for the presence of RLS using an online questionnaire. Results: The frequency of RLS in migraine patients was significantly higher than in controls (22% vs. 5% ( p Discussion: This is the first study suggesting an association between RLS and migraine in the pediatric population. Future studies are needed to determine the extent of sleep disruption in children and adolescents with migraine and comorbid RLS.

Flowering behavior of the major allergenic species Betula pendula Roth (silver birch), Dactylis glomerata L. (cocksfoot) and Alopecurus pratensis L. (meadow foxtail), was examined by phenological observations in 2009 along an altitudinal gradient (from 700 m up to 1,700 m a.s.l.) in the topographically complex Zugspitze area on the German–Austrian border. The results were compared with pollen counts derived from pollen traps located at different altitudes (720 m, 1,503 m, 2,650 m a.s.l.). Phenological onset dates showed a great dependence on altitude and on exposition. Altitudinal gradients of the two grass species showed a delay of between 6 and 7 days (100 m)−1 and can be interpreted as a temperature response rate varying between −9 and −10 days (1 °C)−1. For birch phenophases, the altitudinal gradients were ca. 3 days (100 m)−1, corresponding to temperature response rates of circa −7 days (1 °C)−1. Northern and western exposed birch trees at the same altitude showed large differences in flowering dates (5–7 days). A comparison of phenological and aerobiological data in the phenological survey area revealed good agreement in the start of season dates, especially at lower altitude. Therefore, it was local pollen emissions, not long- or medium-range pollen transport that accounted for the timing of the aerobiological start of the season. Pollen counts at the highest and vegetation-free site were particularly affected by medium-range transport. More pronounced responses to altitude and therefore to temperature for the analyzed grass species indicate a greater temperature sensitivity. This suggests that further temperature increase could result in a remarkably earlier grass pollen season and, in turn, lead to major consequences for human health. Particular wind patterns can contribute to high and medically relevant pollen concentrations even at high elevation sites, implying less favourable conditions for those people allergic to pollen.

The relationship between number of species and area observed has been described using numerous approaches and has been discussed for more than a century. The general objectives of our study were fourfold: (1) to evaluate the behaviour of species–area curves across geographic scales, (2) to determine sample sizes necessary to produce acceptably precise estimates of tree species diversity, (3) to evaluate relationships among estimates of tree species diversity for local to large geographic scales, and (4) to determine whether the proportion of native tree species may be precisely estimated using sample sizes smaller than those necessary to estimate total tree species diversity. Such investigations are necessary to improve biodiversity monitoring at large scales. The analytical approaches included Monte Carlo bootstrap simulations and two geospatial methods and relied on a database populated with data for more than 12,000 national forest inventory plots (NFI) from 16 regional units, 13 European countries and three ecoprovinces of the United States of America (USA). Four primary results were obtained. First, tree species diversity may be precisely estimated using observations for a random subsample of 2,000–4,000 NFI plots. Second, large sample sizes are necessary to estimate tree species diversity for regional units or forest categories, except possibly for boreal forests for which the number of tree species is small. Third, estimates of the proportion of native tree species may be precisely estimated using tree species information for a random sample of approximately 30 NFI plots. Finally, our estimated species–area curves show that the curve shapes and relationships among estimates of tree species diversity at large scales clearly depend on the relative geographic location of the anchor regional unit (a European country or ecoprovince of the USA) relative to the other regional units. None of the well-known models for species–area curves adequately describes our results. The conclusion was that the uncertainties of the estimates reflect the unfavourable state of global biodiversity monitoring of species groups. The total numbers of tree species in our regional units, which cannot be adequately estimated, are small relative to other tree species-rich regions. Consequently, monitoring of tree species diversity is currently a highly uncertain enterprise at large scales.

Als heute 50-Jahriger erinnert man sich nicht immer gerne an die eigene Ausbildung als Medizinstudent. Zu oft mussten wir wahrend unserer sogenannten „Praktika“ die Aufforderung horen „aus dem Weg zu gehen“ bzw. den klinischen Routinebetrieb „nicht zu storen“. Und man war uberzeugt, das alles einmal besser und studentenfreundlicher zu gestalten, sollte man jemals die Gelegenheit dazu haben ... seit 2002 neue medizin-Curricula in Osterreich

Korperliche Befunde sind meist der Ausgangspunkt des Verdachtes auf Misshandlung. Fachgerechte und wissenschaftlich abgesicherte Befunderhebung, Interpretation, Diagnose und Differentialdiagnose konnen weit reichende Folgen haben, weshalb der Erstbegutachtung ein essentieller Stellenwert zukommt. Als Konsequenzen der gestellten Diagnose »Kindesmisshandlung« konnen Einbeziehung des Jugendamtes, familienrechtliche Eingriffe bis hin zur Entziehung des Sorgerechts stehen. Die Verantwortung, hier fundiert, korrekt und im Sinne des Kindes empathisch zu agieren, ist auserordentlich.

We present 2 patients with swelling of the groin after metal-on-metal total hip arthroplasty without radiological signs of component loosening. Magnetic resonance imaging in both patients showed a round intrapelvic lesion ventral to the femoral head. During surgery, we found cystic structures filled with fluid and necrotic masses. After resection of the cyst, the metal head and insert were replaced by a new ceramic head and a polyethylene liner. Although 2 different kinds of alloy were used (Sikomet, low carbon content; Metasul, high carbon content), histopathological analysis in both cases showed typical morphological signs of a hypersensitively determined inflammation. Despite the distinct soft tissue reaction, bony component integration was unaffected. In our opinion, open resection of the cystic lesion and changing of the metal-on-metal articulation is the treatment of choice.

Sixty patients (16 children, 44 adults) participated in the study aiming at evaluating: (i) IgG levels when switching patients from intravenous IgG (IVIG) infusions in hospital to subcutaneous (SCIG) self-infusions at home using the same cumulative monthly dose, (ii) protections against infections, and (iii) safety of a new, ready-to-use 16% IgG preparation. All children and 33 adults had received IVIG therapy for >6 months at enrolment. Ten adults who had been on SCIG therapy for many years served as controls. Mean serum IgG trough levels increased in the pre-IVIG children from 7.8 to 9.2 g/L (non-inferiority: p < 0.001) and in the adults from 8.6 to 8.9 g/L (non-inferiority: p < 0.001). Totally 114 respiratory tract infections occurred, 90% of them mild. One serious bacterial infection (pneumonia) was reported for one adult. The annualized rate of serious infections was 0.04 episodes/patient. In total 2297 infusions were given and 28 (1%) systemic adverse reactions occurred, none of them severe. Local tissue reactions declined over time, this being particularly distinct after 8 to 10 weeks. In conclusion, the SCIG administration route was safe. High IgG levels were easily maintained resulting in a very good protection against infections.

A large number of children and adults with primary antibody deficiencies need lifelong IgG replacement therapy. It is mostly unknown what effect the choice of replacement therapy has on the patients' health-related quality of life (HRQOL) and treatment satisfaction (TS).To investigate whether a switch from hospital-based intravenous IgG (IVIG) to home-based subcutaneous IgG (SCIG) therapy would improve the HRQOL and TS.Fifteen children (14 years; hospital-based IVIG therapy at enrollment) and 32 adults (or =14 years; 22 on hospital-based IVIG and 10 on home-based SCIG therapy at enrollment) were included. Questionnaires were completed at baseline and at 6 and 10 months: the Child Health Questionnaire-Parental Form 50 (children) or Short Form 36 (adults), the Life Quality Index, and questions regarding therapy preferences.The SCIG home therapy was reported to give better health (P=.001) and improved school/social functioning (P=.02) for the children, reduced emotional distress (P=.02) and limitations on personal time for the parents (P=.004), and fewer limitations on family activities (P=.002). Adults switching therapy reported improved vitality (P=.04), mental health ( P=.05), and social functioning ( P=.01). Adults already on SCIG home therapy at enrollment retained high HRQOL and TS scores. The SCIG home therapy improved TS because it led to greater independence and better therapy convenience ( P.05). The patients preferred the SCIG administration route and having the treatment at home.Home-based SCIG therapy improves several important aspects of HRQOL and provides the patients with primary antibody deficiencies and their families with greater independence and better control of the therapy situation and daily life. SCIG home therapy is an appreciated therapeutic alternative for adults and children in need of lifelong IgG replacement therapy.

Using a wall element filled with loose-fill cellulose insulation a settling test according to the draft standard ISO CD 18393, method B was performed. The drop height and the hardness of the absorber of the test stand were varied. Acceleration was measured at the bottom of the wall element and on three levels inside the insulation. Results show that certain maximum values are not exceeded inside the insulation, although acceleration at the bottom of the wall element is rising with increasing drop height and absorber hardness. Fast-Fourier-transform of the acceleration signals shows that only low frequencies mostly below 100 Hz are transferred into the insulation body while higher frequencies were absorbed by the insulation material.

Background Childhood asthma is classified into allergic asthma (AA) and nonallergic asthma (NA), yet both are treated identically, with only partial success. Objective We sought to identify novel immune phenotypes for childhood AA and NA. Methods The Clinical Asthma Research Association cohort study includes 275 steroid-naive 4- to 15-year-old German children (healthy control subjects [HCs], patients with AA, and patients with NA). In PBMCs both quantitative and functional analysis of regulatory T (Treg) and T H 17 cells (flow cytometry/Treg cell suppression) before/after anti-CD3/CD28, lipid A, and peptidoglycan stimulation were performed. Cytokines and gene expression, as assessed by using Luminex or transcriptomics/quantitative real-time RT-PCR, were analyzed by means of regression analysis. Linear discriminant analysis was applied to discriminate between phenotypes. Results The 3 phenotypes were immunologically well discriminated by means of microarray and protein analysis with linear discriminant analysis. Patients with AA were characterized by increased Treg cells compared with those in HCs but not those in patients with NA. Treg cells from patients with AA, but not patients with NA, significantly suppressed IL-5, IL-13, and IFN-γ secretion. Patients with AA had decreased expression of chloride intracellular channel 4 (CLIC4) and tuberous sclerosis 1 (TSC1) , important innate immunity regulators. Patients with NA were characterized by increased proinflammatory IL-1β levels, neutrophil counts, and IL-17–shifted immunity. In parallel, expressions of anti-inflammatory IL37 , proline-serine-threonine phosphatase–interacting protein 2 (PSTPIP2) , and the neutrophil-associated genes CD93 , triggering receptor expressed on myeloid cells 1 (TREM1) , and regulator of G-protein signaling 13 (RGS13) were increased in patients with NA. A shared T H 2 immunity was present in both asthma phenotypes. Conclusion Novel immune-regulatory mechanisms in childhood asthma identified increased Treg cells in patients with AA compared with those in HCs but not those in NA and decreased innate immunity genes for patients with AA, the first potentially indicating a counterregulatory mechanism to suppress cytokines yet not sufficient to control allergic inflammation. Very distinctly, patients with NA showed an IL-17–shifted proinflammatory immunity, promoting neutrophil inflammation and less functional Treg cells. Identification of these unique pathways provides a profound basis for future strategies for individualized prediction of asthma development, disease course, and prevention.

Several features common to a Western lifestyle, including obesity and low levels of physical activity, are known risk factors for gastrointestinal cancers. There is substantial evidence suggesting that diet markedly affects the composition of the intestinal microbiota. Moreover, there is now unequivocal evidence linking dysbiosis to cancer development. However, the mechanisms by which high-fat diet (HFD)-mediated changes in the microbial community affect the severity of tumorigenesis in the gut remain to be determined. Here we demonstrate that an HFD promotes tumour progression in the small intestine of genetically susceptible, K-ras(G12Dint), mice independently of obesity. HFD consumption, in conjunction with K-ras mutation, mediated a shift in the composition of the gut microbiota, and this shift was associated with a decrease in Paneth-cell-mediated antimicrobial host defence that compromised dendritic cell recruitment and MHC class II molecule presentation in the gut-associated lymphoid tissues. When butyrate was administered to HFD-fed K-ras(G12Dint) mice, dendritic cell recruitment in the gut-associated lymphoid tissues was normalized, and tumour progression was attenuated. Importantly, deficiency in MYD88, a signalling adaptor for pattern recognition receptors and Toll-like receptors, blocked tumour progression. The transfer of faecal samples from HFD-fed mice with intestinal tumours to healthy adult K-ras(G12Dint) mice was sufficient to transmit disease in the absence of an HFD. Furthermore, treatment with antibiotics completely blocked HFD-induced tumour progression, suggesting that distinct shifts in the microbiota have a pivotal role in aggravating disease. Collectively, these data underscore the importance of the reciprocal interaction between host and environmental factors in selecting a microbiota that favours carcinogenesis, and they suggest that tumorigenesis is transmissible among genetically predisposed individuals.

This study reports on alterations in the magnitude and frequency of extremes in reproductive phenology using long-term records (1951–2008) for plant species widely distributed across Germany. For each of fourteen indicator phases studied, time series of annual onset dates at up to 119 stations, providing 50–58 years of observation, were standardized by their station mean and standard deviation. Four alternative statistical models were applied and compared to derive probabilities of extreme early or late onset times for the phases: (1) Gaussian models were used to describe decadal probabilities of standardized anomalies, defined by data either falling below the 5th or exceeding the 95th percentile. (2) Semi-parametric quantile regression was employed for flexible and robust modelling of trends in different quantiles of onset dates. (3) Generalized extreme value distributions (GEV) were fitted to annual detrended minima and maxima of standardized anomalies, and (4) Generalized Pareto distributions (GPD) were fitted to extremes defined as peaks over threshold. Probabilities of extreme early phenological events inferred from Gaussian models, increased on average from 3 to 12%, whereas probabilities of extreme late phenological events decreased from 6 to 2% over the study period. Based on quantile regressions, summer and autumn phases revealed a more pronounced advancing pattern than spring phases. Estimated return levels by GEV were similar for the GPD methods, indicating that extreme early phenological events of magnitudes 2.5, 2.8, and 3.6 on the detrended standardized anomaly scale would occur every 20 years for spring, summer and autumn phases, respectively. This corresponds to absolute onset advances of up to 2 months depending on the season and species. This study demonstrates how extreme phenological events can be accurately modelled even in cases of inherently small numbers of observations, and underlines the need for additional evaluation related to their impacts on ecosystem functioning.

Using a stepwise logistic regression analysis, we investigated clinical data, allergologic findings, spirometric data, and the cellular and humoral immune system in order to gain new insights into the role these parameters play in bronchial hyperresponsiveness to methacholine in children and to create a model for the prediction thereof. Bronchial hyperresponsiveness, which was found in 124 of 462 children (26.8%), was observed to have been influenced by an increased level of eosinophils, the positivity of the skin prick test for any of the allergens tested, a decreased baseline forced expiratory volume in 1 second (FEV 1 ) (percent predicted), a decreased maximum expiratory flow at 50% expiration as a percent of forced vital capacity, and a decreased level of κ-chain-assembled immunoglobulins. Logit analysis disclosed that the influence of all other parameters on the occurrence of bronchial hyperresponsiveness was of no further statistical significance. The degree of bronchial hyperresponsiveness (provocative dose causing a 20% fall in FEV 1 ) showed a statistically significant correlation with the eosinophil count (Spearman's r = −0.198) and FEV 1 (percent predicted) (Spearman's r = 0.203). Our findings suggest that allergic sensitization and eosinophilic reaction in children are major factors in contributing to the occurrence of bronchial hyperresponsiveness to methacholine.

We investigated the changes in the cellular and humoral immune system in bronchoalveolar lavage (BAL) performed in 22 patients with pulmonary sarcoidosis and in 14 normal control subjects and their interactions with lung function parameters. Lymphocytosis, the increase in OKT4+ lymphocytes and OKT4+OKDR+ lymphocytes correlated with the increase in immunoglobulins, especially IgG, IgA and kappa chain assembled immunoglobulins. The transferrin levels obtained in BAL were found to be higher in patients with sarcoidosis, and they correlated with the cellular and, more closely, with other humoral findings. A negative correlation existed between the ventilatory parameters and the cell count and humoral findings. In addition, we found a negative correlation between the diffusing capacity for carbon monoxide and other cellular findings, which was most pronounced with reference to lymphocytes, OKT4+ lymphocytes and the OKT4+/OKT8+ ratio. These results underscore the role of OKT4+ lymphocytes, activated OKT4+OKDR+ lymphocytes and transferrin in the increase in immunoglobulins, mainly kappa chain isotypes. Because of the relationship between these changes and ventilatory parameters, and the diffusing capacity, the above results also reveal the clinical relevance of our findings.

To investigate the lasting effects of high ozone concentrations under environmental conditions, we examined the respiratory health, pulmonary function, bronchial hyperresponsiveness to methacholine, allergic sensitization, and lymphocyte subpopulations of 10- to 14-yr-old children. A total of 218 children recruited from an area with high ozone concentrations (Group A) were tested against 281 children coming from an area with low ozone concentrations (Group B). As to subjective complaints, categorized as "usually cough with or without phlegm," "breathlessness," and "susceptibility to chest colds," there was no difference between the two groups. The lung function parameters were similar, but in Group A subjects' bronchial hyperresponsiveness occurred more frequently and was found to be more severe than in Group B (29.4 versus 19.9%, p less than 0.02; PD20 2,100 +/- 87 versus 2,350 +/- 58 micrograms, p less than 0.05). In both groups the number of children who had been suffering from allergic diseases and sensitization to aeroallergens, found by means of the skin test, was the same. Comparison of the total IgE levels showed no difference at all between the two groups. As far as the white blood cells are concerned, the total and differential cell count was the same, whereas lymphocyte subpopulations showed readily recognizable changes.(ABSTRACT TRUNCATED AT 250 WORDS)