A comprehensive analysis of interleukin-4 receptor polymorphisms and their association with atopy and IgE regulation in childhood

Background: The interleukin (IL) 4/IL13 pathway is involved in the regulation of IgE production associated with atopic diseases. Numerous polymorphisms have been identified in the coding region of the IL4 receptor alpha chain (IL4Ra) and previous association studies have shown conflicting results. Based on their putative functional role, polymorphisms A148G, T1432C and A1652G, located in the coding region of IL4Ra, were selected for association and haplotype studies in a large German population sample (n = 1,120). Methods: Genotyping was performed using allele-specific PCR and restriction-enzyme-based assays. Haplotypes were estimated, and population-derived IgE percentiles (50% IgE >60 IU/ml, 66% IgE >115 IU/ml and 90% IgE >457 IU/ml) were calculated as outcome variables in a haplotype trend regression analysis. Results: In our population, only polymorphism T1432C showed a trend for a protective effect against atopic rhinitis ( odds ratio, OR: 0.52, 95% confidence interval, CI: 0.26 - 1.02, p = 0.05). When haplotypes were calculated, one haplotype was significantly associated with elevated serum IgE levels at the 50th percentile ( OR 1.60, 95% CI 1.08 - 2.37, p = 0.02). Conclusions: These data indicate that IL4Ra polymorphisms, although suggested to be functionally relevant by in vitro studies, have only a minor influence on IgE regulation in our large population sample. Copyright (C) 2004 S. Karger AG, Basel

CX3CR1 Polymorphisms are associated with atopy but not asthma in German children

Chemokines and their receptors are involved in many aspects of immunity. Chemokine CX3CL1, acting via its receptor CX3CR1, regulates monocyte migration and macrophage differentiation as well as T cell-dependent inflammation. Two common, nonsynonymous polymorphisms in CX3CR1 have previously been shown to alter the function of the CX3CL1/CX3CR1 pathway and were suggested to modify the risk for asthma. Using matrix-assisted laser desorption/ionization time-of-flight technology, we genotyped polymorphisms Val249Ile and Thr280Met in a cross-sectional population of German children from Munich (n = 1,159) and Dresden ( n = 1,940). For 249Ile an odds ratio of 0.77 (95% confidence interval 0.63-0.96; p = 0.017) and for 280Met an odds ratio of 0.71 ( 95% confidence interval 0.56-0.89; p = 0.004) were found with atopy in Dresden but not in Munich. Neither polymorphism was associated with asthma. Thus, amino acid changes in CX3CR1 may influence the development of atopy but not asthma in German children. Potentially, other factors such as environmental effects may modify the role of CX3CR1 polymorphisms. Copyright (c) 2007 S. Karger AG, Basel

Workplace risk factors for cancer in the German rubber industry: Part 1. Mortality from respiratory cancers

OBJECTIVES: To determine the cancer specific mortality by work area among active and retired male workers in the German rubber industry. METHODS: A cohort of 11,663 male German workers was followed up for mortality from 1 January 1981 to 31 December 1991. Cohort members were classified as active (n = 7536) or retired (n = 4127) as of 1 January 1981 and had been employed for at least one year in one of five study plants producing tyres or technical rubber goods. Work histories were reconstructed with routinely documented "cost centre codes" which were classified into six categories: I preparation of materials; II production of technical rubber goods; III production of tyres; IV storage and dispatch; V maintenance; and VI others. Standardised mortality ratios (SMRs) adjusted for age and calendar year and 95% confidence intervals (95% CIs), stratified by work area (employment in respective work area for at least one year) and time related variables (year of hire, lagged years of employment in work area), were calculated from national reference rates. RESULTS: SMRs for laryngeal cancer were highest in work area I (SMR 253; 95% CI 93 to 551) and were significant among workers who were employed for > 10 years in this work area (SMR 330; 95% CI 107 to 779). Increased mortality rates from lung cancer were identified in work areas I (SMR 162; 95% CI 129 to 202), II (SMR 134; 95% CI 109 to 163), and V (SMR 131; 95% CI 102 to 167). Mortality from pleural cancer was increased in all six work areas, and significant excesses were found in work areas I (SMR 448; 95% CI 122 to 1146), II (SMR 505; 95% CI 202 to 1040), and V (SMR 554; 95% CI 179 to 1290). CONCLUSION: A causal relation between the excess of pleural cancer and exposure to asbestos among rubber workers is plausible and likely. In this study, the pattern of excess of lung cancer parallels the pattern of excess of pleural cancer. This points to asbestos as one risk factor for the excess deaths from lung cancer among rubber workers. The study provides further evidence for an increased mortality from laryngeal cancer among workers in the rubber industry, particularly in work area I

Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma

Asthma is caused by a combination of poorly understood genetic and environmental factors(1,2). We have systematically mapped the effects of single nucleotide polymorphisms ( SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P=0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P=0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein - Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum(3). The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62682/1/nature06014.pd

First Observation of Self-Amplified Spontaneous Emission in a Free-Electron Laser at 109 nm Wavelength

We present the first observation of Self-Amplified Spontaneous Emission (SASE) in a free-electron laser (FEL) in the Vacuum Ultraviolet regime at 109 nm wavelength (11 eV). The observed free-electron laser gain (approx. 3000) and the radiation characteristics, such as dependency on bunch charge, angular distribution, spectral width and intensity fluctuations all corroborate the existing models for SASE FELs.Comment: 6 pages including 6 figures; e-mail: [email protected]