In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow's milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention-Program (GINI) was supported for the first 3 years by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomized, double-blind intervention study was to investigate the impact of different cow's milk protein hydrolysate infant formulas in the first 4 - 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University Munich and Children's Department Technical University Munich) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow's milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow's milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow's milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow's milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomization to standard cow's milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto’s thyroiditis), as well as autoimmune hyperthyroidism (Graves’ disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations ( P , 5 6 10 2 8 ) were detected at TPO -rs11675434, ATXN2 -rs653178, and BACH2- rs10944479 for TPOAb-positivity, and at TPO- rs11675434, MAGI3 -rs1230666, and KALRN -rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P =8.1 6 10 2 8 ), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P =2.9 6 10 2 6 ), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P =6.5 6 10 2 4 ). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves’ disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2 6 10 2 7 and OR: 1.25, 95% CI 1.12–1.39, P =6.2 6 10 2 5 ). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P =1.9 6 10 2 3 ). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

The German Infant Nutritional Intervention Study (GINI) for the preventive effect of hydrolysed infant formulas in infants at high risk for allergic diseases. Design and selected results In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention-Program (GINI) was supported for the first 3 years of the study by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomised, double-blind intervention study was to investigate the impact of different cow milk protein hydrolysate infant formulas in the first 4 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of an allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University Munchen and Children's Department Technical University Munchen) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula-groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI-intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomisation to standard cow milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions.

Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p=0.0049; odds ratio (OR)9.91, 95% confidence interval (CI) 1.9251.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10−11 and 2.7 × 10−11), which were also in strong linkage disequilibrium (r2=0.7) with each other, lie in the 23-kb long commonly shared 5′ flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10−09) near NRCAM—a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10−09)—an SNP associated with blood pressure—in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10−05) and Parkinson's disease pathways (P-value=3.6 × 10−05).

An easy, fast and reliable method was developed to screen hundreds of Epstein-Barr virus-transformed cell lines (lymphoblastoid cell lines, LCLs) for radiation sensitivity that were generated from lymphocytes isolated from young lung cancer patients. The WST-1 test explores the metabolic activity of the mitochondria as an indicator for the vital status of cells. Cell proliferation as well as indirect cell death can be quantified by this method on a large scale in microtiter plates. Cell survival was measured at 24- and 48-h post-irradiation with 10 Gy (Cs-137 source) by the WST-1 assay and Trypan blue staining. To set up the experimental screening conditions and to establish a positive and a negative control, an ATM-mutated cell line from a radiation-sensitive ATM patient and an ATM proficient cell line from a healthy brother were compared. An optimal differentiation between the two cell lines was demonstrated for 10 Gy and 24- and 48-h cell growth after irradiation. Upon screening 120 LCLs of young lung cancer patients under these conditions, 5 of them were found to be radiation sensitive to a high degree of statistical significance. The results have been confirmed by a second laboratory by means of Trypan blue testing. The WST-1 test represents an efficient and reliable method by means of screening for radiation-sensitive cell lines.

A concept will be presented and discussed on how an improved European-wide monitoring network, air pollution data and health impact assessment could be achieved. The current practise of ambient air quality monitoring has been analysed and limitations have been identified.

In 1998 Congress mandated expanded U.S. Environmental Protection Agency (U.S. EPA) health effects research on ambient air particulate matter (PM) and a National Research Council (NRC) committee to provide research oversight. The U.S. EPA currently supports intramural and extramural PM research, including five academically based PM centers. The PM centers in their first 2.5 years have initiated research directed at critical issues identified by the NRC committee, including collaborative activities, and sponsored scientific workshops in key research areas. Through these activities, there is a better understanding of PM health effects and scientific uncertainties. Future PM centers research will focus on long-term effects associated with chronic PM exposures. This report provides a synopsis of accomplishments to date, short-term goals (during the next 2.5 years) and longer-term goals. It consists of six sections: biological mechanisms, acute effects, chronic effects, dosimetry, exposure assessment, and the specific attributes of a coordinated PM centers program.

In 1998 Congress mandated expanded U.S. Environmental Protection Agency (U.S. EPA) health effects research on ambient air particulate matter (PM) and a National Research Council (NRC) committee to provide research oversight. The U.S. EPA currently supports intramural and extramural PM research, including five academically based PM centers. The PM centers in their first 2.5 years have initiated research directed at critical issues identified by the NRC committee, including collaborative activities, and sponsored scientific workshops in key research areas. Through these activities, there is a better understanding of PM health effects and scientific uncertainties. Future PM centers research will focus on long-term effects associated with chronic PM exposures. This report provides a synopsis of accomplishments to date, short-term goals (during the next 2.5 years) and longer-term goals. It consists of six sections: biological mechanisms, acute effects, chronic effects, dosimetry, exposure assessment, and the specific attributes of a coordinated PM centers program.

BACKGROUND Previous research has demonstrated that adenocarcinoma is the leading cell type among patients with early age onset lung carcinoma. An increase in adenocarcinoma at the expense of squamous cell carcinoma in general was observed in recent years and may be due to the smoking of filtered cigarettes. METHODS To rule out whether shifts in smoking patterns or other etiologic factors are responsible for the high rates of adenocarcinoma in young patients, personal interviews regarding smoking, occupation, and family history of cancer were conducted in 251 young patients (age ≤ 45 years) and 2009 older patients (ages 55–69 years) with histologically confirmed lung carcinoma from selected study clinics in Germany between 1990 and 1996. RESULTS Young male patients were found to have significantly more adenocarcinomas (41%) than older male patients (28%), whereas adenocarcinomas were dominant in young and older women (43% and 47%, respectively). Because smoking patterns were different between young and older patients, the authors stratified for comparable levels of smoking exposure. Histology did not differ in never smokers (dominance of adenocarcinomas in both age groups) and in male heavy smokers (dominance of squamous cell carcinomas in both age groups), whereas young male low dose smokers showed significantly more cases of adenocarcinoma than older low dose smokers. A family history of lung carcinoma was significantly higher in young patients compared with older patients, but no association with histologic type was observed. CONCLUSIONS The results of the current study show that differences in the histologic type of lung carcinoma based on age at onset can be explained in part by differences in smoking patterns. However, there still are unknown factors that appear to favor the development of adenocarcinoma in the young. Cancer 1999;85:1958–65. © 1999 American Cancer Society.

The effects of cadmium on measures of immune-system function were determined from a health survey of school children in heavily polluted regions of eastern Germany. A representative sample of 842 students, aged 5-14 y, was included in logistic regression analyses in which the relationship between urinary cadmium content and blood immunoglobulin levels was examined. Investigators further evaluated a subsample of 807 students to determine cadmium's effect on the immediate hypersensitivity reactions elicited by skin-prick challenges with 12 common aeroallergens. Several potentially confounding factors were controlled for, after which investigators found that increasing body burdens of cadmium were associated consistently with dose-dependent suppression of immediate hypersensitivity and of immunoglobin G, but not immunoglobulins M, A, or E levels. The immunoglobulin pattern observed in exposed children led investigators to suggest that secondary humoral responses were impaired by cadmium.