Joint Linkage and Association Analysis Using GENEHUNTER-MODSCORE with an Application to Familial Pancreatic Cancer.

INTRODUCTION: Joint linkage and association (JLA) analysis combines two disease gene mapping strategies: linkage information contained in families and association information contained in populations. Such a JLA analysis can increase mapping power, especially when the evidence for both linkage and association is low to moderate. Similarly, an association analysis based on haplotypes instead of single markers can increase mapping power when the association pattern is complex. METHODS: In this paper, we present an extension to the GENEHUNTER-MODSCORE software package that enables a JLA analysis based on haplotypes and uses information from arbitrary pedigree types and unrelated individuals. Our new JLA method is an extension of the MOD score approach for linkage analysis, which allows the estimation of trait-model and linkage disequilibrium (LD) parameters, i.e., penetrance, disease-allele frequency, and haplotype frequencies. LD is modeled between alleles at a single diallelic disease locus and up to three diallelic test markers. Linkage information is contributed by additional multi-allelic flanking markers. We investigated the statistical properties of our JLA implementation using extensive simulations, and we compared our approach to another commonly used single-marker JLA test. To demonstrate the applicability of our new method in practice, we analyzed pedigree data from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). RESULTS: Based on the simulated data, we demonstrated the validity of our JLA-MOD score analysis implementation and identified scenarios in which haplotype-based tests outperformed the single-marker test. The estimated trait-model and LD parameters were in good accordance with the simulated values. Our method outperformed another commonly used JLA single-marker test when the LD pattern was complex. The exploratory analysis of the FaPaCa families led to the identification of a promising genetic region on chromosome 22q13.33, which can serve as a starting point for future mutation analysis and molecular research in pancreatic cancer. CONCLUSION: Our newly proposed JLA-MOD score method proves to be a valuable gene mapping and characterization tool, especially when either linkage or association information alone provide insufficient power to identify the disease-causing genetic variants.

Adrenal Steroid Metabolism and Blood Pressure in 5- to 7-Year-Old Children Born Preterm as Compared to Peers Born at Term.

Background: Previous studies indicated preterm birth to be a risk factor for hypertension in adolescence and adulthood. However, studies in children investigating the underlying mechanisms are scarce. Objective: We hypothesized children born preterm to have higher excretion of cortisol and/or androgen metabolites per day concomitantly with higher blood pressure as compared to peers born at term. We thus aimed to compare urinary steroid profiles and blood pressure between 5- to 7-year-old children born preterm and peers born at term. Furthermore, aldosterone precursor excretion per day was compared between both groups. Methods: Blood pressure was measured in 236 children (preterms n = 116; gestational age 29.8 ± 2.6 (30; 24-33) weeks [mean ± standard deviation (median; range)]) using an automatic oscillometric device. Urinary steroid profiles were determined in 24-h urine samples (preterms n = 109; terms n = 113) using gas chromatographic-mass spectrometric analysis. To assess excretion of cortisol and androgen metabolites per day, major cortisol and androgen metabolites were summed, respectively. To assess aldosterone excretion per day tetrahydrocorticosterone, 5α-tetrahydrocorticosterone, and tetrahydro-11-deydrocorticosterone were summed. Results: Multiple regression analyses showed prematurity to be associated with systolic but not with diastolic blood pressure. When adjusted for potential confounders (prematurity, gender, age at day of examination, being born small for gestational age, breastfeeding, accelerated weight gain during infancy, family history of cardiovascular disease, parental hypertension, and body mass index) prematurity was shown to be associated with an increase in systolic blood pressure by 2.87 mmHg (95% confidence interval 0.48-5.27; p = 0.02). Cortisol, androgen metabolite, and aldosterone precursor excretion per day were not higher in individuals born preterm. In contrast to our hypothesis, multiple regression analysis showed prematurity to independently decrease cortisol and aldosterone precursor excretion per day (p < 0.001 and 0.04, respectively). Conclusion: This study provides further evidence for systolic blood pressure to be higher after preterm birth as early as at the age of 5 to 7 years. However, this seems not to be explained by elevated excretion of cortisol and/or androgen metabolites.

In-situ regeneration of P-doped optical fiber dosimeter.

We demonstrate the feasibility of resetting and reusing dosimeters exploiting the measurement of the infrared radiation-induced attenuation (IR-RIA) in phosphosilicate optical fibers (OFs) to provide point or distributed dose measurements in radiation environments. To bleach the room temperature stable IR-RIA, we used the photobleaching (PB) phenomenon. The PB efficiency was evaluated for different wavelengths in the [400-1100] nm range. The best identified PB resetting condition consists in using a continuous-wave Argon-ion laser at 514 nm. This treatment successfully bleached ∼97% of the IR-RIA at 1550 nm of a 30 m-long P-doped single mode optical fiber X-ray irradiated at a dose of 100 Gy. Successive re-irradiations of the same OF sample, regenerated after each run, confirm that the dosimeter keeps the same calibration curve during the whole process.

Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3-Internal Tandem Duplication Mutation (SORMAIN).

PURPOSE: Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the FMS-like tyrosine kinase 3 gene (FLT3-ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT. PATIENTS AND METHODS: In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with FLT3-ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first. RESULTS: With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank P = .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank P = .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib. CONCLUSION: Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for FLT3-ITD-positive AML.

Properties and Evaluation of the MOBIT - a novel Linkage-based Test Statistic and Quantification Method for Imprinting.

Genomic imprinting is a parent-of-origin effect apparent in an appreciable number of human diseases. We have proposed the new imprinting test statistic MOBIT, which is based on MOD score analysis. We were interested in the properties of the MOBIT concerning its distribution under three hypotheses: (1) H0,a: no linkage, no imprinting; (2) H0,b: linkage, no imprinting; (3) H1: linkage and imprinting. More specifically, we assessed the confounding between imprinting and sex-specific recombination frequencies, which presents a major difficulty in linkage-based testing for imprinting, and evaluated the power of the test. To this end, we have performed a linkage simulation study of affected sib-pairs and a three-generation pedigree with two trait models, many two- and multipoint marker scenarios, three genetic map ratios, two sample sizes, and five imprinting degrees. We also investigated the ability of the MOBIT to quantify the degree of imprinting and applied the MOBIT using a real data example on house dust mite allergy. We further proposed and evaluated two approaches to obtain empiric p values for the MOBIT. Our results showed that twopoint analyses assuming a sex-averaged marker map led to an inflated type I error due to confounding, especially for a larger marker-trait locus distance. When the correct sex-specific marker map was assumed, twopoint analyses have a reduced power to detect imprinting, compared to sex-averaged analyses with an appropriate correction for the inflation of the test statistic. However, confounding was not an issue in multipoint analysis unless the map ratio was extreme and marker spacing was sparse. With multipoint analysis, power as well as the ability to quantify the imprinting degree were almost equally high when a sex-averaged or the correct sex-specific map was used in the analysis. We recommend to obtain empiric p values for the MOBIT using genotype simulations based on the best-fitting nonimprinting model of the real dataset analysis. In addition, an implementation of a method based on the permutation of parental sexes is also available. In summary, we propose to perform multipoint analyses using densely spaced markers to efficiently discover new imprinted loci and to reliably quantify the degree of imprinting.

CERN IRRADIATION FACILITIES.

CERN provides unique irradiation facilities for applications in dosimetry, metrology, intercomparison of radiation protection devices, benchmark of Monte Carlo codes and radiation damage studies to electronics.

Psychological risk and protective factors for disability in chronic low back pain - a longitudinal analysis in primary care.

BACKGROUND: Utilizing psychological resources when dealing with chronic low back pain might aid the prevention of disability. The observational study at hand examined the longitudinal impact of resilience and coping resources on disability in addition to established risk factors. METHODS: Four hundred eighty four patients with chronic low back pain (>3 months) were recruited in primary care practices and followed up for one year. Resilience, coping, depression, somatization, pain and demographic variables were measured at baseline. At follow-up (participation rate 89%), data on disability was collected. We first calculated bivariate correlations of all the predictors with each other and with follow-up disability. We then used a multiple regression to evaluate the impact of all the predictors on disability together. RESULTS: More than half of the followed up sample showed a high degree of disability at baseline (53.7%) and had suffered for more than 10 years from pain (50.4%). Besides gender all of the predictors were bivariately associated with follow-up disability. However in the main analysis (multiple regression), disability at follow up was only predicted by baseline disability, age and somatization. There was no relationship between resilience and disability, nor between coping resources and disability. CONCLUSIONS: Although it is known that there are cross-sectional relationships between resilience/coping resources and disability we were not able to replicate it in the multiple regression. This can have several reasons: a) the majority of patients in our sample were much more disabled and suffered for a longer time than in other studies. Therefore our results might be limited to this specific population and resilience and coping resources might still have a protective influence in acute or subacute populations. b) We used a rather broad operationalization of resilience. There is emerging evidence that focusing on more concrete sub facets like (pain) self-efficacy and acceptance might be more beneficial. TRIAL REGISTRATION: German Clinical Trial Register, DRKS00003123 (June 28th 2011).

Safety and Efficacy of Botulinum Toxin to Preserve Gland Function after Radiotherapy in Patients with Head and Neck Cancer: A Prospective, Randomized, Placebo-Controlled, Double-Blinded Phase I Clinical Trial.

This prospective, randomized, placebo-controlled, double-blinded phase I clinical trial investigates safety and efficacy of botulinum toxin (BoNT) to preserve gland function after radiotherapy in patients with head and neck cancer. Twelve patients with advanced head and neck cancer were injected with BoNT into the submandibular glands prior to primary radiochemotherapy. Six patients received BoNT/A and 6 patients BoNT/A and B, half of each subgroup into their left and the other half into their right gland. As an internal control, sodium chloride was injected into the respective contralateral gland (placebo). For the evaluation of the salivary gland function, technetium pertechnetate salivary gland scintigraphy was performed before and after the end of radiotherapy. BoNT/A and B were well tolerated. Analysis of the scintigraphic data revealed no statistically significant difference between BoNT and placebo regarding the scintigraphic uptake difference (pBoNT/A = 0.84 and pBoNT/A-B = 0.56 for BoNT/A vs. placebo and BoNT/A-B vs. placebo, respectively). We also found no significant difference in treatment between BoNT and placebo in terms of salivary excretion fraction (pBoNT/A = 0.44; pBoNT/A-B = 0.44). This study demonstrates that BoNT can be safely combined with radiochemotherapy. Dosing and timing of BoNT injection should be further investigated for efficacy analysis. Trial Registration German Registry for Clinical Trails DRKS00004595.

Estimation of Trait-Model Parameters in a MOD Score Linkage Analysis.

BACKGROUND/AIMS: Theoretically, the trait-model parameters (disease allele frequency and penetrance function) can be estimated without bias in a MOD score linkage analysis. We aimed to practically evaluate the MOD score approach regarding its ability to provide unbiased trait-model parameters for various pedigree-type and trait-model scenarios. We further investigated the ability of the MOD score approach to detect imprinting using affected sib pairs (ASPs) and affected half-sib pairs (AHSPs) when all parental genotypes are missing. METHODS: Simulated pedigree data were analyzed using the GENEHUNTER-MODSCORE software package. Parameter estimation performance in terms of bias and variability was evaluated with regard to trait-model type and pedigree complexity. RESULTS: Generally, parameters were estimated with lower bias and variability with increasing pedigree complexity, especially for recessive and overdominant models. However, dominant and additive models could hardly be distinguished even when using 3-generation pedigrees. Imprinting could clearly be detected for mixtures of mainly ASPs and only few AHSPs with the common parent of the imprinted sex, even though no parental genotypes were available. CONCLUSION: Our results provide guidance to researchers regarding the possibility to estimate trait-model parameters by a MOD score analysis, including the degree of imprinting, with certain types of pedigrees.

Even Worse - Risk Factors and Protective Factors for Transition from Chronic Localized Low Back Pain to Chronic Widespread Pain in General Practice: A Cohort Study.

STUDY DESIGN: Prospective cohort study with patients with chronic low back pain (CLBP) at primary care setting. OBJECTIVE: The aim of our study was to identify predictors for transition from localized CLBP to chronic widespread pain in general practice. In contrast to the typically investigated risk factors, this study also focuses intensively on protective factors, which decrease the probability of chronic widespread pain. For this, we investigated the resources resilience and coping strategies, which are suspected as potential protective factors for incident chronic pain syndromes. SUMMARY OF BACKGROUND DATA: In primary care, about a quarter of patients with CLBP experience chronic widespread pain (CWP). METHODS: Patients experiencing localized CLBP were included and evaluated after a 6- and 12-month follow-up period regarding the development of CWP. Potential risk factors (sociodemographic data, pain characteristics, depression, anxiety, somatization), protective factors (resilience, coping strategies), and sample characteristics were assessed at baseline. Predictor identification was done by multivariate logistic regression analysis. RESULTS: The 1-year incidence for the onset of CWP among patients with CLBP was 23.8%. We identified the 3 risk factors, female sex, long duration of back pain, and a high rate of psychosomatic symptoms, for the onset of CWP among patients with CLBP. Coping resources and resilience had no impact on the transition from CLBP to CWP. CONCLUSION: The results suggest that CWP is no independent entity but rather a particularly negative occurrence on a continuum of chronic pain. Processes of somatization play a major role in the development of this extreme. LEVEL OF EVIDENCE: 2.

Fast linkage analysis with MOD scores using algebraic calculation.

OBJECTIVE: As the mode of inheritance is often unknown for complex diseases, a MOD-score analysis, in which the parametric LOD score is maximized with respect to the trait-model parameters, can be a powerful approach in genetic linkage analysis. Because the calculation of the disease-locus likelihood is the most time-consuming step in a MOD-score analysis, we aimed to optimize this part of the calculation to speed up linkage analysis using the GENEHUNTER-MODSCORE software package. METHODS: Our new algorithm is based on minimizing the effective number of inheritance vectors by collapsing them into classes. To this end, the disease-locus-likelihood contribution of each inheritance vector is represented and stored in its algebraic form as a symbolic sum of products of penetrances and disease-allele frequencies. Simulations were used to assess the speedup of our new algorithm. RESULTS: We were able to achieve speedups ranging from 1.94 to 11.52 compared to the original GENEHUNTER-MODSCORE version, with higher speedups for larger pedigrees. When calculating p values, the speedup ranged from 1.69 to 10.36. CONCLUSION: Computation times for MOD-score analysis, involving the evaluation of many tested sets of trait-model parameters and p value calculation, have been prohibitively high so far. With our new algebraic algorithm, such an analysis is now feasible within a reasonable amount of time.

Epigenetics meets metabolomics: an epigenome-wide association study with blood serum metabolic traits.

Previously, we reported strong influences of genetic variants on metabolic phenotypes, some of them with clinical relevance. Here, we hypothesize that DNA methylation may have an important and potentially independent effect on human metabolism. To test this hypothesis, we conducted what is to the best of our knowledge the first epigenome-wide association study (EWAS) between DNA methylation and metabolic traits (metabotypes) in human blood. We assess 649 blood metabolic traits from 1814 participants of the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) population study for association with methylation of 457 004 CpG sites, determined on the Infinium HumanMethylation450 BeadChip platform. Using the EWAS approach, we identified two types of methylome-metabotype associations. One type is driven by an underlying genetic effect; the other type is independent of genetic variation and potentially driven by common environmental and life-style-dependent factors. We report eight CpG loci at genome-wide significance that have a genetic variant as confounder (P = 3.9 × 10(-20) to 2.0 × 10(-108), r(2) = 0.036 to 0.221). Seven loci display CpG site-specific associations to metabotypes, but do not exhibit any underlying genetic signals (P = 9.2 × 10(-14) to 2.7 × 10(-27), r(2) = 0.008 to 0.107). We further identify several groups of CpG loci that associate with a same metabotype, such as 4-vinylphenol sulfate and 4-androsten-3-beta,17-beta-diol disulfate. In these cases, the association between CpG-methylation and metabotype is likely the result of a common external environmental factor, including smoking. Our study shows that analysis of EWAS with large numbers of metabolic traits in large population cohorts are, in principle, feasible. Taken together, our data suggest that DNA methylation plays an important role in regulating human metabolism.

New radiation protection calibration facility at CERN.

The CERN radiation protection group has designed a new state-of-the-art calibration laboratory to replace the present facility, which is >20 y old. The new laboratory, presently under construction, will be equipped with neutron and gamma sources, as well as an X-ray generator and a beta irradiator. The present work describes the project to design the facility, including the facility placement criteria, the 'point-zero' measurements and the shielding study performed via FLUKA Monte Carlo simulations.

Differences between patients with chronic widespread pain and local chronic low back pain in primary care--a comparative cross-sectional analysis.

BACKGROUND: Chronic pain is a common reason for consultation in general practice. Current research distinguishes between chronic localized pain (CLP) and chronic widespread pain (CWP). The aim of this study was to identify differences between CWP and chronic low back pain (CLBP), a common type of CLP, in primary care settings. METHODS: Fifty-eight German general practitioners (GPs) consecutively recruited all eligible patients who consulted for chronic low back pain during a 5-month period. All patients received a questionnaire on sociodemographic data, pain characteristics, comorbidities, psychosomatic symptoms, and previous therapies. RESULTS: GPs recruited 647 eligible patients where of a quarter (n = 163, 25.2%) met the CWP criteria according to the American College of Rheumatology. CWP patients had significantly more comorbidities and psychosomatic symptoms, showed longer pain duration, and suffered predominantly from permanent pain instead of distinguishable pain attacks. CWP patients were more often females, are less working and reported a current pension application or a state-approved grade of disability more frequently. We found no other differences in demographic parameters such as age, nationality, marital status, number of persons in household, education, health insurance status, or in health care utilization data. CONCLUSIONS: This project is the largest study performed to date which analyzes differences between CLBP and CWP in primary care settings. Our results showed that CWP is a frequent and particularly severe pain syndrome. TRIAL REGISTRATION: German Clinical Trial Register, DRKS00003123.

Chronic low back pain patient groups in primary care--a cross sectional cluster analysis.

BACKGROUND: Due to the heterogeneous nature of chronic low back pain (CLBP), it is necessary to identify patient groups and evaluate treatments within these groups. We aimed to identify groups of patients with CLBP in the primary care setting. METHODS: We performed a k-means cluster analysis on a large data set (n = 634) of primary care patients with CLBP. Variables of sociodemographic data, pain characteristics, psychological status (i.e., depression, anxiety, somatization), and the patient resources of resilience and coping strategies were included. RESULTS: We found three clusters that can be characterized as "pensioners with age-associated pain caused by degenerative diseases", "middle-aged patients with high mental distress and poor coping resources", and "middle-aged patients who are less pain-affected and better positioned with regard to their mental health". CONCLUSIONS: Our results supported current knowledge concerning groups of CLBP patients in primary care. In particular, we identified a group that was most disabled and distressed, and which was mainly characterized by psychological variables. As shown in our study, pain-related coping strategies and resilience were low in these patients and might be addressed in differentiating treatment strategies. Future studies should focus on the identification of this group in order to achieve effective treatment allocation. TRIAL REGISTRATION: German Clinical Trial Register DRKS00003123.

Prematurity is not associated with intra-abdominal adiposity in 5- to 7-year-old children.

OBJECTIVE: To compare body composition and abdominal fat partitioning between 5- to 7-year old children born preterm and born at term. We hypothesized children born preterm to have a higher body fat percentage and higher percentage of intra-abdominal adipose tissue (%IAAT) compared with their peers born at term. STUDY DESIGN: A total of 236 children aged 5-7 years, ie, 116 children born preterm (gestational age 29.8 ± 2.6 [30; 24-33] weeks [mean ± SD {median; range}]) and 120 children born at term were included. Body composition was measured by bioelectrical impedance analysis and %IAAT by magnetic resonance imaging. Body mass index, skin fold thickness, and waist-to-hip ratio were investigated as further measures of body composition. Dietary records were compared between both groups. RESULTS: Children born preterm were shorter (120 cm vs 123 cm, P < .001), lighter (21.8 kg vs 24.3 kg, P < .001), and had a lower body mass index (15.1 kg/m(2) vs 15.9 kg/m(2), P = .003) compared with controls. There were no differences in %IAAT (n = 154), and body fat mass although energy uptake was higher in preterms (335 kJ/kg/d vs 302 kJ/kg/d, P = .03). CONCLUSIONS: At the age of 5-7 years, children born preterm showed neither increased fat mass nor intra-abdominal adiposity.

Genome-wide methylation screen in low-grade breast cancer identifies novel epigenetically altered genes as potential biomarkers for tumor diagnosis.

Aberrant DNA methylation constitutes a well-established epigenetic marker for breast cancer. Changes in methylation early in cancer development may be clinically relevant for cancer detection and prognosis-based therapeutic decisions. In the present study, a combination of methyl-CpG immunoprecipitation (MCIp) and human CpG island (CGI) arrays was applied to compare genome-wide DNA methylation profiles in 10 low-grade in situ and invasive breast cancers against 10 normal breast samples. In total, 214 CGIs were found to be hypermethylated in ≥6 of 10 tumors. Functional term enrichment analyses revealed an overrepresentation of homeobox genes and genes involved in transcription and regulation of transcription. Significant hypermethylation of 11 selected genes in tumor vs. normal tissue was validated in two independent sample sets (45 tumors and 11 controls, 43 tumors and 8 controls) using quantitative EpiTyper technology. In tumors, median methylation levels of BCAN, HOXD1, KCTD8, KLF11, NXPH1, POU4F1, SIM1, and TCF7L1 were ≥30% higher than in normal samples, representing potential biomarkers for tumor diagnosis. Using the 90th percentile of methylation levels in normal tissue as cutoff value, 62-92% of in situ samples (n=13), 72-97% of invasive samples from the first validation set (n=32), and 86-100% of invasive samples from the second validation set (n=43) were classified as hypermethylated. Hypermethylation of KLF11 and SIM1 might also be associated with increased risk of developing metastases. In summary, early methylation changes are frequent in the low-grade pathway of breast cancer and may be useful in the development of differential diagnostic and possibly also prognostic markers.

Study protocol: Transition from localized low back pain to chronic widespread pain in general practice: identification of risk factors, preventive factors and key elements for treatment--a cohort study.

BACKGROUND: Chronic localized pain syndromes, especially chronic low back pain (CLBP), are common reasons for consultation in general practice. In some cases chronic localized pain syndromes can appear in combination with chronic widespread pain (CWP). Numerous studies have shown a strong association between CWP and several physical and psychological factors. These studies are population-based cross-sectional and do not allow for assessing chronology. There are very few prospective studies that explore the predictors for the onset of CWP, where the main focus is identifying risk factors for the CWP incidence. Until now there have been no studies focusing on preventive factors keeping patients from developing CWP. Our aim is to perform a cross sectional study on the epidemiology of CLBP and CWP in general practice and to look for distinctive features regarding resources like resilience, self-efficacy and coping strategies. A subsequent cohort study is designed to identify the risk and protective factors of pain generalization (development of CWP) in primary care for CLBP patients. METHODS/DESIGN: Fifty-nine general practitioners recruit consecutively, during a 5 month period, all patients who are consulting their family doctor because of chronic low back pain (where the pain is lasted for 3 months). Patients are asked to fill out a questionnaire on pain anamnesis, pain-perception, co-morbidities, therapy course, medication, socio demographic data and psychosomatic symptoms. We assess resilience, coping resources, stress management and self-efficacy as potential protective factors for pain generalization. Furthermore, we raise risk factors for pain generalization like anxiety, depression, trauma and critical life events. During a twelve months follow up period a cohort of CLBP patients without CWP will be screened on a regular basis (3 monthly) for pain generalization (outcome: incident CWP). DISCUSSION: This cohort study will be the largest study which prospectively analyzes predictors for transition from CLBP to CWP in primary care setting. In contrast to the typically researched risk factors, which increase the probability of pain generalization, this study also focus intensively on protective factors, which decrease the probability of pain generalization. TRIAL REGISTRATION: German Clinical Trial Register DRKS00003123.

Joint influences of Acidic-Mammalian-Chitinase with Interleukin-4 and Toll-like receptor-10 with Interleukin-13 in the genetics of asthma.

In the genetics of asthma, single genetic polymorphisms confer only a small individual risk factor. Haplotype-based association analyses, including joint analyses of several candidate genes, might therefore yield more convincing results than single-region statistics. We set out to test for joint influences of asthma genes previously identified in our study population that is acidic mammalian chitinase (AMCase), Toll-like receptor (TLR)-10, and the interleukins IL-4, IL-13, IL-8, and IL-15. In particular, we investigated whether haplotypes at two or three genes show stronger association with the trait than at a single gene alone. We genotyped 26 polymorphisms in 321 asthmatic children and 270 controls. Haplotype-based association analyses were performed by the program FAMHAP. Single-, two-, and three-gene analyses were conducted as well as conditional analyses for pairs of genes. In the two-region analyses, best evidence was found for a joint effect on asthma for AMCase and IL-4 (p(raw) < 5 x 10(-7)) as well as AMCase and IL-13 (p(raw) = 5 x 10(-7)). Besides, IL-13 and TLR-10 showed a stronger two-gene result (p(raw) = 0.001607) than the respective single-gene analyses. Conditional analyses yielded similar results for these two-gene combinations and also revealed mutual additional effects for IL-13 and IL-4 (p(stratified) = 0.014831 and 0.001525, respectively). The most significant results demonstrate a joint effect of AMCase with IL-4 or IL-13 on the trait. Furthermore, additional mutual effects were seen for AMCase and IL-4 as well as for TLR-10 and IL-13. The corresponding pathways might therefore be of particular importance in the genetics of asthma. Further studies are needed to elucidate the functional importance of these gene-gene effects and their precise role in asthma pathogenesis.

Risk factors of neonatal respiratory distress following vaginal delivery and caesarean section in the German population.

BACKGROUND: The incidence of caesarean section (CS) is steadily rising world-wide. In particular, CS on maternal demand is performed more frequently. In parts, this might be due to insufficient information of pregnant women about neonatal risks of CS. We sought to specify neonatal outcomes following different modes of delivery, i.e. vaginal delivery, primary CS and secondary CS and to define risk factors for respiratory morbidity and hospitalization. METHODS: We analysed 2073 births (gestational age > 35 weeks) during a two-year period at a tertiary obstetric and neonatal centre in Germany. Statistical analyses were performed for single parameters by SPSS as well as by logistic regression to account for possible confounders. Furthermore, extensive model calculation was done. RESULTS: Respiratory morbidity was increased following primary and secondary CS (p = 0.001). By multiple logistic regression, the strongest effect on respiratory symptoms was seen with gestational age, each week more in utero reducing the risk by an odds ratio (OR) of 0.69 (95% CI: [0.61; 0.79]; p = 1.9 x 10(-8)). Furthermore, a significant interaction between mode of delivery and gestational age was found for the risk of respiratory symptoms (p = 0.0035). CONCLUSION: For every eight newborns delivered by primary CS one more than expected with vaginal delivery is hospitalized. It is highly relevant to recognize that each week of gestational age reduces the risk of respiratory symptoms, especially if primary CS is performed. The higher rate of respiratory morbidity and neonatal admission following CS should be clearly recognized in counselling of pregnant women.