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ObjectivesSmoking has been connected to citrullination of antigens and formation of anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Since smoking can modify proteins by carbamylation (formation of homocitrulline), this study was conducted to investigate these effects on vimentin in animal models and RA.MethodsThe efficiency of enzymatic carbamylation of vimentin was characterised. B-cell response was investigated after immunisation of rabbits with different vimentin isoforms. Effects of tobacco smoke exposure on carbamylation of vimentin and formation of autoantibodies were analysed in mice. The antibody responses against isoforms of vimentin were characterised with respect to disease duration and smoking status of patients with RA.ResultsEnzymatic carbamylation of vimentin was efficiently achieved. Subsequent citrullination of vimentin was not disturbed by homocitrullination. Sera from rabbits immunised with carbamylated vimentin (carbVim), in addition to carbVim also recognised human IgG-Fc showing rheumatoid factor-like reactivity. Smoke-exposed mice contained detectable amounts of carbVim and developed a broad immune response against carbamylated antigens. Although the prevalence of anti-carbamylated antibodies in smokers and non-smokers was similar, the titres of carbamylated antibodies were significantly increased in sera of smoking compared with non-smoking RA. CarbVim antibodies were observed independently of ACPAs in early phases of disease and double-positive patients for anti-mutated citrullinated vimentin (MCV) and anti-carbVim antibodies showed an extended epitope recognition pattern towards MCV.ConclusionsCarbamylation of vimentin is inducible by cigarette smoke exposure. The polyclonal immune response against modified antigens in patients with RA is not exclusively citrulline-specific and carbamylation of antigens could be involved in the pathogenesis of disease.Trial registration number ISRCTN36745608; EudraCT Number: 2006-003146-41.

Elevated cholesterol levels in children can be a risk factor for cardiovascular diseases in later life. In adults, it has been shown that blood lipid levels are strongly influenced by polymorphisms in the fatty acid desaturase (FADS) gene cluster in addition to nutritional and other exogenous and endogenous determinants. Our aim was to investigate whether lipid levels are determined by the FADS genotype already in children and whether this association interacts with dietary intake of n-3 fatty acids. The analysis was based on data of 2006 children from two German prospective birth cohort studies. Total cholesterol, HDL, LDL and triglycerides were measured at 10 years of age. Six single nucleotide polymorphisms (SNPs) of the FADS gene cluster were genotyped. Dietary n-3 fatty acid intake was assessed by food frequency questionnaire. Linear regression modeling was used to assess the association between lipid levels, n-3 fatty acid intake and FADS genotype. Individuals carrying the homozygous minor allele had lower levels of total cholesterol [means ratio (MR) ranging from 0.96 (p = 0.0093) to 0.98 (p = 0.2949), depending on SNPs] and LDL [MR between 0.94 (p = 0.0179) and 0.97 (p = 0.2963)] compared to homozygous major allele carriers. Carriers of the heterozygous allele showed lower HDL levels [β between -0.04 (p = 0.0074) to -0.01 (p = 0.3318)] and higher triglyceride levels [MR ranging from 1.06 (p = 0.0065) to 1.07 (p = 0.0028)] compared to homozygous major allele carriers. A higher n-3 PUFA intake was associated with higher concentrations of total cholesterol, LDL, HDL and lower triglyceride levels, but these associations did not interact with the FADS1 FADS2 genotype. Total cholesterol, HDL, LDL and triglyceride concentrations may be influenced by the FADS1 FADS2 genotype already in 10 year old children. Genetically determined blood lipid levels during childhood might differentially predispose individuals to the development of cardiovascular diseases later in life.

Aims/hypothesisCirculating metabolites have been shown to reflect metabolic changes during the development of type 2 diabetes. In this study we examined the association of metabolite levels and pairwise metabolite ratios with insulin responses after glucose, glucagon-like peptide-1 (GLP-1) and arginine stimulation. We then investigated if the identified metabolite ratios were associated with measures of OGTT-derived beta cell function and with prevalent and incident type 2 diabetes.MethodsWe measured the levels of 188 metabolites in plasma samples from 130 healthy members of twin families (from the Netherlands Twin Register) at five time points during a modified 3 h hyperglycaemic clamp with glucose, GLP-1 and arginine stimulation. We validated our results in cohorts with OGTT data (n = 340) and epidemiological case–control studies of prevalent (n = 4925) and incident (n = 4277) diabetes. The data were analysed using regression models with adjustment for potential confounders.ResultsThere were dynamic changes in metabolite levels in response to the different secretagogues. Furthermore, several fasting pairwise metabolite ratios were associated with one or multiple clamp-derived measures of insulin secretion (all p < 9.2 × 10−7). These associations were significantly stronger compared with the individual metabolite components. One of the ratios, valine to phosphatidylcholine acyl-alkyl C32:2 (PC ae C32:2), in addition showed a directionally consistent positive association with OGTT-derived measures of insulin secretion and resistance (p ≤ 5.4 × 10−3) and prevalent type 2 diabetes (ORVal_PC ae C32:2 2.64 [β 0.97 ± 0.09], p = 1.0 × 10−27). Furthermore, Val_PC ae C32:2 predicted incident diabetes independent of established risk factors in two epidemiological cohort studies (HRVal_PC ae C32:2 1.57 [β 0.45 ± 0.06]; p = 1.3 × 10−15), leading to modest improvements in the receiver operating characteristics when added to a model containing a set of established risk factors in both cohorts (increases from 0.780 to 0.801 and from 0.862 to 0.865 respectively, when added to the model containing traditional risk factors + glucose).Conclusions/interpretationIn this study we have shown that the Val_PC ae C32:2 metabolite ratio is associated with an increased risk of type 2 diabetes and measures of insulin secretion and resistance. The observed effects were stronger than that of the individual metabolites and independent of known risk factors.

Background The European resuscitation council have highlighted emergency medical dispatch centres as an important key player for early recognition of Out-of-Hospital Cardiac Arrest (OHCA) and in providing dispatcher assisted cardiopulmonary resuscitation (CPR) before arrival of emergency medical services. Early recognition is associated with increased bystander CPR and improved survival rates. The aim of this study is to describe OHCA call handling in emergency medical dispatch centres in Copenhagen (Denmark), Stockholm (Sweden) and Oslo (Norway) with focus on sensitivity of recognition of OHCA, provision of dispatcher-assisted CPR and time intervals when CPR is initiated during the emergency call (NO-CPR prior ), and to describe OHCA call handling when CPR is initiated prior to the emergency call (CPR prior ). Methods Baseline data of consecutive OHCA eligible for inclusion starting January 1st 2016 were collected from respective cardiac arrest registries. A template based on the Cardiac Arrest Registry to Enhance Survival definition catalogue was used to extract data from respective cardiac arrest registries and from corresponding audio files from emergency medical dispatch centres. Cases were divided in two groups: NO-CPR prior and CPR prior and data collection continued until 200 cases were collected in the NO-CPR prior -group. Results NO-CPR prior OHCA was recognised in 71% of the calls in Copenhagen, 83% in Stockholm, and 96% in Oslo. Abnormal breathing was addressed in 34, 7 and 98% of cases and CPR instructions were started in 50, 60, and 80%, respectively. Median time (mm:ss) to first chest compression was 02:35 (Copenhagen), 03:50 (Stockholm) and 02:58 (Oslo). Assessment of CPR quality was performed in 80, 74, and 74% of the cases. CPR prior comprised 71 cases in Copenhagen, 9 in Stockholm, and 38 in Oslo. Dispatchers still started CPR instructions in 41, 22, and 40% of the calls, respectively and provided quality assessment in 71, 100, and 80% in these respective instances. Conclusions We observed variations in OHCA recognition in 71–96% and dispatcher assisted-CPR were provided in 50–80% in NO-CPR prior calls. In cases where CPR was initiated prior to emergency calls, dispatchers were less likely to start CPR instructions but provided quality assessments during instructions.

In the last decade, adverse outcome pathways have been introduced in the fields of toxicology and risk assessment of chemicals as pragmatic tools with broad application potential. While their use in the pharmaceutical and cosmetics sectors has been well documented, their application in the food area remains largely unexplored. In this respect, an expert group of the International Life Sciences Institute Europe has recently explored the use of adverse outcome pathways in the safety evaluation of food additives. A key activity was the organization of a workshop, gathering delegates from the regulatory, industrial and academic areas, to discuss the potentials and challenges related to the application of adverse outcome pathways in the safety assessment of food additives. The present paper describes the outcome of this workshop followed by a number of critical considerations and perspectives defined by the International Life Sciences Institute Europe expert group.

Background In Germany, measles vaccination coverage with two doses is not yet sufficient to prevent regional outbreaks. Among the 16 German federal states, vaccination coverage was lowest in Bavaria with 85% in 2008. From March to mid-April 2008, four neighbouring Bavarian counties reported 55 measles-cases mostly linked to an ongoing measles outbreak in an anthroposophic school in Austria. We investigated this outbreak to guide future public health action. Methods We applied the German national case-definition for measles and collected data using the national surveillance system and a questionnaire. Measles cases with disease onset a maximum of 18 days apart and spatial contact (e.g. same household, same school) were summed up in clusters. Two different interventions, which were implemented in schools and kindergartens in Bavaria, were compared by their impact on the size and duration of measles clusters. Susceptible persons were excluded from schools or kindergartens either with the first (intervention A) or second (intervention B) measles case occurring in the respective institution. Results Among the 217 Bavarian measles cases identified from March-July 2008, 28 (13%) cases were attendees of the anthroposophic school in Austria. In total, vaccination status was known in 161 (74%) cases and 156 (97%) of them were not vaccinated. The main factor for non-vaccination was \"fear of vaccine-related adverse events\" (33%). Twenty-nine (18%) of 161 cases suffered complications. Exclusively genotype D5 was detected. Overall, 184 cases could be epidemiologically grouped into 59 clusters. Of those, 41 clusters could be linked to households and 13 to schools or kindergartens. The effect of intervention A and B was analysed in 10 school or kindergarten clusters. Depending on the respective intervention A or B, the median number of cases per cluster was 3 versus 13 (p = 0.05), and the median duration of a cluster was 3 versus 26 days (p = 0.13). Conclusions Introduction of measles virus into a pocket of susceptible persons (e.g. vaccination opponents or sceptics) may lead to large outbreaks in the general population, if the general population's vaccination coverage is below the WHO recommended level. Education on the safety of measles vaccine needs to be strengthened to increase measles vaccination coverage. Early intervention may limit spread in schools or kindergartens. Suspected measles has to be reported immediately to the local health authorities in order to allow intervention as early as possible.

Objective To describe regional differences between eastern and western Germany with regard to food, nutrient and supplement intake in 9-12-year-old children, and analyse its association with parental education and equivalent income. Design Data were obtained from the 10-year follow-up of the two prospective birth cohort studies - GINIplus and LISAplus. Data on food consumption and supplement intake were collected using an FFQ, which had been designed for the specific study population. Information on parental educational level and equivalent income was derived from questionnaires. Logistic regression modelling was used to analyse the effect of parental education, equivalent income and region on food intake, after adjusting for potential confounders. Setting Germany. Subjects A total of 3435 children aged 9-12 years. Results Substantial regional differences in food intake were observed between eastern and western Germany. Intakes of bread, butter, eggs, pasta, vegetables/salad and fruit showed a significant direct relationship with the level of parental education after adjusting for potential confounders, whereas intakes of margarine, meat products, pizza, desserts and soft drinks were inversely associated with parental education. Equivalent income had a weaker influence on the child's food intake. Conclusions Nutritional education programmes for school-age children should therefore account for regional differences and parental education.

There is considerable interest in adverse outcome pathways (AOPs) as a means of organizing biological and toxicological information to assist in data interpretation and method development. While several chemical sectors have shown considerable progress in applying this approach, this has not been the case in the food sector. In the present study, safety evaluation reports of food additives listed in Annex II of Regulation (EC) No 1333/2008 of the European Union were screened to qualitatively and quantitatively characterize toxicity induced in laboratory animals. The resulting database was used to identify the critical adverse effects used for risk assessment and to investigate whether food additives share common AOPs. Analysis of the database revealed that often such scrutiny of AOPs was not possible or necessary. For 69% of the food additives, the report did not document any adverse effects in studies based on which the safety evaluation was performed. For the remaining 31% of the 326 investigated food additives, critical adverse effects and related points of departure for establishing health-based guidance values could be identified. These mainly involved effects on the liver, kidney, cardiovascular system, lymphatic system, central nervous system and reproductive system. AOPs are available for many of these apical endpoints, albeit to different degrees of maturity. For other adverse outcomes pertinent to food additives, including gastrointestinal irritation and corrosion, AOPs are lacking. Efforts should focus on developing AOPs for these particular endpoints.

Objective: To investigate the cross-sectional association between food intake and overweight in children. Methods: Height and weight were measured in 2,565 school-aged children. Intakes of 11 food groups were categorized (low, medium and high) using specific tertile cutoffs. Multivariate energy partition models were applied. Adjustment included energy intake from other food groups, city, family income, parental education and ‘screen' time. Possible underreporters were identified and used in sensitivity analyses. Results: Compared to low intake, high intakes of meat, fish, beverages and bakery products were associated with greater BMI z-scores [β (95% CI) = 0.32 (0.21, 0.42), 0.13 (0.03, 0.24), 0.23 (0.11, 0.35) and 0.10 (-0.01, 0.20)] and increased risk of being overweight [odds ratio (OR) (95% CI) = 2.08 (1.58, 2.73), 1.39 (1.08, 1.80), 1.36 (1.01, 1.84) and 1.62 (1.24, 2.11)]. Conversely, medium and high intakes of confectionery were associated with smaller BMI z-scores [β = -0.18 (-0.28, -0.07) and -0.22 (-0.33, -0.12)] and decreased risk of being overweight [OR = 0.64 (0.50, 0.83) and 0.53 (0.40, 0.68)]. These associations were robust to sensitivity analyses. Conclusions: Intakes of meat, fish, beverages and bakery products correlate with body weight status.

While the former East Germany (FEG) achieved a reduction of measles incidence to <1 case per 100,000 population before reunification in 1990, the former West Germany (FWG) experienced significant measles morbidity. In 2001, according to statutory surveillance data, the incidence of measles was still higher in FWG than in FEG (8.7 vs. 0.7 cases/100,000 population). This article describes the development of the vaccination strategies in FEG and FWG, vaccination coverage, results of seroprevalence studies, measles surveillance in Germany, the epidemiology of a recent outbreak, and the role of laboratory diagnosis for measles control in Germany. Recent establishment of comprehensive nationwide surveillance and prevention programs to attain higher vaccine coverage have led to a decrease in measles incidence. However, further improvement of age‐appropriate vaccine coverage and closure of immunity gaps in school‐age children are necessary to eliminate measles in Germany.