Surveillance of Myelodysplastic Syndrome via Migration Analyses of Blood Neutrophils: A Potential Prognostic Tool.

Autonomous migration is a central characteristic of immune cells, and changes in this function have been correlated to the progression and severity of diseases. Hence, the identification of pathologically altered leukocyte migration patterns might be a promising approach for disease surveillance and prognostic scoring. However, because of the lack of standardized and robust assays, migration patterns have not been clinically exploited so far. In this study, we introduce an easy-to-use and cross-laboratory, standardized two-dimensional migration assay for neutrophil granulocytes from peripheral blood. By combining time-lapse video microscopy and automated cell tracking, we calculated the average migration of neutrophils from 111 individual participants of the German Heinz Nixdorf Recall MultiGeneration study under steady-state, formyl-methionyl-leucyl-phenylalanine-, CXCL1-, and CXCL8-stimulated conditions. Comparable values were obtained in an independent laboratory from a cohort in Belgium, demonstrating the robustness and transferability of the assay. In a double-blinded retrospective clinical analysis, we found that neutrophil migration strongly correlated with the Revised International Prognostic Scoring System scoring and risk category of myelodysplastic syndrome (MDS) patients. In fact, patients suffering from high-risk subtypes MDS with excess blasts I or II displayed highly significantly reduced neutrophil migration. Hence, the determination of neutrophil migration patterns might represent a useful tool in the surveillance of MDS. Taken together, we suggest that standardized migration assays of neutrophils and other leukocyte subtypes might be broadly applicable as prognostic and surveillance tools for MDS and potentially for other diseases.

Association of short-term ozone and temperature with sleep disordered breathing.

Scarce evidence suggests that ambient air pollution and temperature might play a role in incidence and severity of sleep disordered breathing (SDB). We investigated the association of short-term exposure to fine particulate matter (particles with a 50% cut-off aerodynamic diameter of 10 µm (PM10)), ozone and temperature with SDB in the general population. Between 2006 and 2008, 1773 participants (aged 50-80 years) of the Heinz Nixdorf Recall study underwent screening for SDB, as defined by the apnoea-hypopnoea index (AHI). We assessed daily exposure to PM10, ozone, temperature and humidity. We used multiple linear regression to estimate associations of daily PM10, ozone levels and temperature on the day of screening, adjusting for relative humidity, season, age, sex, body mass index, education, smoking habits, alcohol consumption and physical activity. In the study population, the mean±sd AHI was 11.2±11.4 events·h(-1). Over all seasons, an interquartile range increase in temperature (8.6°C) and ozone (39.5 µg·m(-3)) was associated with a 10.2% (95% CI 1.2-20.0%) and 10.1% (95% CI 2.0-18.9%) increase in AHI, respectively. Associations for temperature were stronger in summer, yielding a 32.4% (95% CI 0.0-75.3%) increase in AHI per 8.6°C (p-value for season-temperature interaction 0.08). We observed that AHI was not associated with PM10. This study suggests that short-term variations in ozone concentration and temperature are associated with SDB.

Comparing sampling strategies to recruit migrants for an epidemiological study. Results from a German feasibility study.

BACKGROUND: In 2011, almost 20.0% of the population of Germany had a migration background. Studies on their health tend to have low participation rates. The aim of our study was to compare different sampling strategies and to test different approaches to recruit migrants for an epidemiological study. METHODS: Four recruitment centres of the German National Cohort recruited persons of Turkish origin and ethnic German immigrants from former Soviet Union countries. A register-based (random samples from residents' registration offices) and a community-orientated strategy were applied. Participants underwent a medical examination and self-completed a questionnaire. RESULTS: Used approaches: The community-orientated strategies comprised the acquisition of key persons from migrant networks to support the recruitment, invitation talks and distribution of study materials in migrant settings, etc. The identifying variables in the registry data were name, nationality or country of birth. All but one centres used bilingual study material and study staff. PARTICIPATION: When comparing the two strategies, the register-based participation rates ranged from 10.1 to 21.0% (n = 668 participants) and the community-oriented recruitment resulted in 722 participants. CONCLUSION: Register-based recruitment should use a combination of name, nationality and country of birth in order not to be limited to identifying persons with a foreign nationality. However, according to the study staff, the community-oriented approach involving key persons of the same cultural background leads to a better acceptance by the participants. Also, it covers a more heterogeneous group. Yet, it is time-consuming and needs considerably more staff. Further research should establish the effectiveness of a combination of both strategies.

The loss of α2ß1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis.

OBJECTIVE: Integrin α2ß1 functions as a major receptor for type I collagen on different cell types, including fibroblasts and inflammatory cells. Although in vitro data suggest a role for α2ß1 integrin in regulating both cell attachment and expression of matrix-degrading enzymes such as matrix metalloproteinases (MMPs), mice that lack the α2 integrin subunit (Itga2(-/-) mice) develop normally and are fertile. We undertook this study to investigate the effect of Itga2 deficiency in 2 different mouse models of destructive arthritis: the antigen-induced arthritis (AIA) mouse model and the human tumor necrosis factor α (TNFα)-transgenic mouse model. METHODS: AIA was induced in the knee joints of Itga2(-/-) mice and wild-type controls. Human TNF-transgenic mice were crossed with Itga2(-/-) mice and were assessed clinically and histopathologically for signs of arthritis, inflammation, bone erosion, and cartilage damage. MMP expression, proliferation, fibroblast attachment, and ERK activation were determined. RESULTS: Under arthritic conditions, Itga2 deficiency led to decreased severity of joint pathology. Specifically, Itga2(-/-) mice showed less severe clinical symptoms and dramatically reduced pannus formation and cartilage erosion. Mice lacking α2ß1 integrin exhibited reduced MMP-3 expression, both in their sera and in fibroblast-like synoviocytes (FLS), due to impaired ERK activation. Further, both the proliferation and attachment of FLS to cartilage were partially dependent on α2ß1 integrin in vitro and in vivo. CONCLUSION: Our findings suggest that α2ß1 integrin contributes significantly to inflammatory cartilage destruction by promoting fibroblast proliferation and attachment and MMP expression.

PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis.

The gamma isoform of phosphoinositide 3-kinase (PI3Kgamma) has been viewed as restricted to leukocytes mediating the regulation of chemokine-induced migration and recruitment of neutrophils, monocytes, and macrophages. In line with the observation that PI3Kgamma-deficient mice display defects in adaptive immunity, inhibition of PI3Kgamma reduces synovial inflammation in the collagen-induced arthritis mouse model of inflammatory arthritis [rheumatoid arthritis (RA)], which has been attributed to reduced influx of inflammatory cells. Challenging the concept of leukocyte-restricted PI3Kgamma function, we report here a novel, nonredundant function of PI3Kgamma as an important regulator of fibroblast-induced cartilage destruction during chronic destructive arthritis. We show that in human tumor necrosis factor transgenic mice, the loss of PI3Kgamma leads to a milder inflammatory arthritis. Interestingly, PI3Kgamma deficiency does not alter the recruitment of inflammatory cells, but significantly reduces cartilage damage through reduced expression of matrix metalloproteinases in fibroblasts and chondrocytes. In vitro analyses demonstrate that the decreased invasiveness of fibroblasts is mediated by reduced phosphorylation of Akt and extracellular signal-regulated kinase. Using a PI3Kgamma specific inhibitor, these data are confirmed in human synovial fibroblasts from patients with RA who exhibit a disease-specific up-regulation of PI3Kgamma. Our data indicate that in addition to mediating the recruitment of inflammatory cells, PI3Kgamma is an important regulator of fibroblast-mediated joint destruction in RA and suggest that specific inhibitors of PI3Kgamma will interfere with the activation of RA synovial fibroblasts and reduce cartilage destruction in RA.

Indoor and outdoor road traffic noise and incident diabetes mellitus: Results from a longitudinal German cohort study.

Road traffic noise affects a large number of people in urbanized areas. Recent epidemiological evidence indicates that environmental noise exposure may not only be associated with cardiovascular but also with cardio-metabolic outcomes. This prospective cohort study investigated the effect of outdoor and indoor residential road traffic noise on incident type 2 diabetes mellitus (T2DM). METHODS: We used data from 3,396 participants of age 45-75 years of the Heinz Nixdorf Recall study being non-diabetic at baseline (2000-2003). T2DM was defined via blood glucose level, incident intake of an anti-diabetic drug during follow-up or self-reported physician diagnosis at follow-up examination (2005-2008). Weighted 24-h (Lden) and night-time (Lnight) mean road traffic noise was assessed according to the European Union directive 2002/49/EC. Road traffic noise exposure indoors was modeled taking into account the participants' room orientation, ventilation behavior and window insulation (n = 2,697). We applied Poisson regression analyses to estimate relative risks (RRs) of incident T2DM, adjusting for demographic characteristics, lifestyle factors, and air pollution exposure (NO2 or PM2.5). RESULTS: A 10-dB(A) increase in outdoor road traffic noise (Lden) was associated with an RR of 1.09 (95% confidence interval, 0.96-1.24) for T2DM in the fully adjusted model. Models including PM2.5 or NO2 yielded RRs of 1.09 (0.96-1.24) and 1.11 (0.97-1.27), respectively. In analyses with road traffic noise (Lden) exposure indoors, we observed similar RRs with smaller confidence intervals (1.11 [1.01-1.21]). CONCLUSIONS: Our analyses suggest that long-term exposure to indoor and outdoor road traffic noise may increase the risk of developing T2DM, independent of air pollution exposure.

Normative data from linear and nonlinear quantile regression in CANTAB: Cognition in mid-to-late life in an epidemiological sample.

INTRODUCTION: Normative cognitive data can help to distinguish pathological decline from normal aging. This study presents normative data from the Cambridge Neuropsychological Test Automated Battery, using linear regression and nonlinear quantile regression approaches. METHODS: Heinz Nixdorf Recall study participants completed Cambridge Neuropsychological Test Automated Battery tests: paired-associate learning, spatial working memory, and reaction time. Data were available for 1349-1529 healthy adults aged 57-84 years. Linear and nonlinear quantile regression analyses examined age-related changes, adjusting for sex and education. Quantile regression differentiated seven performance bands (percentiles: 97.7, 93.3, 84.1, 50, 15.9, 6.7, and 2.3). RESULTS: Normative data show age-related cognitive decline across all tests, but with quantile regression revealing heterogeneous trajectories of cognitive aging, particularly for the test of episodic memory function (paired-associate learning). DISCUSSION: This study presents normative data from Cambridge Neuropsychological Test Automated Battery in mid-to-late life. Quantile regression can model heterogeneity in age-related cognitive trajectories as seen in the paired-associate learning episodic memory measure.

Cross-sectional analysis of pulsatile hemodynamics across the adult life span: reference values, healthy and early vascular aging: the Heinz Nixdorf Recall and the MultiGeneration Study.

BACKGROUND: Pulsatile hemodynamics predict major cardiovascular events. We aimed to provide comprehensive population-based reference values and to compare different measures of pulsatile hemodynamics to define early vascular aging (EVA) as well as healthy vascular aging (HVA). METHODS: In 2721 participants from the population-based Heinz Nixdorf Recall Study and the associated MultiGeneration Study, free from diabetes, cardiovascular disease, and antihypertensive drugs, we performed high-fidelity radial tonometry, calibrated waveforms with brachial blood pressures and processed them with a validated transfer function, pulse wave analysis, and wave separation analysis. Aortic pulse wave velocity (aoPWV) was estimated with a validated regression formula. HVA was defined as the lowest, EVA as the highest age-specific decile of central pulse pressure (cPP), backward wave amplitude, and aoPWV. RESULTS: Overall, 56.4% of participants were female, age range 18-90 years. Brachial PP increased from middle age, whereas cPP increased across the entire adult life span. Wave reflections increased across all age groups, apart from a plateau in older male participants. Indices of wave reflection were higher in women than in men. AoPWV showed the most prominent rise with age in both sexes. EVA and HVA, defined by cPP and backward wave amplitude, differed mainly by hemodynamic variables. In contrast, EVA participants were characterized by a worse hemodynamic, anthropometric, metabolic, and inflammatory profile, if aoPWV was used to discriminate EVA and HVA. CONCLUSION: Age-specific and sex-specific reference values for central pulsatile hemodynamics in a general white population cohort are provided and may be utilized to define HVA and EVA.

CAC Score Improves Coronary and CV Risk Assessment Above Statin Indication by ESC and AHA/ACC Primary Prevention Guidelines.

OBJECTIVES: The aim of this study was to assess the difference in indication for statin therapy by European Society of Cardiology (ESC) versus American Heart Association/American College of Cardiology (AHA/ACC) guidelines and to quantify the potential additional role of coronary artery calcification (CAC) score over updated guidelines in a primary prevention cohort. BACKGROUND: Recently, ESC and AHA/ACC updated the guidelines regarding statin therapy in primary prevention. METHODS: In 3,745 subjects (59 ± 8 years of age, 47% men) from the population based longitudinal Heinz Nixdorf Recall cohort study without cardiovascular disease or lipid-lowering therapy at baseline CAC score was assessed between 2000 and 2003. Subjects remained unaware of their initial CAC score. Statin indication was determined according to 2012 ESC and 2013 AHA/ACC guidelines based on subjects individual baseline characteristics. RESULTS: The frequency of statin recommendation was lower according to ESC compared to AHA/ACC guidelines (34% vs. 56%; p < 0.0001), whereas low CAC score (<100) was common in subjects with statin indication by both guidelines (59% for ESC, 62% for AHA/ACC). During 10.4 ± 2.0 years of follow-up, 131 myocardial infarctions occurred. For ESC recommendations, CAC score differentiated risk for subjects without (1.0 [95% confidence interval (CI): 0.4 to 1.5] vs. 6.5 [95% CI: 4.1 to 8.9] coronary events per 1,000 person-years for CAC 0 vs. ≥100) and with statin indication (2.6 [95% CI: 0.6 to 4.7] vs. 9.9 [95% CI: 7.3 to 12.5] per 1,000 person-years for CAC 0 vs. ≥100). Likewise, CAC score stratified proportions experiencing events subjects with statin indication according to AHA/ACC (2.7 [95% CI: 1.1 to 4.2] vs. 9.1 [95% CI: 7.0 to 11.0] per 1,000 person-years for CAC 0 vs. ≥100), whereas event rate in subjects without statin indication was low (1.1 [95% CI: 0.65 to 1.68] per 1,000 person-years). CONCLUSIONS: Current ESC and AHA/ACC guidelines lead to markedly different recommendation regarding statin therapy in a German primary prevention cohort. Quantification of CAC score in addition to the guidelines improves stratification between subjects at high versus low risk for coronary events, indicating that CAC scoring may help to match intensified risk factor modification to atherosclerotic plaque burden as well as actual risk while avoiding therapy in subjects with low coronary atherosclerosis that have low 10-year event rate.

Associations between former exposure to manganese and olfaction in an elderly population: Results from the Heinz Nixdorf Recall Study.

Occupational exposure to manganese (Mn) has been associated with impairments in olfaction and motor functions, but it has yet to be determined if such effects persist upon cessation of exposure. The objective of this study was to evaluate the influence of former occupational Mn exposure on olfaction within the framework of a prospective cohort study among an elderly German population. Information on job tasks with recognized Mn exposure and data on odor identification assessed with Sniffin' sticks was collected during the second follow-up of the Heinz Nixdorf Recall Study. The study population consisted of 1385 men aged 55-86 years, 354 of whom ever worked in jobs with potential Mn exposure (median 58.3µg/m3 years, interquartile range 19.0-185µg/m3 years). Multiple exposure measures, including job tasks, cumulative Mn exposure, and Mn determined in blood samples (MnB) archived at baseline, were used to estimate effects of Mn on olfaction. Having ever worked as welder was associated with better olfaction compared to other blue-collar workers without Mn exposure. Blue-collar workers identified less odors in comparison to white-collar workers. Concentrations of previous Mn exposure >185µg/m3 years or MnB ≥15µg/L were not associated with impaired olfaction. In addition to a strong age effect, participants with lower occupational qualification identified less odors. We found no relevant association of former Mn exposure at relatively low levels with impaired olfaction. Possible neurotoxic Mn effects may not be persistent after cessation.

Influence of age and cognitive performance on resting-state brain networks of older adults in a population-based cohort.

Aging leads to global changes in brain structure and cognitive performance, with reorganization of functional brain networks. Importantly, these age-related changes show higher inter-individual variability in older subjects. To particularly address this variability is a challenge for studies on lifetime trajectories from early to late adulthood. The present study therefore had a dedicated focus on late adulthood to characterize the functional connectivity in resting-state networks (RSFC) in relation to age and cognitive performance in 711 older adults (55-85 years) from the 1000BRAINS project. The executive, left and right frontoparietal resting-state (RS) networks showed age-related increases in RSFC. However, older adults did not show changes in RSFC in the default mode network (DMN). Furthermore, lower performance in working memory (WM) was associated with higher RSFC in the left frontoparietal RS network. The results suggest age-related compensatory increases in RSFC which might help to maintain cognitive performance. Nevertheless, the negative correlation between RSFC and WM performance hints at limited cognitive reserve capacity in lower performing older adults. Consequently, the current results provide evidence for a functional reorganization of the brain until late adulthood that might additionally explain parts of the variability of cognitive abilities in older adults.

Occupational Exposure to Manganese and Fine Motor Skills in Elderly Men: Results from the Heinz Nixdorf Recall Study.

OBJECTIVES: Exposure to manganese (Mn) may cause movement disorders, but less is known whether the effects persist after the termination of exposure. This study investigated the association between former exposure to Mn and fine motor deficits in elderly men from an industrial area with steel production. METHODS: Data on the occupational history and fine motor tests were obtained from the second follow-up of the prospective Heinz Nixdorf Recall Study (2011-2014). The study population included 1232 men (median age 68 years). Mn in blood (MnB) was determined in archived samples (2000-2003). The association between Mn exposure (working as welder or in other at-risk occupations, cumulative exposure to inhalable Mn, MnB) with various motor functions (errors in line tracing, steadiness, or aiming and tapping hits) was investigated with Poisson and logistic regression, adjusted for iron status and other covariates. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated for substantially impaired dexterity (errors >90th percentile, tapping hits <10th percentile). RESULTS: The median of cumulative exposure to inhalable Mn was 58 µg m-3 years in 322 men who ever worked in at-risk occupations. Although we observed a partly better motor performance of exposed workers at group level, we found fewer tapping hits in men with cumulative Mn exposure >184.8 µg m-3 years (OR 2.15, 95% CI 1.17-3.94). MnB ≥ 15 µg l-1, serum ferritin ≥ 400 µg l-1, and gamma-glutamyl transferase ≥74 U l-1 were associated with a greater number of errors in line tracing. CONCLUSIONS: We found evidence that exposure to inhalable Mn may carry a risk for dexterity deficits. Whether these deficits can be exclusively attributed to Mn remains to be elucidated, as airborne Mn is strongly correlated with iron in metal fumes, and high ferritin was also associated with errors in line tracing. Furthermore, hand training effects must be taken into account when testing for fine motor skills.

Noncoronary Measures Enhance the Predictive Value of Cardiac CT Above Traditional Risk Factors and CAC Score in the General Population.

OBJECTIVES: The aim of this study was to determine whether noncoronary measures from cardiac computed tomography (CT) may enhance the prognostic value of this imaging technology. BACKGROUND: When cardiac CT is performed for quantification of coronary artery calcium (CAC) score, information on other cardiac and thoracic structures is available. METHODS: Participants without known cardiovascular disease from the prospective population based Heinz Nixdorf Recall study underwent noncontrast cardiac CT for CAC score quantification. From CT, epicardial adipose tissue (EAT) volume, left ventricular and left atrial (LA) axial area index, ascending and descending aortic diameters, as well as aortic valve, mitral ring, and thoracic aortic calcification (TAC) were assessed. Incident cardiovascular events included myocardial infarction, stroke, and cardiovascular death. The prognostic value of CT-derived parameters was assessed by Cox regression analysis, receiver operating characteristics, and net reclassification improvement. RESULTS: From 3,630 subjects (59 ± 8 years of age, 46% male), 241 (6.6%) developed a cardiovascular event during 9.9 ± 2.6 years of follow-up. In multivariable Cox regression analysis including Framingham Risk Score, CAC (as log[CAC + 1]), and CT parameters, LA index (hazard ratio [HR]: 1.22 [95% confidence interval [CI]: 1.05 to 1.41] per SD; p = 0.010) and EAT volume (HR: 1.15 [95% CI: 1.01 to 1.30] per SD; p = 0.031) were significantly associated with incident events. In addition, presence of TAC showed an elevated event rate (HR: 1.33 [95% CI: 0.97 to 1.81]; p = 0.08), whereas all other CT-derived parameters showed no relevant association. The LA index, EAT volume, and presence of TAC together improved the prediction of events over Framingham Risk Score and CAC in receiver operating characteristics analysis (area under the curve: 0.749 to 0.764; p = 0.011), and let to a significant net reclassification improvement (HR: 38.0%; 95% CI: 25.1% to 50.8%). CONCLUSION: Assessment of LA index, EAT volume, and TAC from non-contrast-enhanced cardiac CT improves the prediction of incident hard cardiovascular events above CAC and established risk factors, indicating that quantification of these noncoronary measures may improve the prognostic value of this imaging technology.

Residential Road Traffic Noise and High Depressive Symptoms after Five Years of Follow-up: Results from the Heinz Nixdorf Recall Study.

BACKGROUND: Traffic noise affects a large number of people, particularly in urbanized areas. Noise causes stress and annoyance, but less is known about the relationship between noise and depression. OBJECTIVE: We investigated the association of residential road traffic noise with depressive symptoms using 5-year follow-up data from a German population-based study. METHODS: We analyzed data from 3,300 participants in the Heinz Nixdorf Recall study who were between 45 and 75 years old and were without depressive symptoms at baseline (2000-2003). Depressive symptoms were defined based on the Center for Epidemiologic Studies Depression scale (CES-D) 15-item questionnaire (total score ≥ 17) and antidepressant medication intake. Road traffic noise was modeled according to European Parliament/Council Directive 2002/49/EC. High noise exposure was defined as annual mean 24-hr noise levels > 55 A-weighted decibels [dB(A)]. Poisson regression with robust variance was used to estimate relative risks (RRs) a) adjusting for the potential confounders age, sex, socioeconomic status (SES), neighborhood-level SES, and traffic proximity; b) additionally adjusting for body mass index and smoking; and c) additionally adjusting for the potential confounders/intermediates comorbidities and insomnia. RESULTS: Overall, 35.7% of the participants were exposed to high residential road traffic noise levels. At follow-up (mean = 5.1 years after baseline), 302 participants were classified as having high depressive symptoms, corresponding to an adjusted RR of 1.29 (95% CI: 1.03, 1.62; Model 1) for exposure to > 55 versus ≤ 55 dB(A). Adjustment for potential confounders/intermediates did not substantially alter the results. Associations were stronger among those who reported insomnia at baseline (RR = 1.62; 95% CI: 1.10, 2.59 vs. RR = 1.21; 95% CI: 0.94, 1.57) and appeared to be limited to those with ≤ 13 years of education (RR = 1.43; 95% CI: 1.10, 1.85 vs. 0.92; 95% CI: 0.56, 1.53 for > 13 years). CONCLUSION: Our results suggest that exposure to residential road traffic noise increases the risk of depressive symptoms. CITATION: Orban E, McDonald K, Sutcliffe R, Hoffmann B, Fuks KB, Dragano N, Viehmann A, Erbel R, Jöckel KH, Pundt N, Moebus S. 2016. Residential road traffic noise and high depressive symptoms after five years of follow-up: results from the Heinz Nixdorf Recall Study. Environ Health Perspect 124:578-585; http://dx.doi.org/10.1289/ehp.1409400.

NT-proBNP is superior to BNP for predicting first cardiovascular events in the general population: the Heinz Nixdorf Recall Study.

BACKGROUND: B-type natriuretic peptide (BNP) as well as N-terminal-proBNP (NT-proBNP) are associated with cardiac events in the general population. Yet, data from the general population comparing both peptides for their prognostic value is lacking. METHODS: Participants from the population-based Heinz-Nixdorf-Recall-study without cardiovascular diseases were included. Associations of BNP and NT-proBNP with incident cardiovascular events (incident myocardial infarction, stroke, or cardiovascular death) were assessed using Cox regression; prognostic value was addressed using Harrell's c statistic. RESULTS: From overall 3589 subjects (mean age: 59.3 ± 7.7 yrs, 52.5% female), 235 subjects developed a cardiovascular event during 8.9 ± 2.2 yrs of follow-up. In regression analysis both natriuretic peptides were associated with incident cardiovascular events, independent of traditional risk factors (hazard ratio (HR) per unit increase on log-scale (95% CI): NT-proBNP: 1.60 (1.39; 1.84); BNP: 1.37 (1.19; 1.58), p<0.0001 respectively). Specifically looking at subjects <60 yrs only NT-proBNP, was linked with events (HR (95% CI): 1.59 (1.19; 2.13) for NT-proBNP, p=0.0019; HR: 1.25 (0.94; 1.65) for BNP, p=0.12, after adjustment for age and gender). Similar results were observed for females (HR (95% CI) 1.65 (1.28; 2.12), p=0.0001 for NT-proBNP, and 1.24 (0.96; 1.61), p=0.10 for BNP after adjustment for age). Adding NT-proBNP/BNP to traditional risk factors increased the prognostic value, with effects being stronger for NT-proBNP (Harrell's c, 0.724 to 0.741, p=0.034) as compared to BNP (0.724 to 0.732, p=0.20). CONCLUSION: Both, NT-proBNP and BNP are associated with future cardiovascular events in the general population. However, when both are available, NT-proBNP seems to be superior due to its higher prognostic value, especially in younger subjects and females.

Long-term effects of elemental composition of particulate matter on inflammatory blood markers in European cohorts.

BACKGROUND: Epidemiological studies have associated long-term exposure to ambient particulate matter with increased mortality from cardiovascular and respiratory disorders. Systemic inflammation is a plausible biological mechanism behind this association. However, it is unclear how the chemical composition of PM affects inflammatory responses. OBJECTIVES: To investigate the association between long-term exposure to elemental components of PM and the inflammatory blood markers high-sensitivity C-reactive protein (hsCRP) and fibrinogen as part of the European ESCAPE and TRANSPHORM multi-center projects. METHODS: In total, 21,558 hsCRP measurements and 17,428 fibrinogen measurements from cross-sections of five and four cohort studies were available, respectively. Residential long-term concentrations of particulate matter <10µm (PM10) and <2.5µm (PM2.5) in diameter and selected elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, zinc) were estimated based on land-use regression models. Associations between components and inflammatory markers were estimated using linear regression models for each cohort separately. Cohort-specific results were combined using random effects meta-analysis. As a sensitivity analysis the models were additionally adjusted for PM mass. RESULTS: A 5ng/m(3) increase in PM2.5 copper and a 500ng/m(3) increase in PM10 iron were associated with a 6.3% [0.7; 12.3%] and 3.6% [0.3; 7.1%] increase in hsCRP, respectively. These associations between components and fibrinogen were slightly weaker. A 10ng/m(3) increase in PM2.5 zinc was associated with a 1.2% [0.1; 2.4%] increase in fibrinogen; confidence intervals widened when additionally adjusting for PM2.5. CONCLUSIONS: Long-term exposure to transition metals within ambient particulate matter, originating from traffic and industry, may be related to chronic systemic inflammation providing a link to long-term health effects of particulate matter.

Treatment pattern of type 2 diabetes differs in two German regions and with patients' socioeconomic position.

BACKGROUND: Diabetes treatment may differ by region and patients' socioeconomic position. This may be particularly true for newer drugs. However, data are highly limited. METHODS: We examined pooled individual data of two population-based German studies, KORA F4 (Cooperative Health Research in the Region of Augsburg, south), and the HNR (Heinz Nixdorf Recall study, west) both carried out 2006 to 2008. To ascertain the association between region and educational level with anti-hyperglycemic medication we fitted poisson regression models with robust error variance for any and newer anti-hyperglycemic medication, adjusting for age, sex, diabetes duration, BMI, cardiovascular disease, lifestyle, and insurance status. RESULTS: The examined sample comprised 662 participants with self-reported type 2 diabetes (KORA F4: 83 women, 111 men; HNR: 183 women, 285 men). The probability to receive any anti-hyperglycemic drug as well as to be treated with newer anti-hyperglycemic drugs such as insulin analogues, thiazolidinediones, or glinides was significantly increased in southern compared to western Germany (prevalence ratio (PR); 95% CI: 1.12; 1.02-1.22, 1.52;1.10-2.11 respectively). Individuals with lower educational level tended to receive anti-hyperglycemic drugs more likely than their better educated counterparts (PR; 95% CI univariable: 1.10; 0.99-1.22; fully adjusted: 1.10; 0.98-1.23). In contrast, lower education was associated with a lower estimated probability to receive newer drugs among those with any anti-hyperglycemic drugs (PR low vs. high education: 0.66; 0.48-0.91; fully adjusted: 0.68; 0.47-0.996). CONCLUSIONS: We found regional and individual social disparities in overall and newer anti-hyperglycemic medication which were not explained by other confounders. Further research is needed.

Studying variability in human brain aging in a population-based German cohort-rationale and design of 1000BRAINS.

The ongoing 1000 brains study (1000BRAINS) is an epidemiological and neuroscientific investigation of structural and functional variability in the human brain during aging. The two recruitment sources are the 10-year follow-up cohort of the German Heinz Nixdorf Recall (HNR) Study, and the HNR MultiGeneration Study cohort, which comprises spouses and offspring of HNR subjects. The HNR is a longitudinal epidemiological investigation of cardiovascular risk factors, with a comprehensive collection of clinical, laboratory, socioeconomic, and environmental data from population-based subjects aged 45-75 years on inclusion. HNR subjects underwent detailed assessments in 2000, 2006, and 2011, and completed annual postal questionnaires on health status. 1000BRAINS accesses these HNR data and applies a separate protocol comprising: neuropsychological tests of attention, memory, executive functions and language; examination of motor skills; ratings of personality, life quality, mood and daily activities; analysis of laboratory and genetic data; and state-of-the-art magnetic resonance imaging (MRI, 3 Tesla) of the brain. The latter includes (i) 3D-T1- and 3D-T2-weighted scans for structural analyses and myelin mapping; (ii) three diffusion imaging sequences optimized for diffusion tensor imaging, high-angular resolution diffusion imaging for detailed fiber tracking and for diffusion kurtosis imaging; (iii) resting-state and task-based functional MRI; and (iv) fluid-attenuated inversion recovery and MR angiography for the detection of vascular lesions and the mapping of white matter lesions. The unique design of 1000BRAINS allows: (i) comprehensive investigation of various influences including genetics, environment and health status on variability in brain structure and function during aging; and (ii) identification of the impact of selected influencing factors on specific cognitive subsystems and their anatomical correlates.

Long-term exposure to ambient air pollution and incidence of cerebrovascular events: results from 11 European cohorts within the ESCAPE project.

BACKGROUND: Few studies have investigated effects of air pollution on the incidence of cerebrovascular events. OBJECTIVES: We assessed the association between long-term exposure to multiple air pollutants and the incidence of stroke in European cohorts. METHODS: Data from 11 cohorts were collected, and occurrence of a first stroke was evaluated. Individual air pollution exposures were predicted from land-use regression models developed within the European Study of Cohorts for Air Pollution Effects (ESCAPE). The exposures were: PM2.5 [particulate matter (PM) ≤ 2.5 µm in diameter], coarse PM (PM between 2.5 and 10 µm), PM10 (PM ≤ 10 µm), PM2.5 absorbance, nitrogen oxides, and two traffic indicators. Cohort-specific analyses were conducted using Cox proportional hazards models. Random-effects meta-analysis was used for pooled effect estimation. RESULTS: A total of 99,446 study participants were included, 3,086 of whom developed stroke. A 5-µg/m3 increase in annual PM2.5 exposure was associated with 19% increased risk of incident stroke [hazard ratio (HR) = 1.19, 95% CI: 0.88, 1.62]. Similar findings were obtained for PM10. The results were robust to adjustment for an extensive list of cardiovascular risk factors and noise coexposure. The association with PM2.5 was apparent among those ≥ 60 years of age (HR = 1.40, 95% CI: 1.05, 1.87), among never-smokers (HR = 1.74, 95% CI: 1.06, 2.88), and among participants with PM2.5 exposure < 25 µg/m3 (HR = 1.33, 95% CI: 1.01, 1.77). CONCLUSIONS: We found suggestive evidence of an association between fine particles and incidence of cerebrovascular events in Europe, even at lower concentrations than set by the current air quality limit value.

Risk for high depressive symptoms in diagnosed and previously undetected diabetes: 5-year follow-up results of the Heinz Nixdorf Recall study.

OBJECTIVE: The objective of this study was to determine the risk for the development of high depressive symptoms in study participants with diagnosed and previously undetected diabetes mellitus compared to those without diabetes in a prospective population-based cohort study in Germany. METHODS: We estimated the 5-year cumulative incidence of high depressive symptoms in participants without high depressive symptoms at baseline (n = 3,633, 51.4% men, mean age (SD) 59.1 (7.6) years, 7.0% diagnosed diabetes, 5.3% previously undetected diabetes) from the population-based Heinz Nixdorf Recall study. Diabetes was assessed by self-report, medication, and blood glucose. High depressive symptoms were assessed using CES-D. We calculated odds ratios and their corresponding 95% confidence interval, using multiple logistic regression analyses. RESULT: Cumulative 5-year incidences (95% CI) of high depressive symptoms in participants with diagnosed, undetected, and without diabetes were 7.1 (4.2-10.9), 4.1 (1.8-8.0), and 6.5 (5.6-7.4), respectively. The age-sex-adjusted OR for developing high depressive symptoms was 1.22 (0.74-2.03) in participants with diagnosed compared to those without diabetes, and 1.00 (0.59-1.68) after adjustment for BMI, physical activity, education, stroke, and myocardial infarction. The age-sex adjusted OR for developing high depressive symptoms in participants with previously undetected diabetes compared to those without diabetes was 0.72; 0.35-1.48; and fully adjusted 0.62; 0.30-1.30. CONCLUSION: We found no significant associations, maybe due to low power. However, our results are in line with a recent meta-analysis suggesting that risk of developing high depressive symptoms in patients with diagnosed diabetes may be moderately higher than in those without diabetes, and that comorbidity may explain in part this association. In participants with previously undetected diabetes, this first longitudinal study indicates that the risk is not increased or may even be decreased. These results support the hypothesis that high depressive symptoms develop due to diabetes-related burden and comorbidity and not due to hyperglycemia or hyperinsulinaemia.