The association of depression and all-cause mortality: Explanatory factors and the influence of gender.

BACKGROUND: The association of depression with mortality and the significance of explanatory factors, in particularly gender, have remained an issue of debate. We therefore aimed to estimate the effect of depression on all-cause mortality, to examine potential explanatory factors and to assess effect modification by gender. METHODS: We used Cox regression models to estimate the effect of depression on mortality based on data from the Gutenberg Health Study, which is a prospective cohort study of the adult population in the districts of Mainz and Mainz-Bingen, Germany. Baseline assessment was between 2007 and 2012. Effect modification by gender was measured on both additive and multiplicative scales. RESULTS: Out of 14,653 participants, 7.7% were depressed according to Patient Health Questionnaire 9 (PHQ-9), and 1,059 (7.2%) died during a median follow-up of 10.7 years. Depression elevated the risk of mortality in men and women in age-adjusted models (HR: 1.41, 95%-CI: 1.03-1.92; resp. HR: 1.96, 95%-CI: 1.43-2.69). Adjustment for social status, physical health and lifestyle covariates attenuated the effect and in the fully-adjusted model the hazard ratio was 0.96 (95%-CI: 0.69-1.33) in men and 1.53 (95%-CI: 1.10-2.12) in women. For effect modification by gender, the measure on multiplicative interaction was 0.68 (95%-CI 0.44-1.07) and on additive interaction was RERI=-0.47 (95%-CI -1.24-0.30). LIMITATIONS: The PHQ-9 is a single self-report measure of depression reflecting symptoms of the past two weeks, limiting a more detailed assessment of depression and course of symptoms, which likely affects the association with mortality. CONCLUSIONS: Depression elevates mortality by multifactorial pathways, which should be taken into account in the biopsychosocially informed treatment of depression. Effect modification by gender was not statistically significant.

A rapid point-of-care assay accurately measures vitamin D.

PURPOSE: Vitamin D (VitD) is a pleiotropic hormone with effects on a multitude of systems and metabolic pathways. Consequently, the relevance of a sufficiently high VitD serum level becomes self-evident. METHODS: A rapid immunofluorescence assay designed for the point-of-care measurement of serum VitD3 solely was tested. Inter- and intra-assay validation, double testing and result comparison with a standardized laboratory method were performed. RESULTS: An overall linear correlation of r = 0.89 (Pearson, 95% CI 0.88-0.92, p < 0.01) between the point of care and the conventional reference assay was registered. Accuracy and precision were of special interest at cut-points (10 ng/ml [mean deviation 1.7 ng/ml, SD 1.98 ng/ml, SE 0.16 ng/ml], 12 ng/ml [MD 0.41, SD 1.89, SE 0.19] and 30 ng/ml [MD - 1.11, SD 3.89, SE 0.35]). Only a slight deviation was detected between the two assays when using fresh (r = 0.91, 95% CI 0.86-0.94, p < 0.01) and frozen serum samples (r = 0.86, 0.82-0.89, p < 0.01). Results remained steady when samples were frozen several times. Inter- and intra-assay validation according to the CLSI protocol as well as multiuser testing showed stable results. CONCLUSION: This novel, innovative, and controlled study indicates that the evaluated rapid point of care VitD assay is reliable, accurate, and suited for clinical practice.

Frequency of cataract surgery and its impact on visual function-results from the German Gutenberg Health Study.

PURPOSE: To determine the frequency of cataract surgery in Germany and to evaluate its impact on visual function in an adult population. METHODS: The population-based Gutenberg Health Study was conducted in Germany with its baseline examination between 2007 and 2012 and a 5-year follow-up examiantion. An ophthalmological examination including slit-lamp examination, ocular biometry, and Scheimpflug imaging was carried out. Overall and age-specific frequencies of unilateral and bilateral cataract surgery within 5 years were computed including the 95% confidential intervals [95%-CI]. Association analyses were conducted to determine social and ocular associated factors using multivariable logistic regression analysis. Vision-related quality of life was assessed using NEI VFQ-25. RESULTS: A total of 10,544 people aged 35 to 74 years were bilateral phakic at baseline and had information on lens status at the 5-year examination. Of these, 168 had unilateral cataract surgery (1.6% [1.4-1.9%]), and 448 had bilateral cataract surgery (4.2% [3.9-4.7%]) in the following 5 years. The frequency of cataract surgery increased with age: 45-54-year-old subjects had twice as often cataract surgery (in at least on eye: OR = 2.32) than at age 35-44 years. The frequency further strongly increases with age (55-64 years: OR = 10.5; 65-74 years: OR = 43.8, p < 0.001). Subjects with glaucoma were more likely to have cataract surgery (OR = 2.52, p < 0.001). Visual function increased when undergoing bilateral cataract surgery. CONCLUSIONS: The frequency of cataract surgery is low at younger ages and increases up to 26% at age 70-74 years. Persons with glaucoma are more likely to undergo cataract surgery at population-based level in Germany.

Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study.

Aims: The cardiac and vascular late sequelae in long-term survivors of childhood cancer (CVSS)-study aimed to quantify the prevalence of cardiovascular risk factors (CVRF) and cardiovascular disease (CVD) in German childhood cancer survivors (CCS). Methods and results: In the CVSS-study (NCT02181049), 1002 CCS (age range 23-48 years) diagnosed with neoplasia prior to 15 years of age between 1980 and 1990 prospectively underwent a systematic, standardized clinical and laboratory cardiovascular screening, identical to the population-based Gutenberg Health Study (GHS) cohort. For 951 individuals, prevalences of CVRF and CVD were primarily compared to the GHS sample and to two further German population-based cohorts. Using log-binomial regression models, an increased risk for occurrence of arterial hypertension [relative risk (RR) 1.38, 95% confidence interval (95% CI 1.21-1.57)] and dyslipidaemia [RR 1.26 (95% CI 1.12-1.42)] was found. This indicates a premature occurrence compared to the general population of approximately 6 and 8 years, respectively [rate advancement period estimator, RAPhypertension 5.75 (95% CI 3.5-8.0) and RAPdyslipidaemia 8.16 (95% CI 4.4-11.9)]. Overall, no differences were observed for obesity and diabetes. Overt CVD was present in 4.5% (95% CI 3.0-6.6%) of CCS [RR 1.89 (95% CI 1.34-2.66), RAPCVD 7.9 (95% CI 4.1-11.7)], of which the most frequent entities were congestive heart failure and venous thromboembolism. Prevalences of CVRF and CVD increased with age without reaching a plateau over time. Conclusion: This large CCS screening examination revealed consistently in comparison to three population samples a considerably increased risk for premature CVD. The findings in these young adult CCS indicate a high burden of cardiovascular morbidity and mortality in the long term. Clinicaltrials. gov-Nr: NCT02181049.

Coagulation and inflammation in long-term cancer survivors: results from the adult population.

Essentials The increase of cancer survival remains curtailed by cardiovascular mortality. We studied a large range of inflammatory and coagulation biomarkers in long-term cancer survivors. Cancer history has an important impact on mortality independent of cardiovascular risk factors. Fibrinogen and von Willebrand factor are potential biomarkers in survivors of increased mortality. SUMMARY: Background The advances in cancer treatment and detection of early cancer have resulted in a steady increase in the number of of cancer survivors over the years. However, because of the long-term toxic effects of chemotherapy and radiotherapy, the incidence of cardiovascular disease (CVD) is increasing in survivors. Objectives To investigate traditional cardiovascular risk factors (CVRFs), inflammation and the coagulation profile in long-term cancer survivors (cancer diagnosis ≥ 5 years) from a large adult population-based study sample. Methods The presence of cardiovascular risk factors (CVRFs) and laboratory markers were compared in individuals with (n = 723) and without (n = 13626) a long-term history of cancer from the Gutenberg Health Study. Data on coagulation factors, D-dimer and von Willebrand factor (VWF) activity were available for 4974 individuals (n = 244 cancer survivors). Results In multivariable regression models, a history of cancer was, independently of CVRFs and CVD, associated with higher fibrinogen levels (ß 6.99, 95% confidence interval [CI] 1.16-12.8), VWF activity (ß 5.08, 95% CI 0.02-10.1), and antithrombin activity (ß 1.85, 95% CI 0.44-3.27). Cancer survivors with CVD showed notably higher VWF activity than individuals with CVD without a history of cancer, with a difference in the means of 23.0 (7.9-38.1). Multivariate Cox regression analysis, adjusted for CVRFs, confirmed that a long-term history of cancer is associated with a 72% higher mortality. Increased mortality in cancer survivors was dependent on fibrinogen level and VWF activity level. Conclusion Cancer survivors showed a worse inflammation and coagulation profile than individuals without a history of cancer. Overall mortality in long-term cancer survivors was increased independently of traditional CVRFs. These results underline the need to further investigate plasma biomarkers as complementary cardiovascular risk predictors in cancer survivors.

[Abnormal laboratory results : Plausibility, reliability, and implications]. / Auffällige Laborwerte : Plausibilität, Aussagekraft und Konsequenzen.

In outpatient care or the emergency room laboratory tests oftentimes provide the first clues to the medical condition that made the patient seek medical help. Quite commonly, rapid medical decisions are required in these situations. Therefore, laboratory results must be evaluated immediately and interpreted within the broader context of the patient's presentation. During this process test results must be checked for plausibility, their positive and/or negative predictive values for the individual patient must be considered, and finally, the potential clinical implications need to be assessed. The latter in particular is of the utmost importance. This article discusses several laboratory tests commonly ordered for emergency patients and provides some guidance on their relevance in the decision to refer an outpatient to an emergency room or for inpatient care, or whether a patient can be safely diagnosed in the outpatient setting.

Subclinical levels of anxiety but not depression are associated with planning performance in a large population-based sample.

BACKGROUND: Major depression and anxiety disorders are known to negatively influence cognitive performance. Moreover, there is evidence for greater cognitive decline in older adults with generalized anxiety disorder. Except for clinical studies, complex executive planning functions and subclinical levels of anxiety have not been examined in a population-based sample with a broad age range. METHODS: Planning performance was assessed using the Tower of London task in a population-based sample of 4240 participants aged 40-80 years from the Gutenberg Health Study (GHS) and related to self-reported anxiety and depression by means of multiple linear regression analysis. RESULTS: Higher anxiety ratings were associated with lower planning performance (ß = -0.20; p < 0.0001) independent of age (ß = 0.03; p = 0.47). When directly comparing the predictive value of depression and anxiety on cognition, only anxiety attained significance (ß = -0.19; p = 0.0047), whereas depression did not (ß = -0.01; p = 0.71). CONCLUSIONS: Subclinical levels of anxiety but not of depression showed negative associations with cognitive functioning independent of age. Our results demonstrate that associations observed in clinical groups might differ from those in population-based samples, also with regard to the trajectory across the life span. Further studies are needed to uncover causal interrelations of anxiety and cognition, which have been proposed in the literature, in order to develop interventions aimed at reducing this negative affective state and to improve executive functioning.

Antiphospholipid antibody-induced cellular responses depend on epitope specificity : implications for treatment of antiphospholipid syndrome.

Essentials Antiphospholipid antibodies (aPL) are heterogeneous and induce different cellular responses. We analyzed signaling events induced by different monoclonal and patient aPL in monocytes. Two major signaling pathways involving either NADPH-oxidase or LRP8 were identified. Our data suggest that these two pathways mediate the majority of aPL effects on monocytes. SUMMARY: Background Antiphospholipid antibodies (aPLs) contribute to the pathogenesis of the antiphospholipid syndrome (APS) by induction of an inflammatory and procoagulant state in different cell types, and several signaling pathways have been described. Objectives To investigate whether signaling depends on the epitope specificity of aPLs. Methods Cellular effects of three human monoclonal aPLs with distinctly different epitope specificities were analyzed in vitro. Expression of tumor necrosis factor-α mRNA by mouse and human monocytes was the major readout. Analysis included cells from genetically modified mice, and the use of specific inhibitors in human monocytes. Data were validated with IgG isolated from 20 APS patients. Results Cofactor-independent anticardiolipin aPLs activated monocytes by induction of endosomal NADPH oxidase. Activation could be blocked by hydroxychloroquine (HCQ). Anti-ß2 -glycoprotein I aPL activated monocytes by interacting with LDL receptor-related protein 8 (LRP8). This could be blocked by rapamycin. Analysis of 20 APS patients' IgG showed that all IgG fractions activated the same two pathways as the monoclonal aPL, depending on their epitope patterns as determined by ELISA. Monocyte activation by APS IgG could be blocked completely by HCQ and/or rapamycin, suggesting that in most, if not all, APS patients there is no other relevant signaling pathway. Conclusions aPLs activate two major proinflammatory signal transduction pathways, depending on their epitope specificity. HCQ and rapamycin, either alone or in combination, completely suppress signaling by APS IgG. These observations may provide a rationale for specific treatment of APS patients according to their aPL profile.

e-Health-based management of patients receiving oral anticoagulation therapy: results from the observational thrombEVAL study.

Essentials e-Health based health care by an expert centre may advance management of oral anticoagulation. Outcome of patients was compared between an e-health based coagulation service and regular care. Patients in the coagulation service cohort experienced a significantly better clinical outcome. Lower risk for adverse events was related to anticoagulation-specific and non-specific outcome. SUMMARY: Background Management of oral anticoagulation (OAC) therapy is essential to minimize adverse events in patients receiving vitamin K-antagonists (VKAs). Data on the effect of e-health-based anticoagulation management systems on the clinical outcome of OAC patients are limited. Objectives To compare the clinical outcome of OAC patients managed by an e-health-based coagulation service (CS) with that of patients receiving regular medical care (RMC). Methods The prospective multicenter cohort study thrombEVAL (NCT01809015) comprised 1558 individuals receiving RMC and 760 individuals managed by a CS. Independent study monitoring and adjudication of endpoints by an independent review panel were implemented. Results The primary study endpoint (composite of thromboembolism, clinically relevant bleeding and death) occurred in 15.7 per 100 patient-years (py) with RMC and in 7.0 per 100 py with the CS (rate ratio [RR], 2.3; 95% confidence interval [CI], 1.7-3.1). Rates for major and clinically relevant bleeding were higher with RMC than with the CS: 6.8 vs. 2.6 and 10.1 vs. 3.6 per 100 py, respectively. Thromboembolic events showed an RR of 1.5 (95% CI, 0.8-2.6) comparing RMC with the CS. Hospitalization (RR, 2.6; 95% CI, 2.3-3.0) and all-cause mortality (RR, 4.6; 95% CI, 2.8-7.7) were markedly more frequent with RMC. In Cox regression analysis with adjustment for age, sex, cardiovascular risk factors, comorbidities, treatment characteristics and sociodemographic status, hazard ratios (HR) for the primary endpoint (HR, 2.2; 95% CI, 1.5-3.4), clinically relevant bleeding (HR, 3.1; 95% CI, 1.7-5.5), hospitalization (HR, 2.2; 95% CI, 1.8-2.8) and all-cause mortality (HR, 5.6; 95% CI, 2.9-11.0) favored CS treatment. Conclusions In this study, e-health-based management of OAC therapy was associated with a lower frequency of OAC-specific and non-specific adverse events.

The predictive value of different equations for estimation of glomerular filtration rate in patients with coronary artery disease - Results from the AtheroGene study.

BACKGROUND: Impaired renal function leads to dramatically increased risk for the development and progression of coronary artery disease (CAD). Therefore we aimed to assess the predictive value of different equations for estimated glomerular filtration rate (eGFR) in CAD-patients. METHODS: From the AtheroGene study 2135 patients were included. eGFR was calculated using the 4-variable Modification of Diet in Renal Disease (4MDRD) equation for serum creatinine (sCr), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for sCr and cystatin C (CysC) each alone, and in combination (CysC/sCr). eGFR was assessed regarding the combined outcome of cardiovascular death and non-fatal myocardial infarction and regarding complex CAD represented by a SYNTAX score ≥23. Median follow-up was 4.3years. RESULTS: Only the CKD-EPI equation using CysC could differentiate between eGFR >90ml/min/1.73m(2) vs. eGFR 60-90ml/min/1.73m(2) according to the occurrence of an endpoint event (log-rank test p=0.009). In the Cox regression analysis only eGFR calculated by CKD-EPI equation for CysC (Hazard ratio per 1 standard deviation (HR) 1.27 (95% CI 1.07-1.50); p=0.007) and for CysC/sCr (HR 1.22 (95% CI 1.02-1.46); p=0.026) were predictive regarding the outcome after adjustment for cardiovascular risk factors and Nt-proBNP. Furthermore, only eGFR calculated by CKD-EPI equation for CysC (odds ratio (OR) 1.57 (95% CI 1.36-1.78); p<0.001) and for CysC/sCr (OR 1.32 (95% CI 1.13-1.53); p<0.001) were significantly associated with a SYNTAX score ≥23. CONCLUSION: In patients with CAD the CKD-EPI equation for CysC and for CysC/sCr provided the best predictive value regarding the prognosis and the severity of CAD.

Current and cumulative night shift work and subclinical atherosclerosis: results of the Gutenberg Health Study.

PURPOSE: The study examines the association between exposure to current and cumulative night shift work and subclinical parameters of atherosclerosis. METHODS: Participants of a population-based cohort study (the Gutenberg Health Study, N = 15,010) aged 35-64 years were examined at baseline (2007-2012). Investigations included measurements of arterial stiffness, vascular function [reactive hyperaemia (RH) index], and intima media thickness (IMT). Also, a complete job history (including up to 15 periods), occupational exposures, a variety of lifestyle, and dispositional variables were enquired. RESULTS: Night shift work was performed by 1071 out of 8065 currently employed individuals. The strongest association after adjustment for age, sex, job complexity level, being a manager, overtime work, and noise appeared for more than 660 night shifts within the last 10 years and a significantly increased arterial stiffness of 0.33 m/s. This reflects a 4 % flow velocity increase for individuals with more than 660 night shifts compared to non-night workers. Regarding the entire professional life, night shift workers showed a significantly decreased vascular function by -0.054 RH index points by using the same adjustment. IMT values did not differ statistically from non-night workers. Lifestyle and dispositional factors showed an influence on all used subclinical atherosclerosis parameters. CONCLUSIONS: The cross-sectional results demonstrate an association between night work and detrimental changes in the atherosclerotic process. The association is more pronounced with more years in night shift and is partly explained by lifestyle and dispositional factors. Longitudinal analyses are necessary to confirm the results.

PO-58 - Cardiovascular risk profile in survivors of adult cancer - results from the general population study.

INTRODUCTION: The advancements in cancer treatment and detection of early cancer have resulted in steady increase of adult cancer survivors over the years. However, due to the long term toxic effects of chemotherapy and radiotherapy, the incidence of cardiovascular diseases (CVD) is increasing in survivors. Identifying risk factors and interventions to reduce the excess burden of CVD in this vulnerable population is urgently needed. AIM: To investigate the cardiovascular risk factors (CVRFs), inflammation and coagulation profile in cancer survivors from a large population-based study. MATERIALS AND METHODS: Presence of CVRFs and laboratory markers have been compared in individuals with (n=1,359) and without (n=13,626) history of cancer. Standard laboratory profile, including blood glucose and lipid profile, has been evaluated in 15,010 individuals from the Gutenberg Health Study (GHS). Coagulation factors, D-dimer and von Willebrand factor (vWF) activity were available in N=4,993. RESULTS: The individuals with history of cancer were older compared to no history of cancer with mean age of 61,5years and 54.4years, respectively (p<0.001). Traditional CVRFs as diabetes (14% vs 8.8%), dyslipidemia (49.6% vs 43.7%) and hypertension (60.3 vs 48.7%) were more frequent whereas smoking was less frequent (14.5% vs 19.9%) in cancer survivors (p<0.001). The standard laboratory profile showed cancer survivors with lower erythrocyte, platelet and white blood cell counts and higher C-reactive protein (CRP), glucose, HbA1c and triglycerides levels (p<0.001). Multivariable logistic regression analysis adjusted for age, sex and CVRFs demonstrated an independent association with diabetes (odds ratio, OR: 1.24, 1.02-1.50; p=0.027) and higher CRP (OR: 1.01, 1.01-1.02; p=0.00071). Fibrinogen, FV, FVII, FVIII and FXI, D-dimer and vWF activity were higher in cancer survivors (p<0.001). Multivariable logistic regression confirmed an independent association with higher fibrinogen (OR: 1.002, 1.000-1.003) and vWF activity (OR: 1.005, 1.001-1.008). CONCLUSIONS: This is the first study investigating CVRFs, inflammation and coagulation profile in individuals with history of cancer from a well characterized population-representative adult sample. It gives evidence for higher prevalence of CVRFs, particularly diabetes in this vulnerable population. Markers of inflammation as CRP and fibrinogen and vWF activity were higher in cancer survivors independent of the cardiovascular risk profile. These results underline the increased risk of CVD and need for development of cardio-oncology programs offering cardiovascular prevention.

Pathogenesis of the antiphospholipid syndrome revisited: time to challenge the dogma.

For more than a decade the antiphospholipid syndrome (APS) has been reported to be caused mainly by antiphospholipid antibodies (aPL), which are not directed against phospholipids but against a complex of phospholipids and phospholipid binding proteins, so called cofactors (e.g. ß2-glycoprotein I [ß2GPI]). In fact, many researchers propose that the only relevant antigens in the APS are the cofactors themselves, with ß2GPI being the most important. Antibodies that bind to phospholipids in a cofactor-independent manner are considered insignificant for the pathogenesis of the APS. We review the evidence for this current pathophysiologic concept and argue that it has never been proven and is now clearly no longer tenable. First, there is undisputable evidence that cofactor-independent aPL are pathogenic and present in the blood of APS patients. Second, available epidemiologic and clinical studies do not support a dominant pathogenic role for anti-ß2GPI.

Cofactor-independent human antiphospholipid antibodies induce venous thrombosis in mice.

UNLABELLED: Essentials Cofactor-independent antiphospholipid antibodies (CI-aPL) are generally considered non-pathogenic. We analyzed the effects of human monoclonal CI-aPL in a mouse model of venous thrombosis. As shown in vitro, CI-aPL induce a procoagulant state in vivo by activation of endosomal NADPH-oxidase. Contrary to common belief, CI-aPL induce venous thrombosis in vivo. SUMMARY: Background There is general consensus that the antiphospholipid syndrome (APS) is caused by antiphospholipid antibodies (aPL) with antibodies against ß2-glycoprotein-I being the most relevant. aPL that bind phospholipids in the absence of protein cofactors are generally considered pathogenetically irrelevant. We showed that cofactor-independent human monoclonal aPL isolated from APS patients induce proinflammatory and procoagulant cellular responses by activating endosomal NADPH-oxidase 2 (NOX2). Similar aPL were detected in all IgG fractions from APS patients analyzed. Objectives We aimed to clarify if cofactor-independent aPL can be thrombogenic in vivo and, if so, whether these effects are mediated via activation of NOX2. Methods Two cofactor-independent human monoclonal aPL, HL5B and RR7F, were tested in a mouse model of venous thrombosis. Genetically modified mice and in vitro assays were used to delineate the mechanisms underlying thrombus induction. Results HL5B and RR7F dramatically accelerate thrombus formation in this mouse model. Thrombus formation depends on tissue factor activation. It cannot be induced in NOX2-deficient mice. Bone marrow chimeras of C57BL/6J mice reconstituted with NOX2-deficient bone marrow showed that leukocyte activation plays a major role in thrombus formation. Neither TLR4 signaling nor platelet activation by our aPL is required for venous thrombus formation. Conclusions Cofactor-independent aPL can induce thrombosis in vivo. This effect is mainly mediated by leukocyte activation, which depends on the previously described signal transduction via endosomal NOX2. Because most APS patients have been shown to harbor aPL with similar activity, our data are of general relevance for the APS.

Inflammatory bowel disease (IBD) locus 12: is glutathione peroxidase-1 (GPX1) the relevant gene?

Genome-wide association studies have identified and repeatedly confirmed the association of rs3197999 in MST1 with inflammatory bowel disease (IBD). However, the underlying pathophysiology remains unclear. rs3197999 is a non-synonymous single-nucleotide polymorphism which modifies the function of macrophage stimulating protein-1 (MST1). We show by haplotyping that rs3197999 is in linkage disequilibrium with rs1050450 in GPX1, with almost complete cosegregation of the minor alleles. As shown by immunoassay, rs3197999 influences the MST-1 level in serum. But also rs1050450 causes an amino acid exchange in glutathione peroxidase 1 (GPx-1) and reduced activity of this antioxidant enzyme. The association of GPx deficiency and IBD in mice was already shown. We propose that GPx-1 is a better candidate than MST1 for the pathophysiologic link between IBD locus 12 and IBD.

[The Gutenberg Health Study]. / Die Gutenberg Gesundheitsstudie.

The Gutenberg Health Study is a population-based, prospective, single-center cohort study that started in 2007 at the University Medical Center Mainz. The project focuses on cardiovascular diseases, cancer, eye diseases, metabolic diseases, diseases of the immune system and mental diseases. The study aims at improving the individual risk prediction for diseases. Therefore, lifestyle, psychosocial factors, environment, laboratory parameters as well as the extent of the subclinical disease are investigated. A comprehensive biobank enables biomolecular examinations including a systems biological approach. During the baseline visit 15,000 individuals aged 35-74 years were invited to a 5 h examination program in the study center. This will be followed by a computer-assisted telephone interview with a standardized interview and assessment of endpoints after 2.5 years. After 5 years a detailed follow-up examination comparable to the visit at study inclusion will be performed in the study center. Further follow-up visits of the cohort are envisaged.

Macrophage-stimulating protein polymorphism rs3197999 is associated with a gain of function: implications for inflammatory bowel disease.

Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg(689) (MSP(wt)) and Cys(689) (MSP(mut)) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP(mut) significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.