Karl J Lackner

Universitätsklinikum Freiburg, Freiburg an der Elbe, Lower Saxony, Germany

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Publications (253)1541.86 Total impact

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    ABSTRACT: Background: -Interleukin-18 (IL-18) is a pleiotropic cytokine centrally involved in the cytokine cascade with complex immunomodulatory functions in innate and acquired immunity. Circulating IL-18 concentrations are associated with type 2 diabetes, cardiovascular events and diverse inflammatory and autoimmune disorders. Methods and results: -To identify causal variants affecting circulating IL-18 concentrations, we applied various omics and molecular biology approaches. By GWAS, we confirmed association of IL-18 levels with a SNP in the untranslated exon 2 of the inflammasome component NLRC4 (NLR family, CARD domain containing 4) gene on chromosome 2 (rs385076, P=2.4×10(-45)). Subsequent molecular analyses by gene expression analysis and reporter gene assays indicated an effect of rs385076 on NLRC4 expression and differential isoform usage by modulating binding of the transcription factor PU.1. Conclusions: -Our study provides evidence for the functional causality of SNP rs385076 within the NLRC4 gene in relation to IL-18 activation.
    Circulation Cardiovascular Genetics 09/2015; DOI:10.1161/CIRCGENETICS.115.001079 · 4.60 Impact Factor
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    ABSTRACT: 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.Genes and Immunity advance online publication, 10 September 2015; doi:10.1038/gene.2015.35.
    Genes and immunity 09/2015; DOI:10.1038/gene.2015.35 · 2.91 Impact Factor
  • Pharmacopsychiatry 09/2015; 48(06). DOI:10.1055/s-0035-1557951 · 1.85 Impact Factor
  • Karl J. Lackner
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    ABSTRACT: The antiphospholipid syndrome (APS) has been the subject of intensive research since its initial description as a disease entity more than 30 years ago. While significant progress in our understanding of the pathophysiology of APS has been made, many unsolved questions remain. Already in the 1990s clear evidence proved that the antiphospholipid antibodies (aPL) associated with APS cause the major clinical symptoms of the disorder, i.e. thrombotic events and abortions. This finding prompted further research into the molecular events elicited by aPL. Research focused initially on the plasmatic coagulation system. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 08/2015; DOI:10.1111/jth.13119 · 5.72 Impact Factor
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    ABSTRACT: The limit of detection (LoD) is the minimal amount of a substance that can be consistently detected. In the diagnosis of acute myocardial infarction (AMI) many patients present with troponin concentrations below the LoD of contemporary sensitive cardiac troponin I (cs-cTnI) assays. These censored values below the LoD influence the diagnostic performance of these assays compared to highly sensitive cTnI (hs-cTnI) assays. Therefore we assessed the impact of a new approach for interpolation of the left-censored data of a cs-cTnI assay in the evaluation of patients with suspected AMI. Our posthoc analysis used a real world cohort of 1818 patients with suspected MI. Data on cs-cTnI was available in 1786 patients. As a comparator the hs-cTnI version of the assay was used. To reconstruct quantities below the LoD of the cs-cTnI assay, a γ regression approach incorporating the GRACE (Global Registry of Acute Coronary Events) score variables was used. Censoring of cs-cTnI data below the LoD yielded weaker diagnostic information [area under the curve (AUC), 0.781; 95% CI, 0.731-0.831] regarding AMI compared to the hs-cTnI assay (AUC, 0.949; CI, 0.936-0.961). Use of our model to estimate cs-cTnI values below the LoD showed an AUC improvement to 0.921 (CI, 0.902-0.940). The cs-cTnI LoD concentration had a negative predictive value (NPV) of 0.950. An estimated concentration that was to be undercut by 25% of patients presenting with suspected AMI was associated with an improvement of the NPV to 0.979. Estimation of values below the LoD of a cs-cTnI assay with this new approach improves the diagnostic performance in evaluation of patients with suspected AMI. © 2015 American Association for Clinical Chemistry.
    Clinical Chemistry 07/2015; 61(9). DOI:10.1373/clinchem.2015.238949 · 7.91 Impact Factor
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    ABSTRACT: The introduction of modern troponin assays has facilitated diagnosis of acute myocardial infarction due to improved sensitivity with corresponding loss of specificity. Atrial fibrillation (AF) is associated with elevated levels of troponin. The aim of the present study was to evaluate the diagnostic performance of troponin I in patients with suspected acute coronary syndrome and chronic AF. Contemporary sensitive troponin I was assayed in a derivation cohort of 90 patients with suspected acute coronary syndrome and chronic AF to establish diagnostic cut-offs. These thresholds were validated in an independent cohort of 314 patients with suspected myocardial infarction and AF upon presentation. Additionally, changes in troponin I concentration within 3 hours were used. In the derivation cohort, optimized thresholds with respect to a rule-out strategy with high sensitivity and a rule-in strategy with high specificity were established. In the validation cohort, application of the rule-out cut-off led to a negative predictive value of 97 %. The rule-in cut-off was associated with a positive predictive value of 88 % compared with 71 % if using the 99th percentile cut-off. In patients with troponin I levels above the specificity-optimized threshold, additional use of the 3-hour change in absolute/relative concentration resulted in a further improved positive predictive value of 96 %/100 %. Troponin I concentration and the 3-hour change in its concentration provide valid diagnostic information in patients with suspected myocardial infarction and chronic AF. With regard to AF-associated elevation of troponin levels, application of diagnostic cut-offs other than the 99th percentile might be beneficial.
    BMC Medicine 07/2015; 13(1):169. DOI:10.1186/s12916-015-0410-8 · 7.25 Impact Factor
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    ABSTRACT: Venous thromboembolism (VTE) with its two manifestations deep vein thrombosis (DVT) and pulmonary embolism (PE) is a major public health problem. The VTEval Project aims to investigate numerous research questions on diagnosis, clinical management, treatment and prognosis of VTE, which have remained uncertain to date. The VTEval Project consists of three observational, prospective cohort studies on VTE comprising cohorts of individuals with a clinical suspicion of acute PE (with or without DVT), with a clinical suspicion of acute DVT (without symptomatic PE) and with an incidental diagnosis of VTE (PE or DVT). The VTEval Project expects to enrol a total of approximately 2000 individuals with subsequent active and passive follow-up investigations over a time period of 5 years per participant. Time points for active follow-up investigations are at months 3, 6, 12, 24 and 36 after diagnosis (depending on the disease cohort); passive follow-up investigations via registry offices and the cancer registry are performed 48 and 60 months after diagnosis for all participants. Primary short-term outcome is defined by overall mortality (PE-related death and all other causes of death), primary long-term outcome by symptomatic VTE (PE-related death, recurrence of non-fatal PE or DVT). The VTEval Project includes three 'all-comer' studies and involves the standardised acquisition of high-quality data, covering the systematic assessment of VTE including symptoms, risk profile, psychosocial, environmental and lifestyle factors as well as clinical and subclinical disease, and it builds up a large state-of-the-art biorepository containing various materials from serial blood samplings. The VTEval Project has been approved by the local data safety commissioner and the responsible ethics committee (reference no. 837.320.12 (8421-F)). Trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. NCT02156401. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    BMJ Open 07/2015; 5(7):e008157. DOI:10.1136/bmjopen-2015-008157 · 2.27 Impact Factor
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    ABSTRACT: Blood viscosity has a role in modulating cardiovascular homeostasis; changes in this parameter have been associated with cardiovascular mortality and morbidity. However, it remains unclear whether these changes are (1) involved in the pathophysiology of disease, (2) an epiphenomenon, or (3) the expression of counterregulatory mechanisms. We report data on the normal values of blood viscosity and its association with cardiovascular risk factors, prevalent cardiovascular disease, and blood pressure in a large population-based cohort study. Viscosity was calculated using validated formulae and its associations were explored in 15,010 participants (mean 55.0, min-max: 35-74 years old; 49.5% women) from the Gutenberg Health Study as well as in a subgroup of 3223 subjects (61.1% women, mean age 49.2, min-max 35-74 years old) without risk factors or self-reported cardiovascular disease. Age- and gender-adjusted mean values for viscosity were defined. Regression models showed a relationship between classical risk factors and blood viscosity measures; the overall R (2) of the multiple linear regression model was however as low as 0.067 and 0.049 for high and low shear stress viscosity, respectively. After correction for cardiovascular risk factors, there was a very mild association between viscosity and prevalent coronary artery disease and heart failure. Systolic, mean and diastolic blood pressure increased with increasing blood viscosity after correction for age and gender. We provide reference values for viscosity in a population-based cohort. Blood viscosity decreases in older subjects and shows a very mild association with cardiovascular risk factors and prevalent disease in our cohort. There is a linear positive association between viscosity and blood pressure. © The Author(s), 2015.
    Therapeutic Advances in Cardiovascular Disease 06/2015; DOI:10.1177/1753944715589887 · 2.13 Impact Factor
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    ABSTRACT: Pathways of oxidative stress, nitric oxide bioavailability and l-arginine derivatives are hypothesized to be related to atrial fibrillation (AF). Circulating methylated l-arginine metabolites can be assessed in the general population and may show an association with AF.
    International Journal of Cardiology 05/2015; DOI:10.1016/j.ijcard.2015.05.102 · 4.04 Impact Factor
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    ABSTRACT: To determine the age- and sex-specific prevalence and determinants of Retinal vein occlusions (RVO) in a large populations-based German cohort. The investigation comprised 15,010 participants (35-74 years) from the Gutenberg Health Study (GHS). We determined the prevalence of RVO (central retinal vein occlusion, CRVO; branch retinal vein occlusion, BRVO) for the local population by assessing fundus photographs of 12,954 (86.3%; 49.8% females, 50.2% males) participants. Furthermore, we analyzed the associations of RVO with cardiovascular, anthropometric, and ophthalmic parameters. The weighted prevalences of RVO, CRVO, and BRVO were 0.40%, 0.8%, and 0.32%, respectively. Males were 1.7 times more frequently affected by RVO than females. Prevalence of RVO was 0.2% in participants aged 35-44 and 45-54 years, respectively, 0.48% from 55-64 and 0.92% in participants between 65-74 years. 91.5% of persons with RVO had one or more cardiovascular risk factors or diseases versus 75.9% of persons without RVO. BRVO was associated with arterial hypertension (OR: 2.69; 95%CI: 1.27-5.70) and atrial fibrillation (3.37; 1.24-9.12) and CRVO with higher age (7.02, 1.63-30.19) and a family history of stroke (4.64; 1.18-18.25). Median visual acuity (base 10 logarithm of minimum angle of resolution; logMAR) was 0.2 in persons with RVO versus 0.05 in those without. The prevalence of RVO in this German population was 0.4% and males were 1.7 times more frequently affected than females. CRVO was associated with higher age and a family history of stroke, and BRVO with arterial hypertension and atrial fibrillation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Thrombosis and Haemostasis 04/2015; 13(7). DOI:10.1111/jth.12982 · 5.72 Impact Factor
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    ABSTRACT: Objective: The inflammatory and immune systems are altered in type 2 diabetes. Here, the aim was to profile the immune and inflammatory response in subjects with prediabetes and diabetes in a large population-representative sample. Research design and methods: In total, 15,010 individuals were analyzed from the population-based Gutenberg Health Study. Glucose status was classified according to HbA1c concentration and history of diagnosis. All samples were analyzed for white blood cells (WBCs), granulocytes, lymphocytes, monocytes, platelets, C-reactive protein (CRP), albumin, fibrinogen, and hematocrit. Interleukin-18 (IL-18), IL-1 receptor antagonist (IL-1RA), and neopterin concentrations were determined in a subcohort. Results: In total, 7,584 men and 7,426 women were analyzed (range 35-74 years), with 1,425 and 1,299 having prediabetes and diabetes, respectively. Biomarkers showed varying dynamics from normoglycemic via subjects with prediabetes to subjects with diabetes: 1) gradual increase (WBCs, granulocytes, monocytes, IL-1RA, IL-18, and fibrinogen), 2) increase with subclinical disease only (lymphocytes and CRP), 3) increase from prediabetes to diabetes only (neopterin), and 4) no variation with glucose status (hematocrit). The strongest relative differences were found for CRP, IL-1RA, and fibrinogen concentrations. Several inflammatory and immune markers were associated with the glucose status independent from cardiovascular risk factors and comorbidities, varied with disease severity and the presence of disease-specific complications in the diabetes subcohort. Conclusions: The inflammatory and immune biomarker profile varies with the development and progression of type 2 diabetes. Markers of inflammation and immunity enable differentiation between the early preclinical and clinical phases of the disease, disease complications, and progression.
    Diabetes care 04/2015; 38(7). DOI:10.2337/dc14-3008 · 8.42 Impact Factor
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    ABSTRACT: Elevated levels of FVIII:c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex-specific distribution and reference ranges of plasma FVIII:c and its cardiovascular determinants is available. FVIII:c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany. Multivariable regression analyses for FVIII:c were performed under adjustment for genetic determinants, cardiovascular risk factors and cardiovascular disease. Females (126.6% (95% CI: 125.2/128)) showed higher FVIII:c levels than males (121.2% (119.8/122.7)). FVIII:c levels increased with age in both sexes (ß per decade: 5.67% (4.22/7.13) male, 6.15% (4.72/7.57) female; p<0.001). Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms for FVIII:c were created. FVIII:c was approximately 25% higher in individuals with non-O blood type. Adjusted for sex and age, ABO-blood group accounted for 18.3% of FVIII:c variation. In multivariable analysis, FVIII:c was notably positively associated with diabetes mellitus, obesity, hypertension and dyslipidemia and negatively with current smoking. In a fully adjusted multivariable model, the strongest associations observed were of elevated FVIII:c with diabetes and peripheral artery disease in both sexes and with obesity in males. Effects of SNPs in the vWF, STAB2 and SCARA5 gene were stronger in females than in males. The use of nomograms for valuation of FVIII:c might be useful to identify high-risk cohorts for thromboembolism. Additionally, the prospective evaluation of FVIII:c as a risk predictor becomes feasible. Copyright © 2015. Published by Elsevier Ireland Ltd.
    International journal of cardiology 03/2015; 187(1):166-174. DOI:10.1016/j.ijcard.2015.03.330 · 4.04 Impact Factor
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    ABSTRACT: Objective to establish and critically evaluate the 99th percentile upper reference limit (URL) for high-sensitivity cardiac troponin I (hs-cTnI) in a large healthy European cohort using different selection criteria. Methods 1368 presumably healthy individuals from 9 countries were evaluated with surrogate biomarkers for diabetes (glycated hemoglobin [HbA1c] < 48 mmoL/mol), myocardial (B-type natriuretic peptide [BNP] < 35 pg/mL) and renal dysfunction (estimated glomerular filtration rate [eGFR] > 60 mL/min/1.73 m2), and dyslipidemia to refine the healthy cohort. The 99th percentile URLs were independently determined by the non-parametric and robust methods. Results The use of biomarker selection criteria resulted in a decrease of the 99th percentile URL for hs-cTnI from 23.7 to 14.1 ng/L and from 11.2 to 7.1 ng/L, when using the non-parametric percentile and robust methods, respectively; a further reduction after exclusion of individuals with dyslipidemia was noted. Male gender, BNP, HbA1c and smoking status were independently associated with hs-cTnI concentration in the presumably healthy population, while the impact of age, present in the univariate analysis, decreased after adjustments for gender and surrogate biomarkers. The BNP-based inclusion criterion had the most pronounced effect on the 99th percentile URL, excluding 21% of the study participants and decreasing its value to 11.0 (7.1) ng/L according to the non-parametric (robust) method. Gender, but not age-specific, differences at 99th percentile URL have been identified. Conclusion The selection of a reference population has a critical impact on the 99th percentile value for hs-cTnI. A uniform protocol for the selection of the healthy reference population is needed.
    International Journal of Cardiology 03/2015; 187(1). DOI:10.1016/j.ijcard.2015.03.282 · 4.04 Impact Factor
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    ABSTRACT: This paper describes the study design, methodology, cohort profile and self-reported diseases in the ophthalmological branch of the Gutenberg Health Study (GHS). The GHS is an ongoing, prospective, interdisciplinary, single-center, population-based cohort study in Germany. The main goals of the ophthalmological section are to assess the prevalence and incidence of ocular diseases and to explore risk factors, genetic determinants and associations with systemic diseases and conditions. The eye examination at baseline included a medical history, self-reported eye diseases, visual acuity, refractive errors, intraocular pressure, visual field, pachymetry, keratometry, fundus photography and tear sampling. The 5-year follow-up visit additionally encompassed optical coherence tomography, anterior segment imaging and optical biometry. The general examination included anthropometry; blood pressure measurement; carotid artery ultrasound; electrocardiogram; echocardiography; spirometry; cognitive tests; questionnaires; assessment of mental conditions; and DNA, RNA, blood and urine sampling. Of 15,010 participants (aged 35-74 years at the time of inclusion), ocular data are available for 14,700 subjects (97.9%). The mean visual acuity (standard deviation), mean spherical equivalent, median decimal visual acuity, and mean intraocular pressure were 0.08 (0.17) logMar, -0.42 (2.43) diopters, 0.9 and 14.24 (2.79) mm Hg, respectively. The frequencies of self-reported strabismus, glaucoma, surgery for retinal detachment and retinal vascular occlusions were 2.7%, 2.3%, 0.2% and 0.4%, respectively. The GHS is the most extensive dataset of ophthalmic diseases and conditions and their risk factors in Germany and one of the largest cohorts worldwide. This dataset will provide new insight in the epidemiology of ophthalmic diseases and related medical specialties.
    PLoS ONE 03/2015; 10(3):e0120476. DOI:10.1371/journal.pone.0120476 · 3.23 Impact Factor
  • Karl J Lackner
    Clinical Chemistry and Laboratory Medicine 03/2015; DOI:10.1515/cclm-2015-0141 · 2.71 Impact Factor
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    ABSTRACT: Primary open-angle glaucoma is the most common optic neuropathy and an important cause of irreversible blindness worldwide. The optic nerve head or optic disc is divided in two parts: a central cup (without nerve fibers) surrounded by the neuroretinal rim (containing axons of the retinal ganglion cells). The International Glaucoma Genetics Consortium conducted a meta-analysis of genome-wide association studies consisting of 17,248 individuals of European ancestry and 6,841 individuals of Asian ancestry. The outcomes of the genome-wide association studies were disc area and cup area. These specific measurements describe optic nerve morphology in another way than the vertical cup-disc ratio, which is a clinically used measurement, and may shed light on new glaucoma mechanisms. We identified 10 new loci associated with disc area (CDC42BPA, F5, DIRC3, RARB, ABI3BP, DCAF4L2, ELP4, TMTC2, NR2F2, and HORMAD2) and another 10 new loci associated with cup area (DHRS3, TRIB2, EFEMP1, FLNB, FAM101, DDHD1, ASB7, KPNB1, BCAS3, and TRIOBP). The new genes participate in a number of pathways and future work is likely to identify more functions related to the pathogenesis of glaucoma. © 2015 WILEY PERIODICALS, INC.
    Genetic Epidemiology 01/2015; 39(3). DOI:10.1002/gepi.21886 · 2.60 Impact Factor
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    ABSTRACT: The antiphospholipid syndrome (APS) is an autoimmune disease characterised by thromboembolic events and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). Here we show that three cofactor independent human monoclonal aPL can induce transcription of NLRP3 and caspase-1 resulting in inflammasome activation specific for NLRP3. This depends fully on activation of endosomal NADPH-oxidase-2 (NOX2) by aPL. Activation of NOX2 and subsequent inflammasome activation by aPL are independent from TLR2 or TLR4. While endosomal superoxide production induces caspase-1 and NLRP3 transcription, it does not affect prae-IL-1β transcription. Therefore, release of IL-1β occurs only after activation of additional pathways like TLR7/8 or TLR2. All effects exerted by the monoclonal aPL can be reproduced with IgG fractions of APS patients proving that the monoclonal aPL are representative for the APS. IgG fractions of healthy controls or patients suffering from systemic lupus erythematosus have no effect. In a mouse model of the APS we can show inflammasome activation in vivo. Furthermore, mononuclear cells isolated from patients with the APS show an increased expression of caspase-1 and NLRP3 which is accompanied by a three-fold increased serum concentration of IL-1β suggesting chronic inflammasome activation in APS patients. In summary, we provide further evidence that endosomal NOX2 can be activated by cofactor independent aPL. This leads to induction of the NLRP3 inflammasome. Our data indicate that cofactor independent aPL might contribute significantly to the pathogenesis of the APS.
    Thrombosis and Haemostasis 01/2015; 113(4). DOI:10.1160/TH14-07-0628 · 4.98 Impact Factor
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    ABSTRACT: Context: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndromes type 1-4 and are associated with multiple and recurrent pheochromocytomas (Pheo) and PGLs. SDHC mutations most frequently result in benign, non-functional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date. Objectives: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue. Design: In three unrelated patients referred for routine genetic testing SDHB, SDHC, and SDHD genes were sequenced and gross deletions were excluded by MLPA (MRC Holland). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry. Results: In a patient with a non-functioning thoracic PGL metastatic to the bone, the lungs and mediastinal lymph nodes we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics but both showed benign HNPGLs. Conclusions We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL even though malignancy is probably rare.
    The Journal of Clinical Endocrinology and Metabolism 12/2014; 99(3):jc20133486. DOI:10.1210/jc.2013-3486 · 6.21 Impact Factor
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    ABSTRACT: Abstract Reference limits are estimators for 'extreme' percentiles of the distribution of a quantitative diagnostic marker in the healthy population. In most cases, interest will be in the 90% or 95% reference intervals. The standard parametric method of determining reference limits consists of computing quantities of the form X̅±c·S. The proportion of covered values in the underlying population coincides with the specificity obtained when a measurement value falling outside the corresponding reference region is classified as diagnostically suspect. Nonparametrically, reference limits are estimated by means of so-called order statistics. In both approaches, the precision of the estimate depends on the sample size. We present computational procedures for calculating minimally required numbers of subjects to be enrolled in a reference study. The much more sophisticated concept of reference bands replacing statistical reference intervals in case of age-dependent diagnostic markers is also discussed.
    Clinical Chemistry and Laboratory Medicine 12/2014; 52(12):1685-94. DOI:10.1515/cclm-2014-0226 · 2.71 Impact Factor
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    ABSTRACT: Background Different biological pathways have been related to atrial fibrillation (AF). Novel biomarkers capturing inflammation, oxidative stress, and neurohumoral activation have not been investigated comprehensively in AF. Methods and Results In the population-based Gutenberg Health Study (n = 5000), mean age 56±11 years, 51% males, we measured ten biomarkers representing inflammation (C-reactive protein, fibrinogen), cardiac and vascular function (midregional pro adrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro-B-type natriuretic peptide [Nt-proBNP], sensitive troponin I ultra [TnI ultra], copeptin, and C-terminal pro endothelin-1), and oxidative stress (glutathioneperoxidase-1, myeloperoxidase) in relation to manifest AF (n = 161 cases). Individuals with AF were older, mean age 64.9±8.3, and more often males, 71.4%. In Bonferroni-adjusted multivariable regression analyses strongest associations per standard deviation increase in biomarker concentrations were observed for the natriuretic peptides Nt-proBNP (odds ratio [OR] 2.89, 99.5% confidence interval [CI] 2.14–3.90; P<0.0001), MR-proANP (OR 2.45, 99.5% CI 1.91–3.14; P<0.0001), the vascular function marker MR-proADM (OR 1.54, 99.5% CI 1.20–1.99; P<0.0001), TnI ultra (OR 1.50, 99.5% CI 1.19–1.90; P<0.0001) and. fibrinogen (OR 1.44, 99.5% CI 1.19–1.75; P<0.0001). Based on a model comprising known clinical risk factors for AF, all biomarkers combined resulted in a net reclassification improvement of 0.665 (99.3% CI 0.441–0.888) and an integrated discrimination improvement of >13%. Conclusions In conclusion, in our large, population-based study, we identified novel biomarkers reflecting vascular function, MR-proADM, inflammation, and myocardial damage, TnI ultra, as related to AF; the strong association of natriuretic peptides was confirmed. Prospective studies need to examine whether risk prediction of AF can be enhanced beyond clinical risk factors using these biomarkers.
    PLoS ONE 11/2014; 9(11):e112486. DOI:10.1371/journal.pone.0112486 · 3.23 Impact Factor

Publication Stats

7k Citations
1,541.86 Total Impact Points


  • 2009–2015
    • Universitätsklinikum Freiburg
      • Institute of Clinical Chemistry and Laboratory Medicine
      Freiburg an der Elbe, Lower Saxony, Germany
    • Boston University
      • Department of Biostatistics
      Boston, Massachusetts, United States
  • 2001–2015
    • Johannes Gutenberg-Universität Mainz
      • • III. Department of Medicine
      • • Institute of Inorganic and Analytical Chemistry
      • • Institut für Klinische Chemie und Laboratoriumsmedizin
      Mayence, Rheinland-Pfalz, Germany
  • 2013
    • Queen Mary, University of London
      • Barts and The London School of Medicine and Dentistry
      Londinium, England, United Kingdom
  • 2012
    • Pierre and Marie Curie University - Paris 6
      Lutetia Parisorum, Île-de-France, France
    • Goethe-Universität Frankfurt am Main
      • Center for Internal Medicine
      Frankfurt, Hesse, Germany
  • 2011
    • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
      • Institute of Clinical Chemistry and Laboratory Medicine (Central Laboratory)
      Mainz, Rhineland-Palatinate, Germany
  • 2008
    • Technische Universität Dresden
      Dresden, Saxony, Germany
  • 2007
    • University of California, San Diego
      San Diego, California, United States
  • 2005
    • Charité Universitätsmedizin Berlin
      • Institute of Clinical Physiology
      Berlin, Land Berlin, Germany
    • Case Western Reserve University
      • Department of Biochemistry
      Cleveland, Ohio, United States
  • 2004–2005
    • State University of New York Downstate Medical Center
      • Department of Cell Biology
      Brooklyn, New York, United States
  • 1994–2003
    • Universität Regensburg
      • • Department of Internal Medicine I
      • • Department of Clinical Chemistry and Laboratory Medicine
      Ratisbon, Bavaria, Germany
  • 1998–2001
    • University Hospital Regensburg
      • Klinik und Poliklinik für Innere Medizin I
      Ratisbon, Bavaria, Germany
  • 1999
    • Friedrich-Alexander Universität Erlangen-Nürnberg
      • Department of Ophthalmology
      Erlangen, Bavaria, Germany