Rolf Fimmers

University of Bonn, Bonn, North Rhine-Westphalia, Germany

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Publications (332)1331.59 Total impact

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    ABSTRACT: Hypomethylation of long interspersed element (LINE)-1 has been observed in tumorigenesis when using degenerate assays, which provide an average across all repeats. However, it is unknown whether individual LINE-1 loci or different CpGs within one specific LINE-1 promoter are equally affected by methylation changes. Conceivably, studying methylation changes at specific LINE-1 may be more informative than global assays for cancer diagnostics. Therefore, with the aim of mapping methylation at individual LINE-1 loci at single-CpG resolution and exploring the diagnostic potential of individual LINE-1 locus methylation, we analyzed methylation at 11 loci by pyrosequencing, next-generation bisulfite sequencing as well as global LINE-1 methylation in bladder, colon, pancreas, prostate, and stomach cancers compared to paired normal tissues and in blood samples from some of the patients compared to healthy donors. Most (72/80) tumor samples harbored significant methylation changes at at least one locus. Notably, our data revealed not only the expected hypomethylation but also hypermethylation at some loci. Specific CpGs within the LINE-1 consensus sequence appeared preferentially hypomethylated suggesting that these could act as seeds for hypomethylation. In silico analysis revealed that these CpG sites more likely faced the histones in the nucleosome. Multivariate logistic regression analysis did not reveal a significant clinical advantage of locus-specific methylation markers over global methylation markers in distinguishing tumors from normal tissues. Methylation changes at individual LINE-1 loci are heterogeneous, whereas specific CpGs within the consensus sequence appear to be more prone to hypomethylation. With a broader selection of loci, locus-specific LINE-1 methylation could become a tool for tumor detection.
    Clinical Epigenetics 12/2015; 7(1):17. DOI:10.1186/s13148-015-0051-y · 4.54 Impact Factor

  • 88. Wissenschaftliche Jahrestagung der Deutschen Gesellschaft für Kieferorthopädie, Mannheim; 11/2015
  • A Flöck · S Weber · N Ferrari · C Fietz · C Graf · R Fimmers · U Gembruch · W Merz ·

    Zeitschrift für Geburtshilfe und Neonatologie 11/2015; 219(S 01). DOI:10.1055/s-0035-1566467 · 0.48 Impact Factor
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    ABSTRACT: Objectives: To determine the total torque play of various rectangular titanium molybdenum alloy (TMA)/stainless steel (SS) wires in various 0.018″ upper incisor lingual brackets and slot size measurements. Methods: TMA (0.0175″ × 0.0175″, 0.0170″ × 0.025″, 0.0182″ × 0.0182″, 0.0182″ × 0.025″) and SS wires (0.016″ × 0.022″, 0.016″ × 0.024″, 0.018″ × 0.025″) were twisted in standard (Hiro, Incognito™, Joy®, Kurz 7th generation, STb™: fixation with elastic modules) and self-ligating brackets (Evolution SLT®, In-Ovation® L MTM: closed ligation mechanism) from -20 degrees to +20 degrees with a custom-made machine. The total torque play was calculated by extrapolating the linear portion of the twist/moment curves to the x-axis and adding the absolute negative and positive angle values at the intercepts. The bracket slot height was measured before and after the experiments with a series of pin gauges with round profile. Results: Brackets in ascending order for total torque play with the most slot-filling wire TMA 0.0182″ × 0.025″: Evolution SLT® (0 degree ± 0 degree), Incognito™ (2.2 degrees ±1.1 degrees), Hiro (5.1 degrees ±3.0 degrees), In-Ovation® L MTM (6.3 degrees ±2.2 degrees), STb™ (6.6 degrees ±1.8 degrees), Kurz 7th generation (7.1 degrees ±0.8 degrees), and Joy® (12.0 degrees ±0.8 degrees). Wires in ascending order for total torque play with the most precise slot Incognito™: TMA 0.0182″ × 0.025″ (2.2 degrees ±1.1 degrees), TMA 0.0182″ × 0.0182″ (2.4 degrees ±0.9 degrees), SS 0.018″ × 0.025″ (5.5 degrees ±1.0 degrees), TMA 0.0170″ × 0.025″ (9.4 degrees ±1.8 degrees), TMA 0.0175″ × 0.0175″ (13.0 degrees ±1.5 degrees), SS 0.016″ × 0.024″ (16.1 degrees ±1.4 degrees), SS 0.016″ × 0.022″ (17.8 degrees ±1.0 degrees); differences between some of the experimental groups were not statistically significant. Bracket slot dimensions in ascending order: Evolution SLT® (less than 0.452mm), Incognito™ (0.460mm ±0.002mm), In-Ovation® L MTM (0.469mm ±0.001mm), Hiro (0.469mm ±0.010mm), STb™ (0.471mm ±0.002mm), Kurz 7th generation (0.473mm ±0.002mm), and Joy® (greater than 0.498mm). Limitations: The applied method must be questioned when used with brackets with incomplete slot walls (Evolution SLT®). Slot measurement with pin gauges may not register bracket wing deformation. Conclusions: All brackets showed a differing slot size from the nominal 0.018″ (0.457mm). Incognito™ presented the most precise and Joy® the widest slot. The main wires for the retraction phase SS 0.016″ × 0.022″/SS 0.016″ × 0.024″ showed poor torque control. Among the finishing TMA wires, TMA 0.0175″ × 0.0175″ exhibited the highest and TMA 0.0182″ × 0.0182″/TMA 0.0182″ × 0.025″ the smallest torque play. Significance: The manufacturers could profit from this investigation towards optimization of the dimensional precision of their products. The orthodontist must be aware of the torque play of the wire-bracket combinations to be able to plan and individualize the appliance by third order customization.
    The European Journal of Orthodontics 10/2015; DOI:10.1093/ejo/cjv063 · 1.48 Impact Factor
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    ABSTRACT: Aim: Cardiac magnetic resonance (CMR) can visualize inflammatory tissue changes in acute myocarditis. Several quantitative image-derived parameters have been described to enhance the diagnostic value of CMR, but no direct comparison of these techniques is available. Methods and results: A total of 34 patients with suspected acute myocarditis and 50 control subjects underwent CMR. CMR protocol included quantitative assessment of T1 relaxation times using modified Look-Locker inversion recovery (MOLLI) and shortened MOLLI (ShMOLLI) acquisition schemes, extracellular volume fraction (ECV), T2 relaxation times, and longitudinal strain. Established Lake-Louise criteria (LLC) consisting of T2-weighted signal intensity ratio (T2-ratio), early gadolinium enhancement ratio (EGEr), and late gadolinium enhancement (LGE) were assessed. Receiver operating characteristics analysis was performed to compare diagnostic performance. Areas under the curve of native T1 (MOLLI: 0.95; ShMOLLI: 0.92) and T2 relaxation times (0.92) were higher compared with those of the other CMR parameters (T2-ratio: 0.71, EGEr: 0.71, LGE: 0.87, LLC: 0.90, ECV MOLLI: 0.77, ECV ShMOLLI: 0.80, longitudinal strain: 0.83). Combined with LGE, each native mapping technique outperformed the diagnostic performance of LLC (P < 0.01, respectively). A combination of native parameters (T1, T2, and longitudinal strain) significantly increased the diagnostic performance of CMR compared with LLC without need of contrast media application (0.99 vs. 0.90; P = 0.008). Conclusion: In patients suspected of having acute myocarditis, diagnostic performance of CMR can be improved by implementation of quantitative CMR parameters. Especially, native mapping techniques have the potential to replace current LLC. Clinicaltrialsgov number: NCT02299856.
    European Heart Journal Cardiovascular Imaging 10/2015; DOI:10.1093/ehjci/jev246 · 4.11 Impact Factor
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    ABSTRACT: In patients undergoing transcatheter aortic valve implantation (TAVI), the high prevalence of periph- eral artery disease (PAD) limits femoral access and increases vascular complications that are associated with mortality and morbidity. Our study assessed the ability of a balloon-expandable large-bore vascular sheath to increase access-site availability and to reduce vascular complications. Methods and results: Among 257 patients from two centres, 43 patients underwent transfemoral TAVI with the use of the SoloPath balloon-expandable sheath due to complex iliofemoral access anatomy. Propensity score matching (2:1) was performed except for the sheath to femoral artery ratio (SFAR). Compared to stand- ard sheath patients, we found no significant difference in 30-day and one-year mortality (SoloPath vs. stand- ard sheath, 9.3% vs. 3.5%; p=0.2, and 18.6% vs. 23.3%; p=0.7), major vascular complications (9.3% vs. 4.7%; p=0.3), and major bleeding (9.3% vs. 10.5%; p=0.5) in the cohort with the balloon-expandable sheath. Conclusions: The use of a balloon-expandable large-bore sheath in patients with a high risk for vascular complications due to complex access-site anatomy proved to be feasible and safe. However, circumferential calcifications and sheath-to-artery ratios account for vascular access complications even in patients treated with the balloon-expandable sheath.
    EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 10/2015; 11(6). DOI:10.4244/EIJY15M01_10 · 3.77 Impact Factor
  • A. Flöck · S.K. Weber · N. Ferrari · C. Fietz · C. Graf · R. Fimmers · U. Gembruch · W.M Merz ·
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    ABSTRACT: Objective: Brain-derived neurotrophic factor (BDNF) plays a fundamental role in brain development; additionally, it is involved in various aspects of cerebral function, including neurodegenerative and psychiatric diseases. Involvement of BDNF in parturition has not been investigated. The aim of our study was to analyze determinants of umbilical cord BDNF (UC-BDNF) concentrations of healthy, term newborns and their respective mothers. Methods: This cross-sectional prospective study was performed at a tertiary referral center. Maternal venous blood samples were taken on admission to labor ward; newborn venous blood samples were drawn from the umbilical cord (UC), before delivery of the placenta. Analysis was performed with a commercially available immunoassay. Univariate analyses and stepwise multivariate regression models were applied. Results: 120 patients were recruited. UC-BDNF levels were lower than maternal serum concentrations (median 641ng/mL, IQR 506 vs. median 780ng/mL, IQR 602). Correlation between UC- and maternal BDNF was low (R=0.251, p=0.01). In univariate analysis, mode of delivery (MoD), gestational age (GA), body mass index at delivery, and gestational diabetes were determinants of UC-BDNF (MoD and smoking for maternal BDNF, respectively). Stepwise multivariate regression analysis revealed a model with MoD and GA as determinants for UC-BDNF (MoD for maternal BDNF). Conclusions: MoD and GA at delivery are determinants of circulating BDNF in the mother and newborn. We hypothesize that BDNF, like other neuroendocrine factors, is involved in the neuroendocrine cascade of delivery. Timing and mode of delivery may exert BDNF-induced effects on the cerebral function of newborns and their mothers.
    Psychoneuroendocrinology 10/2015; 63. DOI:10.1016/j.psyneuen.2015.09.028 · 4.94 Impact Factor
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    ABSTRACT: Livestock-associated bacteria with resistance to two or more antibiotic drug classes have heightened our awareness for the consequences of antibiotic consumption and spread of resistant bacterial strains in the veterinary field. In this study we assessed the prevalence of concomitant colonization with livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) and enterobacteriaceae expressing extended-spectrum betalactamases (ESBL-E) in farms at the German-Dutch border region. Nasal colonization of pigs with MRSA (113/547 (20.7%)) was less frequent than rectal colonization with ESBL-E (163/540 (30.2%)). On the individual farm level MRSA correlated with ESBL-E recovery. The data further provide information on prevalence at different stages of pig production, including abattoirs, as well as in air samples and humans living and working on the farms. Notably, MRSA was detected in stable air samples of 34 out of 35 pig farms, highlighting air as an important MRSA transmission reservoir. The majority of MRSA isolates, including those from humans, displayed tetracycline resistance and spa types t011 and t034 characteristic for LA-MRSA, demonstrating transmission from pigs to humans. ESBL-E positive air samples were detected on 6 out of 35 farms but no pig-to-human transmission was found. Detection of ESBL-E, e.g. mostly Escherichia coli with CTX-M-type ESBL, was limited to these six farms. Molecular typing revealed transmission of ESBL-E within the pig compartments; however, related strains were also found on unrelated farms. Although our data suggest that acquisition of MRSA and ESBL-E might occur among pigs in the abattoirs, MRSA and ESBL-E were not detected on the carcasses. Altogether, our data define stable air (MRSA), pig compartments (ESBL-E) and abattoir waiting areas (MRSA and ESBL-E) as major hot spots for transmission of MRSA and/or ESBL-E along the pig production chain.
    PLoS ONE 09/2015; 10(9):e0138173. DOI:10.1371/journal.pone.0138173 · 3.23 Impact Factor
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    ABSTRACT: Background: The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand. Methods/design: ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables. Discussion: The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system. Trial registration: ID NCT02364986.
    BMC pharmacology & toxicology 09/2015; 16(1):25. DOI:10.1186/s40360-015-0025-x
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    ABSTRACT: Colonization of livestock with bacteria resistant to antibiotics is considered as a risk for the entry of drug-resistant pathogens into the food chain. For this reason there is a need for novel concepts to address the eradication of drug-resistant commensals on farms. In the present report we evaluated the decontamination measures taken on a farm contaminated with methicillin-resistant Staphylococcus aureus (MRSA) and Enterobacteriaceae expressing extended-spectrum ß-lactamases (ESBL-E). The decontamination process preceded the conversion from piglet breeding to gilt production. Microbiological surveillance showed that the decontamination measures eliminated the MRSA and ESBL-E strains that were detected on the farm before the complete removal of pigs, cleaning and disinfection of the stable, and the construction of an additional stable meeting high quality standards. After restarting pig production, ESBL-E remained undetectable over twelve months, but MRSA was recovered from pigs and the environment within the first two days. However, spa (Staphylococcus aureus protein A) typing revealed acquisition of a MRSA strain (type t034) that had not been detected before decontamination. Interestingly, we observed that a farm worker who had been colonized with the prior MRSA strain (t2011) acquired the new strain (t034) after two months. In summary, this report demonstrates that decontamination protocols similar to those used here can lead to successful elimination of contaminating MRSA and ESBL-E in pigs and the stable environment. Nevertheless, decontamination protocols do not prevent the acquisition of new MRSA strains. Copyright © 2015, American Society for Microbiology. All Rights Reserved.
    Applied and Environmental Microbiology 09/2015; 81(21). DOI:10.1128/AEM.01713-15 · 3.67 Impact Factor

  • Forensic Science International Genetics Supplement Series 09/2015; DOI:10.1016/j.fsigss.2015.09.080

  • Zeitschrift für Gastroenterologie 08/2015; 41(08). DOI:10.1055/s-0035-1555166 · 1.05 Impact Factor
  • C C Pieper · V Weis · R Fimmers · I Rajab · M Linhart · H H Schild · C P Nähle ·
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    ABSTRACT: Purpose: To investigate the incidence and possible risk factors of upper deep vein obstruction in patients both prior to first cardiac device implantation and before device revision. Materials and Methods: Records of asymptomatic patients undergoing contrast venography prior to implantation or revision of a cardiac device from 09/2009 to 04/2012 were reviewed. Venograms were used to determine the presence of venous obstruction. Interrelations between the incidence of venous obstruction and patient- or device-related parameters were identified using Fisher's exact test and univariate logistic regression. Multivariate logistic regression was used to identify independent predictors of venous obstruction. Results: 456 patients met the inclusion criteria (330 males, 126 females, 67.8 ± 12.9 years). 100 patients underwent first implantation, and 356 patients underwent device revision (mean time since implantation 82.5 ± 75.3 months). Venous obstruction was present in 11.0 % and 30.1 % before implantation and revision, respectively. Only presence of ventricular escape rhythm was significantly related to venous occlusion (p < 0.001) prior to first implantation. Prior to revision, significant predictors were male sex (p = 0.01), time since implantation (p < 0.0001), presence of escape rhythm (p = 0.02), compromised coagulation (p = 0.02), phenprocoumon (p = 0.005), and peripheral arterial disease (p = 0.01). Conclusion: Although several risk factors could be identified, reliable prediction of venous obstruction was not possible. Therefore, we advocate performing venography in all patients prior to device revision or upgrade to avoid complications. In cases of first device implantation, the risks associated with venography should be weighed against the surprisingly high rate of deep upper vein obstruction. Key points: • Prevalence of upper extremity deep vein obstruction is surprisingly high.• Reliable prediction of venous obstruction is not possible.• Contrast venography should be performed prior to device revision/upgrade.• Before first implantation procedure-related risks must be weighed against high obstruction rates. Citation Format: • Pieper CC, Weis V, Fimmers R et al. Venous Obstruction in Asymptomatic Patients Undergoing First Implantation or Revision of a Cardiac Pacemaker or Implantable Cardioverter-Defibrillator: A Retrospective Single Center Analysis. Fortschr Röntgenstr 2015; DOI: 10.1055/s-0035-1553351. © Georg Thieme Verlag KG Stuttgart · New York.
    RöFo - Fortschritte auf dem Gebiet der R 07/2015; DOI:10.1055/s-0035-1553351 · 1.40 Impact Factor
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    ABSTRACT: In many clinical trials on cutaneous healing, wound closure is the primary endpoint and single most important outcome parameter, making precise assessment of this time point one of utmost importance. The assessment of wound closure can be performed either by subjective clinical inspection or with a variety of methodologies anticipated to provide more objective data. The aim of this study was to examine intra- and interrater variability of blinded photographic analysis of wound closure of human partial thickness wounds, as well as the reliability of remote photographic analysis of wounds with that of direct clinical assessment. Two plastic surgeons, a dermatologist, and a maxillofacial surgeon constituted our rater panel. High-resolution images of patient wounds derived from two randomized controlled clinical trials (EU Clinical Trials Register numbers EudraCT 2009-017418-56 (registered 12 January 2010) and EudraCT 2010-019945-24 (registered 13 July 2010)) were individually assessed by the blinded, experienced study raters. The reliability of photographic image analysis was tested using intraclass and interclass correlation. The validity of photographic image analysis was correlated with clinical assessments of documented time to heal from the study centers' files. The results demonstrated that the mean intraclass correlation coefficient of all four examiners was excellent (r = 0.79; 95% confidence interval (CI), 0.61, 1.00)). The interrater correlation coefficient was good (r = 0.67; 95% CI, 0.57, 1.00)) and therefore acceptable. The agreement between remote visual assessment and clinical assessment at the time of healing was good (r = 0.64; 95% CI, 0.52, 0.76)) with an overall difference of about 1 day. Remote photographic analysis of cutaneous wounds is a feasible instrument in clinical open-label studies to evaluate time to wound closure. We found that it was a reliable method of measuring wound closure that correlated satisfactorily with clinical judgment, bolstering the potential relevance in the current era of evolving application and dependency in the field of telemedicine. EU Clinical Trials Register EudraCT numbers 2009-017418-56 (date of registration: 12 January 2010) and 2010-019945-24 (date of registration: 13 July 2010):; and
    Trials 05/2015; 16(1):235. DOI:10.1186/s13063-015-0742-x · 1.73 Impact Factor
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    ABSTRACT: &Aims: Patients with liver cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective, randomized trial to compare prevention of rebleeding in patients given small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. We performed an open-label study of patients with liver cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were randomly assigned more than 5 days after variceal hemorrhage to groups given a small intrahepatic stent shunt (cTIPS, 8mm; n=90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n=95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with adequate reduction in HVPG (responders) remained on the drugs whereas non-responders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary endpoint was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the SF-36 health survey) were secondary outcome measures. A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 y (7%) than the medical group (26%) (P=.002). A slightly higher proportion of patients in the TIPS group had adverse events, including encephalopathy (18% vs 8% for medical treatment, P=.05). Rebleeding occurred in 6/23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in non-responders who received variceal band ligation (31%) (P=.06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. Placement of a small-diameter cTIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required a step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
    Gastroenterology 05/2015; 149(3). DOI:10.1053/j.gastro.2015.05.011 · 16.72 Impact Factor
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    ABSTRACT: To describe the directional kinetics of the spread of geographic atrophy (GA) spread in eyes with age-related macular degeneration and foveal sparing. Prospective, noninterventional natural history study: Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM; identifier, NCT00393692). Participants of the FAM study exhibiting foveal sparing of GA. Eyes were examined longitudinally with fundus autofluorescence (FAF; excitation wavelength, 488 nm; emission wavelength, >500 nm) and near infrared (NIR) reflectance imaging (Spectralis HRA+OCT or HRA2; Heidelberg Engineering, Heidelberg, Germany). Areas of foveal sparing and GA were measured by 2 independent readers using a semiautomated software tool that allows for combined NIR reflectance and FAF image grading (RegionFinder; Heidelberg Engineering). A linear mixed effect model was used to model GA kinetics over time. Change of GA lesion size over time (central vs. peripheral progression). A total of 47 eyes of 36 patients (mean age, 73.8±7.5 years) met the inclusion criteria. Mean follow-up time was 25.2±16.9 months (range, 5.9-74.6 months). Interreader agreement for measurements of GA and foveal-sparing size were 0.995 and 0.946, respectively. Mean area progression of GA toward the periphery was 2.27±0.22 mm(2)/year and 0.25±0.03 mm(2)/year toward the center. Analysis of square root-transformed data revealed a 2.8-fold faster atrophy progression toward the periphery than toward the fovea. Faster atrophy progression toward the fovea correlated with faster progression toward the periphery in presence of marked interindividual differences. The results demonstrate a significantly faster centrifugal than centripetal GA spread in eyes with GA and foveal sparing. Although the underlying pathomechanisms for differential GA progression remain unknown, local factors may be operative that protect the foveal retina-retinal pigment epithelial complex. Quantification of directional spread characteristics and modeling may be useful in the design of interventional clinical trials aiming to prolong foveal survival in eyes with GA. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.
    Ophthalmology 05/2015; 122(7). DOI:10.1016/j.ophtha.2015.03.027 · 6.14 Impact Factor
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    ABSTRACT: Background. Ivermectin (IVM) has been the drug of choice for the treatment of onchocerciasis. However, there have been reports of persistent microfilaridermia in individuals from an endemic area in Ghana after many rounds of IVM, raising concerns of sub-optimal responses (SOR) or even the emergence of drug resistance. Since it is considered risky to continue relying only on IVM to combat this phenomenon, we assessed the effect of targeting the O. volvulus Wolbachia endosymbionts with doxycycline for these SOR individuals. Methods. 167 patients, most of them with multiple rounds of IVM, were recruited in areas with IVM SOR and treated with 100mg/day doxycycline for 6 weeks. Three and 12 months after doxycycline treatment, patients took part in standard IVM treatment. Results. At 20 months post treatment 80% of living female worms from the placebo group were Wolbachia-positive, whereas only 5.1% in the doxycycline-treated group contained bacteria. Consistent with interruption of embryogenesis, none of the nodules removed from doxycycline treated patients contained Mf, and 97% of those patients were without microfilaridermia, in contrast to placebo patients who remained at pretreatment levels (p<0.001). Moreover, a significantly enhanced number of dead worms were observed after doxycycline. Conclusion. Targeting the Wolbachia in O. volvulus is effective in clearing Mf in the skin of onchocerciasis patients with persistent microfilaridermia and in enhanced killing of adult worms after repeated standard IVM treatment. Strategies can now be developed which include doxycycline to control onchocerciasis in areas where infections persist despite the frequent use of IVM.
    Clinical Infectious Diseases 05/2015; 61(4). DOI:10.1093/cid/civ363 · 8.89 Impact Factor
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    ABSTRACT: Our aim was to retrospectively evaluate the occurrence of respiratory motion artefacts in patients undergoing dynamic liver magnetic resonance (MR) either with gadoxetate disodium or gadobutrol. Two hundred and thirty liver MR studies (115 with gadobutrol, 115 with gadoxetate disodium) were analysed. Respiratory motion artefacts on dynamic 3D T1-weighted MR images (pre-contrast, arterial, venous, and late-dynamic phase) were assessed using a five-point rating scale. Severe motion was defined as a score ≥ 4. Mean motion scores were compared with the Mann-Whitney-U-test. The chi-squared-test was used for dichotomous comparisons. Mean motion scores for gadoxetate disodium and gadobutrol showed no relevant differences for each phase of the dynamic contrast series (pre-contrast: 1.85 ± 0.70 vs. 1.88 ± 0.57, arterial: 1.85 ± 0.81 vs. 1.87 ± 0.74, venous: 1.82 ± 0.67 vs. 1.74 ± 0.64, late-dynamic: 1.75 ± 0.62 vs. 1.79 ± 0.63; p = 0.469, 0.557, 0.382 and 0.843, respectively). Severe motion artefacts had a similar incidence using gadoxetate disodium and gadobutrol (11/460 [2.4 %] vs. 7/460 [1.5 %]; p = 0.341). Gadoxetate disodium is associated with equivalent motion scores compared to gadobutrol in dynamic liver MRI. In addition, both contrast agents demonstrated a comparable and acceptable rate of severe respiratory motion artefacts. • Gadobutrol and gadoxetate disodium showed comparable motion scores in dynamic phase imaging. • The incidence of severe motion artefacts was pronounced in arterial phase imaging. • Adverse respiratory side effects were not recorded in 115 examinations with gadoxetate disodium.
    European Radiology 04/2015; 25(11). DOI:10.1007/s00330-015-3736-x · 4.01 Impact Factor
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    ABSTRACT: Introduction: Endoscopic lung volume reduction (ELVR) is an emerging therapy for emphysematous COPD. However, any resulting changes in lung perfusion and ventilation remain undetermined. Here, we report ELVR-mediated adaptations in lung perfusion and ventilation, as investigated by means of pulmonary scintigraphy. Methods: In this observational study, we enrolled 26 patients (64.9 ± 9.4 yrs, 57.7% male) with COPD heterogeneous emphysema undergoing ELVR with endobronchial valves (Zephyr, Pulmonx, Inc.). Mean baseline FEV1 and RV were 32.9% and 253.8% predicted, respectively. Lung scintigraphy was conducted prior to ELVR and eight weeks thereafter. Analyses of perfusion and ventilation shifts were performed and complemented by correlation analyses between paired zones. Results: After ELVR, target zone perfusion showed a mean relative reduction of 43.32% (p<0.001), which was associated with a significant decrease in target zone ventilation (p<0.001). Perfusion of the contralateral untreated zone and of the contralateral total lung exhibited significant increases post-ELVR (p = 0.002 and p = 0.005, respectively); both correlated significantly with the corresponding target zone perfusion adaptations. Likewise, changes in target zone ventilation correlated significantly with ventilatory changes in the contralateral untreated zone and the total contralateral lung (Pearson's r: -0.42, p = 0.04 and Pearson's r: -0.42, p = 0.03, respectively). These effects were observed in case of clinical responsiveness to ELVR, as assessed by changes in the six-minute walk test distance. Discussion: ELVR induces a relevant decrease in perfusion and ventilation of the treated zone with compensatory perfusional and ventilatory redistribution to the contralateral lung, primarily to the non-concordant, contralateral zone.
    PLoS ONE 03/2015; 10(3):e0118976. DOI:10.1371/journal.pone.0118976 · 3.23 Impact Factor
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    ABSTRACT: 37 million individuals are currently infected with Onchocerca volvulus (O. volvulus), a parasitic nematode that elicits various dermal manifestations and eye damage in man. Disease control is primarily based on distributing ivermectin in mass drug administration (MDA) programmes which aim at breaking transmission by eliminating microfilariae (MF), the worm's offspring. The majority of infected individuals present generalized onchocerciasis, which is characterized by hyporesponsive immune responses and high parasite burden including MF. Recently, in areas that have been part of MDA programmes, individuals have been identified that present nodules but are amicrofilaridermic (a-MF) and our previous study showed that this group has a distinct immune profile. Expanding on those findings we determined the immune responses of O. volvulus-infected individuals to a Plasmodium-derived antigen MSP-1 (merozoite surface protein-1), which is required by the parasite to enter erythrocytes. Isolated PBMCs from O. volvulus-infected individuals (164 MF+ and 46 a-MF) and non-infected volunteers from the same region (NEN), were stimulated with MSP-1 and the resulting supernatant screened for the presence of IL-5, IL-13, IFN-γ, TNF-α, IL-6, IL-17A and IL-10. These findings were then further analyzed following regression analysis using the covariates MF, ivermectin (IVM) and region. The latter referred to the Central or Ashanti regions of Ghana, which, at the time sampling, had received 8 or 1 round of MDA respectively. IL-5, IL-13 and IFN-γ responses to MSP-1 were not altered between NEN and O. volvulus-infected individuals nor were any associations revealed in the regression analysis. IL-10, IL-6 and TNF-α MSP-1 responses were, however, significantly elevated in cultures from infected individuals. Interestingly, when compared to a-MF individuals, MSP-induced IL-17A responses were significantly higher in MF+ patients. Following multivariable regression analysis these IL-10, IL-6, TNF-α and IL-17A responses were all dominantly associated with the regional covariate. Consequently, areas with a lowered infection pressure due to IVM MDA appear to influence bystander responses to Plasmodium-derived antigens in community members even if they have not regularly participated in the therapy.
    Parasites & Vectors 03/2015; 8(1). DOI:10.1186/s13071-015-0786-5 · 3.43 Impact Factor

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  • 1989-2015
    • University of Bonn
      • • Institute of Human Genetics
      • • Medizinische Klinik und Poliklinik II
      • • Institute of Biomedical Statistics, Computer Science and Epidemiology
      • • Zentrum für Innere Medizin
      • • Medizinische Klinik und Poliklinik I
      • • Department of Neurobiology
      Bonn, North Rhine-Westphalia, Germany
  • 2006-2014
    • Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e.V.
      Bonn, North Rhine-Westphalia, Germany
  • 1994-2014
    • University of Bonn - Medical Center
      • Institute for Clinical Chemistry and Clinical Pharmacology
      Bonn, North Rhine-Westphalia, Germany
  • 2012
    • Chung-Ang University
      Sŏul, Seoul, South Korea
  • 2008
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 1994-2004
    • University of Cologne
      Köln, North Rhine-Westphalia, Germany
  • 2002
    • Johannes Gutenberg-Universität Mainz
      • I. Department of Medicine
      Mayence, Rheinland-Pfalz, Germany
  • 1998-2002
    • Sigmund-Freud-Institut
      Frankfurt, Hesse, Germany
  • 1997
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel