TY - JOUR A1 - Chumak, Tetyana A1 - Rüttiger, Lukas A1 - Lee, Sze Chim A1 - Campanelli, Dario A1 - Zuccotti, Annalisa A1 - Singer, Wibke A1 - Popelář, Jiří A1 - Gutsche, Katja A1 - Geisler, Hyun-Soon A1 - Schraven, Sebastian Philipp A1 - Jaumann, Mirko A1 - Panford-Walsh, Rama A1 - Hu, Jing A1 - Schimmang, Thomas A1 - Zimmermann, Ulrike A1 - Syka, Josef A1 - Knipper, Marlies T1 - BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury JF - Molecular Neurobiology N2 - For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNF \(^{Pax2}\) -KO) versus the auditory cortex and hippocampus (BDNF \(^{TrkC}\) -KO). We demonstrate that BDNF \(^{Pax2}\) -KO but not BDNF \(^{TrkC}\) -KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNF \(^{Pax2}\) mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNF \(^{Pax2}\) -KO, but not of BDNF \(^{TrkC}\) -KO mice. Also, BDNF \(^{Pax2}\) -WT but not BDNF \(^{Pax2}\) -KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise. KW - Inner hair cell KW - Neurotropathic Factor KW - Hearing-loss KW - Alzheimers-disease KW - low-threshold fibers KW - cochlear nucleus neurons KW - Frequency-response areas KW - Inferior colliculus KW - Environmental enrichment KW - Synaptic plasticity KW - Cortical plasticity KW - BDNF KW - Central hyperactivity KW - High-spontaneous rate KW - Homeostatic plasticity KW - Sound detection threshold Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187341 VL - 53 IS - 8 ER - TY - JOUR A1 - Groeber, Florian A1 - Schober, Lena A1 - Schmid, Freia F. A1 - Traube, Andrea A1 - Kolbus-Hernandez, Silvia A1 - Daton, Karolina A1 - Hoffmann, Sebastian A1 - Petersohn, Dirk A1 - Schaefer-Korting, Monika A1 - Walles, Heike A1 - Mewes, Karsten R. T1 - Catch-up validation study of an in vitro skin irritation test method based on an open source reconstructed epidermis (phase II) JF - Toxicology in Vitro N2 - To replace the Draize skin irritation assay (OECD guideline 404) several test methods based on reconstructed human epidermis (RHE) have been developed and were adopted in the OECD test guideline 439. However, all validated test methods in the guideline are linked to RHE provided by only three companies. Thus,the availability of these test models is dependent on the commercial interest of the producer. To overcome this limitation and thus to increase the accessibility of in vitro skin irritation testing, an open source reconstructed epidermis (OS-REp) was introduced. To demonstrate the capacity of the OS-REp in regulatory risk assessment, a catch-up-validation study was performed. The participating laboratories used in-house generated OS-REp to assess the set of 20 reference substances according to the performance standards amending the OECD test guideline 439. Testing was performed under blinded conditions. The within-laboratory reproducibility of 87% and the inter-laboratory reproducibility of 85% prove a high reliability of irritancy testing using the OS-REp protocol. In addition, the prediction capacity was with an accuracy of 80% comparable to previous published RHE based test protocols. Taken together the results indicate that the OS-REp test method can be used as a standalone alternative skin irritation test replacing the OECD test guideline 404. KW - Model KW - Chemicals KW - Assay KW - Episkin KW - Vivo KW - RHE KW - In vitro skin irritation testing KW - Open source reconstructed epidermis KW - Validation KW - Alternative test methods Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187311 VL - 36 ER - TY - JOUR A1 - Markert, Sebastian Matthias A1 - Britz, Sebastian A1 - Proppert, Sven A1 - Lang, Marietta A1 - Witvliet, Daniel A1 - Mulcahy, Ben A1 - Sauer, Markus A1 - Zhen, Mei A1 - Bessereau, Jean-Louis A1 - Stigloher, Christian T1 - Filling the gap: adding super-resolution to array tomography for correlated ultrastructural and molecular identification of electrical synapses at the C. elegans connectome JF - Neurophotonics N2 - Correlating molecular labeling at the ultrastructural level with high confidence remains challenging. Array tomography (AT) allows for a combination of fluorescence and electron microscopy (EM) to visualize subcellular protein localization on serial EM sections. Here, we describe an application for AT that combines near-native tissue preservation via high-pressure freezing and freeze substitution with super-resolution light microscopy and high-resolution scanning electron microscopy (SEM) analysis on the same section. We established protocols that combine SEM with structured illumination microscopy (SIM) and direct stochastic optical reconstruction microscopy (dSTORM). We devised a method for easy, precise, and unbiased correlation of EM images and super-resolution imaging data using endogenous cellular landmarks and freely available image processing software. We demonstrate that these methods allow us to identify and label gap junctions in Caenorhabditis elegans with precision and confidence, and imaging of even smaller structures is feasible. With the emergence of connectomics, these methods will allow us to fill in the gap-acquiring the correlated ultrastructural and molecular identity of electrical synapses. KW - caenorhabditis elegans KW - localization micoscopy KW - fluorescent-probes KW - junction proteins KW - resolution limit KW - direct stochasticoptical reconstruction microscopy KW - structured illumination microscopy KW - correlative light and electron microscopy KW - gap junction KW - neural circuits KW - nervous-system KW - image data KW - reconstruction KW - innexins KW - super-resolution microscopy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187292 VL - 3 IS - 4 ER - TY - JOUR A1 - Scharaw, Sandra A1 - Iskar, Murat A1 - Ori, Alessandro A1 - Boncompain, Gaelle A1 - Laketa, Vibor A1 - Poser, Ina A1 - Lundberg, Emma A1 - Perez, Franck A1 - Beck, Martin A1 - Bork, Peer A1 - Pepperkok, Rainer T1 - The endosomal transcriptional regulator RNF11 integrates degradation and transport of EGFR JF - Journal of Cell Biology N2 - Stimulation of cells with epidermal growth factor (EGF) induces internalization and partial degradation of the EGF receptor (EGFR) by the endo-lysosomal pathway. For continuous cell functioning, EGFR plasma membrane levels are maintained by transporting newly synthesized EGFRs to the cell surface. The regulation of this process is largely unknown. In this study, we find that EGF stimulation specifically increases the transport efficiency of newly synthesized EGFRs from the endoplasmic reticulum to the plasma membrane. This coincides with an up-regulation of the inner coat protein complex II (COP II) components SEC23B, SEC24B, and SEC24D, which we show to be specifically required for EGFR transport. Up-regulation of these COP II components requires the transcriptional regulator RNF11, which localizes to early endosomes and appears additionally in the cell nucleus upon continuous EGF stimulation. Collectively, our work identifies a new regulatory mechanism that integrates the degradation and transport of EGFR in order to maintain its physiological levels at the plasma membrane. KW - Epidermal growth-factor KW - finger protein 11 KW - receptor tyrosine kinases KW - early secretory pathway KW - breast-cancer KW - brefeldin-a KW - E3 ligase KW - trafficking KW - export KW - endoplasmic-reticulum Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186731 VL - 215 IS - 4 ER - TY - JOUR A1 - Seydelmann, Nora A1 - Liu, Dan A1 - Krämer, Johannes A1 - Drechsler, Christiane A1 - Hu, Kai A1 - Nordbeck, Peter A1 - Schneider, Andreas A1 - Störk, Stefan A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Weidemann, Frank T1 - High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease JF - Journal of the American Heart Association N2 - Background High‐sensitivity troponin (hs‐TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs‐TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow‐up study to assess longitudinal hs‐TNT changes relative to fibrosis and cardiomyopathy progression. Methods and Results For the prospective analysis, hs‐TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry‐associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs‐TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs‐TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56–302.59]; P=0.002); patients with elevated baseline hs‐TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1–3.3] %; follow‐up, 3.2 [2.3–4.9] %; P<0.001) and slightly elevated hs‐TNT (baseline, 44.7 [30.1–65.3] ng/L; follow‐up, 49.1 [27.6–69.5] ng/L; P=0.116) during follow‐up. Left ventricular wall thickness and EF of patients with elevated hs‐TNT were decreased during follow‐up, indicating potential cardiomyopathy progression. Conclusions hs‐TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs‐TNT could be helpful for staging and follow‐up of Fabry patients. KW - biomarker KW - cardiomyopathy KW - fabry disease KW - myocardial fibrosis KW - troponin T Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165682 VL - 5 IS - e002839 ER - TY - JOUR A1 - Couch, Yvonne A1 - Trofimov, Alexander A1 - Markova, Natalyia A1 - Nikolenko, Vladimir A1 - Steinbusch, Harry W. A1 - Chekhonin, Vladimir A1 - Schroeter, Careen A1 - Lesch, Klaus-Peter A1 - Anthony, Daniel C. A1 - Strekalova, Tatyana T1 - Low-dose lipopolysaccharide (LPS) inhibits aggressive and augments depressive behaviours in a chronic mild stress model in mice JF - Journal of Neuroinflammation N2 - Background Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive. Methods Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress. Results When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels. Conclusions It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours. KW - SERT KW - Chronic stress KW - LPS KW - Aggressive behaviour KW - S-HT KW - Cytokines Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165676 VL - 13 IS - 108 ER - TY - JOUR A1 - Jarius, Sven A1 - Ruprecht, Klemens A1 - Kleiter, Ingo A1 - Borisow, Nadja A1 - Asgari, Nasrin A1 - Pitarokoili, Kalliopi A1 - Pache, Florence A1 - Stich, Oliver A1 - Beume, Lena-Alexandra A1 - Hümmert, Martin W. A1 - Trebst, Corinna A1 - Ringelstein, Marius A1 - Aktas, Orhan A1 - Winkelmann, Alexander A1 - Buttmann, Mathias A1 - Schwarz, Alexander A1 - Zimmermann, Hanna A1 - Brandt, Alexander U. A1 - Franciotta, Diego A1 - Capobianco, Marco A1 - Kuchling, Joseph A1 - Haas, Jürgen A1 - Korporal-Kuhnke, Mirjam A1 - Lillevang, Soeren Thue A1 - Fechner, Kai A1 - Schanda, Kathrin A1 - Paul, Friedemann A1 - Wildemann, Brigitte A1 - Reindl, Markus T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin JF - Journal of Neuroinflammation N2 - Background Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders. Objective To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers. Methods 614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells. Results MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7%) patients with a history of both ON and myelitis, 22/103 (21.4%) with a history of ON but no myelitis and 6/45 (13.3%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89%) follow-up samples obtained over a median period of 16.5 months (range 0–123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment. Conclusions To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status. KW - Neuromyelitis optica (NMO) KW - Devic’s syndrome KW - Optic neuritis KW - Transverse Myelitis KW - Longitudinally extensive transverse myelitis (LETM) KW - Neuromyelitis optica spectrum disorders (NMOSD) KW - Multiple sclerosis KW - Autoantibodies KW - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) KW - Neuromyelitis optica antibodies (NMO-IgG) KW - Aquaporin-4 antibodies (AQP4-IgG) KW - Cell-based assays KW - Cerebrospinal fluid KW - Antibody index Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165659 VL - 13 IS - 279 ER - TY - JOUR A1 - Noster, Rebecca A1 - de Koning, Heleen D. A1 - Maier, Elisabeth A1 - Prelog, Martina A1 - Lainka, Elke A1 - Zielinski, Christina E. T1 - Dysregulation of proinflammatory versus anti-inflammatory human T\(_H\)17 cell functionalities in the autoinflammatory Schnitzler syndrome JF - Journal of Allergy and Clinical Immunology N2 - Background: T\(_H\)17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of T\(_H\)17 cells have been described recently, which differed in their polarization requirement for IL-1b and in their cytokine repertoire. Whether these distinct T\(_H\)17 phenotypes translate into distinct T\(_H\)17 cell functions with implications for human health or disease has not been addressed yet. Objective: We hypothesized the existence of proinflammatory and anti-inflammatory human T\(_H\)17 cell functions based on the differential expression of IL-10, which is regulated by IL-1 beta. Considering the crucial role of IL-1 beta in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1 beta mediates the loss of anti-inflammatory T\(_H\)17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. Methods: To assess proinflammatory versus anti-inflammatory T\(_H\)17 cell functions, we performed suppression assays and tested the effects of IL-1 beta dependent and independent T\(_H\)17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in T\(_H\)17 cell functions before and during therapy with IL-1 beta-blocking drugs. Results: Both T\(_H\)17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1 beta translates into a profound loss of anti-inflammatory T\(_H\)17 cell functionalities, which can be reversed by anti-IL-1b treatment. Conclusion: IL-1 beta signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory T\(_H\)17 cell functions. Our data introduce T\(_H\)17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1 beta mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes. KW - Regulatory T-cells KW - IL-1 blockade KW - Big picture KW - Cytokine GM-CSF KW - Mechanisms KW - IL-1 beta KW - Diseases KW - Gamma KW - Autoinflammation KW - Schnitzler syndrome KW - T\(_H\)17 cells KW - IL-10 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187205 VL - 138 IS - 4 ER - TY - JOUR A1 - Bousquet, J. A1 - Anto, J. M. A1 - Akdis, M. A1 - Auffray, C. A1 - Keil, T. A1 - Momas, I. A1 - Postma, D. S. A1 - Valenta, R. A1 - Wickman, M. A1 - Cambon-Thomsen, A. A1 - Haahtela, T. A1 - Lambrecht, B. N. A1 - Lodrup Carlsen, K. C. A1 - Koppelman, G. H. A1 - Sunyer, J. A1 - Zuberbier, T. A1 - Annesi-Maesano, I. A1 - Arno, A. A1 - Bindslev-Jensen, C. A1 - De Carlo, G. A1 - Forastiere, F. A1 - Heinrich, J. A1 - Kowalski, M. L. A1 - Maier, D. A1 - Melen, E. A1 - Palkonen, S. A1 - Smit, H. A. A1 - Standl, M. A1 - Wright, J. A1 - Asarnoj, A. A1 - Benet, M. A1 - Ballardini, N. A1 - Garcia-Aymerich, J. A1 - Gehring, U. A1 - Guerra, S. A1 - Hohman, C. A1 - Kull, I. A1 - Lupinek, C. A1 - Pinart, M. A1 - Skrindo, I. A1 - Westman, M. A1 - Smagghe, D. A1 - Akdis, C. A1 - Albang, R. A1 - Anastasova, V. A1 - Anderson, N. A1 - Bachert, C. A1 - Ballereau, S. A1 - Ballester, F. A1 - Basagana, X. A1 - Bedbrook, A. A1 - Bergstrom, A. A1 - von Berg, A. A1 - Brunekreef, B. A1 - Burte, E. A1 - Carlsen, K.H. A1 - Chatzi, L. A1 - Coquet, J.M. A1 - Curin, M. A1 - Demoly, P. A1 - Eller, E. A1 - Fantini, M.P. A1 - Gerhard, B. A1 - Hammad, H. A1 - von Hertzen, L. A1 - Hovland, V. A1 - Jacquemin, B. A1 - Just, J. A1 - Keller, T. A1 - Kerkhof, M. A1 - Kiss, R. A1 - Kogevinas, M. A1 - Koletzko, S. A1 - Lau, S. A1 - Lehmann, I. A1 - Lemonnier, N. A1 - McEachan, R. A1 - Makela, M. A1 - Mestres, J. A1 - Minina, E. A1 - Mowinckel, P. A1 - Nadif, R. A1 - Nawijn, M. A1 - Oddie, S. A1 - Pellet, J. A1 - Pin, I. A1 - Porta, D. A1 - Rancière, F. A1 - Rial-Sebbag, A. A1 - Schuijs, M.J. A1 - Siroux, V. A1 - Tischer, C.G. A1 - Torrent, M. A1 - Varraso, R. A1 - De Vocht, J. A1 - Wenger, K. A1 - Wieser, S. A1 - Xu, C. T1 - Paving the way of systems biology and precision medicine in allergic diseases: the MeDALL success story Mechanisms of the Development of ALLergy; EUFP7-CP-IP; Project No: 261357; 2010-2015 JF - Allergy N2 - MeDALL (Mechanisms of the Development of ALLergy; EU FP7-CP-IP; Project No: 261357; 2010-2015) has proposed an innovative approach to develop early indicators for the prediction, diagnosis, prevention and targets for therapy. MeDALL has linked epidemiological, clinical and basic research using a stepwise, large-scale and integrative approach: MeDALL data of precisely phenotyped children followed in 14 birth cohorts spread across Europe were combined with systems biology (omics, IgE measurement using microarrays) and environmental data. Multimorbidity in the same child is more common than expected by chance alone, suggesting that these diseases share causal mechanisms irrespective of IgE sensitization. IgE sensitization should be considered differently in monosensitized and polysensitized individuals. Allergic multimorbidities and IgE polysensitization are often associated with the persistence or severity of allergic diseases. Environmental exposures are relevant for the development of allergy-related diseases. To complement the population-based studies in children, MeDALL included mechanistic experimental animal studies and in vitro studies in humans. The integration of multimorbidities and polysensitization has resulted in a new classification framework of allergic diseases that could help to improve the understanding of genetic and epigenetic mechanisms of allergy as well as to better manage allergic diseases. Ethics and gender were considered. MeDALL has deployed translational activities within the EU agenda. KW - asthma KW - birth cohort KW - atopic-dermatitis KW - immune-responses KW - IgE KW - multimorbidity KW - polysensitization KW - rhinitis KW - chronic respiratory-diseases KW - childhood asthma KW - immunological reactivity KW - IgE sensitazion KW - immunoglobulin-e KW - integraed care Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186858 VL - 71 IS - 11 ER - TY - JOUR A1 - Münch, Miriam A1 - Hsin, Chih-Hsuan A1 - Ferber, Elena A1 - Berger, Susanne A1 - Müller, Martin J. T1 - Reactive electrophilic oxylipins trigger a heat stress-like response through HSFA1 transcription factors JF - Journal of Experimental Botany N2 - Electrophilic oxylipins trigger a heat-shock-like response in the absence of heat through the canonical heat-shock transcription factor A1, thereby helping to cope with stresses associated with protein damage.Abiotic and biotic stresses are often characterized by an induction of reactive electrophile species (RES) such as the jasmonate 12-oxo-phytodienoic acid (OPDA) or the structurally related phytoprostanes. Previously, RES oxylipins have been shown massively to induce heat-shock-response (HSR) genes including HSP101 chaperones. Moreover, jasmonates have been reported to play a role in basal thermotolerance. We show that representative HSR marker genes are strongly induced by RES oxylipins through the four master regulator transcription factors HSFA1a, b, d, and e essential for short-term adaptation to heat stress in Arabidopsis. When compared with Arabidopsis seedlings treated at the optimal acclimation temperature of 37 A degrees C, the exogenous application of RES oxylipins at 20 A degrees C induced a much weaker induction of HSP101 at both the gene and protein expression levels which, however, was not sufficient to confer short-term acquired thermotolerance. Moreover, jasmonate-deficient mutant lines displayed a wild-type-like HSR and were not compromised in acquiring thermotolerance. Hence, the OPDA- and RES oxylipin-induced HSR is not sufficient to protect seedlings from severe heat stress but may help plants to cope better with stresses associated with protein unfolding by inducing a battery of chaperones in the absence of heat. KW - arabidopsis-thaliana KW - shock response KW - gene-expression KW - model KW - acquired thermotolerance KW - 12-oxo-phytodienoic acid KW - thermotolerance KW - plants KW - detoxification KW - acquisition KW - activation KW - heat stress KW - jasmonates KW - phytoprostanes KW - reactive electrophilic species KW - unfolded protein response Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186766 VL - 67 IS - 21 ER - TY - JOUR A1 - Suliman, Salwa A1 - Mustafa, Kamal A1 - Krueger, Anke A1 - Steinmüller-Nethl, Doris A1 - Finne-Wistrand, Anna A1 - Osdal, Tereza A1 - Hamza, Amani O. A1 - Sun, Yang A1 - Parajuli, Himalaya A1 - Waag, Thilo A1 - Nickel, Joachim A1 - Johannessen, Anne Christine A1 - McCormack, Emmet A1 - Costea, Daniela Elena T1 - Nanodiamond modified copolymer scaffolds affects tumour progression of early neoplastic oral keratinocytes JF - Biomaterials N2 - This study aimed to evaluate the tumorigenic potential of functionalising poly(LLA-co-CL) scaffolds. The copolymer scaffolds were functionalised with nanodiamonds (nDP) or with nDP and physisorbed BMP-2 (nDP-PHY) to enhance osteoinductivity. Culturing early neoplastic dysplastic keratinocytes (DOK\(^{Luc}\)) on nDP modified scaffolds reduced significantly their subsequent sphere formation ability and decreased significantly the cells' proliferation in the supra-basal layers of in vitro 3D oral neoplastic mucosa (3D-OT) when compared to DOK\(^{Luc}\) previously cultured on nDP-PHY scaffolds. Using an in vivo non-invasive environmentally-induced oral carcinogenesis model, nDP scaffolds were observed to reduce bioluminescence intensity of tumours formed by DOK\(^{Luc}\) + carcinoma associated fibroblasts (CAF). nDP modification was also found to promote differentiation of DOK\(^{Luc}\) both in vitro in 3D-OT and in vivo in xenografts formed by DOKLuc alone. The nDP-PHY scaffold had the highest number of invasive tumours formed by DOK\(^{Luc}\) + CAF outside the scaffold area compared to the nDP and control scaffolds. In conclusion, in vitro and in vivo results presented here demonstrate that nDP modified copolymer scaffolds are able to decrease the tumorigenic potential of DOK\(^{Luc}\), while confirming concerns for the therapeutic use of BMP-2 for reconstruction of bone defects in oral cancer patients due to its tumour promoting capabilities. KW - Bone morphogenetic protein-2 KW - Sinus floor augmentation KW - Marrow stromal cells KW - Growth; BMP-2 KW - Tumorigenicity KW - Biodegradable polymer scaffolds KW - Mandibular continuity defects KW - Squamous-cell carcinoma KW - In-vitro KW - Mesenchymal transition KW - BMP-2 KW - Bone tissue engineering KW - Biocompatibility KW - Microenvironment KW - Oral squamous cell carcinoma Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188287 VL - 95 ER - TY - JOUR A1 - Ceyman, Harald A1 - Rosspeintner, Arnulf A1 - Schreck, Maximilian H. A1 - Mützel, Carina A1 - Stoy, Andreas A1 - Vauthey, Eric A1 - Lambert, Christoph T1 - Cooperative enhancement versus additivity of two-photon-absorption cross sections in linear and branched squaraine superchromophores JF - Physical Chemistry Chemical Physics N2 - The linear and nonlinear optical properties of a series of oligomeric squaraine dyes were investigated by one-photon absorption spectroscopy (1PA) and two-photon absorption (2PA) induced fluorescence spectroscopy. The superchromophores are based on two indolenine squaraine dyes with transoid (SQA) and cisoid configuration (SQB). Using these monomers, linear dimers and trimers as well as star-shaped trimers and hexamers with benzene or triphenylamine cores were synthesised and investigated. The red-shifted and intensified 1PA spectra of all superchromophores could well be explained by exciton coupling theory. In the linear chromophore arrangements we also found superradiance of fluorescence but not in the branched systems. Furthermore, the 2PA showed enhanced cross sections for the linear oligomers but only additivity for the branched systems. This emphasizes that the enhancement of the 2PA cross section in the linear arrangements is probably caused by orbital interactions of higher excited configurations. KW - 2-photon absorption KW - Vibronic contributions KW - One-photon KW - Molecules KW - Intensity KW - Multibranched structures KW - Optical properties KW - Dyes KW - Chromophores KW - Design Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188299 VL - 18 IS - 24 ER - TY - JOUR A1 - Buttmann, Mathias A1 - Seuffert, Linda A1 - Mäder, Uwe A1 - Toyka, Klaus V. T1 - Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study JF - Neurology N2 - Objective: To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis. Methods: This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence. Results: Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs 75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes. Conclusions: While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable. KW - multiple sclerosis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188300 VL - 86 ER - TY - JOUR A1 - Bert, Bettina A1 - Chmielewska, Justyna A1 - Bergmann, Sven A1 - Busch, Maximilian A1 - Driever, Wolfgang A1 - Finger-Baier, Karin A1 - Hößler, Johanna A1 - Köhler, Almut A1 - Leich, Nora A1 - Misgeld, Thomas A1 - Nöldner, Torsten A1 - Reiher, Annegret A1 - Schartl, Manfred A1 - Seebach-Sproedt, Anja A1 - Thumberger, Thomas A1 - Schönfelder, Gilbert A1 - Grune, Barbara T1 - Considerations for a European animal welfare standard to evaluate adverse phenotypes in teleost fish JF - The EMBO Journal N2 - No abstract available. KW - Danio-rerio KW - Zebrafish KW - Pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188783 VL - 35 IS - 11 ER - TY - JOUR A1 - Hopp, Sarah A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Stetter, Christian A1 - Nieswandt, Bernhard A1 - Schmidt, Peter M. A1 - Monoranu, Camelia-Maria A1 - Alafuzoff, Irina A1 - Marklund, Niklas A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Targeting coagulation factor XII as a novel therapeutic option in brain trauma JF - Annals of Neurology N2 - Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. KW - Molecular-weight heparin KW - Thrombus formation KW - Cerebral-ischemia KW - in-vivo KW - Intravascular coagulation KW - Hemodynamic depression KW - Head-injury KW - Rats KW - Model KW - Mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188800 VL - 79 IS - 6 ER - TY - JOUR A1 - Seifert, Sabine A1 - Shoyama, Kazutaka A1 - Schmidt, David A1 - Würthner, Frank T1 - An electron-poor C\(_{64}\) nanographene by palladium-catalyzed cascade C-C bond formation: one-pot synthesis and single-crystal structure analysis JF - Angewandte Chemie-International Edition N2 - Herein, we report the one-pot synthesis of an electron-poor nanographene containing dicarboximide groups at the corners. We efficiently combined palladium-catalyzed Suzuki-Miyaura cross-coupling and dehydrohalogenation to synthesize an extended two-dimensional pi-scaffold of defined size in a single chemical operation starting from N-(2,6-diisopropylphenyl)-4,5-dibromo-1,8-naphthalimide and a tetrasubstituted pyrene boronic acid ester as readily accessible starting materials. The reaction of these precursors under the conditions commonly used for Suzuki-Miyaura cross-coupling afforded a C\(_{64}\) nanographene through the formation of ten C-C bonds in a one-pot process. Single-crystal X-ray analysis unequivocally confirmed the structure of this unique extended aromatic molecule with a planar geometry. The optical and electrochemical properties of this largest ever synthesized planar electron-poor nanographene skeleton were also analyzed. KW - Graphene nanoribbons KW - Liquid-crystalline KW - dyes/pigments KW - polycyclic aromatic hydrocarbons KW - two-dimensional nanostructures KW - Aromatic-hydrocarbon KW - Carbon KW - Dyes KW - Functionalization KW - cascade reactions KW - nanographene Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188889 VL - 55 IS - 22 ER - TY - JOUR A1 - Nitsche, Wolfgang H. A1 - Kim, Na Young A1 - Roumpos, Georgios A1 - Schneider, Christian A1 - Höfling, Sven A1 - Forchel, Alfred A1 - Yamamoto, Yoshihisa T1 - Spatial correlation of two-dimensional bosonic multimode condensates JF - Physical Review A N2 - The Berezinskii-Kosterlitz-Thouless (BKT) theorem predicts that two-dimensional bosonic condensates exhibit quasi-long-range order which is characterized by a slow decay of the spatial coherence. However previous measurements on exciton-polariton condensates revealed that their spatial coherence can decay faster than allowed under the BKT theory, and different theoretical explanations have already been proposed. Through theoretical and experimental study of exciton-polariton condensates, we show that the fast decay of the coherence can be explained through the simultaneous presence of multiple modes in the condensate. KW - Exciton-polariton condensate KW - Long-range order KW - Microcavity KW - Vortices KW - Systems Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188897 VL - 93 IS - 5 ER - TY - JOUR A1 - Dyksik, M. A1 - Motyka, M. A1 - Kurka, M. A1 - Ryczo, K. A1 - Dallner, M. A1 - Höfling, S. A1 - Kamp, M. A1 - Sęk, G. A1 - Misiwicz, J. T1 - Photoluminescence quenching mechanisms in type IIInAs/GaInSb QWs on InAs substrates JF - Optical and Quantum Electronics N2 - Optical properties of AlSb/InAs/GaInSb/InAs/AlSb quantum wells (QWs) grown on an InAs substrate were investigated from the point of view of room temperature emission in the mid- and long-wavelength infrared ranges. By means of two independent techniques of optical spectroscopy, photoreflectance and temperature-dependent photoluminescence, it was proven that the main process limiting the performance of such InAs substrate-based type II structures is related to the escape of carriers from the hole ground state of the QW. Two nonradiative recombination channels were identified. The main process was attributed to holes tunneling to the valence band of the GaAsSb spacing layer and the second one with trapping of holes by native defects located in the same layer. KW - Interband cascade lasers KW - Quantum wells KW - MU-M KW - Fourier-transform spectroscopy KW - Mid-infrared photoluminescence KW - Type II quantum wells KW - Localized states Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204672 VL - 48 IS - 401 ER - TY - JOUR A1 - Plauth, Annabell A1 - Geikowski, Anne A1 - Cichon, Susanne A1 - Wowro, Sylvia J. A1 - Liedgens, Linda A1 - Rousseau, Morten A1 - Weidner, Christopher A1 - Fuhr, Luise A1 - Kliem, Magdalena A1 - Jenkins, Gail A1 - Lotito, Silvina A1 - Wainwright, Linda J. A1 - Sauer, Sascha T1 - Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress JF - Free Radical Biology and Medicine N2 - Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general < 50 mu M), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61 mV mmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells. In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress. KW - Trans-reservatrol KW - Hydrogen-peroxide KW - In-vitro KW - Hormesis KW - Ethanol KW - Oxygen KW - Nrf2 KW - Glutathione KW - Metabolism KW - Polyphenols KW - ROS KW - Oxidative stress KW - Redox environment KW - Skin KW - Epidermis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187186 VL - 99 ER - TY - JOUR A1 - Regn, Michael A1 - Laggerbauer, Bernhard A1 - Jentzsch, Claudia A1 - Ramanujam, Deepak A1 - Ahles, Andrea A1 - Sichler, Sonja A1 - Calzada-Wack, Julia A1 - Koenen, Rory R. A1 - Braun, Attila A1 - Nieswandt, Bernhard A1 - Engelhardt, Stefan T1 - Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium JF - Journal of Molecular and Cellular Cardiology N2 - A key response of the myocardium to stress is the secretion of factors with paracrine or endocrine function. Intriguing in this respect is peptidase inhibitor 16 (PI16), a member of the CAP family of proteins which we found to be highly upregulated in cardiac disease. Up to this point, the mechanism of action and physiological function of PI16 remained elusive. Here, we show that PI16 is predominantly expressed by cardiac fibroblasts, which expose PI16 to the interstitium via a glycophosphatidylinositol (-GPI) membrane anchor. Based on a reported genetic association of PI16 and plasma levels of the chemokine chemerin, we investigated whether PI16 regulates post-translational processing of its precursor pro-chemerin. PI16-deficient mice were engineered and found to generate higher levels of processed chemerin than wildtype mice. Purified recombinant PI16 efficiently inhibited cathepsin K, a chemerin-activating protease, in vitro. Moreover, we show that conditioned medium from PI16-overexpressing cells impaired the activation of pro-chemerin. Together, our data indicate that PI16 suppresses chemerin activation in the myocardium and suggest that this circuit may be part of the cardiac stress response. KW - Cells KW - Activation KW - Purification KW - Protein KW - Peptidase inhibitor 16 (PI16) KW - Identification KW - Inflammation KW - Adipokine KW - Metabolism KW - Heart KW - Mice KW - Chemerin KW - RARRES2 KW - TIG2 KW - Protease inhibition KW - Chemerin processing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187039 VL - 99 ER - TY - JOUR A1 - Laiho, K. A1 - Pressl, B. A1 - Schlager, A. A1 - Suchomel, H. A1 - Kamp, M. A1 - Höfling, S. A1 - Schneider, C. A1 - Weihs, G. T1 - Uncovering dispersion properties in semiconductor waveguides to study photon-pair generation JF - Nanotechnology N2 - We investigate the dispersion properties of ridge Bragg-reflection waveguides to deduce their phasematching characteristics. These are crucial for exploiting them as sources of parametric down-conversion (PDC). In order to estimate the phasematching bandwidth we first determine the group refractive indices of the interacting modes via Fabry-Perot experiments in two distant wavelength regions. Second, by measuring the spectra of the emitted PDC photons, we gain access to their group index dispersion. Our results offer a simple approach for determining the PDC process parameters in the spectral domain, and provide important feedback for designing such sources, especially in the broadband case. KW - Parametric down-conversion KW - Entanglement KW - CHIP KW - PUMP KW - Bragg-reflection waveguide KW - Information KW - phasematching KW - group refractive index Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187025 VL - 27 IS - 43 ER - TY - JOUR A1 - Schneider, Eberhard A1 - Dittrich, Marcus A1 - Böck, Julia A1 - Nanda, Indrajit A1 - Müller, Tobias A1 - Seidmann, Larissa A1 - Tralau, Tim A1 - Galetzka, Danuta A1 - El Hajj, Nady A1 - Haaf, Thomas T1 - CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development JF - Gene N2 - Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767 m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny. KW - Autism spectrum disorders KW - DNA methylation KW - Genome KW - Autism KW - Frontal cortex KW - Human prefrontal cortex KW - Gene-expression KW - Schizophrenia KW - Patterns KW - Transcription KW - Epigenetics KW - Environment KW - Fetal brain development KW - DNA methylation dynamics KW - Methylome Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186936 VL - 592 IS - 1 ER - TY - JOUR A1 - San-Miguel, Jesus F. A1 - Einsele, Hermann A1 - Moreau, Philippe T1 - The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European Perspective JF - Advances in Therapy N2 - Panobinostat is an oral pan-histone deacetylase inhibitor developed by Novartis. Panobinostat acts via epigenetic modification and inhibition of the aggresome pathway. In August 2015, the European Commission authorized panobinostat for use in combination with bortezomib and dexamethasone for the treatment of relapsed or relapsed and refractory multiple myeloma (MM) in patients who have received aeyen2 prior regimens including bortezomib and an immunomodulatory drug. In January 2016, the National Institute for Health and Care Excellence recommended panobinostat for use in the same combination and patient population. The authorization and recommendation were based on results from the pivotal phase 3 PANORAMA 1 (NCT01023308) clinical trial, which demonstrated an improvement in median progression-free survival of 7.8 months for the three-drug combination compared with placebo plus bortezomib and dexamethasone in this patient population. This review will discuss the current treatment landscape for relapsed/refractory MM, the mechanism of action of panobinostat, clinical data supporting the European authorization, concerns about safety and strategies for mitigating toxicity, and how panobinostat fits into the current MM landscape in Europe. KW - multiple myeloma KW - oncology KW - panobinostat KW - relapsed and refractory KW - daratumumab monotherapy KW - relapsed Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186840 VL - 33 IS - 11 ER - TY - JOUR A1 - Bratengeier, Klaus A1 - Holubyev, Kostyantyn T1 - Anisotropy of dose contributions-an instrument to upgrade real time IMRT and VMAT adaptation? JF - Medical Physics N2 - Purpose: To suggest a definition of dose deposition anisotropy for the purpose of ad hoc adaptation of intensity modulated arc therapy (IMRT) and volumetric arc therapy (VMAT), particularly in the vicinity of important organs at risk (OAR), also for large deformations. Methods: Beam's-eye-view (BEV) based fluence warping is a standard adaptation method with disadvantages for strongly varying OAR shapes. 2-Step-adaptation overcomes these difficulties by a deeper analysis of the 3D properties of adaptation processes, but requires separate arcs for every OAR to spare, which makes it impractical for cases with multiple OARs. The authors aim to extend the 2-Step method to arbitrary intensity modulated plan by analyzing the anisotropy of dose contributions. Anisotropy was defined as a second term of Fourier transformation of gantry angle dependent dose contributions. For a cylindrical planning target volume (PTV) surrounding an OAR of varying diameter, the anisotropy and the dose-normalized anisotropy were analyzed for several scenarios of optimized fluence distributions. 2-Step adaptation to decreasing and increasing OAR diameter was performed, and compared to a usual fluence based adaptation method. For two clinical cases, prostate and neck, the VMAT was generated and the behavior of anisotropy was qualitatively explored for deformed organs at risk. # Results: Dose contribution anisotropy in the PTV peaks around nearby OARs. The thickness of the "anisotropy wall" around OAR increases for increasing OAR radius, as also does the width of 2-Step dose saturating fluence peak adjacent to the OAR K. Bratengeier et al., "A comparison between 2-Step IMRT and conventional IMRT planning," Radiother. Oncol. 84, 298-306 (2007)]. Different optimized beam fluence profiles resulted in comparable radial dependence of normalized anisotropy. As predicted, even for patient cases, anisotropy was inflated even more than increasing diameters of OAR. Conclusions: For cylindrically symmetric cases, the dose distribution anisotropy defined in the present work implicitly contains adaptation-relevant information about 3D relationships between PTV and OAR and degree of OAR sparing. For more complex realistic cases, it shows the predicted behavior qualitatively. The authors claim to have found a first component for advancing a 2-Step adaptation to a universal adaptation algorithm based on the BEV projection of the dose anisotropy. Further planning studies to explore the potential of anisotropy for adaptation algorithms using phantoms and clinical cases of differing complexity will follow. KW - modulated arc therapy KW - 2-step IMRT KW - radiation-therapy KW - online adaption KW - prostate-cancer KW - plans KW - IMAT KW - tracking KW - radiotherapy KW - adaption KW - IMRT KW - VMAT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186833 VL - 43 IS - 11 ER - TY - JOUR A1 - Munz, Eberhard A1 - Jakob, Peter M. A1 - Borisjuk, Ljudmilla T1 - The potential of nuclear magnetic resonance to track lipids in planta JF - Biochimie N2 - Nuclear Magnetic Resonance (NMR) provides a highly flexible platform for non invasive analysis and imaging biological samples, since the manipulation of nuclear spin allows the tailoring of experiments to maximize the informativeness of the data. MRI is capable of visualizing a holistic picture of the lipid storage in living plant/seed. This review has sought to explain how the technology can be used to acquire functional and physiological data from plant samples, and how to exploit it to characterize lipid deposition in vivo. At the same time, we have referred to the current limitations of NMR technology as applied to plants, and in particular of the difficulty of transferring methodologies optimized for animal/medical subjects to plant ones. A forward look into likely developments in the field is included, anticipating its key future role in the study of living plant. KW - coconut cocos-nucifera KW - H-1-NMR spectroscopy KW - NMR-spectroscopy KW - camelina-sativa KW - high-throughput KW - oil storage KW - seeds KW - accumulation KW - field KW - metabolism KW - NMR KW - Lipid KW - MRI KW - CSI KW - Plants KW - Seeds Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186828 VL - 130 ER - TY - JOUR A1 - Scharbatke, Eva C. A1 - Behrens, Frank A1 - Schmalzing, Marc A1 - Koehm, Michaela A1 - Greger, Gerd A1 - Gnann, Holger A1 - Burkhardt, Harald A1 - Tony, Hans-Peter T1 - Association of improvement in pain with therapeutic response as determined by individual improvement criteria in patients with rheumatoid arthritis JF - Arthritis Care & Research N2 - Objective To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis. Methods We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (d(crit)) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort). Results In the discovery cohort (n=700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n=2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-d(crit) (1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-d(crit) response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-d(crit) response at month 12, and 59.1% did not achieve any significant PRO responses. Conclusion The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management. KW - health-assessment questionnaire KW - minimally important difference KW - disease-activity score KW - reported outcomes KW - clinical-practice KW - fatigue KW - care KW - discordance KW - validation KW - physicians Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186817 VL - 68 IS - 11 ER - TY - JOUR A1 - Schlagenhauf, Ulrich A1 - Jakob, Lena A1 - Eigenthaler, Martin A1 - Segerer, Sabine A1 - Jockel-Schneider, Yvonne A1 - Rehn, Monika T1 - Regular consumption of Lactobacillus reuteri-containing lozenges reduces pregnancy gingivitis: an RCT JF - Journal of Clinical Periodontology N2 - Aim: This randomized controlled trial assessed the impact of Lactobacillus reuteri on pregnancy gingivitis in healthy women. Materials and Methods: Forty-five healthy women (24 test/21 placebo) with pregnancy gingivitis in the third trimester of pregnancy were enrolled. At baseline Gingival Index (GI) and Plaque Index (PlI) were assessed at the Ramfjord teeth and venous blood taken for TNF-alpha analysis. Subsequently participants were randomly provided with lozenges to be consumed 2 9 daily until birth (approx. 7 weeks) containing >= 10(8) CFU L. reuteri ATCC PTA 5289 and >= 10(8) CFU L. reuteri DSM 17938 (test) or being devoid of L. reuteri (placebo). Within 2 days after birth recording of GI, PlI and blood sampling were repeated. Results: At baseline, mean GI and mean PlI did not differ significantly between both groups. In the test group mean TNF-alpha serum level was significantly (p < 0.02) lower than in the placebo group. At reevaluation, mean GI and mean PlI of the test group were both significantly (p < 0.0001) lower than in the placebo group. Mean TNF-alpha serum level did no longer differ significantly between the groups. Conclusions: The consumption of L. reuteri lozenges may be a useful adjunct in the control of pregnancy gingivitis. KW - chronic periodontitis KW - probiotic lozenges KW - subgingival KW - bacteria KW - postpartum KW - microbiota KW - disease KW - L. reuteri KW - plaque KW - pregnancy KW - pregnancy gingivitis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186783 VL - 43 IS - 11 ER - TY - JOUR A1 - Dekant, Wolfgang A1 - Bridges, James T1 - Assessment of reproductive and developmental effects of DINP, DnHP and DCHP using quantitative weight of evidence JF - Regulatory Toxicology and Pharmacology N2 - Quantitative weight of evidence (QWoE) methodology utilizes detailed scoring sheets to assess the quality/reliability of each publication on toxicity of a chemical and gives numerical scores for quality and observed toxicity. This QWoE-methodology was applied to the reproductive toxicity data on diisononylphthalate (DINP), di-n-hexylphthalate (DnHP), and dicyclohexylphthalate (DCHP) to determine if the scientific evidence for adverse effects meets the requirements for classification as reproductive toxicants. The scores for DINP were compared to those when applying the methodology DCHP and DnHP that have harmonized classifications. Based on the quality/reliability scores, application of the QWoE shows that the three databases are of similar quality; but effect scores differ widely. Application of QWoE to DINP studies resulted in an overall score well below the benchmark required to trigger classification. For DCHP, the QWoE also results in low scores. The high scores from the application of the QWoE methodology to the toxicological data for DnHP represent clear evidence for adverse effects and justify a classification of DnHP as category 1B for both development and fertility. The conclusions on classification based on the QWoE are well supported using a narrative assessment of consistency and biological plausibility. KW - n-hexyl phthalate KW - male rats KW - dicyclohexyl phthalate KW - Diisononyl phthalate KW - in-vivo KW - 2-Generation reproduction KW - testosterone production KW - sexual development KW - risk-assesment KW - fetal testis KW - weight of evidence KW - classification and labeling KW - reproductive and developmental toxicity KW - quantitative assessments Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186750 VL - 81 ER - TY - JOUR A1 - Dotterweich, Julia A1 - Schlegelmilch, Katrin A1 - Keller, Alexander A1 - Geyer, Beate A1 - Schneider, Doris A1 - Zeck, Sabine A1 - Tower, Robert J. J. A1 - Ebert, Regina A1 - Jakob, Franz A1 - Schütze, Norbert T1 - Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells-implications for myeloma bone disease JF - Bone N2 - Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage. KW - marrow stromal cells KW - Endothelial growth-factor KW - precedes multiple-myeloma KW - monoclonial gammopathy KW - in-vitro KW - mesenchymal stem-cells KW - undetermined significance KW - angiogenic cytokines KW - peripheral-blood KW - gene-expression KW - Multiple myeloma KW - Bone disease KW - Angiopoietin-like 4 KW - Gene expression profiling KW - Mesenchymal stem cells KW - Osteogenic precursor cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186688 VL - 93 ER - TY - JOUR A1 - Hassouna, I. A1 - Ott, C. A1 - Wüstefeld, L. A1 - Offen, N. A1 - Neher, R. A. A1 - Mitkovski, M. A1 - Winkler, D. A1 - Sperling, S. A1 - Fries, L. A1 - Goebbels, S. A1 - Vreja, I. C. A1 - Hagemeyer, N. A1 - Dittrich, M. A1 - Rossetti, M. F. A1 - Kröhnert, K. A1 - Hannke, K. A1 - Boretius, S. A1 - Zeug, A. A1 - Höschen, C. A1 - Dandekar, T. A1 - Dere, E. A1 - Neher, E. A1 - Rizzoli, S. O. A1 - Nave, K.-A. A1 - Sirén, A.-L. A1 - Ehrenreich, H. T1 - Revisiting adult neurogenesis and the role of erythropoietin for neuronal and oligodendroglial differentiation in the hippocampus JF - Molecular Psychiatry N2 - Recombinant human erythropoietin (EPO) improves cognitive performance in neuropsychiatric diseases ranging from schizophrenia and multiple sclerosis to major depression and bipolar disease. This consistent EPO effect on cognition is independent of its role in hematopoiesis. The cellular mechanisms of action in brain, however, have remained unclear. Here we studied healthy young mice and observed that 3-week EPO administration was associated with an increased number of pyramidal neurons and oligodendrocytes in the hippocampus of similar to 20%. Under constant cognitive challenge, neuron numbers remained elevated until >6 months of age. Surprisingly, this increase occurred in absence of altered cell proliferation or apoptosis. After feeding a \(^{15}\)N-leucine diet, we used nanoscopic secondary ion mass spectrometry, and found that in EPO-treated mice, an equivalent number of neurons was defined by elevated \(^{15}\)N-leucine incorporation. In EPO-treated NG2-Cre-ERT2 mice, we confirmed enhanced differentiation of preexisting oligodendrocyte precursors in the absence of elevated DNA synthesis. A corresponding analysis of the neuronal lineage awaits the identification of suitable neuronal markers. In cultured neurospheres, EPO reduced Sox9 and stimulated miR124, associated with advanced neuronal differentiation. We are discussing a resulting working model in which EPO drives the differentiation of non-dividing precursors in both (NG2+) oligodendroglial and neuronal lineages. As endogenous EPO expression is induced by brain injury, such a mechanism of adult neurogenesis may be relevant for central nervous system regeneration. KW - neural stem-cells KW - recombinat-human-erythropoietin KW - cognitive functions KW - pyramidal neurons KW - nervous-sytem KW - brain-injury KW - mouse-brain KW - progenitors KW - mice KW - memory Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186669 VL - 21 IS - 12 ER - TY - JOUR A1 - Huss, André M. A1 - Halbgebauer, Steffen A1 - Öckl, Patrick A1 - Trebst, Corinna A1 - Spreer, Annette A1 - Borisow, Nadja A1 - Harrer, Andrea A1 - Brecht, Isabel A1 - Balint, Bettina A1 - Stich, Oliver A1 - Schlegel, Sabine A1 - Retzlaff, Nele A1 - Winkelmann, Alexander A1 - Roesler, Romy A1 - Lauda, Florian A1 - Yildiz, Özlem A1 - Voß, Elke A1 - Muche, Rainer A1 - Rauer, Sebastian A1 - Bergh, Florian Then A1 - Otto, Markus A1 - Paul, Friedemann A1 - Wildemann, Brigitte A1 - Kraus, Jörg A1 - Ruprecht, Klemens A1 - Stangel, Martin A1 - Buttmann, Mathias A1 - Zettl, Uwe K. A1 - Tumani, Hayrettin T1 - Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome JF - Journal of Neurology N2 - The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21-34) compared to 47 months in OCB-negative individuals (95 % CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria. KW - multiple sklerosis KW - MRI criteria KW - conversion KW - MS KW - CSF KW - biomarker KW - OCB Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186619 VL - 263 IS - 12 ER - TY - JOUR A1 - Perkovic, Vlado A1 - Agarwal, Rajiv A1 - Fioretto, Paola A1 - Hemmelgarn, Brenda R. A1 - Levin, Adeera A1 - Thomas, Merlin C. A1 - Wanner, Christoph A1 - Kasiske, Bertram L. A1 - Wheeler, David C. A1 - Groop, Per-Henrik T1 - Management of patients with diabetes and CKD: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) controversies conference JF - Kidney International N2 - The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population. KW - stage renal-disease KW - converting enzyme-inhibition KW - dietary sodium restriction KW - intensive glucose control KW - albumin excretion rate KW - blood pressure KW - cardiovascular outcomes KW - randomized trial KW - glycemic control KW - receptor KW - antidiabetic agents KW - cardiovascular disease KW - chronic kidney disease KW - diabetes KW - renoprotection KW - antagonist Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186599 VL - 90 IS - 6 ER - TY - JOUR A1 - Ansell, Melvyn B. A1 - Kostakis, George E. A1 - Braunschweig, Holger A1 - Navarro, Oscar A1 - Spencer, John T1 - Synthesis of functionalized hydrazines: facile homogeneous (N-heterocyclic carbene)-palladium(0)-catalyzed diboration and silaboration of azobenzenes JF - Advanced Synthesis & Catalysis N2 - The bis(N-heterocyclic carbene)(diphenylacetylene)palladium complex Pd(ITMe)\(_2\)(PhCCPh)] (ITMe=1,3,4,5-tetramethylimidazol-2-ylidene) acts as a highly active pre-catalyst in the diboration and silaboration of azobenzenes to synthesize a series of novel functionalized hydrazines. The reactions proceed using commercially available diboranes and silaboranes under mild reaction conditions. KW - Palladium-catalyzed silaboration KW - B-B bond KW - molecular-structure KW - terminal alkynes KW - crystal-structure KW - alkenes KW - complexes KW - mechanism KW - boron KW - design KW - azobenzenes KW - dilaboration KW - N-heterocyclic carbenes KW - palladium KW - silaboration Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186582 VL - 358 IS - 23 ER - TY - JOUR A1 - Jarius, Sven A1 - Ruprecht, Klemens A1 - Kleiter, Ingo A1 - Borisow, Nadja A1 - Asgari, Nasrin A1 - Pitarokoili, Kalliopi A1 - Pache, Florence A1 - Stich, Oliver A1 - Beume, Lena-Alexandra A1 - Hümmert, Martin W. A1 - Ringelstein, Marius A1 - Trebst, Corinna A1 - Winkelmann, Alexander A1 - Schwarz, Alexander A1 - Buttmann, Mathias A1 - Zimmermann, Hanna A1 - Kuchling, Joseph A1 - Franciotta, Diego A1 - Capobianco, Marco A1 - Siebert, Eberhard A1 - Lukas, Carsten A1 - Korporal-Kuhnke, Mirjam A1 - Haas, Jürgen A1 - Fechner, Kai A1 - Brandt, Alexander U. A1 - Schanda, Kathrin A1 - Aktas, Orhan A1 - Paul, Friedemann A1 - Reindl, Markus A1 - Wildemann, Brigitte T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome JF - Journal of Neuroinflammation N2 - Background A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG). Objective To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes. Methods Retrospective multicenter study. Results The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis. KW - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) KW - Aquaporin-4 antibodies (AQP4-IgG, NMO-IgG) KW - Optic neuritis KW - Transverse myelitis KW - Longitudinally extensive transverse myelitis KW - Magnetic resonance imaging KW - Autoantibodies KW - Neuromyelitis optica spectrum disorders (NMOSD) KW - Cerebrospinal fluid KW - Oligoclonal bands KW - Electrophysiology KW - Evoked potentials KW - Treatment KW - Therapy KW - Methotrexate KW - Azathioprine KW - Rituximab KW - Ofatumumab KW - Interferon beta KW - Glatiramer acetate KW - Natalizumab KW - Outcome KW - Pregnancy KW - Infections KW - Vaccination KW - Multiple sclerosis KW - Barkhof criteria KW - McDonald criteria KW - Wingerchuk criteria 2006 and 2015 KW - IPND criteria KW - International consensus diagnostic criteria for neuromyelitis optica spectrum disorders Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165570 VL - 13 IS - 280 ER - TY - JOUR A1 - Pache, Florence A1 - Zimmermann, Hanna A1 - Mikolajczak, Janine A1 - Schumacher, Sophie A1 - Lacheta, Anna A1 - Oertel, Frederike C. A1 - Bellmann-Strobl, Judith A1 - Jarius, Sven A1 - Wildemann, Brigitte A1 - Reindl, Markus A1 - Waldman, Amy A1 - Soelberg, Kerstin A1 - Asgari, Nasrin A1 - Ringelstein, Marius A1 - Aktas, Orhan A1 - Gross, Nikolai A1 - Buttmann, Mathias A1 - Ach, Thomas A1 - Ruprecht, Klemens A1 - Paul, Friedemann A1 - Brandt, Alexander U. T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients JF - Journal of Neuroinflammation N2 - Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important. KW - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) KW - aquaporin-4 antibodies (AQP4-IgG) KW - NMO-IgG KW - neuromyelitis optica KW - Devic syndrome KW - neuromyelitis optica spectrum disorders (NMOSD) KW - optic neuritis KW - optical coherence tomography KW - visual evoked potentials KW - visual acuity KW - retinal neuro-axonal damage Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165551 VL - 13 IS - 282 ER - TY - JOUR A1 - Sterkenburg, Anthe S. A1 - Hoffmann, Anika A1 - Reichel, Julia A1 - Lohle, Kristin A1 - Eveslage, Maria A1 - Warmuth-Metz, Monika A1 - Müller, Hermann L. T1 - Nuchal skinfold thickness: A novel parameter for assessment of body composition in childhood craniopharyngioma JF - Journal of Clinical Endocrinology & Metabolism N2 - Context: Hypothalamic obesity, cardiovascular disease (CVD), and relapse/progression have a major impact on prognosis in childhood-onset craniopharyngioma (CP). We analyzed nuchal skinfold thickness (NST) on magnetic resonance imaging performed for follow-up monitoring as a novel parameter for body composition (BC) and CVD in CP. Objective: The objective of the study was to identify the association of NST with body mass index (BMI), waist to height ratio (WHtR), functional capacity, and blood pressure (BP) in CP and controls. Design: This was a cross-sectional and longitudinal prospective study in CP patients. Setting: The study was conducted at HIT-Endo, KRANIOPHARYNGEOM 2000/2007. Patients: Participants included 94 CP patients and 75 controls. Interventions: There were no interventions. Main Outcome Measures: Association of NST with BC and BP in 43 CP and 43 controls was measured. Results: NST correlated with BMI SD score (SDS; r = 0.78; P = .001; n = 169) and WHtR (r = 0.85; P = .001; n = 86) in the total cohort and CP patients (NST-BMI SDS: r = 0.77, P = .001, n = 94); NST-WHtR: r = 0.835, P = .001, n = 43) and controls (NST-BMI SDS: r = 0.792, P = .001, n = 75; NST-WHtR: r = 0.671, P = .001, n = 43). In CP, systolic BP correlated with NST (r = 0.575, P = .001), BMI SDS (r = 0.434, P = .004), and WHtR (r = 0.386, P = .011). Similar results were observed for diastolic BP in CP. In multivariate analyses, NST had a predictive value for hypertension in postpubertal CP and controls (odds ratio 6.98, 95% confidence interval 1.65, 29.5], P = .008). During a longitudinal follow-up, changes in NST correlated with changes in BMI SDS (P = .001) and WHtR (P = .01) but not with changes in BP and functional capacity. Conclusions: Because monitoring of magnetic resonance imaging and BC is essential for follow-up in CP, NST could serve as a novel and clinically relevant parameter for longitudinal assessment of BC and CVD risk in CP. KW - to-height ratio KW - subcutaneous adipose-tissue KW - disease risk-factors KW - long-term survivors KW - guality-of-life KW - mass index KW - neck circumference KW - onset craniopharyngioma KW - german multicenter KW - visceral adiposity Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186562 VL - 101 IS - 12 ER - TY - JOUR A1 - Appel, Mirjam A1 - Scholz, Claus-Jürgen A1 - Kocabey, Samet A1 - Savage, Sinead A1 - König, Christian A1 - Yarali, Ayse T1 - Independent natural genetic variation of punishment- versus relief-memory JF - Biology Letters N2 - A painful event establishes two opponent memories: cues that are associated with pain onset are remembered negatively, whereas cues that coincide with the relief at pain offset acquire positive valence. Such punishment-versus relief-memories are conserved across species, including humans, and the balance between them is critical for adaptive behaviour with respect to pain and trauma. In the fruit fly, Drosophila melanogaster as a study case, we found that both punishment-and relief-memories display natural variation across wild-derived inbred strains, but they do not covary, suggesting a considerable level of dissociation in their genetic effectors. This provokes the question whether there may be heritable inter-individual differences in the balance between these opponent memories in man, with potential psycho-clinical implications. KW - associative memory KW - Drosophila melanogaster KW - natural genetic variation KW - opponent processes KW - punishment KW - fruit-flies KW - relief KW - reward KW - rats Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186554 VL - 12 IS - 12 ER - TY - JOUR A1 - Müller, Stefanie H. A1 - Girard, Simon L. A1 - Hopfner, Franziska A1 - Merner, Nancy D. A1 - Bourassa, Cynthia V. A1 - Lorenz, Delia A1 - Clark, Lorraine N. A1 - Tittmann, Lukas A1 - Soto-Ortolaza, Alexandra I. A1 - Klebe, Stephan A1 - Hallett, Mark A1 - Schneider, Susanne A. A1 - Hodgkinson, Colin A. A1 - Lieb, Wolfgang A1 - Wszolek, Zbigniew K. A1 - Pendziwiat, Manuela A1 - Lorenzo-Betancor, Oswaldo A1 - Poewe, Werner A1 - Ortega-Cubero, Sara A1 - Seppi, Klaus A1 - Rajput, Alex A1 - Hussl, Anna A1 - Rajput, Ali H. A1 - Berg, Daniela A1 - Dion, Patrick A. A1 - Wurster, Isabel A1 - Shulman, Joshua M. A1 - Srulijes, Karin A1 - Haubenberger, Dietrich A1 - Pastor, Pau A1 - Vilariño-Güell, Carles A1 - Postuma, Ronald B. A1 - Bernard, Geneviève A1 - Ladwig, Karl-Heinz A1 - Dupré, Nicolas A1 - Jankovic, Joseph A1 - Strauch, Konstantin A1 - Panisset, Michel A1 - Winkelmann, Juliane A1 - Testa, Claudia M. A1 - Reischl, Eva A1 - Zeuner, Kirsten E. A1 - Ross, Owen A. A1 - Arzberger, Thomas A1 - Chouinard, Sylvain A1 - Deuschl, Günther A1 - Louis, Elan D. A1 - Kuhlenbäumer, Gregor A1 - Rouleau, Guy A. T1 - Genome-wide association study in essential tremor identifies three new loci JF - Brain N2 - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor. KW - quality-control KW - disease KW - tool KW - movement disorders KW - genome-wide association study KW - tremor KW - genetics KW - essential tremor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541 VL - 139 ER - TY - JOUR A1 - Wheeler, Nicole E. A1 - Barquist, Lars A1 - Kingsley, Robert A. A1 - Gardner, Paul P. T1 - A profile-based method for identifying functional divergence of orthologous genes in bacterial genomes JF - Bioinformatics N2 - Motivation: Next generation sequencing technologies have provided us with a wealth of information on genetic variation, but predi cting the functional significance of this variation is a difficult task. While many comparative genomics studies have focused on gene flux and large scale changes, relatively little attention has been paid to quantifying the effects of single nucleotide polymorphisms and indels on protein function, particularly in bacterial genomics. Results: We present a hidden Markov model based approach we call delta-bitscore (DBS) for identifying orthologous proteins that have diverged at the amino acid sequence level in a way that is likely to impact biological function. We benchmark this approach with several widely used datasets and apply it to a proof-of-concept study of orthologous proteomes in an investigation of host adaptation in Salmonella enterica. We highlight the value of the method in identifying functional divergence of genes, and suggest that this tool may be a better approach than the commonly used dN/dS metric for identifying functionally significant genetic changes occurring in recently diverged organisms. KW - Host adaptation KW - Salmonella-enteritidis KW - Sequence identity KW - Rapid evolution KW - Variants KW - Cystic-fibriosis KW - Strains KW - Pathogenicity KW - Typhimurium KW - Yersinia Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186502 VL - 32 IS - 23 ER - TY - JOUR A1 - Vaze, Koustubh M. A1 - Helfrich-Förster, Charlotte T1 - Drosophila ezoana uses an hour-glass or highly damped circadian clock for measuring night length and inducing diapause JF - Physiological Entomology N2 - Insects inhabiting the temperate zones measure seasonal changes in day or night length to enter the overwintering diapause. Diapause induction occurs after the duration of the night exceeds a critical night length (CNL). Our understanding of the time measurement mechanisms is continuously evolving subsequent to Bünning’s proposal that circadian systems play the clock role in photoperiodic time measurement (Bünning, 1936). Initially, the photoperiodic clocks were considered to be either based on circadian oscillators or on simple hour-glasses, depending on ‘positive’ or ‘negative’ responses in Nanda–Hamner and Bünsow experiments (Nanda & Hammer, 1958; Bünsow, 1960). However, there are also species whose responses can be regarded as neither ‘positive’, nor as ‘negative’, such as the Northern Drosophila species Drosophila ezoana, which is investigated in the present study. In addition, modelling efforts show that the ‘positive’ and ‘negative’ Nanda–Hamner responses can also be provoked by circadian oscillators that are damped to different degrees: animals with highly sustained circadian clocks will respond ‘positive’ and those with heavily damped circadian clocks will respond ‘negative’. In the present study, an experimental assay is proposed that characterizes the photoperiodic oscillators by determining the effects of non-24-h light/dark cycles (T-cycles) on critical night length. It is predicted that there is (i) a change in the critical night length as a function of T-cycle period in sustained-oscillator-based clocks and (ii) a fxed night-length measurement (i.e. no change in critical night length) in damped-oscillator-based clocks. Drosophila ezoana flies show a critical night length of approximately 7 h irrespective of T-cycle period, suggesting a damped-oscillator-based photoperiodic clock. The conclusion is strengthened by activity recordings revealing that the activity rhythm of D. ezoana flies also dampens in constant darkness. KW - photoperiodic time mesurement KW - wyeomyia smithii KW - protophormia terraenovae KW - immunoreactive neurons KW - geographical variation KW - reproductive diapause KW - rhythmic components KW - locomotor activity KW - circadian clock KW - damped-oscillator-model of photoperiodic clock KW - diapause KW - Drosophila KW - hour-glass KW - pitcher-plant mosquito KW - bug riptortus-pedestris KW - Nanda-Hamner KW - photoperiodism Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204278 VL - 41 IS - 4 ER - TY - JOUR A1 - Jarius, Sven A1 - Kleiter, Ingo A1 - Ruprecht, Klemens A1 - Asgari, Nasrin A1 - Pitarokoili, Kalliopi A1 - Borisow, Nadja A1 - Hümmert, Martin W. A1 - Trebst, Corinna A1 - Pache, Florence A1 - Winkelmann, Alexander A1 - Beume, Lena-Alexandra A1 - Ringelstein, Marius A1 - Stich, Oliver A1 - Aktas, Orhan A1 - Korporal-Kuhnke, Mirjam A1 - Schwarz, Alexander A1 - Lukas, Carsten A1 - Haas, Jürgen A1 - Fechner, Kai A1 - Buttmann, Mathias A1 - Bellmann-Strobl, Judith A1 - Zimmermann, Hanna A1 - Brandt, Alexander U. A1 - Franciotta, Diego A1 - Schanda, Kathrin A1 - Paul, Friedemann A1 - Reindl, Markus A1 - Wildemann, Brigitte T1 - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome JF - Journal of Neuroinflammation N2 - Background Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients. Objective To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis. Methods Retrospective case study. Results Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up). Conclusions Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis. KW - Myelin oligodendrocyte glycoprotein (MOG) antibodies KW - MOG-IgG KW - Neuromyelitis optica spectrum disorders (NMOSD) KW - Brainstem encephalitis KW - Rhombencephalitis KW - Optic neuritis KW - Myelitis KW - Longitudinally extensive transverse myelitis (LETM) KW - Cerebellitis KW - Ataxia KW - Respiratory insufficiency KW - Intractable nausea and vomiting KW - Facial nerve palsy KW - Diplopia Internuclear ophthalmoplegia (INO) KW - Hearing loss KW - Aquaporin-4 antibodies (AQP4-Ig, NMO-IgG)G Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165543 VL - 13 IS - 281 ER - TY - JOUR A1 - Litts, Katie M. A1 - Ach, Thomas A1 - Hammack, Kristen M. A1 - Sloan, Kenneth R. A1 - Zhang, Yuhua A1 - Freund, K. Bailey A1 - Curcio, Christine A. T1 - Quantitative Analysis of Outer Retinal Tubulation in Age-Related Macular Degeneration From Spectral-Domain Optical Coherence Tomography and Histology JF - Investigative Ophthalmology & Visual Science N2 - Purpose: To assess outer retinal tubulation (ORT) morphology from spectral-domain optical coherence tomography (SD-OCT) volumes and donor eye histology, analyze ORT reflectivity, and estimate the number of cones surviving in ORT. Methods: In SD-OCT volumes from nine patients with advanced AMD, ORT was analyzed en face and in B-scans. The hyperreflective ORT border in cross-section was delineated and surface area calculated. Reflectivity was compared between ORT types (Closed, Open, Forming, and Branching). A flatmount retina from a donor with neovascular AMD was labeled to visualize the external limiting membrane that delimits ORT and allow measurements of cross-sectional cone area, center-to-center cone spacing, and cone density. The number of cones surviving in ORT was estimated. Results: By en face SD-OCT, ORT varies in complexity and shape. Outer retinal tubulation networks almost always contain Closed cross-sections. Spectral-domain OCT volumes containing almost exclusively Closed ORTs showed no significant direction-dependent differences in hyperreflective ORT border intensity. The surface areas of partial ORT assessed by SD-OCT volumes ranged from 0.16 to 1.76 mm2. From the flatmount retina, the average cross-sectional area of cone inner segments was 49.1 ± 7.9 μm2. The average cone spacing was 7.5 ± 0.6 μm. Outer retinal tubulation cone density was 20,351 cones/mm2. The estimated number of cones in ORT in a macula ranged from 26,399 to 186,833 cones, which is 6% to 44% of the cones present in a healthy macula. Conclusions: These first estimates for cone density and number of cones surviving in ORT suggest that ORT formation considerably distorts the photoreceptor mosaic. Results provide additional insight into the reflectivity characteristics and number of ORT cones observable in living patients by SD-OCT, as cones persist and disease progresses. KW - spectral-domain optical coherence tomography KW - photoreceptors KW - cones KW - Müller cells KW - age-related macular degeneration KW - outer retinal tubulation KW - ellipsoid KW - histology Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165532 VL - 57 ER - TY - JOUR A1 - Domschke, Katharina A1 - Zwanzger, Peter A1 - Rehbein, Maimu A. A1 - Steinberg, Christian A1 - Knoke, Kathrin A1 - Dobel, Christian A1 - Klinkenberg, Isabelle A1 - Kugel, Harald A1 - Kersting, Anette A1 - Arolt, Volker A1 - Pantev, Christo A1 - Junghofer, Markus T1 - Magnetoencephalographic Correlates of Emotional Processing in Major Depression Before and After Pharmacological Treatment JF - International Journal of Neuropsychopharmacology N2 - Background: In major depressive disorder (MDD), electrophysiological and imaging studies suggest reduced neural activity in the parietal and dorsolateral prefrontal cortex regions. In the present study, neural correlates of emotional processing in MDD were analyzed for the first time in a pre-/post-treatment design by means of magnetoencephalography (MEG), allowing for detecting temporal dynamics of brain activation. Methods: Twenty-five medication-free Caucasian in-patients with MDD and 25 matched controls underwent a baseline MEG session with passive viewing of pleasant, unpleasant, and neutral pictures. Fifteen patients were followed-up with a second MEG session after 4 weeks of antidepressant monopharmacotherapy with mirtazapine. The corresponding controls received no intervention between the measurements. The clinical course of depression was assessed using the Hamilton Depression scale. Results: Prior to treatment, an overall neocortical hypoactivation during emotional processing, particularly at the parietal regions and areas at the right temporoparietal junction, as well as abnormal valence-specific reactions at the right parietal and bilateral dorsolateral prefrontal cortex (dlPFC) regions were observed in patients compared to controls. These effects occurred <150ms, suggesting dysfunctional processing of emotional stimuli at a preconscious level. Successful antidepressant treatment resulted in a normalization of the hypoactivation at the right parietal and right temporoparietal regions. Accordingly, both dlPFC regions revealed an increase of activity after therapy. Conclusions: The present study provides neurophysiological evidence for dysfunctional emotional processing in a fronto-parieto-temporal network, possibly contributing to the pathogenesis of MDD. These activation patterns might have the potential to serve as biomarkers of treatment success. KW - Dorsolateral prefrontal cortex KW - IAPS KW - MDD KW - EEG KW - MEG KW - parietal hypoactivation KW - temporoparietal junction Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165523 VL - 2016 ER - TY - JOUR A1 - Ludwig, Nicole A1 - Werner, Tamara V. A1 - Backes, Christina A1 - Trampert, Patrick A1 - Gessler, Manfred A1 - Keller, Andreas A1 - Lenhof, Hans-Peter A1 - Graf, Norbert A1 - Meese, Eckart T1 - Combining miRNA and mRNA Expression Profiles in Wilms Tumor Subtypes JF - International Journal of Mokecular Sciences N2 - Wilms tumor (WT) is the most common childhood renal cancer. Recent findings of mutations in microRNA (miRNA) processing proteins suggest a pivotal role of miRNAs in WT genesis. We performed miRNA expression profiling of 36 WTs of different subtypes and four normal kidney tissues using microarrays. Additionally, we determined the gene expression profile of 28 of these tumors to identify potentially correlated target genes and affected pathways. We identified 85 miRNAs and 2107 messenger RNAs (mRNA) differentially expressed in blastemal WT, and 266 miRNAs and 1267 mRNAs differentially expressed in regressive subtype. The hierarchical clustering of the samples, using either the miRNA or mRNA profile, showed the clear separation of WT from normal kidney samples, but the miRNA pattern yielded better separation of WT subtypes. A correlation analysis of the deregulated miRNA and mRNAs identified 13,026 miRNA/mRNA pairs with inversely correlated expression, of which 2844 are potential interactions of miRNA and their predicted mRNA targets. We found significant upregulation of miRNAs-183, -301a/b and -335 for the blastemal subtype, and miRNAs-181b, -223 and -630 for the regressive subtype. We found marked deregulation of miRNAs regulating epithelial to mesenchymal transition, especially in the blastemal subtype, and miRNAs influencing chemosensitivity, especially in regressive subtypes. Further research is needed to assess the influence of preoperative chemotherapy and tumor infiltrating lymphocytes on the miRNA and mRNA patterns in WT KW - miRNA KW - Wilms tumor KW - blastemal KW - regressive Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165430 VL - 17 IS - 4 ER - TY - JOUR A1 - Tsiligianni, Ioanna G. A1 - Alma, Harma J. A1 - Kocks, Janwillem W. H. A1 - de Jong, Corina A1 - Jelusic, Danijel A1 - Wittmann, Michael A1 - Schuler, Michael A1 - Schultz, Konrad A1 - Kollen, Boudewijn J. A1 - van der Molen, Thys T1 - Investigating sensitivity, specificity, and area under the curve of the Clinical COPD Questionnaire, COPD Assessment Test, and Modified Medical Research Council scale according to GOLD using St George's Respiratory Questionnaire cutoff 25 (and 20) as reference JF - International Journal of COPD N2 - Background: In the GOLD (Global initiative for chronic Obstructive Lung Disease) strategy document, the Clinical COPD Questionnaire (CCQ), COPD Assessment Test (CAT), or modified Medical Research Council (mMRC) scale are recommended for the assessment of symptoms using the cutoff points of CCQ ≥1, CAT ≥10, and mMRC scale ≥2 to indicate symptomatic patients. The current study investigates the criterion validity of the CCQ, CAT and mMRC scale based on a reference cutoff point of St George’s Respiratory Questionnaire (SGRQ) ≥25, as suggested by GOLD, following sensitivity and specificity analysis. In addition, areas under the curve (AUCs) of the CCQ, CAT, and mMRC scale were compared using two SGRQ cutoff points (≥25 and ≥20). Materials and methods: Two data sets were used: study A, 238 patients from a pulmonary rehabilitation program; and study B, 101 patients from primary care. Receiver-operating characteristic (ROC) curves were used to assess the correspondence between the recommended cutoff points of the questionnaires. Results: Sensitivity, specificity, and AUC scores for cutoff point SGRQ ≥25 were: study A, 0.99, 0.43, and 0.96 for CCQ ≥1, 0.92, 0.48, and 0.89 for CAT ≥10, and 0.68, 0.91, and 0.91 for mMRC ≥2; study B, 0.87, 0.77, and 0.9 for CCQ ≥1, 0.76, 0.73, and 0.82 for CAT ≥10, and 0.21, 1, and 0.81 for mMRC ≥2. Sensitivity, specificity, and AUC scores for cutoff point SGRQ ≥20 were: study A, 0.99, 0.73, and 0.99 for CCQ ≥1, 0.91, 0.73, and 0.94 for CAT ≥10, and 0.66, 0.95, and 0.94 for mMRC ≥2; study B, 0.8, 0.89, and 0.89 for CCQ ≥1, 0.69, 0.78, and 0.8 for CAT ≥10, and 0.18, 1, and 0.81 for mMRC ≥2. Conclusion: Based on data from these two different samples, this study showed that the suggested cutoff point for the SGRQ (≥25) did not seem to correspond well with the established cutoff points of the CCQ or CAT scales, resulting in low specificity levels. The correspondence with the mMRC scale seemed satisfactory, though not optimal. The SGRQ threshold of ≥20 corresponded slightly better than SGRQ ≥25, recently suggested by GOLD 2015, with the established cutoff points for the CCQ, CAT, and mMRC scale. KW - pulmonary disease KW - chronic obstructive KW - health status Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165427 VL - 11 ER - TY - JOUR A1 - Jiang, Yuxiang A1 - Oron, Tal Ronnen A1 - Clark, Wyatt T. A1 - Bankapur, Asma R. A1 - D'Andrea, Daniel A1 - Lepore, Rosalba A1 - Funk, Christopher S. A1 - Kahanda, Indika A1 - Verspoor, Karin M. A1 - Ben-Hur, Asa A1 - Koo, Da Chen Emily A1 - Penfold-Brown, Duncan A1 - Shasha, Dennis A1 - Youngs, Noah A1 - Bonneau, Richard A1 - Lin, Alexandra A1 - Sahraeian, Sayed M. E. A1 - Martelli, Pier Luigi A1 - Profiti, Giuseppe A1 - Casadio, Rita A1 - Cao, Renzhi A1 - Zhong, Zhaolong A1 - Cheng, Jianlin A1 - Altenhoff, Adrian A1 - Skunca, Nives A1 - Dessimoz, Christophe A1 - Dogan, Tunca A1 - Hakala, Kai A1 - Kaewphan, Suwisa A1 - Mehryary, Farrokh A1 - Salakoski, Tapio A1 - Ginter, Filip A1 - Fang, Hai A1 - Smithers, Ben A1 - Oates, Matt A1 - Gough, Julian A1 - Törönen, Petri A1 - Koskinen, Patrik A1 - Holm, Liisa A1 - Chen, Ching-Tai A1 - Hsu, Wen-Lian A1 - Bryson, Kevin A1 - Cozzetto, Domenico A1 - Minneci, Federico A1 - Jones, David T. A1 - Chapman, Samuel A1 - BKC, Dukka A1 - Khan, Ishita K. A1 - Kihara, Daisuke A1 - Ofer, Dan A1 - Rappoport, Nadav A1 - Stern, Amos A1 - Cibrian-Uhalte, Elena A1 - Denny, Paul A1 - Foulger, Rebecca E. A1 - Hieta, Reija A1 - Legge, Duncan A1 - Lovering, Ruth C. A1 - Magrane, Michele A1 - Melidoni, Anna N. A1 - Mutowo-Meullenet, Prudence A1 - Pichler, Klemens A1 - Shypitsyna, Aleksandra A1 - Li, Biao A1 - Zakeri, Pooya A1 - ElShal, Sarah A1 - Tranchevent, Léon-Charles A1 - Das, Sayoni A1 - Dawson, Natalie L. A1 - Lee, David A1 - Lees, Jonathan G. A1 - Sillitoe, Ian A1 - Bhat, Prajwal A1 - Nepusz, Tamás A1 - Romero, Alfonso E. A1 - Sasidharan, Rajkumar A1 - Yang, Haixuan A1 - Paccanaro, Alberto A1 - Gillis, Jesse A1 - Sedeño-Cortés, Adriana E. A1 - Pavlidis, Paul A1 - Feng, Shou A1 - Cejuela, Juan M. A1 - Goldberg, Tatyana A1 - Hamp, Tobias A1 - Richter, Lothar A1 - Salamov, Asaf A1 - Gabaldon, Toni A1 - Marcet-Houben, Marina A1 - Supek, Fran A1 - Gong, Qingtian A1 - Ning, Wei A1 - Zhou, Yuanpeng A1 - Tian, Weidong A1 - Falda, Marco A1 - Fontana, Paolo A1 - Lavezzo, Enrico A1 - Toppo, Stefano A1 - Ferrari, Carlo A1 - Giollo, Manuel A1 - Piovesan, Damiano A1 - Tosatto, Silvio C. E. A1 - del Pozo, Angela A1 - Fernández, José M. A1 - Maietta, Paolo A1 - Valencia, Alfonso A1 - Tress, Michael L. A1 - Benso, Alfredo A1 - Di Carlo, Stefano A1 - Politano, Gianfranco A1 - Savino, Alessandro A1 - Rehman, Hafeez Ur A1 - Re, Matteo A1 - Mesiti, Marco A1 - Valentini, Giorgio A1 - Bargsten, Joachim W. A1 - van Dijk, Aalt D. J. A1 - Gemovic, Branislava A1 - Glisic, Sanja A1 - Perovic, Vladmir A1 - Veljkovic, Veljko A1 - Almeida-e-Silva, Danillo C. A1 - Vencio, Ricardo Z. N. A1 - Sharan, Malvika A1 - Vogel, Jörg A1 - Kansakar, Lakesh A1 - Zhang, Shanshan A1 - Vucetic, Slobodan A1 - Wang, Zheng A1 - Sternberg, Michael J. E. A1 - Wass, Mark N. A1 - Huntley, Rachael P. A1 - Martin, Maria J. A1 - O'Donovan, Claire A1 - Robinson, Peter N. A1 - Moreau, Yves A1 - Tramontano, Anna A1 - Babbitt, Patricia C. A1 - Brenner, Steven E. A1 - Linial, Michal A1 - Orengo, Christine A. A1 - Rost, Burkhard A1 - Greene, Casey S. A1 - Mooney, Sean D. A1 - Friedberg, Iddo A1 - Radivojac, Predrag A1 - Veljkovic, Nevena T1 - An expanded evaluation of protein function prediction methods shows an improvement in accuracy JF - Genome Biology N2 - Background A major bottleneck in our understanding of the molecular underpinnings of life is the assignment of function to proteins. While molecular experiments provide the most reliable annotation of proteins, their relatively low throughput and restricted purview have led to an increasing role for computational function prediction. However, assessing methods for protein function prediction and tracking progress in the field remain challenging. Results We conducted the second critical assessment of functional annotation (CAFA), a timed challenge to assess computational methods that automatically assign protein function. We evaluated 126 methods from 56 research groups for their ability to predict biological functions using Gene Ontology and gene-disease associations using Human Phenotype Ontology on a set of 3681 proteins from 18 species. CAFA2 featured expanded analysis compared with CAFA1, with regards to data set size, variety, and assessment metrics. To review progress in the field, the analysis compared the best methods from CAFA1 to those of CAFA2. Conclusions The top-performing methods in CAFA2 outperformed those from CAFA1. This increased accuracy can be attributed to a combination of the growing number of experimental annotations and improved methods for function prediction. The assessment also revealed that the definition of top-performing algorithms is ontology specific, that different performance metrics can be used to probe the nature of accurate predictions, and the relative diversity of predictions in the biological process and human phenotype ontologies. While there was methodological improvement between CAFA1 and CAFA2, the interpretation of results and usefulness of individual methods remain context-dependent. KW - Protein function prediction KW - Disease gene prioritization Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166293 VL - 17 IS - 184 ER - TY - JOUR A1 - Diao, Wenwen A1 - Mousset, Mathilde A1 - Horsburgh, Gavin J. A1 - Vermeulen, Cornelis J. A1 - Johannes, Frank A1 - van de Zande, Louis A1 - Ritchie, Michael G. A1 - Schmitt, Thomas A1 - Beukeboom, Leo W. T1 - Quantitative Trait Locus Analysis of Mating Behavior and Male Sex Pheromones in Nasonia Wasps JF - G3: Genes Genomes Genetics N2 - A major focus in speciation genetics is to identify the chromosomal regions and genes that reduce hybridization and gene flow. We investigated the genetic architecture of mating behavior in the parasitoid wasp species pair Nasonia giraulti and Nasonia oneida that exhibit strong prezygotic isolation. Behavioral analysis showed that N. oneida females had consistently higher latency times, and broke off the mating sequence more often in the mounting stage when confronted with N. giraulti males compared with males of their own species. N. oneida males produce a lower quantity of the long-range male sex pheromone (4R,5S)-5-hydroxy-4-decanolide (RS-HDL). Crosses between the two species yielded hybrid males with various pheromone quantities, and these males were used in mating trials with females of either species to measure female mate discrimination rates. A quantitative trait locus (QTL) analysis involving 475 recombinant hybrid males (F2), 2148 reciprocally backcrossed females (F3), and a linkage map of 52 equally spaced neutral single nucleotide polymorphism (SNP) markers plus SNPs in 40 candidate mating behavior genes revealed four QTL for male pheromone amount, depending on partner species. Our results demonstrate that the RS-HDL pheromone plays a role in the mating system of N. giraulti and N. oneida, but also that additional communication cues are involved in mate choice. No QTL were found for female mate discrimination, which points at a polygenic architecture of female choice with strong environmental influences. KW - Nasonia courtship KW - female choice KW - sex pheromone KW - QTL analysis KW - speciation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165412 VL - 6 IS - 6 ER - TY - JOUR A1 - Sadovnick, A. Dessa A1 - Traboulsee, Anthony L. A1 - Bernales, Cecily Q. A1 - Ross, Jay P. A1 - Forwell, Amanda L. A1 - Yee, Irene M. A1 - Guillot-Noel, Lena A1 - Fontaine, Bertrand A1 - Cournu-Rebeix, Isabelle A1 - Alcina, Antonio A1 - Fedetz, Maria A1 - Izquierdo, Guillermo A1 - Matesanz, Fuencisla A1 - Hilven, Kelly A1 - Dubois, Bénédicte A1 - Goris, An A1 - Astobiza, Ianire A1 - Alloza, Iraide A1 - Antigüedad, Alfredo A1 - Vandenbroeck, Koen A1 - Akkad, Denis A. A1 - Aktas, Orhan A1 - Blaschke, Paul A1 - Buttmann, Mathias A1 - Chan, Andrew A1 - Epplen, Joerg T. A1 - Gerdes, Lisa-Ann A1 - Kroner, Antje A1 - Kubisch, Christian A1 - Kümpfel, Tania A1 - Lohse, Peter A1 - Rieckmann, Peter A1 - Zettl, Uwe K. A1 - Zipp, Frauke A1 - Bertram, Lars A1 - Lill, Christina M. A1 - Fernandez, Oscar A1 - Urbaneja, Patricia A1 - Leyva, Laura A1 - Alvarez-Cermeño, Jose Carlos A1 - Arroyo, Rafael A1 - Garagorri, Aroa M. A1 - García-Martínez, Angel A1 - Villar, Luisa M. A1 - Urcelay, Elena A1 - Malhotra, Sunny A1 - Montalban, Xavier A1 - Comabella, Manuel A1 - Berger, Thomas A1 - Fazekas, Franz A1 - Reindl, Markus A1 - Schmied, Mascha C. A1 - Zimprich, Alexander A1 - Vilariño-Güell, Carles T1 - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients JF - G3: Genes Genomes Genetics N2 - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. KW - multiple sclerosis KW - genetics KW - linkage KW - association KW - plasminogen Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405 VL - 6 IS - 7 ER - TY - JOUR A1 - Citron, Francesca M. M. A1 - Abugaber, David A1 - Herbert, Cornelia T1 - Approach and Withdrawal Tendencies during Written Word Processing: Effects of Task, Emotional Valence, and Emotional Arousal JF - frontiers in Psychology N2 - The affective dimensions of emotional valence and emotional arousal affect processing of verbal and pictorial stimuli. Traditional emotional theories assume a linear relationship between these dimensions, with valence determining the direction of a behavior (approach vs. withdrawal) and arousal its intensity or strength. In contrast, according to the valence-arousal conflict theory, both dimensions are interactively related: positive valence and low arousal (PL) are associated with an implicit tendency to approach a stimulus, whereas negative valence and high arousal (NH) are associated with withdrawal. Hence, positive, high-arousal (PH) and negative, low-arousal (NL) stimuli elicit conflicting action tendencies. By extending previous research that used several tasks and methods, the present study investigated whether and how emotional valence and arousal affect subjective approach vs. withdrawal tendencies toward emotional words during two novel tasks. In Study 1, participants had to decide whether they would approach or withdraw from concepts expressed by written words. In Studies 2 and 3 participants had to respond to each word by pressing one of two keys labeled with an arrow pointing upward or downward. Across experiments, positive and negative words, high or low in arousal, were presented. In Study 1 (explicit task), in line with the valence-arousal conflict theory, PH and NL words were responded to more slowly than PL and NH words. In addition, participants decided to approach positive words more often than negative words. In Studies 2 and 3, participants responded faster to positive than negative words, irrespective of their level of arousal. Furthermore, positive words were significantly more often associated with “up” responses than negative words, thus supporting the existence of implicit associations between stimulus valence and response coding (positive is up and negative is down). Hence, in contexts in which participants' spontaneous responses are based on implicit associations between stimulus valence and response, there is no influence of arousal. In line with the valence-arousal conflict theory, arousal seems to affect participants' approach-withdrawal tendencies only when such tendencies are made explicit by the task, and a minimal degree of processing depth is required. KW - approach KW - withdrawal KW - valence KW - arousal KW - emotion KW - words KW - polarity effects Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165318 VL - 6 IS - 1935 ER - TY - JOUR A1 - Peperkorn, Henrik M. A1 - Diemer, Julia E. A1 - Alpers, Georg W. A1 - Mühlberger, Andreas T1 - Representation of Patients' Hand Modulates Fear Reactions of Patients with Spider Phobia in Virtual Reality JF - frontiers in Psychology N2 - Embodiment (i.e., the involvement of a bodily representation) is thought to be relevant in emotional experiences. Virtual reality (VR) is a capable means of activating phobic fear in patients. The representation of the patient’s body (e.g., the right hand) in VR enhances immersion and increases presence, but its effect on phobic fear is still unknown. We analyzed the influence of the presentation of the participant’s hand in VR on presence and fear responses in 32 women with spider phobia and 32 matched controls. Participants sat in front of a table with an acrylic glass container within reaching distance. During the experiment this setup was concealed by a head-mounted display (HMD). The VR scenario presented via HMD showed the same setup, i.e., a table with an acrylic glass container. Participants were randomly assigned to one of two experimental groups. In one group, fear responses were triggered by fear-relevant visual input in VR (virtual spider in the virtual acrylic glass container), while information about a real but unseen neutral control animal (living snake in the acrylic glass container) was given. The second group received fear-relevant information of the real but unseen situation (living spider in the acrylic glass container), but visual input was kept neutral VR (virtual snake in the virtual acrylic glass container). Participants were instructed to touch the acrylic glass container with their right hand in 20 consecutive trials. Visibility of the hand was varied randomly in a within-subjects design. We found for all participants that visibility of the participant’s hand increased presence independently of the fear trigger. However, in patients, the influence of the virtual hand on fear depended on the fear trigger. When fear was triggered perceptually, i.e., by a virtual spider, the virtual hand increased fear. When fear was triggered by information about a real spider, the virtual hand had no effect on fear. Our results shed light on the significance of different fear triggers (visual, conceptual) in interaction with body representations. KW - virtual reality KW - presence KW - immersion KW - perception KW - fear KW - specific phobia Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165307 VL - 7 IS - 268 ER -