Recent Submissions

  • Journal Article

    Medial prefrontal cortex supports perceptual memory 

    Schwiedrzik, Caspar M.; Sudmann, Sandrin S.; Thesen, Thomas; Wang, Xiuyuan; Groppe, David M.; Mégevand, Pierre; Doyle, Werner; Mehta, Ashesh D.; Devinsky, Orrin; Melloni, Lucia
    Current Biology 2018; 28(18) p.R1094-R1095
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  • Journal Article

    Nanomachinery Organizing Release at Neuronal and Ribbon Synapses 

    Chakrabarti; Wichmann
    International Journal of Molecular Sciences 2019; 20(9): Art. 2147
    A critical aim in neuroscience is to obtain a comprehensive view of how regulated neurotransmission is achieved. Our current understanding of synapses relies mainly on data from electrophysiological recordings, imaging, and molecular biology. Based on these methodologies, proteins involved in a synaptic vesicle (SV) formation, mobility, and fusion at the active zone (AZ) membrane have been identified. In the last decade, electron tomography (ET) combined with a rapid freezing immobilization of neuronal samples opened a window for understanding the structural machinery with the highest spatial resolution in situ. ET provides significant insights into the molecular architecture of the AZ and the organelles within the presynaptic nerve terminal. The specialized sensory ribbon synapses exhibit a distinct architecture from neuronal synapses due to the presence of the electron-dense synaptic ribbon. However, both synapse types share the filamentous structures, also commonly termed as tethers that are proposed to contribute to different steps of SV recruitment and exocytosis. In this review, we discuss the emerging views on the role of filamentous structures in SV exocytosis gained from ultrastructural studies of excitatory, mainly central neuronal compared to ribbon-type synapses with a focus on inner hair cell (IHC) ribbon synapses. Moreover, we will speculate on the molecular entities that may be involved in filament formation and hence play a crucial role in the SV cycle.
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  • Journal Article

    Prolonged Cannabidiol Treatment Lacks on Detrimental Effects on Memory, Motor Performance and Anxiety in C57BL/6J Mice 

    Schleicher, Eva M.; Ott, Frederik W.; Müller, Melanie; Silcher, Barbara; Sichler, Marius E.; Löw, Maximilian J.; Wagner, Jannek M.; Bouter, Yvonne
    Frontiers in Behavioral Neuroscience 2019; 13: Art. 94
    The Cannabis plant contains more than 100 currently known phytocannabinoids. Regarding the rising consumption of the non-psychotropic phytocannabinoid cannabidiol (CBD) in people’s everyday life (e.g., beauty products, food and beverages), the importance of studies on the influence of CBD on healthy humans and rodents is evident. Therefore, the behavioral profile of CBD was investigated with a battery of behavioral tests, including motor, anxiety, and memory tests after prolonged CBD treatment. Adult C57Bl/6J wildtype (WT) mice were daily intraperitoneally injected with 20 mg/kg CBD for 6 weeks starting at two different points of ages (3 months and 5 months) to compare the influence of prolonged CBD treatment with a washout period (former group) to the effects of long term CBD treatment (current group). Our results show that CBD treatment does not influence motor performance on an accelerating Rotarod test, while it also results in a lower locomotor activity in the open field (OF). No influence of CBD on spatial learning and long term memory in the Morris Water Maze (MWM) was observed. Memory in the Novel Object Recognition test (NORT) was unaffected by CBD treatment. Two different anxiety tests revealed that CBD does not affect anxiety behavior in the Dark-Light Box (DLB) and OF test. Although, anxiety is altered by current CBD treatment in the Elevated Plus Maze (EPM). Moreover, CBDtreated C57Bl/6J mice showed an unaltered acoustic startle response (ASR) compared to vehicle-treated mice. However, current CBD treatment impairs prepulse inhibition (PPI), a test to analyze sensorimotor gating. Furthermore, prolonged CBD treatment did not affect the hippocampal neuron number. Our results demonstrate that prolonged CBD treatment has no negative effect on the behavior of adult C57Bl/6J mice.
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  • Journal Article

    Amygdalar reactivity is associated with prefrontal cortical thickness in a large population-based sample of adolescents 

    Albaugh, Matthew D.; Hudziak, James. J.; Orr, Catherine; Spechler, Philip A.; Chaarani, Bader; Mackey, Scott; Lepage, Claude; Fonov, Vladimir; Rioux, Pierre; Evans, Alan C.; et al.
    Banaschewski, TobiasBokde, Arun L. W.Bromberg, UliBüchel, ChristianQuinlan, Erin BurkeDesrivières, SylvaneFlor, HertaGrigis, AntoineGowland, PennyHeinz, AndreasIttermann, BerndMartinot, Jean-LucMartinot, Marie-Laure PaillèreNees, FraukeOrfanos, Dimitri PapadopoulosPaus, TomášPoustka, LuiseMillenet, SabinaFröhner, Juliane H.Smolka, Michael N.Walter, HenrikWhelan, RobertSchumann, GunterPotter, Alexandra S.Garavan, Hugh
    PLOS ONE 2019; 14(5): Art. e0216152
    In structural neuroimaging studies, reduced cerebral cortical thickness in orbital and ventromedial prefrontal regions is frequently interpreted as reflecting an impaired ability to downregulate neuronal activity in the amygdalae. Unfortunately, little research has been conducted in order to test this conjecture. We examine the extent to which amygdalar reactivity is associated with cortical thickness in a population-based sample of adolescents. Data were obtained from the IMAGEN study, which includes 2,223 adolescents. While undergoing functional neuroimaging, participants passively viewed video clips of a face that started from a neutral expression and progressively turned angry, or, instead, turned to a second neutral expression. Left and right amygdala ROIs were used to extract mean BOLD signal change for the angry minus neutral face contrast for all subjects. T1-weighted images were processed through the CIVET pipeline (version 2.1.0). In variable-centered analyses, local cortical thickness was regressed against amygdalar reactivity using first and second-order linear models. In a follow-up person-centered analysis, we defined a "high reactive" group of participants based on mean amygdalar BOLD signal change for the angry minus neutral face contrast. Between-group differences in cortical thickness were examined ("high reactive" versus all other participants). A significant association was revealed between the continuous measure of amygdalar reactivity and bilateral ventromedial prefrontal cortical thickness in a second-order linear model (p < 0.05, corrected). The "high reactive" group, in comparison to all other participants, possessed reduced cortical thickness in bilateral orbital and ventromedial prefrontal cortices, bilateral anterior temporal cortices, left caudal middle temporal gyrus, and the left inferior and middle frontal gyri (p < 0.05, corrected). Results are consistent with non-human primate studies, and provide empirical support for an association between reduced prefrontal cortical thickness and amygdalar reactivity. Future research will likely benefit from investigating the degree to which psychopathology qualifies relations between prefrontal cortical structure and amygdalar reactivity.
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  • Journal Article

    Subparaneural injection in popliteal sciatic nerve blocks evaluated by MRI 

    Büttner, Benedikt; Schwarz, Alexander; Mewes, Caspar; Kristof, Katalin; Hinz, José; Quintel, Michael; Mansur, Ashham; Bergmann, Ingo
    Open Medicine 2019; 14(1) p.346-353
    Intraneural injection of a local anesthetic can damage the nerve, yet it occurs frequently during distal sciatic block with no neurological sequelae. This has led to a controversy about the optimal needle tip placement that results from the particular anatomy of the sciatic nerve with its paraneural sheath. The study population included patients undergoing lower extremity surgery under popliteal sciatic nerve block. Ultrasound-guidance was used to position the needle tip subparaneurally and to monitor the injection of the local anesthetic. Sonography and magnetic resonance imaging were used to assess the extent of the subparaneural injection. Twenty-two patients participated. The median sciatic cross-sectional area increased from 57.8 mm2 pre-block to 110.8 mm2 immediately post-block. An intraneural injection according to the current definition was seen in 21 patients. Two patients had sonographic evidence of an intrafascicular injection, which was confirmed by MRI in one patient (the other patient refused further examinations). No patient reported any neurological symptoms. A subparaneural injection in the popliteal segment of the distal sciatic nerve is actually rarely intraneural, i.e. intrafascicular. This may explain the discrepancy between the conventional sonographic evidence of an intraneural injection and the lack of neurological sequelae.
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  • Journal Article

    Spreading of α-Synuclein and Tau: A Systematic Comparison of the Mechanisms Involved 

    Vasili, Eftychia; Dominguez-Meijide, Antonio; Outeiro, Tiago Fleming
    Frontiers in Molecular Neuroscience 2019; 12: Art. 107
    Alzheimer's disease (AD) and Parkinson's disease (PD) are age-associated neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn) and tau, respectively. The coexistence of aSyn and tau aggregates suggests a strong overlap between tauopathies and synucleinopathies. Interestingly, misfolded forms of aSyn and tau can propagate from cell to cell, and throughout the brain, thereby templating the misfolding of native forms of the proteins. The exact mechanisms involved in the propagation of the two proteins show similarities, and are reminiscent of the spreading characteristic of prion diseases. Recently, several models were developed to study the spreading of aSyn and tau. Here, we discuss the mechanisms involved, the similarities and differences between the spreading of the two proteins and that of the prion protein, and the different cell and animal models used for studying these processes. Ultimately, a deeper understanding of the molecular mechanisms involved may lead to the identification of novel targets for therapeutic intervention in a variety of devastating neurodegenerative diseases.
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  • Journal Article

    How Uncertainty Influences Lay People’s Attitudes and Risk Perceptions Concerning Predictive Genetic Testing and Risk Communication 

    Wöhlke, Sabine; Schaper, Manuel; Schicktanz, Silke
    Frontiers in Genetics 2019; 10: Art. 380
    The interpretation of genetic information in clinical settings raises moral issues about adequate risk communication and individual responsibility about one’s health behavior. However, it is not well-known what role numeric probabilities and/or the conception of disease and genetics play in the lay understanding of predictive genetic diagnostics. This is an important question because lay understanding of genetic risk information might have particular implications for self-responsibility of the patients. Aim: Analysis of lay attitudes and risk perceptions of German lay people on genetic testing with a special focus on how they deal with the numerical information. Methods: We conducted and analyzed seven focus group discussions (FG) with lay people (n = 43). Results: Our participants showed a positive attitude toward predictive genetic testing. We identified four main topics: (1) Anumeric risk instead of statistical information; (2) Treatment options as a factor for risk evaluation; (3) Epistemic and aleatory uncertainty as moral criticism; (4) Ambivalence as a sign of uncertainty. Conclusion: For lay people, risk information, including the statistical numeric part, is perceived as highly normatively charged, often as an emotionally significant threat. It seems necessary to provide lay people with a deeper understanding of risk information and of the limitations of genetic knowledge with respect to one’s own health responsibility.
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  • Journal Article

    Optogenetic Hyperpolarization of Cardiomyocytes Terminates Ventricular Arrhythmia 

    Funken, Maximilian; Malan, Daniela; Sasse, Philipp; Bruegmann, Tobias
    Frontiers in Physiology 2019; 10: Art. 498
    Cardiac defibrillation to terminate lethal ventricular arrhythmia (VA) is currently performed by applying high energy electrical shocks. In cardiac tissue, electrical shocks induce simultaneously de- and hyperpolarized areas and only depolarized areas are considered to be responsible for VA termination. Because electrical shocks do not allow proper control over spatial extent and level of membrane potential changes, the effects of hyperpolarization have not been explored in the intact heart. In contrast, optogenetic methods allow cell type-selective induction of de- and hyperpolarization with unprecedented temporal and spatial control. To investigate effects of cardiomyocyte hyperpolarization on VA termination, we generated a mouse line with cardiomyocyte-specific expression of the light-driven proton pump ArchT. Isolated cardiomyocytes showed light-induced outward currents and hyperpolarization. Free-running VA were evoked by electrical stimulation of explanted hearts perfused with low K+ and the KATP channel opener Pinacidil. Optogenetic hyperpolarization was induced by epicardial illumination, which terminated VA with an average efficacy of ∼55%. This value was significantly higher compared to control hearts without illumination or ArchT expression (p = 0.0007). Intracellular recordings with sharp electrodes within the intact heart revealed hyperpolarization and faster action potential upstroke upon illumination, which should fasten conduction. However, conduction speed was lower during illumination suggesting enhanced electrical sink by hyperpolarization underlying VA termination. Thus, selective hyperpolarization in cardiomyocytes is able to terminate VA with a completely new mechanism of increased electrical sink. These novel insights could improve our mechanistic understanding and treatment strategies of VA termination.
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  • Journal Article

    Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O2 Consumption and ROS Release 

    Can, Karolina; Menzfeld, Christiane; Rinne, Lena; Rehling, Peter; Kügler, Sebastian; Golubiani, Gocha; Dudek, Jan; Müller, Michael
    Frontiers in Physiology 2019; 10: Art. 479
    Rett syndrome (RTT), an X chromosome-linked neurodevelopmental disorder affecting almost exclusively females, is associated with various mitochondrial alterations. Mitochondria are swollen, show altered respiratory rates, and their inner membrane is leaking protons. To advance the understanding of these disturbances and clarify their link to redox impairment and oxidative stress, we assessed mitochondrial respiration in defined brain regions and cardiac tissue of male wildtype (WT) and MeCP2-deficient (Mecp2-/y) mice. Also, we quantified for the first time neuronal redox-balance with subcellular resolution in cytosol and mitochondrial matrix. Quantitative roGFP1 redox imaging revealed more oxidized conditions in the cytosol of Mecp2-/y hippocampal neurons than in WT neurons. Furthermore, cytosol and mitochondria of Mecp2-/y neurons showed exaggerated redox-responses to hypoxia and cell-endogenous reactive oxygen species (ROS) formation. Biochemical analyzes exclude disease-related increases in mitochondrial mass in Mecp2-/y hippocampus and cortex. Protein levels of complex I core constituents were slightly lower in Mecp2-/y hippocampus and cortex than in WT; those of complex V were lower in Mecp2-/y cortex. Respiratory supercomplex-formation did not differ among genotypes. Yet, supplied with the complex II substrate succinate, mitochondria of Mecp2-/y cortex and hippocampus consumed more O2 than WT. Furthermore, mitochondria from Mecp2-/y hippocampus and cortex mediated an enhanced oxidative burden. In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT.
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  • Journal Article

    A modular transcriptome map of mature B cell lymphomas 

    Loeffler-Wirth, Henry; Kreuz, Markus; Hopp, Lydia; Arakelyan, Arsen; Haake, Andrea; Cogliatti, Sergio B.; Feller, Alfred C.; Hansmann, Martin-Leo; Lenze, Dido; Möller, Peter; et al.
    Genome Medicine. 2019 Apr 30;11(1):27
    Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
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  • Journal Article

    X-linked myotubular myopathy and recurrent spontaneous pneumothorax 

    Carstens, Per-Ole; Schwaibold, Eva Maria Christina; Schregel, Katharina; Obermaier, Carolin D.; Wrede, Arne; Zechel, Sabrina; Pauli, Silke; Schmidt, Jens
    Neurology Genetics 2019; 5(3): Art. e327
    X-linked myotubular myopathy (XLMTM) is a rare hereditary disorder of the skeletal muscle. Symptoms include impaired respiration and muscular hypotonia, usually present at birth and leading to death during infancy or early childhood.1 Pneumothorax, defined as trapping of air in the pleural cavity, can be caused by surgery or can occur spontaneously.2 Pneumothorax has been reported only in a small number of cases with hereditary myopathies, but usually not spontaneously and never in XLMTM.
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  • Journal Article

    Tumor laterality in renal cancer as a predictor of survival in large patient cohorts: A STROBE compliant study 

    Strauss, Arne; Uhlig, Johannes; Lotz, Joachim; Trojan, Lutz; Uhlig, Annemarie
    Medicine 2019; 98(17): Art. e15346
    To assess whether left and right-sided renal cell carcinoma (RCC) carry side-specific outcomes. Surgically treated RCC patients were included from the United States Surveillance, Epidemiology and End Results database (Surveillance, Epidemiology and End Results database [SEER]; 2013 version) and the German Centre for Cancer Registry Data (ZfKD; 2000–2014). Bilateral RCC, those with missing RCC staging, follow-up time, and survival status were excluded. Cancer-specific survival (CSS) according to RCC side was compared using multivariable Cox regression. Seventeen thousand seven hundred nine SEER patients and 41,967 ZfKD patients were included. In both datasets, patients with left-sided RCC had higher T status and more often presented with nodal positive or metastatic disease. In the SEER dataset 1258 (14.33%) patients with left-sided RCC underwent lymphadenectomy (LAD), compared to 908 (10.17%) LADs in right-sided RCC (P <.001). CSS was inferior for left-sided in both datasets after multivariable adjustment (SEER HR = 1.187, 95% CI 1.048–1.345, P = .007, P = .008; ZfKD HR = 1.155, 95% CI 1.046–1.275, P = .004). In the SEER population, site-specific CSS differences were driven by whether or not a LAD was performed. Among SEER patients with LAD no statistically significant differences in laterality were observed (HR 1.096, 95% CI 0.8977–1.337, P = .396) whereas, in absence of LAD, CSS was shorter for individuals with left-sided tumor (HR = 1.176, 95%CI 1.002–1.38, P = .0468). Although the overall survival difference was only marginal, left-sided RCC in surgically treated patients tends to present at more advanced stage and has in general worse CSS, especially in patients without LAD. Site-specific lymphogenic spread patterns might contribute to these findings. Further prospective studies should evaluate, whether side-adapted LAD protocols influence outcomes in RCC patients.
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  • Journal Article

    Fully automated quantification of biventricular volumes and function in cardiovascular magnetic resonance: applicability to clinical routine settings 

    Backhaus, Sören J.; Staab, Wieland; Steinmetz, Michael; Ritter, Christian O.; Lotz, Joachim; Hasenfuß, Gerd; Schuster, Andreas; Kowallick, Johannes T.
    Journal of Cardiovascular Magnetic Resonance. 2019 Apr 25;21(1):24
    Background Cardiovascular magnetic resonance (CMR) represents the clinical gold standard for the assessment of biventricular morphology and function. Since manual post-processing is time-consuming and prone to observer variability, efforts have been directed towards automated volumetric quantification. In this study, we sought to validate the accuracy of a novel approach providing fully automated quantification of biventricular volumes and function in a “real-world” clinical setting. Methods Three-hundred CMR examinations were randomly selected from the local data base. Fully automated quantification of left ventricular (LV) mass, LV and right ventricular (RV) end-diastolic and end-systolic volumes (EDV/ESV), stroke volume (SV) and ejection fraction (EF) were performed overnight using commercially available software (suiteHEART®, Neosoft, Pewaukee, Wisconsin, USA). Parameters were compared to manual assessments (QMass®, Medis Medical Imaging Systems, Leiden, Netherlands). Sub-group analyses were further performed according to image quality, scanner field strength, the presence of implanted aortic valves and repaired Tetralogy of Fallot (ToF). Results Biventricular automated segmentation was feasible in all 300 cases. Overall agreement between fully automated and manually derived LV parameters was good (LV-EF: intra-class correlation coefficient [ICC] 0.95; bias − 2.5% [SD 5.9%]), whilst RV agreement was lower (RV-EF: ICC 0.72; bias 5.8% [SD 9.6%]). Lowest agreement was observed in case of severely altered anatomy, e.g. marked RV dilation but normal LV dimensions in repaired ToF (LV parameters ICC 0.73–0.91; RV parameters ICC 0.41–0.94) and/or reduced image quality (LV parameters ICC 0.86–0.95; RV parameters ICC 0.56–0.91), which was more common on 3.0 T than on 1.5 T. Conclusions Fully automated assessments of biventricular morphology and function is robust and accurate in a clinical routine setting with good image quality and can be performed without any user interaction. However, in case of demanding anatomy (e.g. repaired ToF, severe LV hypertrophy) or reduced image quality, quality check and manual re-contouring are still required.
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  • Journal Article

    Taking patient involvement seriously: a critical ethical analysis of participatory approaches in data-intensive medical research 

    Beier, Katharina; Schweda, Mark; Schicktanz, Silke
    BMC Medical Informatics and Decision Making. 2019 Apr 25;19(1):90
    Background Data-intensive research in medicine and healthcare such as health-related big data research (HBDR) implies that data from clinical routine, research and patient-reported data, but also non-medical social or demographic data, are aggregated and linked in order to optimize biomedical research. In this context, notions of patient participation and involvement are frequently invoked to legitimize this kind of research and improve its governance. The aim of this debate paper is to critically examine the specific use and ethical role of participatory concepts in the context of HBDR and data-intensive research in medicine and healthcare. Discussion We introduce basic conceptual distinctions for the understanding of participation by looking at relevant fields of application in politics, bioethics and medical research. Against this backdrop, we identify three paradigmatic participatory roles that patients/subjects are assigned within the field of HBDR: participants as providers of biomaterials and data, participants as administrators of their own research participation and participants as (co-)principal investigators. We further illustrate these roles by exemplary data-intensive research-initiatives. Our analysis of these initiatives and their respective participatory promises reveals specific ethical and practical shortcomings and challenges. Central problems affecting, amongst others, ethical and methodological research standards, as well as public trust in research, result from the negligence of essential political-ethical dimensions of genuine participation. Conclusions Based on the conceptual distinctions introduced, we formulate basic criteria for justified appeals to participatory approaches in HBDR and data-intensive research in medicine and healthcare in order to overcome these shortcomings. As we suggest, this is not only a matter of conceptual clarity, but a crucial requirement for maintaining ethical standards and trust in HBDR and related medical research.
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  • Journal Article

    Endoscopic submucosal dissection of an esophageal granular cell tumor 

    Knoop, Richard F.; Schmidt, Arthur; Kayser, Gian; Thimme, Robert; Fischer, Andreas
    VideoGIE 2019; 4(2) p.58-61
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  • Journal Article

    Stent-retriever assisted vacuum-locked extraction (SAVE) versus a direct aspiration first pass technique (ADAPT) for acute stroke: data from the real-world 

    Brehm, Alex; Maus, Volker; Tsogkas, Ioannis; Colla, Ruben; Hesse, Amélie C.; Gera, Roland G.; Psychogios, Marios-Nikos
    BMC Neurology. 2019 Apr 15;19(1):65
    Background Embolectomy is the standard of care in acute ischemic stroke (AIS) caused by large vessel occlusion (LVO). Aim of this study was to compare two techniques: A Direct Aspiration First Pass Technique (ADAPT) and Stent-retriever Assisted Vacuum-locked Extraction (SAVE) stratified by the occluded vessel. Methods One hundred seventy-one patients (71 male) treated between January 2014 and September 2017 with AIS due to LVO of the anterior circulation (55 carotid T, 94 M1, 22 M2) were included. Treatment techniques were divided into two categories: ADAPT and SAVE. Primary endpoints were successful reperfusion (mTICI ≥2b), near-perfect reperfusion (mTICI ≥2c) and groin puncture to reperfusion time. Secondary endpoints were the number of device-passes, first-pass reperfusion, the frequency of emboli to new territory (ENT), clinical outcome at 90 days, and the frequency of symptomatic intracranial hemorrhage (sICH). Analysis was performed on an intention to treat basis. Results Overall, SAVE resulted in significant higher rates of successful reperfusion (mTICI≥2b) compared to ADAPT (93.5% vs 75.0%; p = 0.006). After stratification for the occluded vessel only the carotid T remained significant with higher rates of near-perfect reperfusion (mTICI≥2c) (55.2% vs 15.4%; p = 0.025), while for successful reperfusion a trend remained (93.1% vs 65.4%; p = 0.10). Groin to reperfusion times were not significantly different. Secondary analysis revealed higher rates of first-pass successful reperfusion (59.6% vs 33.3%; p = 0.019), higher rates of first-pass near-perfect reperfusion in the carotid T (35.4% vs 16.7%; p = 0.038) and a lower number of device-passes overall (median 1 IQR 1–2 vs 2 IQR 2–3; p <  0.001) and in the carotid T (median 2 IQR 1.3 vs 3 IQR 2–5; p <  0.001) for SAVE. Clinical outcome and safety parameters were comparable between groups. Conclusions Embolectomy using SAVE appears superior to ADAPT, especially for carotid T occlusions with regard to reperfusion success.
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  • Journal Article

    Influence of oral premedication and prewarming on core temperature of cardiac surgical patients: a prospective, randomized, controlled trial 

    Bräuer, Anselm; Müller, Michaela M.; Wetz, Anna J.; Quintel, Michael; Brandes, Ivo F.
    BMC Anesthesiology. 2019 Apr 12;19(1):55
    Background Perioperative hypothermia is still very common and associated with numerous adverse effects. The effects of benzodiazepines, administered as premedication, on thermoregulation have been studied with conflicting results. We investigated the hypotheses that premedication with flunitrazepam would lower the preoperative core temperature and that prewarming could attenuate this effect. Methods After approval by the local research ethics committee 50 adult cardiac surgical patients were included in this prospective, randomized, controlled, single-centre study with two parallel groups in a university hospital setting. Core temperature was measured using a continuous, non-invasive zero-heat flux thermometer from 30 min before administration of the oral premedication until beginning of surgery. An equal number of patients was randomly allocated via a computer-generated list assigning them to either prewarming or control group using the sealed envelope method for blinding. The intervention itself could not be blinded. In the prewarming group patients received active prewarming using an underbody forced-air warming blanket. The data were analysed using Student’s t-test, Mann-Whitney U-test and Fisher’s exact test. Results Of the randomized 25 patients per group 24 patients per group could be analysed. Initial core temperature was 36.7 ± 0.2 °C and dropped significantly after oral premedication to 36.5 ± 0.3 °C when the patients were leaving the ward and to 36.4 ± 0.3 °C before induction of anaesthesia. The patients of the prewarming group had a significantly higher core temperature at the beginning of surgery (35.8 ± 0.4 °C vs. 35.5 ± 0.5 °C, p = 0.027), although core temperature at induction of anaesthesia was comparable. Despite prewarming, core temperature did not reach baseline level prior to premedication (36.7 ± 0.2 °C). Conclusions Oral premedication with benzodiazepines on the ward lowered core temperature significantly at arrival in the operating room. This drop in core temperature cannot be offset by a short period of active prewarming. Trial registration This trial was prospectively registered with the German registry of clinical trials under the trial number DRKS00005790 on 20th February 2014.
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  • Journal Article

    Serum vitamin D but not zinc levels are associated with different disease activity status in patients with inflammatory bowel disease 

    Mechie, Nicolae-Catalin; Mavropoulou, Eirini; Ellenrieder, Volker; Petzold, Golo; Kunsch, Steffen; Neesse, Albrecht; Amanzada, Ahmad
    Medicine 2019; 98(15): Art. e15172
    The incidence of inflammatory bowel disease (IBD) is increasing and the pathogenesis is still not completely understood. Micronutrients like vitamin D [25 (OH)D] and zinc play an important role in enzyme activities and the immune system. As the 25 (OH)D-receptor has been shown to be downregulated in patients with IBD, 25 (OH)D may emerge as a predictive marker for disease improvement. Studies on relationship of both micronutrients in IBD patients are lacking.We retrospectively evaluated serum levels of 25(OH)D and zinc together with baseline characteristics of 232 IBD patients. Uni- and multivariate analyses were performed for association between serum levels of 25(OH)D and zinc with clinical and deep remission (CR and DR).155 Crohn's disease (CD) and 77 ulcerative colitis (UC) patients were included. 54% (n = 125) and 6% (n = 14) of IBD patients showed deficient serum 25(OH)D levels below 20 ng/mL and zinc levels below 7 μmol/L. Serum 25(OH)D levels were significantly higher in IBD patients with CR (P = .02) and DR (P < .001) but not serum zinc levels, respectively. Serum 25(OH)D levels (P = .008), anti-tumor-necrosis-factor-α-trough-concentration (anti-TNF-α-TC) (P = .02) and CRP level (P = .02) were independently associated with CR in CD patients. Serum 25(OH)D threshold of 19 ng/mL discriminated CD patients with or without CR, having an area under the receiver operating curve analysis (AUROC) of 0.77 [95%-confidence interval (CI): 0.68-0.85]. In multivariate analysis serum 25(OH)D levels (P = .04) and anti-TNF-α-TC (P = .04) were associated with DR in CD patients. Serum 25(OH)D threshold of 26 ng/mL discriminated CD patients with or without DR, having an AUROC of 0.75 (95%-CI: 0.68-0.83).Serum 25(OH)D (P = .04) and fecal calprotectin levels (P = .04) were independently correlated with CR in UC patients. Serum 25(OH)D threshold of 32 ng/mL discriminated UC patients in CR with an AUROC of 0.83 (95%-CI: 0.71-0.95). Zinc levels did not correlate with disease activity status in CD or UC patients either.In conclusion, beside CRP and fecal calprotectin, serum 25(OH)D levels, but not serum zinc levels, may be an additional useful and noninvasive marker for characterizing different disease activity status of IBD patients. Measurement of serum 25(OH)D in IBD patients may be warranted. 25(OH)D supplementation in deficient IBD patients is recommended.
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  • Journal Article

    Transcriptomic and epigenetic profiling of ‘diffuse midline gliomas, H3 K27M-mutant’ discriminate two subgroups based on the type of histone H3 mutated and not supratentorial or infratentorial location 

    Castel, David; Philippe, Cathy; Kergrohen, Thomas; Sill, Martin; Merlevede, Jane; Barret, Emilie; Puget, Stéphanie; Sainte-Rose, Christian; Kramm, Christof M.; Jones, Chris; et al.
    Varlet, PascalePfister, Stefan M.Grill, JacquesJones, David T. W.Debily, Marie-Anne
    Acta Neuropathologica Communications 2018; 6(1): Art. 117
    Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the updated WHO classification grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histones H3 tail.Two hundred and fifteen patients younger than 18 years old with centrally-reviewed pediatric high-grade gliomas (pHGG) were included in this study. Comprehensive transcriptomic (n = 140) and methylation (n = 80) profiling was performed depending on the material available, in order to assess the biological uniqueness of this new entity compared to other midline and hemispheric pHGG.Tumor classification based on gene expression (GE) data highlighted the similarity of K27M DMG independently of their location along the midline. T-distributed Stochastic Neighbor Embedding (tSNE) analysis of methylation profiling confirms the discrimination of DMG from other well defined supratentorial tumor subgroups. Patients with diffuse intrinsic pontine gliomas (DIPG) and thalamic DMG exhibited a similarly poor prognosis (11.1 and 10.8 months median overall survival, respectively). Interestingly, H3.1-K27M and H3.3-K27M primary tumor samples could be distinguished based both on their GE and DNA methylation profiles, suggesting that they might arise from a different precursor or from a different epigenetic reorganization.These differences in DNA methylation profiles were conserved in glioma stem-like cell culture models of DIPG which mimicked their corresponding primary tumor. ChIP-seq profiling of H3K27me3 in these models indicate that H3.3-K27M mutated DIPG stem cells exhibit higher levels of H3K27 trimethylation which are correlated with fewer genes expressed by RNAseq. When considering the global distribution of the H3K27me3 mark, we observed that intergenic regions were more trimethylated in the H3.3-K27M mutated cells compared to the H3.1-K27M mutated ones.H3 K27M-mutant DMG represent a homogenous group of neoplasms compared to other pediatric gliomas that could be further separated based on the type of histone H3 variant mutated and their respective epigenetic landscapes. As these characteristics drive different phenotypes, these findings may have important implication for the design of future trials in these specific types of neoplasms.
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  • Journal Article

    Are smokers who are regularly exposed to e-cigarette use by others more or less motivated to stop or to make a quit attempt? A cross-sectional and longitudinal survey 

    Jackson, Sarah E.; Beard, Emma; Michie, Susan; Shahab, Lion; Raupach, Tobias; West, Robert; Brown, Jamie
    BMC Medicine 2018; 16(1): Art. 206
    BACKGROUND: Concerns have been raised that observing other people using e-cigarettes may undermine motivation to quit by renormalising smoking. This study aimed to explore associations between regular exposure to other people's e-cigarette use and motivation to stop smoking and quit attempts in smokers. METHODS: Data were from 12,787 smokers in England who participated in the Smoking Toolkit Study between November 2014 and May 2018. At baseline, respondents were asked whether anyone other than themselves regularly used an e-cigarette in their presence, whether they had made a quit attempt in the past year and how motivated they were to stop. Data at 6-month follow-up were available for 1580 respondents, who reported on whether they had attempted to quit in the past 6 months. RESULTS: Smokers who reported regular exposure to e-cigarette use by others were more likely than those who did not to have tried to stop smoking in the past year (32.3% vs. 26.8%; unadjusted RR 1.21, 95% CI 1.11-1.31) and have high motivation to quit (16.6% vs. 14.2%; unadjusted RR 1.17, 95% CI 1.05-1.30) but were not significantly more or less likely to make a quit attempt over the subsequent 6 months (34.4% vs. 31.3%; unadjusted RR 1.10, 95% CI 0.88-1.38). In models that adjusted for participants' own current e-cigarette use and unadjusted and adjusted models excluding current e-cigarette users from the sample, there were no significant associations between exposure to e-cigarette use by others and past quit attempts (RR 0.97-1.00), high current motivation to quit (RR 0.97-1.00) or prospective quit attempts (RR 0.94-1.12). In contrast, exposure to use of cigarettes was associated with low motivation to quit even after adjustment (RR 0.89) but not with quit attempts. Participants' own use of e-cigarette was strongly associated with high motivation to quit (RR 1.95) and past quit attempts (RR 2.14) and appeared to account for the bivariate associations with reported exposure to e-cigarettes. CONCLUSION: Smokers who report regular exposure to other people using e-cigarettes are more likely to report past quit attempts and high current motivation to quit, but there does not appear to be an independent association with motivation or quit attempts after adjustment for their own current use of e-cigarettes. In contrast, reported exposure to other people using cigarettes was independently and negatively associated with high motivation.
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