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    An opposing function of paralogs in balancing developmental synapse maturation. 

    Favaro, Plinio D.; Huang, Xiaojie; Hosang, Leon; Stodieck, Sophia; Cui, Lei; Liu, Yu-Zhang; Engelhardt, Karl-Alexander; Schmitz, Frank; Dong, Yan; Löwel, Siegrid; et al.
    Schlüter, Oliver M.
    PLOS Biology 2018; 16(12): Art. e2006838
    The disc-large (DLG)-membrane-associated guanylate kinase (MAGUK) family of proteins forms a central signaling hub of the glutamate receptor complex. Among this family, some proteins regulate developmental maturation of glutamatergic synapses, a process vulnerable to aberrations, which may lead to neurodevelopmental disorders. As is typical for paralogs, the DLG-MAGUK proteins postsynaptic density (PSD)-95 and PSD-93 share similar functional domains and were previously thought to regulate glutamatergic synapses similarly. Here, we show that they play opposing roles in glutamatergic synapse maturation. Specifically, PSD-95 promoted, whereas PSD-93 inhibited maturation of immature α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptor (AMPAR)-silent synapses in mouse cortex during development. Furthermore, through experience-dependent regulation of its protein levels, PSD-93 directly inhibited PSD-95's promoting effect on silent synapse maturation in the visual cortex. The concerted function of these two paralogs governed the critical period of juvenile ocular dominance plasticity (jODP), and fine-tuned visual perception during development. In contrast to the silent synapse-based mechanism of adjusting visual perception, visual acuity improved by different mechanisms. Thus, by controlling the pace of silent synapse maturation, the opposing but properly balanced actions of PSD-93 and PSD-95 are essential for fine-tuning cortical networks for receptive field integration during developmental critical periods, and imply aberrations in either direction of this process as potential causes for neurodevelopmental disorders.
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    Estrogen Signaling in ERα-Negative Breast Cancer: ERβ and GPER 

    Girgert, Rainer; Emons, Günter; Gründker, Carsten
    Frontiers in Endocrinology 2019; 9: Art. 781
    Estrogen receptors are important regulators of the growth of breast tumors. Three different receptors for estrogens have been identified in breast tumors, two nuclear receptors, ERa and ERb, and a G-protein coupled estrogen receptor 1 (GPER) that initiates non-genomic effects of estrogens in the cytosol. Recent findings show that the stimulation of cytoplasmic ERa and ERb also triggers non-genomic signaling pathways. The treatment of breast cancer with anti-estrogens depends on the presence of ERa. About 40% of all breast cancers, however, do not express ERa. One subgroup of these tumors overexpress Her-2, another important group is designated as triple-negative breast cancer, as they neither express ERa, nor progesterone receptors, nor do they overexpress Her-2. This review addresses the signaling of ERb and GPER in ERa-negative breast tumors. In addition to the well-established EGF-receptor transactivation pathways of GPER, more recent findings of GPER-dependent activation of FOXO3a, the Hippo-pathway, and HOTAIR-activation are summarized.
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    18F-FDG-PET Detects Drastic Changes in Brain Metabolism in the Tg4–42 Model of Alzheimer’s Disease 

    Bouter, Caroline; Henniges, Philipp; Franke, Timon N.; Irwin, Caroline; Sahlmann, Carsten Oliver; Sichler, Marius E.; Beindorff, Nicola; Bayer, Thomas A.; Bouter, Yvonne
    Frontiers in Aging Neuroscience 2019; 10: Art. 125
    The evaluation of new therapeutic strategies in Alzheimer’s disease (AD) relies heavily on in vivo imaging and suitable animal models that mimic the pathological changes seen in patients. 18F-Fluorodeoxyglucose (18F-FDG)-positron-emission tomography (PET) is a well-established non-invasive imaging tool for monitoring changes in cerebral brain glucose metabolism in vivo. 18F-FDG-PET is used as a functional biomarker for AD as patients show an early and progressive reduction of cerebral glucose metabolism. However, earlier studies in preclinical models of AD showed conflicting results. The aim of this study was the evaluation of cerebral glucose metabolism in the Tg4–42 mouse model of AD using 18F-FDG-PET/magnetic resonance imaging (MRI). Tg4–42 mice show an age-dependent reduction in glucose metabolism together with severe neuron loss and memory deficits. Similar to AD patients early decrease in 18F-FDG uptake was already detected in young (3 months) Tg4–42 mice. The altered glucose metabolism coupled with age- and disease related cognitive decline of Tg4–42 mice make it a well-suited model for preclinical testing of AD-relevant therapeutics.
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    Likelihood-based random-effects meta-analysis with few studies: empirical and simulation studies. 

    Seide, Svenja E; Röver, Christian; Friede, Tim
    BMC medical research methodology 2019-01-11; 19: Art. 16
    BACKGROUND: Standard random-effects meta-analysis methods perform poorly when applied to few studies only. Such settings however are commonly encountered in practice. It is unclear, whether or to what extent small-sample-size behaviour can be improved by more sophisticated modeling. METHODS: We consider likelihood-based methods, the DerSimonian-Laird approach, Empirical Bayes, several adjustment methods and a fully Bayesian approach. Confidence intervals are based on a normal approximation, or on adjustments based on the Student-t-distribution. In addition, a linear mixed model and two generalized linear mixed models (GLMMs) assuming binomial or Poisson distributed numbers of events per study arm are considered for pairwise binary meta-analyses. We extract an empirical data set of 40 meta-analyses from recent reviews published by the German Institute for Quality and Efficiency in Health Care (IQWiG). Methods are then compared empirically as well as in a simulation study, based on few studies, imbalanced study sizes, and considering odds-ratio (OR) and risk ratio (RR) effect sizes. Coverage probabilities and interval widths for the combined effect estimate are evaluated to compare the different approaches. RESULTS: Empirically, a majority of the identified meta-analyses include only 2 studies. Variation of methods or effect measures affects the estimation results. In the simulation study, coverage probability is, in the presence of heterogeneity and few studies, mostly below the nominal level for all frequentist methods based on normal approximation, in particular when sizes in meta-analyses are not balanced, but improve when confidence intervals are adjusted. Bayesian methods result in better coverage than the frequentist methods with normal approximation in all scenarios, except for some cases of very large heterogeneity where the coverage is slightly lower. Credible intervals are empirically and in the simulation study wider than unadjusted confidence intervals, but considerably narrower than adjusted ones, with some exceptions when considering RRs and small numbers of patients per trial-arm. Confidence intervals based on the GLMMs are, in general, slightly narrower than those from other frequentist methods. Some methods turned out impractical due to frequent numerical problems. CONCLUSIONS: In the presence of between-study heterogeneity, especially with unbalanced study sizes, caution is needed in applying meta-analytical methods to few studies, as either coverage probabilities might be compromised, or intervals are inconclusively wide. Bayesian estimation with a sensibly chosen prior for between-trial heterogeneity may offer a promising compromise.
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    Memory-Efficient Deep Learning on a SpiNNaker 2 Prototype 

    Liu, Chen; Bellec, Guillaume; Vogginger, Bernhard; Kappel, David; Partzsch, Johannes; Neumärker, Felix; Höppner, Sebastian; Maass, Wolfgang; Furber, Steve B.; Legenstein, Robert; et al.
    Mayr, Christian G.
    Frontiers in Neuroscience 2018; 12: Art. 840
    The memory requirement of deep learning algorithms is considered incompatible with the memory restriction of energy-efficient hardware. A low memory footprint can be achieved by pruning obsolete connections or reducing the precision of connection strengths after the network has been trained. Yet, these techniques are not applicable to the case when neural networks have to be trained directly on hardware due to the hard memory constraints. Deep Rewiring (DEEP R) is a training algorithm which continuously rewires the network while preserving very sparse connectivity all along the training procedure. We apply DEEP R to a deep neural network implementation on a prototype chip of the 2nd generation SpiNNaker system. The local memory of a single core on this chip is limited to 64 KB and a deep network architecture is trained entirely within this constraint without the use of external memory. Throughout training, the proportion of active connections is limited to 1.3%. On the handwritten digits dataset MNIST, this extremely sparse network achieves 96.6% classification accuracy at convergence. Utilizing the multi-processor feature of the SpiNNaker system, we found very good scaling in terms of computation time, per-core memory consumption, and energy constraints. When compared to a X86 CPU implementation, neural network training on the SpiNNaker 2 prototype improves power and energy consumption by two orders of magnitude.
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    Sex differences in outcomes of primary prevention implantable cardioverter-defibrillator therapy: combined registry data from eleven European countries. 

    Sticherling, Christian; Arendacka, Barbora; Svendsen, Jesper Hastrup; Wijers, Sofieke; Friede, Tim; Stockinger, Jochem; Dommasch, Michael; Merkely, Bela; Willems, Rik; Lubinski, Andrzej; et al.
    Scharfe, MichaelBraunschweig, FriederSvetlosak, MartinZürn, Christine S.Huikuri, HeikkiFlevari, PanagiotaLund-Andersen, CasparSchaer, Beat A.Tuinenburg, Anton E.Bergau, LeonardSchmidt, GeorgSzeplaki, GaborVandenberk, BertKowalczyk, EmiliaEick, ChristianJuntilla, JuhaniConen, DavidZabel, Markus
    Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 2018; 20(6) p.963-970
    Aims: Therapy with an implantable cardioverter defibrillator (ICD) is established for the prevention of sudden cardiac death (SCD) in high risk patients. We aimed to determine the effectiveness of primary prevention ICD therapy by analysing registry data from 14 centres in 11 European countries compiled between 2002 and 2014, with emphasis on outcomes in women who have been underrepresented in all trials. Methods and results: Retrospective data of 14 local registries of primary prevention ICD implantations between 2002 and 2014 were compiled in a central database. Predefined primary outcome measures were overall mortality and first appropriate and first inappropriate shocks. A multivariable model enforcing a common hazard ratio for sex category across the centres, but allowing for centre-specific baseline hazards and centre specific effects of other covariates, was adjusted for age, the presence of ischaemic cardiomyopathy or a CRT-D, and left ventricular ejection fraction ≤25%. Of the 5033 patients, 957 (19%) were women. During a median follow-up of 33 months (IQR 16-55 months) 129 women (13%) and 807 men (20%) died (HR 0.65; 95% CI: [0.53, 0.79], P-value < 0.0001). An appropriate ICD shock occurred in 66 women (8%) and 514 men (14%; HR 0.61; 95% CI: 0.47-0.79; P = 0.0002). Conclusion: Our retrospective analysis of 14 local registries in 11 European countries demonstrates that fewer women than men undergo ICD implantation for primary prevention. After multivariate adjustment, women have a significantly lower mortality and receive fewer appropriate ICD shocks.
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    Adverse pregnancy outcomes among pregnant women with acute Rubella infections in Mwanza city, Tanzania. 

    Mirambo, Mariam M.; Aboud, Said; Majigo, Mtebe; Groβ, Uwe; Mshana, Stephen E.
    International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2019; 78 p.72-77
    OBJECTIVE: This study investigated the adverse pregnancy outcomes among pregnant women with acute Rubella infections in the city of Mwanza, Tanzania. METHODS: A longitudinal study was conducted between 2014 and 2016 among pregnant women attending antenatal clinics. Women were screened for Rubella IgG and IgM antibodies using enzyme immunoassay (EIA). IgM seropositive pregnant women were followed up until the end of the pregnancy to determine Congenital Rubella Syndrome, congenital infections and other pregnancy outcomes. RESULTS: The median age of 685 enrolled pregnant women was 23 (IQR: 19-27) years. A total of 629(91.8%) were Rubella IgG seropositive while 61 (8.9%) were IgM seropositive. The IgM seropositivity was found to decrease significantly from first trimester to third trimester, p<0.001. Forty six (83.6%) of 55 Rubella IgM seropositive women had adverse pregnancy outcomes and 6 (10.9%) delivered neonates with CRS, making the overall incidence of CRS to be 6/685 (0.87%). First trimester IgM seropositive women had significantly higher adverse pregnancy outcomes than those in second/third trimesters (70.4% vs. 35.7, p=0.01). CONCLUSION: There is one case of CRS in every 100 pregnancies necessitating additional strategies to reach a goal of elimination of CRS in developing countries.
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    Data on differential multivariable risk prediction of appropriate shock vs. competing mortality 

    Bergau, Leonard; Willems, Rik; Sprenkeler, David J; Fischer, Thomas H; Flevari, Panayota; Hasenfuß, Gerd; Katsaras, Dimitrios; Kirova, Aleksandra; Lehnart, Stephan E; Lüthje, Lars; et al.
    Röver, ChristianSeegers, JoachimSossalla, SamuelDunnink, AlbertSritharan, RajevaaTuinenburg, Anton EVandenberk, BertVos, Marc AWijers, Sofieke CFriede, TimZabel, Markus
    Data in Brief 2018-12; 21 p.2110-2116
    This data article features supplementary figures and tables related to the article "Differential Multivariable risk prediction of appropriate shock vs. competing mortality - a prospective cohort study to estimate benefits from implantable cardioverter defibrillator therapy" (Bergau et al., 2018) [1]. The figures show the clinical study CONSORT graph (data that show the number of patients not-analyzable as well as a distribution of patients by outcomes) and the correlation scatter plot for risk scores of appropriate shock vs. mortality (data that show the calculated score values of the two scores plotted against each other). The tables show the results for the univariate Cox regressions for prediction of mortality and appropriate shock. For further information, please see Bergau et al. (2018) [1].
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    Down syndrome phenotype in a boy with a mosaic microduplication of chromosome 21q22 

    Schnabel, Franziska; Smogavec, Mateja; Funke, Rudolf; Pauli, Silke; Burfeind, Peter; Bartels, Iris
    2018; 11(1): Art. 62
    Abstract Background Down syndrome, typically caused by trisomy 21, may also be associated by duplications of the Down syndrome critical region (DSCR) on chromosome 21q22. However, patients with small duplications of DSCR without accompanying deletions have rarely been reported. Case presentation Here we report a 5½-year-old boy with clinical features of Down syndrome including distinct craniofacial dysmorphism and sandal gaps as well as developmental delay. Conventional karyotype was normal, whereas interphase FISH analysis revealed three signals for DSCR in approximately 40% of lymphocytes and 80% of buccal mucosa cells. Array-CGH analysis confirmed a 2.56 Mb duplication of chromosome 21q22.13q22.2 encompassing DYRK1A. Conclusion This presents one of the smallest duplications within DSCR leading to a Down syndrome phenotype. Since the dosage sensitive gene DYRK1A is the only duplicated candidate DSCR gene in our patient, this finding supports the hypothesis that DYRK1A contributes to dysmorphic and intellectual features of Down syndrome even in a mosaic state.
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    Therapeutic Fluorescent Hybrid Nanoparticles for Traceable Delivery of Glucocorticoids to Inflammatory Sites 

    Napp, Joanna; Markus, M. Andrea; Heck, Joachim G.; Dullin, Christian; Möbius, Wiebke; Gorpas, Dimitris; Feldmann, Claus; Alves, Frauke
    Theranostics 2018; 8(22) p.6367-6383
    Treatment of inflammatory disorders with glucocorticoids (GCs) is often accompanied by severe adverse effects. Application of GCs via nanoparticles (NPs), especially those using simple formulations, could possibly improve their delivery to sites of inflammation and therefore their efficacy, minimising the required dose and thus reducing side effects. Here, we present the evaluation of NPs composed of GC betamethasone phosphate (BMP) and the fluorescent dye DY-647 (BMP-IOH-NPs) for improved treatment of inflammation with simultaneous in vivo monitoring of NP delivery. Methods: BMP-IOH-NP uptake by MH-S macrophages was analysed by fluorescence and electron microscopy. Lipopolysaccharide (LPS)-stimulated cells were treated for 48 h with BMP-IOH-NPs (1×10-5-1×10-9 M), BMP or dexamethasone (Dexa). Drug efficacy was assessed by measurement of interleukin 6. Mice with Zymosan-A-induced paw inflammation were intraperitoneally treated with BMP-IOH-NPs (10 mg/kg) and mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI) were treated intranasally with BMP-IOH-NPs, BMP or Dexa (each 2.5 mg/kg). Efficacy was assessed in vivo by paw volume measurements with µCT and ex vivo by measurement of paw weight for Zymosan-A-treated mice, or in the AAI model by in vivo x-ray-based lung function assessment and by cell counts in the bronchoalveolar lavage (BAL) fluid and histology. Delivery of BMP-IOH-NPs to the lungs of AAI mice was monitored by in vivo optical imaging and by fluorescence microscopy. Results: Uptake of BMP-IOH-NPs by MH-S cells was observed during the first 10 min of incubation, with the NP load increasing over time. The anti-inflammatory effect of BMP-IOH-NPs in vitro was dose dependent and higher than that of Dexa or free BMP, confirming efficient release of the drug. In vivo, Zymosan-A-induced paw inflammation was significantly reduced in mice treated with BMP-IOH-NPs. AAI mice that received BMP-IOH-NPs or Dexa but not BMP revealed significantly decreased eosinophil numbers in BALs and reduced immune cell infiltration in lungs. Correspondingly, lung function parameters, which were strongly affected in non-treated AAI mice, were unaffected in AAI mice treated with BMP-IOH-NPs and resembled those of healthy animals. Accumulation of BMP-IOH-NPs within the lungs of AAI mice was detectable by optical imaging for at least 4 h in vivo, where they were preferentially taken up by peribronchial and alveolar M2 macrophages. Conclusion: Our results show that BMP-IOH-NPs can effectively be applied in therapy of inflammatory diseases with at least equal efficacy as the gold standard Dexa, while their delivery can be simultaneously tracked in vivo by fluorescence imaging. BMP-IOH-NPs thus have the potential to reach clinical applications.
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    Functional equivalence of germ plasm organizers 

    Krishnakumar, Pritesh; Riemer, Stephan; Perera, Roshan; Lingner, Thomas; Goloborodko, Alexander; Khalifa, Hazem; Bontems, Franck; Kaufholz, Felix; El-Brolosy, Mohamed A.; Dosch, Roland
    PLOS Genetics 2018; 14(11): Art. e1007696
    The proteins Oskar (Osk) in Drosophila and Bucky ball (Buc) in zebrafish act as germ plasm organizers. Both proteins recapitulate germ plasm activities but seem to be unique to their animal groups. Here, we discover that Osk and Buc show similar activities during germ cell specification. Drosophila Osk induces additional PGCs in zebrafish. Surprisingly, Osk and Buc do not show homologous protein motifs that would explain their related function. Nonetheless, we detect that both proteins contain stretches of intrinsically disordered regions (IDRs), which seem to be involved in protein aggregation. IDRs are known to rapidly change their sequence during evolution, which might obscure biochemical interaction motifs. Indeed, we show that Buc binds to the known Oskar interactors Vasa protein and nanos mRNA indicating conserved biochemical activities. These data provide a molecular framework for two proteins with unrelated sequence but with equivalent function to assemble a conserved core-complex nucleating germ plasm.
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    Endoscopic submucosal dissection for esophageal granular cell tumor using the clutch cutter 

    Komori, Keishi
    World Journal of Gastrointestinal Endoscopy 2012; 4(1)
    Endoscopic submucosal dissection (ESD) with a knife is a technically demanding procedure associated with a high complication rate. The shortcomings of this method are the deficiencies of fixing the knife to the target lesion, and of compressing it. These shortcomings can lead to major complications such as perforation and bleeding. To reduce the risk of complications related to ESD, we developed a new grasping type scissors forceps (Clutch Cutter®, Fujifilm, Japan) which can grasp and incise the targeted tissue using an electrosurgical current. Esophagogastroduodenoscopy on a 59-year-old Japanese man revealed a 16mm esophageal submucosal nodule with central depression. Endoscopic ultrasonography demonstrated a hypoechoic solid tumor limited to the submucosa without lymph node involvement. The histologic diagnosis of the specimen obtained by biopsy was granular cell tumor. It was safely and accurately resected without unexpected incision by ESD using the CC. No delayed hemorrhage or perforation occurred. Histological examination confirmed that the granular cell tumor was completely excised with negative resection margin.We report herein a case of esophageal granular cell tumor successfully treated by an ESD technique using the CC.
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    Assessing the risk for major injuries in equestrian sports 

    Krüger, Lara; Hohberg, Maike; Lehmann, Wolfgang; Dresing, Klaus
    BMJ Open Sport & Exercise Medicine 2018; 4(1): Art. e000408
    Background/aim: Horse riding is a popular sport, which bears the risk of serious injuries. This study aims to assess whether individual factors influence the risk to sustain major injuries. Methods: Retrospective data were collected from all equine-related accidents at a German Level I Trauma Centre between 2004 and 2014. Logistic regression was used to identify the risk factors for major injures. Results: 770 patients were included (87.9% females). Falling off the horse (67.7%) and being kicked by the horse (16.5%) were the two main injury mechanisms. Men and individuals of higher age showed higher odds for all tested parameters of serious injury. Patients falling off a horse had higher odds for being treated as inpatients, whereas patients who were kicked had higher odds for a surgical therapy (OR 1.7) and intensive care unit/intermediate care unit (ICU/IMC) treatment (OR 1.2). The head was the body region most often injured (32.6%) and operated (32.9%). Patients with head injuries had the highest odds for being hospitalised (OR 6.13). Head or trunk injuries lead to the highest odds for an ICU/IMC treatment (head: OR 4.37; trunk: OR 2.47). Upper and lower limb injuries showed the highest odds for a surgical therapy (upper limb: OR 2.61; lower limb: OR 1.7). Conclusion: Risk prevention programmes should include older individuals and males as target groups. Thus a rethinking of the overall risk assessment is necessary. Not only horseback riding itself, but also handling a horse bears a relevant risk for major injuries. Serious head injures remain frequent, serious and an important issue to be handled in equestrians sports.
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    Modulation of Chemokine- and Adhesion-Molecule Gene Expression and Recruitment of Neutrophil Granulocytes in Rat and Mouse Liver after a Single Gadolinium Chloride or Zymosan Treatment 

    Ahmad, Shakil; Ramadori, Giuliano; Moriconi, Federico
    International Journal of Molecular Sciences 2018; 19(12): Art. 3891
    Kupffer cells are professional phagocytes of the liver clearing bacteria from portal blood. Their clearance capacity, however, can be overwhelmed, transforming them into critical mediators of hepatic-injury. We investigated the consequences of selective Kupffer cell-overload by intraperitoneally administering pyrogen-free gadolinium chloride (GdCl3) or Zymosan into rats and into endotoxin-resistant mice (C3H/HeJ). The number of myeloperoxidase-positive (MPO+) cells increased at 3 h mainly around the portal vessel after both GdCl3 and Zymosan treatment. Simultaneously, GdCl3 administration reduced detectability of ED-1+ (but not ED-2) cells near the portal vessel. Serum chemokine (C-X-C motif) ligand 1 (CXCL-1), CXCL-2 and chemokine (C-C motif) ligand 2 (CCL-2) showed a peak at 3 h after both treatment regimens although at a higher extent after Zymosan administration. Accordingly, CXCL-1, CXCL-5 and CCL-2 gene expression in the liver was up-regulated after GdCl3 treatment at 3 h. After Zymosan administration a significant up-regulation of CXCL-1, CXCL-2, CXCL-10, CCL-2, CCL-3 and CCL-20 gene expression in liver at 3 h was observed. After Zymosan administration intracellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) gene expression was up-regulated in rat liver tissue. In C3H/HeJ mice both treatment regimens up-regulated CCL-2 and ICAM-1 gene expression after 3 h and down-regulated platelet endothelial cell adhesion molecule 1 (PECAM-1) gene expression. In conclusion, phagocytosis overload of Kupffer cells causes induction of several CXC, CC-chemokines, upregulation of “positive” adhesion molecule gene expression, down-regulation of the “negative” adhesion molecule PECAM-1 and a recruitment of neutrophil granulocytes in the portal area of the liver of treated rats and mice mainly in close contact to the liver macrophages.
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    Cognitive Control Over Visual Motion Processing – Are Children With ADHD Especially Compromised? A Pilot Study of Flanker Task Event-Related Potentials 

    Lange-Malecki, Bettina; Treue, Stefan; Rothenberger, Aribert; Albrecht, Björn
    Frontiers in Human Neuroscience 2018; 12: Art. 491
    Performance deficits and diminished brain activity during cognitive control and error processing are frequently reported in attention deficit/hyperactivity disorder (ADHD), indicating a “top-down” deficit in executive attention. So far, these findings are almost exclusively based on the processing of static visual forms, neglecting the importance of visual motion processing in everyday life as well as important attentional and neuroanatomical differences between processing static forms and visual motion. For the current study, we contrasted performance and electrophysiological parameters associated with cognitive control from two Flanker-Tasks using static stimuli and moving random dot patterns. Behavioral data and event-related potentials were recorded from 16 boys with ADHD (combined type) and 26 controls (aged 8–15 years). The ADHD group showed less accuracy especially for moving stimuli, and prolonged response times for both stimulus types. Analyses of electrophysiological parameters of cognitive control revealed trends for diminished N2-enhancements and smaller error-negativities (indicating medium effect sizes), and we detected significantly lower error positivities (large effect sizes) compared to controls, similarly for both static and moving stimuli. Taken together, the study supports evidence that motion processing is not fully developed in childhood and that the cognitive control deficit in ADHD is of higher order and independent of stimulus type.
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    Workshop on Germ Cells 

    Dosch, Roland
    Frontiers in Cell and Developmental Biology 2018; 6: Art. 157
    Germ cell research in vertebrates has traditionally been challenging, but recent breakthroughs have overcome technical difficulties, demonstrating and expanding the power of the zebrafish experimental system for their analysis in vivo. Exploiting the transparency of the zebrafish embryo, germ cell migration was the first topic that moved the germ cells of this organism into the spotlight of modern research. In recent years, research on teleost germ cells has expanded into additional fields, manifested by a session dedicated to this cell type at the European Zebrafish PI meeting in Trento.
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    Prophylactic Palmitoylethanolamide Prolongs Survival and Decreases Detrimental Inflammation in Aged Mice With Bacterial Meningitis 

    Heide, Ev Christin; Bindila, Laura; Post, Julia Maria; Malzahn, Dörthe; Lutz, Beat; Seele, Jana; Nau, Roland; Ribes, Sandra
    Frontiers in Immunology 2018; 9: Art. 2671
    Easy-to-achieve interventions to promote healthy longevity are desired to diminish the incidence and severity of infections, as well as associated disability upon recovery. The dietary supplement palmitoylethanolamide (PEA) exerts anti-inflammatory and neuroprotective properties. Here, we investigated the effect of prophylactic PEA on the early immune response, clinical course, and survival of old mice after intracerebral E. coli K1 infection. Nineteen-month-old wild type mice were treated intraperitoneally with two doses of either 0.1 mg PEA/kg in 250 μl vehicle solution (n = 19) or with 250 μl vehicle solution only as controls (n = 19), 12 h and 30 min prior to intracerebral E. coli K1 infection. The intraperitoneal route was chosen to reduce distress in mice and to ensure exact dosing. Survival time, bacterial loads in cerebellum, blood, spleen, liver, and microglia counts and activation scores in the brain were evaluated. We measured the levels of IL-1β, IL-6, MIP-1α, and CXCL1 in cerebellum and spleen, as well as of bioactive lipids in serum in PEA- and vehicle-treated animals 24 h after infection. In the absence of antibiotic therapy, the median survival time of PEA-pre-treated infected mice was prolonged by 18 h compared to mice of the vehicle-pre-treated infected group (P = 0.031). PEA prophylaxis delayed the onset of clinical symptoms (P = 0.037). This protective effect was associated with lower bacterial loads in the spleen, liver, and blood compared to those of vehicle-injected animals (P ≤ 0.037). PEA-pre-treated animals showed diminished levels of pro-inflammatory cytokines and chemokines in spleen 24 h after infection, as well as reduced serum concentrations of arachidonic acid and of one of its metabolites, 20-hydroxyeicosatetraenoic acid. In the brain, prophylactic PEA tended to reduce bacterial titers and attenuated microglial activation in aged infected animals (P = 0.042). Our findings suggest that prophylactic PEA can counteract infection associated detrimental responses in old animals. Accordingly, PEA treatment slowed the onset of infection symptoms and prolonged the survival of old infected mice. In a clinical setting, prophylactic administration of PEA might extend the potential therapeutic window where antibiotic therapy can be initiated to rescue elderly patients.
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    Pantoprazole Does not Affect Serum Trough Levels of Tacrolimus and Everolimus in Liver Transplant Recipients 

    Bremer, Sebastian C. B.; Reinhardt, Lars; Sobotta, Michael; Hasselluhn, Marie C.; Lorf, Thomas; Ellenrieder, Volker; Schwörer, Harald
    Frontiers in Medicine 2018; 5: Art. 320
    Background: Liver transplant recipients are frequently treated with proton pump inhibitors. Drug interactions have been described especially with respect to omeprazole. Due to the lower binding capacity of pantoprazole to CYP2C19 this drug became preferred and became the most used proton pump inhibitor in Germany. The data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients a very scarce. Methods: The authors performed a single center analysis in liver transplant recipients on the effect of pantoprazole on the serum trough levels of different immunosuppressants. The trough levels were compared over a period of 1 year before and after start or stop of a continuous oral co-administration of 40 mg pantoprazole once daily. Results: The serum trough levels of tacrolimus (n = 30), everolimus (n = 7), or sirolimus (n = 3) remain constant during an observation period of at least 1 year before and after co-administration of pantoprazole. None of the included patients needed a change of dosage of the observed immunosuppressants during the observation period. Conclusions: The oral co-administration of pantoprazole is safe in immunosuppressed liver transplant recipients according to the serum trough levels of tacrolimus, everolimus, and sirolimus. This analysis provides first data on the influence of pantoprazole on immunosuppressive drugs in liver transplant recipients.
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    Modifications of Surgical Suction Tip Geometry for Flow Optimisation: Influence on Suction-Induced Noise Pollution 

    Friedrich, M. G.; Tirilomis, T.; Kollmeier, J. M.; Wang, Y.; Hanekop, G. G.
    Surgery Research and Practice 2018; 2018 p.1-8
    Introduction. Suction devices for clearing the surgical field are among the most commonly used tools of every surgeon because a better view of the surgical field is essential. Forced suction may produce disturbingly loud noise, which acts as a nonnegligible stressor. Especially, in emergency situations with heavy bleeding, this loud noise has been described as an impeding factor in the medical decision-making process. In addition, there are reports of inner ear damage in patients due to suction noises during operations in the head area. These problems have not been solved yet. The purpose of this study was to analyse flow-dependent suction noise effects of different surgical suction tips. Furthermore, we developed design improvements to these devices. Methods. We compared five different geometries of suction tips using an in vitro standardised setup. Two commercially available standard suction tips were compared to three adapted new devices regarding their flow-dependent (10–2000 mL/min) noise emission (dB, weighting filter (A), distance 10 cm) and acoustic quality of resulting noises (Hamilton fast Fourier analysis) during active suction at the liquid-air boundary. Noise maps at different flow rates were created for all five suction devices, and the proportion of extracted air was measured. The geometries of the three custom-made suction tips (new models 1, 2, and 3) were designed considering the insights after determining the key characteristics of the two standard suction models. Results. The geometry of a suction device tip has significant impact on its noise emission. For the standard models, the frequency spectrum at higher flow rates significantly changes to high-frequency noise patterns (>3 kHz). A number of small side holes designed to prevent tissue adhesion lead to increased levels of high-frequency noise. Due to modifications of the tip geometry in our new models, we are able to achieve a highly significant reduction of noise level at low flow rates (new model 2 vs. standard models ) and also the acoustic quality improved. Additionally, we attain a highly significant reduction of secondary air intake (new model 2 vs. the other models ). Conclusion. Improving flow-relevant features of the geometry of suction heads is a suitable way to reduce noise emissions. Optimized suction tips are significantly quieter. This may help us to reduce noise-induced hearing damage in patients as well as stress of medical staff during surgery and should lead to quieter operation theatres overall. Furthermore, the turbulence reduction and reduced secondary air intake during the suction process are expected to result in protective effects on the collected blood and thus could improve the quality of autologous blood retransfusions. We are on the way to evaluate potential benefits.
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    CD8+-T Cells With Specificity for a Model Antigen in Cardiomyocytes Can Become Activated After Transverse Aortic Constriction but Do Not Accelerate Progression to Heart Failure 

    Gröschel, Carina; Sasse, André; Monecke, Sebastian; Röhrborn, Charlotte; Elsner, Leslie; Didié, Michael; Reupke, Verena; Bunt, Gertrude; Lichtman, Andrew H.; Toischer, Karl; et al.
    Zimmermann, Wolfram-HubertusHasenfuß, GerdDressel, Ralf
    Frontiers in Immunology 2018; 9: Art. 2665
    Heart failure due to pressure overload is frequently associated with inflammation. In addition to inflammatory responses of the innate immune system, autoimmune reactions of the adaptive immune system appear to be triggered in subgroups of patients with heart failure as demonstrated by the presence of autoantibodies against myocardial antigens. Moreover, T cell-deficient and T cell-depleted mice have been reported to be protected from heart failure induced by transverse aortic constriction (TAC) and we have shown recently that CD4+-helper T cells with specificity for an antigen in cardiomyocytes accelerate TAC-induced heart failure. In this study, we set out to investigate the potential contribution of CD8+-cytotoxic T cells with specificity to a model antigen (ovalbumin, OVA) in cardiomyocytes to pressure overload-induced heart failure. In 78% of cMy-mOVA mice with cardiomyocyte-specific OVA expression, a low-grade OVA-specific cellular cytotoxicity was detected after TAC. Adoptive transfer of OVA-specific CD8+-T cells from T cell receptor transgenic OT-I mice before TAC did not increase the risk of OVA-specific autoimmunity in cMy-mOVA mice. After TAC, again 78% of the mice displayed an OVA-specific cytotoxicity with on average only a three-fold higher killing of OVA-expressing target cells. More CD8+ cells were present after TAC in the myocardium of cMy-mOVA mice with OT-I T cells (on average 17.5/mm2) than in mice that did not receive OVA-specific CD8+-T cells (3.6/mm2). However, the extent of fibrosis was similar in both groups. Functionally, as determined by echocardiography, the adoptive transfer of OVA-specific CD8+-T cells did not significantly accelerate the progression from hypertrophy to heart failure in cMy-mOVA mice. These findings argue therefore against a major impact of cytotoxic T cells with specificity for autoantigens of cardiomyocytes in pressure overload-induced heart failure.
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