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    Using phase II data for the analysis of phase III studies: An application in rare diseases. 

    Wandel, Simon; Neuenschwander, Beat; Röver, Christian; Friede, Tim
    Clinical trials (London, England) 2017-06; 14(3) p.277-285
    BACKGROUND: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. METHODS: A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. RESULTS: An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. CONCLUSION: To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.
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    Atrial fibrillation in retinal vascular occlusion disease and non-arteritic anterior ischemic optic neuropathy. 

    Callizo, Josep; Feltgen, Nicolas; Ammermann, Antje; Ganser, Janina; Bemme, Sebastian; Bertelmann, Thomas; Pfeiffer, Sebastian; Duvinage, Andre; Gröschel, Klaus; Hoerauf, Hans; et al.
    Wachter, Rolf
    PloS one 2017; 12(8): Art. e0181766
    BACKGROUND: Patients with retinal vascular occlusion disease have an increased risk for ischemic stroke and share some risk factors with cerebrovascular disease. The purpose of this study was to analyze the prevalence of atrial fibrillation (AF) in subjects with retinal vascular occlusive disease and anterior ischemic optic neuropathy and to compare these data to an ischemic stroke group. METHODS: Prospective, observational single-center trial. Subjects with retinal artery occlusion (RAO), retinal vein occlusion (RVO) and anterior ischemic optic neuropathy (AION) were included. Patients with ischemic stroke (IS) from a previous observational trial were used as control. Investigation included 7-day Holter ECG, echocardiography, duplex ultrasonography of the carotid arteries, and 24-hour blood pressure monitoring. Further vascular risk factors were documented. RESULTS: During the 1-year study period, 101 patients were recruited. The control group with ischemic stroke consisted of 272 subjects. At inclusion, the prevalence of AF was 12% (RAO), 10.2% (RVO), 11.1% (NAION) and 15.8% (IS). The final prevalence after Holter ECG rose to 16% (RAO), 18.4% (RVO), 14.8% (NAION) and 26.5% (IS). No significant difference was measured between groups. CONCLUSIONS: We detected a similar prevalence of AF in all groups. RVO patients tended to exhibit a higher AF detection rate and lower number needed to screen than RAO and NAION. The detection of AF rose considerably via Holter ECG. As a consequence, we recommend prolonged ECG monitoring in patients with acute ophthalmic vascular diseases.
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    Anodal tDCS Over the Left DLPFC Did Not Affect the Encoding and Retrieval of Verbal Declarative Information 

    Lara, Gabriel A. de; Knechtges, Philipp N.; Paulus, Walter; Antal, Andrea
    Frontiers in Neuroscience 2017; 11: Art. 452
    Several studies imply that anodal transcranial direct current stimulation (tDCS) over the left dorsolateral prefrontal cortex (DLPFC) can modulate the formation of verbal episodic memories. The aim of this study was to test if tDCS through a multi-electrode Laplacian montage over the left DLPFC could differentially modulate declarative memory performance depending on the application phase. Two groups of healthy participants (n = 2 × 15) received 1mA anodal or sham stimulation for 20min during the encoding or during the recall phase on a delayed cued-recall, using a randomized, double-blinded, repeated-measures experimental design. Memory performance was assessed at two time points: 10min and 24 h after learning. We found no significant difference between anodal and sham stimulation with regard to the memory scores between conditions (stimulation during encoding or recall) or between time points, suggesting that anodal tDCS over the left DLPFC with these stimulation parameters had no effect on the encoding and the consolidation of associative verbal content.
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    Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders 

    Sokpor, Godwin; Xie, Yuanbin; Rosenbusch, Joachim; Tuoc, Tran
    Frontiers in Molecular Neuroscience 2017; 10: Art. 243
    The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra’s syndrome spectrum, Hirschsprung’s disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.
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    The Role of Peripheral CNS-Directed Antibodies in Promoting Inflammatory CNS Demyelination. 

    Kinzel, Silke; Weber, Martin S
    Brain sciences 2017-06-22; 7(7)
    In central nervous system (CNS) demyelinating disorders, such as multiple sclerosis (MS), neuromyelitis optica (NMO) and related NMO-spectrum disorders (NMO-SD), a pathogenic role for antibodies is primarily projected into enhancing ongoing CNS inflammation by directly binding to target antigens within the CNS. This scenario is supported at least in part, by antibodies in conjunction with complement activation in the majority of MS lesions and by deposition of anti-aquaporin-4 (AQP-4) antibodies in areas of astrocyte loss in patients with classical NMO. A currently emerging subgroup of AQP-4 negative NMO-SD patients expresses antibodies against myelin oligodendrocyte glycoprotein (MOG), again suggestive of their direct binding to CNS myelin. However, both known entities of anti-CNS antibodies, anti-AQP-4- as well as anti-MOG antibodies, are predominantly found in the serum, which raises the questions why and how a humoral response against CNS antigens is raised in the periphery, and in a related manner, what pathogenic role these antibodies may exert outside the CNS. In this regard, recent experimental and clinical evidence suggests that peripheral CNS-specific antibodies may indirectly activate peripheral CNS-autoreactive T cells by opsonization of otherwise unrecognized traces of CNS antigen in peripheral compartments, presumably drained from the CNS by its newly recognized lymphatic system. In this review, we will summarize all currently available data on both possible roles of antibodies in CNS demyelinating disorders, first, directly enhancing damage within the CNS, and second, promoting a peripheral immune response against the CNS. By elaborating on the latter scenario, we will develop the hypothesis that peripheral CNS-recognizing antibodies may have a powerful role in initiating acute flares of CNS demyelinating disease and that these humoral responses may represent a therapeutic target in its own right.
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    Immunological Properties of Murine Parthenogenetic Stem Cells and Their Differentiation Products 

    Johannsen, Hannah; Muppala, Vijayakumar; Gröschel, Carina; Monecke, Sebastian; Elsner, Leslie; Didié, Michael; Zimmermann, Wolfram-Hubertus; Dressel, Ralf
    Frontiers in Immunology 2017; 8: Art. 924
    The perspective to transplant grafts derived from pluripotent stem cells has gained much attention in recent years. Parthenogenetic stem cells (PSCs) are an alternative pluripotent stem cell type that is attractive as source of grafts for allogeneic transplantations because most PSCs are haploidentical for the major histocompatibility complex (MHC). This reduced immunogenetic complexity of PSCs could tremendously simplify the search for MHC-matched allogeneic stem cells. In this study, we have characterized immunological properties of the MHC haploidentical PSC line A3 (H2d/d) and the heterologous PSC line A6 (H2b/d). Both PSC lines largely lack MHC class I molecules, which present peptides to cytotoxic T lymphocytes (CTLs) and serve as ligands for inhibitory natural killer (NK) receptors. They express ligands for activating NK receptors, including the NKG2D ligand RAE-1, and the DNAM-1 ligands CD112 and CD155. Consequently, both PSC lines are highly susceptible to killing by IL-2-activated NK cells. In vitro-differentiated cells acquire resistance and downregulate ligands for activating NK receptors but fail to upregulate MHC class I molecules. The PSC line A6 and differentiated A6 cells are largely resistant to CTLs derived from T cell receptor transgenic OT-I mice after pulsing of the targets with the appropriate peptide. The high susceptibility to killing by activated NK cells may constitute a general feature of pluripotent stem cells as it has been also found with other pluripotent stem cell types. This activity potentially increases the safety of transplantations, if grafts contain traces of undifferentiated cells that could be tumorigenic in the recipient.
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    The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis 

    Gründker, Carsten; Emons, Günter
    Frontiers in Endocrinology 2017; 8: Art. 187
    In several human malignant tumors of the urogenital tract, including cancers of the endometrium, ovary, urinary bladder, and prostate, it has been possible to identify expression of gonadotropin-releasing hormone (GnRH) and its receptor as part of an autocrine system, which regulates cell proliferation. The expression of GnRH receptor has also been identified in breast cancers and non-reproductive cancers such as pancreatic cancers and glioblastoma. Various investigators have observed dose- and timedependent growth inhibitory effects of GnRH agonists in cell lines derived from these cancers. GnRH antagonists have also shown marked growth inhibitory effects on most cancer cell lines. This indicates that in the GnRH system in cancer cells, there may not be a dichotomy between GnRH agonists and antagonists. The well-known signaling mechanisms of the GnRH receptor, which are present in pituitary gonadotrophs, are not involved in forwarding the antiproliferative effects of GnRH analogs in cancer cells. Instead, the GnRH receptor activates a phosphotyrosine phosphatase (PTP) and counteracts with the mitogenic signal transduction of growth factor receptors, which results in a reduction of cancer cell proliferation. The PTP activation, which is induced by GnRH, also inhibits G-protein-coupled estrogen receptor 1 (GPER), which is a membrane- bound receptor for estrogens. GPER plays an important role in breast cancers, which do not express the estrogen receptor α (ERα). In metastatic breast, ovarian, and endometrial cancer cells, GnRH reduces cell invasion in vitro, metastasis in vivo, and the increased expression of S100A4 and CYR61. All of these factors play important roles in epithelial–mesenchymal transition. This review will summarize the present state of knowledge about the GnRH receptor and its signaling in human cancers.
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    Efficient Killing of Murine Pluripotent Stem Cells by Natural Killer (NK) Cells Requires Activation by Cytokines and Partly Depends on the Activating NK Receptor NKG2D 

    Gröschel, Carina; Hübscher, Daniela; Nolte, Jessica; Monecke, Sebastian; Sasse, André; Elsner, Leslie; Paulus, Walter; Trenkwalder, Claudia; Polić, Bojan; Mansouri, Ahmed; et al.
    Guan, KaomeiDressel, Ralf
    Frontiers in Immunology 2017; 8: Art. 870
    Natural killer (NK) cells play an important role as cytotoxic effector cells, which scan the organism for infected or tumorigenic cells. Conflicting data have been published whether NK cells can also kill allogeneic or even autologous pluripotent stem cells (PSCs) and which receptors are involved. A clarification of this question is relevant since an activity of NK cells against PSCs could reduce the risk of teratoma growth after transplantation of PSC-derived grafts. Therefore, the hypothesis has been tested that the activity of NK cells against PSCs depends on cytokine activation and specifically on the activating NK receptor NKG2D. It is shown that a subcutaneous injection of autologous iPSCs failed to activate NK cells against these iPSCs and can give rise to teratomas. In agreement with this result, several PSC lines, including two iPSC, two embryonic stem cell (ESC), and two so-called multipotent adult germline stem cell (maGSC) lines, were largely resistant against resting NK cells although differences in killing were found at low level. All PSC lines were killed by interleukin (IL)-2-activated NK cells, and maGSCs were better killed than the other PSC types. The PSCs expressed ligands of the activating NK receptor NKG2D and NKG2D-deficient NK cells from Klrk1−/− mice were impaired in their cytotoxic activity against PSCs. The low-cytotoxic activity of resting NK cells was almost completely dependent on NKG2D. The cytotoxic activity of IL-2-activated NKG2D-deficient NK cells against PSCs was reduced, indicating that also other activating receptors on cytokine-activated NK cells must be engaged by ligands on PSCs. Thus, NKG2D is an important activating receptor involved in killing of murine PSCs. However, NK cells need to be activated by cytokines before they efficiently target PSCs and then also other NK receptors become relevant. These features of NK cells might be relevant for transplantation of PSC-derived grafts since NK cells have the capability to kill undifferentiated cells, which might be present in grafts in trace amounts.
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    MPA Modulates Tight Junctions' Permeability via Midkine/PI3K Pathway in Caco-2 Cells: A Possible Mechanism of Leak-Flux Diarrhea in Organ Transplanted Patients. 

    Khan, Niamat; Binder, Lutz; Pantakani, D. V. Krishna; Asif, Abdul R.
    Frontiers in physiology 2017; 8: Art. 438
    Mycophenolic acid (MPA) is prescribed to prevent allograft rejection in organ transplanted patients. However, its use is sporadically linked to leak flux diarrhea and other gastrointestinal (GI) disturbances in around 75% of patients through yet unknown mechanisms. Recently, we identified Midkine as a modulator of tight junctions (TJs) permeability in MPA treated Caco-2 monolayer. In the present study, we investigated the possible involvement of Midkine dependent PI3K pathway in alteration of TJs under MPA treatment. Caco-2 cells were grown as monolayer to develop TJs and were treated for 72 h with DMSO (control) or MPA in presence and absence of Midkine inhibitor (iMDK) or PI3K inhibitors (LY/AMG). Caco-2 monolayer integrity was assessed by transepithelial electrical resistance (TEER) and FITC-dextran assays. Our functional assays showed that PI3K inhibitors (LY/AMG) can significantly inhibit the compromised TJs integrity of MPA-treated Caco-2 cells monolayer. Chromatin immunoprecipitation analyses showed a significant epigenetic activation of Midkine, PI3K, Cdx-2, and Cldn-2 genes and epigenetic repression of Cldn-1 gene after MPA treatment. The MPA-induced epigenetic alterations were further confirmed by mRNA and protein expression analysis. Collectively, our data shows that PI3K pathway as the downstream target of Midkine which in turn modulates p38MAPK and pAKT signaling to alter TJs permeability in Caco-2 cell monolayers treated with MPA. These results highlight the possible use of either Midkine or PI3K inhibitors as therapeutic agents to prevent MPA induced GI disturbances.
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    More Pathogenicity or Just More Pathogens?-On the Interpretation Problem of Multiple Pathogen Detections with Diagnostic Multiplex Assays. 

    Zautner, Andreas E.; Groß, Uwe; Emele, Matthias F.; Hagen, Ralf M.; Frickmann, Hagen
    Frontiers in microbiology 2017; 8: Art. 1210
    Modern molecular diagnostic approaches in the diagnostic microbiological laboratory like real-time quantitative polymerase chain reaction (qPCR) have led to a considerable increase of diagnostic sensitivity. They usually outperform the diagnostic sensitivity of culture-based approaches. Culture-based diagnostics were found to be insufficiently sensitive for the assessment of the composition of biofilms in chronic wounds and poorly standardized for screenings for enteric colonization with multi-drug resistant bacteria. However, the increased sensitivity of qPCR causes interpretative challenges regarding the attribution of etiological relevance to individual pathogen species in case of multiple detections of facultative pathogenic microorganisms in primarily non-sterile sample materials. This is particularly the case in high-endemicity settings, where continuous exposition to respective microorganisms leads to immunological adaptation and semi-resistance while considerable disease would result in case of exposition of a non-adapted population. While biofilms in chronic wounds show higher pathogenic potential in case of multi-species composition, detection of multiple pathogens in respiratory samples is much more difficult to interpret and asymptomatic enteric colonization with facultative pathogenic microorganisms is frequently observed in high endemicity settings. For respiratory samples and stool samples, cycle-threshold-value-based semi-quantitative interpretation of qPCR results has been suggested. Etiological relevance is assumed if cycle-threshold values are low, suggesting high pathogen loads. Although the procedure is challenged by lacking standardization and methodical issues, first evaluations have led to promising results. Future studies should aim at generally acceptable quantitative cut-off values to allow discrimination of asymptomatic colonization from clinically relevant infection.
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    A cross-cultural analysis of posthumous reproduction: The significance of the gender and margins-of-life perspectives 

    Hashiloni-Dolev, Yael; Schicktanz, Silke
    Reproductive Biomedicine & Society Online 2017; 4 p.21-32
    The scholarly discussion of posthumous reproduction (PHR) focuses on informed consent and the welfare of the future child, for the most part overlooking cultural differences between societies. Based on a cross-cultural comparison of legal and regulatory documents, analysis of pivotal cases and study of scholarly and media discussions in Israel and Germany, this paper analyses the relevant ethical and policy issues, and questions how cultural differences shape the practice of PHR. The findings challenge the common classifications of PHR by highlighting the gender perspective and adding brain-dead pregnant women to the debate. Based on this study’s findings, four neglected cultural factors affecting social attitudes towards PHR are identified: (i) the relationship between the pregnant woman and her future child; (ii) what constitutes the beginning of life; (iii) what constitutes dying; and (iv) the social agent(s) seeking to have the future child. The paper argues that PHR can be better understood by adding the gender and margins-of-life perspectives, and that future ethical and practical discussions of this issue could benefit from the criteria emerging from this cross-cultural analysis.
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    Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model. 

    Hüttenrauch, M; Brauß, A; Kurdakova, A; Borgers, H; Klinker, F; Liebetanz, D; Salinas-Riester, G; Wiltfang, J; Klafki, H W; Wirths, O
    Translational psychiatry 2016-05-03; 6: Art. e800
    The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress Aβ4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia.
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    Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study. 

    Carreras-Torres, Robert; Johansson, Mattias; Haycock, Philip C.; Wade, Kaitlin H.; Relton, Caroline L.; Martin, Richard M.; Davey Smith, George; Albanes, Demetrius; Aldrich, Melinda C.; Andrew, Angeline; et al.
    Arnold, Susanne M.Bickeböller, HeikeBojesen, Stig E.Brunnström, HansManjer, JonasBrüske, IreneCaporaso, Neil E.Chen, ChuChristiani, David C.Christian, W. JayDoherty, Jennifer A.Duell, Eric J.Field, John K.Davies, Michael P. A.Marcus, Michael W.Goodman, Gary E.Grankvist, KjellHaugen, AageHong, Yun-ChulKiemeney, Lambertus A.van der Heijden, Erik H. F. M.Kraft, PeterJohansson, Mikael B.Lam, StephenLandi, Maria TeresaLazarus, PhilipLe Marchand, LoïcLiu, GeoffreyMelander, OllePark, Sungshim L.Rennert, GadRisch, AngelaHaura, Eric B.Scelo, GhislaineZaridze, DavidMukeriya, AnushSavić, MilanLissowska, JolantaSwiatkowska, BeataJanout, VladimirHolcatova, IvanaMates, DanaSchabath, Matthew B.Shen, HongbingTardon, AdoninaTeare, M. DawnWoll, PenellaTsao, Ming-SoundWu, XifengYuan, Jian-MinHung, Rayjean J.Amos, Christopher I.McKay, JamesBrennan, Paul
    PloS one 2017; 12(6): Art. e0177875
    BACKGROUND: Assessing the relationship between lung cancer and metabolic conditions is challenging because of the confounding effect of tobacco. Mendelian randomization (MR), or the use of genetic instrumental variables to assess causality, may help to identify the metabolic drivers of lung cancer. METHODS AND FINDINGS: We identified genetic instruments for potential metabolic risk factors and evaluated these in relation to risk using 29,266 lung cancer cases (including 11,273 adenocarcinomas, 7,426 squamous cell and 2,664 small cell cases) and 56,450 controls. The MR risk analysis suggested a causal effect of body mass index (BMI) on lung cancer risk for two of the three major histological subtypes, with evidence of a risk increase for squamous cell carcinoma (odds ratio (OR) [95% confidence interval (CI)] = 1.20 [1.01-1.43] and for small cell lung cancer (OR [95%CI] = 1.52 [1.15-2.00]) for each standard deviation (SD) increase in BMI [4.6 kg/m2]), but not for adenocarcinoma (OR [95%CI] = 0.93 [0.79-1.08]) (Pheterogeneity = 4.3x10-3). Additional analysis using a genetic instrument for BMI showed that each SD increase in BMI increased cigarette consumption by 1.27 cigarettes per day (P = 2.1x10-3), providing novel evidence that a genetic susceptibility to obesity influences smoking patterns. There was also evidence that low-density lipoprotein cholesterol was inversely associated with lung cancer overall risk (OR [95%CI] = 0.90 [0.84-0.97] per SD of 38 mg/dl), while fasting insulin was positively associated (OR [95%CI] = 1.63 [1.25-2.13] per SD of 44.4 pmol/l). Sensitivity analyses including a weighted-median approach and MR-Egger test did not detect other pleiotropic effects biasing the main results. CONCLUSIONS: Our results are consistent with a causal role of fasting insulin and low-density lipoprotein cholesterol in lung cancer etiology, as well as for BMI in squamous cell and small cell carcinoma. The latter relation may be mediated by a previously unrecognized effect of obesity on smoking behavior.
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    Revisiting the co-existence of Attention-Deficit/Hyperactivity Disorder and Chronic Tic Disorder in childhood-The case of colour discrimination, sustained attention and interference control. 

    Uebel-von Sandersleben, Henrik; Albrecht, Björn; Rothenberger, Aribert; Fillmer-Heise, Anke; Roessner, Veit; Sergeant, Joseph; Tannock, Rosemary; Banaschewski, Tobias
    PloS one 2017; 12(6): Art. e0178866
    OBJECTIVE: Attention Deficit / Hyperactivity Disorder (ADHD) and Chronic Tic Disorder (CTD) are two common and frequently co-existing disorders, probably following an additive model. But this is not yet clear for the basic sensory function of colour processing sensitive to dopaminergic functioning in the retina and higher cognitive functions like attention and interference control. The latter two reflect important aspects for psychoeducation and behavioural treatment approaches. METHODS: Colour discrimination using the Farnsworth-Munsell 100-hue Test, sustained attention during the Frankfurt Attention Inventory (FAIR), and interference liability during Colour- and Counting-Stroop-Tests were assessed to further clarify the cognitive profile of the co-existence of ADHD and CTD. Altogether 69 children were classified into four groups: ADHD (N = 14), CTD (N = 20), ADHD+CTD (N = 20) and healthy Controls (N = 15) and compared in cognitive functioning in a 2×2-factorial statistical model. RESULTS: Difficulties with colour discrimination were associated with both ADHD and CTD factors following an additive model, but in ADHD these difficulties tended to be more pronounced on the blue-yellow axis. Attention problems were characteristic for ADHD but not CTD. Interference load was significant in both Colour- and Counting-Stroop-Tests and unrelated to colour discrimination. Compared to Controls, interference load in the Colour-Stroop was higher in pure ADHD and in pure CTD, but not in ADHD+CTD, following a sub-additive model. In contrast, interference load in the Counting-Stroop did not reveal ADHD or CTD effects. CONCLUSION: The co-existence of ADHD and CTD is characterized by additive as well as sub-additive performance impairments, suggesting that their co-existence may show simple additive characteristics of both disorders or a more complex interaction, depending on demand. The equivocal findings on interference control may indicate limited validity of the Stroop-Paradigm for clinical assessments.
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    Integrating Tenascin-C protein expression and 1q25 copy number status in pediatric intracranial ependymoma prognostication: A new model for risk stratification. 

    Andreiuolo, Felipe; Le Teuff, Gwénaël; Bayar, Mohamed Amine; Kilday, John-Paul; Pietsch, Torsten; von Bueren, André O.; Witt, Hendrik; Korshunov, Andrey; Modena, Piergiorgio; Pfister, Stefan M.; et al.
    Pagès, MélanieCastel, DavidGiangaspero, FeliceChimelli, LeilaVarlet, PascaleRutkowski, StefanFrappaz, DidierMassimino, MauraGrundy, RichardGrill, Jacques
    PloS one 2017; 12(6): Art. e0178351
    PURPOSE: Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. EXPERIMENTAL DESIGN: This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. RESULTS: Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. CONCLUSION: Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.
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    Human cyclophilin 40 unravels neurotoxic amyloids. 

    Baker, Jeremy D.; Shelton, Lindsey B.; Zheng, Dali; Favretto, Filippo; Nordhues, Bryce A.; Darling, April; Sullivan, Leia E.; Sun, Zheying; Solanki, Parth K.; Martin, Mackenzie D.; et al.
    Suntharalingam, AmirthaaSabbagh, Jonathan J.Becker, StefanMandelkow, EckhardUversky, Vladimir N.Zweckstetter, MarkusDickey, Chad A.Koren, JohnBlair, Laura J.
    PLoS biology 2017-06; 15(6): Art. e2001336
    The accumulation of amyloidogenic proteins is a pathological hallmark of neurodegenerative disorders. The aberrant accumulation of the microtubule associating protein tau (MAPT, tau) into toxic oligomers and amyloid deposits is a primary pathology in tauopathies, the most common of which is Alzheimer's disease (AD). Intrinsically disordered proteins, like tau, are enriched with proline residues that regulate both secondary structure and aggregation propensity. The orientation of proline residues is regulated by cis/trans peptidyl-prolyl isomerases (PPIases). Here we show that cyclophilin 40 (CyP40), a PPIase, dissolves tau amyloids in vitro. Additionally, CyP40 ameliorated silver-positive and oligomeric tau species in a mouse model of tau accumulation, preserving neuronal health and cognition. Nuclear magnetic resonance (NMR) revealed that CyP40 interacts with tau at sites rich in proline residues. CyP40 was also able to interact with and disaggregate other aggregating proteins that contain prolines. Moreover, CyP40 lacking PPIase activity prevented its capacity for disaggregation in vitro. Finally, we describe a unique structural property of CyP40 that may permit disaggregation to occur in an energy-independent manner. This study identifies a novel human protein disaggregase and, for the first time, demonstrates its capacity to dissolve intracellular amyloids.
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    Morgagnian cataract resulting from a naturally occurring nonsense mutation elucidates a role of CPAMD8 in mammalian lens development. 

    Hollmann, Anne K.; Dammann, Insa; Wemheuer, Wiebke M.; Wemheuer, Wilhelm E.; Chilla, Almuth; Tipold, Andrea; Schulz-Schaeffer, Walter J.; Beck, Julia; Schütz, Ekkehard; Brenig, Bertram
    PloS one 2017; 12(7): Art. e0180665
    To investigate the genetic basis of hereditary lens opacities we analyzed 31 cases of bilateral congenital cataract in Red Holstein Friesian cattle. A genome-wide association study revealed a significant association on bovine chromosome 7 at positions 6,166,179 and 12,429,691. Whole genome re-sequencing of one case and four relatives showed a nonsense mutation (g.5995966C>T) in the PZP-like, alpha-2-macroglobulin domain containing 8 (CPAMD8) gene leading to a premature stop codon (CPAMD8 p.Gln74*) associated with cataract development in cattle. With immunohistochemistry we confirmed a physiological expression of CPAMD8 in the ciliary body epithelium of the eye in unaffected cattle, while the protein was not detectable in the ciliary body of cattle with cataracts. RNA expression of CPAMD8 was detected in healthy adult, fetal and cataractous lenses.
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    Patient-reported outcomes and survival in multiple sclerosis: A 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale-29. 

    Raffel, Joel; Wallace, Alison; Gveric, Djordje; Reynolds, Richard; Friede, Tim; Nicholas, Richard
    PLoS medicine 2017-07; 14(7): Art. e1002346
    BACKGROUND: There is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases. The Multiple Sclerosis Impact Scale-29 (MSIS-29) is a PRO sensitive to short-term change in MS, with questions covering both physical and psychological quality of life. This study aimed to investigate whether MSIS-29 scores can be prognostic for survival time in MS, using a large observational cohort of people with MS. METHODS AND FINDINGS: From 15 July 2004 onwards, MSIS-29 questionnaires were completed by people with MS registered with the MS Society Tissue Bank (n = 2,126, repeated 1 year later with n = 872 of the original respondents). By 2014, 264 participants (12.4%) had died. Higher baseline MSIS-29 physical (MSIS-29-PHYS) score was associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: hazard ratio [HR] 5.7, 95% CI 3.1-10.5, p < 0.001). Higher baseline MSIS-29 psychological score was also associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: HR 2.8, 95% CI 1.8-4.4, p < 0.001). In those with high baseline MSIS-29 scores, mortality risk was even greater if the MSIS-29 score worsened over 1 year (HR 2.3, 95% CI 1.2-4.4, p = 0.02). MSIS-29-PHYS scores were associated with survival time independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis (per 1-SD increase in MSIS-29-PHYS score: HR 1.8, 95% CI 1.1-2.9, p = 0.03). A limitation of the study is that this cohort had high baseline age and disability levels; the prognostic value of MSIS-29 for survival time at earlier disease stages requires further investigation. CONCLUSIONS: This study reports that PROs can be prognostic for hard clinical outcomes in neurological disease, and supports PROs as a meaningful clinical outcome for use in research and clinical settings.
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    Loss of Neuroligin3 specifically downregulates retinal GABAAα2 receptors without abolishing direction selectivity. 

    Hoon, Mrinalini; Krishnamoorthy, Vidhyasankar; Gollisch, Tim; Falkenburger, Bjoern; Varoqueaux, Frederique
    PloS one 2017; 12(7): Art. e0181011
    The postsynaptic adhesion proteins Neuroligins (NLs) are essential for proper synapse function, and their alterations are associated with a variety of neurodevelopmental disorders. It is increasingly clear that each NL isoform occupies specific subsets of synapses and is able to regulate the function of discrete networks. Studies of NL2 and NL4 in the retina in particular have contributed towards uncovering their role in inhibitory synapse function. In this study we show that NL3 is also predominantly expressed at inhibitory postsynapses in the retinal inner plexiform layer (IPL), where it colocalizes with both GABAA- and glycinergic receptor clusters in a 3:2 ratio. In the NL3 deletion-mutant (knockout or KO) mouse, we uncovered a dramatic reduction of the number of GABAAα2-subunit containing GABAA receptor clusters at the IPL. Retinal activity was thereafter assessed in KO and wild-type (WT) littermates by multi-electrode-array recordings of the output cells of retina, the retinal ganglion cells (RGCs). RGCs in the NL3 KO showed reduced spontaneous activity and an altered response to white noise stimulation. Moreover, upon application of light flashes, the proportion of cells firing at light offset (OFF RGCs) was significantly lower in the NL3 KO compared to WT littermates, whereas the relative number of cells firing at light onset (ON RGCs) increased. Interestingly, although GABAAα2-bearing receptors have been related to direction-selective circuits of the retina, features of direction selective-retinal ganglion cells recorded remained unperturbed in the NL3 KO. Together our data underscore the importance of NL3 for the integrity of specific GABAAergic retinal circuits and identifies NL3 as an important regulator of retinal activity.
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    Inference of neuronal functional circuitry with spike-triggered non-negative matrix factorization 

    Liu, Jian K.; Schreyer, Helene M.; Onken, Arno; Rozenblit, Fernando; Khani, Mohammad H.; Krishnamoorthy, Vidhyasankar; Panzeri, Stefano; Gollisch, Tim
    Nature Communications 2017; 8 p.1-14: Art. 149
    An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-β, a TGF-β family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-β has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined.
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