116 results on '"Goebels N"'
Search Results
2. Modified recombinant human IgG1‐Fc is superior to natural IVIG at inhibiting immune‐mediated demyelination
- Author
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Baksmeier, C, Blundell, P, Steckel, J, Schultz, V, Gu, Q, Da Silva Filipe, A, Kohl, A, Linnington, C, Lu, D, Dell, A, Haslam, S, Wang, J, Czajkowsky, D, Goebels, N, Pleass, RJ, and Biotechnology and Biological Sciences Research Council (BBSRC)
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IVIG ,qw_575 ,Science & Technology ,BLOOD ,IGG ,Immunology ,FC PORTION ,Fc multimers ,wl_140 ,IN-VITRO ,COMPLEMENT ,ANTIINFLAMMATORY ACTIVITY ,ANTIBODY ,1107 Immunology ,intravenous immunoglobulin ,hemic and lymphatic diseases ,1114 Paediatrics and Reproductive Medicine ,demyelination ,SPINAL-CORD ,BRAIN ,qw_571 ,Life Sciences & Biomedicine ,Fc monomers ,immunoglobulin - Abstract
Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Although Fc fragments derived from IVIG have shown efficacy in controlling immune thrombocytopenia (ITP) in children, the mechanisms of action are unclear and controversial. The aim of this study is to dissect IVIG effector mechanisms using further adapted Fc fragments on demyelination in an ex vivo model of the central nervous system (CNS)-immune interface. Using organotypic cerebellar slice cultures (OSC) from transgenic mice we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective effects of adapted Fc fragments were assessed by live imaging of GFP expression, immunohistochemistry and confocal microscopy. Cysteine and glycan adapted Fc fragments protected OSC from demyelination in a dose-dependent manner where equimolar concentrations of either IVIG or control Fc were ineffective. The protective effects of the adapted Fc fragments are partly attributed to interference with complement-mediated oligodendroglia damage. Transcriptome analysis ruled out signatures associated with inflammatory or innate immune responses. Taken together our findings show that recombinant biomimetics can be made that are at least two hundred-fold more effective than IVIG in controlling demyelination by anti-MOG antibodies.
- Published
- 2021
3. Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper)
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Wiendl, H., Gold, R., Berger, T., Derfuss, T., Linker, R., Mäurer, M., Aktas, O., Baum, K., Berghoff, M., Bittner, S., Chan, A., Czaplinski, A., Deisenhammer, F., Di Pauli, F., Du Pasquier, R., Enzinger, C., Fertl, E., Gass, A., Gehring, K., Gobbi, C., Goebels, N., Guger, M., Haghikia, A., Hartung, H.P., Heidenreich, F., Hoffmann, O., Kallmann, B., Kleinschnitz, C., Klotz, L., Leussink, V.I., Leutmezer, F., Limmroth, V., Lünemann, J.D., Lutterotti, A., Meuth, S.G., Meyding-Lamadé, U., Platten, M., Rieckmann, P., Schmidt, S., Tumani, H., Weber, F., Weber, M.S., Zettl, U.K., Ziemssen, T., Zipp, F., and ‘Multiple Sclerosis Therapy Consensus Group' (MSTCG)
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disease-modifying therapy ,guideline ,multiple sclerosis ,treatment recommendation - Abstract
Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).
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- 2021
4. CNS Live Imaging Reveals a New Mechanism of Myelination: The Liquid Croissant Model (P02.065)
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Goebels, N., primary, Sobottka, B., additional, Kaech, A., additional, Becher, B., additional, and Ziegler, U., additional
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- 2012
- Full Text
- View/download PDF
5. A Case of Relapsing-Remitting Neuroborreliosis? Challenges in the Differential Diagnosis of Recurrent Myelitis
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Albrecht, P., primary, Henke, N., additional, Lehmann, H.C., additional, Macht, S., additional, Hefter, H., additional, Goebels, N., additional, Mackenzie, C., additional, Rupprecht, T.A., additional, Fingerle, V., additional, Hartung, H.P., additional, and Methner, A., additional
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- 2012
- Full Text
- View/download PDF
6. 6. Diffusion tensor MRI study of the spinal cord in patients with multiple sclerosis
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von Meyenburg, J., primary, Wilm, B., additional, Weck, A., additional, Petersen, J., additional, Gallus, E., additional, Mathys, J., additional, Schätzle, E., additional, von Meyenburg, K., additional, Goebels, N., additional, and Kollias, S., additional
- Published
- 2011
- Full Text
- View/download PDF
7. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis
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Mehling, M., primary, Brinkmann, V., additional, Antel, J., additional, Bar-Or, A., additional, Goebels, N., additional, Vedrine, C., additional, Kristofic, C., additional, Kuhle, J., additional, Lindberg, R.L.P., additional, and Kappos, L., additional
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- 2008
- Full Text
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8. Therapie der multiplen Sklerose
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Bereznai, B., primary, Goebels, N., additional, Dang, T., additional, Voltz, R., additional, Walther, E., additional, Zimmermann, C., additional, and Hohlfeld, R., additional
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- 2008
- Full Text
- View/download PDF
9. Der Einfluß von Muskelarbeit auf das Myosonogramm
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Reimers, C., primary, Lochmüller, H., additional, Goebels, N., additional, Schlotter, B., additional, and Stempfle, U., additional
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- 2008
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10. Extensive myelitis associated with Mycoplasma pneumoniae infection: magnetic resonance imaging and clinical long-term follow-up
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Goebels, N., Helmchen, C., Abele-Horn, M., Gasser, T., and Pfister, H.-W.
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- 2001
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11. Interferon β-1b zur Behandlung der sekundär chronisch progredienten multiplen Sklerose
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Zimmermann, C., Walther, E.U., Goebels, N., Lienert, C., Kappos, L., Hartung, H.-P., and Hohlfeld, R.
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- 1999
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12. Inflammatory myopathy in POEMS syndrome
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Goebels, N., primary, Walther, E. U., additional, Schaller, M., additional, Pongratz, D., additional, and Mueller-Felber, W., additional
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- 2000
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- View/download PDF
13. Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: Epitope spreading versus clonal persistence
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Goebels, N., primary
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- 2000
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- View/download PDF
14. Interferon ?-1b zur Behandlung der sekund�r chronisch progredienten multiplen Sklerose
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Zimmermann, C., primary, Walther, E.U., additional, Goebels, N., additional, Lienert, C., additional, Kappos, L., additional, Hartung, H.-P., additional, and Hohlfeld, R., additional
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- 1999
- Full Text
- View/download PDF
15. Copolymer-1 (Glatirameracetat) zur Therapie der schubförmigen multiplen Sklerose
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Dang, T., primary, Goebels, N., additional, Walther, E. U., additional, and Hohlfeld, R., additional
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- 1998
- Full Text
- View/download PDF
16. Fourth meeting of the European Neurological Society 25–29 June 1994 Barcelona, Spain: Abstracts of Symposia and free communications
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Harms, L., Bock, A., JÄnisch, W., Valdueza, J., Weber, J., Link, I., De Keyser, J., Goossens, A., Wilczak, N., Vedeler, C., Bjorge, L., Uvestad, E., Conti, G., Williams, K., Ginsberg, L., Rafique, S., Rapoport, S. I., Gershfeld, N. L., De La Meilleure, G., Crevits, L., Faiss, J. H., Heye, N., Blanke, J., Sackmann, A., Kastrup, O., Doornbos, R., van der Worp, H. B., Kappelle, L. J., Bar, P. R., Davie, C. A., Barker, G. J., Brenton, D., Miller, D. H., Thompson, A. J., Block, F., Schwarz, M., Delodovici, L., Baruzzi, F., Bonaldi, G., Dario, A., Marra, A., Mercuri, A., Dworzak, F., Cavallari, P., Confalonieri, P., Zuffi, M., Antozzi, C., Cornelio, F., Baldissera, F., Chassande, B., Ameri, A., Eymard, B., Poisson, M., Vérier, A., Brunet, P., Congia, S., Murgia, P. L., Cannas, A., Borghero, G., Uselli, S., Mellino, G., Ferrai, R., Lampis, R., Massa, R., Muzzetto, B., Giannini, F., Rossi, S., Cioni, R., d'Aniello, C., Guarneri, A., Battistini, N., Ceriani, F., Del Santo, A., Poloni, M., Campo, J. F., Iglesias, F., Guitera, M. V., Farinas, C., Pascual, J., Leno, C., Berciano, J., Thorpe, I. W., Kendall, B. E., McDonald, W. I., Moulignier, A., Dromer, F., Baudrimont, M., Dupont, B., Gozlan, J., El Amrani, M., Petit, J. C., Roullet, E., Sterzi, R., Causaran, R., Protti, A., Riva, M., Erminio, F., Arena, O., Villa, F., Maccagnano, E., Miletta, M., Spinelli, F., Ben-Hur, T., Weidenfeldl, J., Rao, N. S., Chari, C. C., Laforet, P., Matheron, S., Adams, D., Chemouilli, Ph., Desi, M., Said, G., Davous, P., Lionnet, F., Pulik, M., Genet, P., Rozenberg, F., Cartier, L. M., Castillo, J. L., Cea, J. G., Villagra, R., de Saint Martin, L., Mahieux, F., Manifacier, M. J., Mattos, K., Queiros, C., Publio, L., Vinhas, V., PeÇanha-Martins, A. C., Melo, A., Liska, U., Zifko, U., Budka, H., Drlicek, M., Grisold, W., Kaufmann, R., Kaiser, R., Czygan, M., Gomes, I., Jones, N., Cunha, S., EmbiruÇu, E. Katiane, Vieira, V., Araujo, I., Alexandra, M., Ferreira, A., Goes, J., Chemouilli, P., Israel-Biet, Masson, H., Lacroix, C., Gasnault, J., Hildebrandt-Müller, B., Oschmann, P., Krack, P., Willems, W. R., Dorndorf, W., Freitas, V., Bittencourt, A., Fernandes, D., Nascimento, M. H., Severo, M., Moraes, D., Muller, M., Hasert, K., Merkelbach, S., Schimrigk, K., van Oosten, B. W., Lai, M., Polman, C. H., Bertelsmann, F. W., Hodgkinson, S., Cabre, P. H., Volpe, L., Smadja, D., Vernant, J. P., Villaroya, H., Violleau, K., Younes-Chennoufi, A. Ben, Baumann, N., Villanueva-Hemandez, P., Ballabriga, J., Basart, E., Arbizu, T. X., Perez-Serra, J., Vinuels, F., Giron, J. M., Castilla, J. M., Redondo, L., Izquierdo, G., Lauer, K., Henneberg, A., Bittmann, N., Link, D., Wollinsky, K. H., Mobner, R., Fassbender, K., Kuhnen, J., Schwartz, A., Hennerici, M., Miller, A., Lider, O., Abramsky, O., Weiner, H. L., Offner, H., Vanderbark, A. A., Paoino, E., Fainardi, E., Addonizio, M. C., Ruppi, P., Tola, M. R., Granieri, E., Carreras, M., Sazdovitch, V., Joutel, A., Verdier-taillefer, M. H., Heinzlef, O., Radder, C., Tournier-Lasserve, E., Brenner, R. E., Munro, P. M. G., Williams, S. C. R., Bell, J. D., Hawkins, C. P., Filippi, M., Campi, A., Dousset, V., Canal, N., Comi, G., Zhu, J., Weber, F., Retska, R., List, J., Zhang, L., Brock, M., Taphoorn, M. J. B., Heimans, J. J., van der Veen, E. A., Karim, A. B. M. F., Sarazin, M., Argentino, N., Delattre, J. Y., Derkinderen, P., Buchwald, B., Schroter, G., Serve, G., Franke, C. H., Conrad, B., Kitchen, N. D., Thomas, D. G. T., Forman, A. D., Ang, Kie- Kian, Price, R., Stephens, C., Salmaggi, A., Nermni, R., Silvani, A., Forno, M. G., Luksch, R., Boiardi, A., Grzelec, H., Fryze, C., Nowacki, P., Zdziarska, B., Sanson, M., Merel, P., Richard, S., Rouleau, G., Thomas, G., Olsen, N. K., Pfeiffer, P., Egund, N., Bentzen, S. M., Johannesen, L., Mondrup, K., Rose, C., Zyluk, B., Wondrusch, E., Berger, O., Fast, N., Jellinger, K., Lindner, K., Urman, A., Thibault, J. L., Duyckaerts, Ch., Strik, H., Muller, B., Richter, E., Krauseneck, P., Steinbrecher, A., Schabet, M., Hess, C., Bamberg, M., Dichgans, J., Counsell, C. E., McLeod, M., Grant, R., Creel, G. B., Claus, D., Sieber, E., Engelhardt, A., Rechlin, T., Thierauf, P., Neubauer, U., Peresson, M., Di Giovacchino, G., Romani, G. L., Di Silverio, F., Danek, A., Kuffner, M., Hoermann, R., Schopohl, J., Laska, M., Heye, B., Zangaladze, A. T., Valls-SoIè, J., Cammarota, A., Alvarez, R., Tolosa, E., Hallett, M., Ulbricht, D., Ganslandt, O., Kober, H., Vieth, J., Grummich, P., Pongratz, H., Brigel, C., Fahlbusch, R., Serra, F. P., Palma, V., Nolfe, G., Buscaino, G. A., Rothstein, T. L., Gibson J. M., Morrison P. M., Collins A. D., Eiselt, M., Wagnur, H., Zwiener, U., Schindler, T., Efendi, H., Ertekin, C., Erfas, M., Larsson, L. E., Sirin, H., AraÇ, N., Toygar, A., Demir, Y., Seddigh, S., Vogt, T. H., Hundemer, H., Visbeck, A., Pastena, L., Faralli, F., Mainardi, G., Gagliardi, R., Linden, D., Berlit, P., Lopez, O. L., Becker, J. T., Jungreis, C., Brenner, R., Rezek, D., Dekesky, S. T., Estol, C., Boller, F., Fernandez, J. M., Mederer, S., Batlle, J., Turon, A., Codina, A., Hitzenberger, P., Vila, N., Valls-SolÇ, J., Chamorro, A., Pouget, J., Schmied, A., Morin, D., Azulay, J. Ph., Vedel, J. P., Montalt, J., Escudero, J., Barona, R., Campos, A., Varli, K., Ertem, E., Uludag, B., Yagiz, A., Privorkin, Z., Steinvil, Y., Kott, E., Combarros, O., Sanchez-Pernaute, R., Orizaola, P., Mokrusch, Th., Kutluaye, E., Selcuki, D., Ertikin, C., Zettl, U., Gold, R., Harvey, G. K., Hartung, H. P., Toyka, K. V., Wokke, J. H. J., Oey, P. L., Ippel, P. F., Jansen, G. H., Franssen, H., Toyooka, K., Fujimura, H., Ueno, S., Yoshikawa, H., Yorifuji, S., Yanagihara, T., Talamon, C., Tzourio, C., Kiefer, R., Jung, S., Toyka, K., Ruolt, I., Tranchant, C., Mohr, M., Warter, J. M., Younger, D. S., Rosoklija, G., Hays, A. P., Kurita, R., Hasegawa, O., Matsumto, M., Komiyama, A., Nara, Y., Oueslati, S., Belal, S., Turki, I., Ben Hamida, C., Hentati, F., Ben Hamida, M., Kwiecinski, H., Krolicki, L., Domzal-Stryga, A., Dellemijn, P. L. I., van Deventer, P., van Moll, B., Drogendijk, T., Vecht, Ch. J., Nemni S., Amadio, Fazio, R., Galardin, G., Delodovici, M. L., Peghi, E., Monticelli, M. L., Sessa, A., Viguera, M. L., Palomar, M., Gamez, J., Cervera, C., Navarro, C., Serena, J., Duran, I., Fernandez, A. L., Comabella, M., Nos, C., Rio, J., Montalban, J., Navarro, X., Verdu, E., Darbra, S., Buti, M., Mrabet, A., Fredj, M., Gouider, R., Tounsi, H., Khalfallah, N., Haddad, A., Dbaiss, T., Ghnassia, R., Rouillet, E., Chedru, F., Porsche, H., Strenge, H., Li, S. W., Young, Y. P., Garcia, A. A., Baron, P., Scarpini, E., Bianchi, R., Conti, A., Livraghi, S., Rees, J. H., Gregson, N. A., Hughes, R. A. C., Sedano, M. J., Calleja, J., Canga, E., Bahou, Y., Biary, N., Al Deeb, S. M., Guern, E. L. E., Gugenheim, M., Tardieu, S., Aisonobe, T. M., Agid, Y., Bouche, P., Brice, A., Rautenstrauss, B., Nelis, E., Grehl, H., Van Broeckhoven, C., Pfeiffer, R. A., Liehr, T., Ganzmann, E., Gehring, C., Neundörfer, B., Geremia, L., Doronzo, R., Sacilotto, G., Sergi, P., Pastorino, G. C., Scarlato, G., Planté-Bordeneuve, V., Mantel, A., Baas, F., Moser, H., Antonini, A., Psylla, M., Günther, I., Vontobell, P., Beer, H. F., Leenders, K. L., Chaudhuri, K. Ray, Parker, J., Pye, I. F., Millac, P. A. H., Abbott, R. J., Sutter, M., Albani, C., de Rijk, M. C., Breteler, M. M. B., Graveland, G. A., van der Mechè, F. G. A., Hofman, A., Keipes, M., Hilger, Ch., Diederich, N., Metz, H., Hentges, F., Pollak, P., Benabid, A. L., Limousin, P., Hoffmann, D., Benazzouz, A., Perret, J., Laihinen, A., Rinne, J. O., Ruottinen, H., Nagren, K., Lehikoinen, P., Oikonen, V., Ruotsalainen, U., Rinne, U. K., Cocozza, S., Pizzuti, A., Cavalcanti, F., Monticelli, A., Pianese, L., Redolfi, E., Paiau, F., Di Donato, S., Pandolfo, M., Palau, F., Monros, E., De Michele, G., Smeyers, P., Lopez-ArLandis, J., Uilchez, J., Filla, A., Genis, D., Matilla, T., Volpini, V., Blanchs, M. I., Davalos, A., Molins, A., Rosell, J., Estivill, X., De Jonghe, P., Smeyers, G., Krols, L., Mercelis, R., Hazan, J., Weissenbach, J., Martin, J. J., Warner, T. A. T., Williams, L., Orb, A. S., Harding, A. E., Giunti, P., Sweeney, M. G., Spadaro, M., Jodice, C., Novelletto, A., Malaspina, P., Frontali, M., Salmon, E., Gregoire, Del Fiore, Comar, Franck, G., Scheltens, P. H., Siegfried, K., Dartigues, E., De Deyn, P., Horn, R., Nelson, I., Hanna, M. G., Morgan-Hughes, J. A., Collinge, J., Palmer, M. S., Campbell, T., Mahal, S., Sidle, K., Humphreys, C., Tavitian, B., Pappata, S., Jobert, A., Crouzel, A. M., DiGiamberardino, L., Steimetz, G., Barbanti, P., Fabbrini, G., Salvatore, M., Buzzi, M. G., Di Piero, V., Petraroli, R., Sbriccoli, A., Pocchiari, M., Macchi, G., Lenzi, G. L., Spiegel, R., Maguire, P., Schmid, W., Ott, A., Bots, M. L., Grobbe, D. E., Hofman, A., Howard, R. S., Russell, S., Losseff, N., Hirsch, N. P., Couderc, R., Bailleul, S., Nargeot, M. C., Touchon, J., Picot, M. C., Rizzo, M., Watson, G., McGehee, D., Dingus, T., Kappos, L., Radü, E. W., Haas, J., Hartard, C. H., Spuler, S., Yousry, T., Voltz, R., Scheller, A., Holler, E., Hohlfeld, R., Scolding, N. J., Sussman, J., Kolar, O. J., Farlow, M. R., Rice, P. H., Zipp, F., Sotgiu, S., Weiss, E. H., Wekerle, H., Chalmers, R., Robertson, N., Compston, D. A. S., Martino, G., Clementi, E., Brambilla, E., Moiola, L., Martinelli, V., Colombo, B., Poggi, A., Rovaris, M., Grimaldi, L. M. E., Roth, M. P., Descoins, P., Ballivet, S., Ruidavets, J. B., Waubant, E., Nogueira, L., Cambon-Thomsen, A., Clanet, M., Leppert, D., Hauser, S., Lugaresi, A., Tartaro, A., D'aurelio, P., Befalo, L. L. O., Thomas, A., Malatesta, G., Gambi, D., Benedikz, J. E. G., Magnusson, H., Poser, C. M., Guomundsson, G., Bates, T. E., Davies, S. E. C., Clark, J. B., Landon, D. N., ùther, J. R., Rautenberg, W., Overgaard, K., Sereghy, T., Pedersen, H., Boysen, G., Diez-Tejedor, E., Carceller, F., Gutierrez, M., Lopez-Pajares, R., Roda, J. M., Chandra, B., Ricart, W., Gonzalez-Huix, F., Molina, A., Rundek, T., Demarin, V., De Reuck, J., Boon, P., Decoq, D., Strijckmans, K., Goethals, P., Lemahieu, I., Nibbio, A., Chabriat, H., Vahedi, K., Nagy, T., Verin, M., Mas, J. L., Julien, J., Ducrocq, X., Iba-Zizen, M. T., Cabanis, E. A., Bousser, M. G., Rolland, Y., Landgraf, F., Bompais, B., Lemaitre, M. H., Edan, G., Vorstrup, S., Knudsen, L., Olsen, K. Skovgaard, Videbaek, C., Schroeder, T., van Gijn, J., Jansen, H. M. L., Pruim, J., Paans, A. M. J., Willemsen, A. T. M., Hew, J. M., vd Vliet, A. M., Haaxma, R., Vaalburg, W., Minderhoud, J. M., Korf, J., Soudain, S. E., Ho, T. W., Mishu, B., Li, C. Y., Nachainkin, I., Gao, C. Y., Cornblath, D. R., Griffin, J. W., Asbury, A. K., Blaser, M. J., McKhann, G. M., Ho, T., Macko, C., Xue, P., Stadlan, E. M., Ramos-Alvarez, M., Valenciano, L., Visser, L. H., van der Meché, F. G. A., van Darn, P. A., Meulstee, J., Schmitz, P. I. M., Jacobs, B., Oomes, P. G., Kleyweg, R. P., Jacobs, B. C., Endtz, H. P., van Doorn, P. A., van der Mech, F. G. A., Van den Berg, L. H., Mollee, I., Logtenberg, T., Thomas, P. K., Plant, G., Baxter, P. J., Luis, R. Santiago, Matsumoto, M., Notermans, N. C., Wokke, J. H. J., Lokhorst, H. M., van der Graaf, Y., Jennekens, F. G. I., Azulay, J. P., Bille-Turg, F., Valentin, P., Farnarier, G. G., Pellissier, J. F., Serratrice, G., Quasthoff, S., Schneider, U., Grafe, P., Hilkens, P. H. E., Moll, J. W. B., van der Burg, M. E. L., Planting, A. S. T., van Putten, W. L. J., van den Bent, M. J., Birklein, F., Spitzer, A., Lang, E., Neundorfer, B., Diehl, R. R., Lücke, D., Smith, G. D. P., Mathias, C. J., Serra, J., Campera, M., Ochoa, J. L., Ray Chaudhuri, K., Pavitt, D., Alam, M., Handwerker, H. O., Bleasdale-Barr, K., Smith, G., Murray, N. M. F., Hawkins, P., Pepys, M., Gellera, C., DiDonato, S., Taroni, F., Uncini, A., Di Muzio, A., Servidei, S., Silvestri, G., Lodi, R., Iotti, S., Barbiroli, B., Morrissey, S. P., Borruat, F. X., Francis, D., Mosely, I., Hansen, H. C., Helmke, K., Kunze, K., Sadzot, B., Maquet, P., Lemaire, Plenevaux, Damhaut, Sommer, C., Myers, R. R., Berta, E., Mantegazza, R., Argov, Z., Shapira, Y., Wirguin, I., Beuuer, J., Franke, C., Roberts, M., Willison, H., Vincent, A., Newsom-Davis, J., Morrison, K. E., Damels, R., Francis, M., Campbell, L., Davies, K. E., Kohler, W., Bucka, C., Hertel, G., Kanovsky, P., Auer, D., Ackermann, H., Klose, U., Naegele, Th., Bien, S., Voigt, K., Fink, G. R., Stephan, K. M., Wise, R. J. S., Mullatti, N., Hewer, L., Frackowiak, R. S. J., Weiller, C. S., Rijnites, M., Jueptner, M., Bauermann, T., Krams, M., Diener, H. C., van Walderveen, M. A. A., Barkhof, F., Hommes, O. R., Valk, J., Willmer, J. P., Guzman, D. A., Passingham, R. E., Silbersweig, D., Ceballos-Baumann, A., Frith, C. D., Frackowiak, R., Lucas, C. H., Goullard, L., Marchau, M. J., Godefroy, O., Rondepierre, P. H., Chamas, E., Mounier-Vehier, F., Leys, D., Renato, J., Verdugo, M. S. C., Campero, M., Jose, L., Ochoa, D. S. C., Vivancos, F., Tejedor, E. Diez, Martinez, N., Roda, J., Frank, A., Barreiro, P., Satoh, Y., Nagata, K., Maeda, T., Hirata, Y., YalÇinerner, B., Ozkara, C., Ozer, F., Ozer, S., Hanoglu, L., Zunker, P., Pozo, J. L., Oberwittler, C., Schick, A., Buschmann, H. -Ch., Ringelstein, E. Bernd, Lara, M., Anzola, G. P., Magoni, M., Volta, G. Dalla, Tarasov, A., Feigin, V., Beaudry, M. G., Carrier, S., Chicoutimi, Henriques, I. L., Bogoussslavsky, J., van Melle, G., Mathieu, J., Perusse, L., Allard, P., Prevost, C., Cantin, L., Bouchard, J. M., De Braekeleer, M., Agbo, C., Neau, J. P., Tantot, A. M., Dary-Auriol, M., Ingrand, P., Gil, R., Baltadjiev, D., Zekin, D., Sabey, K., Gennaula, C. P., Pope, B. A., Caparros-Lefebvre, D., Girard-Buttaz, I., Pruvo, J. P., Petit, H., Hipola, D., Martin, M., Giménez-Roldan, S., Ivanez, V., Japaridze, G., Carrasco, J. L., Picomell, I., Herranz, J. L., Macias, J. A., Nieto, M., Noya, M., Oller, L., Kiteva-Trencevska, G., Delgado, M. R., Liu, H., Luengo, A., Parra, J., Colas, J., Fernandez, M. J., Manzanares, R., Kornhuber, M. E., Malashkhia, V., Orkodashili, G., Martinez, M., Bonaventura, I., Porta, G., Martinez, I., Fernandez, A., Aguilar, M., Masnou, P., Drouet, A., Dreyfus, M., Cartron, J., Morel-Kopp, M. C., Tchernia, G., Kaplan, C., Lammers, M. W., Hekster, Y. A., Keyser, A., Meinardi, H., Renier, W. O., Boon, P. A. J. M., Have, M. D., Kint, B., Cruz, P., Cadilha, A., Almeida, R., Goncalves, M., Pimenta, M., Ramos, L. M. P., Polder, T. W., Broere, C. A., Polman, L., Rother, I., Rother, M., Schlaug, G., Arnold, S., Holthausen, H., Wunderlich, G., Ebner, A., Luders, H., Witte, O. W., Seitz, R. J., Serra, L. L., Gallicchio, B., Rotondi, F., Wieshmann, U., Meierkord, H., Sabev, K., Di Carlo, V., Gueguen, B., Derouesné, Ch., Ancri, D., Bourdel, M. C., Guillou, S., Aliaga, R., Chornet, M. A., Rodrigo, A., Pascual, A. Pascual -Leone, Catala, M. D., Pascual-Leone, A., Benbadis, S. R., Dinner, D. S., Chelune, G. J., Lüders, H. O., Piedmonte, M. R., Blanco, T., Lopez, M. P., Romero, B., Deltoro, A., Pascual, A., Pascual, Leone, Bolgert, F., Josse, M. O., Tassan, P., Touze, E., Laplane, D., Godenberg, F., Brizioli, E., Del Gobbo, M., Pelliccioni, G., Scarpino, O., Durak, H., Damlacik, G., Tunca, Z., Fidaner, H., Yurekli, Y., Yemez, B., Kaygisiz, A., Anllo, E. A., Esperet, E., Giovagnoli, A. R., Casazza, M., Spreafico, R., Avanzini, G., Mascheroni, S., Vecchio, I., Tornali, C., Antonuzzo, A., Grasso, A. A., Bella, R., Pennisi, G., Raffaele, R., Broeckx, J., Schildermans, F., Hospers, W., Deberdt, W., Carney, J. M., Aksenova, M., Chen, M. S., Juncadella, M., Busquets, N., De la Fuente, I., Rodriguez, A., Rubio, F., Soler, R., Khati, C., Pillon, B., Deweer, B., Malapani, C., Malichard, N., Dubois, B., Rancurel, G., Lopez, D. L., Jungreia, G., DeKosky, S. T., Boiler, F., Weiller, C., Rijntjes, M., Mueller, S. P., Maguire, E. A., Burke, E. T., Staunton, H., Phillips, J., Rousseaux, M., Pena, J., Bertran, I., Santacruz, P., Lopez, R., Catafau, A., Lomena, F., Blesa, R., Rampello, L., Nicoletti, A., Cabaret, M., Lesoin, F., Steinling, M., Tournev, I., Maier-Hauff, K., Schroeder, M., Wolf, A., Cochin, J. P., Noel, I., Augustin, P., Auzou, P., Hannequin, D., Maria, V., Lopez-Bresnahan, Danielle, D. M., Antin-Ozerkis B. A., Bartels, E., Rodiek, S. O., Flugel, K. A., Campos, D. M., Salas-Puig, J., Del Rio, J. Sanhez, Vidal, J. A., Lahoz, C. H., Eraksoy, M., Barlas, O., Barlas, M., Bayindir, C., Ozcan, H., Birbamer, G., Gerstenbrand, F., Felber, S., Luz, G., Aichner, F., Seidel, G., Kaps, M., Hutzelmann, A., Gerriets, T., Kruggel, F., Martin, P. J., Gaunt, M. E., Abbot, R. J., Naylor, A. R., Meary, E., Dilouya, A., Meder, J. F., De Recondo, J., Lebtahi, R., Neff, K. W., Meairs, S., Viola, S., Matta, E., Aquilone, L., Rise, I. R., Authier, F. J., Kondo, H., Ghnassia, R. T., Degos, J. D., Gherardi, R. K., Bardoni A., Ciafaloni E., Comi G. P., Bresolin N., Robotti M., Moggio M., Rigoletto C., Roses A., Scarlato G., Castelli, E., Turconi, A., Bresolin, N., Perani, D., Felisari, G., Chariot, P., de Pinieux, G., Astier, A., Jacotot, B., Gherardi, R., Fischer-Gagnepain, V., Louboutin, J. P., Crespo, F., Florea-Strat, A., Fromont, G., Sabourin, J. -C., Gonano, E. -F., Moroni, I., Prelle, A., Iannaccone, S., Quattrini, A., deRino, F., Sessa, M., Golzi, V., Smirne, S., Nemni, R., Turpin, J. C., Lucotte, G., Jacobs, S. C. J. M., Willems, P. W. A., Bootsma, A. L., Lasa, A., Calaf, M., Baiget, M., Gallano, B., Fichter-Gagnepain, V., Mazzucchelli, F., D'Angelo, M. G., Velicogna, M., Bet, L., Comi, G. P., Bordoni, A., Gonano, E. F., Bazzi, P., Rapuzzi, S., Moggio, M., Fagiolari, G., Ciscato, P., Messina, A., Battistel, A., Ryniewicz, B., Sangla, I., Desnuelle, C., Paquis, V., Cozzone, P. J., Bendahan, D., Sturenburg, H. J., Kohncke, G., Castellli, E., Linssen, W., Stegeman, D., Binkhorst, R., Notermans, S., Jaspert, A., Fahsold, R., de Munain, A. Lopez, Cobo, A., Martorell, L., Poza, J. J., Navarrete Palau, D., Emparanza, J. I., Sanchez-Roy, R., Vilchez, J. J., Hernandez, M., Tena, J. Garcia, Perla, C., Koutroumanidis, M., Papathanasopoulos, P., Papadimitriou, A., Papapetropoulos, T. H., Divari, R., Hadjigeorgiou, G. M., Anastasopoulos, I., Sansone, V., Rotondo, G., Meola, G., Rigoletto, C., Messina, S., Szwabowska-Orzeszko, E., Jozwiak, S., Michalowicz, R., Szaplyko, W., Petrella, M. A., Della Marca, G., Masullo, G., Mennuni, G. F., Kompf, D., Wascher, E., Verleger, R., Kaido, M., Soga, F., Toyooka, H., Bayon, C., Rubio, J., Carlomagno, S., Parlato, V., Santoro, A., Lavarone, A., Bonavita, V., Pentore, R., Venneri, A., Pasquier, F., Lebert, F., Grymonprez, L., Lefebvre, C., Van der Linden, M., Derouesné, C., Renault, B., Lacomblez, L., Homeyer, P., Ouss, L., Neuman, E., Malbezin, M., Barrandon, S., Guez, D., Stevens, M., van Swieten, J. C., Franke, C. L., Sanchez, A., Castellvirel, S., Mila, M., Jimenez, D., Pallesta, F., Ruiz, P. J. Garcia, Barrio, A., Barroso, T., Benitez, J., de Yebenes, J. Garcia, Manubens, J. M., Martinez-Lage, J. M., Larumbe, R., Muruzabal, J., Lacruz, F., Quesada, Pedro, Gallego, J., Ferini-Strambi, L., Marcone, A., Garancini, P., Tedesi, B., Jacob, B., Rozewicz, L., Langdon, D., Davie, C., Ron, M., Thompson, A., Koepp, M. J., Hansen, M. L., Guldin, B., Pressler, R. M., Ried, S., Scholz, C., Monaco, F., Gianelli, M., Schiavalla, M. P., Naldi, P., Cantello, R., Torta, R., Verze, L., Mutani, R., Knott, H., Ferbert, A., Schulze-Bonhage, A., Aust, W., Di Mascio, R., Marchioli, R., Vitullo, F., Di Pasquale, A., Sciulli, L., Kramer, V., Tognoni, G., Santacruz, P., Lopez, R., Marti, M. J., Charques, I., Catafau, A., Lomeila, F., Peila, J., Bertran, I., Blesa, R., Krendel, D. A., Costiga, D. A., Koeppen, S., Korn, W. M., Brugge, S., Schmitz, D., Scheulen, M. E., King, R. H. M., Robertson, A. M., Thomas, P. K., Kerkhofs, A., Vermersch, P., Dereeper, O., Daems Monpeun, C., Parent, M., Deplanque, D., Petit, H., Campero, M., Serra, J., Ochoa, J. L., Martinez-Matos, J. A., Montero, J., Olivé, M., Rene, R., Vidaller, A., Gugenheim, M., Gouider, R., Le Guern, E., Brice, A., Agid, Y., Bouche, P., Grisold, W., Ziflo, U., Drlicek, M., Budka, H., Jellinger, K., Zielinski, C. H., Ginsberg, L., King, R. H. M., Workman, J., Platts, A. D., Thomas, P. K., Gherardi, R. K., Florea-Strat, A., Poron, F., Sabourin, J. -C., Fazio, R., Nemni, R., Franceschi, M., Lorenzetti, I., Rinaldi, L., Canal, N., Weilbach, F. X., Sennlaub, A., Jung, S., Gold, R., Toyka, K. V., Hartung, H. P., Giegerich, G., Ellie, E., Vital, A., Steck, A. J., Vital, C., Julien, J., Doneda, P., Pizzul, S., Scarpini, E., Chiodi, P., Ramacci, M. T., Livraghi, S., Maimone, D., Annunziata, P., Salvadori, C., Guazzi, G. C., Arne-Bes, M. C., Delisle, M. B., Fabre, N., Hurtevent, J. F., Bes, A., Baudoin-Martin, D., Laborde, E., Viallet, F., Creisson, C., Crespi, V., Bogliun, G., Marzorati, L., Zincone, A., D'Angelo, L., Liberani, A., Merlini, M., Rivolta, R., Creange, A., Sabourin, J. -C., Theodorou, I., Gherardi, R. K., Conti, A. M., Malosio, M. L., Baron, P. L., Scarlato, G., Chorao, R., Rosas, M. J., Leite, I., Callea, L., Donati, E., Bargnani, C., Bud, M., Verdu, E., Navarro, X., Braun, S., Einius, S., Poindron, P., Warier, J. M., Bradley, J., Bekkelund, S. I., Torbergsen, T., Mellgren, S. I., Carlomagno, S., Parlato, V., Santoro, A., Lavarone, A., Boller, F., Bonavita, V., Engelhardt, A., Lörler, H., Robeck, S., Kluglein, C., Comi, G., Avoledo, V., Locatelli, T., Leocani, L., Galardi, G., Magnani, G., Medaglini, S., Chkhikvishvili, T. S., Zangaladze, A., Bratoeva, M., Kovachev, P., Chavdarov, D., Artemis, N., Karacostas, D., Milonas, I., Arpa, J., Lopez-Pajares, R., Cruz-Matinez, A., Sarria, J., Palomo, F., Alonso, M., Rodriguez-Al-barino, A., Lacasa, T., Nos, J., Barreiro, P., Martinez, A. Cruz, Villoslada, C., Alons, M., Taghavy, A., Hamer, H., Kratzer, A., Dethy, S., Pauwels, T., Monclus, M., Luxen, A., Goldman, S., Ziegler, M., Crambes, O., Ragueneau, I., Arnaud, F., Zappia, M., Montesanti, R., Colao, R., Palmieri, A., Branca, D., Nicoletti, G., Rizzo, M., Parlato, G., Quattrone, A., Vanacore, N., Zuchegna, P., Bonifati, V., Meco, G., Scholz, J., Friedrich, H. -J., Rohl, A., Ulm, G., Vieregge, P., Savettieri, G., Rocca, W. A., Meneghini, F., Grigoletto, F., Morgante, L., Reggio, A., Salemi, G., Di Pierri, R., OzckmekÇi, S., Ertan, S., Yeni, N., Apaydin, H., Erkol, G., Kiziltan, G., Denktas, F., Ranoux, D., de Recondo, J., Ostergaard, L., Werdelin, L., Odin, P., Lindvall, O., Dupont, E., Christensen, P. B., Boisen, E., Jensen, N. B., Schmiegelow, M., Ingwersen, S. H., Matias-Guiu, J., Canet, T., Falip, R., Martin, R., Galiano, L., Voloshin, M. Y., Burchinskaya, L. F., Cabrera-Valdivia, F., Jimenez-Jimenez, F. J., Molina, J. A., Fernandez-Calle, P., Vazquez, A., Canizares-Liebana, F., Larumbe-Lobalde, S., Ayuso-Peralta, L., Rabasa, M., Codoceo, R., Arrieta, F. J., Aguilar, M. V., Jorge-Santamaria, A., Martinez-Para, M. C., Alarcon, J., Mateo, D., Gimenez-Roldan, S., Gencheva, E., Tzonev, T. z., Georgiev, G., Petkova, P., Gasparini, M., Vanacore, N., Meco, N. G., de la Sierra, G., Aguado, F., Revilla, M., Varela, L., Rico, H., Feve, A., N'Guyen, J. P., Bathien, N., Fenelon, G., Veroust, J., Cesaro, P., Egersbach, G., Hattig, H., Schelosky, L., Wissel, J., Poewe, W., Durif, F., Albuisson, E., Debilly, B., Tournilhac, M., Magnani, C., Mocellini, C., Soffietti, R., Schiffer, D., Cardozo, A., Cruz-Sanchez, F. F., Falip, L., Potagas, G., Ziegler, M., Rondot, P., Bonifati, V., Fabrizio, E., Meco, G., Bostantjopoulou, S., Katsarou, Z., Kyriazis, G., Baas, H., Demisch, L., Esser, A., Zoeller, F., Burklin, F., Harder, S., Fischer, P. A., Arcusa, M. J., Hermandez, S., Claramonte, F. J., Pascual, A. Pascual- Leone, Alonso, M. D., Catata, M. D., Alessandri, A., Giustini, P., Dufour, A., Ciusani, E., Nespolo, A., Roelcke U., Radu E. W., von Ammon K., Maguire R. P., Leenders K. L., Radionova, M., Chavdarov, D., Bratoeva, M., Tzekov, Ch., Pietrangeli, A., Bove, L., Pace, A., Falqui, L., Jandolo, B., Potemkowski, A., Muller B., Reinhard I., Krone A., Warmuth M., Brocker E. M., Krauseneck P., Meyding-Lamadé, U., Krieger, D., Sartor, K., Hacke, W., Maugard-Louboutin, C., Fayet, G., Sagan, C., Martin, S., Ménégalli, D., Lajat, Y., Resche, F., Koriech, O. M., Al Moutaery, K., Yaqub, B., Jochens, R., Wolters, A., Venz, S., Cordes, M., Hecht, B. K., Chatel, M., Gaudray, P., Turc-Carel, C., Gioanni, J., Ayraud, N., Hecht, F., Rumbach, L., Racadot, E., Bataillard, M., Billot, M., Pariset, J., Wijdenes, J., Montalban, Rio J., Tintoré, M., Galan, I., Acarin, N., Rapaport, S., Huberman, M., Shechtcr, D., Karabudak, R., Kilinc, M., Boyacigil, S., Cila, A., Polo, J. M., Setien, S., Sanchez, R., Figols, J., Zubimendi, A., Nadareishvili, Z. G., Massot, R., Marés, R., Gallecho, F., Richart, C., Hernandez, M. A., Garcia, M. R., Lorenzo, J. N., Leon, C., Muros, M., Togores, J., Kutluk, K., Damlacik, G. A., Tekinsoy, B., Obuz, O., Baklan, B., Idiman, E., Genc, K., Zielasek, J., Schmidt, B., Liew, F. Y., Gulay, Z., Yulug, N., Wong, K. S., Wong, T. W., Yu, T. S., Kay, R., Poupon, R., Giral, P., Roberti, C., Zanette, E. M., Chiarotti, F., Brusa, L., Cerbo, R., Prusinski, A., Pondal, M., Canton, R., Dominigo, Erodriguez J., Pereira Monteino J. M., Pereira Monteino X., Pardo, J., Carroacedo, A., Barros, F., Lema, M., Castillo, J., Melchor, A., Montiel, I., Guiu, J. Matias, Kloss, T. M., Keidel, M., Jacob, M., Idiman, F., Idman, E., Ozturk, V., Metin, E., Yilmaz, M., Gerard, J. M., Bouton, R., Decamps, D., Herbaut, A. G., Delecluse, F., Cavenaile, M., Divano, L., Chazot, G., Boureau, F., Emile, J., Bertin, L., d'Allens, H., Ferro, J. M., Costa, I., Carletto, F., Catarci, T., Padovani, A., Iandolo, B., Bartoli, M., Bonamini, M., Pulcinelli, F., Pignatelli, P., Russo, M., Gazzaniga, P. P., Barros, J., Pinheiro, J., Correia, A. P., Monteiro, J. M. Pereira, Alvarez-Cermeno, J. C., Avello, G., Sastre, J. L., Vecino, A., Cesar, J. M., Leone, M., Stankov, B., D'Amico, D., Maltempo, C., Moschian, F., Fraschini, F., Bussone, G., Molto, J. M., Fernandez, E., Fernandez, A. Morento, Barreiro, A., Siclia, J., Castejon, P., Mihout, B., Malberin, M., Salzman, V., Bogousslavsky, J., Meneghetti, G., Baracchini, C., Bozzato, G., Marini, B., Mendel, T., Czlonkowska, A., Pasierski, T., Szwed, H., Marta-Moreno, J., Lopez-Delval, J., Mostacero, E., Morales, F., Mahagne, M. H., Rogopoulos, A., Bertrand, F., Bedoucha, P., Lanteri-Minet, M., Riva, D., Zorzi, C., Milani, N., Vajsar, J., Ronen, G., Macgregor, D., Becker, L., Susseve, J., Seidl, Z., Faber, J., Obenberger, J., Springer, R., Bax, R. T., Eckardt, T., Czettritz, G. V., Emmrich, P., Vlaski-Jekic, S., Petrova, V., Cherninkova, S., Gudeva, T., Tzekov, C., Devoti, M., Franceschetti, S., Mientus, S., Vienna, P., Vashtang, Y., Tazir, M., Assami, S., Oulbani, D., Kaci Ahmed, M. Ait, Andersen, G., Vestergaard, K., Riis, J. O., Chavdarov, D., Corbo, M., Previtali, S., Allen, R. R., McKay, W. C., Rowbotham, M. 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B., Roelcke, U., von Ammon, K., Pellikka, R., Lucking, C. H., Walon, C., Boucquey, D., -Van Rijckevorsel, K. Harmant, Lannoy, N., Verellen-Dunoulin, Ch., Liszka, U., Cavaletti, G., Casati, B., Kolig, C., Bogliun, G., Marzorati, L., Johannsen, L., Chio, A., Ruda, R., Vigliani, M. C., Sciolla, R., Seliak, D., Hoang-Xuang, K., Villanueva, J. A., Montalban, X., Arboix, A., Colosimo, C., Albanese, A., Hughes, A. J., de Bruin, V., Lees, A. J., Kowalski, J. W., Banfi, S., Santoro, L., Perretti, A., Castaldo, I., Barbieri, F., Campanella, G., Bhatia, K. P., Mardsen, C. D., de Bruin, V. S., Machedo, C., Ceballos-Baumann, D., Marsden, C. D., Brooks, D. B. J., Wennlng, G. K., Quinn, N., McDonald, W. l., Warner, T. T., Bain, P. C., Davis, M. B., Conway, D., Shaunak, S., O'Sullivan, E., Crawford, T., Lawden, M., Blunt, S., Rapoport, A., Sarova-Pinchas, I., de Beyl, D. Zegers, Mavroudakis, N., Blanc, S., Godinot, C., Lenoir, G., Barkhof, M. S. F., Tas, M. W., Baron, P. L., Constantin, C., Cassatella, M. A., Langdon, D. W., Webb, S., Gasparini, P., Zeviani, A., Kidd, D., Mammi, S., Cahalon, L., Hershkoviz, R., Lahat, N., Wallach, D., Annunziata, P., Martino, T., Maimone, D., Guazzi, G. C., Porrini, A. M., Dell'Arciprete, L., Rothwell, P. M., Stewart, R. R. C., Cull, R. E., Willmes, K., Poeck, K., Russell, D., Braekken, S. K., Brucher, R., Svennevig, J., Hermesl, M., Bruckmann, H., Biraben, A., Sliwka, U., Meyer, B., Schondube, F., Noth, J., Lavenu, I., Lammers, C., Waldecker, B., Haberbosch, W., Stam, J., Schneider, R., Gautier, J. C., Berlit, T. P., Fauser, B., Kuhne, D., Geraud, G., Danielli, A., Larrue, V., Bes, A., Timmerman, E., Bono, F., Bruni, A. C., Valalentino, P., Montesi, M. P., Talerico, G., Zappia, M., Sabatelli, M., Quattrone, A., Pareyson, D., Lorenzetti, D., Sghirlanzoni, A., Castellotti, B., Lupski, J. R., Archidiacono, N., Antonacci, R., Marzella, R., Rocchi, M., Samuel, D., Goulon-Goeau, C., Costa, P. P., Bismuth, H., Said, G., De Jongh P., Lofgren A., Timmerman V., Vance J. M., Van Broeckhoven C., Martin J. -J., Martinez, A. Cruz, Bort, S., Arpa, J., Misra, P., King, R. H. M., Badhia, K., Anderson, M., Caballo, A., Vichez, J., Gabriel, J. M., Erne, B., Miescher, G. C., Ulrich, J., Vital, A., Vital, C., Steck, A., Petry, K., Labatut, I., Hilmi, S., Ellie, E., Ferrini-Strambi, L., Zucconl, M., Marchettini, P., Palazzi, S., Oehlschlager, M., Pepinsky, R. B., Gemignani, F., Marbini, A., Pavesi, G., Di Vittorio, S., Manganelli, P., Mancia, D., Vermersh, P., Roche, J., Durocher, A. M., Dewailly, Ph., Dettmers, C., Fink, G., Lemon, R., Stephan, K., Passingham, D., Weder, B., Knorr, U., Huang, Y., Butterfield, D. A., Peris, M. L., Peiro, C., Pascual, A. Pascual-Leone, Bottini, G., Folnegovic-Smalc, V., Knezevic, S., Bokonjic, R., Ersmark, B., Torres, M. Gonzalez, Guiraud-Chaumeil, B., Haugaard, K., Jovicic, A., Chr, Lang, Levic, Z., Parra, C. Martinez, Ochoa, J. Patrignani, Titlbach, O., Wikkelso, C., Caparros-Lefevre, D., Debachy, B., Verier, A., Cantinho, G., Santos, A. I., Godinho, F., Bagunya, J., Roig, T., Ensenyat, A., Santiag, O., Trabucchi, H., De Leo, D., Koch, Ch., Zeumer, H., Matkovic, Z., Morris, P., Donaghy, M., Köhler, W., Kammer, T., Röther, J., Navon, R., Fontaine, B., Wu, Y., Capdevila, A., Guardiola, M. J., van Dijk, G. W., Notermans, N. C., Kruize, A. A., Kater, L., Bertelt, C., Hesse, S., Friedrich, H., Mauritz, K. -H., Giron, L. T., Watanabe, I. S., Ewing, D., Koepp, M., Lempert, T., Sander, B., Kauerz, U., Mehdorn, H. M., Hezel, J., Eickhoff, W., Kryst, T., Timsit, S., Gardeur, D., Reis, Mitermayer Galvao dos, Secor, E., Filho, A. Andrade, Silva, M. Cardoso, Santos, S. R. Silveira, Vasilaski, G., Reis, E. A. dos, Velupillai, P., Harn, D. A., Tigera, J. Garcia, Dreke, R. Martinez, Crespo, R. Piedra, Besses, C., Acin, P., Massons, J., Florensa, L., Oliveres, M., Sans-Sabrafen, J., Wicklein, E. M., Pleiffer, G., Kunre, K., Dieterich, M., Brandt, Th., Guarino, M., Stracciari, A., Pazzaglia, P., D'Alessandro, R., Santilli, I., Donato, M., The European Velnacrine Study Group, The Dutch Guillain-Barré study group, The COP-1 Multicenter Clinical and Research Group Study, and European Study Group
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- 1994
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17. Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.
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Goebels, N, primary, Michaelis, D, additional, Engelhardt, M, additional, Huber, S, additional, Bender, A, additional, Pongratz, D, additional, Johnson, M A, additional, Wekerle, H, additional, Tschopp, J, additional, Jenne, D, additional, and Hohlfeld, R, additional
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- 1996
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18. The role of autoimmune T lymphocytes in the pathogenesis of multiple sclerosis
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Hohlfeld, R., primary, Meinl, E., additional, Weber, F., additional, Zipp, F., additional, Schmidt, S., additional, Sotgiu, S., additional, Goebels, N., additional, Voltz, R., additional, Spuler, S., additional, Iglesias, A., additional, and Wekerle, H., additional
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- 1995
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19. Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones.
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Meinl, E, primary, Weber, F, additional, Drexler, K, additional, Morelle, C, additional, Ott, M, additional, Saruhan-Direskeneli, G, additional, Goebels, N, additional, Ertl, B, additional, Jechart, G, additional, and Giegerich, G, additional
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- 1993
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20. Body composition analysis with bioelectric impedance measurement in neuromuscular diseases
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Krause, K.-H., primary, Reimers, C.-D., additional, Goebels, N., additional, and Berlit, P., additional
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- 1993
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21. Human myoblasts as antigen-presenting cells.
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Goebels, N, primary, Michaelis, D, additional, Wekerle, H, additional, and Hohlfeld, R, additional
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- 1992
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22. Human myoblasts as antigen presenting cells
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Goebels, N., primary and Hohlfeld, R., additional
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- 1991
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23. A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis
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Giovannoni, G, Comi, G, Cook, S, Rammohan, K, Rieckmann, P, Soelberg Sørensen, P, Vermersch, P, Sandberg Wollheim, M, Cuzick, J, Juliusson, G, Reingold, S, King, J, Pollard, J, Sedal, L, Aichner, F, Eggers, C, Dive, D, Medaer, R, Ferreira, M, Manchev, I, Milanov, I, Haralanov, L, Deleva, N, Petrova, N, Bozhinov, P, Zahariev, Z, Stamenov, B, Shotekov, P, Petrov, I, Moskov, R, Emond, F, Freedman, M, Grand'Maison, F, Jacques, F, Vorobeychik, G, Demarin, V, Kovacicek, M, Lusic, I, Perhat Bucevic, T, Havrdova, E, Talab, R, Kanovsky, P, Petersen, T, Gross Paju, K, Kalbe, I, Toomsoo, T, Elovaara, I, Eralinna, Jp, Reunanen, M, Clavelou, P, Damier, P, Debouverie, M, Edan, G, Gout, O, Labauge, P, Laplaud, D, Wiertlewski, S, Heidenreich, F, Mäurer, M, Kieseier, B, Limmroth, V, Oschmann, P, Schimrigk, S, Steinbrecher, A, Zettl, U, Ziemann, U, Karageorgiou, K, Kyritsis, A, Papadimitriou, A, Amato, Mp, Bernardi, G, Morra, Vb, Galgani, S, Gallo, Paolo, Patti, F, Marrosu, M, Pozzilli, C, Trojano, M, Mancardi, Gl, Gebeily, S, Koussa, S, Wehbe, M, Yamout, B, Vaitkus, A, Metra, M, Messouak, O, Mossaddaq, R, Slassi, I, Yahyaoui, M, Hupperts, Rm, Czlonkowska, A, Kozubski, W, Nyka, W, Selmaj, K, Szczudlik, A, Figueiredo, J, Pedrosa, R, Alifirova, V, Balyazin, V, Barbarash, O, Belova, A, Boyko, A, Gusev, E, Elchaninov, A, Jacoupov, E, Julev, N, Kotov, S, Kudryavtsev, A, Laskov, V, Lesnyak, O, Odinak, M, Pasechnik, E, Poverennonva, I, Skoromets, A, Spirin, N, Stolyarov, I, Vorobieva, O, Voskresenskaya, O, Zaslavskiy, L, Zonova, E, Bohlega, S, El Jumah, M, Drulovic, J, Nadj, C, Goebels, N, Schluep, M, Ayed Frih, M, Hentati, F, Mhiri, C, Mrabet, A, Mrissa, R, Idiman, E, Karabudak, R, Turan, Of, Ahmed, F, Constantinescu, C, Hawkins, C, Palace, J, Sharrack, B, Loganovsky, K, Moskovko, S, Nehrych, T, Voloshyna, Np, Carlini, W, English, J, Garmany, G, Glyman, S, Huddlestone, J, Hurwitz, B, Kresa Reahl, K, Mikol, D, Pardo, G, Rao, H, Reif, M, Thrower, B, Royal, W, Webb, R, Wynn, D, Naga, C, Allen, N, Lin, K, Stefoski, D, Balabanov, R., Klinische Neurowetenschappen, RS: MHeNs School for Mental Health and Neuroscience, G., Giovannoni, G., Comi, S., Cook, K., Rammohan, P., Rieckmann, P. S., Sorensen, P., Vermersch, P., Chang, A., Hamlett, B., Musch, S. J., Greenberg, Altri, and BRESCIA MORRA, Vincenzo
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Male ,Medizin ,Placebo-controlled study ,Administration, Oral ,Relapsing-Remitting ,drug therapy/pathology ,Gastroenterology ,Disability Evaluation ,Cladribine ,Hazard ratio ,Brain ,General Medicine ,Middle Aged ,Administration ,Oral, Adolescent, Adult, Aged, Analysis of Variance, Brain ,pathology, Cladribine ,adverse effects/therapeutic use, Disability Evaluation, Disease Progression, Double-Blind Method, Female, Herpes Zoster ,etiology, Humans, Immunosuppressive Agents ,adverse effects/therapeutic use, Intention to Treat Analysis, Lymphopenia ,chemically induced, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis ,drug therapy/pathology, Young Adult ,Magnetic Resonance Imaging ,Intention to Treat Analysis ,adverse effects/therapeutic use ,Disease Progression ,chemically induced ,Female ,Immunosuppressive Agents ,medicine.drug ,Oral ,Adult ,medicine.medical_specialty ,Multiple Sclerosis ,Adolescent ,etiology ,cladribine ,immunomodulation ,multiple sclerosis ,trial ,Lower risk ,Placebo ,DIAGNOSIS ,Herpes Zoster ,Young Adult ,Multiple Sclerosis, Relapsing-Remitting ,Double-Blind Method ,Lymphopenia ,Internal medicine ,medicine ,Humans ,Adverse effect ,Aged ,Analysis of Variance ,business.industry ,MS ,medicine.disease ,Confidence interval ,Surgery ,CELLS ,pathology ,Lymphocytopenia ,business - Abstract
Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing–remitting multiple sclerosis. We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks. Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33 ; P
- Published
- 2010
24. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial
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Mikol, Dd1, Barkhof, F, Chang, P, Coyle, Pk, Jeffery, Dr, Schwid, Sr, Stubinski, B, Uitdehaag, B, Ballario, Ch, Caceres, Fj, Correale, J, Cristiano, E, Garcea, Do, Leutic, Gg, Aicher, F, Barreira, Aa, Freedman, M, Grand'Maison, F, Jacques, F, Lee, L, Stefanelli, M, Edan, G, Pelletier, J, Berghoff, M, Keifer, R, Koehler, J, Hardiman, O, Comi, G, Mancardi, GIOVANNI LUIGI, Pozzilli, C, Trojano, Mp, Jongen, P, Uitdehaag, Bm, Belova, An, Boyko, An, Elchaninov, Ap, Kozlov, Va, Odinak, Mm, Shvarkov, Sb, Skoromets, Aa, Spirin, Nn, Stolyarov, Id, Vorobieva, Ov, Zavalishin, I, Arbizu, T, Fernandez, O, Izquierdo, G, Montalban, X, Goebels, N, Bates, D, Constantinescu, C, Turner, B, Bashir, K, Bever, Ct, Birnbaum, G, Brod, Sa, Carlini, W, Dunne, P, Elias, S, Estronza, N, Fox, E, Glyman, S, Gross, J, Guarnaccia, Jb, Gupta, A, Kaufman, M, Khan, O, Khatri, B, Kresa reahl, K, Lava, N, Leist, T, Markowitz, C, Mihai, C, Mikol, Dd, Miller, T, Panitch, H, Parry, G, Rammohan, Kw, Reder, A, Sheppard, C, Simsarian, Jp, Smiroldo, J, Spier, L, Thrower, B, Vollmer, T, Wendt, J, Wray, S, Wynn, D., Radiology and nuclear medicine, Epidemiology and Data Science, Neurology, and Neuroscience Campus Amsterdam 2008
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Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Adolescent ,Injections, Subcutaneous ,Population ,Placebo-controlled study ,Relapsing-Remitting ,drug therapy/pathology ,Drug Administration Schedule ,Injections ,methods ,law.invention ,Disability Evaluation ,Multiple Sclerosis, Relapsing-Remitting ,Randomized controlled trial ,law ,Internal medicine ,Adolescent, Adult, Confidence Intervals, Disability Evaluation, Disease Progression, Drug Administration Schedule, Female, Humans, Immunologic Factors ,administration /&/ dosage, Injections ,Subcutaneous ,methods, Interferon-beta ,administration /&/ dosage, Magnetic Resonance Imaging ,methods, Male, Middle Aged, Multiple Sclerosis ,drug therapy/pathology, Peptides ,administration /&/ dosage, Retrospective Studies, Treatment Outcome ,Confidence Intervals ,medicine ,Humans ,Immunologic Factors ,Glatiramer acetate ,administration /&/ dosage ,education ,Retrospective Studies ,education.field_of_study ,Intention-to-treat analysis ,business.industry ,Interferon beta-1a ,McDonald criteria ,Glatiramer Acetate ,Interferon-beta ,Middle Aged ,Magnetic Resonance Imaging ,Treatment Outcome ,Tolerability ,Immunology ,Disease Progression ,Female ,Neurology (clinical) ,Peptides ,business ,medicine.drug - Abstract
Summary Background Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS. Methods In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 μg subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338. Findings Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0·94, 95% CI 0·74 to 1·21; p=0·64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0·24 vs 0·41 lesions per patient per scan, 95% CI −0·4 to 0·1; p=0·0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks. Interpretation There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS. Funding EMD Serono; Pfizer.
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- 2008
25. Der Einfluß von Muskelarbeit auf das Myosonogramm
- Author
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Lochmüller H, Carl D. Reimers, Schlotter B, Stempfle U, and Goebels N
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medicine.medical_specialty ,Muscle exercise ,Contraction (grammar) ,business.industry ,Isometric exercise ,body regions ,Internal medicine ,Reference values ,Healthy volunteers ,medicine ,Cardiology ,Vastus intermedius muscle ,Radiology, Nuclear Medicine and imaging ,Bicycle ergometer ,business ,Echo intensity - Abstract
AIM: The purpose of this study was to examine quantitatively the change of muscle thickness and echo intensity caused by muscle exercise in healthy persons. METHOD: 16 healthy volunteers (7 women, 9 men), aged 23 to 37 years, underwent static exercises of the rectus abdominis, rectus femoris/vastus intermedius, and tibialis anterior muscles. In addition, the rectus femoris/vastus intermedius muscles were exercised dynamically. Thicknesses of these muscles were measured before and during/after exercise using the electronic caliper and computer-assisted gray-scale analysis of the echo signals. RESULTS: Short, maximal isometric contraction resulted in an increase of thickness by 5 to 18% depending on the examined muscle (p < 0.01). The echo intensity of the rectus femoris and vastus intermedius muscles decreased significantly (-8% and -26%, p < 0.01). The increase of muscle thickness immediately after isometric exercise for up to 90 s was significantly correlated to the duration of contraction (r = 0.26 to 0.49, p < 0.05). Muscle echo intensities did not significantly correlate with the duration of the contraction. After dynamic exercise on a bicycle ergometer both thickness of the rectus femoris/vastus intermedius muscles (+12.5%, p < 0.01) and echo intensity of the vastus intermedius muscle increased (+19.5%, p < 0.01). The change of echo intensity of the vastus intermedius muscle after static and dynamic exercise was significantly different (-26% vs. +18%, p < 0.001). CONCLUSION: Muscle thickness increases during and after static as well as dynamic exercise. Echo intensity may be unchanged, decreased or increased, depending on the exercised muscle and mode of exercise.
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- 2008
26. Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study
- Author
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Khatri, B, Barkhof, F, Comi, G, Hartung, Hp, Kappos, L, Montalban, X, Pelletier, J, Stites, T, Wu, S, Holdbrook, F, Zhang auberson, L, Francis, G, Cohen, Ja, Cohen, J, Easton, Jd, Calandra, T, Dimarco, J, Hudson, L, Kesselring, J, Laupacis, A, Temkin, N, Weinshenker, B, Zarbin, M, Poppe, P, Luetic, G, Cristiano, E, Caceres, F, Garcea, O, Correale, J, Ballario, C, Piedrabuena, R, Pollard, J, Beran, R, Hodgkinson, S, Schwartz, R, Heard, R, King, J, Butzkueven, H, Maida, Em, Vass, K, Franta elmer, C, Berger, T, Aichner, F, Ladurner, G, Bissay, V, Sindic, C, D'Hooghe, M, Mulleners, E, Damasceno, B, Barreira, A, Naylor, R, Alvarenga, R, Bacellar, A, Haussen, S, Duquette, P, Antel, J, Lamontagne, A, Grand'Maison, F, Freedman, M, Christie, S, O'Connor, P, Vorobeychik, G, Devonshire, V, Ramadan, M, Hamdy, S, Reda, E, Hashem, S, Fouad, M, Lebrun frenay, C, Clanet, M, Brochet, B, Debouverie, M, Heinzlef, O, Ziemssen, T, Koehler, W, Tiel wilck, K, Bachus, R, Altmann, N, Faiss, J, Baum, K, Dressel, A, Luckner, K, Ebke, M, Stangel, M, Diener, Hc, Bethke, F, Limmroth, V, Maschke, M, Thoemke, F, Reifschneider, G, Diehm, R, Wildemann, B, Melms, A, Rauer, S, Karlbauer, G, Berthele, A, Lang, M, Tumani, H, Krauseneck, P, Klein, M, Papadimitriou, A, Karageorgiou, K, Liakopoulos, D, Tascos, N, Plaitakis, A, Papathanasopoulos, P, Panczel, G, Jakab, G, Csiba, L, Komoly, S, Csanyi, A, Bartos, L, Centonze, D, Pozzilli, C, Marrosu, Mg, Bertolotto, A, Mancardi, GIOVANNI LUIGI, Scarpini, E, Protti, A, Ghezzi, A, Capra, R, Bergamaschi, R, Gallo, P, Stecchi, S, Montanari, E, Tola, Mr, Amato, Mp, Silvestrini, M, Lugaresi, A, Trojano, M, Morra, Vb, Ruggieri, S, Patti, F, Kim, Sm, Lee, Kh, Kim, Hj, Park, Sp, Ginestal, R, Salgado, Av, Fontoura, P, Cunha, L, Sousa, L, Mj, Sá, Pedrosa, R, Arbizu, T, Arroyo, R, Merino, Ja, Fernandez, O, Izquierdo, G, Casanova, B, Antigüedad, A, Goebels, N, Young, C, Lee, M, Chaudhuri, A, Nicholas, R, Martinez, Ac, Preiningerova, J, Greco, D, Gross, J, Newman, S, Mitchell, G, Pawar, G, Freedman, Sm, Kaufman, M, Absher, J, Kantor, D, Ayala, R, Honeycutt, W, Shafer, S, Steingo, B, Delgado, S, Cascione, M, Brock, C, Keegan, A, Laganke, C, Hunter, S, Wilson, E, Mazhari, A, Bauer, W, Singer, B, Lynch, S, Rowe, V, Hutton, G, Gazda, S, Dihenia, B, Campagnolo, D, Chippendale, T, Ash, P, Jung, L, Olek, M., Radiology and nuclear medicine, NCA - Multiple Sclerosis and Other Neuroinflammatory Diseases, Khatri B, Barkhof F, Comi G, Hartung HP, Kappos L, Montalban X, Pelletier J, Stites T, Wu S, Holdbrook F, Zhang-Auberson L, Francis G, Cohen JA, TRANSFORMS Study Group, Lugaresi A, Diener, Hans Christoph (Beitragende*r), Khatri, B, Barkhof, F, Comi, G, Hartung, Hp, Kappos, L, Montalban, X, Pelletier, J, Stites, T, Wu, S, Holdbrook, F, Zhang Auberson, L, Francis, G, Cohen, Ja, BRESCIA MORRA, Vincenzo, Comi, Giancarlo, TRANSFORMS Study, Group, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, and UCL - (SLuc) Service de neurologie
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Adult ,Male ,medicine.medical_specialty ,multiple sclerosis, interferon beta, fingolimod, treatment ,Multiple Sclerosis ,Adolescent ,Medizin ,Phases of clinical research ,Relapsing-Remitting ,Injections, Intramuscular ,Young Adult ,Humans ,Adjuvants, Immunologic ,Interferon-beta ,Immunosuppressive Agents ,Multiple Sclerosis, Relapsing-Remitting ,Treatment Outcome ,Middle Aged ,Propylene Glycols ,Sphingosine ,Female ,law.invention ,Injections ,Randomized controlled trial ,law ,Immunologic ,analogs /&/ derivatives/therapeutic use ,Internal medicine ,Fingolimod Hydrochloride ,Medicine ,Adjuvants ,Young adult ,Intramuscular ,business.industry ,Multiple sclerosis ,Interferon beta-1a ,medicine.disease ,Fingolimod ,Surgery ,drug therapy/pathology/physiopathology ,Clinical research ,therapeutic use, Adolescent, Adult, Female, Humans, Immunosuppressive Agents ,therapeutic use, Injections ,Intramuscular, Interferon-beta ,therapeutic use, Male, Middle Aged, Multiple Sclerosis ,drug therapy/pathology/physiopathology, Propylene Glycols ,therapeutic use, Sphingosine ,analogs /&/ derivatives/therapeutic use, Treatment Outcome, Young Adult ,therapeutic use ,Settore MED/26 - Neurologia ,Neurology (clinical) ,business ,medicine.drug - Abstract
In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod. METHODS: Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. FINDINGS: 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p
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- 2011
27. Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results
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Comi, G, O'Connor, P, Montalban, X, Antel, J, Radue, Ew, Karlsson, G, Pohlmann, H, Aradhye, S, Kappos, L, Easton, Jd, Kesselring, J, Weinshenker, Bg, Laupacis, A, Zarbin, M, Calandra, T, Temkin, N, Dimarco, J, Hudson, Ld, Durcan, L, Bar Or, A, Duquette, P, Bernier, G, Freedman, M, Maclean, H, Costello, F, Gray, Ta, Hohol, M, Devonshire, V, Oger, J, Hashimoto, S, Sørensen, Ps, Datta, P, Faber Rod JC, Frederiksen, J, Knudsen, S, Petrenaite, V, Färkkila, M, Harno, H, Halavaara, J, Elovaara, I, Kuusisto, H, Palmio, J, Airas, L, Kaasinen, V, Laaksonen, M, Vermersch, P, Pelletier, J, Feuillet, L, Suchet, L, Mauch, E, Gunser, C, Oberbeck, K, Rieckmann, P, Buttmann, M, Klein, M, Ghezzi, A, Zaffaroni, M, Baldini, S, Mancardi, G, Cioli, F, Capello, E, Rodegher, M, Radaelli, M, Pozzilli, C, Onesti, Emanuela, Romano, Silvia, Czlonkowska, A, Litwin, T, Darda Ledzion, L, Kwiecinski, H, Golebiowski, M, Podlecka, A, Cunha, L, Sousa, L, Matias, F, Pedrosa, R, Almeida, M, Pena, Je, de Sá, J, Ferreira, J, Rosa, M, Arbizu, T, Carmona, O, Casado, V, Tintore, M, Pelayo, R, Arroyo, R, Bartolome, M, De las Heras, V, Casanova, B, Bosca, I, Fernandez, O, Leon, A, Romero, F, Izquierdo, G, Gamero, M, Garcia, Jm, Kuhle, J, Mehling, M, Achtnichts, L, Goebels, N, Skulina, C, Waskoenig, J, Bates, D, Nichols, P, Bendfeldt, K, de Vera, A, Gruenbauer, W., Ben Dahan, David, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), and Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Oral ,Adult ,Male ,medicine.medical_specialty ,Multiple Sclerosis ,Time Factors ,Adolescent ,Phases of clinical research ,Administration, Oral ,Kaplan-Meier Estimate ,Relapsing-Remitting ,administration /&/ dosage/adverse effects ,Placebo ,law.invention ,Pulmonary function testing ,03 medical and health sciences ,Disability Evaluation ,Young Adult ,0302 clinical medicine ,Multiple Sclerosis, Relapsing-Remitting ,Randomized controlled trial ,law ,Sphingosine ,Internal medicine ,Fingolimod Hydrochloride ,administration /&/ dosage/adverse effects/analogs /&/ derivatives ,medicine ,Humans ,Adverse effect ,business.industry ,Fingolimod ,Magnetic Resonance Imaging ,diagnosis/drug therapy/pathology ,Administration ,Oral, Adolescent, Adult, Disability Evaluation, Female, Humans, Immunosuppressive Agents ,administration /&/ dosage/adverse effects, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Multiple Sclerosis ,diagnosis/drug therapy/pathology, Propylene Glycols ,administration /&/ dosage/adverse effects, Sphingosine ,administration /&/ dosage/adverse effects/analogs /&/ derivatives, Time Factors, Treatment Outcome, Young Adult ,3. Good health ,Surgery ,Clinical trial ,Treatment Outcome ,Neurology ,Propylene Glycols ,030220 oncology & carcinogenesis ,Female ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Immunosuppressive Agents ,medicine.drug - Abstract
In a 6-month, placebo-controlled trial, oral fingolimod (FTY720) 1.25 or 5.0 mg, once daily, significantly reduced MRI inflammatory activity and annualized relapse rate compared with placebo in patients with relapsing multiple sclerosis (MS). The objectives were to monitor the 36-month, interim efficacy and safety results of the ongoing extension of this study. In the extension (months 7—36), placebo-treated patients were re-randomized to either dose of fingolimod; fingolimod-treated patients continued at the same dose. During months 15—24, all patients receiving fingolimod 5.0 mg switched to 1.25 mg. Of the 250 patients who entered the extension study, 173 (69%) continued to month 36. Most patients were free from gadolinium-enhanced lesions (88—89%) or new T2 lesions (70—78%) at month 36. Patients receiving continuous fingolimod treatment had sustained low annualized relapse rates of 0.20—0.21, and 68—73% remained relapse-free at month 36. Over 36 months, nasopharyngitis (34%), headache (30%), fatigue (19%) and influenza (18%) were the most commonly reported adverse events. Pulmonary function remained stable and blood pressure was stable after an initial increase (3—5 mmHg) during the first 6 months of fingolimod treatment; serious adverse events included infections and skin cancer. The low MRI and clinical disease activity at 6 months were maintained at 36 months with fingolimod, which was generally well tolerated by most patients. The efficacy and safety of oral fingolimod are being further evaluated in a large phase III MS study programme.
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- 2010
28. Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study
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O'Connor, P, Comi, G, Montalban, X, Antel, J, Radue, Ew, de Vera, A, Pohlmann, H, Kappos, L, Easton, Jd, Kesselring, J, Weinshenker, Bg, Laupacis, A, Zarbin, M, Calandra, T, Temkin, N, Dimarco, J, Hudson, Ld, Durcan, L, Bar Or, A, Duquette, P, Bernier, G, Freedman, M, Maclean, H, Costello, F, Gray, Ta, Hohol, M, Devonshire, V, Hashimoto, S, Sørensen, Ps, Datta, P, Faber Rod JC, Frederiksen, J, Knudsen, S, Petrenaite, V, Harno, H, Färkkila, M, Halavaara, J, Elovaara, I, Kuusisto, H, Palmio, J, Airas, L, Kaasinen, V, Laaksonen, M, Vermersch, P, Pelletier, J, Feuillet, L, Suchet, L, Mauch, E, Gunser, C, Oberbeck, K, Rieckmann, P, Buttmann, M, Klein, M, Ghezzi, A, Zaffaroni, M, Baldini, S, Mancardi, G, Cioli, F, Capello, E, Rodegher, M, Radaelli, M, Pozzilli, C, Onesti, Emanuela, Romano, Silvia, Czlonkowska, A, Litwin, T, Darda Ledzion, L, Kwiecinski, H, Golebiowski, M, Podlecka, A, Nojszewska, K, Cunha, L, Sousa, L, Matias, F, Pedrosa, R, Almeida, M, Pena, Je, de Sá, J, Ferreira, J, Rosa, M, Arbizu, T, Carmona, O, Casado, V, Tintore, M, Pelayo, R, Arroyo, R, Bartolome, M, De las Heras, V, Casanova, B, Bosca, I, Fernandez, O, Leon, A, Romero, F, Izquierdo, G, Gamero, M, Garcia, Jm, Kuhle, J, Mehling, M, Achtnichts, L, Goebels, N, Skulina, C, Waskoenig, J, Bates, D, Nichols, P, Bendfeldt, K, Karlsson, G, Burtin, P, Zubal, T., Oconnor, P., Comi, G., Montalban, X., Antel, J., Radue, E. W., De Vera, A., Pohlmann, H., Kappos, L., and Radaelli, M
- Subjects
Male ,Time Factors ,Administration, Oral ,Kaplan-Meier Estimate ,Gastroenterology ,Severity of Illness Index ,law.invention ,Immunosuppressive Agent ,Disability Evaluation ,Randomized controlled trial ,law ,Oral administration ,Sphingosine ,hemic and lymphatic diseases ,Multiple Sclerosi ,administration /&/ dosage ,Respiratory Function Test ,Incidence ,Middle Aged ,Fingolimod ,Propylene Glycol ,Magnetic Resonance Imaging ,Respiratory Function Tests ,Tolerability ,Administration ,Female ,Oral, Adolescent, Adult, Disability Evaluation, Double-Blind Method, Female, Humans, Immunosuppressive Agents ,administration /&/ dosage, Incidence, Kaplan-Meier Estimate, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis ,drug therapy/mortality, Propylene Glycols ,administration /&/ dosage, Respiratory Function Tests ,methods, Severity of Illness Index, Sphingosine ,administration /&/ dosage/analogs /&/ derivatives, Time Factors, Young Adult ,medicine.symptom ,Immunosuppressive Agents ,medicine.drug ,Human ,Oral ,Adult ,medicine.medical_specialty ,Multiple Sclerosis ,Time Factor ,Adolescent ,Placebo ,methods ,Lesion ,Young Adult ,Double-Blind Method ,Internal medicine ,administration /&/ dosage/analogs /&/ derivatives ,Severity of illness ,medicine ,drug therapy/mortality ,Humans ,business.industry ,Fingolimod Hydrochloride ,Surgery ,Clinical trial ,Propylene Glycols ,Neurology (clinical) ,business - Abstract
Objective:: To report the results of a 24-month extension of a phase II trial assessing the efficacy, safety, and tolerability of the once-daily oral sphingosine-1-phosphate receptor modulator, fingolimod (FTY720), in relapsing multiple sclerosis (MS). METHODS:: In the randomized, double-blind, placebo-controlled core study, 281 patients received placebo or FTY720, 1.25 or 5.0 mg/day, for 6 months. During the subsequent dose-blinded extension, patients assigned to placebo were re-randomized to either dose of FTY720; those originally assigned to FTY720 continued at the same dose. Patients receiving FTY720 5.0 mg were switched to 1.25 mg during the month 15 to month 24 study visits. RESULTS:: Of 281 patients randomized in the core study, 250 (89%) entered the extension phase, and 189 (75.6%) received treatment for 24 months. During the core study, FTY720 significantly reduced gadolinium-enhanced (Gd) lesions and annualized relapse rate (ARR) compared with placebo, with no differences between doses. During the extension phase, patients who switched from placebo to FTY720 showed clear reductions in ARR and lesion counts compared with the placebo phase; ARR and lesion counts remained low in patients who continued FTY720 treatment. After 24 months, 79 to 91% of patients were free from Gd lesions and up to 77% of patients remained relapse free. FTY720 was well tolerated; no new safety concerns emerged during months 7 to 24 compared with the 6-month core study. CONCLUSIONS:: Once-daily oral treatment with FTY720, 1.25 or 5.0 mg, for up to 2 years, was well tolerated and was associated with low relapse rates and lesion activity. © 2009 AAN Enterprises, Inc.
- Published
- 2009
29. IL-2 production in human T lymphotropic virus I-infected leukemic T lymphocytes analyzed by in situ hybridization.
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Goebels, N, primary, Waase, I, additional, Pfizenmaier, K, additional, and Krönke, M, additional
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- 1988
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30. Intrathecal antibody production against Chlamydia pneumoniae in multiple sclerosis is part of a polyspecific immune response.
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Derfuss, T, Gürkov, R, Then Bergh, F, Goebels, N, Hartmann, M, Barz, C, Wilske, B, Autenrieth, I, Wick, M, Hohlfeld, R, and Meinl, E
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- 2001
31. Cellular immune mechanisms in inflammatory myopathies.
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Hohlfeld, R, Engel, A G, Goebels, N, and Behrens, L
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- 1997
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32. The role of autoimmune t lymphocytes in the pathogenesis of multiple sclerosis
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Hohlfeld, R., Meinl, E., Weber, F., Zipp, F., Schmidt, S., Sotgiu, S., Goebels, N., Voltz, R., Spuler, S., Iglesias, A., Wekerle, H., Staudt, L. M., Lenardo, M. J., Matis, L. A., Germain, R. N., Margulies, D. H., Bjorkman, P. J., Saper, M. A., Samraoui, B., Brown, J. H., Jardetzky, T. S., Gorga, J. C., Ben-Nun, A., Cohen, I. R., Toyka, K. V., Heininger, K., Drexler, K., Fleckenstein, B., Allegretta, M., Nicklas, J. A., Sriram, S., Albertini, R. J., Ofosu-Appiah, W., Mokhtarian, F., Miller, A., Grob, D., Zhang, J., Markovic, S., Lacet, B., Oksenberg, J. R., Panzara, M. A., Begovich, A. B., Kojima, K., Lannes-Vieira, J., Lassmann, H., Fritz Zimprich, Rossler, K., Berger, T., Wucherpfennig, K. W., Weiner, H. L., Hafler, D. A., Martin, R., Mcfarland, H. F., Mcfarlin, D. E., Uematsu, Y., Wege, H., Straus, A., Salvetti, M., Ristori, G., D Amato, M., Witek, C., Selmaj, K., Brosnan, C. F., Raine, C. S., Battistini, L., Kowal, C., Arnason, B. G. W., Steinman, L., Medaer, R., Stinissen, P., Bourdette, D. N., Whitham, R. H., Chou, Y. K., and Friedman, A.
33. Effects of dimethyl fumarate on neuroprotection and immunomodulation
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Albrecht Philipp, Bouchachia Imane, Goebels Norbert, Henke Nadine, Hofstetter Harald H, Issberner Andrea, Kovacs Zsuzsa, Lewerenz Jan, Lisak Dmitrij, Maher Pamela, Mausberg Anne-Kathrin, Quasthoff Kim, Zimmermann Corinna, Hartung Hans-Peter, and Methner Axel
- Subjects
Dimethyl fumarate ,Oxidative stress ,Neuroprotection ,Neuromodulation ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background Neuronal degeneration in multiple sclerosis has been linked to oxidative stress. Dimethyl fumarate is a promising novel oral therapeutic option shown to reduce disease activity and progression in patients with relapsing-remitting multiple sclerosis. These effects are presumed to originate from a combination of immunomodulatory and neuroprotective mechanisms. We aimed to clarify whether neuroprotective concentrations of dimethyl fumarate have immunomodulatory effects. Findings We determined time- and concentration-dependent effects of dimethyl fumarate and its metabolite monomethyl fumarate on viability in a model of endogenous neuronal oxidative stress and clarified the mechanism of action by quantitating cellular glutathione content and recycling, nuclear translocation of transcription factors, and the expression of antioxidant genes. We compared this with changes in the cytokine profiles released by stimulated splenocytes measured by ELISPOT technology and analyzed the interactions between neuronal and immune cells and neuronal function and viability in cell death assays and multi-electrode arrays. Our observations show that dimethyl fumarate causes short-lived oxidative stress, which leads to increased levels and nuclear localization of the transcription factor nuclear factor erythroid 2-related factor 2 and a subsequent increase in glutathione synthesis and recycling in neuronal cells. Concentrations that were cytoprotective in neuronal cells had no negative effects on viability of splenocytes but suppressed the production of proinflammatory cytokines in cultures from C57BL/6 and SJL mice and had no effects on neuronal activity in multi-electrode arrays. Conclusions These results suggest that immunomodulatory concentrations of dimethyl fumarate can reduce oxidative stress without altering neuronal network activity.
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- 2012
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34. Vignette.
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Goebels, N. and Hamann, G. F.
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MAGNETIC resonance imaging ,SUBDURAL hematoma ,WARFARIN ,ANTIPHOSPHOLIPID syndrome ,HEMORRHAGE - Abstract
Describes a magnetic resonance images of an excessive subdural hemorrhage associated with warfarin treatment in antiphospholipid antibody syndrome.
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- 2001
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35. Collateral Bystander Damage by Myelin-Directed CD8+ T Cells Causes Axonal Loss
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Urs Ziegler, Melanie D. Harrer, Katja Fischer, Norbert Goebels, Bettina Sobottka, Heinz Wiendl, Burkhard Becher, Thomas Hünig, University of Zurich, and Goebels, N
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Central Nervous System ,Cytotoxicity, Immunologic ,Pathology ,medicine.medical_specialty ,Multiple Sclerosis ,Central nervous system ,Axonal loss ,Autoimmunity ,Mice, Transgenic ,610 Medicine & health ,Inflammation ,CD8-Positive T-Lymphocytes ,Biology ,10263 Institute of Experimental Immunology ,Autoantigens ,Pathology and Forensic Medicine ,Mice ,03 medical and health sciences ,Myelin ,Organ Culture Techniques ,0302 clinical medicine ,Antigen ,medicine ,Animals ,Cytotoxic T cell ,Axon ,Myelin Sheath ,Multiple sclerosis ,medicine.disease ,Axons ,2734 Pathology and Forensic Medicine ,Oligodendroglia ,medicine.anatomical_structure ,nervous system ,570 Life sciences ,biology ,10024 Center for Microscopy and Image Analysis ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery ,Regular Articles ,030215 immunology - Abstract
Permanent disability of patients suffering from central nervous system (CNS) inflammation such as multiple sclerosis, the most common chronic inflammatory disorder of the CNS, originates mainly from demyelination and axonal damage. Although many studies in the past focused on the role of CD4(+) T cells, several recent findings postulate the relevance of autoaggressive, cytotoxic CD8(+) T cells in the effector phase of multiple sclerosis. Yet, it remains unresolved whether axonal injury is the result of a CD8(+) T cell-targeted hit against the axon itself or the consequence of an attack against the myelin structure. To address this issue of CD8-mediated tissue damage in CNS inflammation, we performed continuous confocal imaging of autoaggressive, cytotoxic CD8(+) T cells in living organotypic cerebellar brain slices. We observed that loading brain slices with the cognate peptide antigen caused CD8-mediated damage of myelinated axons. To exclude the possibility that the cognate peptide loaded onto the brain slices was presented by axons directly, we restricted the cognate antigen expression exclusively to the cytosol of oligodendrocytes. Aside from vast myelin damage, extensive axonal bystander injury occurred. Using this model system of inflammatory CNS injury, we visualize that axonal loss can be the consequence from "collateral bystander damage" by autoaggressive, cytotoxic CD8(+) T cells, targeting their cognate antigen processed and presented by oligodendrocytes.
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- 2009
36. Die Bedeutung löslicher TNF-Familienmitglieder für die multiple Sklerose
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Ehrlich, Stefan, Zipp, F., Goebels, N., and Sommer, N.
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Multiple Sklerose ,Multiple Sclerosis ,YG 6021 ,Apoptose ,sCD95 ,610 Medizin ,YG 6004 ,IFN-beta ,Apoptosis ,B-cell ,YG 6018 ,Monocyte ,TNF-related apoptosis-inducing Ligand (TRAIL) ,T-Zelle ,T-cell ,Monozyt ,ddc:610 ,33 Medizin ,B-Zelle - Abstract
Bei Autoimmunkrankheiten wie der Multiplen Sklerose (MS) kommt es zu einer fehlgesteuerten Immunantwort mit Aktivierung und Persistenz autoreaktiver T-Zellen. Apoptose-regulierende Mechanismen wie das CD95-Rezeptor/CD95-Ligand- und TRAIL-Rezeptor/TRAIL-System könnten dabei eine wichtige Rolle spielen. Die lösliche Form des CD95-Rezeptor (sCD95) kann an CD95L binden und so die Apoptose aktivierter T-Zellen verhindern. Die systemische Blockade von TRAIL führt zur Exazerbation von Autoimmunerkrankungen in Tierversuchen. In der vorliegenden Arbeit wurden deshalb die Expression, Regulation und Bedeutung sowohl von sCD95 als auch von löslichem TRAIL (sTRAIL) und membranständigem TRAIL bei gesunden Probanden und Patienten mit schubförmig remittierender MS (RRMS) untersucht. Zytokine wurden mit ELISAs, Zelloberflächenproteine sowie Apoptose im Durchflusszytometer gemessen. Die Untersuchungen mit magnetisch gereinigten humanen Leukozytensubpopulationen und Zelllinien zeigten, dass sCD95 lediglich von zelltyp-spezifisch aktivierten humanen T-Zellen, sezerniert wird. TRAIL wurde vor allem von Monozyten, die mit IFN-beta stimuliert waren, sezerniert und auf der Zelloberfläche exprimiert. Zellkulturüberstände, die sTRAIL enthielten, lösten Apoptose in suszeptiblen Tumorzellen aus. TRAIL führte zu einer signifikanten Inhibition der Proliferation und der Produktion von Th1- und Th2-spezifischen Zytokinen bei humanen (auto)antigenspezifischen T-Zellen. Weder für die sCD95- noch für die TRAIL-Expression wurden Unterschiede zwischen RRMS-Patienten und gesunden Probanden nachgewiesen. Die Ergebnisse dieser Arbeit zeigen ein komplexes Regulations- und Expressionsmuster von sCD95 und TRAIL, ohne jedoch Anhaltspunkte für Unterschiede zwischen MS-Patienten und Gesunden zu liefern. Es ergaben sich wichtige Hinweise darauf, dass der protektive immunomodulatorische Effekt einer systemischen IFN-beta-Therapie bei MS durch TRAIL vermittelt werden könnte. Autoimmune disorders such as Multiple Sclerosis (MS) are characterized by an aberrant immune response with activation and persistence of autoreactive T-cells. Apoptosis-regulating mechanism such as the CD95-Rezeptor/CD95-Ligand- and the TRAIL-Rezeptor/TRAIL-System may play a major role in this process. The soluble CD95 receptor (sCD95) can bind to CD95L and subsequently inhibit apoptosis of activated T-cells. The systemic blockade of TRAIL leads to the exacerbation of autoimmune disease in animal experiments. In this work I investigated the expression, regulation and significance of sCD95, soluble TRAIL (sTRAIL) and membrane-bound TRAIL in patients with remitting-relapsing MS (RRMS), and in healthy controls. Cytokines were measured by ELISA, membrane bound proteins and apoptosis were measured by flow cytometry. The experiments with magnetically sorted human leucocyte subpopulations and cell lines showed, that only cell-type specific activated human T-cells secrete sCD95. Both forms of TRAIL were expressed by monocytes stimulated with IFN-beta. Cell supernatants containing sTRAIL induced apoptosis in susceptible tumour cells. Furthermore TRAIL inhibited proliferation of (auto)antigen-specific T cells and the production of Th-1 and Th-2 specific cytokines. There were no differences in the expression of sCD95 and TRAIL between RRMS patients and healthy controls. This work shows a complex regulation pattern of sCD95 and TRAIL without being able to detect differences between MS patients and healthy controls. However, results point out that TRAIL could be an important mediator of the immunomodulatory effects of systemic IFN-beta therapy in MS.
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- 2006
37. A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.
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Strippel C, Herrera-Rivero M, Wendorff M, Tietz AK, Degenhardt F, Witten A, Schroeter C, Nelke C, Golombeck KS, Madlener M, Rüber T, Ernst L, Racz A, Baumgartner T, Widman G, Doppler K, Thaler F, Siebenbrodt K, Dik A, Kerin C, Räuber S, Gallus M, Kovac S, Grauer OM, Grimm A, Prüss H, Wickel J, Geis C, Lewerenz J, Goebels N, Ringelstein M, Menge T, Tackenberg B, Kellinghaus C, Bien CG, Kraft A, Zettl U, Ismail FS, Ayzenberg I, Urbanek C, Sühs KW, Tauber SC, Mues S, Körtvélyessy P, Markewitz R, Paliantonis A, Elger CE, Surges R, Sommer C, Kümpfel T, Gross CC, Lerche H, Wellmer J, Quesada CM, Then Bergh F, Wandinger KP, Becker AJ, Kunz WS, Meyer Zu Hörste G, Malter MP, Rosenow F, Wiendl H, Kuhlenbäumer G, Leypoldt F, Lieb W, Franke A, Meuth SG, Stoll M, and Melzer N
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- Humans, Proteome genetics, Histocompatibility Antigens Class II, HLA Antigens, Haplotypes, Alleles, Autoantibodies, HLA-DRB1 Chains genetics, Genome-Wide Association Study, Genetic Predisposition to Disease genetics
- Abstract
Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
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38. Myelinating Co-Culture as a Model to Study Anti-NMDAR Neurotoxicity.
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Sabet MF, Barman S, Beller M, Meuth SG, Melzer N, Aktas O, Goebels N, and Prozorovski T
- Subjects
- Humans, Coculture Techniques, Receptors, N-Methyl-D-Aspartate metabolism, Neuroglia metabolism, Myelin-Oligodendrocyte Glycoprotein, Autoantibodies, Aquaporin 4, Neuromyelitis Optica, Anti-N-Methyl-D-Aspartate Receptor Encephalitis
- Abstract
Anti-NMDA receptor (NMDAR) encephalitis is frequently associated with demyelinating disorders (e.g., multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD)) with regard to clinical presentation, neuropathological and cerebrospinal fluid findings. Indeed, autoantibodies (AABs) against the GluN1 (NR1) subunit of the NMDAR diminish glutamatergic transmission in both neurons and oligodendrocytes, leading to a state of NMDAR hypofunction. Considering the vital role of oligodendroglial NMDAR signaling in neuron-glia communication and, in particular, in tightly regulated trophic support to neurons, the influence of GluN1 targeting on the physiology of myelinated axon may be of importance. We applied a myelinating spinal cord cell culture model that contains all major CNS cell types, to evaluate the effects of a patient-derived GluN1-specific monoclonal antibody (SSM5) on neuronal and myelin integrity. A non-brain reactive (12D7) antibody was used as the corresponding isotype control. We show that in cultures at the late stage of myelination, prolonged treatment with SSM5, but not 12D7, leads to neuronal damage. This is characterized by neurite blebbing and fragmentation, and a reduction in the number of myelinated axons. However, this significant toxic effect of SSM5 was not observed in earlier cultures at the beginning of myelination. Anti-GluN1 AABs induce neurodegenerative changes and associated myelin loss in myelinated spinal cord cultures. These findings may point to the higher vulnerability of myelinated neurons towards interference in glutamatergic communication, and may refer to the disturbance of the NMDAR-mediated oligodendrocyte metabolic supply. Our work contributes to the understanding of the emerging association of NMDAR encephalitis with demyelinating disorders.
- Published
- 2022
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39. Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity.
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Ruck T, Barman S, Schulte-Mecklenbeck A, Pfeuffer S, Steffen F, Nelke C, Schroeter CB, Willison A, Heming M, Müntefering T, Melzer N, Krämer J, Lindner M, Riepenhausen M, Gross CC, Klotz L, Bittner S, Muraro PA, Schneider-Hohendorf T, Schwab N, Meyer Zu Hörste G, Goebels N, Meuth SG, and Wiendl H
- Subjects
- Alemtuzumab adverse effects, Humans, Phenotype, Proteomics, Autoimmune Diseases chemically induced, Autoimmunity
- Abstract
Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
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40. Multimodal electrophysiological analyses reveal that reduced synaptic excitatory neurotransmission underlies seizures in a model of NMDAR antibody-mediated encephalitis.
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Wright SK, Rosch RE, Wilson MA, Upadhya MA, Dhangar DR, Clarke-Bland C, Wahid TT, Barman S, Goebels N, Kreye J, Prüss H, Jacobson L, Bassett DS, Vincent A, Greenhill SD, and Woodhall GL
- Subjects
- Animals, Anti-N-Methyl-D-Aspartate Receptor Encephalitis chemically induced, Disease Models, Animal, Male, Rats, Rats, Wistar, Autoantibodies adverse effects, Synaptic Transmission
- Abstract
Seizures are a prominent feature in N-Methyl-D-Aspartate receptor antibody (NMDAR antibody) encephalitis, a distinct neuro-immunological disorder in which specific human autoantibodies bind and crosslink the surface of NMDAR proteins thereby causing internalization and a state of NMDAR hypofunction. To further understand ictogenesis in this disorder, and to test a potential treatment compound, we developed an NMDAR antibody mediated rat seizure model that displays spontaneous epileptiform activity in vivo and in vitro. Using a combination of electrophysiological and dynamic causal modelling techniques we show that, contrary to expectation, reduction of synaptic excitatory, but not inhibitory, neurotransmission underlies the ictal events through alterations in the dynamical behaviour of microcircuits in brain tissue. Moreover, in vitro application of a neurosteroid, pregnenolone sulphate, that upregulates NMDARs, reduced established ictal activity. This proof-of-concept study highlights the complexity of circuit disturbances that may lead to seizures and the potential use of receptor-specific treatments in antibody-mediated seizures and epilepsy., (© 2021. The Author(s).)
- Published
- 2021
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41. Modified recombinant human IgG1-Fc is superior to natural intravenous immunoglobulin at inhibiting immune-mediated demyelination.
- Author
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Baksmeier C, Blundell P, Steckel J, Schultz V, Gu Q, Da Silva Filipe A, Kohl A, Linnington C, Lu D, Dell A, Haslam S, Wang J, Czajkowsky D, Goebels N, and Pleass RJ
- Subjects
- Animals, Autoantibodies genetics, Cerebellum drug effects, Demyelinating Diseases immunology, HEK293 Cells, Humans, Immunoglobulin Fc Fragments genetics, Immunoglobulin G genetics, Immunoglobulins, Intravenous therapeutic use, Mice, Mice, Inbred C57BL, Myelin-Oligodendrocyte Glycoprotein immunology, Oligodendroglia drug effects, Organ Culture Techniques, Recombinant Fusion Proteins genetics, Autoantibodies therapeutic use, Cerebellum pathology, Demyelinating Diseases therapy, Immunoglobulin Fc Fragments therapeutic use, Immunoglobulin G therapeutic use, Oligodendroglia pathology, Recombinant Fusion Proteins therapeutic use
- Abstract
Intravenous immunoglobulin (IVIG) is an established treatment for numerous autoimmune conditions. Although Fc fragments derived from IVIG have shown efficacy in controlling immune thrombocytopenia in children, the mechanisms of action are unclear and controversial. The aim of this study was to dissect IVIG effector mechanisms using further adapted Fc fragments on demyelination in an ex vivo model of the central nervous system-immune interface. Using organotypic cerebellar slice cultures (OSCs) from transgenic mice, we induced extensive immune-mediated demyelination and oligodendrocyte loss with an antibody specific for myelin oligodendrocyte glycoprotein (MOG) and complement. Protective effects of adapted Fc fragments were assessed by live imaging of green fluorescent protein expression, immunohistochemistry and confocal microscopy. Cysteine- and glycan-adapted Fc fragments protected OSC from demyelination in a dose-dependent manner where equimolar concentrations of either IVIG or control Fc were ineffective. The protective effects of the adapted Fc fragments are partly attributed to interference with complement-mediated oligodendroglia damage. Transcriptome analysis ruled out signatures associated with inflammatory or innate immune responses. Taken together, our findings show that recombinant biomimetics can be made that are at least two hundred-fold more effective than IVIG in controlling demyelination by anti-MOG antibodies., (© 2021 The Authors. Immunology published by John Wiley & Sons Ltd.)
- Published
- 2021
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42. [Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)].
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Wiendl H, Gold R, Berger T, Derfuss T, Linker R, Mäurer M, Stangel M, Aktas O, Baum K, Berghoff M, Bittner S, Chan A, Czaplinski A, Deisenhammer F, Di Pauli F, Du Pasquier R, Enzinger C, Fertl E, Gass A, Gehring K, Gobbi C, Goebels N, Guger M, Haghikia A, Hartung HP, Heidenreich F, Hoffmann O, Hunter ZR, Kallmann B, Kleinschnitz C, Klotz L, Leussink V, Leutmezer F, Limmroth V, Lünemann JD, Lutterotti A, Meuth SG, Meyding-Lamadé U, Platten M, Rieckmann P, Schmidt S, Tumani H, Weber MS, Weber F, Zettl UK, Ziemssen T, and Zipp F
- Subjects
- Central Nervous System, Consensus, Europe, Germany, Humans, Multiple Sclerosis diagnosis, Multiple Sclerosis drug therapy
- Abstract
Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland)., (© 2021. The Author(s).)
- Published
- 2021
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43. Association of Retinal Layer Thickness With Cognition in Patients With Multiple Sclerosis.
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Baetge SJ, Dietrich M, Filser M, Renner A, Stute N, Gasis M, Weise M, Lepka K, Graf J, Goebels N, Hartung HP, Aktas O, Meuth S, Albrecht P, and Penner IK
- Subjects
- Adolescent, Adult, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Neuropsychological Tests, Tomography, Optical Coherence, Young Adult, Cognitive Dysfunction diagnosis, Cognitive Dysfunction etiology, Cognitive Dysfunction physiopathology, Multiple Sclerosis, Chronic Progressive complications, Multiple Sclerosis, Chronic Progressive diagnostic imaging, Multiple Sclerosis, Chronic Progressive pathology, Multiple Sclerosis, Relapsing-Remitting complications, Multiple Sclerosis, Relapsing-Remitting diagnostic imaging, Multiple Sclerosis, Relapsing-Remitting pathology, Retinal Neurons pathology
- Abstract
Objective: Retinal layer thickness (RLT) measured by optical coherence tomography (OCT) is considered a noninvasive, cost-efficient marker of neurodegeneration in multiple sclerosis (MS). We aimed to investigate associations of RLT with cognitive performance and its potential as indicator of cognitive status in patients with MS by performing generalized estimating equation (GEE) analyses., Methods: In this cross-sectional study, patients with at least mild signs of cognitive impairment were examined by OCT as well as by the Brief International Cognitive Assessment for MS and tests assessing attention and executive functions (Trail Making Test [TMT] A and B). Associations of these factors were investigated using GEE models controlling for demographic and disease-related factors and correcting for multiple testing., Results: A total of 64 patients entered the study. In the final sample (n = 50 [n = 14 excluded due to missing data or drop-outs]; n = 44 relapsing-remitting MS and n = 6 secondary progressive MS, mean Expanded Disability Status Scale score = 2.59 [SD = 1.17], disease duration [median] = 7.34 [interquartile range = 12.1]), 36.0% were cognitively impaired. RLT of the macular retinal nerve fiber layer was associated with performance in TMT-B (β = -0.259). Analyses focusing on the upper and lower tertile of RLT additionally revealed associations between macular ganglion cell-inner plexiform layer and TMT-B and verbal short-term memory and learning, respectively., Conclusion: In patients with MS, at less advanced disease stages, RLT was especially associated with cognitive flexibility promoting OCT as a potential marker advocating further extensive neuropsychological examination., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2021
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44. Serum neurofilament light chain: No clear relation to cognition and neuropsychiatric symptoms in stable MS.
- Author
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Aktas O, Renner A, Huss A, Filser M, Baetge S, Stute N, Gasis M, Lepka K, Goebels N, Senel M, Graf J, Enzinger C, Pinter D, Antoch G, Turowski B, Hartung HP, Albrecht P, Otto M, Tumani H, and Penner IK
- Subjects
- Adolescent, Adult, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Patient Reported Outcome Measures, Severity of Illness Index, Young Adult, Anxiety blood, Anxiety etiology, Anxiety physiopathology, Cognitive Dysfunction blood, Cognitive Dysfunction etiology, Cognitive Dysfunction physiopathology, Depression blood, Depression etiology, Depression physiopathology, Fatigue blood, Fatigue etiology, Fatigue physiopathology, Multiple Sclerosis blood, Multiple Sclerosis complications, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis physiopathology, Neurofilament Proteins blood
- Abstract
Objective: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety., Methods: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions., Results: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup ( p = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning ( r = -0.950, p = 0.001) and memory ( r = -0.813; p = 0.026) disappeared when further controlling for age, educational level, and sex., Conclusions: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2020
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45. Case Report: A Case of Severe Clinical Deterioration in a Patient With Multiple Sclerosis.
- Author
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Breitkopf K, Aytulun A, Förster M, Kraus B, Turowski B, Huppert D, Goebels N, Hefter H, Aktas O, Metz I, Brück W, Reifenberger G, Hartung HP, and Albrecht P
- Abstract
Tumefactive multiple sclerosis (MS) is a rare variant of MS that may lead to a rapidly progressive clinical deterioration requiring a multidisciplinary diagnostic workup. Our report describes the diagnostic and therapeutic approach of a rare and extremely severe course of MS. A 51-year-old man with an 8-year history of relapsing-remitting MS (RRMS) was admitted with a subacute progressive left lower limb weakness and deterioration of walking ability. After extensive investigations including repeated MRI, microbiological, serological, cerebrospinal fluid (CSF) studies, and finally brain biopsy, the diagnosis of a tumefactive MS lesion was confirmed. Despite repeated intravenous (IV) steroids as well as plasma exchanges and IV foscarnet and ganciclovir owing to low copy numbers of human herpesvirus 6 (HHV-6) DNA in polymerase chain reaction (PCR) analysis, the patient did not recover. The clinical presentation of tumefactive MS is rare and variable. Brain biopsy for histopathological workup should be considered in immunocompromised patients with rapidly progressive clinical deterioration with brain lesions of uncertain cause., (Copyright © 2020 Breitkopf, Aytulun, Förster, Kraus, Turowski, Huppert, Goebels, Hefter, Aktas, Metz, Brück, Reifenberger, Hartung and Albrecht.)
- Published
- 2020
- Full Text
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46. [Erratum to: Ocrelizumab for treatment of multiple sclerosis].
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Graf J, Albrecht P, Goebels N, Aktas O, and Hartung HP
- Published
- 2020
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47. [Ocrelizumab for treatment of multiple sclerosis].
- Author
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Graf J, Albrecht P, Goebels N, Aktas O, and Hartung HP
- Subjects
- Humans, Immunologic Factors adverse effects, Antibodies, Monoclonal, Humanized therapeutic use, Multiple Sclerosis drug therapy
- Abstract
Ocrelizumab is a monoclonal antibody directed against the differentiation antigen CD20, which leads to an effective long-term depletion of lymphocytes, in particular B cells. Recently published phase 3 studies confirmed that ocrelizumab is effective in the treatment of both relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS). Based on these results, ocrelizumab was the first drug to be approved for primary chronic progressive MS. To place this therapeutic breakthrough in the context of the current MS therapeutic landscape, it is worthwhile taking a look back at the development of antibody-mediated CD20 depletion, the studies underlying the approval of ocrelizumab and their open extension phases. This review article discusses the available data on the efficacy and safety of long-term B‑cell depletion in MS patients and reviews current knowledge on the role of B‑lymphocytes in the immunopathogenesis of MS.
- Published
- 2020
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48. N-Methyl-D-Aspartate Receptor Antibodies in Autoimmune Encephalopathy Alter Oligodendrocyte Function.
- Author
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Matute C, Palma A, Serrano-Regal MP, Maudes E, Barman S, Sánchez-Gómez MV, Domercq M, Goebels N, and Dalmau J
- Subjects
- Adolescent, Adult, Animals, Anti-N-Methyl-D-Aspartate Receptor Encephalitis immunology, Autoantibodies cerebrospinal fluid, Autoantibodies pharmacology, Autoantigens immunology, Cells, Cultured, Child, Female, Glucose Transporter Type 1 biosynthesis, Humans, Male, Oligodendroglia drug effects, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate immunology, Young Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis metabolism, Autoantibodies immunology, Oligodendroglia metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
Objective: Antibodies against neuronal N-methyl-D-aspartate receptors (NMDARs) in patients with anti-NMDAR encephalitis alter neuronal synaptic function and plasticity, but the effects on other cells of the nervous system are unknown., Methods: Cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis (preabsorbed or not with GluN1) and a human NMDAR-specific monoclonal antibody (SSM5) derived from plasma cells of a patient, along the corresponding controls, were used in the studies. To evaluate the activity of oligodendrocyte NMDARs and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in vitro after exposure to patients' CSF antibodies or SSM5, we used a functional assay based on cytosolic Ca
2+ imaging. Expression of the glucose transporter (GLUT1) in oligodendrocytes was assessed by immunocytochemistry., Results: NMDAR agonist responses were robustly reduced after preincubation of oligodendrocytes with patients' CSF or SSM5 but remained largely unaltered with the corresponding controls. These effects were NMDAR specific, as patients' CSF did not alter responses to AMPA receptor agonists and was abrogated by preabsorption of CSF with HEK cells expressing GluN1 subunit. Patients' CSF also reduced oligodendrocyte expression of glucose transporter GLUT1 induced by NMDAR activity., Interpretation: Antibodies from patients with anti-NMDAR encephalitis specifically alter the function of NMDARs in oligodendrocytes, causing a decrease of expression of GLUT1. Considering that normal GLUT1 expression in oligodendrocytes and myelin is needed to metabolically support axonal function, the findings suggest a link between antibody-mediated dysfunction of NMDARs in oligodendrocytes and the white matter alterations reported in patients with this disorder. ANN NEUROL 2020;87:670-676., (© 2020 American Neurological Association.)- Published
- 2020
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49. Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.
- Author
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Dietrich M, Koska V, Hecker C, Göttle P, Hilla AM, Heskamp A, Lepka K, Issberner A, Hallenberger A, Baksmeier C, Steckel J, Balk L, Knier B, Korn T, Havla J, Martínez-Lapiscina EH, Solà-Valls N, Manogaran P, Olbert ED, Schippling S, Cruz-Herranz A, Yiu H, Button J, Caldito NG, von Gall C, Mausberg AK, Stettner M, Zimmermann HG, Paul F, Brandt AU, Küry P, Goebels N, Aktas O, Berndt C, Saidha S, Green AJ, Calabresi PA, Fischer D, Hartung HP, and Albrecht P
- Subjects
- Adult, Aged, Animals, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Humans, Male, Mice, Mice, Inbred C57BL, Middle Aged, Neural Stem Cells drug effects, Potassium Channel Blockers pharmacology, Rats, Rats, Wistar, 4-Aminopyridine pharmacology, Multiple Sclerosis pathology, Neuroprotective Agents pharmacology, Optic Neuritis pathology, Retinal Degeneration pathology
- Abstract
Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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50. An Assay to Determine Mechanisms of Rapid Autoantibody-Induced Neurotransmitter Receptor Endocytosis and Vesicular Trafficking in Autoimmune Encephalitis.
- Author
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Amedonu E, Brenker C, Barman S, Schreiber JA, Becker S, Peischard S, Strutz-Seebohm N, Strippel C, Dik A, Hartung HP, Budde T, Wiendl H, Strünker T, Wünsch B, Goebels N, Meuth SG, Seebohm G, and Melzer N
- Abstract
N-Methyl-D-aspartate (NMDA) receptors (NMDARs) are among the most important excitatory neurotransmitter receptors in the human brain. Autoantibodies to the human NMDAR cause the most frequent form of autoimmune encephalitis involving autoantibody-mediated receptor cross-linking and subsequent internalization of the antibody-receptor complex. This has been deemed to represent the predominant antibody effector mechanism depleting the NMDAR from the synaptic and extra-synaptic neuronal cell membrane. To assess in detail the molecular mechanisms of autoantibody-induced NMDAR endocytosis, vesicular trafficking, and exocytosis we transiently co-expressed rat GluN1-1a-EGFP and GluN2B-ECFP alone or together with scaffolding postsynaptic density protein 95 (PSD-95), wild-type (WT), or dominant-negative (DN) mutant Ras-related in brain (RAB) proteins (RAB5WT, RAB5DN, RAB11WT, RAB11DN) in HEK 293T cells. The cells were incubated with a pH-rhodamine-labeled human recombinant monoclonal GluN1 IgG1 autoantibody (GluN1-aAb
pH-rhod ) genetically engineered from clonally expanded intrathecal plasma cells from a patient with anti-NMDAR encephalitis, and the pH-rhodamine fluorescence was tracked over time. We show that due to the acidic luminal pH, internalization of the NMDAR-autoantibody complex into endosomes and lysosomes increases the pH-rhodamine fluorescence. The increase in fluorescence allows for mechanistic assessment of endocytosis, vesicular trafficking in these vesicular compartments, and exocytosis of the NMDAR-autoantibody complex under steady state conditions. Using this method, we demonstrate a role for PSD-95 in stabilization of NMDARs in the cell membrane in the presence of GluN1-aAbpH-rhod , while RAB proteins did not exert a significant effect on vertical trafficking of the internalized NMDAR autoantibody complex in this heterologous expression system. This novel assay allows to unravel molecular mechanisms of autoantibody-induced receptor internalization and to study novel small-scale specific molecular-based therapies for autoimmune encephalitis syndromes.- Published
- 2019
- Full Text
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