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1. Plasma Exchange versus Intravenous Immunoglobulin in Worsening Myasthenia Gravis: A Systematic Review and Meta-Analysis with Special Attention to Faster Relapse Control

Author

Mark Pavlekovics, Marie Anne Engh, Katalin Lugosi, Laszlo Szabo, Peter Hegyi, Tamas Terebessy, Gabor Csukly, Zsolt Molnar, Zsolt Illes, and Gabor Lovas

Subjects
myasthenia gravis, relapse, plasma exchange, intravenous immunoglobulin, meta-analysis, Biology (General), QH301-705.5
Abstract

Currently used rescue interventions to prevent rapid myasthenic deterioration are plasma exchange (PLEX) and intravenous immunoglobulin (IVIG). We investigated the evidence to determine whether the two methods were interchangeable or whether one was superior to the other. This review was registered on PROSPERO (CRD42021285985). Only randomized controlled trials (RCTs) comparing the efficacy and safety of PLEX and IVIG in patients with moderate-to-severe myasthenia gravis (MG) were included. Five major databases were systematically searched (PubMed, CENTRAL, Embase, Scopus, and Web of Science). Odds ratios (OR) with 95% confidence intervals (CI) were calculated for adverse events and mean differences (MD) for changes in quantitative myasthenia gravis scores (QMG). Three RCTs met the inclusion criteria. Two investigating 114 patients in total were eligible for meta-analysis to analyze efficacy and safety. For the change in QMG score, the MD was −2.8 (95% CI: −5.614–0.113), with PLEX performing better. For adverse events, an OR of 1.04 was found (95% CI: 0.25–4.27). This study demonstrated a low risk of bias in evaluating treatment efficacy but indicated a high risk of bias in assessing procedural safety outcomes. Although the results did not show any significant difference, there was a tendency indicating faster efficacy of PLEX in the first two weeks of treatment. In such a critical clinical condition, this tendency may be clinically meaningful, but further studies should clarify this benefit.

Published
2023
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2. Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

Author

Mantegazza, R., Wolfe, G. I., Muppidi, S., Wiendl, H., Fujita, K. P., O'Brien, F. L., Booth, H. D. E., Howard, J. F., Claudio Gabriel Mazia, Miguel, Wilken, Fabio, Barroso, Juliet, Saba, Marcelo, Rugiero, Mariela, Bettini, Marcelo, Chaves, Gonzalo, Vidal, Alejandra Dalila Garcia, Jan De Bleecker, Guy Van den Abeele, Kathy de Koning, Katrien De Mey, Rudy, Mercelis, Délphine, Mahieu, Linda, Wagemaekers, Philip Van Damme, Annelies, Depreitere, Caroline, Schotte, Charlotte, Smetcoren, Olivier, Stevens, Sien Van Daele, Nicolas, Vandenbussche, Annelies, Vanhee, Sarah, Verjans, Jan, Vynckier, Ann, D'Hont, Petra, Tilkin, Alzira Alves de Siqueira Carvalho, Igor Dias Brockhausen, David, Feder, Daniel, Ambrosio, Gabor Lovasamela César, Ana Paula Melo, Renata Martins Ribeiro, Rosana, Rocha, Bruno Bezerra Rosa, Thabata, Veiga, Luiz Augusto da Silva, Murilo Santos Engel, Jordana Gonçalves Geraldo, Maria da Penha Ananias Morita, Erica Nogueira Coelho, Gabriel, Paiva, Marina, Pozo, Natalia, Prando, Debora Dada Martineli Torres, Cristiani Fernanda Butinhao, Gustavo, Duran, Tomás Augusto Suriane Fialho, Tamires Cristina Gomes da Silva, Luiz Otavio Maia Gonçalves, Lucas Eduardo Pazetto, Luciana Renata Cubas Volpe, Luciana Souza Duca, Maurício AndréGheller Friedrich, Alexandre, Guerreiro, Henrique, Mohr, Maurer Pereira Martins, Daiane da Cruz Pacheco, Luciana, Ferreira, Ana Paula Macagnan, Graziela, Pinto, Aline de Cassia Santos, Acary Souza Bulle Oliveira, Ana Carolina Amaral de Andrade, Marcelo, Annes, Liene Duarte Silva, Valeria Cavalcante Lino, Wladimir, Pinto, Natália, Assis, Fernanda, Carrara, Carolina, Miranda, Iandra, Souza, Patrícia, Fernandes, Zaeem, Siddiqi, Cecile, Phan, Jeffrey, Narayan, Derrick, Blackmore, Ashley, Mallon, Rikki, Roderus, Elizabeth, Watt, Stanislav, Vohanka, Josef, Bednarik, Magda, Chmelikova, Marek, Cierny, Stanislava, Toncrova, Jana, Junkerova, Barbora, Kurkova, Katarina, Reguliova, Olga, Zapletalova, Jiri, Pitha, Iveta, Novakova, Michaela, Tyblova, Ivana, Jurajdova, Marcela, Wolfova, Henning, Andersen, Thomas, Harbo, Lotte, Vinge, Susanne, Krogh, Anita, Mogensen, John, Vissing, Joan, Højgaard, Nanna, Witting, Anne Mette Ostergaard Autzen, Jane, Pedersen, Juha-Pekka, Erälinna, Mikko, Laaksonen, Olli, Oksaranta, Tuula, Harrison, Jaana, Eriksson, Csilla, Rozsa, Melinda, Horvath, Gabor, Lovas, Judit, Matolcsi, Gedeonne, Jakab, Gyorgyi, Szabo, Brigitta, Szabadosne, Laszlo, Vecsei, Livia, Dezsi, Edina, Varga, Monika, Konyane, Antonini, Giovanni, Antonella Di Pasquale, Garibaldi, Matteo, Morino, Stefania, Troili, Fernanda, Fionda, Laura, Amelia, Evoli, Paolo Emilio Alboini, Valentina, D'Amato, Raffaele, Iorio, Inghilleri, Maurizio, Frasca, Vittorio, Elena, Giacomelli, Gori, MARIA CRISTINA, Diego, Lopergolo, Onesti, Emanuela, Maria, Gabriele, Francesco, Saccà, Alessandro, Filla, Teresa, Costabile, Enrico, Marano, Angiola, Fasanaro, Angela, Marsili, Giorgia, Puorro, Carlo, Antozzi, Silvia, Bonanno, Giorgia, Camera, Alberta, Locatelli, Lorenzo, Maggi, Maria, Pasanisi, Angela, Campanella, Akiyuki, Uzawa, Tetsuya, Kanai, Naoki, Kawaguchi, Masahiro, Mori, Yoko, Kaneko, Akiko, Kanzaki, Eri, Kobayashi, Hiroyuki, Murai, Katsuhisa, Masaki, Dai, Matsuse, Takuya, Matsushita, Taira, Uehara, Misa, Shimpo, Maki, Jingu, Keiko, Kikutake, Yumiko, Nakamura, Yoshiko, Sano, Kimiaki, Utsugisawa, Yuriko, Nagane, Ikuko, Kamegamori, Tomoko, Tsuda, Yuko, Fujii, Kazumi, Futono, Yukiko, Ozawa, Aya, Mizugami, Yuka, Saito, Makoto, Samukawa, Hidekazu, Suzuki, Miyuki, Morikawa, Sachiko, Kamakura, Eriko, Miyawaki, Meinoshin, Okumura, Soichiro, Funaka, Tomohiro, Kawamura, Masayuki, Nakamori, Masanori, Takahashi, Namie, Taichi, Tomoya, Hasuike, Eriko, Higuchi, Hisako, Kobayashi, Kaori, Osakada, Hirokazu, Shiraishi, Teiichiro, Miyazaki, Masakatsu, Motomura, Akihiro, Mukaino, Shunsuke, Yoshimura, Shizuka, Asada, Seiko, Yoshida, Shoko, Amamoto, Tomomi, Kobashikawa, Megumi, Koga, Maeda, Yasuko, Kazumi, Takada, Mihoko, Takada, Masako, Tsurumaru, Yumi, Yamashita, Yasushi, Suzuki, Tetsuya, Akiyama, Koichi, Narikawa, Ohito, Tano, Kenichi, Tsukita, Rikako, Kurihara, Fumie, Meguro, Yusuke, Fukuda, Miwako, Sato, Tomihiro, Imai, Emiko, Tsuda, Shun, Shimohama, Takashi, Hayashi, Shin, Hisahara, Jun, Kawamata, Takashi, Murahara, Masaki, Saitoh, Shuichiro, Suzuki, Daisuke, Yamamoto, Yoko, Ishiyama, Naoko, Ishiyama, Mayuko, Noshiro, Rumi, Takeyama, Kaori, Uwasa, Ikuko, Yasuda, Anneke van der Kooi, Marianne de Visser, Tamar, Gibson, Byung-Jo, Kim, Chang Nyoung Lee, Yong Seo Koo, Hung Youl Seok, Hoo Nam Kang, Hyejin, Ra, Byoung Joon Kim, Eun Bin Cho, Misong, Choi, Hyelim, Lee, Ju-Hong, Min, Jinmyoung, Seok, Jieun, Lee, Da Yoon Koh, Juyoung, Kwon, Sangae, Park, Eun Haw Choi, Yoon-Ho, Hong, So-Hyun, Ahn, Dae Lim Koo, Jae-Sung, Lim, Chae Won Shin, Ji Ye Hwang, Miri, Kim, Seung Min Kim, Ha-Neul, Jeong, Jinwoo, Jung, Yool-Hee, Kim, Hyung Seok Lee, Ha Young Shin, Eun Bi Hwang, Miju, Shin, Carlos, Casasnovas, Maria Antonia Alberti Aguilo, Christian, Homedes-Pedret, Natalia Julia Palacios, Laura Diez Porras, Valentina Velez Santamaria, Ana, Lazaro, Josep Gamez Carbonell, Pilar, Sune, Maria Salvado Figueras, Gisela, Gili, Gonzalo, Mazuela, Isabel, Illa, Elena Cortes Vicente, Jordi, Diaz-Manera, Luis Antonio Querol Gutiérrez, Ricardo Rojas Garcia, Nuria, Vidal, Elisabet, Arribas-Ibar, Exuperio Diez Tejedor, Pilar Gomez Salcedo, Mireya, Fernandez-Fournier, Pedro Lopez Ruiz, Francisco Javier Rodriguez de Rivera, Maria, Sastre, Fredrik, Piehl, Albert, Hietala, Lena, Bjarbo, Ihsan, Sengun, Arzu, Meherremova, Pinar, Ozcelik, Bengu, Balkan, Celal, Tuga, Muzeyyen, Ugur, Sevim, Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Nazire Pinar Acar, Ezgi, Yilmaz, Yagmur, Caliskan, Gulsah, Orsel, Husnu, Efendi, Seda, Aydinlik, Hakan, Cavus, Ayse, Kutlu, Gulsah, Becerikli, Cansu, Semiz, Ozlem, Tun, Murat, Terzi, Baki, Dogan, Musa Kazim Onar, Sedat, Sen, Tugce Kirbas Cavdar, Adife, Veske, Fiona, Norwood, Aikaterini, Dimitriou, Jakit, Gollogly, Mohamed, Mahdi-Rogers, Arshira, Seddigh, Giannis, Sokratous, Gal, Maier, Faisal, Sohail, Saiju, Jacob, Girija, Sadalage, Pravin, Torane, Claire, Brown, Amna, Shah, Sivakumar, Sathasivam, Heike, Arndt, Debbie, Davies, Dave, Watling, Anthony, Amato, Thomas, Cochrane, Mohammed, Salajegheh, Kristen, Roe, Katherine, Amato, Shirli, Toska, Nicholas, Silvestri, Kara, Patrick, Karen, Zakalik, Jonathan, Katz, Robert, Miller, Marguerite, Engel, Dallas, Forshew, Elena, Bravver, Benjamin, Brooks, Mohammed, Sanjak, Sarah, Plevka, Maryanne, Burdette, Scott, Cunningham, Megan, Kramer, Joanne, Nemeth, Clara, Schommer, Tierney, Scott, Vern, Juel, Jeffrey, Guptill, Lisa, Hobson-Webb, Janice, Massey, Kate, Beck, Donna, Carnes, John, Loor, Amanda, Anderson, Robert, Pascuzzi, Cynthia, Bodkin, John, Kincaid, Riley, Snook, Sandra, Guingrich, Angela, Micheels, Vinay, Chaudhry, Andrea, Corse, Betsy, Mosmiller, Andrea, Kelley, Doreen, Ho, Jayashri, Srinivasan, Michal, Vytopil, Jordan, Jara, Nicholas, Ventura, Cynthia, Carter, Craig, Donahue, Carol, Herbert, Stephanie, Scala, Elaine, Weiner, Sharmeen, Alam, Jonathan, Mckinnon, Laura, Haar, Naya, Mckinnon, Karan, Alcon, Kaitlyn, Mckenna, Nadia, Sattar, Kevin, Daniels, Dennis, Jeffery, Miriam, Freimer, Joseph Chad Hoyle, John, Kissel, Julie, Agriesti, Sharon, Chelnick, Louisa, Mezache, Colleen, Pineda, Filiz, Muharrem, Chafic, Karam, Julie, Khoury, Tessa, Marburger, Harpreet, Kaur, Diana, Dimitrova, James, Gilchrist, Brajesh, Agrawal, Mona, Elsayed, Stephanie, Kohlrus, Angela, Ardoin, Taylor, Darnell, Laura, Golden, Barbara, Lokaitis, Jenna, Seelbach, Neelam, Goyal, Sarada, Sakamuri, Yuen, T So, Shirley, Paulose, Sabrina, Pol, Lesly, Welsh, Ratna, Bhavaraju-Sanka, Alejandro Tobon Gonzalez, Lorraine, Dishman, Floyd, Jones, Anna, Gonzalez, Patricia, Padilla, Amy, Saklad, Marcela, Silva, Sharon, Nations, Jaya, Trivedi, Steve, Hopkins, Mohamed, Kazamel, Mohammad, Alsharabati, Liang, Lu, Kenkichi, Nozaki, Sandi, Mumfrey-Thomas, Amy, Woodall, Tahseen, Mozaffar, Tiyonnoh, Cash, Namita, Goyal, Gulmohor, Roy, Veena, Mathew, Fatima, Maqsood, Brian, Minton, H James Jones, Jeffrey, Rosenfeld, Rebekah, Garcia, Laura, Echevarria, Sonia, Garcia, Michael, Pulley, Shachie, Aranke, Alan Ross Berger, Jaimin, Shah, Yasmeen, Shabbir, Lisa, Smith, Mary, Varghese, Laurie, Gutmann, Ludwig, Gutmann, Nivedita, Jerath, Christopher, Nance, Andrea, Swenson, Heena, Olalde, Nicole, Kressin, Jeri, Sieren, Richard, Barohn, Mazen, Dimachkie, Melanie, Glenn, April, Mcvey, Mamatha, Pasnoor, Jeffery, Statland, Yunxia, Wang, Tina, Liu, Kelley, Emmons, Nicole, Jenci, Jerry, Locheke, Alex, Fondaw, Kathryn, Johns, Gabrielle, Rico, Maureen, Walsh, Laura, Herbelin, Charlene, Hafer-Macko, Justin, Kwan, Lindsay, Zilliox, Karen, Callison, Valerie, Young, Beth, Disanzo, Kerry, Naunton, Michael, Benatar, Martin, Bilsker, Khema, Sharma, Anne, Cooley, Eliana, Reyes, Sara-Claude, Michon, Danielle, Sheldon, Julie, Steele, Rebecca, Traub, Manisha, Chopra, Tuan, Vu, Lara, Katzin, Terry, Mcclain, Brittany, Harvey, Adam, Hart, Kristin, Huynh, Said, Beydoun, Amaiak, Chilingaryan, Victor, Doan, Brian, Droker, Hui, Gong, Sanaz, Karimi, Frank, Lin, Krishna, Polaka, Akshay, Shah, Anh, Tran, Salma, Akhter, Ali, Malekniazi, Rup, Tandan, Michael, Hehir, Waqar, Waheed, Shannon, Lucy, Michael, Weiss, Jane, Distad, Susan, Strom, Sharon, Downing, Bryan, Kim, Tulio, Bertorini, Thomas, Arnold, Kendrick, Henderson, Rekha, Pillai, Liu, Ye, Lauren, Wheeler, Jasmine, Hewlett, Mollie, Vanderhook, Richard, Nowak, Daniel, Dicapua, Benison, Keung, Aditya, Kumar, Huned, Patwa, Kimberly, Robeson, Irene, Yang, Joan, Nye, and Hong, Vu

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Clinical Neurology, Antibodies, Monoclonal, Humanized, Placebo, Article, Antibodies, Post-intervention, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Refractory, law, Internal medicine, Monoclonal, Myasthenia Gravis, Medicine and Health Sciences, Humans, Medicine, Humanized, Science & Technology, business.industry, Middle Aged, Eculizumab, Complement Inactivating Agents, Female, Treatment Outcome, EFFICACY, medicine.disease, Myasthenia gravis, Clinical trial, 030104 developmental biology, SAFETY, Neurosciences & Neurology, Neurology (clinical), business, Life Sciences & Biomedicine, COMPLEMENT INHIBITOR ECULIZUMAB, 030217 neurology & neurosurgery, medicine.drug
Abstract

ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Published
2020
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3. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Author

Kazumi Takada, Vladislav Abramov, Seiko Yoshida, Pinar Ozcelik, Carolina Miranda, Jennifer Kane, Kaitlyn McKenna, Natasha Campbell, Sharon P. Nations, Shitiz Kumar Sriwastava, Yuko Fujii, Mayumi Murata, Linda Wagemaekers, Angela Andoin, Mollie Vanderhook, Yoshinori Okubo, Martin Bilsker, Taira Uehara, Vera Bril, Julia Wanschitz, Stanislava Toncrova, Mariela Bettini, Kazumi Futono, Shachie Aranke, Yool-hee Kim, Hiroyuki Murai, Anne Nyrhinen, Vinay Chaudhry, Raffaele Iorio, Takashi Kanda, Brittany Harvey, Francisco Javier Rodriguez de Rivera, Henning Andersen, Marianne de Visser, Miwako Sato, Yasuhiro Maeda, Fabienne Deruelle, Marina Pozo, Adam Hart, Masaki Saitoh, Wladimir Bocca Vieira de Rezende Pinto, Said R. Beydoun, Lindsay Zilliox, Akihiro Mukaino, Cinzia Caserta, Mahi Jasinarachchi, Andrea M. Corse, Nikoletta Papadopoulou, JuYoung Kwon, Fernanda Carrara, Juliet Saba, Masayuki Makamori, Vittorio Frasca, Luciana Souza Duca, Hoo Nam Kang, C. Trebst, Celile Phan, Muzeyyen Ugur, Eduardo Ng, Jonathan McKinnon, Hila Bali Kuperman, David Feder, Judit Matolcsi, Jiri Pitha, Martin Stangel, Kate Beck, Gabriel Paiva, Diego Lopergolo, Katrien De Mey, Hidenori Matsuo, Lucas Eduardo Pazetto, Eugene Lai, Amanda Anderson, Ann D'Hondt, Tetsuya Akiyama, Beverly Fyfe, Bella Gross, Elisabet Arribas-Ibar, Kathy de Koning, Gulmohor Roy, Dmitry Pokhabov, Maria Johanna Keijzers, Nicholas Ventura, Tessa Marburger, John Loor, Ji Eun Lee, Alessandro Filla, Celal Tuga, Stephanie Scala, Rudy Mercelis, Marc H. De Baets, Hisako Kobayashi, Stanislav Vohanka, Ana Paula Macagnan, Ana Carolina Amaral de Andrade, Heike Arndt, Giovanni Antonini, Yumi Yamashita, Gwendal Le Masson, Sonia Garcia, Sarah Verjans, James F. Howard, Zaeem A. Siddiqi, Yuen T. So, Megumi Koga, Exuperio Diez Tejedor, Teresa Costabile, Mihoko Takada Takada, Steve Hopkins, Jonathan S. Katz, Charlene Hafer-Macko, Erica Nogueira Coelho, Hung Youl Seok, Carol Herbert, Yuriko Nagane, Didem Altiparmak, Sachiko Kamakura, Mohammad Sanjak, Caroline Moreau, Jordi Díaz-Manera, Sivakumar Sathasivam, Michael Vytopil, Amelia Evoli, Masakatsu Motomura, Ester Reggio, Guy Van den Abeele, Hélène Zéphir, Asya Yarmoschuk, Jasmine Hewlett, Amy Wilson, Sachie Fukui, Cavit Boz, Iandra Souza, Morgane Gaboreau, Ivana Jurajdova, Sonia Decressac, Yong Seo Koo, Valentina Pegoraro, Seung Min Kim, Benison Keung, Rosana Rocha, Nanna Witting, John Vissing, Elaine Weiner, Ali Malekniazi, Larisa Babenko, Amanda C. Guidon, Gal Maier, Charlotte Smetcoren, Robert M. Pascuzzi, Domenico Marco Bonifati, Yumiko Nakamura, Tamires Cristina Gomes da Silva, Takashi Murahara, Sarah Plevka, Tomoko Tsuda, John C. Kincaid, Arnaud Lacour, Ibrez Bandukwala, Alan R. Berger, Chang Nyoung Lee, Jae-Sung Lim, Vern C. Juel, Tulio E. Bertorini, Valeria Cavalcante Lino, Namie Taichi, Ju-Hong Min, Josep Gamez, Nelly Greenbereg, William S. David, Srikanth Muppidi, Husnu Efendi, Pedro Lopez Ruiz, Baki Dogan, Cansu Semiz, Natalia Julia Palacios, Sharon Downing, Paola Cudia, Daniel Jacobs, Can Ebru Bekircan-Kurt, Takayasu Fukudome, Kristen Roe, Lena Bjarbo, Nicole Kassebaum, Makoto Samukawa, Shizuka Asada, Christina Dheel, Fatima Maqsood, Eun Bi Hwang, Kevin Daniels, Sevim Erdem-Ozdamar, Olivier Stevens, Claudio Mazia, Karan Alcon, Sibel Gazioglu, Keiko Kikutake, Luis Lay, Petra Tilkin, Corrado Angelini, Derrick Blackmore, Kimiaki Utsugisawa, Despoina Charalambous, Tuula Harrison, Kristin Huynh, Huned S. Patwa, Laura Echevarria, Henrique Mohr, Christian Homedes-Pedret, Richard J. Barohn, Byung Jo Kim, Daniel DiCapua, Terry McClain, Debora Dada Martineli Torres, Maria Salvado Figueras, Ana Paula Melo, Riley Snook, Miki Ogawa, Marcelo Annes, Yuka Saito, Isabel Illa, Evanthia Bernitsas, Nicole Smalley, Molly Lindsay, Robert G. Miller, Olga Azrilin, Silvia Bonanno, Evgeniya Kosykh, Marcela Wolfova, Olivier Outteryck, Shirli Toska, Anna Kostera-Pruszczyk, HyeJin Ra, Rup Tandan, Sotirios Papagiannopoulos, Natasha Willlems, Anne Mette Ostergaard Autzen, Meinoshin Okumura, Patrick Vermersch, Sarada Sakamuri, Maria Antonia Alberti Aguilo, Shigemi Shimose, Cynthia Carter, Ira Blount, Lisa Thompson, Maurer Pereira Martins, Richard Nowak, Hyung Seok Lee, Anna Kaminska, Joan Bratton, Nazire Pinar Acar, Junichi Ogasawara, Mohamed Mahdi-Rogers, Teiichiro Mitazaki, Marek Čierny, Craig Donahue, Jaya Trivedi, Neelam Goyal, Gonzalo Vidal, Brandy Quarles, Akiko Kanzaki, Yasuko Ikeda, Tomomi Kobashikawa, Morris Brown, Daisuke Yamamoto, Michel Deneve, Denis Korobko, Beth DiSanzo, Benedikt Schoser, Heidi Boterhoven, Eri Kobayashi, Maoko Shirane, Cristiani Fernanda Butinhao, Eriko Higuchi, Takashi Hayashi, Masanori Takahashi, Anne-Cécile Wielanek-Bachelet, Benjamin Rix Brooks, Emanuela Onesti, Tahseen Mozaffar, Liang Lu, Sevasti Bostantzopoulou, Christophe Vial, Shawn J. Bird, Sandi Mumfrey-Thomas, Julie Khoury, Kara Patrick, Kenichi Tsukita, Yoshiko Sano, Hiroshi Nakazora, David P. Richman, Gavin Brown, Yoon-Ho Hong, Tomohiro Kawamura, Igor Dias Brockhausen, Ye Liu, Acary Souza Bulle Oliveira, Soichiro Funaka, Tomoya Hasuike, Frank Lin, Luis Antonio Querol Gutierrez, Namita Goyal, Elena Pinzan, Michelle Mellion, Silvia Messina, Christopher Lindberg, Csilla Rozsa, J. Chad Hoyle, Yoko Kaneko, Gustavo Duran, Francesco Patti, Arshira Seddigh, Ele Kim Perez, Jayashri Srinivasan, Michael Benatar, Philip Van Damme, Salma Akhter, Daniel Ambrosio, Maria Salvado, Floyd Jones, Mark Sivak, Anneke J. van der Kooi, Karen Callison, Catherine Nigro, Rebekah Garcia, Thomas Arnold, Hideki Arima, Brigid Crabtree, Mary Varghese, Aditya Kumar, Miri Kim, Fanny O'Brien, Naya McKinnon, Lauren Wheeler, Hong Vu, Shunsuke Yoshimura, Masatoshi Omoto, Jeffrey T. Guptill, Maria Gabriele, Francoise Bouhour, Veena Mathew, Ritsu Nakayama, Rosa Hasan, Francesco Saccà, Mohammed Salajegheh, Diana Dimitrova, Alzira Alves de Siqueira Carvalho, Maurizio Inghilleri, George Sachs, Rekha Pillai, Enrico Marano, Monika Konyane, Anh Tran, Seda Aydinlik, Kendrick Henderson, Fumie Meguro, Alexandre Guerreiro, Amaiak Chilingaryan, Tiyonnoh Cash, Jun Kawamata, Julie Steele, Helene Gervais-Bernard, Thomas Harbo, Alejandra Dalila Garcia, Musa Kazim Onar, Sabrina Sacconi, Carlos Casasnovas Pons, Nadezhda Malkova, Denis Sazonov, Mireya Fernandez-Fournier, Karin Fricke, Laurie Gutmann, Amy Saklad, Clara Schommer, Sandra Taber, Fiona Norwood, Tugce Kirbas Cavdar, Monique Miesen, Fernanda Troili, Masanori Watanabe, Ratna Bhavaraju-Sanka, Ted M. Burns, Sari Atula, Faisal Sohail, Barbora Kurkova, Brigitta Szabadosne, Luciana Renata Cubas Volpe, Jane Pedersen, Jing Jing Wang, Masashi Inoue, Antonella Di Pasquale, Megan Kramer, Magda Chmelikova, Mehran Soltani, Tuan Vu, Laura Fionda, Eliz Agopian, Susan Shin, Anthony A. Amato, Lotte Vinge, Hakan Cavus, Gil I. Wolfe, Joan Nye, Delphine Mahieu, Miguel Wilken, Markus Färkkilä, Catherine Faber, Erin Manning, Emiko Tsuda, Rami Massie, Paolo Emilio Alboini, Yasmeen Shabbir, Angela Campanella, Aikaterini Dimitriou, Marcelo Rugiero, Cynthia Bodkin, Gyorgyi Szabo, Sharon Halton, Akshay Shah, Yasuko Maeda, Hans D. Katzberg, Yagmur Caliskan, Jaimin Shah, Katsuhisa Masaki, Valentina Damato, Blanka Andersson, Aline de Cassia Santos, Masahiro Mori, Renato Mantegazza, Misa Shimpo, Joanne Nemeth, Livia Dezsi, Anna De Rosa, Doreen Ho, Julie Moutarde, Efstathia Mitropoulou, Amy Woodall, Angela Micheels, László Vécsei, Byoung Joon Kim, Lisa Smith, Tomihiro Imai, Harpreet Kaur, Lorenzo Maggi, Jane Distad, Anita Mogensen, Ericka Simpson, Anne Cooley, Eliana Reyes, Ha Young Shin, Da Yoon Koh, Stefan Gingele, Susan Strom, Ezgi Yilmaz, Manisha Chopra, Anna Melnikova, Edouard Millois, Ludwig Gutmann, Miriam Freimer, Hirokazu Shinozaki, Heena Olalde, Kerry Naunton, Shunya Nakane, Ihsan Sengun, Dimos-Dimitrios Mitsikostas, Edina Varga, Juha-Pekka Erälinna, Wolfgang Löscher, Jan De Bleecker, Elena Bravver, Ana Lazaro, Eun Bin Cho, Thomas Cochrane, Jonathan Goldstein, Lisa D. Hobson-Webb, Michaela Tyblova, Angela Marsil, J. Edward Hartmann, Miyuki Morikawa, Karen Zakalik, Claude Desnuelle, Iveta Novakova, Michiaki Koga, Melinda Horvath, Luiz Otavio Maia Gonçalves, Elena Cortes Vicente, Alejandro Tobon Gonzalez, Stanley H. Appel, Brian Minton, Daniele Orrico, Brian Droker, Jacob Kaufman, Erica Coelho, Chafic Karam, Mikko Laaksonen, Katherine Amato, Jinmyoung Seok, Natalia Prando, Pauline Lahaut, Kaori Osakada, Phillipa Lamont, Alexandros Tselis, Daiane da Cruz Pacheco, Joan Højgaard, Hirokazu Shiraishi, Josef Bednarik, Stefania Morino, Mark Levine-Weinberg, Sara-Claude Michon, Yusuke Fukuda, Michael Pulley, Koichi Narikawa, Ricardo Rojas Garcia, Betsy Mosmiller, James Gilchrist, Maria da Penha Morita Ananias, Maryanne Burdette, Shingo Konno, Janelle Butters, Stephan Wenninger, Debbie Davies, Thomas Skripuletz, Mohammad Alsharabati, Katarina Reguliova, Gabor Lovas, Yuichiro Gondo, Miju Shin, HyeLim Lee, Bruno Bezerra Rosa, Michael D. Weiss, Martha Zampaki, Andrea Caramma, Jeffrey V. 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Mihoko Takada, Yamashita, Yumi, Yoshida, Seiko, Suzuki, Yasushi, Akiyama, Tetsuya, Narikawa, Koichi, Tsukita, Kenichi, Meguro, Fumie, Fukuda, Yusuke, Sato, Miwako, Matsuo, Hidenori, Fukudome, Takayasu, Gondo, Yuichiro, Maeda, Yasuhiro, Nagaishi, Akiko, Nakane, Shunya, Okubo, Yoshinori, Okumura, Meinoshin, Funaka, Soichiro, Kawamura, Tomohiro, Makamori, Masayuki, Takahashi, Masanori, Hasuike, Tomoya, Higuchi, Eriko, Kobayashi, Hisako, Osakada, Kaori, Taichi, Namie, Tsuda, Emiko, Hayashi, Takashi, Hisahara, Shin, Imai, Tomihiro, Kawamata, Jun, Murahara, Takashi, Saitoh, Masaki, Shimohama, Shun, Suzuki, Shuichiro, Yamamoto, Daisuke, Konno, Shingo, Imamura, Tomomi, Inoue, Masashi, Murata, Mayumi, Nakazora, Hiroshi, Nakayama, Ritsu, Ikeda, Yasuko, Ogawa, Miki, Shirane, Maoko, Kanda, Takashi, Kawai, Motoharu, Koga, Michiaki, Ogasawara, Junichi, Omoto, Masatoshi, Sano, Yasuteru, Arima, Hideki, Fukui, Sachie, Shimose, Shigemi, Shinozaki, Hirokazu, Watanabe, Masanori, Yoshikawa, Chieko, van der 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Subjects
Male, 0301 basic medicine, medicine.medical_treatment, Drug Resistance, Adult, Aged, Antibodies, Monoclonal, Humanized, Autoantibodies, Double-Blind Method, Female, Humans, Middle Aged, Myasthenia Gravis, Receptors, Cholinergic, Outcome Assessment (Health Care), Severity of Illness Index, Neurology (clinical), law.invention, Complement inhibitor, 0302 clinical medicine, Randomized controlled trial, law, Monoclonal, Receptors, Clinical endpoint, Humanized, Cholinergic, education.field_of_study, Eculizumab, Autoantibodie, Myasthenia Gravi, Settore MED/26 - NEUROLOGIA, Human, medicine.drug, Meningitides, medicine.medical_specialty, Population, Placebo, Antibodies, 03 medical and health sciences, Internal medicine, medicine, education, business.industry, Surgery, Thymectomy, 030104 developmental biology, business, 030217 neurology & neurosurgery
Abstract

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

Published
2017
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4. Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

Author

Hiroyuki Murai, Akiyuki Uzawa, Yasushi Suzuki, Tomihiro Imai, Hirokazu Shiraishi, Hidekazu Suzuki, Meinoshin Okumura, Fanny O’Brien, Jing-Jing Wang, Kenji P. Fujita, Kimiaki Utsugisawa, Claudio Gabriel Mazia, Miguel Wilken, Fabio Barroso, Juliet Saba, Marcelo Rugiero, Mariela Bettini, Marcelo Chaves, Gonzalo Vidal, Alejandra Dalila Garcia, Jan De Bleecker, Guy Van den Abeele, Kathy de Koning, Katrien De Mey, Rudy Mercelis, Délphine Mahieu, Linda Wagemaekers, Philip Van Damme, Annelies Depreitere, Caroline Schotte, Charlotte Smetcoren, Olivier Stevens, Sien Van Daele, Nicolas Vandenbussche, Annelies Vanhee, Sarah Verjans, Jan Vynckier, Ann D'Hondt, Petra Tilkin, Alzira Alves de Siqueira Carvalho, Igor Dias Brockhausen, David Feder, Daniel Ambrosio, Pamela César, Ana Paula Melo, Renata Martins Ribeiro, Rosana Rocha, Bruno Bezerra Rosa, Thabata Veiga, Luiz Augusto da Silva, Murilo Santos Engel, Jordana Gonçalves Geraldo, Maria da Penha Ananias Morita, Erica Nogueira Coelho, Gabriel Paiva, Marina Pozo, Natalia Prando, Debora Dada Martineli Torres, Cristiani Fernanda Butinhao, Gustavo Duran, Tamires Cristina Gomes da Silva, Luiz Otavio Maia Gonçalves, Lucas Eduardo Pazetto, Tomás Augusto Suriane Fialho, Luciana Renata Cubas Volpe, Luciana Souza Duca, Acary Souza Bulle Oliveira, Ana Carolina Amaral Andrade, Marcelo Annes, Liene Duarte Silva, Valeria Cavalcante Lino, Wladimir Pinto, Natália Assis, Fernanda Carrara, Carolina Miranda, Iandra Souza, Patricia Fernandes, Zaeem Siddiqi, Cecile Phan, Jeffrey Narayan, Derrick Blackmore, Ashley Mallon, Rikki Roderus, Elizabeth Watt, Jana Junkerova, Barbora Kurkova, Katarina Reguliova, Olga Zapletalova, Jiri Pitha, Iveta Novakova, Michaela Tyblova, Ivana Jurajdova, Marcela Wolfova, Henning Andersen, Thomas Harbo, Lotte Vinge, Susanne Krogh, Anita Mogensen, John Vissing, Joan Højgaard, Nanna Witting, Anne Mette Ostergaard Autzen, Jane Pedersen, Juha-Pekka Eralinna, Mikko Laaksonen, Olli Oksaranta, Tuula Harrison, Jaana Eriksson, Csilla Rozsa, Melinda Horvath, Gabor Lovas, Judit Matolcsi, Gyorgyi Szabo, Gedeonne Jakab, Brigitta Szabadosne, Giovanni Antonini, Antonella Di Pasquale, Matteo Garibaldi, Stefania Morino, Fernanda Troili, Laura Fionda, Allessandro Filla, Teresa Costabile, Enrico Marano, Francesco Saccà, Angiola Fasanaro, Angela Marsili, Giorgia Puorro, Renato Mantegazza, Carlo Antozzi, Silvia Bonanno, Giorgia Camera, Alberta Locatelli, Lorenzo Maggi, Maria Pasanisi, Angela Campanella, Amelia Evoli, Paolo Emilio Alboini, Valentina D'Amato, Raffaele Iorio, Tetsuya Kanai, Naoki Kawaguchi, Masahiro Mori, Yoko Kaneko, Akiko Kanzaki, Eri Kobayashi, Katsuhisa Masaki, Dai Matsuse, Takuya Matsushita, Taira Uehara, Misa Shimpo, Maki Jingu, Keiko Kikutake, Yumiko Nakamura, Yoshiko Sano, Yuriko Nagane, Ikuko Kamegamori, Tomoko Tsuda, Yuko Fujii, Kazumi Futono, Yukiko Ozawa, Aya Mizugami, Yuka Saito, Miyuki Morikawa, Makoto Samukawa, Sachiko Kamakura, Eriko Miyawaki, Teiichiro Mitazaki, Masakatsu Motomura, Akihiro Mukaino, Shunsuke Yoshimura, Shizuka Asada, Seiko Yoshida, Shoko Amamoto, Tomomi Kobashikawa, Megumi Koga, Yasuko Maeda, Kazumi Takada, Mihoko Takada, Masako Tsurumaru, Yumi Yamashita, Tetsuya Akiyama, Koichi Narikawa, Ohito Tano, Kenichi Tsukita, Rikako Kurihara, Fumie Meguro, Yusuke Fukuda, Miwako Sato, Soichiro Funaka, Tomohiro Kawamura, Masayuki Makamori, Masanori Takahashi, Namie Taichi, Tomoya Hasuike, Eriko Higuchi, Hisako Kobayashi, Kaori Osakada, Emiko Tsuda, Shun Shimohama, Takashi Hayashi, Shin Hisahara, Jun Kawamata, Takashi Murahara, Masaki Saitoh, Shuichiro Suzuki, Daisuke Yamamoto, Yoko Ishiyama, Naoko Ishiyama, Mayuko Noshiro, Rumi Takeyama, Kaori Uwasa, Ikuko Yasuda, Anneke van der Kooi, Marianne de Visser, Tamar Gibson, Carlos Casasnovas, Maria Antonia Alberti Aguilo, Christian Homedes-Pedret, Natalia Julia Palacios, Laura Diez Porras, Valentina Velez Santamaria, Ana Lazaro, Exuperio Diez Tejedor, Pilar Gomez Salcedo, Mireya Fernandez-Fournier, Pedro Lopez Ruiz, Francisco Javier Rodriguez de Rivera, Maria Sastre, Josep Gamez, Pilar Sune, Maria Salvado, Gisela Gili, Gonzalo Mazuela, Isabel Illa, Elena Cortes Vicente, Jordi Diaz-Manera, Luis Antonio Querol Gutierrez, Ricardo Rojas Garcia, Nuria Vidal, Elisabet Arribas-Ibar, Fredrik Piehl, Albert Hietala, Lena Bjarbo, Ihsan Sengun, Arzu Meherremova, Pinar Ozcelik, Bengu Balkan, Celal Tuga, Muzeyyen Ugur, Sevim Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Nazire Pinar Acar, Ezgi Yilmaz, Yagmur Caliskan, Gulsah Orsel, Husnu Efendi, Seda Aydinlik, Hakan Cavus, Ayse Kutlu, Gulsah Becerikli, Cansu Semiz, Ozlem Tun, Murat Terzi, Baki Dogan, Musa Kazim Onar, Sedat Sen, Tugce Kirbas Cavdar, Adife Veske, Fiona Norwood, Aikaterini Dimitriou, Jakit Gollogly, Mohamed Mahdi-Rogers, Arshira Seddigh, Giannis Sokratous, Gal Maier, Faisal Sohail, Saiju Jacob, Girija Sadalage, Pravin Torane, Claire Brown, Amna Shah, Sivakumar Sathasivam, Heike Arndt, Debbie Davies, Dave Watling, Anthony Amato, Thomas Cochrane, Mohammed Salajegheh, Kristen Roe, Katherine Amato, Shirli Toska, Gil Wolfe, Nicholas Silvestri, Kara Patrick, Karen Zakalik, Jonathan Katz, Robert Miller, Marguerite Engel, Dallas Forshew, Elena Bravver, Benjamin Brooks, Sarah Plevka, Maryanne Burdette, Scott Cunningham, Mohammad Sanjak, Megan Kramer, Joanne Nemeth, Clara Schommer, Scott Tierney, Vern Juel, Jeffrey Guptill, Lisa Hobson-Webb, Janice Massey, Kate Beck, Donna Carnes, John Loor, Amanda Anderson, Robert Pascuzzi, Cynthia Bodkin, John Kincaid, Riley Snook, Sandra Guingrich, Angela Micheels, Vinay Chaudhry, Andrea Corse, Betsy Mosmiller, Andrea Kelley, Doreen Ho, Jayashri Srinivasan, Michal Vytopil, Jordan Jara, Nicholas Ventura, Stephanie Scala, Cynthia Carter, Craig Donahue, Carol Herbert, Elaine Weiner, Sharmeen Alam, Jonathan McKinnon, Laura Haar, Naya McKinnon, Karan Alcon, Kaitlyn McKenna, Nadia Sattar, Kevin Daniels, Dennis Jeffery, Miriam Freimer, Joseph Chad Hoyle, John Kissel, Julie Agriesti, Sharon Chelnick, Louisa Mezache, Colleen Pineda, Filiz Muharrem, Chafic Karam, Julie Khoury, Tessa Marburger, Harpreet Kaur, Diana Dimitrova, James Gilchrist, Brajesh Agrawal, Mona Elsayed, Stephanie Kohlrus, Angela Andoin, Taylor Darnell, Laura Golden, Barbara Lokaitis, Jenna Seelback, Srikanth Muppidi, Neelam Goyal, Sarada Sakamuri, Yuen T. So, Shirley Paulose, Sabrina Pol, Lesly Welsh, Ratna Bhavaraju-Sanka, Alejandro Tobon Gonzales, Lorraine Dishman, Floyd Jones, Anna Gonzalez, Patricia Padilla, Amy Saklad, Marcela Silva, Mohamed Kazamel, Mohammad Alsharabati, Liang Lu, Kenkichi Nozaki, Sandi Mumfrey-Thomas, Amy Woodall, Tahseen Mozaffar, Tiyonnoh Cash, Namita Goyal, Gulmohor Roy, Veena Mathew, Fatima Maqsood, Brian Minton, H. James Jones, Jeffrey Rosenfeld, Rebekah Garcia, Laura Echevarria, Sonia Garcia, Michael Pulley, Shachie Aranke, Alan Ross Berger, Jaimin Shah, Yasmeen Shabbir, Lisa Smith, Mary Varghese, Laurie Gutmann, Ludwig Gutmann, Nivedita Jerath, Christopher Nance, Andrea Swenson, Heena Olalde, Nicole Kressin, Jeri Sieren, Richard Barohn, Mazen Dimachkie, Melanie Glenn, April McVey, Mamatha Pasnoor, Jeffery Statland, Yunxia Wang, Tina Liu, Kelley Emmons, Nicole Jenci, Jerry Locheke, Alex Fondaw, Kathryn Johns, Gabrielle Rico, Maureen Walsh, Laura Herbelin, Charlene Hafer-Macko, Justin Kwan, Lindsay Zilliox, Karen Callison, Valerie Young, Beth DiSanzo, Kerry Naunton, Michael Benatar, Martin Bilsker, Khema Sharma, Anne Cooley, Eliana Reyes, Sara-Claude Michon, Danielle Sheldon, Julie Steele, James Howard Jr, Manisha Chopra, Rebecca Traub, Tuan Vu, Lara Katzin, Terry McClain, Brittany Harvey, Adam Hart, Kristin Huynh, Said Beydoun, Amaiak Chilingaryan, Victor Doan, Brian Droker, Hui Gong, Sanaz Karimi, Frank Lin, Krishna Pokala, Akshay Shah, Anh Tran, Salma Akhter, Ali Malekniazi, Rup Tandan, Michael Hehir, Waqar Waheed, Shannon Lucy, Michael Weiss, Jane Distad, Susan Strom, Sharon Downing, Bryan Kim, Richard Nowak, Daniel Dicapua, Benison Keung, Aditya Kumar, Huned Patwa, Kimberly Robeson, Irene Yang, Joan Nye, Hong Vu, H., Murai, A., Uzawa, Y., Suzuki, T., Imai, H., Shiraishi, H., Suzuki, M., Okumura, F., O'Brien, J. -J., Wang, K. P., Fujita, K., Utsugisawa, Gabriel Mazia 11, Claudio, Wilken 11, Miguel, Barroso 11, Fabio, Saba 11, Juliet, Rugiero 12, Marcelo, Bettini 12, Mariela, Chaves 12, Marcelo, Vidal 12, Gonzalo, Dalila Garcia 12, Alejandra, De Bleecker 13, Jan, Van den Abeele 13, Guy, de Koning 13, Kathy, De Mey 13, Katrien, Mercelis 14, Rudy, Mahieu 14, Délphine, Wagemaekers 14, Linda, Van Damme 15, Philip, Depreitere 16, Annelie, Schotte 16, Caroline, Smetcoren 16, Charlotte, Stevens 16, Olivier, Van Daele 16, Sien, Vandenbussche 16, Nicola, Vanhee 16, Annelie, Verjans 16, Sarah, Vynckier 16, Jan, D'Hondt 16, Ann, Tilkin 16, Petra, Alves de Siqueira Carvalho 17, Alzira, Dias Brockhausen 17, Igor, Feder 17, David, Ambrosio 17, Daniel, César 17, Pamela, Paula Melo 17, Ana, Martins Ribeiro 17, Renata, Rocha 17, Rosana, Bezerra Rosa 17, Bruno, Veiga 17, Thabata, Augusto da Silva 17, Luiz, Santos Engel 17, Murilo, Gonçalves Geraldo 17, Jordana, da Penha Ananias Morita 18, Maria, Nogueira Coelho 18, Erica, Paiva 18, Gabriel, Pozo 18, Marina, Prando 18, Natalia, Dada Martineli Torres 18, Debora, Fernanda Butinhao 18, Cristiani, Duran 18, Gustavo, Cristina Gomes da Silva 18, Tamire, Otavio Maia Gonçalves 18, Luiz, Eduardo Pazetto 18, Luca, Augusto Suriane Fialho 18, Tomá, Renata Cubas Volpe 18, Luciana, Souza Duca 18, Luciana, Souza Bulle Oliveira 19, Acary, Carolina Amaral Andrade 19, Ana, Annes 19, Marcelo, Duarte Silva 19, Liene, Cavalcante Lino 19, Valeria, Pinto 19, Wladimir, Assis 19, Natália, Carrara 19, Fernanda, Miranda 19, Carolina, Souza 19, Iandra, Fernandes 19, Patricia, Siddiqi 20, Zaeem, Phan 20, Cecile, Narayan 20, Jeffrey, Blackmore 20, Derrick, Mallon 20, Ashley, Roderus 20, Rikki, Watt 20, Elizabeth, Junkerova 21, Jana, Kurkova 21, Barbora, Reguliova 21, Katarina, Zapletalova 21, Olga, Pitha 22, Jiri, Novakova 22, Iveta, Tyblova 22, Michaela, Jurajdova 22, Ivana, Wolfova 22, Marcela, Andersen 23, Henning, Harbo 23, Thoma, Vinge 23, Lotte, Krogh 23, Susanne, Mogensen 23, Anita, Vissing 24, John, Højgaard 24, Joan, Witting 24, Nanna, Mette Ostergaard Autzen 24, Anne, Pedersen 24, Jane, Eralinna 25, Juha-Pekka, Laaksonen 25, Mikko, Oksaranta 25, Olli, Harrison 25, Tuula, Eriksson 25, Jaana, Rozsa 26, Csilla, Horvath 26, Melinda, Lovas 26, Gabor, Matolcsi 26, Judit, Szabo 26, Gyorgyi, Jakab 26, Gedeonne, Szabadosne 26, Brigitta, Antonini 27, Giovanni, Di Pasquale 27, Antonella, Garibaldi 27, Matteo, Morino 27, Stefania, Troili 27, Fernanda, Fionda 27, Laura, Filla, Allessandro, Costabile, Teresa, Marano, Enrico, Sacca', Francesco, Fasanaro, Angiola, Marsili, Angela, Puorro, Giorgia, Mantegazza 29, Renato, Antozzi 29, Carlo, Bonanno 29, Silvia, Camera 29, Giorgia, Locatelli 29, Alberta, Maggi 29, Lorenzo, Pasanisi 29, Maria, Campanella 29, Angela, Evoli 30, Amelia, Emilio Alboini 30, Paolo, D'Amato 30, Valentina, Iorio 30, Raffaele, Kanai 31, Tetsuya, Kawaguchi 31, Naoki, Mori 31, Masahiro, Kaneko 31, Yoko, Kanzaki 31, Akiko, Kobayashi 31, Eri, Masaki 32, Katsuhisa, Matsuse 32, Dai, Matsushita 32, Takuya, Uehara 32, Taira, Shimpo 32, Misa, Jingu 32, Maki, Kikutake 32, Keiko, Nakamura 32, Yumiko, Sano 32, Yoshiko, Nagane 33, Yuriko, Kamegamori 33, Ikuko, Tsuda 33, Tomoko, Fujii 33, Yuko, Futono 33, Kazumi, Ozawa 33, Yukiko, Mizugami 33, Aya, Saito 33, Yuka, Morikawa 34, Miyuki, Samukawa 34, Makoto, Kamakura 34, Sachiko, Miyawaki 34, Eriko, Mitazaki 35, Teiichiro, Motomura 35, Masakatsu, Mukaino 35, Akihiro, Yoshimura 35, Shunsuke, Asada 35, Shizuka, Yoshida 35, Seiko, Amamoto 35, Shoko, Kobashikawa 35, Tomomi, Koga 35, Megumi, Maeda 35, Yasuko, Takada 35, Kazumi, Takada 35, Mihoko, Tsurumaru 35, Masako, Yamashita 35, Yumi, Akiyama 36, Tetsuya, Narikawa 36, Koichi, Tano 36, Ohito, Tsukita 36, Kenichi, Kurihara 36, Rikako, Meguro 36, Fumie, Fukuda 36, Yusuke, Sato 36, Miwako, Funaka 37, Soichiro, Kawamura 37, Tomohiro, Makamori 37, Masayuki, Takahashi 37, Masanori, Taichi 37, Namie, Hasuike 37, Tomoya, Higuchi 37, Eriko, Kobayashi 37, Hisako, Osakada 37, Kaori, Tsuda 38, Emiko, Shimohama 38, Shun, Hayashi 38, Takashi, Hisahara 38, Shin, Kawamata 38, Jun, Murahara 38, Takashi, Saitoh 38, Masaki, Suzuki 38, Shuichiro, Yamamoto 38, Daisuke, Ishiyama 38, Yoko, Ishiyama 38, Naoko, Noshiro 38, Mayuko, Takeyama 38, Rumi, Uwasa 38, Kaori, Yasuda 38, Ikuko, van der Kooi 39, Anneke, de Visser 39, Marianne, Gibson 39, Tamar, Casasnovas 40, Carlo, Antonia Alberti Aguilo 40, Maria, Homedes-Pedret 40, Christian, Julia Palacios 40, Natalia, Diez Porras 40, Laura, Velez Santamaria 40, Valentina, Lazaro 40, Ana, Diez Tejedor 41, Exuperio, Gomez Salcedo 41, Pilar, Fernandez-Fournier 41, Mireya, Lopez Ruiz 41, Pedro, Javier Rodriguez de Rivera 41, Francisco, Sastre 41, Maria, Gamez 42, Josep, Sune 42, Pilar, Salvado 42, Maria, Gili 42, Gisela, Mazuela 42, Gonzalo, Illa 43, Isabel, Cortes Vicente 43, Elena, Diaz-Manera 43, Jordi, Antonio Querol Gutierrez 43, Lui, Rojas Garcia 43, Ricardo, Vidal 43, Nuria, Arribas-Ibar 43, Elisabet, Piehl 44, Fredrik, Hietala 44, Albert, Bjarbo 44, Lena, Sengun 45, Ihsan, Meherremova 45, Arzu, Ozcelik 45, Pinar, Balkan 45, Bengu, Tuga 45, Celal, Ugur 45, Muzeyyen, Erdem-Ozdamar 46, Sevim, Ebru Bekircan-Kurt 46, Can, Pinar Acar 46, Nazire, Yilmaz 46, Ezgi, Caliskan 46, Yagmur, Orsel 46, Gulsah, Efendi 47, Husnu, Aydinlik 47, Seda, Cavus 47, Hakan, Kutlu 47, Ayse, Becerikli 47, Gulsah, Semiz 47, Cansu, Tun 47, Ozlem, Terzi 48, Murat, Dogan 48, Baki, Kazim Onar 48, Musa, Sen 48, Sedat, Kirbas Cavdar 48, Tugce, Veske 48, Adife, Norwood 49, Fiona, Dimitriou 49, Aikaterini, Gollogly 49, Jakit, Mahdi-Rogers 49, Mohamed, Seddigh 49, Arshira, Sokratous 49, Gianni, Maier 49, Gal, Sohail 49, Faisal, Jacob 50, Saiju, Sadalage 50, Girija, Torane 50, Pravin, Brown 50, Claire, Shah 50, Amna, Sathasivam 51, Sivakumar, Arndt 51, Heike, Davies 51, Debbie, Watling 51, Dave, Amato 52, Anthony, Cochrane 52, Thoma, Salajegheh 52, Mohammed, Roe 52, Kristen, Amato 52, Katherine, Toska 52, Shirli, Wolfe 53, Gil, Silvestri 53, Nichola, Patrick 53, Kara, Zakalik 53, Karen, Katz 54, Jonathan, Miller 54, Robert, Engel 54, Marguerite, Forshew 54, Dalla, Bravver 55, Elena, Brooks 55, Benjamin, Plevka 55, Sarah, Burdette 55, Maryanne, Cunningham 55, Scott, Sanjak 55, Mohammad, Kramer 55, Megan, Nemeth 55, Joanne, Schommer 55, Clara, Tierney 55, Scott, Juel 56, Vern, Guptill 56, Jeffrey, Hobson-Webb 56, Lisa, Massey 56, Janice, Beck 56, Kate, Carnes 56, Donna, Loor 56, John, Anderson 56, Amanda, Pascuzzi 57, Robert, Bodkin 57, Cynthia, Kincaid 57, John, Snook 57, Riley, Guingrich 57, Sandra, Micheels 57, Angela, Chaudhry 58, Vinay, Corse 58, Andrea, Mosmiller 58, Betsy, Kelley 58, Andrea, Ho 59, Doreen, Srinivasan 59, Jayashri, Vytopil 59, Michal, Jara 59, Jordan, Ventura 59, Nichola, Scala 59, Stephanie, Carter 59, Cynthia, Donahue 59, Craig, Herbert 59, Carol, Weiner 59, Elaine, Alam 59, Sharmeen, McKinnon 60, Jonathan, Haar 60, Laura, McKinnon 60, Naya, Alcon 60, Karan, McKenna 60, Kaitlyn, Sattar 60, Nadia, Daniels 60, Kevin, Jeffery 60, Denni, Freimer 61, Miriam, Chad Hoyle 61, Joseph, Kissel 61, John, Agriesti 61, Julie, Chelnick 61, Sharon, Mezache 61, Louisa, Pineda 61, Colleen, Muharrem 61, Filiz, Karam 62, Chafic, Khoury 62, Julie, Marburger 62, Tessa, Kaur 62, Harpreet, Dimitrova 62, Diana, Gilchrist 63, Jame, Agrawal 63, Brajesh, Elsayed 63, Mona, Kohlrus 63, Stephanie, Andoin 63, Angela, Darnell 63, Taylor, Golden 63, Laura, Lokaitis 63, Barbara, Seelback 63, Jenna, Muppidi 64, Srikanth, Goyal 64, Neelam, Sakamuri 64, Sarada, T So 64, Yuen, Paulose 64, Shirley, Pol 64, Sabrina, Welsh 64, Lesly, Bhavaraju-Sanka 65, Ratna, Tobon Gonzales 65, Alejandro, Dishman 65, Lorraine, Jones 65, Floyd, Gonzalez 65, Anna, Padilla 65, Patricia, Saklad 65, Amy, Silva 65, Marcela, Kazamel 66, Mohamed, Alsharabati 66, Mohammad, Lu 66, Liang, Nozaki 66, Kenkichi, Mumfrey-Thomas 66, Sandi, Woodall 66, Amy, Mozaffar 67, Tahseen, Cash 67, Tiyonnoh, Goyal 67, Namita, Roy 67, Gulmohor, Mathew 67, Veena, Maqsood 67, Fatima, Minton 67, Brian, James Jones 68, H, Rosenfeld 68, Jeffrey, Garcia 68, Rebekah, Echevarria 68, Laura, Garcia 68, Sonia, Pulley 69, Michael, Aranke 69, Shachie, Ross Berger 69, Alan, Shah 69, Jaimin, Shabbir 69, Yasmeen, Smith 69, Lisa, Varghese 69, Mary, Gutmann 70, Laurie, Gutmann 70, Ludwig, Jerath 70, Nivedita, Nance 70, Christopher, Swenson 70, Andrea, Olalde 70, Heena, Kressin 70, Nicole, Sieren 70, Jeri, Barohn 71, Richard, Dimachkie 71, Mazen, Glenn 71, Melanie, McVey 71, April, Pasnoor 71, Mamatha, Statland 71, Jeffery, Wang 71, Yunxia, Liu 71, Tina, Emmons 71, Kelley, Jenci 71, Nicole, Locheke 71, Jerry, Fondaw 71, Alex, Johns 71, Kathryn, Rico 71, Gabrielle, Walsh 71, Maureen, Herbelin 71, Laura, Hafer-Macko 72, Charlene, Kwan 72, Justin, Zilliox 72, Lindsay, Callison 72, Karen, Young 72, Valerie, DiSanzo 72, Beth, Naunton 72, Kerry, Benatar 73, Michael, Bilsker 73, Martin, Sharma 73, Khema, Cooley 73, Anne, Reyes 73, Eliana, Michon 73, Sara-Claude, Sheldon 73, Danielle, Steele 73, Julie, Howard Jr 74, Jame, Karam 74, Chafic, Chopra 74, Manisha, Traub 74, Rebecca, Vu 75, Tuan, Katzin 75, Lara, McClain 75, Terry, Harvey 75, Brittany, Hart 75, Adam, Huynh 75, Kristin, Beydoun 76, Said, Chilingaryan 76, Amaiak, Doan 76, Victor, Droker 76, Brian, Gong 76, Hui, Karimi 76, Sanaz, Lin 76, Frank, McClain 76, Terry, Pokala 76, Krishna, Shah 76, Akshay, Tran 76, Anh, Akhter 76, Salma, Malekniazi 76, Ali, Tandan 77, Rup, Hehir 77, Michael, Waheed 77, Waqar, Lucy 77, Shannon, Weiss 78, Michael, Distad 78, Jane, Strom 78, Susan, Downing 78, Sharon, Kim 78, Bryan, Nowak 79, Richard, Dicapua 79, Daniel, Keung 79, Benison, Kumar 79, Aditya, Patwa 79, Huned, Robeson 79, Kimberly, Yang 79, Irene, Nye 79, Joan, and Hong Vu

Subjects
Male, Pediatrics, Myasthenia gravi, Open-label extension study, Complement inhibitor, 0302 clinical medicine, Quality of life, Japan, Medicine and Health Sciences, Medicine, 030212 general & internal medicine, Myasthenia gravis, education.field_of_study, MG-ADL, Japanese patient, Eculizumab, Middle Aged, HLA, MG-QoL15, Treatment Outcome, Neurology, Female, Life Sciences & Biomedicine, COMPLEMENT INHIBITOR ECULIZUMAB, medicine.drug, Adult, medicine.medical_specialty, Population, Clinical Neurology, Subgroup analysis, Placebo, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Refractory, Asian People, Myasthenia Gravis, Humans, education, Aged, Science & Technology, business.industry, Neurosciences, medicine.disease, Complement Inactivating Agents, Japanese patients, ONSET, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population. ispartof: JOURNAL OF THE NEUROLOGICAL SCIENCES vol:407 ispartof: location:Netherlands status: published

Published
2019

5. Treatment of relapsing multiple sclerosis in Hungary – consensus recommendation from the Hungarian neuroimmunology society

Author

Cecilia Rajda, Csilla Rózsa, Andrea Mike, Gábor Lovas, Zsolt Mezei, Gábor Jakab, Péter Ács, Gábor Rum, Magdolna Simó, Zita Jobbágy, Zita Bíró, Anita Trauninger, Piroska Imre, Klotild Mátyás, István Deme, Zsolt Illés, and Tunde Csepany

Subjects
Consensus, Multiple sclerosis, Recommendation, Treatment, Medicine
Abstract

Abstract Multiple sclerosis (MS) may impact quality of life, careers and family plans of the affected individuals. The current treatments with disease modifying therapies aim to prevent people with MS (pwMS) from disability accumulation and progression. Different countries have different reimbursement policies resulting in inequalities in patient care among geographical regions. Access to anti-CD20 therapies for relapsing MS is restricted in Hungary because therapy of individual cases only is reimbursed. In the light of the latest research and national guidelines, 17 Hungarian MS experts agreed on 8 recommendations regarding relapsing pwMS using the Delphi round method. Strong agreement (> 80%) was achieved in all except one recommendation after three rounds, which generated a fourth Delphi round. The experts agreed on treatment initiation, switch, follow-up and discontinuation, as well as on special issues such as pregnancy, lactation, elderly population, and vaccination. Well-defined national consensus protocols may facilitate dialogue between policymakers and healthcare professionals and thus contribute to better patient care in the long run.

Published
2023
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6. Synchrotron XPS studies of illuminated and annealed flash evaporated a-Ge2S3 films

Author

Vladimír Matolín, Nataliya Tsud, Vladimir Mitsa, Gabor Lovas, Stepan Petretskiy, Nataliya Popovych, Sára Tóth, Roman Holomb, Kevin C. Prince, and O. Kondrat

Subjects
Materials science, Analytical chemistry, chemistry.chemical_element, Synchrotron radiation, Condensed Matter Physics, Laser, Spectral line, Synchrotron, Electronic, Optical and Magnetic Materials, law.invention, Flash (photography), chemistry, X-ray photoelectron spectroscopy, law, Thermal, Materials Chemistry, Ceramics and Composites, Carbon
Abstract

The atomic composition, local structure and coordination of flash evaporated Ge2S3 films and their changes induced by laser illumination and thermal annealing in vacuum were investigated by means of high resolution synchrotron radiation and X-ray photoelectron spectroscopy. The top surface and subsurface layers of the films are found to be enriched by Ge in comparison with the composition of target glass and contain oxygen and a significant contribution of physisorbed carbon. The influence of laser and thermal treatments of flash evaporated Ge–S films in vacuum on their composition is analyzed. The local atomic coordination obtained by curve fitting of Ge 3d, S 2p, O 1s and C 1s core level spectra is discussed in detail.

Published
2014
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7. Expression of a catalytically inactive transmembrane protein tyrosine phosphatase ? (tm-PTP?) delays optic nerve myelination

Author

Dietrich Machleder, Mukul Ranjan, Vittorio Gallo, Naser Muja, Elena Romm, Lynn D. Hudson, and Gabor Lovas

Subjects
Oligodendrocyte differentiation, Tyrosine phosphorylation, Protein tyrosine phosphatase, Biology, Retinal ganglion, Oligodendrocyte, Cell biology, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Myelin, medicine.anatomical_structure, nervous system, Neurology, chemistry, Biochemistry, Optic nerve, medicine, Neuroglia
Abstract

Reversible tyrosine phosphorylation is integral to the process of oligodendrocyte differentiation. To interfere with the subset of the phosphorylation cycle overseen by protein tyrosine phosphatase epsilon (PTP epsilon) in oligodendrocytes, we applied a substrate-trapping approach in the development of transgenic mice overexpressing a catalytically inactive, transmembrane PTP epsilon-hemaglutinin (tm-PTP epsilon-HA) from the dual promoter element of the gene encoding the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Transgene expression peaked during the active myelinating period, at 2-3 weeks postnatal. Two tyrosine phosphoproteins, alpha-enolase and beta-actin, were phosphorylated to a greater degree in transgenic mice. Despite a high degree of tm-PTP epsilon-HA expression, myelin was grossly normal in nearly all axonal tracts. Phenotypic abnormalities were limited to optic nerve, where a decrease in the degree of myelination was reflected by reduced levels of myelin proteins on postnatal day 21 (PND21), as well as a decrease in the density of differentiated oligodendrocytes. The optic chiasm was reduced in thickness in transgenic mice; optic nerves similarly exhibited a reduction in transverse width. Further analyses of the optic pathway demonstrated that transgenic protein was unexpectedly present in retinal ganglion cells, whose axons are the targets of myelination by optic nerve oligodendrocytes. On PND28, transgenic protein declined dramatically in both oligodendrocytes and retinal ganglion cells contributing to the recovery of optic nerve myelination. Thus, delayed myelination arises only when tm-PTP epsilon-HA is simultaneously expressed in myelin-forming glia and their neuronal targets. While tm-PTP epsilon related signaling pathways may figure in axon-glial interactions, interfering with tm-PTP epsilon activity does not perceptibly affect the development or myelinating capacity of most oligodendrocytes.

Published
2004
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8. Expression of theKrüppel-type zinc finger protein rKr2 in the developing nervous system†

Author

Uwe Pott, Gabor Lovas, Wen Li, Trevor Verga, and Lynn D. Hudson

Subjects
Regulation of gene expression, Zinc finger, Subventricular zone, Biology, Neural stem cell, Oligodendrocyte, Cell biology, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Neurology, Krüppel, Immunology, medicine, Neuroglia, Immunostaining
Abstract

Zinc finger transcription factors of the Kruppel-class figure prominently in cell fate specification and differentiation in the nervous system. One of the Kruppel-type genes that was originally cloned from an oligodendrocyte library by virtue of its homology with the prototypic Kruppel motif is the rat rKr2 gene (Pott et al., 1995). In primary cultures of rat glial cells, the rKr2 protein was only present in the oligodendrocyte lineage, predominantly in progenitors. Ninety percent of A2B5(+) oligodendrocyte progenitors displayed rKr2 immunoreactivity, while most MBP(+) oligodendrocytes lacked detectable rKr2. A similar pattern was found in vivo, in which the peak expression of rKr2 in the oligodendrocyte lineage of rats coincided with the wave of progenitor proliferation in early postnatal life. The subventricular zone, a source of neuronal and glial progenitors, displayed intense staining for rKr2 at late embryonic and postnatal stages. In the adult, cells within the remnants of this germinal zone continued to express rKr2 protein strongly. Some populations of mature neurons also displayed rKr2 immunostaining. Astrocytes and microglia were not labeled with the polyclonal anti-rKr2 antibody in vitro or in vivo. At all developmental stages, the rKr2 protein was localized to the nucleus. The stage-specific expression pattern and the subcellular localization of rKr2 recommend a role for this Kruppel-type gene in the progression of neural stem cells and in the early development of the oligodendrocyte lineage.

Published
2001
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9. Computer-Tomographie von Bäumen

Author

Hans-Werner Ridder, Gabor Lovas, Adolf Habermehl, and Aloys Hüttermann

Subjects
0106 biological sciences, 010608 biotechnology, General Agricultural and Biological Sciences, 01 natural sciences, 010606 plant biology & botany
Abstract

Die Computer-Tomographie ist ein zerstorungsfreies Schnittbildverfahren, das die ortsabhangigen Absorptionskoeffizienten fur Rontgen- oder Gammastrahlung auch an Orten ermitteln kann, die einer direkten Messung nicht zuganglich sind. Neben der Uberlagerungsfreiheit zeichnet es sich durch hohe Kontrastauflosung aus. Es eignet sich als zerstorungsfreies Verfahren nicht nur zur Untersuchung von Patienten im Rahmen der medizinischen Diagnostik, wo es seit etwa 15 Jahren etabliert ist, sondern auch fur Untersuchungen in der Werkstoffprufung. Neben Einsatzmoglichkeiten, bei denen die zu prufenden Objekte – zumindest im Prinzip – transportabel sind und in einem Pruflabor mit einem fest installierten CT-System tomographiert werden konnen, besteht ein nicht geringes Interesse an der Untersuchung von ortsfesten Objekten.

Published
1990
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10. Expression of a catalytically inactive transmembrane protein tyrosine phosphatase epsilon (tm-PTP epsilon) delays optic nerve myelination

Author

Naser, Muja, Gabor, Lovas, Elena, Romm, Dietrich, Machleder, Mukul, Ranjan, Vittorio, Gallo, and Lynn D, Hudson

Subjects
Male, Mice, Inbred C3H, Receptor-Like Protein Tyrosine Phosphatases, Class 4, Membrane Proteins, Mice, Transgenic, Optic Nerve, Nerve Fibers, Myelinated, Gene Expression Regulation, Enzymologic, Rats, Mice, Oligodendroglia, Catalytic Domain, Animals, Humans, Female, Protein Tyrosine Phosphatases
Abstract

Reversible tyrosine phosphorylation is integral to the process of oligodendrocyte differentiation. To interfere with the subset of the phosphorylation cycle overseen by protein tyrosine phosphatase epsilon (PTP epsilon) in oligodendrocytes, we applied a substrate-trapping approach in the development of transgenic mice overexpressing a catalytically inactive, transmembrane PTP epsilon-hemaglutinin (tm-PTP epsilon-HA) from the dual promoter element of the gene encoding the myelin protein 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP). Transgene expression peaked during the active myelinating period, at 2-3 weeks postnatal. Two tyrosine phosphoproteins, alpha-enolase and beta-actin, were phosphorylated to a greater degree in transgenic mice. Despite a high degree of tm-PTP epsilon-HA expression, myelin was grossly normal in nearly all axonal tracts. Phenotypic abnormalities were limited to optic nerve, where a decrease in the degree of myelination was reflected by reduced levels of myelin proteins on postnatal day 21 (PND21), as well as a decrease in the density of differentiated oligodendrocytes. The optic chiasm was reduced in thickness in transgenic mice; optic nerves similarly exhibited a reduction in transverse width. Further analyses of the optic pathway demonstrated that transgenic protein was unexpectedly present in retinal ganglion cells, whose axons are the targets of myelination by optic nerve oligodendrocytes. On PND28, transgenic protein declined dramatically in both oligodendrocytes and retinal ganglion cells contributing to the recovery of optic nerve myelination. Thus, delayed myelination arises only when tm-PTP epsilon-HA is simultaneously expressed in myelin-forming glia and their neuronal targets. While tm-PTP epsilon related signaling pathways may figure in axon-glial interactions, interfering with tm-PTP epsilon activity does not perceptibly affect the development or myelinating capacity of most oligodendrocytes.

Published
2004

12. Ethanol inhibition of stress-related tachycardia involves medullary NMDA receptors

Author

George Kunos, Gabor Lovas, Miklos Palkovits, and Karoly Varga

Subjects
Male, medicine.medical_specialty, Baclofen, Stimulation, GABAB receptor, Bicuculline, Receptors, N-Methyl-D-Aspartate, GABA Antagonists, Rats, Sprague-Dawley, Stress, Physiological, Internal medicine, Tachycardia, medicine, Solitary Nucleus, Animals, Microinjection, GABA Agonists, Pharmacology, Ethanol, GABAA receptor, Chemistry, Muscimol, Solitary nucleus, Rats, Endocrinology, nervous system, Hypothalamus, NMDA receptor, circulatory and respiratory physiology, medicine.drug
Abstract

In rats, neurons in the perifornical area of the hypothalamus send descending projections to the commissural part of the nucleus tractus solitarii as demonstrated by an anterograde tracer study. In urethane-anaesthetised rats, stimulation of neurons in the perifornical area by microinjection of bicuculline or 6-OH-saclofen causes tachycardia and inhibits baroreflex bradycardia. The effects elicited from the perifornical area are similar in magnitude to those elicited from the adjacent dorsomedial nucleus, also called the hypothalamic defense area. Microinjection into the nucleus tractus solitarii of the NMDA (N-methyl-d-aspartate) receptor antagonist, AP-7 (2-amino-7-phosphonoheptanoic acid), inhibits the tachycardic response to stimulation of the perifornical area. Injection of ethanol intravenously or into the nucleus tractus solitarii also inhibits this tachycardic response, but causes no further inhibition when combined with AP-7. We conclude that the perifornical area is part of the hypothalamic defense area, and it is under strong, tonic GABAergic inhibition mediated by both GABAA and GABAB receptors. Furthermore, descending input from the perifornical area to the nucleus tractus solitarii is via an NMDA synapse, and ethanol inhibits stress-related tachycardia by inhibiting these NMDA receptors in the nucleus tractus solitarii.

Published
1996

14. Induction of transforming growth factor beta receptors following focal ischemia in the rat brain.

Author

Gabriella Pál, Gábor Lovas, and Arpád Dobolyi

Subjects
Medicine, Science
Abstract

Transforming growth factor-βs (TGF-βs) regulate cellular proliferation, differentiation, and survival. TGF-βs bind to type I (TGF-βRI) and II receptors (TGF-βRII), which are transmembrane kinase receptors, and an accessory type III receptor (TGF-βRIII). TGF-β may utilize another type I receptor, activin-like kinase receptor (Alk1). TGF-β is neuroprotective in the middle cerebral artery occlusion (MCAO) model of stroke. Recently, we reported the expression pattern of TGF-β1-3 after MCAO. To establish how TGF-βs exert their actions following MCAO, the present study describes the induction of TGF-βRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-βRI had significant expression: neurons in cortical layer IV contained TGF-βRI. At 24 h after the occlusion, no TGF-β receptors showed induction. At 72 h following MCAO, all four types of TGF-β receptors were induced in the infarct area, while TGF-βRI and RII also appeared in the penumbra. Most cells with elevated TGF-βRI mRNA levels were microglia. TGF-βRII co-localized with both microglial and endothelial markers while TGF-βRIII and Alk1 were present predominantly in endothels. All four TGF-β receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-βRIII was further induced as compared to 72 h after MCAO. At this time point, TGF-βRIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-β receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-β receptor expression is preceded by increased TGF-β expression. TGF-βRI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-βRII, and RIII in endothels within the infarct where TGF-β1 may be their ligand. At later time points, TGF-βRIII may also appear in glial cells to potentially affect signal transduction via TGF-βRI and RII.

Published
2014
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15. Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain.

Author

Gabriella Pál, Csilla Vincze, Éva Renner, Edina A Wappler, Zoltán Nagy, Gábor Lovas, and Arpád Dobolyi

Subjects
Medicine, Science
Abstract

Transforming growth factor-βs (TGF-β1-3) are cytokines that regulate the proliferation, differentiation, and survival of various cell types. The present study describes the induction of TGF-β1-3 in the rat after focal ischemia at 3 h, 24 h, 72 h and 1 month after transient (1 h) or permanent (24 h) middle cerebral artery occlusion (MCAO) using in situ hybridization histochemistry and quantitative analysis. Double labeling with different markers was used to identify the localization of TGF-β mRNA relative to the penumbra and glial scar, and the types of cells expressing TGF-βs. TGF-β1 expression increased 3 h after MCAO in the penumbra and was further elevated 24 h after MCAO. TGF-β1 was present mostly in microglial cells but also in some astrocytes. By 72 h and 1 month after the occlusion, TGF-β1 mRNA-expressing cells also appeared in microglia within the ischemic core and in the glial scar. In contrast, TGF-β2 mRNA level was increased in neurons but not in astrocytes or microglial cells in layers II, III, and V of the ipsilateral cerebral cortex 24 h after MCAO. TGF-β3 was not induced in cells around the penumbra. Its expression increased in only a few cells in layer II of the cerebral cortex 24 h after MCAO. The levels of TGF-β2 and -β3 decreased at subsequent time points. Permanent MCAO further elevated the levels of all 3 subtypes of TGF-βs suggesting that reperfusion is not a major factor in their induction. TGF-β1 did not co-localize with either Fos or ATF-3, while the co-localization of TGF-β2 with Fos but not with ATF-3 suggests that cortical spreading depolarization, but not damage to neural processes, might be the mechanism of induction for TGF-β2. The results imply that endogenous TGF-βs are induced by different mechanisms following an ischemic attack in the brain suggesting that they are involved in distinct spatially and temporally regulated inflammatory and neuroprotective processes.

Published
2012
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