Author: "Mantegazza, A." / Topic: medicine.disease - Searchworks@Jio Institute Digital Library Search Results

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385 results on '"Mantegazza, A."'

1. Prevalence and significance of mesentery thickening and lymph nodes enlargement in Crohn's disease

Author: Gianluca M. Sampietro, Francesco Colombo, Dario Dilillo, Giovanni Maconi, C. Mantegazza, Diego Foschi, Paolo Fiorina, Gian Vincenzo Zuccotti, Francesca D'Addio, Alberto Corona, Manuela Nebuloni, Sandro Ardizzone, Cristian Loretelli, and Fabio Corsi
Subjects: medicine.medical_specialty, Crohn's disease, Surgical approach, Hepatology, business.industry, medicine.medical_treatment, Gastroenterology, Nutritional status, medicine.disease, Lymph nodes enlargement, Increased risk, medicine.anatomical_structure, Crohn Disease, Recurrence, Prevalence, Strictureplasty, Humans, Medicine, Mesentery, Lymph Nodes, Radiology, Thickening, business, Retrospective Studies
Abstract: Background Mesentery thickening and enlarged lymphnodes are typical findings of Crohn's disease (CD), but their role is unknown. Aim of the present study was to evaluate their prevalence and significance on postoperative complications and long-term surgical recurrence after CD surgery. Methods 1272 consecutive, unselected patients were retrospectively reviewed, divided into 4 groups based on the presence or absence of a thickened mesentery and enlarged lymphnodes, and stratified for primary or recurrent surgical procedure. In all patients but those treated with strictureplasty the mesentery and lymphnodes were removed. Patients’ characteristics, peri-operative findings, and long-term recurrence were compared by univariate and multivariate analysis. Results Thickened mesentery and enlarged lymphnodes were not present in all cases, were typical of ileal location and penetrating behaviour, had a constant decrease over recurrences, were independent of either pre-operative medical therapy or surgical approach, did not increase the duration of surgery and complications, presented similar 20-years recurrence rate to normal mesentery and lymphnodes. Lymphopathy was associated to a worst nutritional status during disease recurrences. At multivariate analysis, age, location, and behaviour, but not mesenteric characteristics, were related to an increased risk of surgical recurrence. Conclusions This study provides new information on mesentery and lymphnodes in CD patients. Further studies are needed to clarify the appropriate surgical approach.
Published: 2022
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2. Mutations associated with hypokalemic periodic paralysis: from hotspot regions to complete analysis of CACNA1S and SCN4A genes

Author: Paola Tonin, Marica Eoli, Antonella Pini, Giuseppe Lauria, Gabriele Siciliano, Carlotta Canavese, Lorenzo Maggi, Raffaella Brugnoni, Renato Mantegazza, Tommaso Rossi, Eleonora Canioni, and Massimiliano Filosto
Subjects: Calcium Channels, L-Type, Biology, medicine.disease_cause, Genetic analysis, DNA sequencing, Cellular and Molecular Neuroscience, symbols.namesake, Hypokalemic periodic paralysis, Genetics, medicine, Humans, Genetic Testing, NAV1.4 Voltage-Gated Sodium Channel, Muscle, Skeletal, Gene, Genetics (clinical), Sanger sequencing, Mutation, Massive parallel sequencing, Autosomal dominant trait, Sanger method, CACNA1S and SCN4A genes, medicine.disease, Next-generation sequencing, symbols
Abstract: Familial periodic paralyses (PPs) are inherited disorders of skeletal muscle characterized by recurrent episodes of flaccid muscle weakness. PPs are classified as hypokalemic (HypoPP), normokalemic (NormoPP), or hyperkalemic (HyperPP) according to the potassium level during the paralytic attacks. HypoPP is an autosomal dominant disease caused by mutations in the CACNA1S gene, encoding for Cav1.1 channel (HypoPP-1), or SCN4A gene, encoding for Nav1.4 channel (HypoPP-2). In the present study, we included 60 patients with a clinical diagnosis of HypoPP. Fifty-one (85%) patients were tested using the direct sequencing (Sanger method) of all reported HypoPP mutations in CACNA1S and SCN4A genes; the remaining 9 (15%) patients were analyzed through a next-generation sequencing (NGS) panel, including the whole CACNA1S and SCN4A genes, plus other genes rarely associated to PPs. Fifty patients resulted mutated: 38 (76%) cases showed p.R528H and p.R1239G/H CACNA1S mutations and 12 (24%) displayed p.R669H, p.R672C/H, p.R1132G/Q, and p.R1135H SCN4A mutations. Forty-one mutated cases were identified among the 51 patients managed with Sanger sequencing, while all the 9 cases directly analyzed with the NGS panel showed mutations in the hotspot regions of SCN4A and CACNA1S. Ten out of the 51 patients unresolved through the Sanger sequencing were further analyzed with the NGS panel, without the detection of any mutation. Hence, our data suggest that in HypoPP patients, the extension of genetic analysis from the hotspot regions using the Sanger method to the NGS sequencing of the entire CACNA1S and SCN4A genes does not lead to the identification of new pathological mutations.
Published: 2021
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3. Sodium channelopathies of skeletal muscle and brain

Author: Massimo Mantegazza, William A. Catterall, Sandrine Cestèle, and Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis
Subjects: 0301 basic medicine, Physiology, [SDV]Life Sciences [q-bio], Sodium, chemistry.chemical_element, Review, Sodium Channels, Mice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Channelopathy, Physiology (medical), medicine, Animals, Humans, Muscle, Skeletal, Molecular Biology, Sodium channel, Brain, Skeletal muscle, Periodic paralysis, General Medicine, medicine.disease, Pathophysiology, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, chemistry, Structural biology, Channelopathies, Nervous System Diseases, Neuroscience, 030217 neurology & neurosurgery
Abstract: International audience; Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivation, and both biosynthesis and assembly. Mutations that cause different forms of periodic paralysis in skeletal muscle were discovered first and have provided a template for understanding structure, function, and pathophysiology at the molecular level. More recent work has revealed multiple sodium channelopathies in the brain. Here we review the well-characterized genetics and pathophysiology of the periodic paralyses of skeletal muscle and then use this information as a foundation for advancing our understanding of mutations in the structurally homologous α-subunits of brain sodium channels that cause epilepsy, migraine, autism, and related comorbidities. We include studies based on molecular and structural biology, cell biology and physiology, pharmacology, and mouse genetics. Our review reveals unexpected connections among these different types of sodium channelopathies.
Published: 2021
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4. Rest and exercise oxygen uptake and cardiac output changes 6 months after successful transcatheter mitral valve repair

Author: Gaia Cattadori, Francesco Alamanni, Carlo Vignati, Manuela Muratori, Stefania Farina, Valentina Mantegazza, Piergiuseppe Agostoni, Gloria Tamborini, Mauro Pepi, Antonio L. Bartorelli, Elisabetta Salvioni, and Fabiana De Martino
Subjects: Cardiac output, medicine.medical_specialty, medicine.medical_treatment, medicine.artery, Internal medicine, medicine, Humans, Diseases of the circulatory (Cardiovascular) system, Exercise, Mitral valve repair, Ejection fraction, business.industry, Mitral Valve Insufficiency, Stroke Volume, Original Articles, Stroke volume, Blood flow, medicine.disease, Oxygen, Oxygen uptake, Blood pressure, RC666-701, Heart failure, Pulmonary artery, Transcatheter mitral valve repair, Cardiology, Mitral Valve, Original Article, Percutaneous edge‐to‐edge mitral valve repair, Cardiology and Cardiovascular Medicine, business
Abstract: Aims Changes in peak exercise oxygen uptake (VO2) and cardiac output (CO) 6 months after successful percutaneous edge‐to‐edge mitral valve repair (pMVR) in severe primary (PMR) and functional mitral regurgitation (FMR) patients are unknown. The aim of the study was to assess the efficacy of pMVR at rest by echocardiography, VO2 and CO (inert gas rebreathing) measurement and during cardiopulmonary exercise test with CO measurement. Methods and results We evaluated 145 and 115 patients at rest and 98 and 66 during exercise before and after pMVR, respectively. After successful pMVR, significant reductions in MR and NYHA class were observed in FMR and PMR patients. Cardiac ultrasound showed reverse remodelling (left ventricular end‐diastolic volume from 158 ± 63 mL to 147 ± 64, P
Published: 2021
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5. Tricuspid annular dilation in patients undergoing early mitral valve surgery: is it an old story?

Author: Manuela Muratori, Marco Zanobini, Valentina Volpato, Francesco Alamanni, Paola Gripari, Gloria Tamborini, Valentina Mantegazza, Mauro Pepi, and Laura Fusini
Subjects: medicine.medical_specialty, Elevated pulmonary artery pressure, Population, Regurgitation (circulation), 030204 cardiovascular system & hematology, Cardiac Valve Annuloplasty, 03 medical and health sciences, Basal (phylogenetics), 0302 clinical medicine, Predictive Value of Tests, Internal medicine, medicine, Humans, Mitral valve prolapse, Radiology, Nuclear Medicine and imaging, Sinus rhythm, 030212 general & internal medicine, education, education.field_of_study, business.industry, medicine.disease, Dilatation, Pulmonary hypertension, Tricuspid Valve Insufficiency, Concomitant, Cardiology, Mitral Valve, Tricuspid Valve, Cardiology and Cardiovascular Medicine, business
Abstract: Patients with mitral valve prolapse (MVP), undergoing early surgery for severe regurgitation, are usually characterized by a low degree of right chambers’ remodeling. In this selected population, the mechanisms leading to tricuspid annular (TA) dilatation (TAD) are not well understood. In this setting, we aimed to evaluate, using three-dimensional echocardiography (3DE), how right chambers affect TA size and might contribute to functional tricuspid regurgitation (FTR) progression. We studied 159 patients treated with early isolated surgery for MVP, characterized by: sinus rhythm; normal biventricular function; normal or elevated pulmonary artery pressure; tricuspid regurgitation (TR) ≤ mild; no concomitant cardiac disease. All patients reached a 3-year echocardiographic follow-up. Based on two-dimensional echocardiography, patients were divided in Group 1 (N = 68, 43%, TAD, TA ≥ 21 mm/m2) and Group 2 (N = 91, 57%, no TAD, TA
Published: 2021
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6. Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3

Author: Veria Vacchiano, Luca Bello, Renato Mantegazza, Eustachio D'Errico, Tiziana Mongini, Riccardo Zanin, Gabriele Siciliano, Francesca Trojsi, Elena Saccani, Federica Cerri, Marina Grandis, Michela Coccia, Stefano C. Previtali, Alessandra Govoni, Massimiliano Filosto, L. Passamano, Giovanni Pavesi, Luisa Politano, Mauro Silvestrini, Claudia Caponnetto, Silvia Bonanno, Virginia Bozzoni, Manfredi Ferraro, Elena Pegoraro, Raffaella Tanel, Lorenzo Verriello, Angelo Schenone, Sara Bortolani, Lorenzo Maggi, Angela Berardinelli, Giacomo P. Comi, Megi Meneri, Rocco Liguori, Gianni Sorarù, G. Marrosu, Mara Turri, Luca Caumo, Irene Tramacere, Rachele Piras, Giulia Ricci, Isabella Laura Simone, Maggi, Lorenzo, Bello, Luca, Bonanno, Silvia, Govoni, Alessandra, Caponnetto, Claudia, Passamano, Luigia, Grandis, Marina, Trojsi, Francesca, Cerri, Federica, Ferraro, Manfredi, Bozzoni, Virginia, Caumo, Luca, Piras, Rachele, Tanel, Raffaella, Saccani, Elena, Meneri, Megi, Vacchiano, Veria, Ricci, Giulia, Soraru', Gianni, D'Errico, Eustachio, Tramacere, Irene, Bortolani, Sara, Pavesi, Giovanni, Zanin, Riccardo, Silvestrini, Mauro, Politano, Luisa, Schenone, Angelo, Previtali, Stefano Carlo, Berardinelli, Angela, Turri, Mara, Verriello, Lorenzo, Coccia, Michela, Mantegazza, Renato, Liguori, Rocco, Filosto, Massimiliano, Marrosu, Gianni, Siciliano, Gabriele, Simone, Isabella Laura, Mongini, Tiziana, Comi, Giacomo, Pegoraro, Elena, Maggi L., Bello L., Bonanno S., Govoni A., Caponnetto C., Passamano L., Grandis M., Trojsi F., Cerri F., Ferraro M., Bozzoni V., Caumo L., Piras R., Tanel R., Saccani E., Meneri M., Vacchiano V., Ricci G., Soraru' G., D'Errico E., Tramacere I., Bortolani S., Pavesi G., Zanin R., Silvestrini M., Politano L., Schenone A., Previtali S.C., Berardinelli A., Turri M., Verriello L., Coccia M., Mantegazza R., Liguori R., Filosto M., Marrosu G., Siciliano G., Simone I.L., Mongini T., Comi G., and Pegoraro E.
Subjects: Male, Pediatrics, spinal muscular atrophy type 3, Vital Capacity, spinal muscular atrophy type 2, Oligonucleotides, Walking, Spinal Muscular Atrophies of Childhood, Cohort Studies, Efficacy, 0302 clinical medicine, Forced Expiratory Volume, Age of Onset, Young adult, Injections, Spinal, Sitting Position, 0303 health sciences, Middle Aged, Psychiatry and Mental health, Treatment Outcome, Italy, Female, Nusinersen, Cohort study, Adult, medicine.medical_specialty, Adolescent, Spinal, Walk Test, Injections, Young Adult, 03 medical and health sciences, Rating scale, medicine, Humans, Aged, Functional Status, Oligonucleotides, Antisense, Retrospective Studies, Antisense, 030304 developmental biology, business.industry, Retrospective cohort study, Spinal muscular atrophy, medicine.disease, Surgery, Neurology (clinical), Age of onset, business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA).MethodsInclusion criteria were: (1) clinical and molecular diagnosis of SMA2 or SMA3; (2) nusinersen treatment started in adult age (>18 years); (3) clinical data available at least at baseline (T0-beginning of treatment) and 6 months (T6).ResultsWe included 116 patients (13 SMA2 and 103 SMA3) with median age at first administration of 34 years (range 18–72). The Hammersmith Functional Rating Scale Expanded (HFMSE) in patients with SMA3 increased significantly from baseline to T6 (median change +1 point, pConclusionsOur data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.
Published: 2020

7. Complement Inhibition for the Treatment of Myasthenia Gravis

Author: Fiammetta Vanoli, Rita Frangiamore, Paola Cavalcante, and Renato Mantegazza
Subjects: biology, business.industry, Immunology, Eculizumab, medicine.disease, Neuromuscular junction, Complement inhibition, Myasthenia gravis, Complement system, Nicotinic acetylcholine receptor, medicine.anatomical_structure, medicine, biology.protein, Immunology and Allergy, Antibody, business, Acetylcholine receptor, medicine.drug
Abstract: Generalized myasthenia gravis (gMG) is a rare autoimmune disorder affecting the neuromuscular junction (NMJ). Approximately 80-90% of patients display antibodies directed against the nicotinic acetylcholine receptor (AChR). A major drive of AChR antibody-positive MG pathology is represented by complement activation. The role of the complement cascade has been largely demonstrated in patients and in MG animal models. Complement activation at the NMJ leads to focal lysis of the post-synaptic membrane, disruption of the characteristic folds, and reduction of AChR. Given that the complement system works as an activation cascade, there are many potential targets that can be considered for therapeutic intervention. Preclinical studies have confirmed the efficacy of complement inhibition in ameliorating MG symptoms. Eculizumab, an antibody directed towards C5, has recently been approved for the treatment of AChR antibody-positive gMG. Other complement inhibitors, targeting C5 as well, are currently under phase III study. Complement inhibitors, however, may present prohibitive costs. Therefore, the identification of a subset of patients more or less prone to respond to such therapies would be beneficial. For such purpose, there is a critical need to identify possible biomarkers predictive of therapeutic response, a field not yet sufficiently explored in MG. This review aims to give an overview of the complement cascade involvement in MG, the evolution of complement-inhibiting therapies and possible biomarkers useful to tailor and monitor complement-directed therapies.
Published: 2020
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8. 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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9. Pharmacogenetic and pharmaco-miR biomarkers for tailoring and monitoring myasthenia gravis treatments

Author: Pia Bernasconi, Renato Mantegazza, and Paola Cavalcante
Subjects: Pharmacology, Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunosuppression, medicine.disease, Myasthenia gravis, Efficacy, Tolerability, Internal medicine, Drug Discovery, Genetics, Molecular Medicine, Medicine, business, Pharmacogenetics
Abstract: Inter-individual variation in drug efficacy and tolerability in myasthenia gravis (MG), an autoimmune disorder mostly treated by chronic immunosuppression, highlights the need of specific, safe and...
Published: 2020
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10. Multimodality imaging assessment of mitral annular disjunction in mitral valve prolapse

Author: Manuela Muratori, Valentina Mantegazza, Paola Gripari, Gianluca Pontone, Sarah Ghulam Ali, Laura Fusini, Mauro Pepi, Gloria Tamborini, Gianpiero Italiano, and Valentina Volpato
Subjects: Adult, Male, medicine.medical_specialty, Hemodynamics, Settore MED/11 - Malattie dell'Apparato Cardiovascolare, 030204 cardiovascular system & hematology, Transoesophageal echocardiography, Multimodal Imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, cardiac magnetic resonance (CMR) imaging, Humans, Medicine, Mitral valve prolapse, Aged, Retrospective Studies, Mitral regurgitation, Mitral Valve Prolapse, business.industry, Mitral Valve Insufficiency, echocardiography, mitral regurgitation, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Cardiac Imaging Techniques, Echocardiography, Cardiology, Female, Cardiology and Cardiovascular Medicine, Cardiac magnetic resonance, business, Echocardiography, Transesophageal, 030217 neurology & neurosurgery
Abstract: ObjectiveMitral annular disjunction (MAD) is an abnormality linked to mitral valve prolapse (MVP), possibly associated with malignant ventricular arrhythmias. We assessed the agreement among different imaging techniques for MAD identification and measurement.Methods131 patients with MVP and significant mitral regurgitation undergoing transthoracic echocardiography (TTE) and cardiac magnetic resonance (CMR) were retrospectively enrolled. Transoesophageal echocardiography (TOE) was available in 106 patients. MAD was evaluated in standard long-axis views (four-chamber, two-chamber, three-chamber) by each technique.ResultsConsidering any-length MAD, MAD prevalence was 17.3%, 25.5%, 42.0% by TTE, TOE and CMR, respectively (pConclusionsAn integrated imaging approach could be necessary for a comprehensive assessment of patients with MVP and symptoms suggestive for arrhythmias. If echocardiography is fundamental for the anatomic and haemodynamic characterisation of the MV disease, CMR may better identify small length MAD as well as myocardial fibrosis.
Published: 2020
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11. Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic elongation factor 2 kinase (eEF2K)

Author: Chiara Verpelli, Stefania Beratta, Luisa Ponzoni, Carlo Sala, Mariaelvina Sala, Laura Gritti, Paolo Scalmani, and Massimo Mantegazza
Subjects: Elongation Factor 2 Kinase, Epilepsies, Myoclonic, Biology, Eukaryotic Elongation Factor-2 Kinase, Mice, Developmental Neuroscience, Dravet syndrome, medicine, Animals, EEG, RC346-429, Molecular Biology, Epilepsy, Protein translation, Research, medicine.disease, Cell biology, SCN1A gene, Mice, Inbred C57BL, NAV1.1 Voltage-Gated Sodium Channel, Psychiatry and Mental health, Disease Models, Animal, Neurology. Diseases of the nervous system, Epileptic Syndromes, Inhibitory synapses, Developmental Biology
Abstract: Background Dravet Syndrome is a severe childhood pharmaco-resistant epileptic disorder mainly caused by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that causes imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. Thus, we investigated the effect of inhibition of eEF2K on the epileptic and behavioral phenotype of Scn1a ± mice, a murine model of Dravet Syndrome. Methods To elucidate the role of eEF2K pathway in the etiopathology of Dravet syndrome we generated a new mouse model deleting the eEF2K gene in Scn1a ± mice. By crossing Scn1a ± mice with eEF2K−/− mice we obtained the three main genotypes needed for our studies, Scn1a+/+ eEF2K+/+ (WT mice), Scn1a ± eEF2K+/+ mice (Scn1a ± mice) and Scn1a ± eEF2K−/− mice, that were fully characterized for EEG and behavioral phenotype. Furthermore, we tested the ability of a pharmacological inhibitor of eEF2K in rescuing EEG alterations of the Scn1a ± mice. Results We showed that the activity of eEF2K/eEF2 pathway was enhanced in Scn1a ± mice. Then, we demonstrated that both genetic deletion and pharmacological inhibition of eEF2K were sufficient to ameliorate the epileptic phenotype of Scn1a ± mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a ± mice were reverted by eEF2K deletion. The analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathological phenotype was driven by the potentiation of GABAergic synapses. Limitations Even if we found that eEF2K deletion was able to increase inhibitory synapses function, the molecular mechanism underlining the inhibition of eEF2K/eEF2 pathway in rescuing epileptic and behavioral alterations in the Scn1a ± needs further investigations. Conclusions Our data indicate that pharmacological inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.
Published: 2022

12. Dysregulation of Muscle-Specific MicroRNAs as Common Pathogenic Feature Associated with Muscle Atrophy in ALS, SMA and SBMA: Evidence from Animal Models and Human Patients

Author: Angelo Poletti, Viviana Pensato, Monica Nizzardo, Paola Cavalcante, Cinzia Gellera, Mariarita Galbiati, Silvia Bonanno, Michela Taiana, Davide Pareyson, Giuseppe Lauria, Lorenzo Maggi, Franco Salerno, Stefania Corti, Silvia Fenu, Francesca Andreetta, Anna Venerando, Claudia Malacarne, Renato Mantegazza, Eleonora Dalla Bella, Riccardo Masson, Stefania Marcuzzo, Pia Bernasconi, Cinza Cagnoli, Eleonora Giagnorio, Malacarne, C, Galbiati, M, Giagnorio, E, Cavalcante, P, Salerno, F, Andreetta, F, Cagnoli, C, Taiana, M, Nizzardo, M, Corti, S, Pensato, V, Venerando, A, Gellera, C, Fenu, S, Pareyson, D, Masson, R, Maggi, L, Bella, E, Lauria, G, Mantegazza, R, Bernasconi, P, Poletti, A, Bonanno, S, and Marcuzzo, S
Subjects: muscle-specific microRNAs, Pathology, medicine.medical_specialty, amyotrophic lateral sclerosis, motor neuron diseases, QH301-705.5, Muscle-specific microRNA, Mutation, Missense, Mice, Transgenic, Bulbo-Spinal Atrophy, X-Linked, Catalysis, Article, Mouse model, Inorganic Chemistry, Pathogenesis, Mice, Superoxide Dismutase-1, Medicine, Animals, Humans, spinal bulbar muscular atrophy, mouse models, Motor neuron disease, Physical and Theoretical Chemistry, Amyotrophic lateral sclerosis, Biology (General), Molecular Biology, QD1-999, Spectroscopy, Amyotrophic lateral sclerosi, spinal muscular atrophy, business.industry, Superoxide Dismutase, Organic Chemistry, Skeletal muscle, General Medicine, Spinal muscular atrophy, Motor neuron, medicine.disease, SMA, Muscle atrophy, Computer Science Applications, Spinal and bulbar muscular atrophy, Chemistry, MicroRNAs, medicine.anatomical_structure, Amino Acid Substitution, medicine.symptom, business
Abstract: Motor neuron diseases (MNDs) are neurodegenerative disorders characterized by upper and/or lower MN loss. MNDs include amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and spinal and bulbar muscular atrophy (SBMA). Despite variability in onset, progression, and genetics, they share a common skeletal muscle involvement, suggesting that it could be a primary site for MND pathogenesis. Due to the key role of muscle-specific microRNAs (myomiRs) in skeletal muscle development, by real-time PCR we investigated the expression of miR-206, miR-133a, miR-133b, and miR-1, and their target genes, in G93A-SOD1 ALS, Δ7SMA, and KI-SBMA mouse muscle during disease progression. Further, we analyzed their expression in serum of SOD1-mutated ALS, SMA, and SBMA patients, to demonstrate myomiR role as noninvasive biomarkers. Our data showed a dysregulation of myomiRs and their targets, in ALS, SMA, and SBMA mice, revealing a common pathogenic feature associated with muscle impairment. A similar myomiR signature was observed in patients’ sera. In particular, an up-regulation of miR-206 was identified in both mouse muscle and serum of human patients. Our overall findings highlight the role of myomiRs as promising biomarkers in ALS, SMA, and SBMA. Further investigations are needed to explore the potential of myomiRs as therapeutic targets for MND treatment.
Published: 2021

13. Arrhythmic Mitral Valve Prolapse: Introducing an Era of Multimodality Imaging-Based Diagnosis and Risk Stratification

Author: Mauro Pepi, Andrea Baggiano, Andrea Mazzanti, Marco Guglielmo, Manuela Muratori, Deni Kukavica, Silvia G. Priori, Valentina Mantegazza, Alessandro Trancuccio, Giuseppe Muscogiuri, Carlo Arnò, Gianluca Pontone, Laura Fusini, Gloria Tamborini, Kukavica, D, Guglielmo, M, Baggiano, A, Muscogiuri, G, Fusini, L, Muratori, M, Tamborini, G, Mantegazza, V, Trancuccio, A, Arnò, C, Mazzanti, A, Pepi, M, Priori, S, and Pontone, G
Subjects: medicine.medical_specialty, Clinical Biochemistry, Settore MED/11 - Malattie dell'Apparato Cardiovascolare, Review, 030204 cardiovascular system & hematology, arrhythmia, cardiovascular magnetic resonance, echocardiography, mitral valve prolapse, multimodality imaging, risk factors, sudden cardiac death, Sudden cardiac death, 03 medical and health sciences, 0302 clinical medicine, Mitral valve, Internal medicine, Epidemiology, medicine, Mitral valve prolapse, In patient, 030212 general & internal medicine, cardiovascular diseases, lcsh:R5-920, business.industry, medicine.disease, Young age, medicine.anatomical_structure, Risk stratification, Etiology, Cardiology, cardiovascular system, Risk factor, business, lcsh:Medicine (General)
Abstract: Mitral valve prolapse is a common cardiac condition, with an estimated prevalence between 1% and 3%. Most patients have a benign course, but ever since its initial description mitral valve prolapse has been associated to sudden cardiac death. Although the causal relationship between mitral valve prolapse and sudden cardiac death has never been clearly demonstrated, different factors have been implicated in arrhythmogenesis in patients with mitral valve prolapse. In this work, we offer a comprehensive overview of the etiology and the genetic background, epidemiology, pathophysiology, and we focus on the state-of-the-art imaging-based diagnosis of mitral valve prolapse. Going beyond the classical, well-described clinical factors, such as young age, female gender and auscultatory findings, we investigate multimodality imaging features, such as alterations of anatomy and function of the mitral valve and its leaflets, the structural and contractile anomalies of the myocardium, all of which have been associated to sudden cardiac death. This research received no external funding Sí
Published: 2021

14. MyomiRs and their multifaceted regulatory roles in muscle homeostasis and amyotrophic lateral sclerosis

Author: Eleonora Giagnorio, Stefania Marcuzzo, Claudia Malacarne, Silvia Bonanno, Renato Mantegazza, Giagnorio, E, Malacarne, C, Mantegazza, R, Bonanno, S, and Marcuzzo, S
Subjects: Muscle tissue, Disease, Degeneration (medical), Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Paralysis, Homeostasis, Humans, Amyotrophic lateral sclerosis, Muscle, Skeletal, Amyotrophic lateral sclerosi, 030304 developmental biology, Motor Neurons, 0303 health sciences, Myogenesis, MyomiR, Amyotrophic Lateral Sclerosis, Skeletal muscle, Neurodegenerative Diseases, Cell Biology, Muscle homeostasi, medicine.disease, Muscle atrophy, medicine.anatomical_structure, medicine.symptom, Neuroscience, 030217 neurology & neurosurgery
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of both upper and lower motor neurons (MNs). The main clinical features of ALS are motor function impairment, progressive muscle weakness, muscle atrophy and, ultimately, paralysis. Intrinsic skeletal muscle deterioration plays a crucial role in the disease and contributes to ALS progression. Currently, there are no effective treatments for ALS, highlighting the need to obtain a deeper understanding of the molecular events underlying degeneration of both MNs and muscle tissue, with the aim of developing successful therapies. Muscle tissue is enriched in a group of microRNAs called myomiRs, which are effective regulators of muscle homeostasis, plasticity and myogenesis in both physiological and pathological conditions. After providing an overview of ALS pathophysiology, with a focus on the role of skeletal muscle, we review the current literature on myomiR network dysregulation as a contributing factor to myogenic perturbations and muscle atrophy in ALS. We argue that, in view of their critical regulatory function at the interface between MNs and skeletal muscle fiber, myomiRs are worthy of further investigation as potential molecular targets of therapeutic strategies to improve ALS symptoms and counteract disease progression.
Published: 2021

15. Epstein-Barr Virus in Myasthenia Gravis: Key Contributing Factor Linking Innate Immunity with B-Cell-Mediated Autoimmunity

Author: Federica Bortone, Paola Cavalcante, Letizia Scandiffio, Pia Bernasconi, and Renato Mantegazza
Subjects: 0301 basic medicine, Innate immune system, business.industry, InformationSystems_INFORMATIONSTORAGEANDRETRIEVAL, medicine.disease_cause, medicine.disease, Epstein–Barr virus, Myasthenia gravis, Autoimmunity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Immunology, Medicine, business, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), 030217 neurology & neurosurgery, B cell
Abstract: Epstein-Barr virus (EBV), a common human herpes virus latently infecting most of the world’s population with periodic reactivations, is the main environmental factor suspected to trigger and/or sustain autoimmunity by its ability to disrupt B-cell tolerance checkpoints. Myasthenia gravis (MG) is a prototypic autoimmune disorder, mostly caused by autoantibodies to acetylcholine receptor (AChR) of the neuromuscular junction, which cause muscle weakness and fatigability. Most patients display hyperplastic thymus, characterized by ectopic germinal center formation, chronic inflammation, exacerbated Toll-like receptor activation, and abnormal B-cell activation. After an overview on MG clinical features and intra-thymic pathogenesis, in the present chapter, we describe our main findings on EBV presence in MG thymuses, including hyperplastic and thymoma thymuses, in relationship with innate immunity activation and data from other autoimmune conditions. Our overall data strongly indicate a critical contribution of EBV to innate immune dysregulation and sustained B-cell-mediated autoimmune response in the pathological thymus of MG patients.
Published: 2021
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16. Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels

Author: Mathieu Desroches, Martin Krupa, Paolo Scalmani, Alexandre Loucif, Sandrine Cestèle, Lara Pizzamiglio, Louisiane Lemaire, Massimo Mantegazza, Isabelle Léna, Sarah Zerimech, Fabrice Duprat, Marion Ayrault, Oana Chever, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire Jean Alexandre Dieudonné (JAD), Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Mathématiques pour les Neurosciences (MATHNEURO), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Université Côte d'Azur (UCA), Laboratoire Jean Alexandre Dieudonné (LJAD), and Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Migraine Disorders, [SDV]Life Sciences [q-bio], FHM, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], Sodium channels, Mice, Transgenic, Neocortex, Hm1a, Biology, Neurotransmission, Mice, 03 medical and health sciences, Glutamatergic, 0302 clinical medicine, aura, spreading depolarization, Interneurons, medicine, Animals, migraine, SCN1A, GABAergic Neurons, Familial hemiplegic migraine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SCCO.NEUR]Cognitive science/Neuroscience, Cortical Spreading Depression, General Medicine, medicine.disease, Migraine with aura, NAV1.1 Voltage-Gated Sodium Channel, medicine.anatomical_structure, Migraine, Cortical spreading depression, GABAergic, medicine.symptom, Neuroscience, Neurological disorders, 030217 neurology & neurosurgery, Research Article, Genetic diseases
Abstract: International audience; Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause familial hemiplegic migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain of function to CSD generation in FHM3. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.
Published: 2021
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17. Cardiac Reverse Remodelling by 2D and 3D Echocardiography in Heart Failure Patients Treated with Sacubitril/Valsartan

Author: Valentina Mantegazza, Gloria Tamborini, Piergiuseppe Agostoni, Valentina Volpato, Massimo Mapelli, Mauro Pepi, Valentina Sassi, I. Mattavelli, and Elisabetta Salvioni
Subjects: sacubitril/valsartan, heart failure with reduced ejection fraction, heart failure aetiology, reverse remodelling, 3D echocardiography, Medicine (General), medicine.medical_specialty, medicine.drug_class, Clinical Biochemistry, Article, Sacubitril, Biventricular function, R5-920, Internal medicine, Natriuretic peptide, Medicine, Ejection fraction, business.industry, medicine.disease, Valsartan, Heart failure, Cardiology, business, 3d echocardiography, Sacubitril, Valsartan, medicine.drug
Abstract: In terms of sacubitril/valsartan (S/V)-induced changes in heart failure with reduced ejection fraction (HFrEF) via three-dimensional (3D) transthoracic echocardiography (TTE) and S/V effects based on HF aetiology, data are lacking. We prospectively enrolled 51 HFrEF patients (24 ischaemic, 27 non-ischaemic). At baseline and at 6-month follow-up (6MFU) after S/V treatment optimisation, we assessed the N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac remodelling by two-dimensional (2D) and 3DTTE. In non-ischaemic patients, 2D and 3DTTE showed an improvement in left ventricular (LV) size and biventricular function at 6MFU vs. baseline: 3D-LV end-diastolic volume (EDV) 103 ± 30 vs. 125 ± 32 mL/m2 (p < 0.05), 3D-LV ejection fraction (EF) 40 ± 9 vs. 32 ± 5% (p < 0.05), right ventricular (RV) 3D-EF 48.4 ± 6.5 vs. 44.3 ± 7.5% (p < 0.05); only the 3D method detected RV size reduction: 3D-RVEDV 63 ± 27 vs. 71 ± 30 mL/m2 (p < 0.05). In ischaemic patients, only 3DTTE showed biventricular size and LV function improvement: 3D-LVEDV 112 ± 29 vs. 121 ± 27 mL/m2 (p < 0.05), 3D-LVEF 35 ± 6 vs. 32 ± 5% (p < 0.05), 3D-RVEDV 57 ± 11 vs. 63 ± 14 mL/m2 (p < 0.05); RV function did not ameliorate. In both ischaemic and non-ischaemic patients, diastolic function and NT-proBNP significantly improved. In HFrEF patients treated with S/V, 3DTTE helps to ascertain subtle changes in heart chambers’ size and function, which have a major impact on HFrEF prognosis. S/V has significantly different effects on LV function in non-ischaemic vs. ischaemic patients.
Published: 2021
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18. Is the COVID‐19 pandemic impacting on the risk of African Swine Fever virus (ASFV) introduction into the United States? A short‐term assessment of the risk factors

Author: Marco De Nardi, Ilaria Capua, Angela Fanelli, Luca Mantegazza, and Olga Munoz
Subjects: medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Swine, global connections, Sus scrofa, African swine fever virus, Disease Outbreaks, transboundary disease, Risk Factors, Pandemic, medicine, Animals, Humans, African Swine Fever, China, Socioeconomics, Pandemics, Swine Diseases, General Veterinary, General Immunology and Microbiology, biology, Public health, Zoonosis, COVID-19, Outbreak, COVID‐19 pandemic, Original Articles, General Medicine, biology.organism_classification, medicine.disease, African Swine Fever Virus, United States, Contagious disease, Geography, Original Article
Abstract: Summary African swine fever (ASF) is a contagious disease with high mortality in domestic and feral swine populations. Although it is not a zoonosis, its spread may have severe socio‐economic and public health consequences. The activities of veterinary services are essential for controlling ASF outbreaks within a country, but also for diminishing its threat of spread to neighbouring countries, and for recognizing its entry into countries that are currently free. ASF requires quick responses and permanent monitoring to identify outbreaks and prevent spread, and both aspects can be heavily undercut during the COVID‐19 pandemic. This paper analyses changing patterns of the main drivers and pathways for the potential introduction of ASFV into the United States during the COVID‐19 pandemic, including international movements of people, swine products and by‐products. Data on commercial flights and merchant ships was used as a proxy to indirectly assess the flow of illegal products coming from ASF affected countries. Results from this study highlight a decreasing trend in the legal imports of swine products and by‐products from ASF affected countries (Sen's slope = −99, 95% CI: −215.34 to −21.26, p‐value < 0.05), while no trend was detected for confiscations of illegal products at ports of entry. Additionally, increasing trends were detected for the monthly number of merchant ships coming from ASF affected countries (Sen's slope = 0.46, 95%CI 0.25–0.59), the monthly value of imported goods ($) through merchant ships (Sen's slope = 1513196160, 95%CI 1072731702–1908231855), and the monthly percentage of commercial flights (Sen's slope = 0.005, 95%CI 0.003–0.007), with the majority of them originating from China. Overall, the findings show an increased connection of the United States with ASF affected countries, highlighting the risk posed by ASF during a global public health crisis.
Published: 2021
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19. Cardiac reverse remodelling by 2D and 3D echocardiography in heart failure patients treated with sacubitril/valsartan: a prospective study

Author: Valentina Mantegazza, Valentina Volpato, Mauro Pepi, V. Sassi, G. Tamborini, I Mattavelli, Massimo Mapelli, Elisabetta Salvioni, and Piergiuseppe Agostoni
Subjects: medicine.medical_specialty, business.industry, Internal medicine, Heart failure, medicine, Cardiology, Cardiology and Cardiovascular Medicine, Prospective cohort study, business, medicine.disease, 3d echocardiography, Sacubitril, Valsartan
Abstract: Background Left ventricular (LV) reverse remodelling induced by sacubitril/valsartan (S/V) has been shown in heart failure patients with reduced ejection fraction (HFrEF) by two-dimensional (2D) transthoracic echocardiography (TTE). Data about S/V effect on the right ventricle (RV) are scarce. Aims We aimed to evaluate S/V-induced changes in NT-proBNP levels, and cardiac remodelling indices by 2D and three-dimensional (3D) TTE in HFrEF patients, classifying patients according to aetiology. Methods We prospectively enrolled 51 HFrEF patients (24 ischaemic, 27 non-ischaemic). At baseline and at 6-months follow-up (6MFU) after S/V treatment optimization, we i) assessed NT-proBNP; ii) performed 2D TTE according to guidelines for the assessment of biventricular size and function, mitral regurgitation grade and LV diastolic function; and iii) performed 3D TTE, using the Dynamic HeartModel software for the evaluation of LV volumes and function, the 4D LV-Analysis software for the assessment of LV longitudinal strain, and the 4D RV-Analysis software for the assessment of RV volumes and function (Figure 1). Results In non-ischaemic patients, both 2D and 3D TTE showed an improvement in LV volumes and biventricular function, whereas only 3D detected a reduction in RV size at 6MFU vs baseline (Table 1). In ischaemic patients, only 3D TTE showed an improvement in biventricular size and LV function (Table 1). Finally, S/V induced a significant improvement in NT-proBNP (Table 1) and diastolic function both in ischaemic and non-ischaemic groups: patients with elevated left atrial pressure (as assessed by 2D parameters of diastolic function) decreased from 45% to 20% in ischaemic and from 40% to 10% in non-ischaemic patients (p Conclusions S/V induced a significant improvement in NTproBNP and diastolic function in both aetiologic groups. A clinically significant improvement in biventricular function was shown only in non-ischaemic patients. 3D TTE may be advantageous to ascertain subtle changes in LV size and function, undetected by 2D imaging, and to evaluate RV dimensions and function, which have a major impact on HFrEF prognosis. Funding Acknowledgement Type of funding sources: None. Figure 1Table 1
Published: 2021
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20. Clinical and Molecular Spectrum of Myotonia and Periodic Paralyses Associated With Mutations in SCN4A in a Large Cohort of Italian Patients

Author: Lorenzo Maggi, Raffaella Brugnoni, Eleonora Canioni, Paola Tonin, Veronica Saletti, Patrizia Sola, Stefano Cotti Piccinelli, Lara Colleoni, Paola Ferrigno, Antonella Pini, Riccardo Masson, Fiore Manganelli, Daniele Lietti, Liliana Vercelli, Giulia Ricci, Claudio Bruno, Giorgio Tasca, Antonio Pizzuti, Alessandro Padovani, Carlo Fusco, Elena Pegoraro, Lucia Ruggiero, Sabrina Ravaglia, Gabriele Siciliano, Lucia Morandi, Raffaele Dubbioso, Tiziana Mongini, Massimiliano Filosto, Irene Tramacere, Renato Mantegazza, Pia Bernasconi, Maggi, L., Brugnoni, R., Canioni, E., Tonin, P., Saletti, V., Sola, P., Piccinelli, S. C., Colleoni, L., Ferrigno, P., Pini, A., Masson, R., Manganelli, F., Lietti, D., Vercelli, L., Ricci, G., Bruno, C., Tasca, G., Pizzuti, A., Padovani, A., Fusco, C., Pegoraro, E., Ruggiero, L., Ravaglia, S., Siciliano, G., Morandi, L., Dubbioso, R., Mongini, T., Filosto, M., Tramacere, I., Mantegazza, R., and Bernasconi, P.
Subjects: 0301 basic medicine, periodic paralysis, medicine.medical_specialty, Weakness, SCN4A gene mutation, channelopathies, myotonia, SNEL, voltage-gated sodium channel Na, V, 1.4, Gastroenterology, lcsh:RC346-429, voltage-gated sodium channel NaV1.4, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Paralysis, Medicine, Laryngospasm, lcsh:Neurology. Diseases of the nervous system, Original Research, business.industry, channelopathie, Periodic paralysis, Congenital myasthenic syndrome, medicine.disease, Myotonia, Congenital myopathy, 030104 developmental biology, Neurology, Paramyotonia congenita, Neurology (clinical), medicine.symptom, business, periodic paralysi, 030217 neurology & neurosurgery
Abstract: Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis.Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A.Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains.Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.
Published: 2020

21. Foreign body and caustic ingestions in children: A clinical practice guideline

Author: Federica Gaiani, Serena Arrigo, Maristella Pellegrino, Marco Deganello Saccomani, M.T. Illiceto, Enrico Felici, Massimo Martinelli, Barbara Bizzarri, Lorenzo Norsa, Francesco Macchini, Paolo Quitadamo, Claudio Romano, Sara Renzo, C. Mantegazza, Angelo Zullo, Filippo Torroni, Gian Luigi De' Angelis, Sara Isoldi, E Dabizzi, Paola De Angelis, Endoscopists (Aigo), Caterina Strisciuglio, Salvatore Oliva, Paolo Orizio, Alessandro Raffaele, Giorgio Fava, Giovanni Di Nardo, Fabio Cisarò, Francesco Bortoluzzi, Matteo Bramuzzo, Oliva, S., Romano, C., De Angelis, P., Isoldi, S., Mantegazza, C., Felici, E., Dabizzi, E., Fava, G., Renzo, S., Strisciuglio, C., Quitadamo, P., Saccomani, M. D., Bramuzzo, M., Orizio, P., Nardo, G. D., Bortoluzzi, F., Pellegrino, M., Illiceto, M. T., Torroni, F., Cisaro, F., Zullo, A., Macchini, F., Gaiani, F., Raffaele, A., Bizzarri, B., Arrigo, S., de' Angelis, G. L., Martinelli, M., and Norsa, L.
Subjects: medicine.medical_specialty, Caustics, Gastrointestinal Diseases, Food impaction, Caustic ingestions, Physical examination, Caustic ingestion, Pediatrics, Button battery, Foreign body ingestion, Magnet, 03 medical and health sciences, Eating, 0302 clinical medicine, Button battery, Caustic ingestions, Food impaction, Foreign body ingestion, Magnet, Burns, Chemical, medicine, Humans, Medical history, Child, Competence (human resources), Pediatric gastroenterology, Societies, Medical, Hepatology, medicine.diagnostic_test, business.industry, Gastroenterology, Endoscopy, Guideline, medicine.disease, Foreign Bodies, Clinical Practice, Pediatric patient, Italy, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Medical emergency, Foreign body, business, Digestive System
Abstract: Foreign body and caustic ingestions in children are usually the most common clinical challenges for emergency physicians, general pediatricians and pediatric gastroenterologists. Management of these conditions often requires different levels of expertise and competence. Endoscopy is often necessary but there is a high risk of misusing this tool with incorrect timing and indications. The imprecise clinical history frequently leaves clinicians uncertain about timing and nature of the ingestion. Few clinical guidelines regarding management of these ingestions in children have been published, none of which from the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP). An expert panel of Italian endoscopists was convened by the SIGENP Endoscopy Working Group to produce the present article that outlines practical clinical approaches to the pediatric patient with a variety of foreign body and caustic ingestions. The Italian Association of Hospital Gastroenterologists and Endoscopists (AIGO) has also endorsed the project since many adult endoscopists usually manage children with these conditions. Differently from the other published guidelines, the proposed one focuses on the role of the endoscopists (regardless of whether they are adult or pediatric gastroenterologists) in the diagnostic process of children with foreign body and caustic ingestions.
Published: 2020

22. ETNK1 mutations in atypical chronic myeloid leukemia induce a mutator phenotype that can be reverted with phosphoethanolamine

Author: Clizia Chinello, Giovanni Zambrotta, Francesca Fanelli, Roberta Corti, Mi Jang, Steen Larsen, Carlo Gambacorti-Passerini, Rossella Renso, Rocco Piazza, Barbara Crescenzi, Mattia Docci, Lisa Marie Røst, Mayla Bertagna, Cristina Mecucci, Stefania Citterio, Deborah D'Aliberti, Francesco Mantegazza, Fulvio Magni, Ilaria Crespiatico, Guido Cavaletti, Antonio Niro, Diletta Fontana, Delphine Rea, Valeria Cassina, Mario Mauri, Domenico Salerno, Per Bruheim, M Bossi, Luca Nardo, Luca Massimino, Fontana, D, Mauri, M, Renso, R, Docci, M, Crespiatico, I, Rost, L, Jang, M, Niro, A, D'Aliberti, D, Massimino, L, Bertagna, M, Zambrotta, G, Bossi, M, Citterio, S, Crescenzi, B, Fanelli, F, Cassina, V, Corti, R, Salerno, D, Nardo, L, Chinello, C, Mantegazza, F, Mecucci, C, Magni, F, Cavaletti, G, Bruheim, P, Rea, D, Larsen, S, Piazza, R, and Gambacorti-Passerini, C
Subjects: business.industry, Kinase, Somatic cell, Immunology, Mutator phenotype, Chronic myelomonocytic leukemia, Cell Biology, Hematology, medicine.disease, Biochemistry, medicine, Atypical chronic myeloid leukemia, Cancer research, Eosinophilia, Phosphorylation, Systemic mastocytosis, medicine.symptom, business, ETNK1, chronic myeloid leukemia
Abstract: ETNK1 kinase is responsible for the phosphorylation of ethanolamine to phosphoethanolamine (P-Et) (Kennedy, 1956, J Biol Chem). Recurrent somatic mutations occurring on ETNK1 were identified in about 13% of patients affected by atypical chronic myeloid leukemia (aCML), in 3-14% of chronic myelomonocytic leukemia (CMML), and in 20% of systemic mastocytosis (SM) patients with eosinophilia (Gambacorti-Passerini, 2015, Blood; Lasho, 2015, Blood Cancer J). ETNK1 mutations, encoding for H243Y, N244S/T/K, and G245V/A amino acid substitutions, cluster in a very narrow region of the ETNK1 catalytic domain and cause an impairment of ETNK1 enzymatic activity leading to a significant decrease in the intracellular concentration of P-Et (Gambacorti-Passerini, 2015, Blood). Despite this evidence, however, their oncogenic role remained largely unexplained. Here, we investigated the specific role of these mutations by using cellular CRISPR/Cas9 and ETNK1 overexpression models as well as aCML patients' samples. We showed that mutated ETNK1 causes a significant increase in mitochondrial activity (1.87 fold increase compared to WT; p=0.0002) and in ROS production (2.05 fold increase compared to WT; p Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Myers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.
Published: 2020

23. The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

Author: Luca Nardo, Domenico Salerno, Francesco Stellacci, Paulo Jacob Silva, Claudia Adriana Marrano, Roberta Corti, Valeria Cassina, Alysia Cox, Roberta Dal Magro, Francesca Re, Francesco Mantegazza, Natalia Missana, Patrizia Andreozzi, Corti, R, Cox, A, Cassina, V, Nardo, L, Salerno, D, Marrano, C, Missana, N, Andreozzi, P, Silva, P, Stellacci, F, Dal Magro, R, Re, F, and Mantegazza, F
Subjects: fibrils, 0301 basic medicine, Apolipoprotein E, Gold nanoparticle, Metal Nanoparticles, Plaque, Amyloid, Peptide, 02 engineering and technology, lcsh:Chemistry, inhibitors, Cluster Analysis, lcsh:QH301-705.5, Spectroscopy, Plaque, chemistry.chemical_classification, biology, Chemistry, Neurodegeneration, Brain, General Medicine, 021001 nanoscience & nanotechnology, amyloid-beta, Computer Science Applications, Colloidal gold, Drug delivery, AFM, 0210 nano-technology, Protein Binding, liposomes, Amyloid, Amyloid beta, mechanism, Fibril, Article, Catalysis, oligomerization, Inorganic Chemistry, 03 medical and health sciences, Apolipoproteins E, Amyloid-β, Gold nanoparticles, MApoE, Alzheimer Disease, Amyloid beta-Peptides, Gold, Humans, Peptide Fragments, mental disorders, medicine, atomic-force microscopy, Physical and Theoretical Chemistry, Molecular Biology, therapy, synaptic plasticity, Organic Chemistry, toxicity, medicine.disease, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, gold nanoparticles, Synaptic plasticity, biology.protein, Biophysics, protein
Abstract: The deposition of amyloid-&beta, (A&beta, ) plaques in the brain is a significant pathological signature of Alzheimer&rsquo, s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop A&beta, aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit A&beta, aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling A&beta, aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed A&beta, fibrils or to hinder the A&beta, aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling A&beta, aggregation processes.
Published: 2020
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24. Consistent improvement with eculizumab across muscle groups in myasthenia gravis

Author: Mantegazza, R., O'Brien, F. L., Yountz, M., Howard, J. F., Gabriel Mazia, C., Wilken, M., Barroso, F., Saba, J., Rugiero, M., Bettini, M., Chaves, M., Vidal, G., Dalila Garcia, A., De Bleecker, J., Van den Abeele, G., de Koning, K., De Mey, K., Mercelis, R., Mahieu, D., Wagemaekers, L., Van Damme, P., Depreitere, A., Schotte, C., Smetcoren, C., Stevens, O., Van Daele, S., Vandenbussche, N., Vanhee, A., Verjans, S., Vynckier, J., D'Hont, A., Tilkin, P., Alves de Siqueira Carvalho, A., Dias Brockhausen, I., Feder, D., Ambrosio, D., Cesar, P., Paula Melo, A., Martins Ribeiro, R., Rocha, R., Bezerra Rosa, B., Veiga, T., Augusto da Silva, L., Santos Engel, M., Goncalves Geraldo, J., da Penha Ananias Morita, M., Nogueira Coelho, E., Paiva, G., Pozo, M., Prando, N., Torres, D. D. M., Fernanda Butinhao, C., Duran, G., Augusto Suriane Fialho, T., Gomes da Silva, T. C., Goncalves, L. O. M., Eduardo Pazetto, L., Renata Cubas Volpe, L., Souza Duca, L., Friedrich, M. A. G., Guerreiro, A., Mohr, H., Pereira Martins, M., da Cruz Pacheco, D., Ferreira, L., Paula Macagnan, A., Pinto, G., de Cassia Santos, A., Souza Bulle Oliveira, A., Amaral de Andrade, A. C., Annes, M., Duarte Silva, L., Cavalcante Lino, V., Pinto, W., Assis, N., Carrara, F., Miranda, C., Souza, I., Fernandes, P., Siddiqi, Z., Phan, C., Narayan, J., Blackmore, D., Mallon, A., Roderus, R., Watt, E., Vohanka, S., Bednarik, J., Chmelikova, M., Cierny, M., Toncrova, S., Junkerova, J., Kurkova, B., Reguliova, K., Zapletalova, O., Pitha, J., Novakova, I., Tyblova, M., Jurajdova, I., Wolfova, M., Andersen, H., Harbo, T., Vinge, L., Krogh, S., Mogensen, A., Vissing, J., Hojgaard, J., Witting, N., Mette Ostergaard Autzen, A., Pedersen, J., Eralinna, J. -P., Laaksonen, M., Oksaranta, O., Harrison, T., Eriksson, J., Rozsa, C., Horvath, M., Lovas, G., Matolcsi, J., Szabo, G., Jakab, G., Szabadosne, B., Vecsei, L., Dezsi, L., Varga, E., Konyane, M., Antonini, G., Di Pasquale, A., Garibaldi, M., Morino, S., Troili, F., Fionda, L., Pasquale, A., Evoli, A., Emilio Alboini, P., D'Amato, V., Iorio, R., Inghilleri, M., Frasca, V., Giacomelli, E., Gori, M., Lopergolo, D., Onesti, E., Gabriele, M., Sacca, F., Filla, A., Costabile, T., Marano, E., Fasanaro, A., Marsili, A., Puorro, G., Antozzi, C., Bonanno, S., Camera, G., Locatelli, A., Maggi, L., Pasanisi, M., Campanella, A., Uzawa, A., Kanai, T., Kawaguchi, N., Mori, M., Kaneko, Y., Kanzaki, A., Kobayashi, E., Murai, H., Masaki, K., Matsuse, D., Matsushita, T., Uehara, T., Shimpo, M., Jingu, M., Kikutake, K., Nakamura, Y., Sano, Y., Utsugisawa, K., Nagane, Y., Kamegamori, I., Tsuda, T., Fujii, Y., Futono, K., Ozawa, Y., Mizugami, A., Saito, Y., Samukawa, M., Suzuki, H., Morikawa, M., Kamakura, S., Miyawaki, E., Okumura, M., Funaka, S., Kawamura, T., Nakamori, M., Takahashi, M., Taichi, N., Hasuike, T., Higuchi, E., Kobayashi, H., Osakada, K., Shiraishi, H., Miyazaki, T., Motomura, M., Mukaino, A., Yoshimura, S., Asada, S., Yoshida, S., Amamoto, S., Kobashikawa, T., Koga, M., Maeda, Y., Takada, K., Takada, M., Tsurumaru, M., Yamashita, Y., Suzuki, Y., Akiyama, T., Narikawa, K., Tano, O., Tsukita, K., Kurihara, R., Meguro, F., Fukuda, Y., Sato, M., Imai, T., Tsuda, E., Shimohama, S., Hayashi, T., Hisahara, S., Kawamata, J., Murahara, T., Saitoh, M., Suzuki, S., Yamamoto, D., Ishiyama, Y., Ishiyama, N., Noshiro, M., Takeyama, R., Uwasa, K., Yasuda, I., van der Kooi, A., de Visser, M., Gibson, T., Kim, B. -J., Nyoung Lee, C., Seo Koo, Y., Youl Seok, H., Nam Kang, H., Ra, H., Joon Kim, B., Bin Cho, E., Choi, M., Lee, H., Min, J. -H., Seok, J., Lee, J., Koh, D. Y., Kwon, J., Park, S., Haw Choi, E., Hong, Y. -H., Ahn, S. -H., Lim Koo, D., Lim, J. -S., Won Shin, C., Ye Hwang, J., Kim, M., Min Kim, S., Jeong, H. -N., Jung, J., Kim, Y. -H., Seok Lee, H., Young Shin, H., Bi Hwang, E., Shin, M., Casasnovas, C., Antonia Alberti Aguilo, M., Homedes-Pedret, C., Julia Palacios, N., Diez Porras, L., Velez Santamaria, V., Lazaro, A., Gamez Carbonell, J., Sune, P., Salvado Figueras, M., Gili, G., Mazuela, G., Illa, I., Cortes Vicente, E., Diaz-Manera, J., Antonio Querol Gutierrez, L., Rojas Garcia, R., Vidal, N., Arribas-Ibar, E., Diez Tejedor, E., Gomez Salcedo, P., Fernandez-Fournier, M., Lopez Ruiz, P., Rodriguez de Rivera, F. J., Sastre, M., Piehl, F., Hietala, A., Bjarbo, L., Sengun, I., Meherremova, A., Ozcelik, P., Balkan, B., Tuga, C., Ugur, M., Erdem-Ozdamar, S., Bekircan-Kurt, C., Pinar Acar, N., Yilmaz, E., Caliskan, Y., Orsel, G., Efendi, H., Aydinlik, S., Cavus, H., Kutlu, A., Becerikli, G., Semiz, C., Tun, O., Terzi, M., Dogan, B., Kazim Onar, M., Sen, S., Kirbas Cavdar, T., Veske, A., Norwood, F., Dimitriou, A., Gollogly, J., Mahdi-Rogers, M., Seddigh, A., Sokratous, G., Maier, G., Sohail, F., Jacob, S., Sadalage, G., Torane, P., Brown, C., Shah, A., Sathasivam, S., Arndt, H., Davies, D., Watling, D., Amato, A., Cochrane, T., Salajegheh, M., Roe, K., Amato, K., Toska, S., Wolfe, G., Silvestri, N., Patrick, K., Zakalik, K., Katz, J., Miller, R., Engel, M., Forshew, D., Bravver, E., Brooks, B., Sanjak, M., Plevka, S., Burdette, M., Cunningham, S., Kramer, M., Nemeth, J., Schommer, C., Scott, T., Juel, V., Guptill, J., Hobson-Webb, L., Massey, J., Beck, K., Carnes, D., Loor, J., Anderson, A., Pascuzzi, R., Bodkin, C., Kincaid, J., Snook, R., Guingrich, S., Micheels, A., Chaudhry, V., Corse, A., Mosmiller, B., Kelley, A., Ho, D., Srinivasan, J., Vytopil, M., Jara, J., Ventura, N., Carter, C., Donahue, C., Herbert, C., Scala, S., Weiner, E., Alam, S., Mckinnon, J., Haar, L., Mckinnon, N., Alcon, K., Mckenna, K., Sattar, N., Daniels, K., Jeffery, D., Freimer, M., Chad Hoyle, J., Kissel, J., Agriesti, J., Chelnick, S., Mezache, L., Pineda, C., Muharrem, F., Karam, C., Khoury, J., Marburger, T., Kaur, H., Dimitrova, D., Gilchrist, J., Agrawal, B., Elsayed, M., Kohlrus, S., Ardoin, A., Darnell, T., Golden, L., Lokaitis, B., Seelbach, J., Muppidi, S., Goyal, N., Sakamuri, S., Y. T., So, Paulose, S., Pol, S., Welsh, L., Bhavaraju-Sanka, R., Tobon Gonzalez, A., Dishman, L., Jones, F., Gonzalez, A., Padilla, P., Saklad, A., Silva, M., Nations, S., Trivedi, J., Hopkins, S., Kazamel, M., Alsharabati, M., Lu, L., Nozaki, K., Mumfrey-Thomas, S., Woodall, A., Mozaffar, T., Cash, T., Roy, G., Mathew, V., Maqsood, F., Minton, B., James Jones, H., Rosenfeld, J., Garcia, R., Echevarria, L., Garcia, S., Pulley, M., Aranke, S., Ross Berger, A., Shah, J., Shabbir, Y., Smith, L., Varghese, M., Gutmann, L., Jerath, N., Nance, C., Swenson, A., Olalde, H., Kressin, N., Sieren, J., Barohn, R., Dimachkie, M., Glenn, M., Mcvey, A., Pasnoor, M., Statland, J., Wang, Y., Liu, T., Emmons, K., Jenci, N., Locheke, J., Fondaw, A., Johns, K., Rico, G., Walsh, M., Herbelin, L., Hafer-Macko, C., Kwan, J., Zilliox, L., Callison, K., Young, V., Disanzo, B., Naunton, K., Benatar, M., Bilsker, M., Sharma, K., Cooley, A., Reyes, E., Michon, S. -C., Sheldon, D., Steele, J., Traub, R., Chopra, M., Vu, T., Katzin, L., Mcclain, T., Harvey, B., Hart, A., Huynh, K., Beydoun, S., Chilingaryan, A., Doan, V., Droker, B., Gong, H., Karimi, S., Lin, F., Polaka, K., Tran, A., Akhter, S., Malekniazi, A., Tandan, R., Hehir, M., Waheed, W., Lucy, S., Weiss, M., Distad, J., Strom, S., Downing, S., Kim, B., Bertorini, T., Arnold, T., Henderson, K., Pillai, R., Liu, Y., Wheeler, L., Hewlett, J., Vanderhook, M., Nowak, R., Dicapua, D., Keung, B., Kumar, A., Patwa, H., Robeson, K., Yang, I., Nye, J., Vu, H., Mantegazza, R., O'Brien, F. L., Yountz, M., Howard, J. F., Gabriel Mazia, C., Wilken, M., Barroso, F., Saba, J., Rugiero, M., Bettini, M., Chaves, M., Vidal, G., Dalila Garcia, A., De Bleecker, J., Van den Abeele, G., de Koning, K., De Mey, K., Mercelis, R., Mahieu, D., Wagemaekers, L., Van Damme, P., Depreitere, A., Schotte, C., Smetcoren, C., Stevens, O., Van Daele, S., Vandenbussche, N., Vanhee, A., Verjans, S., Vynckier, J., D'Hont, A., Tilkin, P., Alves de Siqueira Carvalho, A., Dias Brockhausen, I., Feder, D., Ambrosio, D., Cesar, P., Paula Melo, A., Martins Ribeiro, R., Rocha, R., Bezerra Rosa, B., Veiga, T., Augusto da Silva, L., Santos Engel, M., Goncalves Geraldo, J., da Penha Ananias Morita, M., Nogueira Coelho, E., Paiva, G., Pozo, M., Prando, N., Torres, D. D. M., Fernanda Butinhao, C., Duran, G., Augusto Suriane Fialho, T., Gomes da Silva, T. C., Goncalves, L. O. M., Eduardo Pazetto, L., Renata Cubas Volpe, L., Souza Duca, L., Friedrich, M. A. G., Guerreiro, A., Mohr, H., Pereira Martins, M., da Cruz Pacheco, D., Ferreira, L., Paula Macagnan, A., Pinto, G., de Cassia Santos, A., Souza Bulle Oliveira, A., Amaral de Andrade, A. C., Annes, M., Duarte Silva, L., Cavalcante Lino, V., Pinto, W., Assis, N., Carrara, F., Miranda, C., Souza, I., Fernandes, P., Siddiqi, Z., Phan, C., Narayan, J., Blackmore, D., Mallon, A., Roderus, R., Watt, E., Vohanka, S., Bednarik, J., Chmelikova, M., Cierny, M., Toncrova, S., Junkerova, J., Kurkova, B., Reguliova, K., Zapletalova, O., Pitha, J., Novakova, I., Tyblova, M., Jurajdova, I., Wolfova, M., Andersen, H., Harbo, T., Vinge, L., Krogh, S., Mogensen, A., Vissing, J., Hojgaard, J., Witting, N., Mette Ostergaard Autzen, A., Pedersen, J., Eralinna, J. -P., Laaksonen, M., Oksaranta, O., Harrison, T., Eriksson, J., Rozsa, C., Horvath, M., Lovas, G., Matolcsi, J., Szabo, G., Jakab, G., Szabadosne, B., Vecsei, L., Dezsi, L., Varga, E., Konyane, M., Antonini, G., Di Pasquale, A., Garibaldi, M., Morino, S., Troili, F., Fionda, L., Pasquale, A., Evoli, A., Emilio Alboini, P., D'Amato, V., Iorio, R., Inghilleri, M., Frasca, V., Giacomelli, E., Gori, M., Lopergolo, D., Onesti, E., Gabriele, M., Saccà, Francesco, Filla, Alessandro, Costabile, T., Marano, E., Fasanaro, A., Marsili, Angela, Puorro, Giorgia, Antozzi, C., Bonanno, S., Camera, G., Locatelli, A., Maggi, L., Pasanisi, M., Campanella, A., Uzawa, A., Kanai, T., Kawaguchi, N., Mori, M., Kaneko, Y., Kanzaki, A., Kobayashi, E., Murai, H., Masaki, K., Matsuse, D., Matsushita, T., Uehara, T., Shimpo, M., Jingu, M., Kikutake, K., Nakamura, Y., Sano, Y., Utsugisawa, K., Nagane, Y., Kamegamori, I., Tsuda, T., Fujii, Y., Futono, K., Ozawa, Y., Mizugami, A., Saito, Y., Samukawa, M., Suzuki, H., Morikawa, M., Kamakura, S., Miyawaki, E., Okumura, M., Funaka, S., Kawamura, T., Nakamori, M., Takahashi, M., Taichi, N., Hasuike, T., Higuchi, E., Kobayashi, H., Osakada, K., Shiraishi, H., Miyazaki, T., Motomura, M., Mukaino, A., Yoshimura, S., Asada, S., Yoshida, S., Amamoto, S., Kobashikawa, T., Koga, M., Maeda, Y., Takada, K., Takada, M., Tsurumaru, M., Yamashita, Y., Suzuki, Y., Akiyama, T., Narikawa, K., Tano, O., Tsukita, K., Kurihara, R., Meguro, F., Fukuda, Y., Sato, M., Imai, T., Tsuda, E., Shimohama, S., Hayashi, T., Hisahara, S., Kawamata, J., Murahara, T., Saitoh, M., Suzuki, S., Yamamoto, D., Ishiyama, Y., Ishiyama, N., Noshiro, M., Takeyama, R., Uwasa, K., Yasuda, I., van der Kooi, A., de Visser, M., Gibson, T., Kim, B. -J., Nyoung Lee, C., Seo Koo, Y., Youl Seok, H., Nam Kang, H., Ra, H., Joon Kim, B., Bin Cho, E., Choi, M., Lee, H., Min, J. -H., Seok, J., Lee, J., Koh, D. Y., Kwon, J., Park, S., Haw Choi, E., Hong, Y. -H., Ahn, S. -H., Lim Koo, D., Lim, J. -S., Won Shin, C., Ye Hwang, J., Kim, M., Min Kim, S., Jeong, H. -N., Jung, J., Kim, Y. -H., Seok Lee, H., Young Shin, H., Bi Hwang, E., Shin, M., Casasnovas, C., Antonia Alberti Aguilo, M., Homedes-Pedret, C., Julia Palacios, N., Diez Porras, L., Velez Santamaria, V., Lazaro, A., Gamez Carbonell, J., Sune, P., Salvado Figueras, M., Gili, G., Mazuela, G., Illa, I., Cortes Vicente, E., Diaz-Manera, J., Antonio Querol Gutierrez, L., Rojas Garcia, R., Vidal, N., Arribas-Ibar, E., Diez Tejedor, E., Gomez Salcedo, P., Fernandez-Fournier, M., Lopez Ruiz, P., Rodriguez de Rivera, F. J., Sastre, M., Piehl, F., Hietala, A., Bjarbo, L., Sengun, I., Meherremova, A., Ozcelik, P., Balkan, B., Tuga, C., Ugur, M., Erdem-Ozdamar, S., Bekircan-Kurt, C., Pinar Acar, N., Yilmaz, E., Caliskan, Y., Orsel, G., Efendi, H., Aydinlik, S., Cavus, H., Kutlu, A., Becerikli, G., Semiz, C., Tun, O., Terzi, M., Dogan, B., Kazim Onar, M., Sen, S., Kirbas Cavdar, T., Veske, A., Norwood, F., Dimitriou, A., Gollogly, J., Mahdi-Rogers, M., Seddigh, A., Sokratous, G., Maier, G., Sohail, F., Jacob, S., Sadalage, G., Torane, P., Brown, C., Shah, A., Sathasivam, S., Arndt, H., Davies, D., Watling, D., Amato, A., Cochrane, T., Salajegheh, M., Roe, K., Amato, K., Toska, S., Wolfe, G., Silvestri, N., Patrick, K., Zakalik, K., Katz, J., Miller, R., Engel, M., Forshew, D., Bravver, E., Brooks, B., Sanjak, M., Plevka, S., Burdette, M., Cunningham, S., Kramer, M., Nemeth, J., Schommer, C., Scott, T., Juel, V., Guptill, J., Hobson-Webb, L., Massey, J., Beck, K., Carnes, D., Loor, J., Anderson, A., Pascuzzi, R., Bodkin, C., Kincaid, J., Snook, R., Guingrich, S., Micheels, A., Chaudhry, V., Corse, A., Mosmiller, B., Kelley, A., Ho, D., Srinivasan, J., Vytopil, M., Jara, J., Ventura, N., Carter, C., Donahue, C., Herbert, C., Scala, S., Weiner, E., Alam, S., Mckinnon, J., Haar, L., Mckinnon, N., Alcon, K., Mckenna, K., Sattar, N., Daniels, K., Jeffery, D., Freimer, M., Chad Hoyle, J., Kissel, J., Agriesti, J., Chelnick, S., Mezache, L., Pineda, C., Muharrem, F., Karam, C., Khoury, J., Marburger, T., Kaur, H., Dimitrova, D., Gilchrist, J., Agrawal, B., Elsayed, M., Kohlrus, S., Ardoin, A., Darnell, T., Golden, L., Lokaitis, B., Seelbach, J., Muppidi, S., Goyal, N., Sakamuri, S., So, Y. T., Paulose, S., Pol, S., Welsh, L., Bhavaraju-Sanka, R., Tobon Gonzalez, A., Dishman, L., Jones, F., Gonzalez, A., Padilla, P., Saklad, A., Silva, M., Nations, S., Trivedi, J., Hopkins, S., Kazamel, M., Alsharabati, M., Lu, L., Nozaki, K., Mumfrey-Thomas, S., Woodall, A., Mozaffar, T., Cash, T., Roy, G., Mathew, V., Maqsood, F., Minton, B., James Jones, H., Rosenfeld, J., Garcia, R., Echevarria, L., Garcia, S., Pulley, M., Aranke, S., Ross Berger, A., Shah, J., Shabbir, Y., Smith, L., Varghese, M., Gutmann, L., Jerath, N., Nance, C., Swenson, A., Olalde, H., Kressin, N., Sieren, J., Barohn, R., Dimachkie, M., Glenn, M., Mcvey, A., Pasnoor, M., Statland, J., Wang, Y., Liu, T., Emmons, K., Jenci, N., Locheke, J., Fondaw, A., Johns, K., Rico, G., Walsh, M., Herbelin, L., Hafer-Macko, C., Kwan, J., Zilliox, L., Callison, K., Young, V., Disanzo, B., Naunton, K., Benatar, M., Bilsker, M., Sharma, K., Cooley, A., Reyes, E., Michon, S. -C., Sheldon, D., Steele, J., Traub, R., Chopra, M., Vu, T., Katzin, L., Mcclain, T., Harvey, B., Hart, A., Huynh, K., Beydoun, S., Chilingaryan, A., Doan, V., Droker, B., Gong, H., Karimi, S., Lin, F., Polaka, K., Tran, A., Akhter, S., Malekniazi, A., Tandan, R., Hehir, M., Waheed, W., Lucy, S., Weiss, M., Distad, J., Strom, S., Downing, S., Kim, B., Bertorini, T., Arnold, T., Henderson, K., Pillai, R., Liu, Y., Wheeler, L., Hewlett, J., Vanderhook, M., Nowak, R., Dicapua, D., Keung, B., Kumar, A., Patwa, H., Robeson, K., Yang, I., Nye, J., Vu, H., Neurology, and Amsterdam Neuroscience - Neuroinfection & -inflammation
Subjects: 0301 basic medicine, Malalties neuromusculars, Activities of daily living, Autoimmune diseases, Severity of Illness Index, Complement inhibitor, 0302 clinical medicine, CYCLOPHOSPHAMIDE, Activities of Daily Living, Outcome Assessment, Health Care, Medicine and Health Sciences, Research Articles, Malalties autoimmunitàries, General Neuroscience, Eculizumab, myasthenia, Neuromuscular diseases, Life Sciences & Biomedicine, medicine.drug, RC321-571, Research Article, Adult, medicine.medical_specialty, Cyclophosphamide, Gross motor skill, Clinical Neurology, Neurosciences. Biological psychiatry. Neuropsychiatry, Placebo, Antibodies, Monoclonal, Humanized, ACETYLCHOLINE-RECEPTOR, 03 medical and health sciences, Refractory, Double-Blind Method, Internal medicine, Myasthenia Gravis, medicine, Humans, Muscle Strength, Patient Reported Outcome Measures, RC346-429, Muscle, Skeletal, Science & Technology, business.industry, Neurosciences, medicine.disease, Myasthenia gravis, 030104 developmental biology, Complement Inactivating Agents, ANTIBODY, Monoclonal antibodies, Neurosciences & Neurology, Neurology (clinical), Neurology. Diseases of the nervous system, business, Anticossos monoclonals, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. METHODS: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. RESULTS: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. INTERPRETATION: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. ispartof: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY vol:7 issue:8 pages:1327-1339 ispartof: location:United States status: published
Published: 2020

25. Feasibility and Accuracy of the Automated Software for Dynamic Quantification of Left Ventricular and Atrial Volumes and Function in a Large Unselected Population

Author: Valentina Mantegazza, Manuela Muratori, Roberto M. Lang, Gianpiero Italiano, Gloria Tamborini, Paola Gripari, Marco Doldi, Laura Fusini, Mauro Pepi, and Fabrizio Celeste
Subjects: 2d images, Ejection fraction, 3D echocardiography, business.industry, Large series, Settore MED/11 - Malattie dell'Apparato Cardiovascolare, Atrial fibrillation, General Medicine, medicine.disease, Article, left ventricular function, machine learning, Left atrial, Unselected population, cardiac chamber quantification, Medicine, business, Cardiac magnetic resonance, Nuclear medicine, 3d echocardiography
Abstract: We aimed to evaluate the feasibility and accuracy of machine learning-based automated dynamic quantification of left ventricular (LV) and left atrial (LA) volumes in an unselected population. We enrolled 600 unselected patients (12% in atrial fibrillation) clinically referred for transthoracic echocardiography (2DTTE), who also underwent 3D echocardiography (3DE) imaging. LV ejection fraction (EF), LV, and LA volumes were obtained from 2D images, 3D images were analyzed using dynamic heart model (DHM) software (Philips) resulting in LV and LA volume–time curves. A subgroup of 140 patients also underwent cardiac magnetic resonance (CMR) imaging. Average time of analysis, feasibility, and image quality were recorded, and results were compared between 2DTTE, DHM, and CMR. The use of DHM was feasible in 522/600 cases (87%). When feasible, the boundary position was considered accurate in 335/522 patients (64%), while major (n = 38) or minor (n = 149) border corrections were needed. The overall time required for DHM datasets was approximately 40 seconds. As expected, DHM LV volumes were larger than 2D ones (end-diastolic volume: 173 ± 64 vs. 142 ± 58 mL, respectively), while no differences were found for LV EF and LA volumes (EF: 55% ± 12 vs. 56% ± 14, LA volume 89 ± 36 vs. 89 ± 38 mL, respectively). The comparison between DHM and CMR values showed a high correlation for LV volumes (r = 0.70 and r = 0.82, p &lt, 0.001 for end-diastolic and end-systolic volume, respectively) and an excellent correlation for EF (r = 0.82, p &lt, 0.001) and LA volumes. The DHM software is feasible, accurate, and quick in a large series of unselected patients, including those with suboptimal 2D images or in atrial fibrillation.
Published: 2021

26. Foreign Body Ingestion in Neurologically Impaired Children: A Challenging Diagnosis and Management in Pediatric Surgery

Author: Mario Milazzo, Federica Pederiva, Gloria Pelizzo, Francesca Destro, Milena Meroni, Luciano Maestri, Carlo Acierno, Valeria Calcaterra, Gian Vincenzo Zuccotti, Anna Maria Caruso, and C. Mantegazza
Subjects: medicine.medical_specialty, Pediatrics, medicine.diagnostic_test, business.industry, foreign body ingestion, neurological impairment, medicine.disease, RJ1-570, Article, Endoscopy, children, disability, Pediatrics, Perinatology and Child Health, Pediatric surgery, Intellectual disability, medicine, Evaluated data, pediatric surgery, Ingestion, Complication, business, Foreign Body Ingestion, Neurologically impaired
Abstract: Children with intellectual disability/neurodevelopmental delay (ID-ND) commonly ingest foreign bodies (FB) and often present complications due to peculiar aspects of their condition. The aim of this paper is to report the experience of two centers in the management of ID-ND patients after FB ingestion and to discuss a possible algorithm for clinical practice. We retrospectively evaluated data of patients managed for FB ingestion (period: 2017–2021), focusing on those with ID-ND, specifically demographics and baseline diagnosis, elements related to the event, symptoms, time to endoscopy, FB location, endoscopic details, and follow-up. A total of 457 patients were managed in the study period and 19 had ID-ND (mean age 9.8 ± 3.5 years, 15 males). A total of 16/19 (84.2%) were symptomatic and required an operative approach. Recurrent ingestions and multiple FB were found in 2 and 11 patients, respectively. Endoscopy (mean time 65.6 ± 41 min) was effective in 14 cases (73.6%) and 6 patients (31.6%) developed a complication. FB ingestion in ID-ND patients represents a challenging condition for the clinician and a potentially dangerous situation. It should be addressed specifically by a multidisciplinary team considering a tailored diagnostic and management protocol.
Published: 2021

27. Rescuing epileptic and behavioral alterations in a Dravet syndrome mouse model by inhibiting eukaryotic eEF2K

Author: Carlo Sala, Chiara Verpelli, Massimo Mantegazza, Paolo Scalmani, S. Beretta, Mariaelvina Sala, Laura Gritti, and Luisa Ponzoni
Subjects: Epilepsy, Dravet syndrome, business.industry, Sodium channel, Knockout mouse, medicine, GABAergic, Long-term potentiation, Pharmacology, Inhibitory postsynaptic potential, medicine.disease, business, Motor coordination
Abstract: Dravet Syndrome is a severe childhood pharmacoresistant epileptic disorder caused mainly by mutations in the SCN1A gene, which encodes for the α1 subunit of the type I voltage-gated sodium channel (NaV1.1), that cause imbalance between excitation and inhibition in the brain. We recently found that eEF2K knock out mice displayed enhanced GABAergic transmission and tonic inhibition and were less susceptible to epileptic seizures. In Scn1a+/- mice, a mouse model of the Dravet syndrome, we found that the activity of eEF2K/eEF2 pathway was enhanced. Then, we demonstrated that both genetic deletion and pharmacological inhibition of eEF2K were able to reduce the epileptic phenotype of Scn1a+/- mice. Interestingly we also found that motor coordination defect, memory impairments, and stereotyped behavior of the Scn1a+/- mice were reverted by eEF2K deletion. The analysis of spontaneous inhibitory postsynaptic currents (sIPSCs) suggested that the rescue of the pathological phenotype was driven by the potentiation of GABAergic synapses. Our data indicate that pharmacological inhibition of eEF2K could represent a novel therapeutic intervention for treating epilepsy and related comorbidities in the Dravet syndrome.
Published: 2021
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28. Diagnosis and treatment of myasthenia gravis

Author: Paola Cavalcante and Renato Mantegazza
Subjects: 0301 basic medicine, medicine.medical_specialty, Treatment outcome, MEDLINE, Diagnostic tools, Biological drugs, Biological Factors, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, Myasthenia Gravis, Humans, Medicine, Intensive care medicine, Autoantibodies, 030203 arthritis & rheumatology, Electromyography, business.industry, Autoantibody, Precision medicine, medicine.disease, Myasthenia gravis, Biologic Agents, Treatment Outcome, 030104 developmental biology, business, Immunosuppressive Agents
Abstract: This article provides an update on the most recent advances in diagnostic procedures and therapeutic approaches for myasthenia gravis, spanning from autoantibody and neuroelectrophysiological tests as diagnostic tools, to innovative and promising treatments based on biological drugs.Novel studies performed by cell-based assays (CBAs) indicate an improvement in the chance of identifying serum autoantibodies in myasthenic patients. Clinical trials on the use of biological drugs were recently concluded, providing important data on safety and efficacy of eculizumab, efgartigimod and amifampridine phosphate: the first, a complement blocker, showed long-term safety and efficacy in acetylcholine receptor (AChR)-positive myasthenic patients with refractory generalized disease; the second, the neonatal Fc receptor blocker, was well tolerated and clinically effective in both AChR-specific and muscle-specific kinase receptor (MuSK)-positive patients; the third, a blocker of presynaptic potassium channels, was found to be well tolerated and effective in MuSK-positive patients.CBAs can lead to a significant reduction of seronegative patients, improving myasthenia gravis diagnostic process. New biological drugs offer innovative approaches to treat myasthenic patients with generalized disease, promising to change the paradigm of treatment and to significantly enhance therapeutic success within a precision medicine framework.
Published: 2019
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29. Syngeneic B16-F1 cells are more efficient than allogeneic Cloudman cells as antigen source in DC-based vaccination in the B16-F1 murine melanoma model

Author: José Mordoh, Adriana R. Mantegazza, Sofia Bentivegna, Rosa Wainstok, Soledad Mac Keon, Estrella Mariel Levy, and Michael S. Marks
Subjects: Male, Syngeneic cells, Melanoma, Experimental, purl.org/becyt/ford/1 [https], Mice, 0302 clinical medicine, Melanocyte differentiation, 030212 general & internal medicine, Melanoma, Vaccination, Neoepitopes, Specific Pathogen-Free Organisms, Infectious Diseases, Molecular Medicine, Otros Tópicos Biológicos, NEOEPITOPES, CIENCIAS NATURALES Y EXACTAS, B16 melanoma, Tumor-associated antigens, Allogeneic cells, SYNGENEIC CELLS, 030231 tropical medicine, Biology, DENDRITIC CELLS, Cancer Vaccines, Anti-melanoma vaccination, Article, Ciencias Biológicas, 03 medical and health sciences, Antigen, Antigens, Neoplasm, Cell Line, Tumor, medicine, Animals, purl.org/becyt/ford/1.6 [https], TUMOR-ASSOCIATED ANTIGENS, ALLOGENEIC CELLS, General Veterinary, General Immunology and Microbiology, Public Health, Environmental and Occupational Health, Cancer, Dendritic Cells, Dendritic cell, medicine.disease, Immunity, Humoral, ANTI-MELANOMA VACCINATION, Mice, Inbred C57BL, Disease Models, Animal, Cell culture, Cancer research
Abstract: A major obstacle to obtaining relevant results in cancer vaccination has been the lack of identification of immunogenic antigens. Dendritic cell (DC)-based cancer vaccines used preventively may afford protection against tumor inoculation, but the effect of antigen choice on anti-tumor protection is not clear. When using irradiated syngeneic tumor cells to load DCs, tumor self-antigens are provided, including tumor-associated antigens (TAAs) and neoantigens generated by tumor mutations. On the other hand, allogeneic tumor cells could only supply shared TAAs. To assess the advantages of each source in protective vaccination, we analyzed in C57BL/6 mice the effect of loading DCs with irradiated syngeneic B16-F1 or allogeneic Cloudman melanoma cells; both cell lines were characterized by whole exome sequencing and RNAseq. Tumor cell components from the two irradiated cell lines were efficiently internalized by DCs, and transported to MHC-class II positive tubulovesicular compartments (MIICs). DCs loaded with allogeneic irradiated Cloudman cells (DC-ApoNecALLO) induced a partially effective anti-melanoma protection, although Cloudman and B16-F1 cells share the expression of melanocyte differentiation antigens (MDAs), cancer-testis antigens (CTAs) and other TAAs. DCs loaded with syngeneic B16-F1 cells (DC-ApoNecSYN) established a more potent and long-lasting protection and induced a humoral anti-B16F1 response, thus suggesting that neoepitopes are needed for inducing long-lasting protection. Fil: Mac Keon, Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Bentivegna, Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Levy, Estrella Mariel. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina Fil: Marks, Michael S.. The Children's Hospital Of Philadelphia; Estados Unidos Fil: Mantegazza, Adriana Rita. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Wainstok, Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Mordoh, Jose. Instituto Alexander Fleming; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Fundación Cáncer. Centro de Investigaciones Oncológicas; Argentina
Published: 2019
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30. HEART FAILURE 3

Author: A. Dalla Cia, A. Del Torto, Nicola Cosentino, Massimo Mapelli, Jeness Campodonico, Carlo Vignati, Giancarlo Marenzi, Valentina Mantegazza, Piergiuseppe Agostoni, and F. De Martino
Subjects: medicine.medical_specialty, Acute decompensated heart failure, business.industry, Internal medicine, medicine.medical_treatment, medicine, Cardiology, Cardiology and Cardiovascular Medicine, medicine.disease, business, Saline
Published: 2019
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31. Pharmacogenetics of myotonic hNav1.4 sodium channel variants situated near the fast inactivation gate

Author: Jean-François Desaphy, Livia Pasquali, Damien Sternberg, Renato Mantegazza, Alessandro Farinato, Concetta Altamura, Lorenzo Maggi, Gabriele Siciliano, Maria Rosaria Carratù, Diana Conte, Mauro Lo Monaco, Paola Imbrici, Pia Bernasconi, and Christophe Vial
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Mexiletine, Gating, Propafenone, Pharmacology, Myotonia, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Sodium channel blocker, medicine, Humans, NAV1.4 Voltage-Gated Sodium Channel, Child, Flecainide, Sodium channel, Chemistry, Infant, Newborn, Middle Aged, medicine.disease, HEK293 Cells, 030104 developmental biology, Paramyotonia congenita, Child, Preschool, 030220 oncology & carcinogenesis, Mutation, Female, Ion Channel Gating, Myotonic Disorders, medicine.drug
Abstract: Sodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses. We previously showed that two hNav1.4 mutations, p.G1306E and p.P1158L, reduce mexiletine potency in vitro, whereas another sodium channel blocker, flecainide, is less sensitive to mutation-induced gating defects. This observation was successfully translated to p.G1306E and p.P1158L carriers. Thus, the aim of this study was to perform a pharmacological characterization of myotonic Nav1.4 mutations clustered near the fast inactivation gate of the channel. We chose seven mutations (p.V1293I, p.N1297S, p.N1297K, p.F1298C, p.G1306E, p.I1310N, and p.T1313M) from the database of Italian and French networks for muscle channelopathies. Recombinant hNav1.4 mutants were expressed in HEK293T cells for functional and pharmacological characterization using the patch-clamp technique. All the studied mutations impair the kinetics and/or voltage dependence of fast inactivation, which is likely the main mechanism responsible for myotonia. The severity of myotonia is well-correlated to the enhancement of window currents generated by the intersection of the activation and fast inactivation voltage dependence. Five of the six mutants displaying a significant positive shift of fast inactivation voltage dependence reduced mexiletine inhibition in an experimental condition mimicking myotonia. In contrast, none of the mutations impairs flecainide block nor does p.T1313M impair propafenone block, indicating that class Ic antiarrhythmics may constitute a valuable alternative. Our study suggests that mutation-driven therapy would be beneficial to myotonic patients, greatly improving their quality of life.
Published: 2019
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32. Head to Head Comparison between Different 3-Dimensional Echocardiographic Rendering Tools in the Imaging of Percutaneous Edge-to-Edge Mitral Valve Repair

Author: Valentina Mantegazza, Anna Maltagliati, Manuela Muratori, Gloria Tamborini, Claudia Cefalù, Sarah Ghulam Ali, Paola Gripari, Marco Penso, Anna Garlaschè, Laura Fusini, Mauro Pepi, and Gianpiero Italiano
Subjects: Percutaneous, medicine.medical_treatment, mitraClip procedure, mitral valve prolapse, three-dimensional transesophageal echocardiography, transesophageal echocardiographic monitoring, Settore MED/11 - Malattie dell'Apparato Cardiovascolare, Transillumination, 030204 cardiovascular system & hematology, Article, Rendering (computer graphics), 03 medical and health sciences, 0302 clinical medicine, Mitral valve, medicine, Diseases of the circulatory (Cardiovascular) system, Mitral valve prolapse, Pharmacology (medical), 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, Mitral valve repair, Mitral regurgitation, business.industry, MitraClip, medicine.disease, medicine.anatomical_structure, RC666-701, Nuclear medicine, business
Abstract: MitraClip (MC) is the most common percutaneous treatment for severe mitral regurgitation (MR). An accurate two-dimensional and three-dimensional echocardiographic (3DTEE) imaging is mandatory for the optimal procedural result. Recently transillumination 3DTEE rendering (3DTr) has been introduced integrating a virtual light source into the dataset and with the addition of glass effect (3DGl) allows to adjust tissue transparency improving depth perception and anatomical structure delineation in comparison with the standard 3DTEE (3DSt). The aim of this retrospective study in 30 patients undergoing MC, was to compare 3DSt, 3DTr, and 3DGl in mitral valve (MV) evaluation and procedural result assessment. 3DTEE acquisitions obtained before and after MC were processed with 3DSt, 3DTr, and 3DGl rendering. Each reconstruction was scored for quality and for ability to recognize MV anatomy, MR origin, clip position, dimension and grasping. Imaging quality was judged good or optimal in 52%, 76%, and 96% in 3DSt, 3DTr, and 3DGl reconstructions respectively. In 26/30 patients a diagnostic incremental value was found with 3DTr vs. 3DSt and in 15/26 with 3DGl vs. 3DTr and 3DSt. Only 3DGl with perpendicular cropping of the clip allowed to visualize and measure the grasped portion of each mitral leaflets. 3DTEE imaging during MC may be improved by 3DTr and 3DGl providing a better evaluation of MV, of leaflet grasping and of residual MR jets after MC.
Published: 2021
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33. Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients

Author: Valentina Alari, Maria Orietta Borghi, Sabrina Avignone, Sara Perego, Ilaria Catusi, Benedetta Terragni, Paolo Scalmani, Palma Finelli, Paola Adele Lonati, Silvia Russo, Lidia Larizza, Massimo Mantegazza, and Paola Francesca Ajmone
Subjects: Male, Patch-Clamp Techniques, hypoexcitability, Hydroxamic Acids, trichostatin A, Membrane Potentials, morphological abnormalities, iPSC-neurons, Neurodevelopmental disorder, Biology (General), Child, Cells, Cultured, Spectroscopy, Neurons, Rubinstein-Taybi Syndrome, Valproic Acid, Histone deacetylase inhibitor, Cell Differentiation, Electroencephalography, General Medicine, Magnetic Resonance Imaging, Computer Science Applications, Chemistry, medicine.anatomical_structure, intellectual disability, medicine.drug, medicine.medical_specialty, Adolescent, Cell Survival, medicine.drug_class, QH301-705.5, Induced Pluripotent Stem Cells, partial rescue, Biology, histone deacetylase inhibitors, Article, Catalysis, Inorganic Chemistry, valproic acid, Internal medicine, medicine, Humans, Patch clamp, Physical and Theoretical Chemistry, EP300, Molecular Biology, QD1-999, Rubinstein-Taybi, Organic Chemistry, medicine.disease, Endocrinology, Trichostatin A, Mutation, Histone deacetylase, Neuron, E1A-Associated p300 Protein
Abstract: Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients’ iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients’ neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.
Published: 2021

34. Predicting Long-Term Mortality in TAVI Patients Using Machine Learning Techniques

Author: Manuela Muratori, Mauro Pepi, Claudia Cefalù, Sarah Ghulam Ali, Marco Penso, Gloria Tamborini, Franco Fabbiocchi, Valentina Mantegazza, Enrico G. Caiani, Paola Gripari, Laura Fusini, and Antonio L. Bartorelli
Subjects: Transcatheter aortic, 030204 cardiovascular system & hematology, Machine learning, computer.software_genre, Article, TAVI, 03 medical and health sciences, Clinical prognosis, 0302 clinical medicine, medicine, Diseases of the circulatory (Cardiovascular) system, Pharmacology (medical), 030212 general & internal medicine, General Pharmacology, Toxicology and Pharmaceutics, mortality prediction, Mitral regurgitation, business.industry, Mortality rate, Area under the curve, Gold standard (test), aortic valve disease, medicine.disease, machine learning, Aortic valve stenosis, RC666-701, Long term mortality, Artificial intelligence, business, computer
Abstract: Background: Whereas transcatheter aortic valve implantation (TAVI) has become the gold standard for aortic valve stenosis treatment in high-risk patients, it has recently been extended to include intermediate risk patients. However, the mortality rate at 5 years is still elevated. The aim of the present study was to develop a novel machine learning (ML) approach able to identify the best predictors of 5-year mortality after TAVI among several clinical and echocardiographic variables, which may improve the long-term prognosis. Methods: We retrospectively enrolled 471 patients undergoing TAVI. More than 80 pre-TAVI variables were collected and analyzed through different feature selection processes, which allowed for the identification of several variables with the highest predictive value of mortality. Different ML models were compared. Results: Multilayer perceptron resulted in the best performance in predicting mortality at 5 years after TAVI, with an area under the curve, positive predictive value, and sensitivity of 0.79, 0.73, and 0.71, respectively. Conclusions: We presented an ML approach for the assessment of risk factors for long-term mortality after TAVI to improve clinical prognosis. Fourteen potential predictors were identified with the organic mitral regurgitation (myxomatous or calcific degeneration of the leaflets and/or annulus) which showed the highest impact on 5 years mortality.
Published: 2021

35. Immune Soluble Factors in the Cerebrospinal Fluid of Progressive Multiple Sclerosis Patients Segregate Into Two Groups

Author: Gloria Donninelli, Valeria Studer, Laura Brambilla, Chiara Zecca, Daniele Peluso, Alice Laroni, Daniele Michelis, Renato Mantegazza, Paolo Confalonieri, and Elisabetta Volpe
Subjects: lcsh:Immunologic diseases. Allergy, 0301 basic medicine, Adult, Male, Chemokine, Immunology, chemokines, cerebrospinal fluid, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cerebrospinal fluid, Immunology and Allergy, Medicine, Humans, Original Research, Progressive multiple sclerosis, Inflammation, Expanded Disability Status Scale, biology, medicine.diagnostic_test, business.industry, Multiple sclerosis, expanded disability status scale, Magnetic resonance imaging, cytokines, progressive multiple sclerosis, Middle Aged, Multiple Sclerosis, Chronic Progressive, medicine.disease, Magnetic Resonance Imaging, 030104 developmental biology, biology.protein, Immune Mediators, Female, lcsh:RC581-607, business, 030217 neurology & neurosurgery
Abstract: Primary-progressive (PP) and secondary-progressive (SP) multiple sclerosis (MS) are characterized by neurological deficits caused by a permanent neuronal damage, clinically quantified by the expanded disability status scale (EDSS). Neuronal tissue damage is also mediated by immune infiltrates producing soluble factors, such as cytokines and chemokines, which are released in the cerebrospinal fluid (CSF). The mechanisms regulating the production of a soluble factor are not completely defined. Using multiplex bead-based assays, we simultaneously measured 27 immune soluble factors in the CSF collected from 38 patients, 26 with PP-MS and 12 with SP-MS. Then, we performed a correlation matrix of all soluble factors expressed in the CSF. The CSF from patients with PP-MS and SP-MS had similar levels of cytokines and chemokines; however, the stratification of patients according to active or inactive magnetic resonance imaging (MRI) unveils some differences. Correlative studies between soluble factors in the CSF of patients with PP-MS and SP-MS revealed two clusters of immune mediators with pro-inflammatory functions, namely IFN-γ, MCP-1, MIP-1α, MIP-1β, IL-8, IP-10, and TNF-α (group 1), and anti-inflammatory functions, namely IL-9, IL-15, VEGF, and IL-1ra (group 2). However, most of the significant correlations between cytokines of group 1 and of group 2 were lost in patients with more severe disability (EDSS ≥ 4) compared to patients with mild to moderate disability (EDSS < 4). These results suggest a common regulation of cytokines and chemokines belonging to the same group and indicate that, in patients with more severe disability, the production of those factors is less coordinated, possibly due to advanced neurodegenerative mechanisms that interfere with the immune response.
Published: 2021

36. Next-Generation Sequencing Identifies Extended HLA Class I and II Haplotypes Associated With Early-Onset and Late-Onset Myasthenia Gravis in Italian, Norwegian, and Swedish Populations

Author: Lisa E. Creary, Sridevi Gangavarapu, Stacy J. Caillier, Paola Cavalcante, Rita Frangiamore, Benedicte A. Lie, Mats Bengtsson, Hanne Flinstad Harbo, Susanna Brauner, Jill A. Hollenbach, Jorge R. Oksenberg, Pia Bernasconi, Angelina Hatlø Maniaol, Lennart Hammarström, Renato Mantegazza, and Marcelo A. Fernández-Viña
Subjects: 0301 basic medicine, Male, susceptibility, 0302 clinical medicine, 2.1 Biological and endogenous factors, Immunology and Allergy, Aetiology, Age of Onset, Original Research, Genetics, Norway, High-Throughput Nucleotide Sequencing, Middle Aged, protection, Italy, Medical Microbiology, Medical genetics, Female, Medical Genetics, Adult, medicine.medical_specialty, Immunology, Human leukocyte antigen, Biology, European, Autoimmune Disease, DNA sequencing, 03 medical and health sciences, Rare Diseases, Clinical Research, human leukocyte antigen, Myasthenia Gravis, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, Alleles, Medicinsk genetik, Sweden, myasthenia gravis, Human Genome, Haplotype, Neurosciences, HLA-DR Antigens, RC581-607, medicine.disease, Myasthenia gravis, 030104 developmental biology, Haplotypes, HLA-B Antigens, next-generation sequencing, Immunologic diseases. Allergy, 030217 neurology & neurosurgery
Abstract: Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E−05), Norwegians (OR = 3.52, P = 4.41E−16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P HLA-DRB7, and HLA-DRB13.1 class II haplotypes in Italians and Norwegians, whereas in Swedes HLA-DRB7 exhibited the main protective effect. For AChR-LOMG patients, the HLA-DRB15.1 haplotype and associated alleles were significantly associated with susceptibility in all groups. The HLA-DR13–HLA-DR–HLA-DQ haplotype was associated with protection in all AChR-LOMG groups. This study has confirmed and extended previous findings that the immunogenetic predisposition profiles for EOMG and LOMG are distinct. In addition, the results are consistent with a role for non-coding HLA genetic variants in the pathogenesis of MG.
Published: 2021

37. Iatrogenic Kaposi’s sarcoma in myasthenia gravis: learnings from two case reports

Author: Lorenzo Maggi, Fiammetta Vanoli, Renato Mantegazza, Lucia Brambilla, Riccardo Giossi, Athanasia Tourlaki, and Rita Frangiamore
Subjects: medicine.medical_specialty, Neuromuscular disease, medicine.medical_treatment, Iatrogenic Disease, Azathioprine, Dermatology, Brief Communication, 03 medical and health sciences, Kaposi’s sarcoma, 0302 clinical medicine, Prednisone, Myasthenia Gravis, Case report, medicine, Humans, Corticosteroids, 030212 general & internal medicine, Kaposi's sarcoma, Sarcoma, Kaposi, Immunodeficiency, Immunosuppression Therapy, business.industry, Immunosuppressive agents, Myasthenia gravis, Immunosuppression, General Medicine, medicine.disease, Psychiatry and Mental health, Pyridostigmine, Herpesvirus 8, Human, Neurology (clinical), business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Introduction Myasthenia gravis (MG) is an autoimmune neuromuscular disease whose treatment encompasses acetylcholinesterase inhibitors, oral steroids, and other immunosuppressants. Kaposi’s sarcoma (KS) is a lymphangioproliferative disease associated with human herpesvirus 8 (HHV-8) infection and immunodeficiency or immunosuppression, mainly corticosteroids. Case reports We present two cases of MG patients treated with oral steroids who developed KS. Patient 1 was diagnosed with three oral KS lesions. Prednisone was discontinued with lesion regression and stabilization, while azathioprine and pyridostigmine prompted control of MG. Patient 2 developed KS lesions on the trunk and lower limbs while taking prednisone and azathioprine. Steroid tapering was started but new oral and lymph nodal lesions appeared. Paclitaxel therapy was introduced and the patient experienced pulmonary embolism and developed sensitive neuropathy. Complete remission of KS lesions was achieved and maintained with azathioprine and pyridostigmine as MG medications. Conclusions KS is an uncommon but clinically relevant adverse event (AE) often induced by steroid therapy. It can be controlled by steroid withdrawal but could necessitate chemotherapy, which associates with further potential AEs. Skin evaluation should be performed in all patients with chronic steroid therapy. Steroid-sparing strategies, including new drugs, could reduce KS and other steroid-related comorbidities. HHV-8 testing should be considered before starting chronic immunosuppression.
Published: 2021

38. Eculizumab in refractory generalized myasthenia gravis previously treated with rituximab:subgroup analysis of REGAIN and its extension study

Author: Siddiqi, Z. A., Nowak, R. J., Mozaffar, T., O'Brien, F., Yountz, M., Patti, F., Mazia, C. G., Wilken, M., Barroso, F., Saba, J., Rugiero, M., Bettini, M., Chaves, M., Vidal, G., Garcia, A. D., De Bleecker, J., Van den Abeele, G., de Koning, K., De Mey, K., Mercelis, R., Mahieu, D., Wagemaekers, L., Van Damme, P., Depreitere, A., Schotte, C., Smetcoren, C., Stevens, O., Van Daele, S., Vandenbussche, N., Vanhee, A., Verjans, S., Vynckier, J., D'Hont, A., Tilkin, P., de Siqueira Carvalho, A. A., Brockhausen, I. D., Feder, D., Ambrosio, D., Cesar, P., Melo, A. P., Ribeiro, R. M., Rocha, R., Rosa, B. B., Veiga, T., da Silva, L. A., Engel, M. S., Geraldo, J. G., da Penha Ananias Morita, M., Coelho, E. N., Paiva, G., Pozo, M., Prando, N., Torres, D. D. M., Butinhao, C. F., Duran, G., Fialho, T. A. S., da Silva, T. C. G., Goncalves, L. O. M., Pazetto, L. E., Volpe, L. R. C., Duca, L. S., Friedrich, M. A. G., Guerreiro, A., Mohr, H., Martins, M. P., da Cruz Pacheco, D., Ferreira, L., Macagnan, A. P., Pinto, G., de Cassia Santos, A., Oliveira, A. S. B., de Andrade, A. C. A., Annes, M., Silva, L. D., Lino, V. C., Pinto, W., Assis, N., Carrara, F., Miranda, C., Souza, I., Fernandes, P., Phan, C., Narayan, J., Blackmore, D., Mallon, A., Roderus, R., Watt, E., Vohanka, S., Bednarik, J., Chmelikova, M., Cierny, M., Toncrova, S., Junkerova, J., Kurkova, B., Reguliova, K., Zapletalova, O., Pitha, J., Novakova, I., Tyblova, M., Jurajdova, I., Wolfova, M., Andersen, H., Harbo, T., Vinge, L., Krogh, S., Mogensen, A., Vissing, J., Hojgaard, J., Witting, N., Autzen, A. M. O., Pedersen, J., Eralinna, J. -P., Laaksonen, M., Oksaranta, O., Harrison, T., Eriksson, J., Rozsa, C., Horvath, M., Lovas, G., Matolcsi, J., Szabo, G., Jakab, G., Szabadosne, B., Vecsei, L., Dezsi, L., Varga, E., Konyane, M., Antonini, G., Di Pasquale, A., Garibaldi, M., Morino, S., Troili, F., Fionda, L., Sacca, F., Filla, A., Costabile, T., Marano, E., Fasanaro, A., Marsili, A., Puorro, G., Mantegazza, R., Antozzi, C., Bonanno, S., Camera, G., Locatelli, A., Maggi, L., Pasanisi, M., Campanella, A., Evoli, A., Alboini, P. E., D'Amato, V., Iorio, R., Inghilleri, M., Frasca, V., Giacomelli, E., Gori, M., Lopergolo, D., Onesti, E., Gabriele, M., Uzawa, A., Kanai, T., Kawaguchi, N., Mori, M., Kaneko, Y., Kanzaki, A., Kobayashi, E., Murai, H., Masaki, K., Matsuse, D., Matsushita, T., Uehara, T., Shimpo, M., Jingu, M., Kikutake, K., Nakamura, Y., Sano, Y., Utsugisawa, K., Nagane, Y., Kamegamori, I., Tsuda, T., Fujii, Y., Futono, K., Ozawa, Y., Mizugami, A., Saito, Y., Samukawa, M., Suzuki, H., Morikawa, M., Kamakura, S., Miyawaki, E., Shiraishi, H., Miyazaki, T., Motomura, M., Mukaino, A., Yoshimura, S., Asada, S., Yoshida, S., Amamoto, S., Kobashikawa, T., Koga, M., Maeda, Y., Takada, K., Takada, M., Tsurumaru, M., Yamashita, Y., Suzuki, Y., Akiyama, T., Narikawa, K., Tano, O., Tsukita, K., Kurihara, R., Meguro, F., Fukuda, Y., Sato, M., Okumura, M., Funaka, S., Kawamura, T., Nakamori, M., Takahashi, M., Taichi, N., Hasuike, T., Higuchi, E., Kobayashi, H., Osakada, K., Imai, T., Tsuda, E., Shimohama, S., Hayashi, T., Hisahara, S., Kawamata, J., Murahara, T., Saitoh, M., Suzuki, S., Yamamoto, D., Ishiyama, Y., Ishiyama, N., Noshiro, M., Takeyama, R., Uwasa, K., Yasuda, I., Kim, B. -J., Lee, C. N., Koo, Y. S., Seok, H. Y., Kang, H. N., H. J., Ra, Kim, B. J., Cho, E. B., Choi, M. S., Lee, H. L., Min, J. -H., Seok, J., Lee, J. E., Koh, D. Y., Kwon, J. Y., Park, S. A., Choi, E. H., Hong, Y. -H., Ahn, S. -H., Koo, D. L., Lim, J. -S., Shin, C. W., Hwang, J. Y., Kim, M., Kim, S. M., Jeong, H. -N., Jung, J. W., Kim, Y. -H., Lee, H. S., Shin, H. Y., Hwang, E. B., Shin, M., van der Kooi, A., de Visser, M., Gibson, T., Casasnovas, C., Aguilo, M. A. A., Homedes-Pedret, C., Palacios, N. J., Porras, L. D., Santamaria, V. V., Lazaro, A., Tejedor, E. D., Salcedo, P. G., Fernandez-Fournier, M., Ruiz, P. L., de Rivera, F. J. R., Sastre, M., Carbonell, J. G., Sune, P., Figueras, M. S., Gili, G., Mazuela, G., Illa, I., Vicente, E. C., Diaz-Manera, J., Gutierrez, L. A. Q., Garcia, R. R., Vidal, N., Arribas-Ibar, E., Piehl, F., Hietala, A., Bjarbo, L., Sengun, I., Meherremova, A., Ozcelik, P., Balkan, B., Tuga, C., Ugur, M., Erdem-Ozdamar, S., Bekircan-Kurt, C. E., Acar, N. P., Yilmaz, E., Caliskan, Y., Orsel, G., Efendi, H., Aydinlik, S., Cavus, H., Kutlu, A., Becerikli, G., Semiz, C., Tun, O., Terzi, M., Dogan, B., Onar, M. K., Sen, S., Cavdar, T. K., Veske, A., Norwood, F., Dimitriou, A., Gollogly, J., Mahdi-Rogers, M., Seddigh, A., Sokratous, G., Maier, G., Sohail, F., Jacob, S., Sadalage, G., Torane, P., Brown, C., Shah, A., Sathasivam, S., Arndt, H., Davies, D., Watling, D., Amato, A., Cochrane, T., Salajegheh, M., Roe, K., Amato, K., Toska, S., Wolfe, G., Silvestri, N., Patrick, K., Zakalik, K., Katz, J., Miller, R., Engel, M., Forshew, D., Bravver, E., Brooks, B., Sanjak, M., Plevka, S., Burdette, M., Cunningham, S., Kramer, M., Nemeth, J., Schommer, C., Scott, T., Juel, V., Guptill, J., Hobson-Webb, L., Massey, J., Beck, K., Carnes, D., Loor, J., Anderson, A., Pascuzzi, R., Bodkin, C., Kincaid, J., Snook, R., Guingrich, S., Micheels, A., Chaudhry, V., Corse, A., Mosmiller, B., Kelley, A., Ho, D., Srinivasan, J., Vytopil, M., Jara, J., Ventura, N., Carter, C., Donahue, C., Herbert, C., Scala, S., Weiner, E., Alam, S., Mckinnon, J., Haar, L., Mckinnon, N., Alcon, K., Mckenna, K., Sattar, N., Daniels, K., Jeffery, D., Freimer, M., Hoyle, J. C., Kissel, J., Agriesti, J., Chelnick, S., Mezache, L., Pineda, C., Muharrem, F., Karam, C., Khoury, J., Marburger, T., Kaur, H., Dimitrova, D., Gilchrist, J., Agrawal, B., Elsayed, M., Kohlrus, S., Ardoin, A., Darnell, T., Golden, L., Lokaitis, B., Seelbach, J., Muppidi, S., Goyal, N., Sakamuri, S., Y. T., So, Paulose, S., Pol, S., Welsh, L., Bhavaraju-Sanka, R., Gonzalez, A. T., Dishman, L., Jones, F., Gonzalez, A., Padilla, P., Saklad, A., Silva, M., Nations, S., Trivedi, J., Hopkins, S., Kazamel, M., Alsharabati, M., Lu, L., Nozaki, K., Mumfrey-Thomas, S., Woodall, A., Cash, T., Roy, G., Mathew, V., Maqsood, F., Minton, B., Jones, H. J., Rosenfeld, J., Garcia, R., Echevarria, L., Garcia, S., Pulley, M., Aranke, S., Berger, A. R., Shah, J., Shabbir, Y., Smith, L., Varghese, M., Gutmann, L., Jerath, N., Nance, C., Swenson, A., Olalde, H., Kressin, N., Sieren, J., Barohn, R., Dimachkie, M., Glenn, M., Mcvey, A., Pasnoor, M., Statland, J., Wang, Y., Liu, T., Emmons, K., Jenci, N., Locheke, J., Fondaw, A., Johns, K., Rico, G., Walsh, M., Herbelin, L., Hafer-Macko, C., Kwan, J., Zilliox, L., Callison, K., Young, V., Disanzo, B., Naunton, K., Benatar, M., Bilsker, M., Sharma, K., Cooley, A., Reyes, E., Michon, S. -C., Sheldon, D., Steele, J., Howard, J., Traub, R., Chopra, M., Vu, T., Katzin, L., Mcclain, T., Harvey, B., Hart, A., Huynh, K., Beydoun, S., Chilingaryan, A., Doan, V., Droker, B., Gong, H., Karimi, S., Lin, F., Polaka, K., Tran, A., Akhter, S., Malekniazi, A., Tandan, R., Hehir, M., Waheed, W., Lucy, S., Weiss, M., Distad, J., Strom, S., Downing, S., Kim, B., Bertorini, T., Arnold, T., Henderson, K., Pillai, R., Liu, Y., Wheeler, L., Hewlett, J., Vanderhook, M., Dicapua, D., Keung, B., Kumar, A., Patwa, H., Robeson, K., Yang, I., Nye, J., Vu, H., Neurology, ANS - Neuroinfection & -inflammation, and EURO-NMD
Subjects: medicine.medical_specialty, Physiology, Population, Subgroup analysis, Antibodies, Monoclonal, Humanized, Placebo, Cellular and Molecular Neuroscience, rituximab, Refractory, immune system diseases, Physiology (medical), Internal medicine, Activities of Daily Living, medicine, Humans, education, education.field_of_study, myasthenia gravis, acetylcholine receptor, business.industry, Eculizumab, medicine.disease, Confidence interval, Myasthenia gravis, refractory, Rituximab, eculizumab, Neurology (clinical), business, medicine.drug
Abstract: Introduction/Aims: Individuals with refractory generalized myasthenia gravis (gMG) who have a history of rituximab use and experience persistent symptoms represent a population with unmet treatment needs. The aim of this analysis was to evaluate the efficacy and safety of eculizumab in patients with refractory anti-acetylcholine receptor antibody-positive (AChR+) gMG previously treated with rituximab. Methods: This post hoc subgroup analysis of the phase 3 REGAIN study (NCT01997229) and its open-label extension (OLE; NCT02301624) compared baseline characteristics, safety, and response to eculizumab in participants who had previously received rituximab with those who had not. Rituximab use was not permitted within the 6 months before screening or during REGAIN/OLE. Results: Of 125 REGAIN participants, 14 had received rituximab previously (7 received placebo and 7 received eculizumab). In the previous-rituximab group, 57% had used at least four other immunosuppressants compared with 16% in the no-previous-rituximab group. Myasthenia Gravis Activities of Daily Living total scores from eculizumab baseline to week 130 of eculizumab treatment improved in both the previous-rituximab and no-previous-rituximab groups (least-squares mean −4.4, standard error of the mean [SEM] 1.0 [n = 9] and least-squares mean −4.6, SEM 0.3 [n = 67], respectively; difference = 0.2, 95% confidence interval −1.88 to 2.22). In addition, in both groups, most patients who were treated with eculizumab for 130 weeks achieved a Myasthenia Gravis Foundation of America post-intervention status of minimal manifestations (66.7% and 65.0%, respectively). The eculizumab safety profile was similar between groups and consistent with its established profile. Discussion: Eculizumab is an effective therapy for patients with refractory AChR+ gMG, irrespective of whether they had received rituximab treatment previously.
Published: 2021
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39. Anti-Spike IgG in multiple sclerosis patients after BNT162b2 vaccine: An exploratory case-control study in Italy

Author: Alessandra Consonni, Fiammetta Vanoli, Carlo Antozzi, Antonio Zito, Valentina Torri Clerici, Emilio Ciusani, Sebastiano Giuseppe Crisafulli, Paolo Confalonieri, Francesca Andreetta, Antonella Bellino, Silvia Bonanno, Rita Frangiamore, Renato Mantegazza, Laura Brambilla, Riccardo Giossi, Roberto Bergamaschi, Eleonora Rigoni, Fulvio Baggi, Elena Corsini, Antonella Conte, and Irene Tramacere
Subjects: COVID-19 Vaccines, Multiple Sclerosis, Antibodies, Viral, Article, Antibodies, Medicine, Humans, Disease-modifying therapies, Viral, BNT162 Vaccine, Vaccine, BNT162b2, COVID-19, Multiple sclerosis, Case-Control Studies, Immunoglobulin G, SARS-CoV-2, business.industry, Case-control study, General Medicine, medicine.disease, Neurology, Immunology, Spike (software development), BNT162b2, Neurology (clinical), business, Vaccine
Abstract: Background Patients with neuroimmunological conditions such as multiple sclerosis (MS) often receive disease-modifying therapies (DMTs) or immunosuppressants which may reduce the response to vaccines. BNT162b2 (Pfizer-BioNTech) is the first COVID-19 vaccine authorized in Italy. Its clinical efficacy and serological response were not evaluated in MS patients receiving DMTs or immunosuppressants. This early multicenter study evaluated serological response to BNT162b2 and safety in these patients. Methods From February 2021 we enrolled consecutive MS patients, treated with at least one DMT and all healthcare workers (HCWs), having received or being scheduled to receive the first dose of BNT162b2. Blood samples were collected after the second vaccine dose and analyzed to quantitatively detect the presence of anti-Spike antibodies. Serological response was compared to the one from a control population of HCWs, with neither neuroimmunological conditions nor receiving immunosuppressants. Patients receiving treatments associated with a possible reduced response (Under-scrutiny treatment group) were also compared to those undergoing other treatments. Anti-Spike levels were described as median and interquartile range (IQR). Comparisons were performed with Wilcoxon-Mann-Whitney test. Solicited and unsolicited adverse events (AEs) were collected. Results 39 MS patients and a control population of 273 HCWs were included. One patient, under treatment with ocrelizumab, did not respond to BNT162b2, while all the remaining patients and all controls developed a serological response to the vaccine. Median anti-Spike levels were similar between patients (1471.0 BAU/ml; IQR 779.7 to 2357.0) and controls (1479.0 BAU/ml; IQR 813.1 to 2528.0) (p = 0.53). Patients included in the Under-scrutiny treatments group showed reduced anti-Spike levels (156.4 BAU/ml; IQR 33.4 to 559.1) compared to those receiving other treatments (1582.4 BAU/ml; IQR 1296.5 to 2219.0) (p = 0.001). Solicited AEs were all mild to moderate in severity, generally reported in the first days after vaccination, and resolved in the following days. Two MS patients reported a clinical relapse after the second vaccine dose. Conclusion BNT162b2 induced a serological response in MS patients treated with DMTs similar to controls not receiving DMTs or immunosuppressants. Some treatments were associated with reduced levels of anti-Spike antibodies in patients. These observations have relevant implications for treated patients receiving BNT162b2 and the community.
Published: 2021

40. Cytokine Profile in Striated Muscle Laminopathies: New Promising Biomarkers for Disease Prediction

Author: Alessandra Gambineri, Nicola Carboni, Renato Mantegazza, Elena Biagini, Adele D'Amico, Elisa Schena, Luisa Politano, Maria Rosaria D'Apice, Lorenzo Maggi, Tiziana Mongini, Gabriele Siciliano, Giulia Ricci, Paola Cavalcante, Irene Tramacere, Pia Bernasconi, Liliana Vercelli, Cristina Cappelletti, Giuseppe Boriani, Giovanna Lattanzi, Matteo Ziacchi, Lucia Ruggiero, Cappelletti, C., Tramacere, I., Cavalcante, P., Schena, E., Politano, L., Carboni, N., Gambineri, A., D'Amico, A., Ruggiero, L., Ricci, G., Siciliano, G., Boriani, G., Mongini, T. E., Vercelli, L., Biagini, E., Ziacchi, M., D'Apice, M. R., Lattanzi, G., Mantegazza, R., Maggi, L., Bernasconi, P., Cristina Cappelletti , Irene Tramacere, Paola Cavalcante, Elisa Schena, Luisa Politano , Nicola Carboni, Alessandra Gambineri, Adele D’Amico, Lucia Ruggiero, Giulia Ricci, Gabriele Siciliano, Giuseppe Boriani, Tiziana Enrica Mongini, Liliana Vercelli, Elena Biagini, Matteo Ziacchi, Maria Rosaria D’Apice, Giovanna Lattanzi , Renato Mantegazza, Lorenzo Maggi, Pia Bernasconi, Cappelletti, Cristina, Tramacere, Irene, Cavalcante, Paola, Schena, Elisa, Politano, Luisa, Carboni, Nicola, Gambineri, Alessandra, D’Amico, Adele, Ruggiero, Lucia, Ricci, Giulia, Siciliano, Gabriele, Boriani, Giuseppe, Mongini, Tiziana Enrica, Vercelli, Liliana, Biagini, Elena, Ziacchi, Matteo, D’Apice, Maria Rosaria, Lattanzi, Giovanna, Mantegazza, Renato, Maggi, Lorenzo, and Bernasconi, Pia
Subjects: Adult, Male, Laminopathy, macrophage, Disease, medicine.disease_cause, Article, Striated, LMNA, muscle damage, Immune system, Muscular Diseases, cytokine, medicine, Humans, skeletal muscle, lcsh:QH301-705.5, laminopathie, Mutation, biology, business.industry, laminopathies, General Medicine, Transforming growth factor beta, medicine.disease, cytokines, macrophages, Biomarkers, Cytokines, Female, Laminopathies, Muscle, Striated, Phenotype, lcsh:Biology (General), Immunology, biology.protein, Muscle, business, Genetic screen
Abstract: Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-&beta, 2) levels significantly discriminated Musc-LMNA from controls, interleukin-1&beta, (IL-1&beta, ), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.
Published: 2020
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41. A propensity score analysis for comparison of T-3b and VATET in myasthenia gravis

Author: Cristina Montomoli, Laura Brambilla, Silvia Bonanno, Carlo Antozzi, Confalonieri Paolo, Renato Mantegazza, Fulvio Baggi, Francesca Andreetta, Brenna, G, Antozzi, C, Montomoli, C, Baggi, F, and Mantegazza, R
Subjects: Adult, Male, Sternum, medicine.medical_specialty, medicine.medical_treatment, Aftercare, Extended thymectomy, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Myasthenia Gravis, medicine, Thoracoscopy, Humans, Treatment effect, In patient, Propensity Score, Aged, Surgical approach, medicine.diagnostic_test, business.industry, Remission Induction, Middle Aged, Outcome and Process Assessment (Health Care), Thymectomy, medicine.disease, Myasthenia gravis, Myasthenia Gravi, Surgery, Outcome and Process Assessment, Health Care, Propensity score matching, Female, Neurology (clinical), business, 030217 neurology & neurosurgery, Human
Abstract: Objective:We performed propensity score (PS) models to compare the outcome of patients with myasthenia gravis (MG) submitted to 2 different surgical approaches: extended transsternal (T-3b) or thoracoscopic extended thymectomy (VATET).Methods:Patients' clinical data were retrieved from the MG database of the C. Besta Neurologic Institute Foundation. In the PS analysis, a matching ratio of 1:1 of the main clinical variables was obtained for the 2 groups of patients and treatment effect was estimated by comparing their outcome.Results:A total of 210 patients met the inclusion criteria, by having a complete set of clinical data, and were included in the PS model; a matched dataset of 122 participants (61 per group) showed an adequate balance of all the covariates. Our analysis demonstrated that 68.9% of patients who had thymectomy by the VATET technique reached the pharmacologic remission/remission status at 2 years from thymectomy compared to 34.4% of those operated on by the T-3b technique (p < 0.001), had a lower INCB-MG score (p < 0.001), and had less muscle fatigability (p = 0.004). Similar results were found considering only nonthymomatous patients with MG. Results were also confirmed by paired statistical tests.Conclusions:Our PS matching analysis showed that VATET is a reliable and effective surgical approach alternative to T-3b in patients with MG who are candidates for thymectomy.Classification of evidence:This study provides Class IV evidence that for patients with MG, VATET is more effective than T-3b thymectomy.
Published: 2017
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42. A novel ABCC6 haplotype is associated with azathioprine drug response in myasthenia gravis

Author: Colleoni, L, Galbardi, B, Barzago, C, BONANNO, SILVIA, Franzi, S, Frangiamore, R, Camera, G, Foti, M, Biancolini, D, Canioni, E, Maggi, L, Antozzi, C, Mantegazza, R, Bernasconi, P, Kapetis, D, BARZAGO, CLAUDIA, FOTI, MARIA, Kapetis, D., Colleoni, L, Galbardi, B, Barzago, C, Bonanno, S, Franzi, S, Frangiamore, R, Camera, G, Foti, M, Biancolini, D, Canioni, E, Maggi, L, Antozzi, C, Mantegazza, R, Bernasconi, P, and Kapetis, D
Subjects: Adult, Male, 0301 basic medicine, Pharmacogenomic Variants, Drug response, Myasthenia gravi, ABCC6, Azathioprine, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetic, Myasthenia Gravis, Genetics, medicine, Humans, General Pharmacology, Toxicology and Pharmaceutics, Molecular Biology, Genetic Association Studies, Genetics (clinical), Aged, biology, business.industry, Drug-metabolizing enzymes and transport, Haplotype, Sequence Analysis, DNA, Middle Aged, medicine.disease, Molecular medicine, Myasthenia gravis, 030104 developmental biology, Haplotypes, Immunology, biology.protein, Molecular Medicine, Female, Multidrug Resistance-Associated Proteins, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Objective We investigated the association of single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes and transporters (DMETs) with the response to azathioprine (AZA) in patients affected by myasthenia gravis (MG) to determine possible genotype-phenotype correlations. Patients and methods Genomic DNA from 180 AZA-treated MG patients was screened through the Affymetrix DMET platform, which characterizes 1931 SNPs in 225 genes. The significant SNPs, identified to be involved in AZA response, were subsequently validated by allelic discrimination and direct sequencing. SNP analysis was carried out using the SNPassoc R package and the haploblocks were determined using haploview software. Results We studied 127 patients in the discovery phase and 53 patients in the validation phase. We showed that two SNPs (rs8058694 and rs8058696) found in ATP-binding cassette subfamily C member 6, a subfamily member of ATP-binding cassette genes, constituted a new haplotype associated with AZA response in MG patients in the discovery cohort (P =0.011; odds ratio: 0.40; 95% confidence interval: 0.20-0.83) and in the combined cohort (P= 0.04; odds ratio: 1.58). Conclusion These findings highlight the role that the ATP-binding cassette subfamily C member 6 haplotype may play in AZA drug response. In view of the significant effects and AZA intolerance, these novel SNPs should be taken into consideration in pharmacogenetic profiling for AZA.
Published: 2017
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43. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author: Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.
Subjects: 0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract: BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
Published: 2018
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44. COVID-19-associated risks and effects in myasthenia gravis (CARE-MG)

Author: Srikanth Muppidi, Jeffrey T Guptill, Saiju Jacob, Yingkai Li, Maria E Farrugia, Amanda C Guidon, Jinny O Tavee, Henry Kaminski, James F Howard, Gary Cutter, Heinz Wiendl, Matthew B Maas, Isabel Illa, Renato Mantegazza, Hiroyuki Murai, Kimiaki Utsugisawa, Richard J Nowak, Alok Tyagi, Ana Paula Sousa, Anthony A Amato, Ashwin Pinto, Bhaskar Roy, Caroline Carmichael, Dubravka Dodig, Georgina Burke, Gary R Cutter, Henry J Kaminski, Ikjae Lee, Jeffrey Guptill, James F. Howard, James Caress, Jane Pritchard, John Vissing, Kamla Best, Mahtab Ramezani, Mathew Maas, Michael K Hehir, Michelle Kaku, Natalia Jiménez Esquivel, Paul Gallagher, Paul Maddison, Philip A Ambrose, Renato E Mantegazza, Rocio Vazquez Do Campo, Sami Saba, Shahriar Nafissi, Shannon Itoyama, Stuart Viegas Viegas, Victoria Marshall, and Yingkai Li Li
Subjects: 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), SARS-CoV-2, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Clinical Neurology, COVID-19, medicine.disease, Virology, Myasthenia gravis, Risk Factors, Correspondence, Myasthenia Gravis, medicine, Humans, Registries, Neurology (clinical), business
Published: 2020
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45. 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

46. Hyperexcitability in Cultured Cortical Neuron Networks from the G93A-SOD1 Amyotrophic Lateral Sclerosis Model Mouse and its Molecular Correlates

Author: Giulia Regalia, Paola Cavalcante, Marco Rasponi, Benedetta Terragni, Ludovico Minati, Giovanni Stefano Ugolini, Giulia Bechi, Stefania Marcuzzo, Massimo Mantegazza, Pia Bernasconi, Natsue Yoshimura, Davide Isaia, Silvia Bonanno, Ambra Rizzo, Renato Mantegazza, Emilio Ciusani, Cristina Cappelletti, Department of Neurophysiopathology, Besta Neurological Institute, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and University of Trento [Trento]
Subjects: 0301 basic medicine, amyotrophic lateral sclerosis, Dendritic spine, [SDV]Life Sciences [q-bio], SOD1, Mice, Transgenic, Biology, Receptors, N-Methyl-D-Aspartate, 03 medical and health sciences, Bursting, 0302 clinical medicine, medicine, Animals, Amyotrophic lateral sclerosis, multi-electrode array (MEA), Motor Neurons, Cell Death, Superoxide Dismutase, cortical neurons, General Neuroscience, hyperexcitability, Neurodegeneration, Motor Cortex, APAF1 apoptosis-related gene, G93A-SOD1 mice, Neurodegenerative Diseases, Motor neuron, medicine.disease, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Corticospinal tract, Neuroscience, 030217 neurology & neurosurgery, Motor cortex
Abstract: International audience; Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the corticospinal tract and leading to motor neuron death. According to a recent study, magnetic resonance imaging-visible changes suggestive of neurodegeneration seem absent in the motor cortex of G93A-SOD1 ALS mice. However, it has not yet been ascertained whether the cortical neural activity is intact, or alterations are present, perhaps even from an early stage. Here, cortical neurons from this model were isolated at post-natal day 1 and cultured on multielectrode arrays. Their activity was studied with a comprehensive pool of neurophysiological analyses probing excitability, criticality and network architecture, alongside immunocytochemistry and molecular investigations. Significant hyperexcitability was visible through increased network firing rate and bursting, whereas topological changes in the synchronization patterns were apparently absent. The number of dendritic spines was increased, accompanied by elevated transcriptional levels of the DLG4 gene, NMDA receptor 1 and the early pro-apoptotic APAF1 gene. The extracellular Na+, Ca2+, K+ and Cl- concentrations were elevated, pointing to perturbations in the culture micro-environment. Our findings highlight remarkable early changes in ALS cortical neuron activity and physiology. These changes suggest that the causative factors of hyperexcitability and associated toxicity could become established much earlier than the appearance of disease symptoms, with implications for the discovery of new hypothetical therapeutic targets.
Published: 2019
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47. Eculizumab Improves Fatigue in Refractory Generalized Myasthenia Gravis

Author: Andersen H., Mantegazza R., Wang J. J., O'Brien F., Patra K., Howard J. F., Mazia C. G., Wilken M., Barroso F., Saba J., Rugiero M., Bettini M., Chaves M., Vidal G., Garcia A. D., DeBleecker J., Van denAbeele G., deKoning K., DeMey K., Mercelis R., Mahieu D., Wagemaekers L., VanDamme P., Depreitere A., Schotte C., Smetcoren C., Stevens O., VanDaele S., Vandenbussche N., Vanhee A., Verjans S., Vynckier J., D'Hondt A., Tilkin P., AlvesdeSiqueira Carvalho A., DiasBrockhausen I., Feder D., Ambrosio D., Cesar P., Melo A. P., MartinsRibeiro R., Rocha R., BezerraRosa B., Veiga T., daSilva L. A., SantosEngel M., GoncalvesGeraldo J., daPenha AnaniasMorita M., NogueiraCoelho E., Paiva G., Pozo M., Prando N., MartineliTorres D. D., Butinhao C. F., Duran G., Gomes daSilva T. C., Otavio MaiaGoncalves L., Pazetto L. E., Fialho T. A. S., Renata CubasVolpe L., SouzaDuca L., GhellerFriedrich M. A., Guerreiro A., Mohr H., PereiraMartins M., daCruz Pacheco D., Ferreira L., Macagnan A. P., Pinto G., deCassia Santos A., Souza BulleOliveira A., AmaralAndrade A. C., Annes M., Duarte Silva L., CavalcanteLino V., Pinto W., Assis N., Carrara F., Miranda C., Souza I., Fernandes P., Siddiqi Z., Phan C., Narayan J., Blackmore D., Mallon A., Roderus R., Watt E., Vohanka S., Bednarik J., Chmelikova M., Cierny M., Toncrova S., Junkerova J., Kurkova B., Reguliova K., Zapletalova O., Pitha J., Novakova I., Tyblova M., Jurajdova I., Wolfova M., Harbo T., Vinge L., Krogh S., Mogensen A., Vissing J., Hojgaard J., Witting N., OstergaardAutzen A., Pedersen J., Eralinna J. -P., Laaksonen M., Oksaranta O., Harrison T., Eriksson J., Rozsa C., Horvath M., Lovas G., Matolcsi J., Szabo G., Jakab G., Szabadosne B., Vecsei L., Dezsi L., Varga E., Konyane M., Antonini G., DiPasquale A., Garibaldi M., Morino S., Troili F., Fionda L., Filla A., Costabile T., Marano E., Sacca F., Fasanaro A., Marsili A., Puorro G., Antozzi C., Bonanno S., Camera G., Locatelli A., Maggi L., Pasanisi M., Campanella A., Evoli A., Alboini P. E., D'Amato V., Iorio R., Inghilleri M., Frasca V., Giacomelli E., Gori M., Lopergolo D., Onesti E., Gabriele M., Uzawa A., Kanai T., Kawaguchi N., Mori M., Kaneko Y., Kanzaki A., Kobayashi E., Murai H., Masaki K., Matsuse D., Matsushita T., Uehara T., Shimpo M., Jingu M., Kikutake K., Nakamura Y., Sano Y., Utsugisawa K., Nagane Y., Kamegamori I., Tsuda T., Fujii Y., Futono K., Ozawa Y., Mizugami A., Saito Y., Suzuki H., Morikawa M., Samukawa M., Kamakura S., Miyawaki E., Shiraishi H., Mitazaki T., Motomura M., Mukaino A., Yoshimura S., Asada S., Yoshida S., Amamoto S., Kobashikawa T., Koga M., Maeda Y., Takada K., Takada M., Tsurumaru M., Yamashita Y., Suzuki Y., Akiyama T., Narikawa K., Tano O., Tsukita K., Kurihara R., Meguro F., Fukuda Y., Sato M., Okumura M., Funaka S., Kawamura T., Makamori M., Takahashi M., Taichi N., Hasuike T., Higuchi E., Kobayashi H., Osakada K., Imai T., Tsuda E., Shimohama S., Hayashi T., Hisahara S., Kawamata J., Murahara T., Saitoh M., Suzuki S., Yamamoto D., Ishiyama Y., Ishiyama N., Noshiro M., Takeyama R., Uwasa K., Yasuda I., van derKooi A., deVisser M., Gibson T., Kim B. -J., Lee C. N., Koo Y. S., Seok H. Y., Kang H. N., Ra H. J., Kim B. J., Cho E. B., Choi M. S., Lee H. L., Min J. -H., Seok J., Lee J. E., Koh D. Y., Kwon J. Y., Park S. A., Choi E. H., Hong Y. -H., Ahn S. -H., Koo D. L., Lim J. -S., Shin C. W., Hwang J. Y., Kim M., Kim S. M., Jeong H. -N., Jung J. W., Kim Y. -H., Lee H. S., Shin H. Y., Hwang E. B., Shin M., Casasnovas C., AlbertiAguilo M. A., Homedes-Pedret C., JuliaPalacios N., DiezPorras L., VelezSantamaria V., Lazaro A., DiezTejedor E., Gomez Salcedo P., Fernandez-Fournier M., LopezRuiz P., Rodriguez deRivera F. J., Sastre M., Gamez J., Sune P., Salvado M., Gili G., Mazuela G., Illa I., CortesVicente E., Diaz-Manera J., QuerolGutierrez L. A., RojasGarcia R., Vidal N., Arribas-Ibar E., Piehl F., Hietala A., Bjarbo L., Sengun I., Meherremova A., Ozcelik P., Balkan B., Tuga C., Ugur M., Erdem-Ozdamar S., Bekircan-Kurt C. E., Acar N. P., Yilmaz E., Caliskan Y., Orsel G., Efendi H., Aydinlik S., Cavus H., Kutlu A., Becerikli G., Semiz C., Tun O., Terzi M., Dogan B., Onar M. K., Sen S., KirbasCavdar T., Veske A., Norwood F., Dimitriou A., Gollogly J., Mahdi-Rogers M., Seddigh A., Sokratous G., Maier G., Sohail F., Jacob S., Sadalage G., Torane P., Brown C., Shah A., Sathasivam S., Arndt H., Davies D., Watling D., Amato A., Cochrane T., Salajegheh M., Roe K., Amato K., Toska S., Wolfe G., Silvestri N., Patrick K., Zakalik K., Katz J., Miller R., Engel M., Forshew D., Bravver E., Brooks B., Plevka S., Burdette M., Cunningham S., Sanjak M., Kramer M., Nemeth J., Schommer C., Tierney S., Juel V., Guptill J., Hobson-Webb L., Massey J., Beck K., Carnes D., Loor J., Anderson A., Pascuzzi R., Bodkin C., Kincaid J., Snook R., Guingrich S., Micheels A., Chaudhry V., Corse A., Mosmiller B., Kelley A., Ho D., Srinivasan J., Vytopil M., Jara J., Ventura N., Scala S., Carter C., Donahue C., Herbert C., Weiner E., Alam S., McKinnon J., Haar L., McKinnon N., Alcon K., McKenna K., Sattar N., Daniels K., Jeffery D., Kissel J., Freimer M., Hoyle J. C., Agriesti J., Chelnick S., Mezache L., Pineda C., Muharrem F., Karam C., Khoury J., Marburger T., Kaur H., Dimitrova D., Gilchrist J., Agrawal B., Elsayed M., Kohlrus S., Andoin A., Darnell T., Golden L., Lokaitis B., Seelback J., Muppidi S., Goyal N., Sakamuri S., So Y. T., Paulose S., Pol S., Welsh L., Bhavaraju-Sanka R., TobonGonzales A., Dishman L., Jones F., Gonzalez A., Padilla P., Saklad A., Silva M., Nations S., Trivedi J., Hopkins S., Kazamel M., Alsharabati M., Lu L., Nozaki K., Mumfrey-Thomas S., Woodall A., Mozaffar T., Cash T., Roy G., Mathew V., Maqsood F., Minton B., Jones H. J., Rosenfeld J., Garcia R., Echevarria L., Garcia S., Pulley M., Aranke S., Berger A. R., Shah J., Shabbir Y., Smith L., Varghese M., Gutmann L., Jerath N., Nance C., Swenson A., Olalde H., Kressin N., Sieren J., Barohn R., Dimachkie M., Glenn M., McVey A., Pasnoor M., Statland J., Wang J., Liu T., Emmons K., Jenci N., Locheke J., Fondaw A., Johns K., Rico G., Walsh M., Herbelin L., Hafer-Macko C., Kwan J., Zilliox L., Callison K., Young V., DiSanzo B., Naunton K., Benatar M., Bilsker M., Sharma K., Cooley A., Reyes E., Michon S. -C., Sheldon D., Steele J., Chopra M., Traub R., Vu T., Katzin L., McClain T., Harvey B., Hart A., Huynh K., Beydoun S., Chilingaryan A., Doan V., Droker B., Gong H., Karimi S., Lin F., Pokala K., Tran A., Akhter S., Malekniazi A., Tandan R., Hehir M., Waheed W., Lucy S., Weiss M., Distad J., Strom S., Downing S., Kim B., Bertorini T., Arnold T., Hendersen K., Pillai R., Liu Y., Wheeler L., Hewlett J., Vanderhook M., Nowak R., Dicapua D., Keung B., Kumar A., Patwa H., Robeson K., Yang I., Nye J., Vu H., Andersen, H., Mantegazza, R., Wang, J. J., O'Brien, F., Patra, K., Howard, J. F., Mazia, C. G., Wilken, M., Barroso, F., Saba, J., Rugiero, M., Bettini, M., Chaves, M., Vidal, G., Garcia, A. D., Debleecker, J., Van denAbeele, G., Dekoning, K., Demey, K., Mercelis, R., Mahieu, D., Wagemaekers, L., Vandamme, P., Depreitere, A., Schotte, C., Smetcoren, C., Stevens, O., Vandaele, S., Vandenbussche, N., Vanhee, A., Verjans, S., Vynckier, J., D'Hondt, A., Tilkin, P., AlvesdeSiqueira Carvalho, A., Diasbrockhausen, I., Feder, D., Ambrosio, D., Cesar, P., Melo, A. P., Martinsribeiro, R., Rocha, R., Bezerrarosa, B., Veiga, T., Dasilva, L. A., Santosengel, M., Goncalvesgeraldo, J., daPenha AnaniasMorita, M., Nogueiracoelho, E., Paiva, G., Pozo, M., Prando, N., Martinelitorres, D. D., Butinhao, C. F., Duran, G., Gomes daSilva, T. C., Otavio MaiaGoncalves, L., Pazetto, L. E., Fialho, T. A. S., Renata CubasVolpe, L., Souzaduca, L., Ghellerfriedrich, M. A., Guerreiro, A., Mohr, H., Pereiramartins, M., daCruz Pacheco, D., Ferreira, L., Macagnan, A. P., Pinto, G., deCassia Santos, A., Souza BulleOliveira, A., Amaralandrade, A. C., Annes, M., Duarte Silva, L., Cavalcantelino, V., Pinto, W., Assis, N., Carrara, F., Miranda, C., Souza, I., Fernandes, P., Siddiqi, Z., Phan, C., Narayan, J., Blackmore, D., Mallon, A., Roderus, R., Watt, E., Vohanka, S., Bednarik, J., Chmelikova, M., Cierny, M., Toncrova, S., Junkerova, J., Kurkova, B., Reguliova, K., Zapletalova, O., Pitha, J., Novakova, I., Tyblova, M., Jurajdova, I., Wolfova, M., Harbo, T., Vinge, L., Krogh, S., Mogensen, A., Vissing, J., Hojgaard, J., Witting, N., Ostergaardautzen, A., Pedersen, J., Eralinna, J. -P., Laaksonen, M., Oksaranta, O., Harrison, T., Eriksson, J., Rozsa, C., Horvath, M., Lovas, G., Matolcsi, J., Szabo, G., Jakab, G., Szabadosne, B., Vecsei, L., Dezsi, L., Varga, E., Konyane, M., Antonini, G., Dipasquale, A., Garibaldi, M., Morino, S., Troili, F., Fionda, L., Filla, A., Costabile, T., Marano, E., Sacca, F., Fasanaro, A., Marsili, A., Puorro, G., Antozzi, C., Bonanno, S., Camera, G., Locatelli, A., Maggi, L., Pasanisi, M., Campanella, A., Evoli, A., Alboini, P. E., D'Amato, V., Iorio, R., Inghilleri, M., Frasca, V., Giacomelli, E., Gori, M., Lopergolo, D., Onesti, E., Gabriele, M., Uzawa, A., Kanai, T., Kawaguchi, N., Mori, M., Kaneko, Y., Kanzaki, A., Kobayashi, E., Murai, H., Masaki, K., Matsuse, D., Matsushita, T., Uehara, T., Shimpo, M., Jingu, M., Kikutake, K., Nakamura, Y., Sano, Y., Utsugisawa, K., Nagane, Y., Kamegamori, I., Tsuda, T., Fujii, Y., Futono, K., Ozawa, Y., Mizugami, A., Saito, Y., Suzuki, H., Morikawa, M., Samukawa, M., Kamakura, S., Miyawaki, E., Shiraishi, H., Mitazaki, T., Motomura, M., Mukaino, A., Yoshimura, S., Asada, S., Yoshida, S., Amamoto, S., Kobashikawa, T., Koga, M., Maeda, Y., Takada, K., Takada, M., Tsurumaru, M., Yamashita, Y., Suzuki, Y., Akiyama, T., Narikawa, K., Tano, O., Tsukita, K., Kurihara, R., Meguro, F., Fukuda, Y., Sato, M., Okumura, M., Funaka, S., Kawamura, T., Makamori, M., Takahashi, M., Taichi, N., Hasuike, T., Higuchi, E., Kobayashi, H., Osakada, K., Imai, T., Tsuda, E., Shimohama, S., Hayashi, T., Hisahara, S., Kawamata, J., Murahara, T., Saitoh, M., Suzuki, S., Yamamoto, D., Ishiyama, Y., Ishiyama, N., Noshiro, M., Takeyama, R., Uwasa, K., Yasuda, I., van derKooi, A., Devisser, M., Gibson, T., Kim, B. -J., Lee, C. N., Koo, Y. S., Seok, H. Y., Kang, H. N., Ra, H. J., Kim, B. J., Cho, E. B., Choi, M. S., Lee, H. L., Min, J. -H., Seok, J., Lee, J. E., Koh, D. Y., Kwon, J. Y., Park, S. A., Choi, E. H., Hong, Y. -H., Ahn, S. -H., Koo, D. L., Lim, J. -S., Shin, C. W., Hwang, J. Y., Kim, M., Kim, S. M., Jeong, H. -N., Jung, J. W., Kim, Y. -H., Lee, H. S., Shin, H. Y., Hwang, E. B., Shin, M., Casasnovas, C., Albertiaguilo, M. A., Homedes-Pedret, C., Juliapalacios, N., Diezporras, L., Velezsantamaria, V., Lazaro, A., Dieztejedor, E., Gomez Salcedo, P., Fernandez-Fournier, M., Lopezruiz, P., Rodriguez deRivera, F. J., Sastre, M., Gamez, J., Sune, P., Salvado, M., Gili, G., Mazuela, G., Illa, I., Cortesvicente, E., Diaz-Manera, J., Querolgutierrez, L. A., Rojasgarcia, R., Vidal, N., Arribas-Ibar, E., Piehl, F., Hietala, A., Bjarbo, L., Sengun, I., Meherremova, A., Ozcelik, P., Balkan, B., Tuga, C., Ugur, M., Erdem-Ozdamar, S., Bekircan-Kurt, C. E., Acar, N. P., Yilmaz, E., Caliskan, Y., Orsel, G., Efendi, H., Aydinlik, S., Cavus, H., Kutlu, A., Becerikli, G., Semiz, C., Tun, O., Terzi, M., Dogan, B., Onar, M. K., Sen, S., Kirbascavdar, T., Veske, A., Norwood, F., Dimitriou, A., Gollogly, J., Mahdi-Rogers, M., Seddigh, A., Sokratous, G., Maier, G., Sohail, F., Jacob, S., Sadalage, G., Torane, P., Brown, C., Shah, A., Sathasivam, S., Arndt, H., Davies, D., Watling, D., Amato, A., Cochrane, T., Salajegheh, M., Roe, K., Amato, K., Toska, S., Wolfe, G., Silvestri, N., Patrick, K., Zakalik, K., Katz, J., Miller, R., Engel, M., Forshew, D., Bravver, E., Brooks, B., Plevka, S., Burdette, M., Cunningham, S., Sanjak, M., Kramer, M., Nemeth, J., Schommer, C., Tierney, S., Juel, V., Guptill, J., Hobson-Webb, L., Massey, J., Beck, K., Carnes, D., Loor, J., Anderson, A., Pascuzzi, R., Bodkin, C., Kincaid, J., Snook, R., Guingrich, S., Micheels, A., Chaudhry, V., Corse, A., Mosmiller, B., Kelley, A., Ho, D., Srinivasan, J., Vytopil, M., Jara, J., Ventura, N., Scala, S., Carter, C., Donahue, C., Herbert, C., Weiner, E., Alam, S., Mckinnon, J., Haar, L., Mckinnon, N., Alcon, K., Mckenna, K., Sattar, N., Daniels, K., Jeffery, D., Kissel, J., Freimer, M., Hoyle, J. C., Agriesti, J., Chelnick, S., Mezache, L., Pineda, C., Muharrem, F., Karam, C., Khoury, J., Marburger, T., Kaur, H., Dimitrova, D., Gilchrist, J., Agrawal, B., Elsayed, M., Kohlrus, S., Andoin, A., Darnell, T., Golden, L., Lokaitis, B., Seelback, J., Muppidi, S., Goyal, N., Sakamuri, S., So, Y. T., Paulose, S., Pol, S., Welsh, L., Bhavaraju-Sanka, R., Tobongonzales, A., Dishman, L., Jones, F., Gonzalez, A., Padilla, P., Saklad, A., Silva, M., Nations, S., Trivedi, J., Hopkins, S., Kazamel, M., Alsharabati, M., Lu, L., Nozaki, K., Mumfrey-Thomas, S., Woodall, A., Mozaffar, T., Cash, T., Roy, G., Mathew, V., Maqsood, F., Minton, B., Jones, H. J., Rosenfeld, J., Garcia, R., Echevarria, L., Garcia, S., Pulley, M., Aranke, S., Berger, A. R., Shah, J., Shabbir, Y., Smith, L., Varghese, M., Gutmann, L., Jerath, N., Nance, C., Swenson, A., Olalde, H., Kressin, N., Sieren, J., Barohn, R., Dimachkie, M., Glenn, M., Mcvey, A., Pasnoor, M., Statland, J., Wang, J., Liu, T., Emmons, K., Jenci, N., Locheke, J., Fondaw, A., Johns, K., Rico, G., Walsh, M., Herbelin, L., Hafer-Macko, C., Kwan, J., Zilliox, L., Callison, K., Young, V., Disanzo, B., Naunton, K., Benatar, M., Bilsker, M., Sharma, K., Cooley, A., Reyes, E., Michon, S. -C., Sheldon, D., Steele, J., Chopra, M., Traub, R., Vu, T., Katzin, L., Mcclain, T., Harvey, B., Hart, A., Huynh, K., Beydoun, S., Chilingaryan, A., Doan, V., Droker, B., Gong, H., Karimi, S., Lin, F., Pokala, K., Tran, A., Akhter, S., Malekniazi, A., Tandan, R., Hehir, M., Waheed, W., Lucy, S., Weiss, M., Distad, J., Strom, S., Downing, S., Kim, B., Bertorini, T., Arnold, T., Hendersen, K., Pillai, R., Liu, Y., Wheeler, L., Hewlett, J., Vanderhook, M., Nowak, R., Dicapua, D., Keung, B., Kumar, A., Patwa, H., Robeson, K., Yang, I., Nye, J., and Vu, H.
Subjects: Male, Activities of daily living, Outcome Assessment, Myasthenia Gravis/drug therapy, Myasthenia gravi, Placebos, 0302 clinical medicine, Quality of life, QUALITY-OF-LIFE, Outcome Assessment, Health Care, Monoclonal, Receptors, Activities of Daily Living, Medicine and Health Sciences, Clinical endpoint, Receptors, Cholinergic, Fatigue/drug therapy, Myasthenia gravis, Humanized, Fatigue, Cholinergic, Public, Environmental & Occupational Health, 030503 health policy & services, Terminal complement inhibition, Eculizumab, Middle Aged, humanities, Antibodies, Monoclonal, Humanized/therapeutic use, 030220 oncology & carcinogenesis, Health Policy & Services, Female, 0305 other medical science, Life Sciences & Biomedicine, medicine.drug, medicine.medical_specialty, Complement, Brief Communication, Antibodies, Monoclonal, Humanized, Placebo, Antibodies, 03 medical and health sciences, Neuro-QOL Fatigue, Refractory, Internal medicine, Myasthenia Gravis, medicine, Humans, Generalized myasthenia, Placebos/therapeutic use, Quality of Life, Receptors, Cholinergic/immunology, Science & Technology, business.industry, Public Health, Environmental and Occupational Health, Correction, medicine.disease, Health Care, Health Care Sciences & Services, business
Abstract: Purpose To evaluate the effect of eculizumab on perceived fatigue in patients with anti-acetylcholine receptor antibody-positive, refractory, generalized myasthenia gravis (MG) using the Quality of Life in Neurological Disorders (Neuro-QOL) Fatigue subscale, and to evaluate correlations between improvements in Neuro-QOL Fatigue and other clinical endpoints. Methods Neuro-QOL Fatigue, MG Activities of Daily Living (MG-ADL), Quantitative MG (QMG), and the 15-item MG Quality of Life (MG-QOL15) scales were administered during the phase 3, randomized, placebo-controlled REGAIN study (eculizumab, n = 62; placebo, n = 63) and subsequent open-label extension (OLE). Data were analyzed using repeated-measures models. Correlations between changes in Neuro-QOL Fatigue and in MG-ADL, QMG, and MG-QOL15 scores were determined at REGAIN week 26. Results At REGAIN week 26, eculizumab-treated patients showed significantly greater improvements in Neuro-QOL Fatigue scores than placebo-treated patients (consistent with improvements in MG-ADL, QMG, and MG-QOL15 scores previously reported in REGAIN). Improvements with eculizumab were sustained through OLE week 52. Correlations between Neuro-QOL Fatigue and MG-QOL15, MG-ADL, and QMG scores were strong for eculizumab-treated patients at REGAIN week 26, and strong, moderate, and weak, respectively, for placebo-treated patients. Conclusions Compared with placebo, eculizumab was associated with improvements in perceived fatigue that strongly correlated with improvements in MG-specific outcome measures. Trial ID Registration: NCT01997229, NCT02301624.
Published: 2019
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48. Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Author: Muppidi, Srikanth, Utsugisawa, Kimiaki, Benatar, Michael, Murai, Hiroyuki, Barohn, Richard J., Illa, Isabel, Jacob, Saiju, Vissing, John, Burns, Ted M., Kissel, John T., Nowak, Richard J., Andersen, Henning, Casasnovas, Carlos, de Bleecker, Jan L., Vu, Tuan H., Mantegazza, Renato, O'Brien, Fanny L., Wang, Jing Jing, Fujita, Kenji P., Howard, James F., Mazia, Claudio Gabriel, Wilken, Miguel, Barroso, Fabio, Saba, Juliet, Rugiero, Marcelo, Bettini, Mariela, Chaves, Marcelo, Vidal, Gonzalo, Garcia, Alejandra Dalila, van den Abeele, Guy, de Koning, Kathy, de Mey, Katrien, Mercelis, Rudy, Mahieu, D. lphine, Wagemaekers, Linda, van Damme, Philip, Depreitere, Annelies, Schotte, Caroline, Smetcoren, Charlotte, Stevens, Olivier, van Daele, Sien, Vandenbussche, Nicolas, Vanhee, Annelies, Verjans, Sarah, Vynckier, Jan, D'Hondt, Ann, Tilkin, Petra, Alves de Siqueira Carvalho, Alzira, Dias Brockhausen, Igor, Feder, David, Ambrosio, Daniel, César, Pamela, Melo, Ana Paula, Martins Ribeiro, Renata, Rocha, Rosana, Bezerra Rosa, Bruno, Veiga, Thabata, da Silva, Luiz Augusto, Santos Engel, Murilo, Gonçalves Geraldo, Jordana, Ananias Morita, Maria da Penha, Nogueira Coelho, Erica, Paiva, Gabriel, Pozo, Marina, Prando, Natalia, Martineli Torres, Debora Dada, Butinhao, Cristiani Fernanda, Duran, Gustavo, Gomes da Silva, Tamires Cristina, Otavio Maia Gonçalves, Luiz, Pazetto, Lucas Eduardo, Fialho, Tomás Augusto Suriane, Renata Cubas Volpe, Luciana, Souza Duca, Luciana, Gheller Friedrich, Maurício André, Guerreiro, Alexandre, Mohr, Henrique, Pereira Martins, Maurer, da Cruz Pacheco, Daiane, Ferreira, Luciana, Macagnan, Ana Paula, Pinto, Graziela, de Cassia Santos, Aline, Souza Bulle Oliveira, Acary, Amaral Andrade, Ana Carolina, Annes, Marcelo, Duarte Silva, Liene, Cavalcante Lino, Valeria, Pinto, Wladimir, Assis, Natália, Carrara, Fernanda, Miranda, Carolina, Souza, Iandra, Fernandes, Patricia, Siddiqi, Zaeem, Phan, Cecile, Narayan, Jeffrey, Blackmore, Derrick, Mallon, Ashley, Roderus, Rikki, Watt, Elizabeth, Vohanka, Stanislav, Bednarik, Josef, Chmelikova, Magda, Cierny, Marek, Toncrova, Stanislava, Junkerova, Jana, Kurkova, Barbora, Reguliova, Katarina, Zapletalova, Olga, Pitha, Jiri, Novakova, Iveta, Tyblova, Michaela, Jurajdova, Ivana, Wolfova, Marcela, Harbo, Thomas, Vinge, Lotte, Krogh, Susanne, Mogensen, Anita, Højgaard, Joan, Witting, Nanna, Ostergaard Autzen, Anne, Pedersen, Jane, Eralinna, Juha-Pekka, Laaksonen, Mikko, Oksaranta, Olli, Harrison, Tuula, Eriksson, Jaana, Rozsa, Csilla, Horvath, Melinda, Lovas, Gabor, Matolcsi, Judit, Szabo, Gyorgyi, Jakab, Gedeonne, Szabadosne, Brigitta, Vecsei, Laszlo, Dezsi, Livia, Varga, Edina, Konyane, Monika, Antonini, Giovanni, di Pasquale, Antonella, Garibaldi, Matteo, Morino, Stefania, Troili, Fernanda, Fionda, Laura, Filla, Allessandro, Costabile, Teresa, Marano, Enrico, Saccà, Francesco, Fasanaro, Angiola, Marsili, Angela, Puorro, Giorgia, Antozzi, Carlo, Bonanno, Silvia, Camera, Giorgia, Locatelli, Alberta, Maggi, Lorenzo, Pasanisi, Maria, Campanella, Angela, Evoli, Amelia, Alboini, Paolo Emilio, D'Amato, Valentina, Iorio, Raffaele, Inghilleri, Maurizio, Frasca, Vittorio, Giacomelli, Elena, Gori, Maria, Lopergolo, Diego, Onesti, Emanuela, Gabriele, Maria, Uzawa, Akiyuki, Kanai, Tetsuya, Kawaguchi, Naoki, Mori, Masahiro, Kaneko, Yoko, Kanzaki, Akiko, Kobayashi, Eri, Masaki, Katsuhisa, Matsuse, Dai, Matsushita, Takuya, Uehara, Taira, Shimpo, Misa, Jingu, Maki, Kikutake, Keiko, Nakamura, Yumiko, Sano, Yoshiko, Nagane, Yuriko, Kamegamori, Ikuko, Tsuda, Tomoko, Fujii, Yuko, Futono, Kazumi, Ozawa, Yukiko, Mizugami, Aya, Saito, Yuka, Suzuki, Hidekazu, Morikawa, Miyuki, Samukawa, Makoto, Kamakura, Sachiko, Miyawaki, Eriko, Shiraishi, Hirokazu, Mitazaki, Teiichiro, Motomura, Masakatsu, Mukaino, Akihiro, Yoshimura, Shunsuke, Asada, Shizuka, Yoshida, Seiko, Amamoto, Shoko, Kobashikawa, Tomomi, Koga, Megumi, Maeda, Yasuko, Takada, Kazumi, Takada, Mihoko, Tsurumaru, Masako, Yamashita, Yumi, Suzuki, Yasushi, Akiyama, Tetsuya, Narikawa, Koichi, Tano, Ohito, Tsukita, Kenichi, Kurihara, Rikako, Meguro, Fumie, Fukuda, Yusuke, Sato, Miwako, Okumura, Meinoshin, Funaka, Soichiro, Kawamura, Tomohiro, Makamori, Masayuki, Takahashi, Masanori, Taichi, Namie, Hasuike, Tomoya, Higuchi, Eriko, Kobayashi, Hisako, Osakada, Kaori, Imai, Tomihiro, Tsuda, Emiko, Shimohama, Shun, Hayashi, Takashi, Hisahara, Shin, Kawamata, Jun, Murahara, Takashi, Saitoh, Masaki, Suzuki, Shuichiro, Yamamoto, Daisuke, Ishiyama, Yoko, Ishiyama, Naoko, Noshiro, Mayuko, Takeyama, Rumi, Uwasa, Kaori, Yasuda, Ikuko, van der Kooi, Anneke, de Visser, Marianne, Gibson, Tamar, Kim, Byung-Jo, Lee, Chang Nyoung, Koo, Yong Seo, Seok, Hung Youl, Kang, Hoo Nam, Ra, HyeJin, Kim, Byoung Joon, Cho, Eun Bin, Choi, MiSong, Lee, HyeLim, Min, Ju-Hong, Seok, Jinmyoung, Lee, JiEun, Koh, Da Yoon, Kwon, JuYoung, Park, SangAe, Choi, Eun Hwa, Hong, Yoon-Ho, Ahn, So-Hyun, Koo, Dae Lim, Lim, Jae-Sung, Shin, Chae Won, Hwang, Ji Ye, Kim, 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Murat, Dogan, Baki, Onar, Musa Kazim, Sen, Sedat, Kirbas Cavdar, Tugce, Veske, Adife, Norwood, Fiona, Dimitriou, Aikaterini, Gollogly, Jakit, Mahdi-Rogers, Mohamed, Seddigh, Arshira, Sokratous, Giannis, Maier, Gal, Sohail, Faisal, Sadalage, Girija, Torane, Pravin, Brown, Claire, Shah, Amna, Sathasivam, Sivakumar, Arndt, Heike, Davies, Debbie, Watling, Dave, Amato, Anthony, Cochrane, Thomas, Salajegheh, Mohammed, Roe, Kristen, Amato, Katherine, Toska, Shirli, Wolfe, Gil, Silvestri, Nicholas, Patrick, Kara, Zakalik, Karen, Katz, Jonathan, Miller, Robert, Engel, Marguerite, Forshew, Dallas, Bravver, Elena, Brooks, Benjamin, Plevka, Sarah, Burdette, Maryanne, Cunningham, Scott, Sanjak, Mohammad, Kramer, Megan, Nemeth, Joanne, Schommer, Clara, Tierney, Scott, Juel, Vern, Guptill, Jeffrey, Hobson-Webb, Lisa, Massey, Janice, Beck, Kate, Carnes, Donna, Loor, John, Anderson, Amanda, Pascuzzi, Robert, Bodkin, Cynthia, Kincaid, John, Snook, Riley, Guingrich, Sandra, Micheels, Angela, Chaudhry, Vinay, Corse, Andrea, Mosmiller, Betsy, Kelley, Andrea, Ho, Doreen, Srinivasan, Jayashri, Vytopil, Michal, Jara, Jordan, Ventura, Nicholas, Scala, Stephanie, Carter, Cynthia, Donahue, Craig, Herbert, Carol, Weiner, Elaine, Alam, Sharmeen, McKinnon, Jonathan, Haar, Laura, McKinnon, Naya, Alcon, Karan, McKenna, Kaitlyn, Sattar, Nadia, Daniels, Kevin, Jeffery, Dennis, Freimer, Miriam, Hoyle, Joseph Chad, Agriesti, Julie, Chelnick, Sharon, Mezache, Louisa, Pineda, Colleen, Muharrem, Filiz, Karam, Chafic, Khoury, Julie, Marburger, Tessa, Kaur, Harpreet, Dimitrova, Diana, Gilchrist, James, Agrawal, Brajesh, Elsayed, Mona, Kohlrus, Stephanie, Andoin, Angela, Darnell, Taylor, Golden, Laura, Lokaitis, Barbara, Seelback, Jenna, Goyal, Neelam, Sakamuri, Sarada, So, Yuen T., Paulose, Shirley, Pol, Sabrina, Welsh, Lesly, Bhavaraju-Sanka, Ratna, Tobon Gonzales, Alejandro, Dishman, Lorraine, Jones, Floyd, Gonzalez, Anna, Padilla, Patricia, Saklad, Amy, Silva, Marcela, Nations, Sharon, Trivedi, Jaya, 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James, Rosenfeld, Jeffrey, Garcia, Rebekah, Echevarria, Laura, Garcia, Sonia, Pulley, Michael, Aranke, Shachie, Berger, Alan Ross, Shah, Jaimin, Shabbir, Yasmeen, Smith, Lisa, Varghese, Mary, Gutmann, Laurie, Gutmann, Ludwig, Jerath, Nivedita, Nance, Christopher, Swenson, Andrea, Olalde, Heena, Kressin, Nicole, Sieren, Jeri, Dimachkie, Mazen, Glenn, Melanie, McVey, April, Pasnoor, Mamatha, Statland, Jeffery, Wang, Yunxia, Liu, Tina, Emmons, Kelley, Jenci, Nicole, Locheke, Jerry, Fondaw, Alex, Johns, Kathryn, Rico, Gabrielle, Walsh, Maureen, Herbelin, Laura, Hafer-Macko, Charlene, Kwan, Justin, Zilliox, Lindsay, Callison, Karen, Young, Valerie, DiSanzo, Beth, Naunton, Kerry, Bilsker, Martin, Sharma, Khema, Cooley, Anne, Reyes, Eliana, Michon, Sara-Claude, Sheldon, Danielle, Steele, Julie, Chopra, Manisha, Traub, Rebecca, Katzin, Lara, McClain, Terry, Harvey, Brittany, Hart, Adam, Huynh, Kristin, Beydoun, Said, Chilingaryan, Amaiak, Doan, Victor, Droker, Brian, Gong, Hui, Karimi, Sanaz, Lin, Frank, Pokala, Krishna, Shah, Akshay, Tran, Anh, Akhter, Salma, Malekniazi, Ali, Tandan, Rup, Hehir, Michael, Waheed, Waqar, Lucy, Shannon, Weiss, Michael, Distad, Jane, Strom, Susan, Downing, Sharon, Kim, Bryan, Bertorini, Tulio, Arnold, Thomas, Hendersen, Kendrick, Pillai, Rekha, Liu, Ye, Wheeler, Lauren, Hewlett, Jasmine, Vanderhook, Mollie, Dicapua, Daniel, Keung, Benison, Kumar, Aditya, Patwa, Huned, Robeson, Kimberly, Yang, Irene, Nye, Joan, Vu, Hong, Muppidi, S., Utsugisawa, K., Benatar, M., Murai, H., Barohn, R. J., Illa, I., Jacob, S., Vissing, J., Burns, T. M., Kissel, J. T., Nowak, R. J., Andersen, H., Casasnovas, C., de Bleecker, J. L., Vu, T. H., Mantegazza, R., O'Brien, F. L., Wang, J. J., Fujita, K. P., Howard, J. F., Mazia, C. G., Wilken, M., Barroso, F., Saba, J., Rugiero, M., Bettini, M., Chaves, M., Vidal, G., Garcia, A. D., Van den Abeele, G., de Koning, K., De Mey, K., Mercelis, R., Mahieu, D., Wagemaekers, L., Van Damme, P., Depreitere, A., Schotte, C., Smetcoren, C., Stevens, O., Van Daele, S., Vandenbussche, N., Vanhee, A., Verjans, S., Vynckier, J., D'Hondt, A., Tilkin, P., Alves de Siqueira Carvalho, A., Dias Brockhausen, I., Feder, D., Ambrosio, D., Cesar, P., Melo, A. P., Martins Ribeiro, R., Rocha, R., Bezerra Rosa, B., Veiga, T., da Silva, L. A., Santos Engel, M., Goncalves Geraldo, J., Ananias Morita, M. D. P., Nogueira Coelho, E., Paiva, G., Pozo, M., Prando, N., Martineli Torres, D. D., Butinhao, C. F., Duran, G., Gomes da Silva, T. 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E., D'Amato, V., Iorio, R., Inghilleri, M., Frasca, V., Giacomelli, E., Gori, M., Lopergolo, D., Onesti, E., Gabriele, M., Uzawa, A., Kanai, T., Kawaguchi, N., Mori, M., Kaneko, Y., Kanzaki, A., Kobayashi, E., Masaki, K., Matsuse, D., Matsushita, T., Uehara, T., Shimpo, M., Jingu, M., Kikutake, K., Nakamura, Y., Sano, Y., Nagane, Y., Kamegamori, I., Tsuda, T., Fujii, Y., Futono, K., Ozawa, Y., Mizugami, A., Saito, Y., Suzuki, H., Morikawa, M., Samukawa, M., Kamakura, S., Miyawaki, E., Shiraishi, H., Mitazaki, T., Motomura, M., Mukaino, A., Yoshimura, S., Asada, S., Yoshida, S., Amamoto, S., Kobashikawa, T., Koga, M., Maeda, Y., Takada, K., Takada, M., Tsurumaru, M., Yamashita, Y., Suzuki, Y., Akiyama, T., Narikawa, K., Tano, O., Tsukita, K., Kurihara, R., Meguro, F., Fukuda, Y., Sato, M., Okumura, M., Funaka, S., Kawamura, T., Makamori, M., Takahashi, M., Taichi, N., Hasuike, T., Higuchi, E., Kobayashi, H., Osakada, K., Imai, T., Tsuda, E., Shimohama, S., Hayashi, T., Hisahara, S., Kawamata, J., Murahara, T., Saitoh, M., Suzuki, S., Yamamoto, D., Ishiyama, Y., Ishiyama, N., Noshiro, M., Takeyama, R., Uwasa, K., Yasuda, I., van der Kooi, A., de Visser, M., Gibson, T., Kim, B. -J., Lee, C. N., Koo, Y. S., Seok, H. Y., Kang, H. N., Ra, H., Kim, B. J., Cho, E. B., Choi, M., Lee, H., Min, J. -H., Seok, J., Lee, J., Koh, D. Y., Kwon, J., Park, S., Choi, E. H., Hong, Y. -H., Ahn, S. -H., Koo, D. L., Lim, J. -S., Shin, C. W., Hwang, J. Y., Kim, M., Kim, S. M., Jeong, H. -N., Jung, J., Kim, Y. -H., Lee, H. S., Shin, H. Y., Hwang, E. B., Shin, M., Alberti Aguilo, M. A., Homedes-Pedret, C., Julia Palacios, N., Diez Porras, L., Velez Santamaria, V., Lazaro, A., Diez Tejedor, E., Gomez Salcedo, P., Fernandez-Fournier, M., Lopez Ruiz, P., Rodriguez de Rivera, F. J., Sastre, M., Gamez, J., Sune, P., Salvado, M., Gili, G., Mazuela, G., Cortes Vicente, E., Diaz-Manera, J., Querol Gutierrez, L. A., Rojas Garcia, R., Vidal, N., Arribas-Ibar, E., Piehl, F., Hietala, A., Bjarbo, L., Sengun, I., Meherremova, A., Ozcelik, P., Balkan, B., Tuga, C., Ugur, M., Erdem-Ozdamar, S., Bekircan-Kurt, C. E., Acar, N. P., Yilmaz, E., Caliskan, Y., Orsel, G., Efendi, H., Aydinlik, S., Cavus, H., Kutlu, A., Becerikli, G., Semiz, C., Tun, O., Terzi, M., Dogan, B., Onar, M. K., Sen, S., Kirbas Cavdar, T., Veske, A., Norwood, F., Dimitriou, A., Gollogly, J., Mahdi-Rogers, M., Seddigh, A., Sokratous, G., Maier, G., Sohail, F., Sadalage, G., Torane, P., Brown, C., Shah, A., Sathasivam, S., Arndt, H., Davies, D., Watling, D., Amato, A., Cochrane, T., Salajegheh, M., Roe, K., Amato, K., Toska, S., Wolfe, G., Silvestri, N., Patrick, K., Zakalik, K., Katz, J., Miller, R., Engel, M., Forshew, D., Bravver, E., Brooks, B., Plevka, S., Burdette, M., Cunningham, S., Sanjak, M., Kramer, M., Nemeth, J., Schommer, C., Tierney, S., Juel, V., Guptill, J., Hobson-Webb, L., Massey, J., Beck, K., Carnes, D., Loor, J., Anderson, A., Pascuzzi, R., Bodkin, C., Kincaid, J., Snook, R., Guingrich, S., Micheels, A., Chaudhry, V., Corse, A., Mosmiller, B., Kelley, A., Ho, D., Srinivasan, J., Vytopil, M., Jara, J., Ventura, N., Scala, S., Carter, C., Donahue, C., Herbert, C., Weiner, E., Alam, S., Mckinnon, J., Haar, L., Mckinnon, N., Alcon, K., Mckenna, K., Sattar, N., Daniels, K., Jeffery, D., Freimer, M., Hoyle, J. C., Agriesti, J., Chelnick, S., Mezache, L., Pineda, C., Muharrem, F., Karam, C., Khoury, J., Marburger, T., Kaur, H., Dimitrova, D., Gilchrist, J., Agrawal, B., Elsayed, M., Kohlrus, S., Andoin, A., Darnell, T., Golden, L., Lokaitis, B., Seelback, J., Goyal, N., Sakamuri, S., So, Y. T., Paulose, S., Pol, S., Welsh, L., Bhavaraju-Sanka, R., Tobon Gonzales, A., Dishman, L., Jones, F., Gonzalez, A., Padilla, P., Saklad, A., Silva, M., Nations, S., Trivedi, J., Hopkins, S., Kazamel, M., Alsharabati, M., Lu, L., Nozaki, K., Mumfrey-Thomas, S., Woodall, A., Mozaffar, T., Cash, T., Roy, G., Mathew, V., Maqsood, F., Minton, B., Jones, H. J., Rosenfeld, J., Garcia, R., Echevarria, L., Garcia, S., Pulley, M., Aranke, S., Berger, A. R., Shah, J., Shabbir, Y., Smith, L., Varghese, M., Gutmann, L., Jerath, N., Nance, C., Swenson, A., Olalde, H., Kressin, N., Sieren, J., Dimachkie, M., Glenn, M., Mcvey, A., Pasnoor, M., Statland, J., Wang, Y., Liu, T., Emmons, K., Jenci, N., Locheke, J., Fondaw, A., Johns, K., Rico, G., Walsh, M., Herbelin, L., Hafer-Macko, C., Kwan, J., Zilliox, L., Callison, K., Young, V., Disanzo, B., Naunton, K., Bilsker, M., Sharma, K., Cooley, A., Reyes, E., Michon, S. -C., Sheldon, D., Steele, J., Chopra, M., Traub, R., Katzin, L., Mcclain, T., Harvey, B., Hart, A., Huynh, K., Beydoun, S., Chilingaryan, A., Doan, V., Droker, B., Gong, H., Karimi, S., Lin, F., Pokala, K., Tran, A., Akhter, S., Malekniazi, A., Tandan, R., Hehir, M., Waheed, W., Lucy, S., Weiss, M., Distad, J., Strom, S., Downing, S., Kim, B., Bertorini, T., Arnold, T., Hendersen, K., Pillai, R., Liu, Y., Wheeler, L., Hewlett, J., Vanderhook, M., Dicapua, D., Keung, B., Kumar, A., Patwa, H., Robeson, K., Yang, I., Nye, J., Vu, H., Neurology, AII - Infectious diseases, ANS - Neuroinfection & -inflammation, APH - Methodology, and APH - Quality of Care
Subjects: 0301 basic medicine, Male, Pediatrics, Exacerbation, Physiology, Heart Diseases/chemically induced, Myasthenia Gravis/drug therapy, 030105 genetics & heredity, THERAPY, DOUBLE-BLIND, 0302 clinical medicine, Quality of life, Monoclonal, Activities of Daily Living, Medicine and Health Sciences, Functional ability, Longitudinal Studies, Humanized, Angioedema/chemically induced, MG-ADL, QMG, Eculizumab, Middle Aged, myasthenia gravi, 3. Good health, Treatment Outcome, Antibodies, Monoclonal, Humanized/therapeutic use, Meningococcal Infections/epidemiology, Disease Progression, Female, eculizumab, Life Sciences & Biomedicine, COMPLEMENT INHIBITOR ECULIZUMAB, medicine.drug, Adult, medicine.medical_specialty, MG-QOL15, Heart Diseases, Clinical Neurology, Meningococcal Vaccines, Antibodies, Monoclonal, Humanized, Placebo, Antibodies, ACETYLCHOLINE-RECEPTOR, Complement Inactivating Agents/therapeutic use, 03 medical and health sciences, Cellular and Molecular Neuroscience, Refractory, Physiology (medical), Injection Site Reaction/epidemiology, Myasthenia Gravis, medicine, Aspergillosis, Aspergillosis/epidemiology, Humans, Muscle Strength, Angioedema, myasthenia gravis, Science & Technology, business.industry, MGC, Neurosciences, Meningococcal Vaccines/therapeutic use, medicine.disease, Interim analysis, Complement Inactivating Agents, Injection Site Reaction, Meningococcal Infections, Quality of Life, Myasthenia gravis, ANTIBODY, Neurosciences & Neurology, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: INTRODUCTION: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. METHODS: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. RESULTS: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P
Published: 2019
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49. FM19G11-Loaded Gold Nanoparticles Enhance the Proliferation and Self-Renewal of Ependymal Stem Progenitor Cells Derived from ALS Mice

Author: Antonella Zacheo, Barbara Sanavio, Claudia Malacarne, Davide Isaia, Victoria Moreno-Manzano, Francesco Stellacci, Patrizia Andreozzi, Silke Krol, Stefania Marcuzzo, Nunzio Denora, Pia Bernasconi, Maravillas Mellado-López, Valentino Laquintana, Elisa Salvati, Renato Mantegazza, Silvia Bonanno, Paola Cavalcante, Marcuzzo, S, Isaia, D, Bonanno, S, Malacarne, C, Cavalcante, P, Zacheo, A, Laquintana, V, Denora, N, Sanavio, B, Salvati, E, Andreozzi, P, Stellacci, F, Krol, S, Mellado-López, M, Mantegazza, R, Moreno-Manzano, V, and Bernasconi, P
Subjects: Pluripotent Stem Cells, amyotrophic lateral sclerosis, Cell, AKT1, Metal Nanoparticles, Mice, Transgenic, AKT3, Article, Superoxide Dismutase-1, Nanoparticle, SOX2, Ependyma, microRNA, medicine, FM19G11, PTEN, Animals, Humans, Uncoupling Protein 2, Progenitor cell, Cell Self Renewal, lcsh:QH301-705.5, Amyotrophic lateral sclerosi, Cell Proliferation, biology, SOXB1 Transcription Factors, Stem Cells, Neurodegeneration, Cell Cycle, PTEN Phosphohydrolase, General Medicine, G93A-SOD1 mouse model, medicine.disease, Cell biology, MicroRNAs, medicine.anatomical_structure, Ependymal stem progenitor cell, Gene Expression Regulation, lcsh:Biology (General), Benzamides, biology.protein, nanoparticles, Gold, Octamer Transcription Factor-3, Proto-Oncogene Proteins c-akt, Biomarkers, ependymal stem progenitor cells
Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. In ALS mice, neurodegeneration is associated with the proliferative restorative attempts of ependymal stem progenitor cells (epSPCs) that normally lie in a quiescent in the spinal cord. Thus, modulation of the proliferation of epSPCs may represent a potential strategy to counteract neurodegeneration. Recent studies demonstrated that FM19G11, a hypoxia-inducible factor modulator, induces epSPC self-renewal and proliferation. The aim of the study was to investigate whether FM19G11-loaded gold nanoparticles (NPs) can affect self-renewal and proliferation processes in epSPCs isolated from G93A-SOD1 mice at disease onset. We discovered elevated levels of SOX2, OCT4, AKT1, and AKT3, key genes associated with pluripotency, self-renewal, and proliferation, in G93A-SOD1 epSPCs at the transcriptional and protein levels after treatment with FM19G11-loaded NPs. We also observed an increase in the levels of the mitochondrial uncoupling protein (UCP) gene in treated cells. FM19G11-loaded NPs treatment also affected the expression of the cell cycle-related microRNA (miR)-19a, along with its target gene PTEN, in G93A-SOD1 epSPCs. Overall our findings establish the significant impact of FM19G11-loaded NPs on the cellular pathways involved in self-renewal and proliferation in G93A-SOD1 epSPCs, thus providing an impetus to the design of novel tailored approaches to delay ALS disease progression.
Published: 2019

50. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial

Author: Lucy Lam, Jiri Pitha, John Vissing, Laura Fionda, Denis Korobko, Michael Pulley, Tony Vangeneugden, Silvia Bonanno, Nobuhiro Ido, Jerrica Farias, Jafar Shabanpour, James Gilchrist, Girolamo Alfieri, Gyorgyi Szabo, Carlayne E. Jackson, Eduardo Ng, Csilla Rozsa, Hans D. Katzberg, Carlo Antozzi, Aleksandra Golenia, Sayaka Ishida, Temur Margania, Andrzej Szczudlik, Richard J. Barohn, Mari Suzuki., Robert Henegar, Kaoru Sakuma, Evanthia Bernitsas, Elena Lapochka, Yukiko Ozawa, Tomihiro Imai, Debbie Hastings, Antonio Guglietta, Benjamin Frishberg, Elena Antipenko, Vera Bril, Stanislav Vohanka, Isela Hernandez, Ivo Bozovic, Ilona Vergunova, Lorenzo Maggi, Andreas Meisel, Ali Malekniazi, Tahseen Mozaffar, Emmanuelle Salort-Campana, Yasmin Camberos, Jan J.G.M. Verschuuren, Masayuki Masuda, Masanori Takahashi, Yoshihiko Okubo, Marek Smilowski, Yasushi Suzuki, Mary Wagoner, Andrew Heim, David Bors, Chiho Watanabe, Fiammetta Vanoli, Antonio Reia, Zubair Quraishi, Omar Jawdat, Makoto Samukawa, Gregory Sahagian, Gedeonne Margo Jakab, Eiichi Nomura, Samantha Colgan, Cindy Benzel, Ayako Mori, Annabel M. Ruiter, Ratna Bharavaju-Sanka, Roman Shakarishvili, Victoria Cannon, Malkova Nadezhda, Tomas Horak, Anna Kostera-Pruszczyk, Eniko Szabo, Emilien Delmont, Alexander Tsiskaridze, Lubna Daniyal, Vidosava Rakocevic Stojanovic, Szilvia Toth, Siegfried Kohler, Iveta Novakova, Katherine Roath, Kazuna Ikeda, Salma Akhter, Claudia Heibutzki, Martijn R. Tannemaat, Marta Pinkosz, Mads Peter Godtfeldt Stemmerik, Chafic Karam, Irys Caristo, Carolyn Paiz, Josef Bednarik, Monika Frasinska, Stefania Morino, Norianne Pimentel, Kanako Minemoto, Rekha Pillai, Linda Wagemaekers, Annelien De Pue, Irina Poverennova, Katerina Reguliova, Jana Junkerova, Angela Marsili, Anne-Marie Peters, Maren Wyckmans, Michaela Tyblova, Debbie Eggleston, Anne Mette Ostergaard Autzen, Takamichi Sugimoto, Kuldeep Kumar Khatri, Niraja Suresh, Jan De Bleecker, Lea Gerischer, Grazyna Zwolinska, Kevin R Keene, Yosuke Onishi, Francesco Saccà, Zaeem A. Siddiqi, Marjolein Van Heur, Jeffrey Statland, Tatiana Romanova, Diana Dimitrova, Stojan Peric, Tomoko Tsuda, Cathy Bailey, Lubov Urtaeva, Lizzie Zafirakos, Katherine Ruzhansky, Tomoya Kubota, Angela Campanella, Nadezhda Kuznetsova, Sarah Jones, Giovanni Antonini, Hiroyuki Murai, Luca Leonardi, Alan R. Berger, Jonathan Baets, Peter Ulrichts, Said R. Beydoun, Michala Jakubikova, Mamatha Pasnoor, James F. Howard, Leila Darki, Katerina Havelkova, Namita Goyal, Akiyuki Uzawa, Tia Nguyen, Miki Takaki, Matteo Garibaldi, Manisha Kak, Ivonne Turner, Aude-Marie Grapperon, Mageda Horakova, Yuebing Li, Ivana Basta, Lech Szczechowski, Shabber Mannan, Aneta Pasko, Caroline Vinck, Riccardo Giossi, Rudolf Mercelis, Ivana Jurajdova, Lesly Welsh, Małgorzata Bilińska, Marek Halas, Dragana Lavrnic, Kimiaki Utsugisawa, Todd Levine, Erik Velasquez, Daisuke Yamamoto, Constantine Farmakidis, John Anthony Morren, Sarah Hoffman, Manisha Chopra, Shingo Konno, Rita Frangiamore, Kelly Jia, Jana Horakova, Anna Melnikova, Piotr Szczudlik, Ali Habib, Giorgia Puorro, Michael D. Weiss, Robert P. Lisak, Hiroyuki Naito, Shahram Attarian, Hiroko Nakamura, Shin Hisahara, Mazen M. Dimachkie, Genya Watanabe, Duaa Jabari, Ekaterina Bulatova, Angela Genge, Makiko Naito, Melissa Currence, Henning Andersen, Katrien De Mey, Kathy de Koning, Yuen T. So, Chiara Pane, Renato Mantegazza, Rebecca Traub, Manato Yasuda, Amy Visser, Dike Remstedt, Yuka Takematsu, Frauke Stascheit, Ayumi Kamei, Tuan Vu, Tulio E. Bertorini, Ludivine Kouton, Neelam Goyal, Flicia Mada, Nizar Chahin, Mihiro Shimizu, Srikanth Muppidi, and Erina Sugano
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, Population, fc fragment, Placebo, Antibodies, Monoclonal, Humanized, law.invention, efgartigimod, myasthenia gravis, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Double-Blind Method, law, Internal medicine, Activities of Daily Living, Myasthenia Gravis, medicine, Clinical endpoint, Humans, Receptors, Cholinergic, Dosing, Longitudinal Studies, education, Biology, Autoantibodies, education.field_of_study, business.industry, Headache, Antibodies, Monoclonal, Middle Aged, medicine.disease, Myasthenia gravis, 3. Good health, Immunoglobulin Fc Fragments, Clinical trial, Chemistry, 030104 developmental biology, Tolerability, Female, Human medicine, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Background: There is an unmet need for treatment options for generalised myasthenia gravis that are effective, targeted, well tolerated, and can be used in a broad population of patients. We aimed to assess the safety and efficacy of efgartigimod (ARGX-113), a human IgG1 antibody Fc fragment engineered to reduce pathogenic IgG autoantibody levels, in patients with generalised myasthenia gravis. Methods: ADAPT was a randomised, double-blind, placebo-controlled, phase 3 trial done at 56 neuromuscular academic and community centres in 15 countries in North America, Europe, and Japan. Patients aged at least 18 years with generalised myasthenia gravis were eligible to participate in the study, regardless of anti-acetylcholine receptor antibody status, if they had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5 (>50% non-ocular), and were on a stable dose of at least one treatment for generalised myasthenia gravis. Patients were randomly assigned by interactive response technology (1:1) to efgartigimod (10 mg/kg) or matching placebo, administered as four infusions per cycle (one infusion per week), repeated as needed depending on clinical response no sooner than 8 weeks after initiation of the previous cycle. Patients, investigators, and clinical site staff were all masked to treatment allocation. The primary endpoint was proportion of acetylcholine receptor antibody-positive patients who were MG-ADL responders (≥2-point MG-ADL improvement sustained for ≥4 weeks) in the first treatment cycle. The primary analysis was done in the modified intention-to-treat population of all acetylcholine receptor antibody-positive patients who had a valid baseline MG-ADL assessment and at least one post-baseline MG-ADL assessment. The safety analysis included all randomly assigned patients who received at least one dose or part dose of efgartigimod or placebo. This trial is registered at ClinicalTrials.gov (NCT03669588); an open-label extension is ongoing (ADAPT+, NCT03770403). Findings: Between Sept 5, 2018, and Nov 26, 2019, 167 patients (84 in the efgartigimod group and 83 in the placebo group) were enrolled, randomly assigned, and treated. 129 (77%) were acetylcholine receptor antibody-positive. Of these patients, more of those in the efgartigimod group were MG-ADL responders (44 [68%] of 65) in cycle 1 than in the placebo group (19 [30%] of 64), with an odds ratio of 4·95 (95% CI 2·21–11·53, p
Published: 2020
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