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1. Emergency lower gastrointestinal endoscopy performed safely in a COVID-19 patient on extracorporeal membrane oxygenation (ECMO) with hemorrhagic shock

Author

Arino Yaguchi, Yoshitsugu Misumi, Kouichi Nonaka, and Yuko Fujii

Subjects
medicine.medical_specialty, VV-ECMO, medicine.medical_treatment, Case Report, Infection control, Shock, Hemorrhagic, Endoscopy, Gastrointestinal, law.invention, 03 medical and health sciences, 0302 clinical medicine, Extracorporeal Membrane Oxygenation, law, Internal medicine, medicine, Extracorporeal membrane oxygenation, Humans, medicine.diagnostic_test, business.industry, SARS-CoV-2, Gastroenterology, COVID-19, Lower Gastrointestinal Endoscopy, General Medicine, Hepatology, medicine.disease, Intensive care unit, Colorectal surgery, Endoscopy, Pneumonia, 030220 oncology & carcinogenesis, Anesthesia, 030211 gastroenterology & hepatology, business, Abdominal surgery
Abstract

Emergency endoscopy in coronavirus disease 2019 (COVID-19) patients should be avoided whenever possible to ensure the safety of medical staff; however, it may be unavoidable in some cases. We report a case of emergency lower gastrointestinal endoscopy performed with full personal protective equipment in a patient on extracorporeal membrane oxygenation with severe COVID-19 pneumonia admitted in a restricted area under negative pressure in the intensive care unit. To avoid the risk of fecal-oral transmission of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the procedure, the patient's lower body was covered with a 2 m2 vinyl sheet with an aperture (diameter, approximately 2 cm). None of the medical staff involved exhibited any signs of SARS-CoV-2 infection after the procedure. Although patients with severe COVID-19 pneumonia on extracorporeal membrane oxygenation have a high risk of bleeding, we believe that emergency lower endoscopy can be safely performed in such patients by reducing exposure to dispersed feces and using full personal protective equipment.

Published
2021

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

Author

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

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

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

Published
2020

3. Genetic analysis diagnosed Bardet–Biedl syndrome in a patient with a clinical diagnosis of Senior–Løken syndrome

Author

Hideki Matsumura, Akira Ashida, Akihiko Shirasu, Satoshi Yamazaki, Yuko Fujii, Naoya Morisada, Hyogo Nakakura, and Kazumoto Iijima

Subjects
medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Urology, government.form_of_government, Ciliopathy, 030232 urology & nephrology, SDCCAG8, Senior–Løken syndrome, lcsh:RC870-923, Ciliopathies, 03 medical and health sciences, 0302 clinical medicine, Bardet–Biedl syndrome, Nephronophthisis, Internal medicine, medicine, Juvenile nephronophthisis, 030304 developmental biology, 0303 health sciences, Transplantation, Polydactyly, business.industry, medicine.disease, lcsh:Diseases of the genitourinary system. Urology, Nephrology, government, business, Kidney disease
Abstract

Background Senior–Løken syndrome (SLS) and Bardet–Biedl syndrome (BBS) are ciliopathies. SLS is characterized by retinitis pigmentosa (RP) and familial nephronophthisis, leading to end-stage kidney disease, while BBS is characterized by six major symptoms: RP, polydactyly, obesity, genital abnormalities, learning difficulties, and renal defects. Ciliopathies have been diagnosed on a phenotypic basis, but diagnosis can now be established by genetic testing, using techniques such as next-generation sequencing. Here, we report a patient clinically diagnosed with SLS but diagnosed with BBS 13 years later using next-generation sequencing. Case presentation The patient was diagnosed with RP at the age of 6 years. She had some difficulty in social interactions and pre-obesity, but no polydactyly. At the age of 8 years, she was diagnosed with chronic kidney disease, anemia, and liver dysfunction. Kidney and liver biopsy revealed renal tubule cysts, tubule membrane disruption, and liver fibrosis. Therefore, SLS was diagnosed but no NPHP1 mutations were detected. Peritoneal dialysis was started at the age of 9 years, and she underwent kidney transplantation with a graft from her father at the age of 13 years. At the age of 21 years, she again underwent genetic testing for most of the mutations associated with ciliopathy. This revealed a homozygous frameshift mutation in intron 11 of SDCCAG8. Conclusions Mutations in SDCCAG8 are known to be causative of SLS and BBS without polydactyly. The fact that the patient had RP, some difficulty in social interactions, pre-obesity, juvenile nephronophthisis, liver fibrosis, bronchial asthma, and otitis media suggested BBS. However, some of these are not specific symptoms for BBS and she had few typical symptoms of BBS. Therefore, a definitive diagnosis of BBS was difficult without genetic analysis. Because many more patients with SDCCAG8 mutations have extrarenal manifestations like the current patient than standard nephronophthisis patients, careful monitoring of extrarenal manifestations is needed to improve patient management.

Published
2020

4. Response to eculizumab in patients with myasthenia gravis recently treated with chronic IVIg: a subgroup analysis of REGAIN and its open-label extension study

Author

Saiju Jacob, Hiroyuki Murai, Kimiaki Utsugisawa, Richard J. Nowak, Heinz Wiendl, Kenji P. Fujita, Fanny O’Brien, James F. Howard, Claudio Gabriel Mazia, Miguel Wilken, Fabio Barroso, Juliet Saba, Jan De Bleecker, Guy Van den Abeele, Kathy de Koning, Katrien De Mey, 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, Yuriko Nagane, Ikuko Kamegamori, Tomoko Tsuda, Yuko Fujii, Kazumi Futono, Yukiko Ozawa, Aya Mizugami, Yuka Saito, Anneke van der Kooi, Marianne de Visser, Tamar Gibson, Seung Min Kim, JinWoo Jeong, Ha-Neul Jung, Yool-hee Kim, Hyung Seok Lee, Ha Young Shin, Eun Bi Hwang, Miju Shin, Josep Gamez Carbonell, Pilar Sune, Maria Salvado Figueras, Gisela Gili, Gonzalo Mazuela, Fredrik Piehl, Albert Hietala, Lena Bjarbo, Sevim Erdem-Ozdamar, Can Ebru Bekircan-Kurt, Nazire Pinar Acar, Ezgi Yilmaz, Yagmur Caliskan, Gulsah Orsel, Anthony Amato, Thomas Cochrane, Mohammed Salajegheh, Kristen Roe, Katherine Amato, Shirli Toska, Jonathan McKinnon, Laura Haar, Naya McKinnon, Karan Alcon, Kaitlyn McKenna, Nadia Sattar, Kevin Daniels, Dennis Jeffery, Tahseen Mozaffar, Tiyonnoh Cash, Namita Goyal, Gulmohor Roy, Veena Mathew, Fatima Maqsood, Brian Minton, Charlene Hafer-Macko, Justin Kwan, Lindsay Zilliox, Karen Callison, Valerie Young, Beth DiSanzo, Kerry Naunton, 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, Tulio Bertorini, Thomas Arnold, Kendrick Hendersen, Rekha Pillai, Ye Liu, Lauren Wheeler, Jasmine Hewlett, and Mollie Vanderhook

Subjects
IVIg, 0301 basic medicine, medicine.medical_specialty, REGAIN, Subgroup analysis, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Refractory, intravenous immunoglobulin, Internal medicine, medicine, In patient, Generalized myasthenia, RC346-429, Original Research, Pharmacology, myasthenia gravis, business.industry, Extension study, Eculizumab, medicine.disease, Myasthenia gravis, 030104 developmental biology, Neurology, eculizumab, Neurology (clinical), Neurology. Diseases of the nervous system, Open label, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background: In the phase III eculizumab for refractory generalized myasthenia gravis REGAIN study [ClinicalTrials.gov identifier: NCT01997229] and its open-label extension (OLE) [ClinicalTrials.gov identifier: NCT02301624], patients with treatment-refractory antiacetylcholine receptor antibody-positive generalized myasthenia gravis had clinically meaningful improvements with eculizumab versus placebo. This subgroup analysis evaluated data from patients with a recent history of chronic intravenous immunoglobulin (IVIg) use before study entry. Methods: The subgroup comprised patients who had received IVIg at least four times in 1 year, with at least one IVIg treatment cycle during the 6 months before the first REGAIN study dose. Data from REGAIN and the OLE were analyzed. Response to eculizumab versus placebo was assessed using four validated, disease-specific measures. Incidences of exacerbations and safety endpoints were recorded. Results: The subgroup had similar patient and disease characteristics as the overall REGAIN population. Clinical assessments showed sustained eculizumab efficacy during REGAIN and the OLE over 18 months. Patients receiving placebo in REGAIN experienced rapid improvements in assessment scores when treated with eculizumab in the OLE. There was a lower rate of disease exacerbations with eculizumab than with placebo during REGAIN, and eculizumab was well tolerated. Conclusion: Eculizumab treatment, compared with placebo, results in meaningful clinical improvements and fewer disease exacerbations for patients who previously received chronic IVIg. Trial registration: REGAIN [ClinicalTrials.gov identifier: NCT01997229]; REGAIN open-label extension [ClinicalTrials.gov identifier: NCT02301624].

Published
2020

5. Everolimus improved renal function without reducing the size of a kidney angiomyolipoma in a patient with tuberous sclerosis complex: a case report

Author

Hiroshi Tamai, Yuko Fujii, Hyogo Nakakura, Akira Ashida, Akihiko Shirasu, and Hideki Matsumura

Subjects
Nephrology, medicine.medical_specialty, Angiomyolipoma, mTOR inhibitor, Urology, medicine.medical_treatment, 030232 urology & nephrology, Renal function, urologic and male genital diseases, lcsh:RC870-923, 03 medical and health sciences, Tuberous sclerosis, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, medicine, Renal replacement therapy, Everolimus, Transplantation, Creatinine, business.industry, Kidney Angiomyolipoma, medicine.disease, lcsh:Diseases of the genitourinary system. Urology, chemistry, Glomerular hyperfiltration, Tuberous sclerosis complex, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Background Tuberous sclerosis complex is an autosomal dominant genetic disorder that affects multiple organ systems and can result in tumors in the brain, skin, heart, and kidneys; it may also cause neurological symptoms. About 1 to 7% of patients develop end-stage renal disease due to bilateral renal angiomyolipoma. We herein describe a patient with a bilateral large kidney angiomyolipoma whose residual renal function was temporarily improved with everolimus treatment. Case presentation A 39-year-old man was diagnosed with tuberous sclerosis complex associated with an angiomyolipoma that was first detected at 12 years of age and had enlarged to a size that completely filled the bilateral kidneys. Although his kidney function was poor at the start of everolimus treatment as indicated by a creatinine-based estimated glomerular filtration rate of 13.7 mL/min/1.73 m2, his kidney function recovered with an annual increase in the glomerular filtration rate of 4.57 mL/min/1.73 m2 without morphological changes or a reduction in the size of the angiomyolipoma after everolimus treatment. As a result, we were able to delay the initiation of renal replacement therapy for more than 1 year. Conclusions Even in patients with tuberous sclerosis complex who exhibit decreased renal function, everolimus treatment can retain the renal function and delay introduction of dialysis without a reduction in the size of the renal angiomyolipoma. The pathophysiological mechanisms for the deterioration of renal function in patients with tuberous sclerosis complex may not involve renal parenchymal loss secondary to angiomyolipoma growth only but may also involve other mechanisms including glomerular hypertrophy and hyperfiltration associated with mTOR complex 1 overactivity.

Published
2018

6. Clinical features in a series of 258 Japanese pediatric patients with thrombotic microangiopathy

Author

Hyogo Nakakura, Hideki Matsumura, Akihiko Shirasu, Yuko Fujii, Akira Ashida, Kazumoto Iijima, Toshihiro Sawai, and Rika Fujimaru

Subjects
Male, Nephrology, medicine.medical_specialty, Thrombotic microangiopathy, Physiology, medicine.medical_treatment, 030232 urology & nephrology, Thrombotic thrombocytopenic purpura, urologic and male genital diseases, 03 medical and health sciences, 0302 clinical medicine, Japan, hemic and lymphatic diseases, Physiology (medical), Internal medicine, Atypical hemolytic uremic syndrome, Humans, Medicine, 030212 general & internal medicine, Renal replacement therapy, Child, neoplasms, Thrombotic Microangiopathies, business.industry, Incidence (epidemiology), medicine.disease, female genital diseases and pregnancy complications, Europe, Cross-Sectional Studies, Child, Preschool, North America, Etiology, Female, business, Kidney disease
Abstract

Thrombotic microangiopathy (TMA) includes hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). This study examined the epidemiological characteristics of pediatric patients with TMA classified according to etiology. The survey evaluated 258 Japanese pediatric patients diagnosed with TMA between 2012 and 2015. The primary diseases responsible for TMA were categorized as TTP (15 cases), Shiga toxin-producing Escherichia coli-associated HUS (STEC-HUS) (166 cases), atypical HUS (aHUS) (40 cases), and secondary TMA (27 cases). The remaining 10 cases were unable to be classified to one of the four categories of the primary disease. Renal replacement therapy was required in the acute phase in 103 patients with TMA, including 65 with STEC-HUS, 22 with aHUS, two with TTP, 10 with secondary TMA, and four unclassified cases. The last observational findings were normal renal function in 95 patients and chronic kidney disease (CKD) stage 1 in 62. For 31 patients, chronic renal insufficiency (CKD stage 2-5) persisted, including four patients with end-stage kidney disease (CKD stage 5). Seventeen patients suffered recurrence of TMA, and eight patients died. This study clarified differences in the relative proportions of primary diseases between patients from Japan and North America and Europe. The difference may be attributable to the lower estimated incidence of STEC-HUS in Japan.

Published
2018

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

Author

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

Subjects
Male, 0301 basic medicine, medicine.medical_treatment, Drug Resistance, Adult, Aged, Antibodies, Monoclonal, Humanized, Autoantibodies, Double-Blind Method, Female, Humans, Middle Aged, Myasthenia Gravis, Receptors, Cholinergic, Outcome Assessment (Health Care), Severity of Illness Index, Neurology (clinical), law.invention, Complement inhibitor, 0302 clinical medicine, Randomized controlled trial, law, Monoclonal, Receptors, Clinical endpoint, Humanized, Cholinergic, education.field_of_study, Eculizumab, Autoantibodie, Myasthenia Gravi, Settore MED/26 - NEUROLOGIA, Human, medicine.drug, Meningitides, medicine.medical_specialty, Population, Placebo, Antibodies, 03 medical and health sciences, Internal medicine, medicine, education, business.industry, Surgery, Thymectomy, 030104 developmental biology, business, 030217 neurology & neurosurgery
Abstract

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

Published
2017

9. Efficacy of a mitochondrion-targeting agent for reducing the level of urinary protein in rats with puromycin aminonucleoside-induced minimal-change nephrotic syndrome

Author

Hideki Matsumura, Satoshi Yamazaki, Akira Ashida, Akihiko Shirasu, Tohru Ogihara, Yuko Fujii, and Hyogo Nakakura

Subjects
Male, 0301 basic medicine, Antioxidant, Physiology, medicine.medical_treatment, Urine, Puromycin Aminonucleoside, Mitochondrion, medicine.disease_cause, Biochemistry, Antioxidants, Lipid peroxidation, chemistry.chemical_compound, Drug Delivery Systems, 0302 clinical medicine, Piperidines, Medicine and Health Sciences, Electron Microscopy, Energy-Producing Organelles, Microscopy, Multidisciplinary, Podocytes, Organic Compounds, Chemistry, Mitochondria, Body Fluids, Proteinuria, 030220 oncology & carcinogenesis, Physical Sciences, Medicine, Cellular Structures and Organelles, Anatomy, Glomeruli, Research Article, medicine.medical_specialty, Science, Nephrosis, Excretion, Bioenergetics, Research and Analysis Methods, 03 medical and health sciences, Organophosphorus Compounds, Internal medicine, medicine, Animals, Rats, Wistar, Ethanol, Nephrosis, Lipoid, Organic Chemistry, Chemical Compounds, Biology and Life Sciences, Kidneys, Cell Biology, Renal System, medicine.disease, Rats, Oxidative Stress, 030104 developmental biology, Endocrinology, Alcohols, Lipid Peroxidation, Physiological Processes, Nephrotic syndrome, Oxidative stress
Abstract

Background Oxidative stress is a major factor responsible for minimal-change nephrotic syndrome (MCNS), which occurs most commonly in children. However, the influence of oxidative stress localized to mitochondria remains unclear. We examined the effect of a mitochondrion-targeting antioxidant, MitoTEMPO, in rats with puromycin aminonucleoside (PAN)-induced MCNS to clarify the degree to which mitochondrial oxidative stress affects MCNS. Materials and methods Thirty Wistar rats were divided into three groups: normal saline group (n = 7), PAN group (n = 12), and PAN + MitoTEMPO group (n = 11). Rats in the PAN and PAN + MitoTEMPO groups received PAN on day 1, and those in the PAN + MitoTEMPO group received MitoTEMPO on days 0 to 9. Whole-day urine samples were collected on days 3 and 9, and samples of glomeruli and blood were taken for measurement of lipid peroxidation products. We also estimated the mitochondrial damage score in podocytes in all 3 groups using electron microscopy. Results Urinary protein excretion on day 9 and the levels of lipid peroxidation products in urine, glomeruli, and blood were significantly lower in the PAN + MitoTEMPO group than in the PAN group (p = 0.0019, p = 0.011, p = 0.039, p = 0.030). The mitochondrial damage score in podocytes was significantly lower in the PAN + MitoTEMPO group than in the PAN group (p

Published
2020

10. Leptin inhibits amyloid β-protein degradation through decrease of neprilysin expression in primary cultured astrocytes

Author

Kenji Suzuki, Naoki Yamamoto, Yoko Ono, Kentaro Ohora, Kazuya Sobue, Mamoru Tanida, Rika Kasahara, and Yuko Fujii

Subjects
Leptin, MAPK/ERK pathway, medicine.medical_specialty, Amyloid, Blotting, Western, Biophysics, Protein degradation, Biology, Insulysin, Biochemistry, Rats, Sprague-Dawley, Pathogenesis, Internal medicine, Nitriles, Butadienes, Extracellular, medicine, Animals, Enzyme Inhibitors, Extracellular Signal-Regulated MAP Kinases, Molecular Biology, Neprilysin, Cells, Cultured, Amyloid beta-Peptides, Dose-Response Relationship, Drug, Kinase, fungi, Cell Biology, Rats, Endocrinology, Astrocytes, Proteolysis
Abstract

Pathogenesis of Alzheimer's disease (AD) is characterized by accumulation of extracellular deposits of amyloid β-protein (Aβ) in the brain. The steady state level of Aβ in the brain is determined by the balance between its production and removal; the latter occurring through egress across blood and CSF barriers as well as Aβ degradation. The major Aβ-degrading enzymes in the brain are neprilysin (NEP) and insulin-degrading enzyme (IDE), which may promote Aβ deposition in patients with sporadic late-onset AD. Epidemiological studies have suggested an inverse relationship between the adipocytokine leptin levels and the onset of AD. However, the mechanisms underlying the relationship remain uncertain. We investigated whether leptin is associated with Aβ degradation by inducing NEP and IDE expression within primary cultured astrocytes. Leptin significantly decreased the expression of NEP but not IDE in a concentration- and time-dependent manner through the activation of extracellular signal-regulated kinase (ERK) in cultured rat astrocytes. Furthermore, leptin inhibited the degradation of exogenous Aβ in primary cultured astrocytes. These results suggest that leptin suppresses Aβ degradation by NEP through activation of ERK.

Published
2014

11. A case of cap polyposis with cytomegalovirus colitis

Author

Yuko Fujii, Satoko Uegaki, Yasuko Ushio, Makoto Nishimura, Miho Matsukawa, Yoko Matsuda, Akira Hirota, Takuya Takemura, and Tomio Arai

Subjects
medicine.medical_specialty, business.industry, Mechanical Engineering, Internal medicine, medicine, Energy Engineering and Power Technology, Cytomegalovirus colitis, Management Science and Operations Research, medicine.disease, business, Gastroenterology, Cap polyposis
Published
2018

12. Su1321 Evaluation of CHST15 Expression for Assessing the Tumor Progression and Overall Survival of EUS-Guided Intratumoral Chst15 Dsrna Injection in Patient With Unresectable Pancreatic Cancer

Author

Yuko Fujii, Naohisa Yahagi, Yoko Matsuda, Makoto Nishimura, and Miho Matsukawa

Subjects
Oncology, Unresectable Pancreatic Cancer, medicine.medical_specialty, RNA silencing, business.industry, Tumor progression, Internal medicine, Gastroenterology, Overall survival, Medicine, Radiology, Nuclear Medicine and imaging, In patient, business
Published
2017

13. A case report of bilateral hydroureteronephrosis associated with systemic sclerosis

Author

Koichi Fujii, Toshiyuki Ota, Atsushi Mizogami, Sumiya Eto, Yoshiya Tanaka, Kazuyoshi Saito, Shingo Nakayamada, Yuko Fujii, Yoshifumi Inada, and Yuichiro Awazu

Subjects
medicine.medical_specialty, integumentary system, medicine.diagnostic_test, business.industry, Urinary retention, medicine.medical_treatment, Urology, medicine.disease, Rheumatology, medicine.anatomical_structure, Submucosa, Internal medicine, Orthopedic surgery, Biopsy, Nephrostomy, Medicine, medicine.symptom, skin and connective tissue diseases, business, Hydronephrosis, Pathological
Abstract

This report describes a case of atrophic bladder and bilateral hydroureteronephrosis that occurred in a patient with systemic sclerosis (SSc). A 49-year-old woman who had a 12-year history of SSc was admitted to our hospital because of bilateral hydroureteronephrosis indicated by uroflowmetric and radiological studies. Histological examination of the patient's bladder after biopsy revealed fibrotic replacement of submucosa and infiltration of mononuclear cells, but no deposition of immunoglobulins and complement components were observed. Nephrostomy to relieve the urinary retention was required. There have been few reports regarding SSc complications in hydronephrosis. The association between hydronephrosis and the pathological disorder of SSc is discussed.

Published
2000

14. Prolonged and ubiquitous inhibition by interferon γ of bone resorption induced by parathyroid hormone-related protein, 1,25-dihydroxyvitamin D3, and interleukin 1 in fetal mouse forearm bones

Author

Toru Fujii, Kanji Sato, Tomoko Satoh, Kazuo Shizume, Keizo Kasono, and Yuko Fujii

Subjects
Calcitonin, medicine.medical_specialty, Calcitriol, Endocrinology, Diabetes and Metabolism, Bone and Bones, Dinoprostone, Bone resorption, Interferon-gamma, Mice, Endocrinology, Pregnancy, Teriparatide, Internal medicine, medicine, Animals, Orthopedics and Sports Medicine, Interferon gamma, Bone Resorption, Prostaglandin E2, Mice, Inbred ICR, Parathyroid hormone-related protein, business.industry, Parathyroid Hormone-Related Protein, Proteins, Interleukin, Peptide Fragments, Resorption, Forearm, Parathyroid Hormone, Female, business, Interleukin-1, medicine.drug
Abstract

To investigate the mechanism of the inhibitory effects of interferon-gamma (IFN-gamma) on bone resorption, the effects of murine IFN-gamma on 45Ca release from prelabeled fetal mouse forearm bones were investigated. Murine IFN-gamma usually did not affect basal 45Ca release but almost completely and equipotently inhibited bone resorption induced by PTH(1-34), PTH-rP(1-34), 1,25(OH)2D3, and interleukin 1 (IL-1). The half-maximal concentration for inhibition of bone resorption induced by IL-1 alpha was 25.8 +/- 14.6 U/ml (mean +/- SD for 13 experiments), which is not different from those for PTH, PTH-rP, and 1,25(OH)2D3. There was no correlation between prostaglandin E2 concentration in the conditioned medium and 45Ca release from the IFN-gamma-treated forearm bones. The inhibitory effect of IFN-gamma on bone resorption induced by PTH-rP (1-34) or IL-1 alpha continued during 6 days of culture, whereas that of calcitonin disappeared after 2 days of culture. These findings suggest that IFN-gamma non-preferentially inhibits bone resorption induced by various bone-resorbing factors in fetal mouse forearm bones via a PGE2-independent mechanism. As no escape phenomenon developed in IFN-gamma-treated bones, the cytokine may be potentially useful for treatment of certain patients with malignancy-associated hypercalcemia.

Published
1990

15. Dimethylsulfoxide maintains human thyroid cells in suspension culture, facilitating synthesis and release of thyroid hormone

Author

Toshio Tsushima, Yuko Fujii, Kazuo Shizume, Kanji Sato, Doo Chol Han, and Minoru Ozawa

Subjects
Thyroid Hormones, endocrine system, medicine.medical_specialty, Time Factors, endocrine system diseases, Cell Survival, Preservation, Biological, Thyroid Gland, Biophysics, Thyrotropin, chemistry.chemical_element, Iodine, Biochemistry, Suspensions, Thyroid peroxidase, Internal medicine, medicine, Humans, Dimethyl Sulfoxide, Molecular Biology, Cells, Cultured, Fetus, biology, Chemistry, Thyroid, Cell Biology, Fetal Blood, Culture Media, medicine.anatomical_structure, Endocrinology, Cell culture, biology.protein, Thyroid Stimulating Immunoglobulin, Thyroid function, Hormone
Abstract

Usually, human thyrocytes in primary culture rapidly lose their thyroid function and fail to synthesize or release thyroid hormone after 3-5 days of culture. By culturing thyroid follicles obtained from patients with Graves' disease in medium supplemented with TSH and a low concentration of fetal calf serum (1%), thyrocytes can maintain thyroid function for several days. We have found that the addition of dimethylsulfoxide to culture medium (1.7%) furthermore enhanced and maintained thyroid function (de novo synthesis and release of [125I] thyroxine) for more than 13 days, probably by inhibiting dedifferentiation of thyrocytes. The present bioassay will be also useful for detecting thyroid stimulating immunoglobulin in patients with Graves' disease.

Published
1988

16. Tumor necrosis factor type α (cachectin) stimulates mouse osteoblast-like cells (MC3T3-E1) to produce macrophage-colony stimulating activity and prostaglandin E2

Author

Toshio Tsushima, Kazuo Shizume, Masanobu Kawakami, Kanji Sato, Yuko Fujii, and Keizo Kasono

Subjects
medicine.medical_specialty, medicine.medical_treatment, Biophysics, Biochemistry, Dinoprostone, Bone resorption, Cell Line, Mice, Internal medicine, medicine, Animals, Macrophage, Prostaglandin E2, Molecular Biology, Glycoproteins, Interleukin 3, Osteoblasts, Cytotoxins, Tumor Necrosis Factor-alpha, Cell growth, Chemistry, Prostaglandins E, Cell Biology, Kinetics, Endocrinology, Cell culture, Interleukin-3, Tumor necrosis factor alpha, Cell Division, Prostaglandin E, medicine.drug
Abstract

To elucidate the mechanism of tumor necrosis factor alpha (TNF-alpha)-induced bone resorption, the effects of recombinant human TNF-alpha on mouse osteoblast-like cells (MC3T3-E1) were studied. TNF-alpha stimulated MC3T3-E1 cells to produce prostaglandin E2 (PGE2) and macrophage colony stimulating activity (M-CSA) in a dose-dependent manner. TNF decreased alkaline phosphatase (AL-P) activity of MC3T3-E1 cells. These TNF effects were observed at 1 ng/ml (approximately 6 X 10(-11)M). The inhibitory effect on AL-P activity was reversible and the cell growth of MC3T3-E1 cells was only slightly affected by TNF. These findings suggest that both PGE2 and M-CSA stimulated by TNF-alpha are possibly involved in osteoblast-mediated osteoclastic bone resorption, whereas inhibition of AL-P activity may lead to a decrease in bone formation.

Published
1987

17. Stimulation of prostaglandin E2 and bone resorption by recombinant human interleukin 1 alpha in fetal mouse bones

Author

Toshio Tsushima, Motoyasu Saji, Kazuo Shizume, Kanji Sato, Yuko Fujii, and Keizo Kasono

Subjects
medicine.medical_specialty, Hydrocortisone, medicine.medical_treatment, Indomethacin, Biophysics, Alpha (ethology), Stimulation, Biochemistry, Bone and Bones, Dinoprostone, Bone resorption, law.invention, Mice, Fetus, Osteogenesis, Pregnancy, law, Internal medicine, medicine, Animals, Bone Resorption, Prostaglandin E2, Molecular Biology, Mice, Inbred C3H, Mice, Inbred ICR, Chemistry, Prostaglandins E, Interleukin, Cell Biology, Recombinant Proteins, Kinetics, Endocrinology, Recombinant DNA, Female, Interleukin-1, medicine.drug, Prostaglandin E
Abstract

Recombinant human interleukin 1 alpha (rhIL-1 alpha) stimulates prostaglandin E2 and bone resorption in cultured forearm bones of fetal mouse in a dose-dependent manner: the minimal rhIL-1 alpha to elicit a significant bone resorption was 1.6 ng/ml (89 pM). The half maximal concentrations to elicit bone resorption and thymocyte proliferation were 3.3 ng/ml (183 pM) and 0.31 ng/ml (17 pM), respectively. The bone resorbing activity induced by IL-1 was partially inhibited by indomethacin and hydrocortisone, and completely inhibited by anti-IL 1-antibody. There was a good correlation between PGE2 production and bone resorption induced by IL-1 alpha. These results suggest that rhIL-1 alpha stimulates bone resorption at approximately 10 times the concentrations necessary for thymocyte proliferation and that PGE2 produced in the bone is at least in part involved in osteoclastic bone resorption.

Published
1986

18. Parathyroid Hormone-Related Protein and Interleukinla 1α Synergistically Stimulate Bone Resorptionin Vitroand Increase the Serum Calcium Concentration in Micein Vivo*

Author

Yoshiharu Kanaji, Keizo Kasono, Kazuo Shizume, Hisashi Kurosawa, Yuko Fujii, Kanji Sato, Toshio Tsushima, Minoru Ozawa, and Hidehito Imamura

Subjects
Male, medicine.medical_specialty, Mice, Nude, chemistry.chemical_element, Parathyroid hormone, Alpha (ethology), In Vitro Techniques, Calcium, Bone resorption, Mice, Endocrinology, In vivo, Teriparatide, Internal medicine, Cyclic AMP, Tumor Cells, Cultured, medicine, Animals, Bone Resorption, Mice, Inbred ICR, Parathyroid hormone-related protein, Osmolar Concentration, Parathyroid Hormone-Related Protein, Interleukin, Drug Synergism, Peptide Fragments, Neoplasm Proteins, Resorption, chemistry, Parathyroid Hormone, Female, Neoplasm Transplantation, hormones, hormone substitutes, and hormone antagonists, Interleukin-1
Abstract

To elucidate the mechanism of humoral hypercalcemia elicited by human esophageal carcinoma cells (EC-GI), which constitutively produced interleukin-1 alpha (IL-1 alpha) and PTH-like factor, the effects of IL-1 alpha and PTH-related protein (PTH-rP) on bone resorption in vitro and on serum calcium concentrations in vivo were investigated. Nude mice transplanted with EC-GI cells invariably developed hypercalcemia, although their urinary cAMP excretion remained within the normal range. IL-1 alpha or PTH-rP-(1-34) stimulated 45Ca release from prelabeled fetal mouse forearm bones in a concentration-dependent manner, and when combined, IL-1 alpha and PTH-rP-(1-34) synergistically stimulated bone resorption in vitro. Injection of PTH-rP-(1-34) into mice three times a day for 2 days increased the serum calcium concentration in a dose-dependent manner. Continuous infusion of IL-1 alpha occasionally increased the serum calcium concentration. Simultaneous administration of IL-1 alpha at rates of 1-2.7 micrograms/day and PTH-rP-(1-34) at doses of 15-30 micrograms/day synergistically increased the serum calcium concentration in vivo. These findings suggest that PTH-rP and IL-1 alpha produced by the tumor cells were synergistically responsible for the humoral hypercalcemia observed in both the original patient and the tumor-bearing nude mice, and that at least two bone-resorbing factors [PTH-rP and another nonadenylate cyclase-stimulating bone-resorbing factor(s)] are active in patients with malignancy-associated hypercalcemia, in whom nephrogenous cAMP excretion is neither increased nor decreased.

Published
1989

19. Thyroid Hormone Stimulates Alkaline Phosphatase Activity in Cultured Osteoblastic Cells with T3 Nuclear Receptors

Author

Yuko Fujii, Kanji Sato, Kazuo Shizume, and Doo Chol Han

Subjects
medicine.medical_specialty, Endocrinology, medicine.anatomical_structure, Nuclear receptor, Chemistry, Internal medicine, Thyroid, medicine, Hyperthyroid patient, Alkaline phosphatase, In patient, Serum alkaline phosphatase, Hormone
Abstract

It is well known that serum alkaline phosphatase (Al-P) activity is frequently increased in patients with Graves’ disease and that the increased Al-P is of bone origin (1). However, the mechanism of hyperphosphatasia had not been elucidated.

Published
1986

20. Recombinant human interleukin 1 alpha and beta stimulate mouse osteoblast-like cells (MC3T3-E1) to produce macrophage-colony stimulating activity and prostaglandin E2

Author

Yuko Fujii, Masanobu Kawakami, Shigetaka Asano, Keizo Kasono, Kazuo Shizume, Kanji Sato, Takemi Ohtsuki, and Toshio Tsushima

Subjects
medicine.medical_specialty, Macromolecular Substances, Biophysics, Alpha (ethology), Calvaria, Biochemistry, Bone resorption, Dinoprostone, law.invention, Cell Line, Mice, Colony-Stimulating Factors, law, Osteoclast, Internal medicine, medicine, Macrophage, Animals, Humans, Prostaglandin E2, Bone Resorption, Molecular Biology, Osteoblasts, Chemistry, Macrophages, Prostaglandins E, Interleukin, Cell Biology, Recombinant Proteins, Cell biology, Endocrinology, medicine.anatomical_structure, Recombinant DNA, medicine.drug, Interleukin-1
Abstract

The effects of interleukin 1 (IL-1) on MC3T3-E1 cells (clonal osteoblast-like cells established from mouse calvaria) were studied to elucidate the mechanism of IL-1-induced bone resorption. Recombinant human interleukin 1 alpha (rhIL-1 alpha) and beta (rhIL-1 beta) stimulated PGE2 production in MC3T3-E1 cells in a dose dependent manner. rhIL-1 alpha and 1 beta also stimulated MC3T3-E1 cells to produce macrophage-colony stimulating activity (M-CSA) in a dose-dependent manner. Indomethacin completely abolished PGE2 production but did not affect CSA. These results suggest that bone resorption induced by IL-1s is at least in part mediated by PGE2 produced by osteoblasts, and that M-CSA produced by osteoblasts may synergistically potentiate bone resorption by recruiting osteoclast precursors.

Published
1986

21. 3,3',5'-Triiodothyronine inhibits iodothyronine-5'-deiodinating activity induced by 3,5,3'-triiodothyronine at equimolar concentrations in cultured fetal mouse liver

Author

Toshio Tsushima, Doo Chol Han, Yuko Fujii, Kanji Sato, and Kazuo Shizume

Subjects
endocrine system, medicine.medical_specialty, Triiodothyronine, Reverse, medicine.medical_treatment, Iodide Peroxidase, chemistry.chemical_compound, Mice, Endocrinology, Organ Culture Techniques, Malate Dehydrogenase, Pregnancy, Internal medicine, medicine, Animals, Malic enzyme activity, Fetus, Triiodothyronine, biology, Dose-Response Relationship, Drug, Insulin, Biological activity, Metabolism, Glutathione, Enzyme assay, Reverse triiodothyronine, Kinetics, chemistry, Liver, biology.protein, Female, hormones, hormone substitutes, and hormone antagonists
Abstract

To investigate the rT3 effect on iodothyronine-5'-deiodinating activity (I-5'-DA) in cultured fetal mouse liver, liver on the 19th day of gestation, in which little or no I-5'-DA was detected and, therefore, rT3 was very stable, was cultured in medium containing thyroid hormone-depleted fetal calf serum supplemented with cortisol, insulin, and various concentrations of iodothyronines. After 4-15 days of culture, I-5'-DA in the homogenate was assessed by the amount of iodide released from outer ring-labeled rT3 and expressed as picomoles of 127I- per mg protein/min. I-5'-DA was induced by T3 (10(-9)-10(-8) M) and T4 (10(-7) M). In contrast, rT3 could not induce I-5'-DA at 10(-8)-10(-6) M. Furthermore, rT3 significantly decreased I-5'-DA induced by T3 (10(-8) M) at almost equimolar concentrations (1-5 X 10(-8) M). The inhibitory action of rT3 was reversible and was specific for I-5'-DA; no alteration in malic enzyme activity or intracellular glutathione concentration was detected. The inhibitory effect of rT3 on I-5'-DA was dose dependent, and the enzyme activity decreased with a half-life of 16 h in the presence of 10(-6) M rT3. The inhibitory effect was not due to contaminating rT3 in the liver homogenates. Lineweaver-Burk analysis revealed that the decrease in I-5'-DA was due to a decrease in the maximum velocity, whereas no alteration in Km was detected, suggesting that rT3 decreases the amount of 5'-deiodinase induced by T3. The minimal free rT3 concentration capable of inhibiting the induction of iodothyronine-5'-deiodinase was approximately 10(-10) M, which may be attainable in vivo, as in amnionic fluid. In summary, we have demonstrated that rT3 exerts a strong antagonistic effect against T3 in inducing I-5'-DA in cultured fetal mouse liver.

Published
1986

22. 3,3′,5′-Triiodothyronine (rT3) Inhibits Iodothyronine-5′-Deiodinating Activity Induced by Equimolar Concentration of 3,5,3′-Triiodothyronine (T3) in Cultured Fetal Liver of Mouse

Author

Toshio Tsushima, Kanji Sato, Kazou Shizume, Doo Chol Han, and Yuko Fujii

Subjects
endocrine system, Fetus, medicine.medical_specialty, Hormone activity, Triiodothyronine, biology, Chemistry, Thyroid, Enzyme assay, In vitro, Endocrinology, medicine.anatomical_structure, Internal medicine, medicine, biology.protein, Gestation, hormones, hormone substitutes, and hormone antagonists, Glucocorticoid, medicine.drug
Abstract

rT3 is generally considered to be without thyroid hormone activity at physiological concentrations and to play no significant physiological role. However, several agonistic and antagonistic effects of rT3 were reported at supraphysiological doses (1,2). As is well known, there exists little or no iodothyronine-5′-deiodinating activity (I-5′-DA) in the fetal liver of rodents (3). The enzyme activity rapidly increases after birth and peaks at 3–4 weeks in the case of mouse (4). We recently demonstrated that this ontogenetic development of iodothyronine-5′-deiodinase in the liver can also be induced in vitro by physiological concentrations of glucocorticoid and thyroid hormones (5). To investigate the rT3 effect on I-5′-DA, fetal liver of mouse on the 19th day of gestation, in which little or no I-5′-DA was detected and, therefore, rT3 was very stable, was cultured for 3–15 days, and I-5′-DA was determined in liver homogenate.

Published
1986

23. 3,3',5'-Triiodothyronine inhibits ontogenetic development of iodothyronine-5'-deiodinase in the liver of the neonatal mouse

Author

Kazuo Shizume, Toshio Tsushima, Yuko Fujii, Minoru Ozawa, Kanji Sato, Hidehito Imamura, and Doo Chol Han

Subjects
medicine.medical_specialty, Triiodothyronine, Reverse, Endocrinology, Diabetes and Metabolism, Microgram, Deiodinase, Mice, Inbred Strains, Iodide Peroxidase, Mice, Endocrinology, In vivo, Internal medicine, Mole, medicine, Animals, chemistry.chemical_classification, Triiodothyronine, biology, Dose-Response Relationship, Drug, Chemistry, General Medicine, Enzyme assay, In vitro, Enzyme, Liver, biology.protein
Abstract

To elucidate the effect of rT3 on iodothyronine-5′-deiodinating activity (I-5′-DA) in the liver of neonatal mice, rT3 was injected sc on the 5–8th day after birth and I-5′-DA in the liver was determined. A single injection of rT3 (0.01–1 μg/g) inhibited the ontogenetically developing I-5′-DA in a dose- and time-dependent manner. The inhibitory effect was reversible and specific for I-5′-DA. Lineweaver-Burk analysis revealed that the time- and dose-dependent decrease in the enzyme activity was due to a decrease in Vmax with no alteration in Km values (5 × 10−8 mol/l). The maximal inhibitory effect was observed at a dose of 1 μg rT3/g, whereas the inhibitory effect was diminished at greater doses (4–10 μg/g), probably owing to a contamination with T4 of the rT3 preparation administered. Furthermore, consistent with our previous in vitro findings, rT3 inhibited the I-5′-DA induced by T3 in the liver of neonatal mice. These findings suggest that rT3 inhibited I-5′-DA in the liver of neonatal mice by decreasing the amount of enzyme available to the substrate and that rT3 also elicited an antagonistic effect against T3 in the induction of I-5′-DA in vivo.

Published
1988

24. Production of interleukin-1 alpha and a parathyroid hormone-like factor by a squamous cell carcinoma of the esophagus (EC-GI) derived from a patient with hypercalcemia

Author

Kazuo Shizume, Kanji Sato, Toshio Tsushima, Yuko Fujii, and Keizo Kasono

Subjects
Male, medicine.medical_specialty, Esophageal Neoplasms, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Indomethacin, Parathyroid hormone, Mice, Nude, Biology, Biochemistry, Mice, Endocrinology, Internal medicine, medicine, Animals, Humans, Northern blot, Bone Resorption, Aged, Antiserum, Chromatography, Biochemistry (medical), Interleukin, DNA, Transplantation, Thymocyte, Sephadex, Cell culture, Parathyroid Hormone, Carcinoma, Squamous Cell, Hypercalcemia, Isoelectric Focusing, Interleukin-1
Abstract

To determine the pathogenesis of humoral hypercalcemia associated with esophageal carcinoma in a 65-yr-old patient, clonal cell lines (EC-GI) were established from the tumor. The EC-GI cells produced bone-resorbing activity which eluted from a Sephadex G-75 column in a broad peak, with an apparent mol wt of 10,000-50,000. In addition to PTH-like factor(s), the EC-GI cells produced a factor with thymocyte proliferation-stimulating activity which had an apparent mol wt of 15,000-20,000. This interleukin-1 (IL-1)-like factor(s) with acidic pI (4.8 and 5.2) exactly coeluted with the bone-resorbing activity upon DEAE-Sepharose ion exchange chromatography. Both bone-resorbing and thymocyte proliferation-stimulating activities were completely inhibited by anti-IL-1 alpha antiserum, but not by anti-IL-1 beta antiserum. Northern blot hybridization studies revealed that EC-GI cells produced exclusively mRNA for IL-1 alpha. Furthermore, fractions containing IL-1-like activity and PTH-like activity synergistically stimulated bone resorption in vitro, and transplantation of EC-GI cells into nude mice caused hypercalcemia in vivo. These findings suggest that IL-1 alpha and PTH-like factor produced by this squamous cell carcinoma synergistically stimulate bone resorption and are related to humoral hypercalcemia in tumor-bearing nude mice and in the patient.

Published
1988

25. Thyroid hormone stimulates alkaline phosphatase activity in cultured rat osteoblastic cells (ROS 17/2.8) through 3,5,3'-triiodo-L-thyronine nuclear receptors

Author

Kanji Sato, Kazuo Shizume, Doo Chol Han, Toshio Tsushima, and Yuko Fujii

Subjects
medicine.medical_specialty, Thyroid Hormones, Hydrocortisone, Triiodothyronine, Reverse, Biology, Cell Line, chemistry.chemical_compound, Endocrinology, Internal medicine, medicine, Animals, Cycloheximide, Receptor, Triiodothyronine, Osteoblasts, Receptors, Thyroid Hormone, Thyroid, Osteoblast, Alkaline Phosphatase, Rats, Thyroxine, medicine.anatomical_structure, chemistry, Nuclear receptor, Thyronine, Dactinomycin, Alkaline phosphatase, Cell Division, Hormone
Abstract

To investigate the increased alkaline phosphatase activity of bone origin in patients with hyperthyroidism, we studied the thyroid hormone effects on alkaline phosphatase activity in a clonal rat osteoblastic cell line (ROS 17/2.8). T4 and T3 increased alkaline phosphatase activity in ROS 17/2.8 cells in a dose-dependent manner. The minimal effective T4 and T3 concentrations in medium containing 10% thyroid hormone-depleted fetal calf serum were 10(-8) M (free T4, 8 X 10(-11) M) and 10(-9) M (free T3, 4 X 10(-11) M), respectively. ROS 17/2.8 cells possessed high affinity, low capacity nuclear receptors specific for T3 [dissociation constant (Kd) approximately 150 pM; maximal binding capacity, approximately 2000 T3 binding sites per nucleus]. The relative affinity of T3, T4, rT3, MIT, and DIT were in good agreement with their biological activity. These findings suggest that rat osteoblast-like cells contain T3 nuclear receptors and that alkaline phosphatase activity is stimulated by thyroid hormone via a nuclear receptor-mediated process at free thyroid hormone concentrations attainable in patients with Graves' disease.

Published
1987

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