{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T07:10:38Z","timestamp":1791443438420,"version":"4.3.3"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2018,9,29]],"date-time":"2018-09-29T00:00:00Z","timestamp":1538179200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["H14-Shouni-006"],"award-info":[{"award-number":["H14-Shouni-006"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Medical Association Center","award":["CCT-B-1803"],"award-info":[{"award-number":["CCT-B-1803"]}]},{"name":"Japan Medical Association Center","award":["CCT-C-2001"],"award-info":[{"award-number":["CCT-C-2001"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Neurol"],"published-print":{"date-parts":[[2018,12]]},"DOI":"10.1007\/s00415-018-9057-7","type":"journal-article","created":{"date-parts":[[2018,9,29]],"date-time":"2018-09-29T00:17:31Z","timestamp":1538180251000},"page":"2861-2874","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Therapeutic regimen of l-arginine for MELAS: 9-year, prospective, multicenter, clinical research"],"prefix":"10.1007","volume":"265","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6664-1295","authenticated-orcid":false,"given":"Yasutoshi","family":"Koga","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataliya","family":"Povalko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eisuke","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidefumi","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Yoneda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumio","family":"Kanda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisashi","family":"Okada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsunori","family":"Fujii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,29]]},"reference":[{"issue":"26","key":"9057_CR1","doi-asserted-by":"publisher","first-page":"2656","DOI":"10.1056\/NEJMra022567","volume":"348","author":"S DiMauro","year":"2003","unstructured":"DiMauro S, Schon EA (2003) Mitochondrial respiratory-chain diseases. N Engl J Med 348(26):2656\u20132668","journal-title":"N Engl J Med"},{"issue":"3","key":"9057_CR2","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1212\/WNL.0b013e31829bfe89","volume":"81","author":"S DiMauro","year":"2013","unstructured":"DiMauro S (2013) Mitochondrial encephalomyopathies\u00ef\u00a3\u00a7fifty years on: the Robert Wartenberg lecture. Neurology 81(3):281\u2013291","journal-title":"Neurology"},{"issue":"3","key":"9057_CR3","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1093\/jnen\/62.3.217","volume":"62","author":"A Oldfors","year":"2003","unstructured":"Oldfors A, Tulinius M (2003) Mitochondrial encephalomyopathies. J Neuropathol Exp Neurol 62(3):217\u2013227","journal-title":"J Neuropathol Exp Neurol"},{"issue":"4","key":"9057_CR4","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1002\/ana.410160409","volume":"16","author":"SG Pavlakis","year":"1984","unstructured":"Pavlakis SG, Phillips PC, DiMauro S et al (1984) Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann Neurol 16(4):481\u2013488","journal-title":"Ann Neurol"},{"issue":"1","key":"9057_CR5","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1002\/ajmg.1426","volume":"106","author":"PF Chinnery","year":"2001","unstructured":"Chinnery PF, Turnbull DM (2001) Epidemiology and treatment of mitochondrial disorders. Am J Med Genet 106(1):94\u2013101","journal-title":"Am J Med Genet"},{"issue":"5","key":"9057_CR6","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/j.bbagen.2011.03.015","volume":"1820","author":"S Yatsuga","year":"2012","unstructured":"Yatsuga S, Povalko N, Nishioka J, For MELAS Study Group in Japan et al (2012) MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta 1820(5):619\u2013624","journal-title":"Biochim Biophys Acta"},{"issue":"6","key":"9057_CR7","doi-asserted-by":"publisher","first-page":"456","DOI":"10.5414\/CN107063","volume":"80","author":"A Seidowsky","year":"2013","unstructured":"Seidowsky A, Hoffmann M, Glowacki F et al (2013) Renal involvement in MELAS syndrome\u2014a series of 5 cases and review of the literature. Clin Nephrol 80(6):456\u2013663","journal-title":"Clin Nephrol"},{"issue":"1","key":"9057_CR8","doi-asserted-by":"publisher","first-page":"29","DOI":"10.2174\/1567202052773544","volume":"2","author":"T Iizuka","year":"2005","unstructured":"Iizuka T, Sakai F (2005) Pathogenesis of stroke-like episodes in MELAS: analysis of neurovascular cellular mechanisms. Curr Neurovasc Res 2(1):29\u201345","journal-title":"Curr Neurovasc Res"},{"issue":"5","key":"9057_CR9","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1212\/WNL.58.5.827","volume":"58","author":"Y Koga","year":"2002","unstructured":"Koga Y, Ishibashi M, Ueki I et al (2002) Effects of l-arginine on the acute phase of strokes in three patients with MELAS. Neurology 58(5):827\u2013828","journal-title":"Neurology"},{"issue":"4","key":"9057_CR10","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1212\/01.WNL.0000151976.60624.01","volume":"64","author":"Y Koga","year":"2005","unstructured":"Koga Y, Akita Y, Nishioka J et al (2005) l-Arginine improves the symptoms of stroke-like episodes in MELAS. Neurology 64(4):710\u2013712","journal-title":"Neurology"},{"issue":"11","key":"9057_CR11","doi-asserted-by":"publisher","first-page":"1766","DOI":"10.1212\/01.wnl.0000220197.36849.1e","volume":"66","author":"Y Koga","year":"2006","unstructured":"Koga Y, Akita Y, Junko N et al (2006) Endothelial dysfunction in MELAS improved by l-arginine supplementation. Neurology 66(11):1766\u20131769","journal-title":"Neurology"},{"issue":"1\u20132","key":"9057_CR12","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.mito.2006.11.006","volume":"7","author":"Y Koga","year":"2007","unstructured":"Koga Y, Akita Y, Nishioka J et al (2007) MELAS and l-arginine therapy. Mitochondrion 7(1\u20132):133\u2013139","journal-title":"Mitochondrion"},{"key":"9057_CR13","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1111\/j.1749-6632.2010.05624.x","volume":"1201","author":"Y Koga","year":"2010","unstructured":"Koga Y, Povalko N, Nishioka J et al (2010) MELAS and l-arginine therapy: pathophysiology of stroke-like episodes. Ann N Y Acad Sci 1201:104\u2013110","journal-title":"Ann N Y Acad Sci"},{"issue":"5","key":"9057_CR14","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1016\/j.bbagen.2011.09.005","volume":"1820","author":"Y Koga","year":"2012","unstructured":"Koga Y, Povalko N, Nishioka J et al (2012) Molecular pathology of MELAS and l-arginine effects. Biochim Biophys Acta 1820(5):608\u2013614","journal-title":"Biochim Biophys Acta"},{"key":"9057_CR15","unstructured":"DiMauro S, Hirano M. Adam MP et al (1993) Seattle (WA), University of Washington Seattle, GeneReviews\u00ae [Internet]. \n                    https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1233\/\n                    \n                  . Accessed 21 Nov 2013"},{"issue":"12","key":"9057_CR16","doi-asserted-by":"publisher","first-page":"1932","DOI":"10.1212\/01.wnl.0000219759.72195.41","volume":"66","author":"AM Schaefer","year":"2006","unstructured":"Schaefer AM, Phoenix C, Elson JL et al (2006) Mitochondrial disease in adults: a scale to monitor progression and treatment. Neurology 66(12):1932\u20131934","journal-title":"Neurology"},{"issue":"4","key":"9057_CR17","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1093\/biomet\/75.4.800","volume":"75","author":"Y Hochberg","year":"1988","unstructured":"Hochberg Y (1988) A sharper Bonferroni procedure for multiple significance testing. Biometrika 75(4):800\u2013802","journal-title":"Biometrika"},{"issue":"5","key":"9057_CR18","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1001\/jamaneurol.2015.5072","volume":"73","author":"MK Koenig","year":"2016","unstructured":"Koenig MK, Emrick L, Karaa A et al (2016) Recommendations for the management of strokelike episodes in patients with mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes. JAMA Neurol 73(5):591\u2013594","journal-title":"JAMA Neurol"},{"issue":"6 Suppl 2","key":"9057_CR19","doi-asserted-by":"publisher","first-page":"1650S","DOI":"10.1093\/jn\/137.6.1650S","volume":"137","author":"RH B\u00f6ger","year":"2007","unstructured":"B\u00f6ger RH (2007) The pharmacodynamics of l-arginine. J Nutr 137(6 Suppl 2):1650S\u20131655S","journal-title":"J Nutr"},{"issue":"1","key":"9057_CR20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0021-9150(96)05953-9","volume":"127","author":"RH B\u00f6ger","year":"1996","unstructured":"B\u00f6ger RH, Bode-B\u00f6ger SM, Fr\u00f6lich JC (1996) The l-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications. Atherosclerosis 127(1):1\u201311","journal-title":"Atherosclerosis"},{"issue":"18","key":"9057_CR21","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1161\/01.CIR.98.18.1842","volume":"98","author":"RH B\u00f6ger","year":"1998","unstructured":"B\u00f6ger RH, Bode-B\u00f6ger SM, Szuba A et al (1998) Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 98(18):1842\u20131847","journal-title":"Circulation"},{"issue":"24","key":"9057_CR22","doi-asserted-by":"publisher","first-page":"3092","DOI":"10.1161\/01.CIR.99.24.3092","volume":"99","author":"A Ito","year":"1999","unstructured":"Ito A, Tsao PS, Adimoolam S et al (1999) Novel mechanism for endothelial dysfunction dysregulation of dimethylarginine dimethylaminohydrolase. Circulation 99(24):3092\u20133095","journal-title":"Circulation"},{"issue":"1","key":"9057_CR23","doi-asserted-by":"publisher","first-page":"55","DOI":"10.2147\/vhrm.1.1.55.58939","volume":"1","author":"H Ding","year":"2005","unstructured":"Ding H, Triggle CR (2005) Endothelial cell dysfunction and the vascular complications associated with type 2 diabetes: assessing the health of the endothelium. Vasc Health Risk Manag 1(1):55\u201371","journal-title":"Vasc Health Risk Manag"},{"issue":"2","key":"9057_CR24","first-page":"2002","volume":"329","author":"S Moncada","year":"1993","unstructured":"Moncada S, Higgs A (1993) The l-arginine-nitric oxide pathway. N Engl J Med 329(2):2002\u20132012","journal-title":"N Engl J Med"},{"issue":"3","key":"9057_CR25","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1161\/01.CIR.0000046489.24563.79","volume":"107","author":"PM Piatti","year":"2003","unstructured":"Piatti PM, Fragasso G, Monti LD et al (2003) Acute intravenous l-arginine infusion decreases endothelin-1 levels and improves endothelial function in patients with angina pectoris and normal coronary arteriograms. Circulation 107(3):429\u2013436","journal-title":"Circulation"},{"issue":"3","key":"9057_CR26","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1016\/S0735-1097(99)00602-6","volume":"35","author":"R Hambrecht","year":"2000","unstructured":"Hambrecht R, Hilbrich L, Erbs S et al (2000) Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral l-arginine supplementation. J Am Coll Cardiol 35(3):706\u2013713","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"9057_CR27","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1111\/j.1365-2990.2006.00731.x","volume":"32","author":"J Betts","year":"2006","unstructured":"Betts J, Jaros E, Perry RH et al (2006) Molecular neuropathology of MELAS: level of heteroplasmy in individual neurons and evidence of extensive vascular involvement. Neuropathol Appl Neurobiol 32(4):359\u2013373","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"2","key":"9057_CR28","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1136\/jcp.2008.061267","volume":"62","author":"B Paepe De","year":"2009","unstructured":"De Paepe B, Smet J, Lammens M et al (2009) Immunohistochemical analysis of the oxidative phosphorylation complexes in skeletal muscle from patients with mitochondrial DNA encoded tRNA gene defects. J Clin Pathol 62(2):172\u2013176","journal-title":"J Clin Pathol"},{"issue":"5","key":"9057_CR29","doi-asserted-by":"publisher","first-page":"e0127066","DOI":"10.1371\/journal.pone.0127066","volume":"10","author":"LH Rodan","year":"2015","unstructured":"Rodan LH, Wells GD, Banks L et al (2015) l-Arginine affects aerobic capacity and muscle metabolism in MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. PLoS One 10(5):e0127066","journal-title":"PLoS One"},{"issue":"8","key":"9057_CR30","doi-asserted-by":"publisher","first-page":"1666","DOI":"10.1007\/s00415-016-8069-4","volume":"263","author":"M Kitamura","year":"2016","unstructured":"Kitamura M, Yatsuga S, Abe T et al (2016) l-Arginine intervention at hyper-acute phase protects the prolonged MRI abnormality in MELAS. J Neurol 263(8):1666\u20131668","journal-title":"J Neurol"},{"issue":"6","key":"9057_CR31","doi-asserted-by":"publisher","first-page":"e8262","DOI":"10.15252\/emmm.201708262","volume":"10","author":"JP Grady","year":"2018","unstructured":"Grady JP, Pickett SJ, Ng YS et al (2018) mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol Med 10(6):e8262","journal-title":"EMBO Mol Med"}],"container-title":["Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s00415-018-9057-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-018-9057-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s00415-018-9057-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,9,28]],"date-time":"2019-09-28T19:14:00Z","timestamp":1569698040000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s00415-018-9057-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,29]]},"references-count":31,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2018,12]]}},"alternative-id":["9057"],"URL":"https:\/\/doi.org\/10.1007\/s00415-018-9057-7","relation":{},"ISSN":["0340-5354","1432-1459"],"issn-type":[{"value":"0340-5354","type":"print"},{"value":"1432-1459","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,29]]},"assertion":[{"value":"3 July 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2018","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 September 2018","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2018","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"The authors declare that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The research was performed at 10 medical institutions in Japan in accordance with international guidelines, including the Declaration of Helsinki, Good Clinical Practice, and Council for International Organizations of Medical Sciences, International Ethical Guidelines (NCT02367014). The study protocol was approved by individual institutional review committees.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical standards"}},{"value":"Written informed consent was obtained from all subjects or from his or her legal representative prior to enrolment.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Informed consent"}}]}}