52 results on '"Mika Ishige"'
Search Results
2. Safety, efficacy and pharmacokinetics of palivizumab in off-label neonates, infants, and young children at risk for serious respiratory syncytial virus infection: a multicenter phase II clinical trialResearch in context
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Masaaki Mori, Kanako Yoshizaki, Shinichi Watabe, Mika Ishige, Akinari Hinoki, Takuya Kondo, Tomoaki Taguchi, Hisaya Hasegawa, Tomoko Hatata, Naoyuki Tanuma, Kosuke Kirino, Akihiro Hirakawa, Takuya Naruto, Minoru Imai, Ryuji Koike, Kenichiro Hosoi, and Satoshi Kusuda
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Airway stenosis ,Congenital esophageal atresia ,Efficacy ,Inherited metabolic disease ,Neuromuscular disease ,Palivizumab ,Public aspects of medicine ,RA1-1270 - Abstract
Summary: Background: Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan. Methods: This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days. Findings: Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period. Interpretation: Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study. Funding: Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.
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- 2023
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3. Clinical perspective on the use of human amniotic epithelial cells to treat congenital metabolic diseases with a focus on maple syrup urine disease
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Chika Takano, Brendan H. Grubbs, Mika Ishige, Erika Ogawa, Ichiro Morioka, Satoshi Hayakawa, and Toshio Miki
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cell transplantation ,cellular therapy ,liver regeneration ,placenta ,stem cell transplantation ,Medicine (General) ,R5-920 ,Cytology ,QH573-671 - Abstract
Abstract Congenital metabolic diseases are a group of hereditary disorders caused by the deficiency of a single specific enzyme activity. Without appropriate therapy, affected patients suffer severe neurologic disability and eventual death. The current mainstays of management attempt to slow disease progression, but are not curative. Several of these diseases have demonstrated significant benefits from liver transplantation; however, this approach is limited by the morbidity associated with this invasive procedure and a shortage of donor organs. Therefore, there is a need to establish a new strategy for improving the quality of a life for these patients. One potential solution is regenerative therapy using hepatocytes generated from stem cells. Herein, we discuss pertinent issues necessary for clinical application of the human amniotic epithelial cell, a type of placental stem cell. Focusing on maple syrup urine disease as an example, where liver replacement is an effective therapy, we explore this approach from a clinician's perspective.
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- 2021
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4. Study protocol: a multicenter, uncontrolled, open-label study of palivizumab in neonates, infants, and preschool children at high risk of severe respiratory syncytial virus infection
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Masaaki Mori, Shinichi Watabe, Tomoaki Taguchi, Hisaya Hasegawa, Mika Ishige, Naoyuki Tanuma, Akihiro Hirakawa, Ryuji Koike, and Satoshi Kusuda
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Airway stenosis ,Congenital esophageal atresia ,Efficacy ,Inherited metabolic disease ,Neuromuscular disease ,Palivizumab ,Pediatrics ,RJ1-570 - Abstract
Abstract Background The prophylactic use of anti-respiratory syncytial virus (RSV) antibody (palivizumab) for severe RSV infection is not approved in Japan in specified groups of infants with neuromuscular diseases or other rare diseases associated with reduced ventilation competence or difficulty in expectoration, which increase the risk of exacerbation of severe RSV infection. The objective of this study is to investigate the efficacy, safety, and pharmacokinetics of palivizumab in pediatric patients with those rare diseases for which palivizumab is not indicated at present. Methods/design This study is a multicenter, uncontrolled, open-label study planned to be carried out between July 1, 2019 and June 30, 2022 at 7 medical institutions in Japan. The study population will be recruited from among neonates, infants, or children aged 24 months or younger with a condition falling under any of the following 5 disease groups: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. The planned sample size is 18 subjects, including at least 3 subjects per disease group. Throughout the RSV season, at least 4 continuous doses of palivizumab will be administered intramuscularly at 15 mg/kg at intervals of 30 days. The efficacy and safety of palivizumab will be comprehensively evaluated based on the incidence of RSV-related hospitalization, and serum palivizumab concentration, serum anti-palivizumab antibody concentration, and the occurrence of adverse events/reactions after the start of palivizumab treatment. Discussion This study will evaluate the efficacy and safety of palivizumab in pediatric patients with rare diseases which place them at high risk of severe RSV infection, but which fall outside the current indications for palivizumab prophylaxis. The generated data will have implications for the regulatory approval of prophylactic palivizumab treatment in this patient group. Trial registration This study has been prospectively registered in Japic Clinical Trials Information, which is managed and administered by the Japan Pharmaceutical Information Center (registration number: JapicCTI-194946 , registration date: September 10, 2019).
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- 2021
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5. Umbilical artery tissue contains p75 neurotrophin receptor-positive pericyte-like cells that possess neurosphere formation capacity and neurogenic differentiation potential
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Rina Fujii-Tezuka, Mika Ishige-Wada, Narihito Nagoshi, Hideyuki Okano, Hideo Mugishima, Shori Takahashi, Ichiro Morioka, and Taro Matsumoto
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Umbilical cord ,p75 neurotrophin receptor ,Neurosphere ,Neural crest stem cells ,Mesenchymal stem cells ,Medicine (General) ,R5-920 ,Cytology ,QH573-671 - Abstract
Introduction: The p75 neurotrophin receptor (p75NTR) is known as an efficient marker for the prospective isolation of mesenchymal stem cells (MSCs) and neural crest-derived stem cells (NCSCs). To date, there is quite limited information concerning p75NTR-expressing cells in umbilical cord (UC), although UC is known as a rich source of MSCs. We show for the first time the localization, phenotype, and functional properties of p75NTR+ cells in UC. Methods: Human UC tissue sections were subjected to immunohistochemistry for MSC markers including p75NTR. Enzymatically isolated umbilical artery (UA) cells containing p75NTR+ cells were assessed for immunophenotype, clonogenic capacity, and differentiation potential. To identify the presence of neural crest-derived cells in the UA, P0-Cre/Floxed-EGFP reporter mouse embryos were used, and immunohistochemical analysis of UC tissue was performed. Results: Immunohistochemical analysis revealed that p75NTR+ cells were specifically localized to the subendothelial area of the UA and umbilical vein. The p75NTR+ cells co-expressed PDGFRβ, CD90, CD146, and NG2, phenotypic markers of MSCs and pericytes. Isolated UA cells possessed the potential to form neurospheres that further differentiated into neuronal and glial cell lineages. Genetic lineage tracing analysis showed that EGFP+ neural crest-derived cells were detected in the subendothelial area of UA with p75NTR immunoreactivity. Conclusions: These results show that UA tissue harbors p75NTR+ pericyte-like cells in the subendothelial area that have the capacity to form neurospheres and the potential for neurogenic differentiation. The lineage tracing data suggests the p75NTR+ cells are putatively derived from the neural crest.
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- 2021
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6. Isolation and characterization of neural crest-like progenitor cells in human umbilical cord blood
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Zena Al-Bakri, Mika Ishige-Wada, Noboru Fukuda, Chikako Yoshida-Noro, Narihito Nagoshi, Hideyuki Okano, Hideo Mugishima, and Taro Matsumoto
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Neural crest stem cells ,Umbilical cord blood ,p75 neurotrophin receptor ,Cell therapy ,Medicine (General) ,R5-920 ,Cytology ,QH573-671 - Abstract
Introduction: Neural crest (NC)-like stem/progenitor cells provide an attractive cell source for regenerative medicine because of their multipotent property and ease of isolation from adult tissue. Although human umbilical cord blood (HUCB) is known to be a rich source of stem cells, the presence of the NC-like stem/progenitor cells in HUCB remains to be elucidated. In this study, we have isolated NC-like progenitor cells using an antibody to p75 neurotrophin receptor (p75NTR) and examined their phenotype and stem cell function in vitro. Methods: To confirm whether p75NTR+ NC-derived cells are present in cord blood, flow cytometric analysis of cord blood derived from P0-Cre/Floxed-EGFP reporter mouse embryos was performed. Freshly isolated HUCB mononuclear cells was subjected to flow cytometry to detect p75NTR+ cells and determined their immunophenotype. HUCB p75NTR+ cells were then collected by immunomagnetic separation and their immunophenotype, clonogenic potential, gene expression profile, and multilineage differentiation potential were examined. Results: NC-derived EGFP+ cells co-expressing p75NTR was detected in cord blood of P0-Cre/Floxed-EGFP reporter mice. We found that freshly isolated HUCB mononuclear cells contained 0.23% of p75NTR+ cells. Isolated p75NTR+ cells from HUCB efficiently formed neurospheres and could differentiate into neuronal and glial cell lineages. The p75NTR+ cells expressed a set of NC-associated genes and undifferentiated neural cell marker genes before and after the culture. Conclusions: These findings revealed that HUCB contained the p75NTR+ NC-like progenitor cell population which have the self-renewal capacity and the potential to differentiate into both neuronal and glial cell lineages.
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- 2020
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7. Physical, cognitive, and social status of patients with urea cycle disorders in Japan
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Jun Kido, Shirou Matsumoto, Tetsuya Ito, Shinichi Hirose, Kaori Fukui, Kanako Kojima-Ishii, Yuichi Mushimoto, Shinobu Yoshida, Mika Ishige, Norio Sakai, and Kimitoshi Nakamura
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Developmental disability ,Intellectual disability ,Physical manifestation ,Urea cycle disorders ,Social support ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.
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- 2021
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8. Nutrient management in the intrapartum period in maternal maple syrup urine disease
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Chika Takano, Mika Ishige, Erika Ogawa, Nobuhiko Nagano, Tamaki Morohashi, Aya Okahashi, Kaori Kawakami, Atsushi Komatsu, Kei Kawana, Tatsuhiko Urakami, and Ichiro Morioka
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Diet therapy ,Maple syrup urine disease ,Perinatal management ,Uterine fibroid ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Women with congenital amino acid disorders, including maple syrup urine disease (MSUD), are at risk of metabolic crisis at delivery. There are still only a few case reports of maternal MSUD globally, and we are the first to report the successful perinatal management of a woman with classical MSUD in Japan. A healthy baby was delivered by scheduled cesarean section despite the presence of several uterine fibroids. With precise diet therapy and accurate preparation, she completed the postpartum period without metabolic decompensation. Although her clinical outcome was favorable, she experienced hypoproteinemia at delivery because the available branched-chain amino acid-free medical food did not contain sufficient protein to meet the recommended nutrient intake. Therefore, this case also indicates a potential issue regarding a shortage of variations in specific amino acid-free medical food in Japan, which should be addressed to achieve a better nutrient status of adults with MSUD and other amino acid disorders.
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- 2021
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9. Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan
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Kenji Yamada, Hideaki Shiraishi, Eishin Oki, Mika Ishige, Toshiyuki Fukao, Yusuke Hamada, Norio Sakai, Fumihiro Ochi, Asami Watanabe, Sanae Kawakami, Kazuyo Kuzume, Kenji Watanabe, Koji Sameshima, Kiyotaka Nakamagoe, Akira Tamaoka, Naoko Asahina, Saki Yokoshiki, Takashi Miyakoshi, Kota Ono, Koji Oba, Toshiyuki Isoe, Hiroshi Hayashi, Seiji Yamaguchi, and Norihiro Sato
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires). Results: The frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed. Conclusion: In this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations. Keywords: Bezafibrate, Fatty acid oxidation disorders (FAODs), Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase-II (CPT-2) deficiency, Clinical trial
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- 2018
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10. Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan; 2nd report QOL survey
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Hideaki Shiraishi, Kenji Yamada, Eishin Oki, Mika Ishige, Toshiyuki Fukao, Yusuke Hamada, Norio Sakai, Fumihiro Ochi, Asami Watanabe, Sanae Kawakami, Kazuyo Kuzume, Kenji Watanabe, Koji Sameshima, Kiyotaka Nakamagoe, Akira Tamaoka, Naoko Asahina, Saki Yokoshiki, Takashi Miyakoshi, Koji Oba, Toshiyuki Isoe, Hiroshi Hayashi, Seiji Yamaguchi, and Norihiro Sato
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9 years; range, 5.8–26.4 years). The bezafibrate administration was continued for a further 102–174 weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. Results: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20 years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases. Conclusion: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs. Keywords: Bezafibrate, Fatty acid oxidation disorders (FAODs), Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase-II (CPT-2) deficiency, Clinical trial, Quality of life
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- 2019
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11. Jagged-1 Signaling in the Bone Marrow Microenvironment Promotes Endothelial Progenitor Cell Expansion and Commitment of CD133+ Human Cord Blood Cells for Postnatal Vasculogenesis.
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Mika Ishige-Wada, Sang-Mo Kwon, Masamichi Eguchi, Katsuto Hozumi, Hideki Iwaguro, Taro Matsumoto, Noboru Fukuda, Hideo Mugishima, Haruchika Masuda, and Takayuki Asahara
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Medicine ,Science - Abstract
Notch signaling is involved in cell fate decisions during murine vascular development and hematopoiesis in the microenvironment of bone marrow. To investigate the close relationship between hematopoietic stem cells and human endothelial progenitor cells (EPCs) in the bone marrow niche, we examined the effects of Notch signals [Jagged-1 and Delta-like ligand (Dll)-1] on the proliferation and differentiation of human CD133+ cell-derived EPCs. We established stromal systems using HESS-5 murine bone marrow cells transfected with human Jagged-1 (hJagged-1) or human Dll-1 (hDll-1). CD133+ cord blood cells were co-cultured with the stromal cells for 7 days, and then their proliferation, differentiation, and EPC colony formation was evaluated. We found that hJagged-1 induced the proliferation and differentiation of CD133+ cord blood EPCs. In contrast, hDll-1 had little effect. CD133+ cells stimulated by hJagged-1 differentiated into CD31+/KDR+ cells, expressed vascular endothelial growth factor-A, and showed enhanced EPC colony formation compared with CD133+ cells stimulated by hDll-1. To evaluate the angiogenic properties of hJagged-1- and hDll-1-stimulated EPCs in vivo, we transplanted these cells into the ischemic hindlimbs of nude mice. Transplantation of EPCs stimulated by hJagged-1, but not hDll-1, increased regional blood flow and capillary density in ischemic hindlimb muscles. This is the first study to show that human Notch signaling influences EPC proliferation and differentiation in the bone marrow microenvironment. Human Jagged-1 induced the proliferation and differentiation of CD133+ cord blood progenitors compared with hDll-1. Thus, hJagged-1 signaling in the bone marrow niche may be used to expand EPCs for therapeutic angiogenesis.
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- 2016
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12. Detection of novel visible-light region absorbance peaks in the urine after alkalization in patients with alkaptonuria.
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Yasunori Tokuhara, Kenichi Shukuya, Masami Tanaka, Mariko Mouri, Ryunosuke Ohkawa, Midori Fujishiro, Tomoo Takahashi, Shigeo Okubo, Hiromitsu Yokota, Makoto Kurano, Hitoshi Ikeda, Seiji Yamaguchi, Shinobu Inagaki, Mika Ishige-Wada, Hiromi Usui, Yutaka Yatomi, and Tatsuo Shimosawa
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Medicine ,Science - Abstract
BACKGROUND: Alkaptonuria, caused by a deficiency of homogentisate 1,2-dioxygenase, results in the accumulation of homogentisic acid (2,5-dihydroxyphenylacetic acid, HGA) in the urine. Alkaptonuria is suspected when the urine changes color after it is left to stand at room temperature for several hours to days; oxidation of homogentisic acid to benzoquinone acetic acid underlies this color change, which is accelerated by the addition of alkali. In an attempt to develop a facile screening test for alkaptonuria, we added alkali to urine samples obtained from patients with alkaptonuria and measured the absorbance spectra in the visible light region. METHODS: We evaluated the characteristics of the absorption spectra of urine samples obtained from patients with alkaptonuria (n = 2) and compared them with those of urine specimens obtained from healthy volunteers (n = 5) and patients with phenylketonuria (n = 3), and also of synthetic homogentisic acid solution after alkalization. Alkalization of the urine samples and HGA solution was carried out by the addition of NaOH, KOH or NH4OH. The sample solutions were incubated at room temperature for 1 min, followed by measurement of the absorption spectra. RESULTS: Addition of alkali to alkaptonuric urine yielded characteristic absorption peaks at 406 nm and 430 nm; an identical result was obtained from HGA solution after alkalization. The absorbance values at both 406 nm and 430 nm increased in a time-dependent manner. In addition, the absorbance values at these peaks were greater in strongly alkaline samples (NaOH- KOH-added) as compared with those in weakly alkaline samples (NH4OH-added). In addition, the peaks disappeared following the addition of ascorbic acid to the samples. CONCLUSIONS: We found two characteristic peaks at 406 nm and 430 nm in both alkaptonuric urine and HGA solution after alkalization. This new quick and easy method may pave the way for the development of an easy method for the diagnosis of alkaptonuria.
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- 2014
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13. Blood glucose trends in glycogen storage disease type Ia: A cross‐sectional study
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Tokiko Fukuda, Tetsuya Ito, Takashi Hamazaki, Ayano Inui, Mika Ishige, Reiko Kagawa, Norio Sakai, Yoriko Watanabe, Hironori Kobayashi, Yosuke Wasaki, Junki Taura, Yuki Imamura, Tsutomu Tsukiuda, and Kimitoshi Nakamura
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Genetics ,Genetics (clinical) - Published
- 2023
14. Clinical perspective on the use of human amniotic epithelial cells to treat congenital metabolic diseases with a focus on maple syrup urine disease
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Satoshi Hayakawa, Brendan H. Grubbs, Toshio Miki, Chika Takano, Mika Ishige, Ichiro Morioka, and Erika Ogawa
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0301 basic medicine ,Medicine (General) ,placenta ,medicine.medical_treatment ,Economic shortage ,Liver transplantation ,Bioinformatics ,Regenerative medicine ,stem cell transplantation ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,R5-920 ,Maple Syrup Urine Disease ,Pregnancy ,medicine ,Humans ,Amnion ,cell transplantation ,liver regeneration ,QH573-671 ,business.industry ,Maple syrup urine disease ,Epithelial Cells ,Cell Biology ,General Medicine ,cellular therapy ,medicine.disease ,Liver regeneration ,030104 developmental biology ,Amniotic epithelial cells ,Female ,Stem cell ,business ,Cytology ,030217 neurology & neurosurgery ,Perspectives ,Developmental Biology - Abstract
Congenital metabolic diseases are a group of hereditary disorders caused by the deficiency of a single specific enzyme activity. Without appropriate therapy, affected patients suffer severe neurologic disability and eventual death. The current mainstays of management attempt to slow disease progression, but are not curative. Several of these diseases have demonstrated significant benefits from liver transplantation; however, this approach is limited by the morbidity associated with this invasive procedure and a shortage of donor organs. Therefore, there is a need to establish a new strategy for improving the quality of a life for these patients. One potential solution is regenerative therapy using hepatocytes generated from stem cells. Herein, we discuss pertinent issues necessary for clinical application of the human amniotic epithelial cell, a type of placental stem cell. Focusing on maple syrup urine disease as an example, where liver replacement is an effective therapy, we explore this approach from a clinician's perspective., Human amniotic epithelial cell (hAEC) transplantation therapy has therapeutic potential for the treatment of congenital metabolic diseases including maple syrup urine disease. hAECs isolated from the placenta can be transplanted by injection into the portal vein system. In this perspective article, we outline practical considerations for hAEC transplantation, which should help to design further studies toward clinical application.
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- 2021
15. Umbilical artery tissue contains p75 neurotrophin receptor-positive pericyte-like cells that possess neurosphere formation capacity and neurogenic differentiation potential
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Narihito Nagoshi, Taro Matsumoto, Rina Fujii-Tezuka, Ichiro Morioka, Hideyuki Okano, Shori Takahashi, Hideo Mugishima, and Mika Ishige-Wada
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0301 basic medicine ,Medicine (General) ,DMEM, Dulbecco's modified Eagle medium ,MSCs, mesenchymal stem cells ,WJ, Wharton's jelly ,FGF-2, fibroblast growth factor-2 ,ASMA, α-smooth muscle actin ,vWF, von Willebrand factor ,PDGF, platelet-derived growth factor ,0302 clinical medicine ,Immunophenotyping ,βME, β-mercaptoethanol ,DAPI, 4′,6-diamino-2-phenylindole ,p75 neurotrophin receptor ,UA, umbilical artery ,CFU-F, colony-forming unit fibroblast ,FSK, forskolin ,EdU, 5-ethynyl-2′-deoxyuridine ,UC, umbilical cord ,Neural crest ,EGFP, enhanced green fluorescent protein ,Cell biology ,medicine.anatomical_structure ,NCSCs, neural crest-derived stem cells ,CD146 ,Original Article ,Pericyte ,Neural crest stem cells ,Stem cell ,α-MEM, alpha-modified minimum essential medium ,BDNF, bone-derived neurotrophic factor ,PBS, phosphate-buffered saline ,Biomedical Engineering ,Neurosphere ,Biology ,p75NTR, p75 neurotrophin receptor ,Biomaterials ,MAP2, microtubule-associated protein 2 ,03 medical and health sciences ,R5-920 ,FBS, fetal bovine serum ,medicine ,CD90 ,NG2, neuron-glial antigen 2 ,Umbilical cord ,EGF, epidermal growth factor ,QH573-671 ,Mesenchymal stem cell ,GFAP, glial fibrillary acidic protein ,NF200, neurofilament 200 ,TBS, Tris-buffered saline ,030104 developmental biology ,UV, umbilical vein ,Mesenchymal stem cells ,sense organs ,Cytology ,RA, all-trans-retinoic acid ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Introduction The p75 neurotrophin receptor (p75NTR) is known as an efficient marker for the prospective isolation of mesenchymal stem cells (MSCs) and neural crest-derived stem cells (NCSCs). To date, there is quite limited information concerning p75NTR-expressing cells in umbilical cord (UC), although UC is known as a rich source of MSCs. We show for the first time the localization, phenotype, and functional properties of p75NTR+ cells in UC. Methods Human UC tissue sections were subjected to immunohistochemistry for MSC markers including p75NTR. Enzymatically isolated umbilical artery (UA) cells containing p75NTR+ cells were assessed for immunophenotype, clonogenic capacity, and differentiation potential. To identify the presence of neural crest-derived cells in the UA, P0-Cre/Floxed-EGFP reporter mouse embryos were used, and immunohistochemical analysis of UC tissue was performed. Results Immunohistochemical analysis revealed that p75NTR+ cells were specifically localized to the subendothelial area of the UA and umbilical vein. The p75NTR+ cells co-expressed PDGFRβ, CD90, CD146, and NG2, phenotypic markers of MSCs and pericytes. Isolated UA cells possessed the potential to form neurospheres that further differentiated into neuronal and glial cell lineages. Genetic lineage tracing analysis showed that EGFP+ neural crest-derived cells were detected in the subendothelial area of UA with p75NTR immunoreactivity. Conclusions These results show that UA tissue harbors p75NTR+ pericyte-like cells in the subendothelial area that have the capacity to form neurospheres and the potential for neurogenic differentiation. The lineage tracing data suggests the p75NTR+ cells are putatively derived from the neural crest.
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- 2021
16. Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency
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Koji Oba, Seiji Yamaguchi, Naoko Asahina, Saki Yokoshiki, Sanae Kawakami, Kiyotaka Nakamagoe, Mika Ishige, Toshiyuki Isoe, Kiyoshi Egawa, Koji Sameshima, Norihiro Sato, Fumihiro Ochi, Kazuyo Kuzume, Akira Tamaoka, Kenji Yamada, Hideaki Shiraishi, Asami Watanabe, Kenji Watanabe, Keiko Kobayashi, Hiroshi Hayashi, and Takashi Miyakoshi
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Adult ,Male ,myalgia ,medicine.medical_specialty ,Mitochondrial Diseases ,Gastroenterology ,Lipid Metabolism, Inborn Errors ,Very Long-Chain Acyl-CoA Dehydrogenase Deficiency ,Mitochondrial fatty acid ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,Developmental Neuroscience ,Internal medicine ,medicine ,Congenital Bone Marrow Failure Syndromes ,Humans ,In patient ,Child ,Bezafibrate ,business.industry ,Everyday activities ,Acyl-CoA Dehydrogenase, Long-Chain ,General Medicine ,medicine.disease ,Hypotonia ,Pediatrics, Perinatology and Child Health ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Rhabdomyolysis ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. Patients and methods We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. Results The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients’ ability to conduct everyday activities was also improved by the treatment. Conclusion Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.
- Published
- 2021
17. Isolation and characterization of neural crest-like progenitor cells in human umbilical cord blood
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Narihito Nagoshi, Hideyuki Okano, Mika Ishige-Wada, Taro Matsumoto, Noboru Fukuda, Zena Al-Bakri, Chikako Yoshida-Noro, and Hideo Mugishima
- Subjects
0301 basic medicine ,Population ,Biomedical Engineering ,Biology ,Cell therapy ,Biomaterials ,03 medical and health sciences ,Umbilical cord blood ,0302 clinical medicine ,Immunophenotyping ,Neurosphere ,p75 neurotrophin receptor ,Progenitor cell ,lcsh:QH573-671 ,education ,education.field_of_study ,lcsh:R5-920 ,lcsh:Cytology ,Neural crest ,Cell biology ,030104 developmental biology ,Cord blood ,Original Article ,sense organs ,Stem cell ,Neural crest stem cells ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Introduction Neural crest (NC)-like stem/progenitor cells provide an attractive cell source for regenerative medicine because of their multipotent property and ease of isolation from adult tissue. Although human umbilical cord blood (HUCB) is known to be a rich source of stem cells, the presence of the NC-like stem/progenitor cells in HUCB remains to be elucidated. In this study, we have isolated NC-like progenitor cells using an antibody to p75 neurotrophin receptor (p75NTR) and examined their phenotype and stem cell function in vitro. Methods To confirm whether p75NTR+ NC-derived cells are present in cord blood, flow cytometric analysis of cord blood derived from P0-Cre/Floxed-EGFP reporter mouse embryos was performed. Freshly isolated HUCB mononuclear cells was subjected to flow cytometry to detect p75NTR+ cells and determined their immunophenotype. HUCB p75NTR+ cells were then collected by immunomagnetic separation and their immunophenotype, clonogenic potential, gene expression profile, and multilineage differentiation potential were examined. Results NC-derived EGFP+ cells co-expressing p75NTR was detected in cord blood of P0-Cre/Floxed-EGFP reporter mice. We found that freshly isolated HUCB mononuclear cells contained 0.23% of p75NTR+ cells. Isolated p75NTR+ cells from HUCB efficiently formed neurospheres and could differentiate into neuronal and glial cell lineages. The p75NTR+ cells expressed a set of NC-associated genes and undifferentiated neural cell marker genes before and after the culture. Conclusions These findings revealed that HUCB contained the p75NTR+ NC-like progenitor cell population which have the self-renewal capacity and the potential to differentiate into both neuronal and glial cell lineages.
- Published
- 2020
18. Mortality of Japanese patients with Leigh syndrome: Effects of age at onset and genetic diagnosis
- Author
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Tomoko Tsuruoka, Atsuko Imai-Okazaki, Akira Ohtake, Makiko Tajika, Minako Ogawa-Tominaga, Masaru Shimura, Taro Yamazaki, Ayako Matsunaga, Yasushi Okazaki, Erika Ogawa, Yoshihito Kishita, Takuya Fushimi, Keiko Ichimoto, Ichiro Morioka, Kei Murayama, Tatsuo Fuchigami, Masakazu Kohda, and Mika Ishige
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,early onset ,Kaplan-Meier Estimate ,Neonatal onset ,DNA, Mitochondrial ,Disease course ,genetic diagnosis ,Young Adult ,Japan ,Genetics ,medicine ,Humans ,SURF1 ,Age of Onset ,Child ,Genetics (clinical) ,Mechanical ventilation ,business.industry ,Mortality rate ,Infant ,Original Articles ,DNA ,Leigh syndrome ,mortality ,Magnetic Resonance Imaging ,Survival Rate ,Japanese patients ,Phenotype ,Mild symptoms ,Child, Preschool ,Mutation ,Breathing ,Original Article ,Female ,Leigh Disease ,Genetic diagnosis ,business - Abstract
Leigh syndrome is a major phenotype of mitochondrial diseases in children. With new therapeutic options being proposed, assessing the mortality and clinical condition of Leigh syndrome patients is crucial for evaluating therapeutics. As data are scarce in Japan, we analysed the mortality rate and clinical condition of Japanese Leigh syndrome patients that we diagnosed since 2007. Data from 166 Japanese patients diagnosed with Leigh syndrome from 2007 to 2017 were reviewed. Patients' present status, method of ventilation and feeding, and degree of disability as of April 2018 was analysed. Overall, 124 (74.7%) were living, 40 (24.1%) were deceased, and 2 (1.2%) were lost to follow‐up. Median age of living patients was 8 years (1‐39 years). Median length of disease course was 91 months for living patients and 23.5 months for deceased patients. Nearly 90% of deaths occurred by age 6. Mortality rate of patients with onset before 6 months of age was significantly higher than that of onset after 6 months. All patients with neonatal onset were either deceased or bedridden. MT‐ATP6 deficiency caused by m.8993T>G mutation and MT‐ND5 deficiency induced a severe form of Leigh syndrome. Patients with NDUFAF6, ECHS1, and SURF1 deficiency had relatively mild symptoms and better survival. The impact of onset age on prognosis varied across the genetic diagnoses. The clinical condition of many patients was poor; however, few did not require mechanical ventilation or tube‐feeding and were not physically dependent. Early disease onset and genetic diagnosis may have prognostic value.
- Published
- 2020
19. Physical, cognitive, and social status of patients with urea cycle disorders in Japan
- Author
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Kaori Fukui, Kanako Kojima-Ishii, Kimitoshi Nakamura, Shinichi Hirose, Shinobu Yoshida, Norio Sakai, Shirou Matsumoto, Mika Ishige, Tetsuya Ito, Yuichi Mushimoto, and Jun Kido
- Subjects
Pediatrics ,medicine.medical_specialty ,Medicine (General) ,QH301-705.5 ,Intellectual disability ,Urea cycle disorders ,Social support ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,R5-920 ,Genetics ,Medicine ,Attention deficit hyperactivity disorder ,Developmental disability ,Biology (General) ,Molecular Biology ,Ornithine transcarbamylase deficiency ,Physical manifestation ,0303 health sciences ,business.industry ,030305 genetics & heredity ,Hyperammonemia ,medicine.disease ,Spouse ,Urea cycle ,Autism ,business ,030217 neurology & neurosurgery ,Research Paper - Abstract
Urea cycle disorders (UCDs) are inherited metabolic diseases that lead to hyperammonemia. Severe hyperammonemia adversely affects the brain. Therefore, we conducted a nationwide study between January 2000 and March 2018 to understand the present status of UCD patients in Japan regarding diagnosis, treatments, and outcomes. A total of 229 patients with UCDs (126 patients: ornithine transcarbamylase deficiency [OTCD]; 33: carbamoyl phosphate synthetase 1 deficiency [CPS1D]; 48: argininosuccinate synthetase deficiency [ASSD]; 14: argininosuccinate lyase deficiency [ASLD]; and 8: arginase 1 deficiency [ARG1D]) were enrolled in the present study. Although growth impairment is common in patients with UCDs, we discovered that Japanese patients with UCDs were only slightly shorter than the mean height of the general adult population in Japan. Patients with neonatal-onset UCDs are more likely to experience difficulty finding employment and a spouse; however, some patients with late-onset UCDs were employed and married. Additionally, intellectual and developmental disabilities, such as attention deficit hyperactivity disorder (ADHD) and autism, hinder patients with UCDs from achieving a healthy social life. Moreover, we identified that it is vital for patients with UCDs presenting with mild to moderate intellectual disabilities to receive social support. Therefore, we believe the more robust social support system for patients with UCDs may enable them to actively participate in society.
- Published
- 2021
20. Primary carnitine deficiency with severe acute hepatitis following rotavirus gastroenteritis
- Author
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Tatsuo Fuchigami, Maki Furukawa, Koji Hashimoto, Toshiyuki Fukao, Nobuyuki Ishige, Mika Ishige, Ryoji Fujiki, Ichiro Morioka, Yasuji Inamo, Hideo Sasai, Erika Ogawa, and Hironori Kobayashi
- Subjects
Rotavirus ,0301 basic medicine ,Microbiology (medical) ,medicine.medical_specialty ,030106 microbiology ,Hypoglycemia ,medicine.disease_cause ,Gastroenterology ,Rotavirus Infections ,Hepatitis ,03 medical and health sciences ,0302 clinical medicine ,Muscular Diseases ,Carnitine ,Internal medicine ,Systemic primary carnitine deficiency ,medicine ,Humans ,Hyperammonemia ,Pharmacology (medical) ,030212 general & internal medicine ,Newborn screening ,business.industry ,Fatty liver ,Infant ,medicine.disease ,Gastroenteritis ,Infectious Diseases ,Acute Disease ,Female ,Steatosis ,Cardiomyopathies ,business ,Primary Carnitine Deficiency ,medicine.drug - Abstract
Rotavirus infection is a major cause of gastroenteritis, which occurs mainly in children. Liver dysfunction due to rotavirus gastroenteritis has been reported; however, acute hepatitis due to this disease is very rare. We present a rare case in which rotavirus gastroenteritis led to sequential diagnosis of acute hepatitis and systemic primary carnitine deficiency (CDSP) in a 1-year-old girl. The patient's symptoms (hypoglycemia, hepatomegaly, and elevated levels of serum transaminases and creatinine kinase) suggested a steatosis causing liver dysfunction. She was initially considered to have a beta oxygenation defect or secondary carnitine deficiency caused by pivalic acid-containing antibiotics; however, repetitive carnitine analysis and free carnitine clearance measurement confirmed primary carnitine deficiency (carnitine transporter deficiency). Children with severe liver dysfunction due to rotavirus infection and presenting with liver steatosis should undergo blood acyl carnitine analysis to detect potential carnitine or other beta oxidation deficiencies, especially if newborn screening for these diseases is not available.
- Published
- 2019
21. Nutrient management in the intrapartum period in maternal maple syrup urine disease
- Author
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Tamaki Morohashi, Tatsuhiko Urakami, Kaori Kawakami, Atsushi Komatsu, Kei Kawana, Nobuhiko Nagano, Ichiro Morioka, Mika Ishige, Erika Ogawa, Chika Takano, and Aya Okahashi
- Subjects
Medical food ,Pediatrics ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Uterine fibroids ,Diet therapy ,Maple syrup urine disease ,Case Report ,Hypoproteinemia ,Endocrinology ,Perinatal management ,Genetics ,Medicine ,Uterine fibroid ,Molecular Biology ,lcsh:QH301-705.5 ,lcsh:R5-920 ,Nutrient management ,business.industry ,nutritional and metabolic diseases ,medicine.disease ,lcsh:Biology (General) ,Metabolic decompensation ,business ,lcsh:Medicine (General) ,Postpartum period - Abstract
Women with congenital amino acid disorders, including maple syrup urine disease (MSUD), are at risk of metabolic crisis at delivery. There are still only a few case reports of maternal MSUD globally, and we are the first to report the successful perinatal management of a woman with classical MSUD in Japan. A healthy baby was delivered by scheduled cesarean section despite the presence of several uterine fibroids. With precise diet therapy and accurate preparation, she completed the postpartum period without metabolic decompensation. Although her clinical outcome was favorable, she experienced hypoproteinemia at delivery because the available branched-chain amino acid-free medical food did not contain sufficient protein to meet the recommended nutrient intake. Therefore, this case also indicates a potential issue regarding a shortage of variations in specific amino acid-free medical food in Japan, which should be addressed to achieve a better nutrient status of adults with MSUD and other amino acid disorders.
- Published
- 2021
22. Study protocol: a multicenter, uncontrolled, open-label study of palivizumab in neonates, infants, and preschool children at high risk of severe respiratory syncytial virus infection
- Author
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Akihiro Hirakawa, Shinichi Watabe, Satoshi Kusuda, Naoyuki Tanuma, Masaaki Mori, Tomoaki Taguchi, Ryuji Koike, Mika Ishige, and Hisaya Hasegawa
- Subjects
Palivizumab ,Pediatrics ,medicine.medical_specialty ,Neuromuscular disease ,Exacerbation ,Efficacy ,Disease ,Respiratory Syncytial Virus Infections ,Antibodies, Monoclonal, Humanized ,Antiviral Agents ,03 medical and health sciences ,Study Protocol ,Pediatric patient ,0302 clinical medicine ,Japan ,030225 pediatrics ,medicine ,Humans ,Multicenter Studies as Topic ,030212 general & internal medicine ,Inherited metabolic disease ,Respiratory syncytial virus infection ,Adverse effect ,Child ,business.industry ,Incidence (epidemiology) ,Airway stenosis ,lcsh:RJ1-570 ,Infant, Newborn ,Antibodies, Monoclonal ,Infant ,lcsh:Pediatrics ,medicine.disease ,Clinical trial ,Hospitalization ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Population study ,Congenital esophageal atresia ,Pulmonary hypoplasia ,business ,medicine.drug - Abstract
Background The prophylactic use of anti-respiratory syncytial virus (RSV) antibody (palivizumab) for severe RSV infection is not approved in Japan in specified groups of infants with neuromuscular diseases or other rare diseases associated with reduced ventilation competence or difficulty in expectoration, which increase the risk of exacerbation of severe RSV infection. The objective of this study is to investigate the efficacy, safety, and pharmacokinetics of palivizumab in pediatric patients with those rare diseases for which palivizumab is not indicated at present. Methods/design This study is a multicenter, uncontrolled, open-label study planned to be carried out between July 1, 2019 and June 30, 2022 at 7 medical institutions in Japan. The study population will be recruited from among neonates, infants, or children aged 24 months or younger with a condition falling under any of the following 5 disease groups: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. The planned sample size is 18 subjects, including at least 3 subjects per disease group. Throughout the RSV season, at least 4 continuous doses of palivizumab will be administered intramuscularly at 15 mg/kg at intervals of 30 days. The efficacy and safety of palivizumab will be comprehensively evaluated based on the incidence of RSV-related hospitalization, and serum palivizumab concentration, serum anti-palivizumab antibody concentration, and the occurrence of adverse events/reactions after the start of palivizumab treatment. Discussion This study will evaluate the efficacy and safety of palivizumab in pediatric patients with rare diseases which place them at high risk of severe RSV infection, but which fall outside the current indications for palivizumab prophylaxis. The generated data will have implications for the regulatory approval of prophylactic palivizumab treatment in this patient group. Trial registration This study has been prospectively registered in Japic Clinical Trials Information, which is managed and administered by the Japan Pharmaceutical Information Center (registration number: JapicCTI-194946, registration date: September 10, 2019).
- Published
- 2021
23. Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan
- Author
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Asami Watanabe, Yusuke Hamada, Saki Yokoshiki, Kenji Watanabe, Kiyotaka Nakamagoe, Takashi Miyakoshi, Hideaki Shiraishi, Norihiro Sato, Fumihiro Ochi, Seiji Yamaguchi, Naoko Asahina, Kota Ono, Toshiyuki Isoe, Koji Oba, Toshiyuki Fukao, Mika Ishige, Hiroshi Hayashi, Norio Sakai, Kazuyo Kuzume, Akira Tamaoka, Kenji Yamada, Eishin Oki, Koji Sameshima, and Sanae Kawakami
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Visual analogue scale ,Carnitine palmitoyltransferase-II (CPT-2) deficiency ,Population ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Quality of life ,Bezafibrate ,Fatty acid oxidation disorders (FAODs) ,Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency ,Clinical trial ,Internal medicine ,Genetics ,Clinical endpoint ,medicine ,Carnitine ,education ,Molecular Biology ,lcsh:QH301-705.5 ,education.field_of_study ,lcsh:R5-920 ,biology ,business.industry ,030104 developmental biology ,lcsh:Biology (General) ,biology.protein ,Creatine kinase ,business ,lcsh:Medicine (General) ,030217 neurology & neurosurgery ,Research Paper ,medicine.drug - Abstract
Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by defects in mitochondrial fatty acid oxidation (FAO) enzymes. While the efficacy of bezafibrate, a peroxisome proliferator-activated receptor agonist, on the in vitro FAO capacity has been reported, the in vivo efficacy remains controversial. Therefore, we conducted a clinical trial of bezafibrate in Japanese patients with FAODs. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in 6 patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and 2 patients with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 8.2 years; ranging from 5.8 to 26.4 years). Bezafibrate was administered for 6 months following a 6-month observation period. The primary endpoint was the frequency of myopathic attacks, and the secondary endpoints were serum acylcarnitines (ACs, C14:1 or C16 + C18:1), creatine kinase (CK) levels, degree of muscle pain (VAS; visual analog scale) during myopathic attacks, and quality of life (QOL; evaluated using validated questionnaires). Results: The frequency of myopathic attacks after bezafibrate administration decreased in 3 patients, increased in 3, and did not change in 2. The CK, AC, and VAS values during attacks could be estimated in only three or four patients, but a half of the patients did not experience attacks before or after treatment. Changes in CK, AC, and VAS values varied across individuals. In contrast, three components of QOL, namely, physical functioning, role limitation due to physical problems (role physical), and social functioning, were significantly elevated. No adverse drug reactions were observed. Conclusion: In this study, the frequency of myopathic attacks and CK, AC, and VAS values during the attacks could not be evaluated due to several limitations, such as a small trial population. Our findings indicate that bezafibrate improves the QOL of patients with FAODs, but its efficacy must be examined in future investigations. Keywords: Bezafibrate, Fatty acid oxidation disorders (FAODs), Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase-II (CPT-2) deficiency, Clinical trial
- Published
- 2018
24. Hypocarnitinemia Observed in an Infant Treated with Short-Term Administration of Antibiotic Containing Pivalic Acid
- Author
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Mika Ishige, Kimitaka Nakazaki, Shori Takahashi, Erika Ogawa, Nobuyuki Ishige, and Tatsuo Fuchigami
- Subjects
Male ,medicine.medical_specialty ,Pivalic acid ,medicine.drug_class ,Antibiotics ,Urine ,Hypoglycemia ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Metabolic Diseases ,Tandem Mass Spectrometry ,Carnitine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Pentanoic Acids ,chemistry.chemical_classification ,Metabolic disorder ,Infant ,Fatty acid ,General Medicine ,Prodrug ,medicine.disease ,Carbon ,Anti-Bacterial Agents ,Oxygen ,Endocrinology ,chemistry ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Carnitine is a water-soluble amino acid derivative required for β-oxidation of long-chain fatty acids. In carnitine cycle abnormalities and low carnitine states, fatty acid β-oxidation is inhibited during fasting, resulting in hypoglycemia. Pivalic acid is a substance used in prodrugs to increase absorption of parent drugs, and antibiotics containing pivalic acid are frequently used as wide spectrum antibiotics for pediatric patients in Japan. Pivalic acid released after absorption is conjugated with free carnitine to form pivaloylcarnitine, which is then excreted in urine. As a consequence, long-term administration of pivalic acid containing antibiotics has been associated with depletion of free carnitine, inhibition of energy production and subsequent hypoglycemia. Here we report a case of a 23-month-old boy treated with an antibiotic containing pivalic acid for 3 days for upper respiratory tract infection. Laboratory data at referral indicated hypoglycemia, decreased free carnitine and elevated five-carbon acylcarnitine. Isomer separation confirmed the major component of increased five-carbon acylcarnitine to be pivaloylcarnitine, thereby excluding the possibility of a genetic metabolic disorder detected with similar acylcarnitine profile. The level of carnitine was normal when the antibiotic was not administered. Our case shows that the use of antibiotics containing pivalic acid in young children requires consideration of hypocarnitinemia, even with short-term administration.
- Published
- 2018
25. Clinical validity of biochemical and molecular analysis in diagnosing Leigh syndrome: a study of 106 Japanese patients
- Author
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Masaru Shimura, Yoshihito Kishita, Ayako Matsunaga, Akira Ohtake, Taro Yamazaki, Erika Ogawa, Tatsuo Fuchigami, Makiko Tajika, Tomoko Tsuruoka, Takuya Fushimi, Masato Mori, Kei Murayama, Mika Ishige, Yasushi Okazaki, Shori Takahashi, Masakazu Kohda, and Keiko Ichimoto
- Subjects
0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Oxygen consumption rate ,Disease ,Biology ,Genetic analysis ,Electron Transport ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Oxygen Consumption ,Asian People ,Genetics ,medicine ,Mitochondrial respiratory chain disorder ,Humans ,Child ,Muscle, Skeletal ,Gene ,Genetics (clinical) ,medicine.diagnostic_test ,Magnetic resonance imaging ,Fibroblasts ,Mitochondrial Proton-Translocating ATPases ,Enzyme assay ,Leigh syndrome ,Human genetics ,Molecular analysis ,Mitochondria ,030104 developmental biology ,Mitochondrial respiratory chain ,Mutation ,biology.protein ,Original Article ,Female ,Leigh Disease ,030217 neurology & neurosurgery - Abstract
Leigh syndrome (LS) is a progressive neurodegenerative disorder of infancy and early childhood. It is clinically diagnosed by typical manifestations and characteristic computed tomography (CT) or magnetic resonance imaging (MRI) studies. Unravelling mitochondrial respiratory chain (MRC) dysfunction behind LS is essential for deeper understanding of the disease, which may lead to the development of new therapies and cure. The aim of this study was to evaluate the clinical validity of various diagnostic tools in confirming MRC disorder in LS and Leigh-like syndrome (LL). The results of enzyme assays, molecular analysis, and cellular oxygen consumption rate (OCR) measurements were examined. Of 106 patients, 41 were biochemically and genetically verified, and 34 had reduced MRC activity but no causative mutations. Seven patients with normal MRC complex activities had mutations in the MT-ATP6 gene. Five further patients with normal activity in MRC were identified with causative mutations. Conversely, 12 out of 60 enzyme assays performed for genetically verified patients returned normal results. No biochemical or genetic background was confirmed for 19 patients. OCR was reduced in ten out of 19 patients with negative enzyme assay results. Inconsistent enzyme assay results between fibroblast and skeletal muscle biopsy samples were observed in 33% of 37 simultaneously analyzed cases. These data suggest that highest diagnostic rate is reached using a combined enzymatic and genetic approach, analyzing more than one type of biological materials where suitable. Microscale oxygraphy detected MRC impairment in 50% cases with no defect in MRC complex activities. Electronic supplementary material The online version of this article (doi:10.1007/s10545-017-0042-6) contains supplementary material, which is available to authorized users.
- Published
- 2017
26. Effect of Dedifferentiated Fat Cell Transplantation in a Mouse Model of Acute Graft-Versus-Host Disease
- Author
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Koichiro Kano, Hideo Mugishima, Takemi Murai, Tomohiko Kazama, Mika Ishige, and Taro Matsumoto
- Subjects
0301 basic medicine ,03 medical and health sciences ,Pathology ,medicine.medical_specialty ,030104 developmental biology ,Cell transplantation ,business.industry ,Acute graft versus host disease ,Medicine ,business - Published
- 2017
27. A Case of Enteric Fever Complicated with Acute Encephalopathy
- Author
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Yuko Moriuchi, Tetsuji Morimoto, Tatsuo Fuchigami, Erika Ogawa, Kei Yoshida, Tsubasa Gibo, Mika Ishige, Shori Takahashi, Junichi Suzuki, and Yuno Takahashi
- Subjects
03 medical and health sciences ,medicine.medical_specialty ,0302 clinical medicine ,business.industry ,Internal medicine ,030231 tropical medicine ,Acute encephalopathy ,Medicine ,business ,Gastroenterology ,Enteric fever - Published
- 2017
28. Unique and abnormal subependymal pseudocysts in a newborn with mitochondrial disease
- Author
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Yasushi Okazaki, Yuki Sato, Chika Takano, Kei Murayama, Ryoji Aoki, Erika Ogawa, Nobuhiko Nagano, Ryota Kato, Mika Ishige, Ichiro Morioka, and Ayako Seimiya
- Subjects
0301 basic medicine ,Brain Diseases ,Mutation ,Pathology ,medicine.medical_specialty ,Mitochondrial Diseases ,Multidisciplinary ,Cysts ,Mitochondrial disease ,Infant, Newborn ,Brain ,Biology ,medicine.disease ,medicine.disease_cause ,Subependymal Pseudocyst ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,IBA57 gene ,medicine ,Subependymal zone ,Humans ,In patient ,Neonatal lethal ,030217 neurology & neurosurgery - Abstract
Neonatal mitochondrial disease is occasionally observed in patients with intraventricular cysts in the brain. Atypical morphology is rarely seen in these cysts. Here, we report a case of neonatal lethal mitochondrial disease with IBA57 gene mutation. We have, for the first time, described a subependymal pseudocyst (SEPC) with a fluctuating membrane. Our findings suggest that SEPCs with fluctuating membranes can be a potential diagnostic indicator of neonatal mitochondrial disease.
- Published
- 2021
29. Severe Acute Subdural Hemorrhages in a Patient with Glutaric Acidemia Type 1 under Recommended Treatment
- Author
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Mika Ishige, Hiromi Usui, Erika Ogawa, Tatsuo Fuchigami, Shori Takahashi, Ryutaro Kohira, and Yoriko Watanabe
- Subjects
Male ,0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Glutaric aciduria type 1 ,Severity of Illness Index ,03 medical and health sciences ,0302 clinical medicine ,Hematoma ,Severity of illness ,medicine ,Craniocerebral Trauma ,Hematoma, Subdural, Acute ,Humans ,Glutaryl-CoA dehydrogenase deficiency ,Amino Acid Metabolism, Inborn Errors ,Newborn screening ,Glutaryl-CoA Dehydrogenase ,Brain Diseases, Metabolic ,business.industry ,Infant ,nutritional and metabolic diseases ,Subdural hemorrhage ,General Medicine ,medicine.disease ,Minor head trauma ,Surgery ,Treatment Outcome ,030104 developmental biology ,Pediatrics, Perinatology and Child Health ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,Glutaric Acidemia Type 1 - Abstract
Glutaric acidemia type 1 is a rare autosomal recessive disease caused by a deficiency of glutaryl-CoA dehydrogenase. Previous studies have reported subdural hemorrhage in untreated patients with glutaric acidemia type 1. However, there is only one report of severe acute subdural hemorrhage after minor head trauma in a patient with glutaric acidemia type 1 under guideline-recommended treatment. We report a second case of life-threatening severe acute subdural hemorrhage after a minor head trauma in a patient with glutaric acidemia type 1. This patient was previously diagnosed by newborn screening, and treatment began at 25 days of age. Early diagnosis and guideline-recommended treatment produce better outcomes for patients with glutaric acidemia type 1, although the risk of subdural hemorrhage remains.
- Published
- 2016
30. Severe hypoglycemic encephalopathy due to hypoallergenic formula in an infant
- Author
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Shori Takahashi, Erika Ogawa, Tatsuo Fuchigami, Hiroko Kodama, Mika Ishige, and Yuno Takahashi
- Subjects
medicine.medical_specialty ,Pediatrics ,Hypoglycemic encephalopathy ,business.industry ,Stupor ,Biotin deficiency ,Hypoallergenic ,Metabolic acidosis ,Brain damage ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Vomiting ,Carnitine ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
A 7-month-old girl was brought to hospital due to vomiting. Upon admission, she was in a convulsive state and stupor with extremely low blood glucose. Head computed tomography showed brain edema, and comprehensive treatment for acute encephalopathy was initiated immediately. Severe hypoglycemia, metabolic acidosis, elevation of ammonia and serum transaminases and creatine kinase suggested metabolic decompensation. Infusion of a high-glucose solution containing vitamins, biotin, and l-carnitine resolved the metabolic crisis quickly, but brain damage was irreversible. She was found to have been fed exclusively on a hypoallergenic formula (HF) for 7 months, although she was found later to be non-allergic. Evidence of inborn metabolic diseases was absent, therefore biotin deficiency and carnitine deficiency were concluded to be a consequence of reliance on a HF for a prolonged period. Health-care professionals should warn parents of the consequences of using HF.
- Published
- 2016
31. Correction: Biallelic GALM pathogenic variants cause a novel type of galactosemia
- Author
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Matsuyuki Shirota, Natsuko Arai-Ichinoi, Erika Ogawa, Osamu Ohara, Keiko Nakayama, Toshiyuki Fukao, Yoko Nakajima, Masayuki Yamamoto, Hideo Sasai, Osamu Sakamoto, Yoichi Wada, Hiromi Nyuzuki, Ryoji Fujiki, Atsuo Kikuchi, Mika Ishige, Yusuke Takezawa, Hiroki Hirai, Shinya Iwasawa, Ryo Funayama, Yoko Aoki, Tetsuya Ito, Shigeo Kure, Tetsuya Niihori, and Seizo Koshiba
- Subjects
Genetics ,business.industry ,Galactosemia ,medicine ,medicine.disease ,business ,Genetics (clinical) - Published
- 2020
32. Biallelic GALM pathogenic variants cause a novel type of galactosemia
- Author
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Hideo Sasai, Yoichi Wada, Matsuyuki Shirota, Osamu Ohara, Ryo Funayama, Atsuo Kikuchi, Hiromi Nyuzuki, Ryoji Fujiki, Toshiyuki Fukao, Osamu Sakamoto, Mika Ishige, Yusuke Takezawa, Shigeo Kure, Tetsuya Niihori, Hiroki Hirai, Yoko Aoki, Tetsuya Ito, Shinya Iwasawa, Seizo Koshiba, Erika Ogawa, Natsuko Arai-Ichinoi, Masayuki Yamamoto, Keiko Nakayama, and Yoko Nakajima
- Subjects
0301 basic medicine ,Galactosemias ,Male ,Biology ,Peripheral blood mononuclear cell ,03 medical and health sciences ,symbols.namesake ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Humans ,education ,Genetics (clinical) ,Exome sequencing ,Alleles ,Sanger sequencing ,chemistry.chemical_classification ,education.field_of_study ,Base Sequence ,Galactosemia ,Galactose ,Genetic Variation ,Infant ,medicine.disease ,Molecular biology ,eye diseases ,Leloir pathway ,030104 developmental biology ,Enzyme ,chemistry ,Child, Preschool ,symbols ,Female ,Galactose mutarotase ,Carbohydrate Epimerases ,030217 neurology & neurosurgery - Abstract
Galactosemia is caused by metabolic disturbances at various stages of galactose metabolism, including deficiencies in enzymes involved in the Leloir pathway (GALT, GALK1, and GALE). Nevertheless, the etiology of galactosemia has not been identified in a subset of patients. This study aimed to explore the causes of unexplained galactosemia. Trio-based exome sequencing and/or Sanger sequencing was performed in eight patients with unexplained congenital galactosemia. In vitro enzymatic assays and immunoblot assays were performed to confirm the pathogenicity of the variants. The highest blood galactose levels observed in each patient were 17.3–41.9 mg/dl. Bilateral cataracts were observed in two patients. In all eight patients, we identified biallelic variants (p.Arg82*, p.Ile99Leufs*46, p.Gly142Arg, p.Arg267Gly, and p.Trp311*) in the GALM encoding galactose mutarotase, which catalyzes epimerization between β- and α-D-galactose in the first step of the Leloir pathway. GALM enzyme activities were undetectable in lymphoblastoid cell lines established from two patients. Immunoblot analysis showed the absence of the GALM protein in the patients’ peripheral blood mononuclear cells. In vitro GALM expression and protein stability assays revealed altered stabilities of the variant GALM proteins. Biallelic GALM pathogenic variants cause galactosemia, suggesting the existence of type IV galactosemia.
- Published
- 2018
33. The Reduced Expression of SDF-1 in Mouse Bone Marrow Stromal Cells by Myeloablative Conditioning Equivalent Irradiation
- Author
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Minako Kazama, Mika Ishige, Takashi Tsuji, Taro Matsumoto, Hideo Mugishima, and Shori Takahashi
- Subjects
medicine.medical_specialty ,business.industry ,Family medicine ,medicine ,business - Published
- 2015
34. Newborn screening for carnitine palmitoyltransferase II deficiency using (C16+C18:1)/C2: Evaluation of additional indices for adequate sensitivity and lower false-positivity
- Author
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Toshiyuki Fukao, Ryoji Fujiki, Akira Ohtake, Yusuke Hamada, Satoshi Okada, Ikue Hata, Ryosuke Bo, Nobuo Sakura, Go Tajima, Hideo Sasai, Atsuko Noguchi, Shinsuke Maruyama, Sayaka Ajihara, Kenji Yamada, Hironori Kobayashi, Yuki Hasegawa, Yosuke Shigematsu, Mika Ishige, Masaki Takayanagi, Masao Kobayashi, Osamu Ohara, Reiko Kagawa, Seiji Yamaguchi, Tomotaka Kono, Nobuyuki Ishige, Ikuma Musha, Miyuki Tsumura, Etsuo Naito, Keiichi Hara, Tomonari Awaya, and Tomoko Asada
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Disease ,Biochemistry ,Gastroenterology ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Neonatal Screening ,Tandem Mass Spectrometry ,Internal medicine ,Genetics ,medicine ,Humans ,False Positive Reactions ,Carnitine ,Allele ,Molecular Biology ,Beta oxidation ,False Negative Reactions ,Alleles ,Newborn screening ,Hypoglycemic encephalopathy ,Carnitine O-Palmitoyltransferase ,business.industry ,Infant, Newborn ,Palmitoylcarnitine ,food and beverages ,Infant ,medicine.disease ,Hypoglycemia ,CPT II Deficiency ,030104 developmental biology ,Female ,Carnitine palmitoyltransferase II deficiency ,Dried Blood Spot Testing ,business ,030217 neurology & neurosurgery ,Metabolism, Inborn Errors ,medicine.drug - Abstract
Background Carnitine palmitoyltransferase (CPT) II deficiency is one of the most common forms of mitochondrial fatty acid oxidation disorder (FAOD). However, newborn screening (NBS) for this potentially fatal disease has not been established partly because reliable indices are not available. Methods We diagnosed CPT II deficiency in a 7-month-old boy presenting with hypoglycemic encephalopathy, which apparently had been missed in the NBS using C16 and C18:1 concentrations as indices. By referring to his acylcarnitine profile from the NBS, we adopted the (C16 + C18:1)/C2 ratio (cutoff 0.62) and C16 concentration (cutoff 3.0 nmol/mL) as alternative indices for CPT II deficiency such that an analysis of a dried blood specimen collected at postnatal day five retroactively yielded the correct diagnosis. Thereafter, positive cases were assessed by measuring (1) the fatty acid oxidation ability of intact lymphocytes and/or (2) CPT II activity in the lysates of lymphocytes. The diagnoses were then further confirmed by genetic analysis. Results The disease was diagnosed in seven of 21 newborns suspected of having CPT II deficiency based on NBS. We also analyzed the false-negative patient and five symptomatic patients for comparison. Values for the NBS indices of the false-negative, symptomatic patient were lower than those of the seven affected newborns. Although it was difficult to differentiate the false-negative patient from heterozygous carriers and false-positive subjects, the fatty acid oxidation ability of the lymphocytes and CPT II activity clearly confirmed the diagnosis. Among several other indices proposed previously, C14/C3 completely differentiated the seven NBS-positive patients and the false-negative patient from the heterozygous carriers and the false-positive subjects. Genetic analysis revealed 16 kinds of variant alleles. The most prevalent, detected in ten alleles in nine patients from eight families, was c.1148T > A (p.F383Y), a finding in line with those of several previous reports on Japanese patients. Conclusions These findings suggested that CPT II deficiency can be screened by using (C16 + C18:1)/C2 and C16 as indices. An appropriate cutoff level is required to achieve adequate sensitivity albeit at the cost of a considerable increase in the false-positive rate, which might be reduced by using additional indices such as C14/C3.
- Published
- 2017
35. Open-label clinical trial of bezafibrate treatment in patients with fatty acid oxidation disorders in Japan ; 2nd report QOL survey
- Author
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Toshiyuki Fukao, Mika Ishige, Hiroshi Hayashi, Hideaki Shiraishi, Asami Watanabe, Takashi Miyakoshi, Koji Oba, Yusuke Hamada, Seiji Yamaguchi, Norihiro Sato, Fumihiro Ochi, Naoko Asahina, Norio Sakai, Eishin Oki, Akira Tamaoka, Kenji Yamada, Kazuyo Kuzume, Sanae Kawakami, Koji Sameshima, Saki Yokoshiki, Toshiyuki Isoe, Kiyotaka Nakamagoe, and Kenji Watanabe
- Subjects
Quality of life ,medicine.medical_specialty ,Carnitine palmitoyltransferase-II (CPT-2) deficiency ,Endocrinology ,Internal medicine ,Genetics ,medicine ,In patient ,Carnitine ,lcsh:QH301-705.5 ,Molecular Biology ,Beta oxidation ,lcsh:R5-920 ,Bezafibrate ,business.industry ,Mental health ,Fatty acid oxidation disorders (FAODs) ,Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency ,Clinical trial ,lcsh:Biology (General) ,Open label ,lcsh:Medicine (General) ,business ,Research Paper ,medicine.drug - Abstract
Introduction: Fatty acid oxidation disorders (FAODs) are rare diseases caused by a defective mitochondrial fatty acid oxidation (FAO) enzyme. We recently reported that bezafibrate improved patient quality of life (QOL) based on the SF-36 questionnaire score in patients with FAODs during a 50-week, open-label, clinical trial. Herein we conducted further survey assessments of the trial patients to define the long-term efficacy and safety of bezafibrate. Materials and methods: This trial was an open-label, non-randomized, and multicenter study of bezafibrate treatment in five patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency and one patient with carnitine palmitoyltransferase-II (CPT-2) deficiency (median age, 15.9 years; range, 5.8–26.4 years). The bezafibrate administration was continued for a further 102–174 weeks after the 24-week treatment described in our previous study. QOL was quantitated using the 36-Item Short Form Health Survey (SF-36) questionnaire, which constitutes eight components: physical functioning (PF), role limitation due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. Results: PF was elevated in all patients and continued to rise during the study, with the total QOL scores increased from baseline in five of the six cases. In particular, three patients older than 20 years showed treatment efficacy, and all subcategories of QOL were elevated in two of these cases. Conclusion: Our findings supported one of the stated benefits of bezafibrate in improving QOL for patients with FAODs. Keywords: Bezafibrate, Fatty acid oxidation disorders (FAODs), Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, Carnitine palmitoyltransferase-II (CPT-2) deficiency, Clinical trial, Quality of life
- Published
- 2019
36. Hematopoietic stem cell transplantation for inborn errors of metabolism: A report from the Research Committee on Transplantation for Inborn Errors of Metabolism of the Japanese Ministry of Health, Labour and Welfare and the Working Group of the Japan Society for Hematopoietic Cell Transplantation
- Author
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Yoji Sasahara, Yasuyuki Suzuki, Ken Tabuchi, Souichi Adachi, Yoshiko Hashii, Akemi Tanaka, Hiromasa Yabe, Hiromitsu Takakura, Shunichi Kato, Nao Yoshida, Koji Kato, Hideo Mugishima, Toya Ohashi, Norio Sakai, and Mika Ishige
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Pediatrics ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Chimerism ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Japan ,HLA Antigens ,Surveys and Questionnaires ,medicine ,Humans ,Transplantation, Homologous ,Registries ,Child ,Alleles ,Societies, Medical ,Bone Marrow Transplantation ,Retrospective Studies ,Transplantation ,Hematopoietic cell ,business.industry ,Data Collection ,Histocompatibility Testing ,Hematopoietic Stem Cell Transplantation ,Infant, Newborn ,Infant ,Surgery ,030104 developmental biology ,Treatment Outcome ,Research Design ,Allogeneic hsct ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Christian ministry ,Female ,Cord Blood Stem Cell Transplantation ,business ,Metabolism, Inborn Errors ,030215 immunology - Abstract
A total of 216 patients with IEM were treated by allogeneic HSCT in Japan from 1985 until 2010. The results of UCBT have improved, and the OS rate of UCBT (81.9%) was not different from those of RBMT (87.2%) or UBMT (73.9%) in 2000-2010. However, EFS rates in RBMT (73.2%) and UBMT (62.2%) were better than that in UCBT (49.5%), and the difference between RBMT and UCBT was significant (p = 0.01). The EFS rate of patients conditioned by RIC (74.6%) was comparable or slightly better than in those who underwent MAC with irradiation (57.9%) or without irradiation (54.2%) in 2000-2010. A more pronounced trend was observed toward differential EFS for UCBT in 2000-2010: RIC (62.9%), MAC with irradiation (20.0%), and MAC without irradiation (42.1%). The difference between RIC and MAC with irradiation was significant (p < 0.03). In summary, we report a Japanese registry analysis of HSCT for IEM with improving survival in UCBT. The introduction of RIC after 2000 was considered to contribute to this improvement. UCBT could be recommended for those who lack an HLA-identical sibling donor.
- Published
- 2015
37. A case of Hyperreninemic hypoaldosteronism with absorptive hypercalciuria, renal hypouricemia and high level of 1,25-dihydroxyvitamin D
- Author
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Hiroshi Saito, Yusuke Mine, Tatsuhiko Urakami, Ayako Yoshida, Mika Ishige, Shori Takahashi, Junichi Suzuki, Hiroshi Watanabe, and Nobuhiko Nagano
- Subjects
medicine.medical_specialty ,Hyperreninemic hypoaldosteronism ,business.industry ,Absorptive hypercalciuria ,medicine ,Urology ,RENAL HYPOURICEMIA ,Hyponatremia ,medicine.disease ,business - Published
- 2011
38. Association between Sex, Age, Insulin Regimens and Glycemic Control in Children and Adolescents with Type 1 Diabetes
- Author
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Ayako Yoshida, Hiroshi Saito, Hideo Mugishima, Mika Ishige, Tatsuhiko Urakami, Junichi Suzuki, and Shori Takahashi
- Subjects
Type 1 diabetes ,Pediatrics ,medicine.medical_specialty ,type 1 diabetes ,business.industry ,Endocrinology, Diabetes and Metabolism ,Insulin ,medicine.medical_treatment ,medicine.disease ,insulin regimen ,Hba1c level ,Endocrinology ,Age groups ,Diabetes mellitus ,Pediatrics, Perinatology and Child Health ,glycemic control ,medicine ,Original Article ,In patient ,business ,Insulin regimen ,Glycemic - Abstract
We examined the association between sex, age, insulin regimens and glycemic control in 133 Japanese children and adolescents, 42 males and 61 females aged 16.8 ± 7.0 yr, with type 1 diabetes mellitus (T1DM). The patients were divided into 5 age groups and were also classified according to the insulin regimen. The annual median HbA1c level in males (7.3 ± 0.2%) was similar to that in females (7.2 ± 0.2%). In regard to the age of the patients, the median HbA1c levels in patients aged 15–19 yr (7.9 ± 0.4%) was significantly higher than those aged 5–9 yr (7.2 ± 0.1%) and those aged 20≤ yr (6.6 ± 0.4%, p
- Published
- 2010
39. Successful living domino liver transplantation in a child with protein C deficiency
- Author
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Seisuke Sakamoto, Hajime Uchida, Takanobu Shigeta, Reiko Horikawa, Hiroyuki Kanazawa, Motoki Ohta, Kengo Sasaki, Akira Ishiguro, Atsuko Nakazawa, Mureo Kasahara, Mika Ishige, Masatoshi Matsunami, Akinari Fukuda, Hisaya Nakadate, and Koichi Mizuta
- Subjects
medicine.medical_specialty ,Heterozygote ,medicine.medical_treatment ,Liver transplantation ,Compound heterozygosity ,Gastroenterology ,Maple Syrup Urine Disease ,Protein C deficiency ,Internal medicine ,Living Donors ,Medicine ,Humans ,Transplantation ,business.industry ,Maple syrup urine disease ,Anticoagulants ,Infant ,Protein C Deficiency ,Perioperative ,medicine.disease ,Liver Transplantation ,Treatment Outcome ,Coagulation ,Liver ,Purpura Fulminans ,Pediatrics, Perinatology and Child Health ,Immunology ,Mutation ,Female ,business ,Purpura fulminans ,Protein C - Abstract
PC is produced in the liver and inhibits blood coagulation by catalyzing active factors V and VIII. PC deficiency causes abnormal blood clotting that is difficult to regulate by anticoagulative treatments. Four reports of PC deficiency treated with LTx have been published; however, no report of DLT as a therapy for PC deficiency is available. We describe a case of a 23-month-old girl who received DLT for compound heterozygous PC deficiency. Her PC activity was below 5%. She developed intracranial lesion and frequent refractory purpura fulminans. Both her parents had heterozygous mutations of PC genes and were excluded as living donors. Furthermore, she was a low priority on the waiting list of deceased-donor transplantation. We performed living DLT using the liver from a patient with MSUD. Activated PC concentrate safely supported the perioperative period. After DLT, she maintained normal PC activities and BCAA levels. This is the first case of PC deficiency successfully treated by living DLT with MSUD. We propose that DLT using liver from patients with MSUD is a treatment option for PC deficiency.
- Published
- 2015
40. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency
- Author
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Toju Tanaka, Toshiyuki Fukao, Naomi Sakaguchi, Hiroko Kouzan, Tomoko Ichihara, Mika Ishige, Katsuaki Ohara, Yasutomi Kinosada, Yuka Aoyama, and Toshiyuki Yamamoto
- Subjects
Male ,uniparental disomy ,Biology ,medicine.disease_cause ,Exon ,Alu Elements ,Genetics ,medicine ,Humans ,Multiplex ligation-dependent probe amplification ,multiplex ligation-dependent probe amplification ,Sequence Deletion ,Mutation ,mitochondrial 3-hydroxy-3-methylglutaryl CoA lyase ,Base Sequence ,Microarray analysis techniques ,Chromosome ,Infant ,Oxo-Acid-Lyases ,General Medicine ,Exons ,Articles ,medicine.disease ,Molecular biology ,Uniparental disomy ,3-hydroxy-3-methylglutaryl-CoA lyase ,Alu element ,Uniparental Isodisomy ,Chromosomes, Human, Pair 1 ,Female ,Multiplex Polymerase Chain Reaction ,microarray ,Metabolism, Inborn Errors - Abstract
Mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) deficiency is an autosomal recessive disorder affecting the leucine catabolic pathway and ketone body synthesis, and is clinically characterized by metabolic crises with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia. In the present study, we initially used PCR with genomic followed by direct sequencing to investigate the molecular genetic basis of HMGCL deficiency in two patients clinically diagnosed with the condition. Although we identified a mutation in each patient, the inheritance patterns of these mutations were not consistent with disease causation. Therefore, we investigated HMGCL using multiplex ligation-dependent probe amplification (MLPA) to determine the copy numbers of all exons. A heterozygous deletion that included exons 2-4 was identified in one of the patients. MLPA revealed that the other patient had two copies for all HMGCL exons. Paternal uniparental isodisomy of chromosome 1 was confirmed in this patient by microarray analysis. These findings indicate that MLPA is useful for the identification of genomic aberrations and mutations other than small-scale nucleotide alterations. To the best of our knowledge, this is the first study describing HMGCL deficiency caused by uniparental disomy.
- Published
- 2014
41. Diabetes caused by Kir6.2 mutation: Successful treatment with oral glibenclamide switched from continuous subcutaneous insulin infusion in the early phase of the disease
- Author
-
Hirofumi Watanabe, Hiroshi Saito, Ayako Yoshida, Tohru Yorifuji, Yusuke Mine, Hideo Mugishima, Tatsuhiko Urakami, Nobuhiko Nagano, Shori Takahashi, Junichi Suzuki, and Mika Ishige
- Subjects
medicine.medical_specialty ,Neonatal diabetes ,business.industry ,Disease ,Kir6.2 ,medicine.disease ,Subcutaneous insulin ,Glibenclamide ,Endocrinology ,Internal medicine ,Diabetes mellitus ,Pediatrics, Perinatology and Child Health ,Mutation (genetic algorithm) ,medicine ,Early phase ,business ,medicine.drug - Published
- 2012
42. A case of classical maple syrup urine disease that was successfully managed by living donor liver transplantation
- Author
-
Erika Ogawa, Mika Ishige, Koichi Mizuta, Hiromi Usui, Chika Takano, Shori Takahashi, Go Tajima, Tatsuo Fuchigami, Reiko Kagawa, Toshiyuki Fukao, and Ryoji Fujiki
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Transplantation ,Deceased donor ,medicine.medical_specialty ,business.industry ,Maple syrup urine disease ,medicine.medical_treatment ,Classical maple syrup urine disease ,nutritional and metabolic diseases ,030230 surgery ,Liver transplantation ,medicine.disease ,Brain findings ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,Pediatrics, Perinatology and Child Health ,Effective treatment ,Medicine ,030211 gastroenterology & hepatology ,Living donor liver transplantation ,business - Abstract
Classical MSUD is often fatal without appropriate medical interventions because of metabolic crisis. There are numerous reports suggesting the therapeutic potential of deceased donor liver transplantation for MSUD. However, the usefulness of LDLT for MSUD is unknown. We report a case of classical MSUD, which was successfully managed by LDLT from the patient's father at 1 year of age. Abnormal brain findings, which were cured with effective treatment, gradually disappeared after LDLT. The patient then developed normally. Findings from this case suggest the importance of LDLT for maintaining low leucine levels and subsequent normal neurological development. Although LDLT involves a modest surgical insult, LDLT with a related donor achieves acceptable leucine levels for life.
- Published
- 2017
43. Successful cord blood transplantation in a 42-day-old boy with infantile Krabbe disease
- Author
-
Hiroyuki Shichino, Hiroshi Yagasaki, Mika Ishige, Maiko Kato, Motoaki Chin, and Hideo Mugishima
- Subjects
medicine.medical_specialty ,Pediatrics ,Hematology ,Infantile Krabbe disease ,business.industry ,Internal medicine ,medicine ,business ,Cord blood transplantation - Published
- 2011
44. Genotype of mucopolysaccharidosis type II severe form and the efficacy of enzyme replacement therapy or hematopoietic stem cell transplantation on cognitive function
- Author
-
Motomichi Kosuga, Norio Sakai, Chiho Kadono, Ken Tabuchi, Takashi Hamazaki, Yasuyuki Suzuki, Torayuki Okuyama, Koji Kato, Tomo Sawada, Shunichi Kato, Michiko Shinpo, Hiromasa Yabe, Mika Ishige, Satoshi Kudo, Akemi Tanaka, and Hideo Mugishima
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Cognition ,Hematopoietic stem cell transplantation ,Enzyme replacement therapy ,Biochemistry ,Endocrinology ,Genotype ,Immunology ,Genetics ,medicine ,Mucopolysaccharidosis type II ,business ,Molecular Biology - Published
- 2015
45. Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: a nationwide survey in Japan
- Author
-
Koji Kato, Hiromitsu Takakura, Norio Sakai, Takanobu Otomo, Torayuki Okuyama, Akemi Tanaka, Shunichi Kato, Toju Tanaka, Toshihiro Ohura, Yasuyuki Suzuki, Nobuhiro Suzuki, Ryoji Kobayashi, Tomo Sawada, Hideo Mugishima, Toya Ohashi, Souichi Adachi, Mika Ishige-Wada, and Hiromasa Yabe
- Subjects
Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Mucopolysaccharidosis ,Biochemistry ,Time ,Iduronidase ,Young Adult ,Endocrinology ,Japan ,Internal medicine ,Mucopolysaccharidosis I ,Activities of Daily Living ,Genetics ,medicine ,Secondary Prevention ,Humans ,Enzyme Replacement Therapy ,Mucopolysaccharidosis type II ,Hurler syndrome ,Child ,Molecular Biology ,Glycosaminoglycans ,Mucopolysaccharidosis II ,Retrospective Studies ,business.industry ,Hematopoietic Stem Cell Transplantation ,Brain ,Mitral Valve Insufficiency ,Hunter syndrome ,Retrospective cohort study ,Enzyme replacement therapy ,medicine.disease ,Magnetic Resonance Imaging ,Surgery ,Treatment Outcome ,Child, Preschool ,Health Care Surveys ,Cohort ,Female ,business - Abstract
Hematopoietic stem cell transplantation (HSCT) has not been indicated for patients with mucopolysaccharidosis II (MPS II, Hunter syndrome), while it is indicated for mucopolysaccharidosis I (MPS I) patients
- Published
- 2012
46. Oxysterol changes along with cholesterol and vitamin D changes in adult phenylketonuric patients diagnosed by newborn mass-screening
- Author
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Akihiko Kimura, Yoshitami Sanayama, Ken-ichi Hirano, Hiromi Usui, Hironori Nagasaka, Yoshiyuki Okano, Susumu Yamato, Tatsuki Mizuochi, Mika Ishige-Wada, Akira Ohtake, Tohru Yorifuji, Tomozumi Takatani, Saori Nakagawa, Eri Hasegawa, Hirokazu Tsukahara, Takashi Miida, Toshihiro Ohura, Hiroshi Mochizuki, and Satoshi Hirayama
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Oxysterol ,Clinical Biochemistry ,Hepatic cholesterol ,Phenylalanine ,Biochemistry ,chemistry.chemical_compound ,Internal medicine ,Phenylketonurias ,polycyclic compounds ,Vitamin D and neurology ,medicine ,Humans ,Mass Screening ,Vitamin D ,Ketocholesterols ,Mass screening ,Cholesterol ,business.industry ,Biochemistry (medical) ,nutritional and metabolic diseases ,General Medicine ,Metabolism ,medicine.disease ,Hypocholesterolemia ,Endocrinology ,chemistry ,lipids (amino acids, peptides, and proteins) ,Female ,sense organs ,business - Abstract
Phenylketonuria (PKU) possibly leads to hypocholesterolemia and lowered vitamin D (VD) status. Metabolism of oxysterols linking with those of cholesterol and VD has never been examined in PKU.Blood oxysterols along with blood phenylalanine, lipids and VD were examined for 33 PKU adults aged 21-38 years and 20 age-matched healthy controls.Total- and low-density cholesterols, and 25-hydroxy VD(3) were decreased significantly in the PKU group (cholesterols, 10% decrease; 25-hydroxy VD(3) 35% decrease vs. the control group). 24S-hydroxycholesterol (24S-OHC) eliminating brain cholesterol, and 27-OHC and 7α-hydroxycholesterol (7α-OHC) representing peripheral and hepatic cholesterol elimination, respectively, were significantly decreased in PKU group: 24S-OHC, 25% decrease, p.01; 27-OHC and 7α-OHC, 35-40% decrease, p.001. 7β-Hydroxycholesterol (7β-OHC) reflecting oxidative stress was increased significantly in PKU group (p.05). 7α-OHC and 27-OHC levels in PKU group always showed similar values, regardless of other parameters while the 24S-OHC and 7β-OHC levels decreased and increased, respectively, showing significant correlations with phenylalanine level (p.005). 27-OHC level showed a significant positive correlation with the 25-hydroxy VD(3) level in this group (p.001).Blood oxysterol changes predominate over blood cholesterol changes and influence on VD status in adult PKU patients.
- Published
- 2012
47. Diabetes caused by Kir6.2 mutation: successful treatment with oral glibenclamide switched from continuous subcutaneous insulin infusion in the early phase of the disease
- Author
-
Nobuhiko, Nagano, Tatsuhiko, Urakami, Yusuke, Mine, Hirofumi, Watanabe, Ayako, Yoshida, Junichi, Suzuki, Hiroshi, Saito, Mika, Ishige, Shori, Takahashi, Hideo, Mugishima, and Tohru, Yorifuji
- Subjects
Male ,Glyburide ,Diabetes Mellitus ,Infant, Newborn ,Administration, Oral ,Humans ,Hypoglycemic Agents ,Insulin ,Potassium Channels, Inwardly Rectifying ,Infusions, Subcutaneous - Published
- 2012
48. Living-donor liver transplantation for propionic acidemia
- Author
-
Mureo, Kasahara, Seisuke, Sakamoto, Hiroyuki, Kanazawa, Chiaki, Karaki, Toshihiko, Kakiuchi, Takanobu, Shigeta, Akinari, Fukuda, Rika, Kosaki, Atsuko, Nakazawa, Mika, Ishige, Masayoshi, Nagao, Yosuke, Shigematsu, Tohru, Yorifuji, Yasuhiro, Naiki, and Reiko, Horikawa
- Subjects
Postoperative Complications ,Propionic Acidemia ,Treatment Outcome ,Carnitine ,Child, Preschool ,Living Donors ,Quality of Life ,Humans ,Infant ,Female ,Citrates ,Liver Transplantation ,Retrospective Studies - Abstract
Propionic acidemia is a rare autosomal recessive disorder affecting the catabolism of branched-chain amino acids because of a genetic defect in PCC. Despite the improvements in medical treatment with protein restriction, sufficient caloric intake, supplementation of l-carnitine, and metronidazole, patients with the severe form of propionic acidemia have life-threatening metabolic acidosis, hyperammonemia, and cardiomyopathy, which results in serious neurologic sequelae and sometimes death. This study retrospectively reviewed three children with neonatal-onset propionic acidemia who received LDLT. Between November 2005 and December 2010, 148 children underwent LDLT, with an overall patient survival of 90.5%, in our center. Three patients were indicated for transplantation because of propionic acidemia. All recipients achieved a resolution of metabolic derangement and better quality of life with protein restriction and medication, although urine methylcitrate and serum propionylcarnitine levels did not decrease markedly. LT can reduce the magnitude of progressive cardiac/neurologic disability as a result of poor metabolic control. Further evaluation is therefore required to determine the long-term suitability of this treatment modality.
- Published
- 2011
49. Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria
- Author
-
Hiromi Usui, Hirokazu Tsukahara, Yoshitami Sanayama, Takashi Miida, Tetsuya Ito, Tohru Yorifuji, Yoshiyuki Okano, Mika Ishige-Wada, Mitsuru Fukui, Toshihiro Ohura, Hironori Nagasaka, Makoto Yoshino, Satoshi Hirayama, Masaki Takayanagi, Akira Ohtake, and Osamu Sakamoto
- Subjects
Adult ,Male ,medicine.medical_specialty ,Erythrocytes ,Adolescent ,Diet therapy ,Thiobarbituric acid ,Endocrinology, Diabetes and Metabolism ,Phenylalanine ,medicine.disease_cause ,Nitric Oxide ,Biochemistry ,Superoxide dismutase ,chemistry.chemical_compound ,Young Adult ,Endocrinology ,Internal medicine ,Phenylketonurias ,Genetics ,medicine ,TBARS ,Humans ,Molecular Biology ,chemistry.chemical_classification ,biology ,Glutathione peroxidase ,Middle Aged ,Oxidative Stress ,chemistry ,biology.protein ,Female ,Asymmetric dimethylarginine ,Oxidative stress ,Biomarkers - Abstract
Few studies have looked at optimal or acceptable serum phenylalanine levels in later life in patients with phenylketonuria (PKU). This study examined the oxidative stress status of adolescents and adults with PKU. Forty PKU patients aged over fifteen years were enrolled, and were compared with thirty age-matched controls. Oxidative stress markers, anti-oxidant enzyme activities in erythrocytes, and blood anti-oxidant levels were examined. Nitric oxide (NO) production was also examined as a measure of oxidative stress. Plasma thiobarbituric acid reactive species and serum malondialdehyde-modified LDL levels were significantly higher in PKU patients than control subjects, and correlated significantly with serum phenylalanine level (P
- Published
- 2011
50. Efficacy of hematopoietic stem cell transplantation versus enzyme replacement therapy on brain function in patients with mucopolysaccharidosis type II
- Author
-
Norio Sakai, Shunichi Kato, Takashi Hamazaki, Yasuyuki Suzuki, Ken Tabuchi, Mika Ishige, Michiko Shinpo, Hiromasa Yabe, Motomichi Kosuga, Torayuki Okuyama, Hideo Mugishima, and Akemi Tanaka
- Subjects
business.industry ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Enzyme replacement therapy ,Hematopoietic stem cell transplantation ,Biochemistry ,Endocrinology ,Genetics ,Cancer research ,Medicine ,In patient ,Mucopolysaccharidosis type II ,business ,Molecular Biology ,Brain function - Published
- 2014
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