164 results on '"Takakuwa Y"'
Search Results
2. Robot-Assisted Surgery for Reversed Intestinal Malrotation with Concurrent Cecal Carcinoma: A Case Report.
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Kuwabara S, Takakuwa Y, Ishido K, Aoki Y, Yamamoto K, Shoji Y, Fukunaga A, Ichimura T, Manase H, and Hirano S
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- Humans, Male, Aged, 80 and over, Intestinal Volvulus surgery, Digestive System Abnormalities surgery, Digestive System Abnormalities complications, Adenocarcinoma surgery, Adenocarcinoma complications, Robotic Surgical Procedures, Cecal Neoplasms surgery, Cecal Neoplasms complications
- Abstract
BACKGROUND Reversed intestinal malrotation is an extremely rare disease, with an incidence of 1 in 250 000. In Japan, application of robotic-assisted colorectal cancer surgery is expected to increase. There are no reports of robot-assisted surgery for cecal cancer with reversed intestinal malrotation. CASE REPORT An 84-year-old Japanese man with epigastric pain and abdominal distention was referred to our hospital's Department of Gastroenterology for thorough examination. Colonoscopy revealed a semicircumferential type 2 tumor in the cecum and ascending colon. Gastrografin contrast study showed that the large intestine was entirely on the patient's right side and the small intestine was shifted to the left side. Contrast-enhanced computed tomography revealed enlarged lymph nodes near the tumor, and masses were observed at the liver, which were believed to be metastases. Following examination, reversed intestinal malrotation and concurrent cecal cancer was diagnosed. The patient was referred to our department for surgery and underwent robot-assisted ileocecal resection with D3 lymphadenectomy. The postoperative course was favorable, and patient was discharged on the sixth postoperative day, without complications. According to the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma 9th edition, the pathological diagnosis was pT4b (ileum), pN1b, cM1a (H1 [grade A]), and pStage IVa cancer. After considering tumor stage and patient's overall condition in consultation with his family, we decided against palliative systemic therapy. The patient was provided with best supportive care. CONCLUSIONS Robot-assisted surgery might be useful in manipulation of the dissection of adhesions, owing to its capacity for high-resolution 3-dimensional imaging and forceps manipulation, using articulated functions.
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- 2024
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3. Evaluating Cellularity Estimation Methods: Comparing AI Counting with Pathologists' Visual Estimates.
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Kiyuna T, Cosatto E, Hatanaka KC, Yokose T, Tsuta K, Motoi N, Makita K, Shimizu A, Shinohara T, Suzuki A, Takakuwa E, Takakuwa Y, Tsuji T, Tsujiwaki M, Yanai M, Yuzawa S, Ogura M, and Hatanaka Y
- Abstract
The development of next-generation sequencing (NGS) has enabled the discovery of cancer-specific driver gene alternations, making precision medicine possible. However, accurate genetic testing requires a sufficient amount of tumor cells in the specimen. The evaluation of tumor content ratio (TCR) from hematoxylin and eosin (H&E)-stained images has been found to vary between pathologists, making it an important challenge to obtain an accurate TCR. In this study, three pathologists exhaustively labeled all cells in 41 regions from 41 lung cancer cases as either tumor, non-tumor or indistinguishable, thus establishing a "gold standard" TCR. We then compared the accuracy of the TCR estimated by 13 pathologists based on visual assessment and the TCR calculated by an AI model that we have developed. It is a compact and fast model that follows a fully convolutional neural network architecture and produces cell detection maps which can be efficiently post-processed to obtain tumor and non-tumor cell counts from which TCR is calculated. Its raw cell detection accuracy is 92% while its classification accuracy is 84%. The results show that the error between the gold standard TCR and the AI calculation was significantly smaller than that between the gold standard TCR and the pathologist's visual assessment (p<0.05). Additionally, the robustness of AI models across institutions is a key issue and we demonstrate that the variation in AI was smaller than that in the average of pathologists when evaluated by institution. These findings suggest that the accuracy of tumor cellularity assessments in clinical workflows is significantly improved by the introduction of robust AI models, leading to more efficient genetic testing and ultimately to better patient outcomes.
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- 2024
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4. Efficacy and safety of tumor necrosis factor inhibitors for systemic juvenile idiopathic arthritis: a systematic review.
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Ishikawa T, Nishimura K, Okamoto N, Akamine K, Inoue N, Irabu H, Kato K, Keino H, Kojima M, Kubo H, Maruyama K, Mizuta M, Shabana K, Shimizu M, Sugita Y, Takakuwa Y, Takanashi S, Takase H, Umebayashi H, Umezawa N, Yamanishi S, Yamazaki K, Yashiro M, Yasumi T, and Mori M
- Abstract
Objectives: This systematic review assessed the efficacy and safety of tumor necrosis factor (TNF) inhibitors in patients with systemic juvenile idiopathic arthritis (JIA)., Methods: Studies were searched using PubMed, Embase, Cochrane, Ichushi-Web, and clinical trial registries (from 2000 to 2021). The risk of bias was assessed using the Cochrane Risk of Bias version 2 for randomized controlled trials (RCTs) and the manual for development clinical practice guidelines by Minds, a project promoting evidence-based medicine in Japan, for observational studies., Results: One RCT and 22 observational studies were included. In the RCT on infliximab, the American College of Rheumatology pediatric (ACR Pedi) 30/50/70 responses at 14 weeks were 63.8%/50.0%/22.4%, with relative risks of 1.30 (95% confidence interval [CI]: 0.94-1.79)/1.48 (95% CI: 0.95-2.29)/1.89 (95% CI: 0.81-4.40), respectively. In the observational studies, ACR Pedi 30/50/70 responses for etanercept at 12 months were 76.7%/64.7%/46.4%, respectively. Infliximab treatment caused anaphylaxis in 17% and an infusion reaction in 23% of patients. The incidence of macrophage activation syndrome, serious infection and malignancy caused by TNF inhibitors was 0%-4%., Conclusions: Thus, although TNF inhibitors were relatively safe, they were unlikely to be preferentially administered in patients with systemic JIA because of their inadequate efficacy. Further studies, particularly well-designed RCTs, are necessary to confirm the efficacy and safety of TNF inhibitors for systemic JIA., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)
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- 2024
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5. Efficacy and safety of abatacept for systemic juvenile idiopathic arthritis: a systematic review.
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Nishimura K, Ishikawa T, Okamoto N, Akamine K, Inoue N, Irabu H, Kato K, Keino H, Kojima M, Kubo H, Maruyama K, Mizuta M, Shabana K, Shimizu M, Sugita Y, Takakuwa Y, Takanashi S, Takase H, Umebayashi H, Umezawa N, Yamanishi S, Yamazaki K, Yashiro M, Yasumi T, and Mori M
- Abstract
Objectives: This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA)., Methods: Studies published between 2000 and 2021 were searched using PubMed, Embase, Cochrane, Ichushi-Web and clinical trial registries. The risk of bias was assessed according to the manual for development clinical practice guidelines by Minds, a project to promote evidence-based medicine in Japan., Results: Seven observational studies were included. American College of Rheumatology pediatric 30/50/70 responses at 3, 6 and 12 months were 64.8%/50.3%/27.9%, 85.7%/71.4%/42.9% and 80.0%/50.0%/40.0%, respectively. Outcomes on systemic symptoms, joint symptoms and activities of daily living were not obtained. No macrophage activation syndrome or infusion reaction occurred. Serious infection occurred in 2.6% of cases., Conclusions: Abatacept improved the disease activity index. In addition, abatacept was as safe as interleukin-6 (IL -6) and IL-1 inhibitors. However, both the efficacy and safety data in this systematic review should be reviewed with caution because their quality of evidence is low or very low. Further studies are needed to confirm the efficacy and safety of abatacept for systemic JIA, especially its efficacy on joint symptoms., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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6. Nursing students' self-assessed level of nursing skills at the time of graduation in a Japanese University: A retrospective observational study.
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Notsu M, Naito T, Notsu A, Saito A, Hiraoka R, Suzuki E, Takano S, Yoda M, Takakuwa Y, Yokoyama E, and Sakai T
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Objective: This study aimed to clarify nursing students' self-assessed levels of nursing skills at a nursing university at graduation and discuss how education and clinical experiences for students and post-licensure nurses should be improved, especially focusing on oncology nursing., Methods: The study population comprised fourth-year students from 2017 to 2019 at the Faculty of Health Science and Nursing, Juntendo University, who had completed all stipulated clinical placements. The Japanese government determined 141 nursing skills and their target levels. Students subjectively evaluated their achieved levels for the 141 nursing skills after the final clinical placement., Results: Of the 141 nursing skills, 81 (57%) were rated as "skills with easy-to-achieve targets" and five were rated as "skills with difficult-to-achieve targets." All nursing skills in the two subcategories of environmental adjustment skills and comfort management skills were rated as "skills with easy-to-achieve targets." Nursing skills with low target achievement rates were for patients with oral intake difficulties, unstable respiratory status, and those requiring glycemic control. These skills are also important in oncology nursing., Conclusions: It cannot be concluded that the nursing university students fully achieved the target levels of nursing skills, as determined by the Japanese government. These findings may facilitate discussions on teaching nursing skills and their target levels at the time of graduation from nursing universities or post-employment., (© 2024 The Author(s).)
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- 2024
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7. Long-term survival, causes of death, and prognostic factors for mortality in patients with microscopic polyangiitis and those with anti-neutrophil cytoplasmic antibody-positive interstitial lung disease: A single-center retrospective study.
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Takakuwa Y, Yamasaki Y, Matsushita H, Kiyokawa T, Mizushima M, Tonooka K, Nagafuchi H, Matsuoka S, Ooka S, and Kawahata K
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- Female, Humans, Antibodies, Antineutrophil Cytoplasmic, Retrospective Studies, Prognosis, Cause of Death, Lung, Microscopic Polyangiitis, Lung Diseases, Interstitial diagnosis, Idiopathic Pulmonary Fibrosis diagnosis
- Abstract
Aim: To elucidate the clinical features, long-term survival, and prognostic factors for mortality among patients with microscopic polyangiitis (MPA), including those with anti-neutrophil cytoplasmic antibody-positive interstitial lung disease (ILD) (ANCA-ILD), which could be a subset of its variant phenotype., Methods: We retrospectively included 76 consecutive patients between 2006 and 2014, diagnosed with MPA according to the European Medicines Agency algorithm using the Chapel Hill Consensus Conference definitions or ANCA-ILD. ILD was classified as usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia pattern using chest computed tomography., Results: The mean (standard deviation) age of the patients (female, 68%) was 69 (12) years. The median (interquartile range) follow-up period was 68 (33-95) months. Comorbid ILD and glomerulonephritis were observed in 44 (58%) (68% UIP) and 54 (71%) patients, respectively. Comorbid ILD was associated with low survival (P = .0563). There were 17 (39%) and 5 (16%) deaths in the ILD and non-ILD groups, respectively (P = .0404). In the ILD group, 6 and 5 of the deaths were attributed to infection and ILD progression, respectively. In the non-ILD group, 1 and 2 patients expired from subsequently developed ILD and aspiration pneumonia, respectively. Age ≥ 70 years (hazard ratio = 2.78; 95% confidential interval 1.15-6.70) and UIP (3.95; 1.60-9.77) were independent risk factors for mortality., Conclusion: Age ≥ 70 years and ILD with a UIP pattern were associated with high mortality, owing to susceptibility to infection and ILD progression. A more effective and less toxic treatment is required for progressive ILD., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)
- Published
- 2023
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8. Roles of excess minority carrier recombination and chemisorbed O 2 species at SiO 2 /Si interfaces in Si dry oxidation: Comparison between p-Si(001) and n-Si(001) surfaces.
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Tsuda Y, Yoshigoe A, Ogawa S, Sakamoto T, Yamamoto Y, Yamamoto Y, and Takakuwa Y
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This study provides experimental evidence for the following: (1) Excess minority carrier recombination at SiO
2 /Si interfaces is associated with O2 dissociative adsorption; (2) the x-ray induced enhancement of SiO2 growth is not caused by the band flattening resulting from the surface photovoltaic effect but by the electron-hole pair creation resulting from core level photoexcitation for the spillover of bulk Si electronic states toward the SiO2 layer; and (3) a metastable chemisorbed O2 species plays a decisive role in combining two types of the single- and double-step oxidation reaction loops. Based on experimental results, the unified Si oxidation reaction model mediated by point defect generation [S. Ogawa et al., Jpn. J. Appl. Phys., Part 1 59, SM0801 (2020)] is extended from the viewpoints of (a) the excess minority carrier recombination at the oxidation-induced vacancy site and (b) the trapping-mediated adsorption through the chemisorbed O2 species at the SiO2 /Si interface.- Published
- 2022
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9. Radical Resection for Second EGFR-mutated Primary Lung Cancer Following Immune Checkpoint Inhibitor Monotherapy for Stage IV Lung Adenocarcinoma.
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Horibe R, Hatakeyama T, Ishikawa T, Sawai T, Hashimoto M, Domen H, Takakuwa Y, Satoh M, and Nishiyama K
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- Aged, ErbB Receptors genetics, Female, Humans, Immune Checkpoint Inhibitors, Lung, Mutation, Adenocarcinoma of Lung drug therapy, Adenocarcinoma of Lung genetics, Adenocarcinoma of Lung surgery, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms surgery
- Abstract
A 78-year-old woman with multiple lung nodules, epithelial growth factor receptor (EGFR) exon 20 insertion mutations, and diagnosed with advanced lung adenocarcinoma (cT4N3M1a, stage IVA), was referred to our hospital. She received immune checkpoint inhibitor (ICI) therapy. The therapy showed remarkable antitumor effects; only a single nodule remained in the right upper lobe. The nodule was diagnosed as adenocarcinoma through a biopsy. We subsequently performed right upper lobectomy for multiple primary lung cancer (MPLC). The surgical specimen contained EGFR exon 19 deletion mutations and not exon 20 insertion mutations.
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- 2022
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10. A new goniopholidid from the Upper Jurassic Morrison Formation, USA: novel insight into aquatic adaptation toward modern crocodylians.
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Yoshida J, Hori A, Kobayashi Y, Ryan MJ, Takakuwa Y, and Hasegawa Y
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Goniopholididae is a group of basal neosuchian crocodyliforms closely related to Paralligatoridae and Eusuchia that lived during the Jurassic and Early Cretaceous. Goniopholidids have the long, flat snout and secondary palate of modern crocodylians, the acquisition of which is regarded as a key feature in the early evolution of crocodylian body plan and their aquatic adaptation. Here, we report a new species, Amphicotylus milesi , with the description from the best-preserved specimen to date of Goniopholididae from Wyoming, USA. Its posterior extension of the nasopharyngeal passage (pterygoid secondary palate) and the shortening and dorsal deflection of the ceratobranchial suggest that basal neosuchians could raise their gular valve to separate oral and pharyngeal cavities as in modern crocodylians. The anatomy of Amphicotylus milesi sheds light on the acquisition of this new respiratory system in the crocodyliform evolution and their early aquatic adaptation, leading to modern crocodylians., (© 2021 The Authors.)
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- 2021
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11. Usefulness of 123I-BMIPP and 201TlCl nuclide scintigraphy in evaluation of myocarditis in patients with polymyositis or dermatomyositis.
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Okada Y, Takakuwa Y, Ooka S, Ogawa Y, Kawahata K, Kobayashi Y, Yamaguchi K, and Akashi Y
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- Female, Humans, Male, Middle Aged, Retrospective Studies, Tomography, Emission-Computed, Single-Photon, Dermatomyositis, Iodine Radioisotopes administration & dosage, Myocarditis diagnostic imaging, Radiopharmaceuticals administration & dosage, Thallium Radioisotopes administration & dosage, Ventricular Dysfunction, Left diagnostic imaging
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Abstract: To investigate the usefulness of 123I-BMIPP/201TlCl scintigraphy for evaluating the presence of myocarditis in patients with polymyositis (PM) or dermatomyositis (DM).We performed a retrospective study of 26 patients diagnosed with new-onset active PM/DM who underwent 123I-BMIPP/201TlCl scintigraphy between 01 April 2010 and 20 March 2015. We determined the 123I-BMIPP/201TlCl ratio and grouped the patients according to presence or absence of a mismatch. We evaluated the relationship between mismatch and the laboratory and echocardiographic findings.Mismatch was found in 13 (50%) patients. There was no statistically significant difference in age, cardiac troponin T, myoglobin, myosin light chain, aldolase levels, E wave/A wave ratio, right ventricular systolic pressure between the mismatch and non-mismatch groups. Left ventricular end-diastolic and end-systolic dimensions were significantly greater in the mismatch group (45.0 vs 42.5 mm, P = < .01 and 29.5 mm vs 25.0 mm, P < .01). Left ventricular ejection fraction was significantly lower in the mismatch group (63.5% vs 71.5%, P = .04). Significant inverse correlation (r = -0.44, P = .03) was observed between left ventricular ejection fraction and mismatch ratio.The use of 123I-BMIPP/ 201TlCl scintigraphy may be considered for evaluating myocarditis in patients with PM/DM., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2021
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12. [Chemo-Resistant Breast Carcinoma with Cartilaginous Differentiation Manifestation after Neoadjuvant Chemotherapy-A Case Report].
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Konishi K, Araya J, Nagabuchi M, Sakamoto T, Takakuwa Y, Sasaki M, Watanabe K, and Hirano S
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- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Axilla, Female, Humans, Lymph Node Excision, Mastectomy, Middle Aged, Breast Neoplasms drug therapy, Breast Neoplasms surgery, Neoadjuvant Therapy
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A 49-year-old woman was admitted to our hospital because of a tumor in her right breast. The tumor was localized to the C area and was approximately 3 cm in size. A right axillary lymphadenopathy was also found. Histopathological examination and needle biopsy of the breast tumor revealed invasive lobular carcinoma, and she was diagnosed with Stage ⅡB triple-negative breast cancer(cT2N1M0). Paclitaxel plus bevacizumab chemotherapy followed by ddAC chemotherapy was administered as neoadjuvant chemotherapy, but the tumor remained stable. Thus, she underwent mastectomy and lymph node dissection. Pathological findings of the resected specimen showed invasive carcinoma with cartilaginous differentiation. She was then treated with capecitabine 15 days after the surgery; however, multiple lung metastases were found on CT after 6 courses. Therefore, she was transferred to another hospital and received other chemotherapies, but died after 5 months.
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- 2021
13. Possible Pseudo-progression of Non-small Cell Lung Carcinoma in a Patient With Clinical Hyper-progression Associated With Trousseau Syndrome Who Was Treated With Pembrolizumab: A Case Report.
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Shionoya Y, Hirohashi Y, Takahashi H, Hashimoto M, Nishiyama K, Takakuwa Y, Nakatsugawa M, Kubo T, Kanaseki T, Tsukahara T, and Torigoe T
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- Aged, CD8-Positive T-Lymphocytes drug effects, Disease Progression, Humans, Male, Antibodies, Monoclonal, Humanized therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung pathology, Immune Checkpoint Inhibitors therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms pathology
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Background/aim: Immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab, have recently been shown to have clinical benefits in patients with advanced non-small cell lung cancer (NSCLC). The novel tumour responses to these agents are changing the management of patients with cancer. Pseudo-progression of disease (pseudo-PD), that is, an initial flare followed by shrinkage of the tumour, has been described as a distinctive response to ICIs. However, pseudo-PD manifest initial progression and is difficult to segregate with hyper progressive disease (HPD). We, therefore, analysed a case with pseudo-PD histologically., Patients and Methods: A 68-year-old Japanese man with stage IV non-small cell lung carcinoma (NSCLC) was treated by anti-PD-1 antibody (pembrolizumab). Four weeks later after second time treatment with pembrolizumab, the patient showed severe melena followed by Trousseau syndrome and died at day 174 after first treatment by pembrolizumab, suggesting HPD clinically. Primary lesion and metastatic lesions were analysed histologically., Results: Histological analysis revealed that NSCLC cells expressed PD-L1, and CD8+ tumor-infiltrated lymphocytes (TILs) were observed. CD8+ TILs showed higher rates of PD-1 indicating that lesions were of the inflamed type and the case was pseudo-PD. Furthermore, it was found that cancer cells expressed MUC1., Conclusion: The clinical appearance of the case was aggressive after treatment by pembrolizumab, and the case seemed to be HPD; however, histological analysis revealed that the case was likely pseudo-PD. Therefore, careful histological evaluation is important when investigating the clinical response to an ICI and mucin expression might be a predictive marker for Trousseau syndrome., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
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- 2021
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14. Treatment of myocardial fibrosis in systemic sclerosis with tocilizumab.
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Ishizaki Y, Ooka S, Doi S, Kawasaki T, Sakurai K, Mizushima M, Kiyokawa T, Takakuwa Y, Tonooka K, and Kawahata K
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- Adult, Cardiomyopathies etiology, Fatty Acids pharmacokinetics, Female, Fibrosis, Humans, Iodobenzenes pharmacokinetics, Mycophenolic Acid therapeutic use, Scleroderma, Systemic complications, Antibodies, Monoclonal, Humanized therapeutic use, Cardiomyopathies drug therapy, Myocardium pathology, Scleroderma, Systemic drug therapy
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- 2021
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15. Reduction in flippase activity contributes to surface presentation of phosphatidylserine in human senescent erythrocytes.
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Seki M, Arashiki N, Takakuwa Y, Nitta K, and Nakamura F
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- Adenosine Triphosphatases genetics, Adenosine Triphosphate metabolism, Biological Transport, Calcium metabolism, Cell-Derived Microparticles metabolism, Cellular Senescence genetics, Enzyme Activation, Erythrocyte Membrane metabolism, Humans, Membrane Transport Proteins genetics, Potassium metabolism, Adenosine Triphosphatases metabolism, Erythrocytes metabolism, Membrane Transport Proteins metabolism, Phosphatidylserines metabolism
- Abstract
Mature human erythrocytes circulate in blood for approximately 120 days, and senescent erythrocytes are removed by splenic macrophages. During this process, the cell membranes of senescent erythrocytes express phosphatidylserine, which is recognized as a signal for phagocytosis by macrophages. However, the mechanisms underlying phosphatidylserine exposure in senescent erythrocytes remain unclear. To clarify these mechanisms, we isolated senescent erythrocytes using density gradient centrifugation and applied fluorescence-labelled lipids to investigate the flippase and scramblase activities. Senescent erythrocytes showed a decrease in flippase activity but not scramblase activity. Intracellular ATP and K
+ , the known influential factors on flippase activity, were altered in senescent erythrocytes. Furthermore, quantification by immunoblotting showed that the main flippase molecule in erythrocytes, ATP11C, was partially lost in the senescent cells. Collectively, these results suggest that multiple factors, including altered intracellular substances and reduced ATP11C levels, contribute to decreased flippase activity in senescent erythrocytes in turn to, present phosphatidylserine on their cell membrane. The present study may enable the identification of novel therapeutic approaches for anaemic states, such as those in inflammatory diseases, rheumatoid arthritis, or renal anaemia, resulting from the abnormally shortened lifespan of erythrocytes., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)- Published
- 2020
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16. Association of Epstein-Barr virus with regression after withdrawal of immunosuppressive drugs and subsequent progression of iatrogenic immunodeficiency-associated lymphoproliferative disorders in patients with autoimmune diseases.
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Fujimoto K, Hatanaka KC, Hatanaka Y, Kasahara I, Yamamoto S, Tsuji T, Nakata M, Takakuwa Y, Haseyama Y, Oyamada Y, Yonezumi M, Suzuki H, Sakai H, Noguchi H, Mori A, Nishihara H, Teshima T, and Matsuno Y
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- Adult, Aged, Aged, 80 and over, Antibodies, Viral blood, Antibodies, Viral immunology, Autoimmune Diseases drug therapy, Biomarkers, Female, Humans, Immunoglobulin G blood, Immunoglobulin G immunology, Immunoglobulin M blood, Immunoglobulin M immunology, Immunologic Deficiency Syndromes drug therapy, Immunosuppressive Agents therapeutic use, Lymphoproliferative Disorders therapy, Male, Middle Aged, Odds Ratio, Patient Outcome Assessment, Severity of Illness Index, Autoimmune Diseases complications, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Infections virology, Herpesvirus 4, Human drug effects, Herpesvirus 4, Human physiology, Immunologic Deficiency Syndromes complications, Immunosuppressive Agents adverse effects, Lymphoproliferative Disorders diagnosis, Lymphoproliferative Disorders etiology
- Abstract
Patients with autoimmune diseases (AIDs) may develop lymphoproliferative disorders (LPDs) during treatment with immunosuppressive agents (IS) such as methotrexate (MTX), biological agents, or tacrolimus. Some LPDs in patients with AIDs (AID-LPDs) regress after withdrawal of IS, and a high incidence of Epstein-Barr virus (EBV) positivity in such patients has been reported. To identify characteristics and factors predictive of the response to treatment and disease progression, we retrospectively analyzed clinical and histopathological data for 81 patients with AID-LPDs. Almost all of them (96%) had been treated with MTX. Diffuse large B cell lymphoma was the most common LPD type (61%) and seven patients (9%) had classical Hodgkin lymphoma (CHL). EBV was detected by in situ hybridization with an EBV-encoded small RNA (EBER) probe in 43% of the examined cases. In 59 patients, IS was discontinued as the initial treatment, resulting in regression of LPDs in 69% of them, and multivariate analysis showed that EBER positivity was an independent factor predictive of such regression (p = 0.022). Two-year progression-free survival (PFS) and overall survival for the patients overall were 63% and 83%, respectively. Poor PFS was associated with advanced stage (p = 0.024), worse performance status (PS, p = 0.031), CHL histology (p = 0.013), and reactivation of EBV-related antibodies (p = 0.029). In conclusion, EBV positivity demonstrated using an EBER probe is useful for prediction of successful regression after withdrawal of IS in patients with AID-LPDs. Patients with advanced stage disease, worse PS, CHL histology, or reactivation of EBV-related antibodies should be closely monitored after initial treatment., (© 2020 John Wiley & Sons Ltd.)
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- 2020
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17. Gas Barrier Properties of Chemical Vapor-Deposited Graphene to Oxygen Imparted with Sub-electronvolt Kinetic Energy.
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Ogawa S, Yamaguchi H, Holby EF, Yamada T, Yoshigoe A, and Takakuwa Y
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Graphene gas-barrier performance holds great interest from both scientific and technological perspectives. Using in situ synchrotron X-ray photoelectron spectroscopy, we demonstrate that chemical vapor-deposited monolayer graphene loses its gas-barrier performance almost completely when oxygen molecules are imparted with sub-electronvolt kinetic energy but retains its gas-barrier performance when the molecules are not energized. The permeation process is nondestructive. Molecular dynamics-based simulation suggests kinetic energy-mediated chemical reactions catalyzed by common graphene defects as a responsible mechanism.
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- 2020
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18. Non-bacterial cystitis with increased expression of programmed death-ligand 1 in the urothelium: An unusual immune-related adverse event during treatment with pembrolizumab for lung adenocarcinoma.
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Ueki Y, Matsuki M, Kubo T, Morita R, Hirohashi Y, Sato S, Horibe R, Matsuo K, Tsukahara T, Kanaseki T, Takakuwa Y, Satoh M, Itoh N, and Torigoe T
- Abstract
Introduction: Immune checkpoint inhibitors are now a standard therapeutic option for lung adenocarcinoma. However, Immune checkpoint inhibitors often induce various immune-related adverse events., Case Presentation: The patient was a 78-year-old woman with lung adenocarcinoma who had a partial response to pembrolizumab. During treatment, she complained of pollakiuria and nocturia with painful micturition. Histological analysis revealed infiltration of CD8-positive and/or TIA-1 cytotoxic granule-associated RNA binding protein-positive lymphocytes and programmed death-ligand 1 expression in the urothelium. A diagnosis of immune-related adverse event cystitis was made based on these clinical and pathological findings. The patient's subjective symptoms and findings on cystoscopy improved dramatically after treatment with prednisolone., Conclusion: Immune checkpoint inhibitors-induced cystitis is extremely rare. This report is the first to include an immunohistochemical analysis of the urothelial epithelium in immune-related adverse event cystitis and describes an instructive case., Competing Interests: K. Matsuo is an employee of Sapporo Clinical Laboratory Inc. The other authors have no conflict of interest in regard to this report., (© 2020 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Urological Association.)
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- 2020
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19. Campylobacter upsaliensis isolated from a giant hepatic cyst.
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Ohkoshi Y, Sato T, Murabayashi H, Sakai K, Takakuwa Y, Fukushima Y, Nakajima C, Suzuki Y, and Yokota SI
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- Aged, Anti-Bacterial Agents administration & dosage, Campylobacter Infections microbiology, Campylobacter Infections therapy, Campylobacter upsaliensis genetics, Catheters, Cefoperazone administration & dosage, Cysts microbiology, Cysts therapy, DNA, Bacterial genetics, DNA, Bacterial isolation & purification, Drug Therapy, Combination, Humans, Liver diagnostic imaging, Liver microbiology, Liver Abscess microbiology, Liver Abscess therapy, Male, Multilocus Sequence Typing, Paracentesis instrumentation, Sulbactam administration & dosage, Tomography, X-Ray Computed, Treatment Outcome, Campylobacter Infections diagnosis, Campylobacter upsaliensis isolation & purification, Cysts diagnosis, Liver Abscess diagnosis
- Abstract
Campylobacter upsaliensis is an enteropathogenic bacterium in animals, and is also rarely isolated from humans, where it can cause enteritis and bacteremia. This report describes the first case of isolation of C. upsaliensis from an infected giant hepatic cyst. This bacterium could not be cultured from abscess punctuate in a usual Campylobacter-selection medium (charcoal cefoperazone deoxycholate agar medium), because of high concentration of cefoperazone as a selection agent. It could not identified by matrix-assisted laser desorption ionization-time of flight mass spectrum. Rather, it was identified as C. upsaliensis by whole genome sequencing, including by multilocus sequence typing., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2020
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20. Acute progressing hepatic angiosarcoma: An autopsy case report.
- Author
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Inoue M, Matsumoto M, Sakuhara Y, Takakuwa Y, Yoshii S, Akakura N, and Sakamoto N
- Abstract
A man in his 50s presented with pitting edema of both lower legs and abdominal distension as his chief complaint. His personal medical history and family history were unremarkable, except that he was a heavy drinker consuming 66 g of alcohol per day and a heavy smoker. Blood tests upon admission showed slight hepatic dysfunction, thrombocytopenia, jaundice, hypoalbuminemia, and decreased coagulability. Tumor marker tests showed elevated levels of CA19-9 and PIVKA-II. Contrast-enhanced computed tomography revealed enhancement of multiple masses predominantly in the right lobe of the liver in the early phase, followed by diffuse enhancement of the entire liver in the delayed phase. Hepatic arteriography demonstrated large hemangioma-like lesions corresponding to the masses revealed by computed tomography. That findings seemed to be cotton wool appearance. On magnetic resonance images, there were multiple mass-like lesions that showed homogeneous or heterogeneous low signal intensity on T1-weighted images, and clearly high signal intensity on T2-weighted images. The findings were atypical and no definite diagnosis could be made. Hepatic failure then rapidly worsened, and the patient died on hospital day 20. Autopsy led to the diagnosis of hepatic angiosarcoma., (© 2020 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)
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- 2020
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21. High plasma mycophenolate acid concentration in the early phase of induction therapy predicts good renal outcome in lupus nephritis.
- Author
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Kiyokawa T, Hanaoka H, Iida H, Ishimori K, Takakuwa Y, Okazaki T, Ozaki S, and Kawahata K
- Subjects
- Adult, Biomarkers blood, Female, Humans, Lupus Nephritis blood, Male, Middle Aged, Immunosuppressive Agents therapeutic use, Lupus Nephritis drug therapy, Mycophenolic Acid blood, Remission Induction methods
- Abstract
Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis. Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated. Results: Ten patients were enrolled. A significantly higher AUC
0-12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without ( p = .03). All the patients with high MPA-AUC0-12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0-12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01-1.45, p = .02). Conclusion: The high AUC0-12 of MPA at the early phase of induction therapy may predict good renal response.- Published
- 2020
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22. Efficacy and Safety of Complete Endoscopic Resection of Colorectal Neoplasia Using a Stepwise Endoscopic Protocol with SOUTEN, a Novel Multifunctional Snare.
- Author
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Yoshii S, Kubo M, Matsumoto M, Kikuchi T, and Takakuwa Y
- Abstract
Background/aims: A multifunctional snare SOUTEN has a sharp tip at the top of the snare loop that enables incision of the mucosa, dissection of the submucosal layer, and snaring of lesion. This study assessed the efficacy and safety of complete endoscopic resection of colorectal neoplasia using SOUTEN., Methods: We analyzed the rates of gross en bloc resection and complete resections of 108 consecutive tumors from 69 patients resected by precutting endoscopic mucosal resection (precutting), hybrid endoscopic submucosal dissection (hybrid), or conventional endoscopic submucosal dissection (conventional) using SOUTEN., Results: Out of the 108 tumors, 50 were resected by precutting, 27 were resected by hybrid after attempting precutting, and the remaining 31 were resected by conventional after attempting precutting and hybrid resections. The median tumor sizes were 14.5 mm for precutting, 16.4 mm for hybrid, and 21.1 mm for conventional. The success rate of gross en bloc resection and histological complete resection were 100% and 94.0% for precutting, 96.4% and 96.4% for hybrid, and 100% and 100% for conventional method, respectively. No procedure-related complication occurred., Conclusion: By using SOUTEN, precutting and hybrid were successfully performed on 10-30 mm tumors with a shorter procedure time than conventional without major complications.
- Published
- 2020
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23. Concurrent onset of acute lupus myocarditis, pulmonary arterial hypertension and digital gangrene in a lupus patient: a possible role of vasculitis to the rare disorders.
- Author
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Ando T, Yamasaki Y, Takakuwa Y, Iida H, Asari Y, Suzuki K, Uchida M, Kotoku N, Tanabe Y, Chosokabe M, Takahashi M, Suzuki K, Akashi YJ, Yamada H, and Kawahata K
- Subjects
- Adult, Anticoagulants administration & dosage, Cyclophosphamide administration & dosage, Female, Humans, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic drug therapy, Myocarditis drug therapy, Prednisone administration & dosage, Pulmonary Arterial Hypertension drug therapy, Treatment Outcome, Vasculitis complications, Gangrene diagnosis, Gangrene etiology, Lupus Erythematosus, Systemic complications, Myocarditis diagnosis, Myocarditis etiology, Pulmonary Arterial Hypertension diagnosis, Pulmonary Arterial Hypertension etiology
- Abstract
Acute lupus myocarditis and pulmonary arterial hypertension (PAH) are rare complications associated with systemic lupus erythematosus (SLE). No previous reports have shown the coexistence of these disorders. Here we present a 41-year-old patient with SLE who concurrently developed severe acute lupus myocarditis and PAH with digital gangrene as an initial manifestation. Acute lupus myocarditis and PAH were successfully treated with prednisolone and intravenous cyclophosphamide pulse therapy (600-700 mg × 6) along with anticoagulant therapy. Catheter-directed thrombolysis was required for digital gangrene caused by vasculitis. Concurrent development of these rare disorders may represent a common mechanism such vasculitis as an underlining cause of SLE.
- Published
- 2020
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24. Adult-onset Still's disease-associated interstitial lung disease represents severe phenotype of the disease with higher rate of haemophagocytic syndrome and relapse.
- Author
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Takakuwa Y, Hanaoka H, Kiyokawa T, Iida H, Ishimori K, Uekusa T, Yamada H, and Kawahata K
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Phenotype, Recurrence, Retrospective Studies, Tomography, X-Ray Computed, Ultrasonography, Lung Diseases, Interstitial diagnosis, Lung Diseases, Interstitial diagnostic imaging, Lung Diseases, Interstitial epidemiology, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic diagnostic imaging, Lymphohistiocytosis, Hemophagocytic epidemiology, Still's Disease, Adult-Onset complications, Still's Disease, Adult-Onset diagnosis
- Abstract
Objectives: Adult-onset Still's disease (AOSD) is an inflammatory disorder characterised by sustained fevers, arthritis, and skin involvement. Interstitial lung disease (ILD) is a rare manifestation, and its clinical characteristics have yet to be determined., Methods: We sought to examine the clinical characteristics of AOSD-associated ILD. We retrospectively investigated 78 patients diagnosed as AOSD. ILD was diagnosed based on chest high-resolution computed tomography (HRCT). Clinical characteristics were compared between patients with and without ILD. Relapse was defined as sustained fevers, re-emergence of arthritis, and skin involvement after remission. We further investigated the pathological features of ILD on available samples., Results: Patients with ILD, found in 9 of 78 (11.5 %), had older age of onset (mean age 62.6) than those without ILD (mean age 38.8) (p<0.01). The 3-year survival rates were comparable between patients with ILD (92.5%) and those without ILD (88.9%) (p=0.23). Patients with ILD had a higher cumulative rate of haemophagocytic syndrome (HPS) and relapse than those without (p<0.0001 and p=0.009, respectively). Chest HRCT showed marked thickening of the interlobular septa, the bronchovascular bundles, or the visceral pleura in all cases. There was no honeycomb or volume loss. Pulmonary pathological findings revealed marked thickening of the visceral pleura and the interlobular septa., Conclusions: Patients with ILD might have higher risks for HPS and relapse. Careful observation and appropriate therapeutic intervention might be needed.
- Published
- 2019
25. Glucocorticoid, immunosuppressant, hydroxychloroquine monotherapy, or no therapy for maintenance treatment in systemic lupus erythematosus without major organ manifestations.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, and Kawahata K
- Subjects
- Adult, Aged, Antirheumatic Agents therapeutic use, Female, Humans, Male, Middle Aged, Prednisolone therapeutic use, Retrospective Studies, Severity of Illness Index, Time Factors, Treatment Outcome, Glucocorticoids therapeutic use, Hydroxychloroquine therapeutic use, Immunosuppressive Agents therapeutic use, Lupus Erythematosus, Systemic drug therapy
- Abstract
Objective: To study maintenance therapy after achievement of the lowest possible disease activity in systemic lupus erythematosus (SLE) without major organ manifestations., Methods: We retrospectively evaluated patients with SLE who visited our hospital from Jan 2015 to Feb 2018 and were taking prednisolone (PSL) < 10 mg/day. After excluding those with neuropsychiatric SLE or severe lupus nephritis, patients were divided into four groups according to their maintenance monotherapy treatment, namely, prednisolone (PSL), immunosuppressant (IS), hydroxychloroquine (HCQ), and no drugs. The groups were then compared with regard to cumulative flare rate and changes in SLE Disease Activity Index (SLEDAI)., Results: There were 47 patients on PSL, 10 on IS, 5 on HCQ, and 11 on no drugs. Flare rate was higher in the no drug group, and no patients with the IS or HCQ group experienced a flare (p = 0.003). A reduction in SLEDAI was only seen in the IS and HCQ groups (p = 0.05 and p = 0.03, respectively). There were no differences in adverse events among groups during the study period., Conclusions: Our results suggest that the cessation of all drugs is associated with disease flare for SLE patients without major organ manifestations. IS or HCQ monotherapy might be a reasonable maintenance strategy comparing with steroid monotherapy. Key Point • Immunosuppressant or hydroxychloroquine monotherapy appears to be a reasonable maintenance strategy.
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- 2019
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26. ATP11C T418N, a gene mutation causing congenital hemolytic anemia, reduces flippase activity due to improper membrane trafficking.
- Author
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Arashiki N, Niitsuma K, Seki M, Takakuwa Y, and Nakamura F
- Subjects
- Adenosine Triphosphatases metabolism, Anemia, Hemolytic, Congenital metabolism, Animals, Biological Transport genetics, COS Cells, Chlorocebus aethiops, Endoplasmic Reticulum metabolism, Erythrocyte Membrane chemistry, Erythrocyte Membrane metabolism, Erythrocytes metabolism, Female, HeLa Cells, Humans, Immunoblotting, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Membrane Transport Proteins metabolism, Phosphatidylserines chemistry, Phosphatidylserines metabolism, Adenosine Triphosphatases genetics, Anemia, Hemolytic, Congenital genetics, Genetic Predisposition to Disease genetics, Membrane Transport Proteins genetics, Mutation, Missense
- Abstract
Distribution of phosphatidylserine (PS) in the erythrocyte membrane is essential for its activity. Flippase transports phospholipids from the outer to the inner leaflet of the lipid bilayer and maintains asymmetric distribution of phospholipids in the plasma membrane. ATP11C, a flippase, catalyzes PS flipping at the plasma membrane in association with cell cycle control protein 50A (CDC50A). ATP11C T418 N mutation causes 90% decrease in erythrocyte PS-flippase activity. However, the mechanism of the activity reduction remains unknown. To study the endogenous expression of ATP11C in erythrocytes, we produced a monoclonal antibody against human ATP11C. Immunoblotting analyses with this antibody revealed the absence of ATP11C in erythrocyte membranes derived from a patient with the T418 N mutation. Transiently expressed ATP11C wild-type in cultured cells localized in the cell membranes in the presence of CDC50A. Contrastingly, ATP11C T418 N mutants stacked at the endoplasmic reticulum (ER) even in the presence of CDC50A, suggesting improper intracellular trafficking. Expression of the T418 N mutant in cultured cells was lower than that in the wild-type. However, reduced expression of the T418 N mutant was partially restored by treatment with proteasome inhibitors, suggesting ER-associated degradation of the mutant protein. Cells expressing T418 N did not show flippase activity at the plasma membrane. These data show that the loss of PS-flippase activity in erythrocytes carrying ATP11C T418 N mutation is due to impaired enzymatic activity, improper membrane trafficking, and increased proteasome degradation., (Copyright © 2019 Elsevier Inc. All rights reserved.)
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- 2019
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27. A low perfusion-metabolic mismatch in 99m Tl and 123 I-BMIPP scintigraphy predicts poor prognosis in systemic sclerosis patients with asymptomatic cardiac involvement.
- Author
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Iida H, Hanaoka H, Okada Y, Kiyokawa T, Takakuwa Y, Yamada H, Okazaki T, Ozaki S, Yamaguchi K, Nakajima Y, and Kawahata K
- Subjects
- Aged, Asymptomatic Diseases, Cause of Death, Disease Progression, Echocardiography, Female, Fibrosis, Heart Diseases etiology, Heart Diseases mortality, Heart Diseases physiopathology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Myocardium pathology, Predictive Value of Tests, Prognosis, Retrospective Studies, Risk Assessment, Risk Factors, Scleroderma, Systemic diagnosis, Scleroderma, Systemic mortality, Coronary Circulation, Fatty Acids administration & dosage, Heart Diseases diagnostic imaging, Iodine Radioisotopes administration & dosage, Iodobenzenes administration & dosage, Myocardial Perfusion Imaging methods, Radiopharmaceuticals administration & dosage, Scleroderma, Systemic complications, Thallium administration & dosage
- Abstract
Aim: This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients., Methods: We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy using
99m thallium (99m Tl) and123 I-β-methyl-P-iodophenyl-pentadecanoic acid (123 I-BMIPP), UCG, and cardiac MRI. We calculated the mismatch score in scintigraphy by subtracting the uptake of123 I-BMIPP from that of99m Tl. Patients were divided into two groups according to whether they survived with no cardiac failure or subsequently proceeded to cardiac failure or death during the study period. We identified prognostic factors by analyzing99m Tl and123 I-BMIPP uptake, mismatch scores, UCG findings, and cardiac delayed enhancement on MRI. We also evaluated pathological evidence of myocardial fibrosis., Results: Of 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases., Conclusions: Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients., (© 2019 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)- Published
- 2019
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28. Histopathological differences of experimental aneurysms treated with bare platinum, fibered, and bioactive coils.
- Author
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Usami Y, Hirokawa N, Saitoh M, Okuda H, Someya M, Hasegawa T, Takakuwa Y, and Sakata KI
- Subjects
- Animals, Disease Models, Animal, Swine, Thrombosis pathology, Treatment Outcome, Embolization, Therapeutic methods, Intracranial Aneurysm therapy, Platinum chemistry
- Abstract
Purpose: To evaluate the histopathological features of experimental aneurysms embolized with bare platinum, fibered, and bioactive coils., Material and Methods: Twelve experimental aneurysms were constructed in three swine. The aneurysms were divided into four groups and were embolized using a bare platinum coil alone (P group, n = 2), a bioactive coil alone (B group, n = 2), a combination of fibered and bare platinum coils (F/P group, n = 4) and a combination of fibered and bioactive coils (F/B group, n = 4). Histopathological data for all aneurysms recorded at 63 days were analyzed in terms of neointima formation, fibrosis, foreign-body giant-cell infiltration, and organization., Results: Fibrosis was significantly greater in group B compared with that in group F/P (p = .02). Inflammation with foreign-body giant-cell infiltration was significantly greater in groups F/P and F/B compared with that in groups P and B (p = .007)., Conclusion: The present study revealed that the embolic effect of fibered coils was not a thrombus but instead was a foreign-body response in the chronic phase.
- Published
- 2019
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29. Hydroxychloroquine Improves the Disease Activity and Allows the Reduction of the Corticosteroid Dose Regardless of Background Treatment in Japanese Patients with Systemic Lupus Erythematosus.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, and Kawahata K
- Subjects
- Adult, Antirheumatic Agents administration & dosage, Drug Administration Schedule, Drug Therapy, Combination, Female, Glucocorticoids therapeutic use, Humans, Hydroxychloroquine administration & dosage, Immunosuppressive Agents administration & dosage, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Prednisolone therapeutic use, Retrospective Studies, Severity of Illness Index, Young Adult, Antirheumatic Agents therapeutic use, Glucocorticoids administration & dosage, Hydroxychloroquine therapeutic use, Lupus Erythematosus, Systemic drug therapy, Prednisolone administration & dosage
- Abstract
Objective Hydroxychloroquine (HCQ) was not approved in Japan until 2015, and its therapeutic potential has not been explored in depth. We evaluated the additional therapeutic effect of HCQ in Japanese patients with systemic lupus erythematosus (SLE) on maintenance therapy. Methods Patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20 mg/day were retrospectively evaluated. All patients were divided into three groups according to their maintenance treatment regimen: PSL + immunosuppressant, PSL alone, and no treatment. We compared the changes in the SLE disease activity index (SLEDAI), PSL dose, and cumulative flare rate between patients who were and were not treated with HCQ. Results Among the 165 patients evaluated, 35 (21.2%) were treated with HCQ. The mean period of observation did not differ markedly between patients who did and did not receive HCQ (p=0.3). The SLEDAI and PSL dose were significantly reduced in patients who received HCQ, regardless of their background treatment regimen. The cumulative flare rate was lower in patients who received HCQ than in those who did not in the PSL + immunosuppressant and no maintenance treatment groups (p=0.03 and 0.05, respectively). Conclusion The addition of HCQ reduced the disease activity and allowed PSL dose reduction, regardless of background treatment, in Japanese patients with SLE.
- Published
- 2019
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30. Low-dose rituximab as induction therapy for ANCA-associated vasculitis.
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Takakuwa Y, Hanaoka H, Kiyokawa T, Iida H, Fujimoto H, Yamasaki Y, Yamada H, and Kawahata K
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Remission Induction methods, Retrospective Studies, Rituximab administration & dosage, Treatment Outcome, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Immunosuppressive Agents therapeutic use, Rituximab therapeutic use
- Abstract
Administration of four once-weekly doses of 375 mg/m
2 rituximab (RTX) is commonly used as remission induction therapy for ANCA-associated vasculitis (AAV). Low-dose RTX has been recently shown to produce closely similar results to conventional treatments in other autoimmune diseases. However, the therapeutic potential of this approach in AAV remains largely unknown. Here, we analyzed the efficacy and tolerability of high- and low-dose regimens of RTX in patients with AAV. We retrospectively examined AAV patients who met the classification algorithm of Watts et al. from 2006 to 2016. Patients were divided into high- (HD) and low-dose (LD) RTX groups. HD-RTX was the original regimen while LD-RTX consisted of two once-weekly doses of 375 mg/m2 . Cumulative complete remission (CR) rates for 1 year were compared, and serial changes in peripheral B cell counts and serious adverse events were monitored. Apart from a higher percentage of elderly patients in the LD group (p < 0.01), the 17 patients with HD-RTX and 11 patients with LD-RTX showed no significant differences in clinical characteristics, including Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI), and the initial dose of glucocorticoid. On 1-year observation, cumulative CR rates did not significantly differ (p = 0.20). Further, peripheral B cell counts and incidence of serious adverse events also did not differ. Cumulative CR rate did not significantly differ between LD and HD groups. Further study is warranted to confirm these results.- Published
- 2019
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31. Anti-IL-10 antibody in systemic lupus erythematosus.
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Uchida M, Ooka S, Goto Y, Suzuki K, Fujimoto H, Ishimori K, Matsushita H, Takakuwa Y, and Kawahata K
- Abstract
Purpose: IL-10 is a cytokine known to inhibit inflammatory cytokines. To determine its role in the pathogenesis of systemic lupus erythematosus (SLE), the presence of anti-IL-10 antibody is required to be examined. Although antibodies against cytokines are known to be present in SLE, no studies have determined the role of IL-10, particularly in Japanese patients. We assayed anti-IL-10 antibody in SLE and examined the clinical significance., Patients and Methods: We performed a retrospective study of 80 Japanese patients with SLE. Sixteen scleroderma patients, 19 rheumatoid arthritis (RA) patients, 23 Behcet's disease patients, and 23 healthy subjects were selected as control groups. Clinical information was abstracted from medical records. Anti-IL-10 antibody level was determined with an ELISA., Results: With the cutoff established as serum absorbance +2 SDs (OD 0.729) in healthy subjects, we defined any sample above this cutoff as anti-IL-10 antibody-positive. Fourteen patients with SLE (17.5%) were found to be anti-IL-10 antibody positive. Absorbance was significantly higher in serum from patients with SLE and RA than in healthy individuals. In SLE, patients with low complement values were significantly more common in the antibody-positive group. Serum IgG levels were significantly higher in the antibody-positive group. In multivariable analysis, high level of serum IgG is associated with anti-IL-10 antibody positive., Conclusion: The present study found that anti-IL-10 antibody is present in SLE and related to clinical parameters. These results suggest that the presence of anti-IL-10 antibody was associated with high level of serum IgG, but is not associated with disease activity in patients with SLE., Competing Interests: Disclosure The authors report no conflicts of interest in this work.
- Published
- 2019
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32. Low additive effect of hydroxychloroquine on Japanese patients with systemic lupus erythematosus taking calcineurin inhibitor.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, and Kawahata K
- Subjects
- Adult, Calcineurin Inhibitors adverse effects, Disease Progression, Drug Therapy, Combination, Female, Glucocorticoids administration & dosage, Humans, Hydroxychloroquine adverse effects, Immunosuppressive Agents adverse effects, Japan, Lupus Erythematosus, Systemic diagnosis, Lupus Erythematosus, Systemic immunology, Male, Middle Aged, Prednisolone administration & dosage, Remission Induction, Retrospective Studies, Time Factors, Treatment Outcome, Young Adult, Calcineurin Inhibitors administration & dosage, Hydroxychloroquine administration & dosage, Immunosuppressive Agents administration & dosage, Lupus Erythematosus, Systemic drug therapy
- Abstract
Aim: To assess for any additive value of hydroxychloroquine (HCQ) in Japanese patients with systemic lupus erythematosus (SLE) depending on calcineurin inhibitors (CNIs)., Methods: We retrospectively evaluated patients with SLE who visited our hospital from 2015 to 2016 and were taking prednisolone (PSL) at <20 mg/d and one immunosuppressant (IS). Patients were divided into two groups depending on HCQ use and the groups were compared for changes in SLE Disease Activity Index (SLEDAI), prednisolone (PSL) dose, and cumulative flare rate between patients who were treated and not treated with CNI., Results: Among the 103 patients evaluated, 19 (18.4%) were treated with HCQ. On analysis of all patients, SLEDAI, PSL doses, and cumulative flare rate were significantly reduced in patients who received HCQ compared to those who did not (P = 0.04, P = 0.01, and P = 0.03, respectively). Regarding IS use, we found less additive therapeutic effect in CNI users than in users of other ISs in terms of reduction in SLEDAI and PSL dose (P = 0.05 and P < 0.01, respectively)., Conclusions: The addition of HCQ reduced disease activity, PSL dose, and flares in Japanese SLE patients but conferred less additive clinical efficacy when added to CNIs., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)
- Published
- 2019
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33. Corticosteroid dose increase is a risk factor for nonalcoholic fatty liver disease and contralateral osteonecrosis of the femoral head: a case report.
- Author
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Shimizu H, Shimizu T, Takahashi D, Asano T, Arai R, Takakuwa Y, and Iwasaki N
- Subjects
- Adult, Dose-Response Relationship, Drug, Female, Femur Head Necrosis diagnostic imaging, Humans, Non-alcoholic Fatty Liver Disease diagnostic imaging, Risk Factors, Adrenal Cortex Hormones adverse effects, Femur Head Necrosis chemically induced, Femur Head Necrosis complications, Non-alcoholic Fatty Liver Disease chemically induced, Non-alcoholic Fatty Liver Disease complications
- Abstract
Background: The incidence of bilateral corticosteroid-induced osteonecrosis of the femoral head (ONFH) is high. Although the precise mechanism of corticosteroid-induced ONFH development is unclear, hepatic enzyme abnormalities such as low activity of hepatic cytochrome P450 3A could be one cause. Herein, we report the case of a patient who developed ONFH in the contralateral hip after the dose of corticosteroids for idiopathic thrombocytopenic purpura was increased. Liver biopsy was done to rule out autoimmune hepatitis., Case Presentation: A 32-year-old woman had been treated with continuous corticosteroids of up to 10 mg/day for Sjögren's syndrome for 25 years and corticosteroid-induced ONFH in the left side. At age 33, idiopathic thrombocytopenia developed, which was treated by increasing the corticosteroid dose (40 mg/day). Two months later, liver enzyme level began to increase slightly and continued to increase. A year after corticosteroid dose increase, contralateral ONFH developed, and a liver biopsy demonstrated nonalcoholic fatty liver disease (NAFLD)., Conclusions: The current case indicates that corticosteroid dose increase is a potential risk factor for NAFLD and contralateral ONFH. Therefore, it would be useful and important for to screen and monitor patients with hepatic enzyme abnormality for ONFH occurrence.
- Published
- 2019
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34. Mycophenolate mofetil treatment with or without a calcineurin inhibitor in resistant inflammatory myopathy.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, and Kawahata K
- Subjects
- Adult, Aged, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Myositis complications, Retrospective Studies, Treatment Outcome, Antibiotics, Antineoplastic therapeutic use, Calcineurin Inhibitors therapeutic use, Mycophenolic Acid therapeutic use, Myositis drug therapy
- Abstract
To evaluate the efficacy and tolerability of mycophenolate mofetil (MMF) with or without calcineurin inhibitors (CNIs) in patients with inflammatory myopathy taking prednisolone, but refractory to conventional immunosuppressive therapy. The records of patients with inflammatory myopathy who had previously failed treatment with at least one immunosuppressant were retrospectively evaluated. We selected patients treated with MMF and divided them into two groups depending on whether or not there was concomitant use of CNIs. We investigated the efficacy by changes in creatine kinase (CK) levels, forced vital capacity (%FVC), prednisolone dose, and high-resolution computed tomography (HRCT) findings. Interstitial lung disease (ILD) progression was defined by more than 10% decline of %FVC from baseline. We identified 19 patients on MMF treatment. There were seven (36.8%) patients on MMF and CNIs, including five on cyclosporine and two on tacrolimus. At baseline, no significant difference was seen in the prevalence of ILD between patients taking or not taking CNIs (85.7% vs. 75.0%, P = 0.68). Improvement in CK was seen in patients treated with CNIs (P = 0.04) but not in those without (P = 0.39). No significant improvement in %FVC and HRCT findings were found in patients with ILD in either group, and there were no differences in death or ILD progression. The combination of CNIs and MMF might be more effective for decreasing CK levels than MMF alone. Neither treatment arm had a beneficial effect on ILD over a variable observation period.
- Published
- 2019
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35. A positive direct Coombs' test in the absence of hemolytic anemia predicts high disease activity and poor renal response in systemic lupus erythematosus.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, and Kawahata K
- Subjects
- Adult, Anemia, Hemolytic, Autoimmune, Antibodies, Antinuclear blood, Antigen-Antibody Complex blood, Female, Humans, Kidney physiopathology, Lupus Erythematosus, Systemic blood, Lupus Nephritis blood, Male, Middle Aged, Multivariate Analysis, Retrospective Studies, Coombs Test, Lupus Erythematosus, Systemic physiopathology, Lupus Nephritis physiopathology, Severity of Illness Index
- Abstract
We determined the clinical utility of the direct Coombs' test in the absence of hemolytic anemia as an indicator of disease activity and therapeutic response in systemic lupus erythematosus (SLE). SLE patients without hemolytic anemia who visited our hospital from January 2016 to November 2016 were retrospectively evaluated with a direct Coombs' test. Clinical features, including SLE disease activity index (SLEDAI), treatment and laboratory findings were analyzed. For patients with lupus nephritis, we additionally evaluated the cumulative complete renal response rate over one year after induction therapy. Among 182 patients evaluated, 10 (5.8%) patients had a positive direct Coombs' test in the absence of hemolytic anemia. They had a higher SLEDAI ( p < 0.01), higher circulating immune complex levels ( p = 0.01), higher anti-DNA titers ( p < 0.01) and a lower complete renal response rate ( p = 0.03) compared with those who were negative. Multivariate analysis indicated that SLEDAI was an independent factor correlated with the direct Coombs' test without hemolytic anemia (odds ratio 2.4, 95% confidence interval 1.66-4.98, p < 0.01). A positive direct Coombs' test in the absence of hemolytic anemia may therefore represent a useful biomarker for assessing disease activity and therapeutic response.
- Published
- 2018
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36. Extracorporeal Shock Wave Therapy for Coronary Artery Disease: Relationship of Symptom Amelioration and Ischemia Improvement.
- Author
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Takakuwa Y, Sarai M, Kawai H, Yamada A, Shiino K, Takada K, Nagahara Y, Miyagi M, Motoyama S, Toyama H, and Ozaki Y
- Abstract
Objectives: The current management of coronary artery disease (CAD) relies on three major therapeutic options, namely medication, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). However, severe CAD that is not indicated for PCI or CABG still bears a poor prognosis due to the lack of effective treatments. In 2006, extracorporeal cardiac shock wave (SW) therapy reported on human for the first time. This treatment resulted in better myocardial perfusion as evaluated by dipyridamole stress thallium scintigraphy, angina symptoms, and exercise tolerance. The aim of the present study was to investigate: myocardial perfusion images and evaluate the relationship between the ischemia improvement and symptom amelioration by SW therapy., Methods: We treated ten patients (i.e., nine males and one female) with cardiac SW therapy who had CAD but not indicated for PCI or CABG and aged 63-89 years old. After the SW therapy, all patients were followed up for three months to evaluate any amelioration of the myocardial ischemia based on symptoms, adenosine stress thallium scintigraphy, transthoracic echocardiography, and blood biochemical examinations., Results: The changes in various parameters were evaluated before and after cardiac SW therapy. The cardiac SW therapy resulted in a significant improvement in the symptoms as evaluated by the Canadian Cardiovascular Society [CCS] class score (P=0.016) and a tendency to improve in summed stress score (SSS) (P=0.068). However, no significant improvement was observed in the summed rest score (SRS), summed difference score (SDS), left ventricular wall motion score index (LVWMSI), N-terminal pro-brain natriuretic, and troponin I. The difference of CCS class score (ΔCCS) was significantly correlated with those of SSS (ΔSSS) and SDS (ΔSDS) (r=0.69, P=0.028 and r=0.70, P=0.025, respectively). There was no significant correlation between ΔCCS and other parameters. Furthermore, no significant difference was observed between the CCS improved and non-improved groups in terms of the baseline characteristics., Conclusion: The current study demonstrated the potential efficacy and safety of Cardiac SW therapy in CAD patients. As the findings indicated, symptom amelioration was associated with ischemia improvement by extracorporeal shock wave therapy for the CAD patients.
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- 2018
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37. Whole genome analysis of a multidrug-resistant Streptococcus pneumoniae isolate from a patient with invasive pneumococcal infection developing disseminated intravascular coagulation.
- Author
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Ohkoshi Y, Sato T, Wada T, Fukushima Y, Murabayashi H, Takakuwa Y, Nishiyama K, Honda H, Shiraishi T, Kuronuma K, Takahashi H, Nakajima C, Suzuki Y, and Yokota SI
- Subjects
- Anti-Bacterial Agents therapeutic use, Disseminated Intravascular Coagulation diagnostic imaging, Disseminated Intravascular Coagulation microbiology, Female, Genome, Bacterial genetics, Humans, Japan, Microbial Sensitivity Tests, Middle Aged, Pneumococcal Infections diagnostic imaging, Pneumococcal Infections microbiology, Serogroup, Streptococcus pneumoniae drug effects, Streptococcus pneumoniae isolation & purification, Tomography, X-Ray Computed, Whole Genome Sequencing, Anti-Bacterial Agents pharmacology, Disseminated Intravascular Coagulation drug therapy, Drug Resistance, Multiple, Bacterial genetics, Pneumococcal Infections drug therapy, Streptococcus pneumoniae genetics
- Abstract
Multidrug-resistant Streptococcus pneumoniae strains were isolated from blood and sputum of a patient with disseminated intravascular coagulation in Sapporo city, Japan. These antibiograms were only susceptible to vancomycin, linezolid, daptomycin, some carbapenems, and some fluoroquinolones. Identical antibiograms, serotypes (19F), and sequence types (ST10017) suggested a shared origin of these isolates. Only one ST10017 strain has been isolated in the same city in Japan previously (2014), and the 2014 isolate is still susceptible to macrolides. The whole genome of the blood-derived isolate was sequenced. The strain harbored resistance mutations in parC, gyrA, pbp1a, pbp2a, pbp2b, and pbp2x, and harbored the resistance genes, ermB and tetM. The nucleotide sequences of parC and pbp2x genes of strain MDRSPN001 were clearly different from those of other S. pneumoniae strains and were similar to those of oral streptococci strains. These findings suggest that strain MDRSPN001 has been rapidly and drastically evolving multidrug resistance by gene replacement and accumulation of genes originating from other strains, such as oral streptococci, Streptococcus mitis., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2018
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38. Renal protective effect of antiplatelet therapy in antiphospholipid antibody-positive lupus nephritis patients without antiphospholipid syndrome.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, Okazaki T, Yamada H, Ozaki S, and Kawahata K
- Subjects
- Adult, Antiphospholipid Syndrome complications, Cytoprotection drug effects, Drug Interactions, Female, Glomerular Filtration Rate drug effects, Humans, Immunosuppression Therapy, Kidney pathology, Lupus Nephritis complications, Lupus Nephritis physiopathology, Male, Platelet Aggregation Inhibitors therapeutic use, Retrospective Studies, Antibodies, Anticardiolipin metabolism, Kidney drug effects, Kidney physiopathology, Lupus Coagulation Inhibitor metabolism, Lupus Nephritis drug therapy, Lupus Nephritis immunology, Platelet Aggregation Inhibitors pharmacology
- Abstract
Objective: We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS)., Methods: Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated., Results: We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment., Conclusion: Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV.
- Published
- 2018
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39. Early achievement of deep remission predicts low incidence of renal flare in lupus nephritis class III or IV.
- Author
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Hanaoka H, Iida H, Kiyokawa T, Takakuwa Y, and Kawahata K
- Subjects
- Adult, Cyclophosphamide therapeutic use, Female, Humans, Incidence, Kidney pathology, Kidney physiopathology, Lupus Nephritis classification, Male, Middle Aged, Prognosis, Remission Induction, Retrospective Studies, Tacrolimus therapeutic use, Immunosuppressive Agents therapeutic use, Induction Chemotherapy methods, Kidney drug effects, Lupus Nephritis drug therapy
- Published
- 2018
- Full Text
- View/download PDF
40. Band 3 phosphorylation induces irreversible alterations of stored red blood cells.
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Azouzi S, Romana M, Arashiki N, Takakuwa Y, El Nemer W, Peyrard T, Colin Y, Amireault P, and Le Van Kim C
- Subjects
- Erythrocytes cytology, Humans, Phosphorylation, Protein Multimerization, Time Factors, Anion Exchange Protein 1, Erythrocyte metabolism, Blood Preservation, Erythrocytes metabolism
- Published
- 2018
- Full Text
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41. Rhabdomyolysis in a Patient with Polyarteritis Nodosa.
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Iida H, Hanaoka H, Asari Y, Ishimori K, Kiyokawa T, Takakuwa Y, Yamasaki Y, Yamada H, Okazaki T, Doi M, and Ozaki S
- Subjects
- Aged, Anti-Inflammatory Agents therapeutic use, Antibodies, Antineutrophil Cytoplasmic blood, Antirheumatic Agents therapeutic use, Humans, Male, Muscle Weakness diagnosis, Polyarteritis Nodosa diagnosis, Treatment Outcome, Cyclophosphamide therapeutic use, Muscle Weakness drug therapy, Polyarteritis Nodosa complications, Polyarteritis Nodosa drug therapy, Prednisolone therapeutic use, Rhabdomyolysis drug therapy, Rhabdomyolysis etiology
- Abstract
Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.
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- 2018
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42. Complete Genome Sequence of Multidrug-Resistant Streptococcus pneumoniae Serotype 19F Isolated from an Invasive Infection in Sapporo, Japan.
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Sato T, Ohkoshi Y, Wada T, Fukushima Y, Murabayashi H, Takakuwa Y, Nishiyama K, Shiraishi T, Nakajima C, Suzuki Y, and Yokota SI
- Abstract
Invasive infection of multidrug-resistant Streptococcus pneumoniae is a serious clinical concern. Here, we report the complete genome sequence of a multidrug-resistant S. pneumoniae serotype 19F strain isolated from a patient with an invasive infection in Sapporo, Japan., (Copyright © 2017 Sato et al.)
- Published
- 2017
- Full Text
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43. Maintenance and regulation of asymmetric phospholipid distribution in human erythrocyte membranes: implications for erythrocyte functions.
- Author
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Arashiki N and Takakuwa Y
- Subjects
- Adenosine Triphosphatases metabolism, Biological Transport, Humans, Membrane Transport Proteins metabolism, Phosphatidylserines metabolism, Phospholipid Transfer Proteins metabolism, Time Factors, Erythrocyte Membrane metabolism, Erythrocytes metabolism, Membrane Lipids metabolism, Phospholipids metabolism
- Abstract
Purpose of Review: The article summarizes new insights into the molecular mechanisms for the maintenance and regulation of the asymmetric distribution of phospholipids in human erythrocyte membranes. We focus on phosphatidylserine, which is primarily found in the inner leaflet of the membrane lipid bilayer under low Ca conditions (<1 μmol/l) and is exposed to the outer leaflet under elevated Ca concentrations (>1 μmol/l), when cells become senescent. Clarification of the molecular basis of phosphatidylserine flipping and scrambling is important for addressing long-standing questions regarding phosphatidylserine functions., Recent Findings: ATP11C, a P-IV ATPase, has been identified as a major flippase in analyses of patient erythrocytes with a 90% reduction in flippase activity. Phospholipid scramblase 1 (PLSCR1) has been defined as a Ca-activated scramblase that is completely suppressed by membrane cholesterol under low Ca concentrations., Summary: For survival, phosphatidylserine surface exposure is prevented by cholesterol-mediated suppression of PLSCR1 under low Ca concentrations, irrespective of flipping by ATP11C. In senescent erythrocytes, PLSCR1 is activated by elevated Ca, resulting in phosphatidylserine exposure, allowing macrophage phagocytosis. These recent molecular findings establish the importance of the maintenance and regulation of phosphatidylserine distribution for both the survival and death of human erythrocytes.
- Published
- 2017
- Full Text
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44. Comparison of renal response to four different induction therapies in Japanese patients with lupus nephritis class III or IV: A single-centre retrospective study.
- Author
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Hanaoka H, Kiyokawa T, Iida H, Ishimori K, Takakuwa Y, Okazaki T, Yamada H, Ichikawa D, Shirai S, Koike J, and Ozaki S
- Subjects
- Adult, Female, Humans, Immunosuppressive Agents therapeutic use, Japan, Lupus Nephritis pathology, Male, Middle Aged, Prognosis, Retrospective Studies, Lupus Nephritis therapy
- Abstract
The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p<0.01 and p<0.01, respectively). There were no significant differences of cumulative CR rates and relapse free survival for 3 years among the four different therapeutic regimens (p = 0.2 and p = 0.2, respectively). There was a tendency to have early response and early relapse in TAC group and late response in MMF group. The SDI increase over 3 years was found more frequently in the TAC group than in the monthly-IVCY group (p = 0.04). Multivariate analysis indicated that CR at 3 months was independent prognosticator for low damage accrual. Regarding lower damage accrual, early CR achievement might be essential in induction therapy regardless of immunosuppressant choice.
- Published
- 2017
- Full Text
- View/download PDF
45. Hypertrophic Cardiomyopathy Accompanied by Spinocerebellar Atrophy With a Novel Mutation in Troponin I Gene.
- Author
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Kawai H, Morimoto S, Takakuwa Y, Ueda A, Inada K, Sarai M, Arimura T, Mutoh T, Kimura A, and Ozaki Y
- Subjects
- Aged, Atrial Fibrillation complications, Cardiomyopathy, Hypertrophic complications, Female, Humans, Pedigree, Spinocerebellar Ataxias complications, Atrial Fibrillation genetics, Cardiomyopathy, Hypertrophic genetics, Mutation, Spinocerebellar Ataxias genetics, Troponin I genetics
- Abstract
We report the case of a 66 year-old woman with chronic atrial fibrillation, hypertrophic cardiomyopathy (HCM), and spinocerebellar atrophy (SCA). Her mother and first-born son had died of heart disease at the ages of 65 and 16 years, respectively. Four of her 8 siblings had died suddenly of unknown cause or of heart disease, and 2 others of cerebral infarction by the 7th decade. Genetic testing revealed that she had a novel mutation (c. 482C > A, p. Ala161Asp) in the troponin I gene (TNNI3), and no abnormality of the GAA repeat in the frataxin gene. Her older brother with SCA but without HCM was also analyzed, with no abnormality noted in either gene. The Ala161Asp mutation in TNNI3 was implicated in the pathogenesis of her HCM, though an association between HCM and SCA was not revealed.
- Published
- 2016
- Full Text
- View/download PDF
46. Eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio as an associated factor of high risk plaque on coronary computed tomography in patients without coronary artery disease.
- Author
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Nagahara Y, Motoyama S, Sarai M, Ito H, Kawai H, Takakuwa Y, Miyagi M, Shibata D, Takahashi H, Naruse H, Ishii J, and Ozaki Y
- Subjects
- Acute Coronary Syndrome blood, Aged, C-Reactive Protein metabolism, Fatty Acids, Omega-3 blood, Female, Humans, Male, Middle Aged, Multivariate Analysis, Proportional Hazards Models, Retrospective Studies, Risk Factors, Tomography, X-Ray Computed, Arachidonic Acid blood, Coronary Artery Disease blood, Eicosapentaenoic Acid blood, Plaque, Atherosclerotic blood
- Abstract
Background and Aims: Coronary computed tomography angiography (CCTA)-verified high risk plaque (HRP) characteristics including positive remodeling and low attenuation plaque have been associated with acute coronary syndromes. Several studies reported that the n-3 polyunsaturated fatty acids have been associated with cardiovascular events. However, the relationship between serum eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio and CCTA-verified HRP in patients without known coronary artery disease (CAD) is unclear. We aimed at investigating the relation between EPA/AA and CCTA-verified HRP in patients without known CAD., Methods: We included 193 patients undergoing CCTA without known CAD (65.5 ± 12.0 years, 55.0% male). No patient has been treated with EPA. The relation of coronary risk factors, lipid profile, high-sensitivity C-reactive protein, coronary artery calcification score (CACS), number of vessel disease, plaque burden, and EPA/AA with the presence of HRP was evaluated by logistic regression analysis. Incremental value of EPA/AA to predict HRP was also analyzed by C-index, NRI, and IDI. A Cox proportional hazards model was used to estimate the time to cardiovascular event., Results: HRP was observed in 37 (19%) patients. Multivariable logistic regression analysis revealed that current smoking (OR 2.58; p=0.046), number of vessel disease (OR 1.87; p=0.031), and EPA/AA ratio (OR 0.65; p=0.0006) were independent associated factors of HRP on CCTA. Although the addition of EPA/AA to the baseline model did not significantly improve C-index, both NRI (0.60, p=0.0049) and IDI (0.054, p=0.0072) were significantly improved. Patients with HRP had significantly higher rate of events compared with patients without HRP (14% vs. 3%, Logrank p=0.0004). On multivariable Cox hazard analysis, baseline EPA/AA ratio was an independent predictor (HR 0.57, p=0.047)., Conclusions: Low EPA/AA was an associated factor of HRP on CCTA in patients without CAD. In addition to conventional coronary risk factors and CACS, EPA/AA and CCTA might be useful for risk stratification of CAD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
47. An Unrecognized Function of Cholesterol: Regulating the Mechanism Controlling Membrane Phospholipid Asymmetry.
- Author
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Arashiki N, Saito M, Koshino I, Kamata K, Hale J, Mohandas N, Manno S, and Takakuwa Y
- Subjects
- Animals, Biological Transport, Calcium metabolism, Cells, Cultured, Erythrocytes cytology, Humans, Mice, Phosphatidylserines metabolism, Adenosine Triphosphatases metabolism, Cholesterol metabolism, Erythrocyte Membrane metabolism, Erythrocytes metabolism, Lipid Bilayers metabolism, Membrane Lipids metabolism, Membrane Transport Proteins metabolism, Phospholipid Transfer Proteins metabolism
- Abstract
An asymmetric distribution of phospholipids in the membrane bilayer is inseparable from physiological functions, including shape preservation and survival of erythrocytes, and by implication other cells. Aminophospholipids, notably phosphatidylserine (PS), are confined to the inner leaflet of the erythrocyte membrane lipid bilayer by the ATP-dependent flippase enzyme, ATP11C, counteracting the activity of an ATP-independent scramblase. Phospholipid scramblase 1 (PLSCR1), a single-transmembrane protein, was previously reported to possess scrambling activity in erythrocytes. However, its function was cast in doubt by the retention of scramblase activity in erythrocytes of knockout mice lacking this protein. We show that in the human erythrocyte PLSCR1 is the predominant scramblase and by reconstitution into liposomes that its activity resides in the transmembrane domain. At or below physiological intracellular calcium concentrations, total suppression of flippase activity nevertheless leaves the membrane asymmetry undisturbed. When liposomes or erythrocytes are depleted of cholesterol (a reversible process in the case of erythrocytes), PS quickly appears at the outer surface, implying that cholesterol acts in the cell as a powerful scramblase inhibitor. Thus, our results bring to light a previously unsuspected function of cholesterol in regulating phospholipid scrambling.
- Published
- 2016
- Full Text
- View/download PDF
48. ATP11C is a major flippase in human erythrocytes and its defect causes congenital hemolytic anemia.
- Author
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Arashiki N, Takakuwa Y, Mohandas N, Hale J, Yoshida K, Ogura H, Utsugisawa T, Ohga S, Miyano S, Ogawa S, Kojima S, and Kanno H
- Subjects
- Adenosine Triphosphatases deficiency, Adolescent, Anemia, Hemolytic, Congenital diagnosis, Biological Transport, Active, Biomarkers, Calcium metabolism, Erythrocyte Indices, Erythrocytes drug effects, Humans, Male, Membrane Transport Proteins deficiency, Mutation, Phosphatidylserines metabolism, Phosphatidylserines pharmacology, Adenosine Triphosphatases genetics, Adenosine Triphosphatases metabolism, Anemia, Hemolytic, Congenital genetics, Anemia, Hemolytic, Congenital metabolism, Erythrocytes metabolism, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism
- Abstract
Phosphatidylserine is localized exclusively to the inner leaflet of the membrane lipid bilayer of most cells, including erythrocytes. This asymmetric distribution is critical for the survival of erythrocytes in circulation since externalized phosphatidylserine is a phagocytic signal for splenic macrophages. Flippases are P-IV ATPase family proteins that actively transport phosphatidylserine from the outer to inner leaflet. It has not yet been determined which of the 14 members of this family of proteins is the flippase in human erythrocytes. Herein, we report that ATP11C encodes a major flippase in human erythrocytes, and a genetic mutation identified in a male patient caused congenital hemolytic anemia inherited as an X-linked recessive trait. Phosphatidylserine internalization in erythrocytes with the mutant ATP11C was decreased 10-fold compared to that of the control, functionally establishing that ATP11C is a major flippase in human erythrocytes. Contrary to our expectations phosphatidylserine was retained in the inner leaflet of the majority of mature erythrocytes from both controls and the patient, suggesting that phosphatidylserine cannot be externalized as long as scramblase is inactive. Phosphatidylserine-exposing cells were found only in the densest senescent cells (0.1% of total) in which scramblase was activated by increased Ca(2+) concentration: the percentage of these phosphatidylserine-exposing cells was increased in the patient's senescent cells accounting for his mild anemia. Furthermore, the finding of similar extents of phosphatidylserine exposure by exogenous Ca(2+)-activated scrambling in both control erythrocytes and the patient's erythrocytes implies that suppressed scramblase activity rather than flippase activity contributes to the maintenance of phosphatidylserine in the inner leaflet of human erythrocytes., (Copyright© Ferrata Storti Foundation.)
- Published
- 2016
- Full Text
- View/download PDF
49. A method for detailed analysis of the structure of mast cell secretory granules by negative contrast imaging.
- Author
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Tanaka S and Takakuwa Y
- Subjects
- Animals, Cell Line, Cell Nucleus, Cell Size, Green Fluorescent Proteins metabolism, Imaging, Three-Dimensional, Rats, Mast Cells cytology, Mast Cells metabolism, Optical Imaging methods, Secretory Vesicles
- Abstract
Secretory granules (SGs) in mast cells contain various molecules that elicit allergy symptoms and are generally considered therapeutic targets. However, the biogenesis, maintenance, regulation, and recycling of these granules remain controversial, mainly due to the lack of suitable live-cell imaging methods. In this study, we applied negative contrast imaging with soluble green fluorescent protein (GFP) expressed in the cytoplasm as a method to validate structural information of mast cell SGs. We evaluated the accuracy of the method in detail, and we demonstrated that it can be used for quantitative analysis. Using this technique, secretory granules, the nucleus, mitochondria, and the cell body were visualized in individual RBL-2H3 mast cells without any influence. When combined with conventional multicolor fluorescence imaging, visualization of SG-associated proteins and SG-SG fusion was achieved. Moreover, 3D images were constructed based on this method, and detailed information on the number, size, and shape of individual SGs was obtained. We found that cell volume was correlated with SG number. In summary, the technique provides valuable and unique data, and will therefore advance SG research.
- Published
- 2016
- Full Text
- View/download PDF
50. Longitudinal PBL in Undergraduate Medical Education Develops Lifelong-Learning Habits and Clinical Competencies in Social Aspects.
- Author
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Okubo Y, Matsushita S, Takakuwa Y, Yoshioka T, and Nitta K
- Published
- 2016
- Full Text
- View/download PDF
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